Journal articles on the topic 'Published patent specifications'

Introduction: Tisagenlecleucel (CTL019, tisa-cel) was recently approved for treatment of relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), high grade B cell lymphoma (r/r HGBCL), and transformed follicular lymphoma (r/r tFL) after second line therapy. Prior to tisa-cel release for commercial use in the United States (US), the final manufactured, patient-specific product must meet specific Lot Release Specifications including requirements that the product's dose contains 0.6 to 6.0 x 108 CAR-positive viable T cells and total cell viability is at least 80%. CAR T cell products that do not meet predetermined release specifications are considered "out of specification" (OOS) and may only be administered via an expanded access protocol or a single patient IND. To date, there are no prospectively reported data with regard to the reasons that commercially manufactured CTL019 products are OOS or clinical outcomes after infusion of OOS CTL019 products. Methods: We are participating in a prospective, managed access protocol to allow administration of CTL019 to patients (pts) with r/r aggressive B-cell lymphomas meeting the approved prescribing information who are intended for treatment with US commercial tisa-cel but have OOS products. Pts were provided product via this managed access program and consent was obtained from all pts enrolled. Pts were unable to receive commercially manufactured product due to failure of apheresis material to meet acceptance specifications, failure of final manufactured product to meet the commercial release specifications, or failure to meet other product specifications within the prescribing information (e.g., interferon gamma release testing). Response was assessed at 3 months post CTL019 infusion by 2014 Lugano Classification criteria applied to FDG-PET/CT imaging. Adverse events were defined by CTCAE and ASTCT criteria. Results: From 9/2018 to 7/2019, 16 pts were enrolled at our institution. Nine pts were diagnosed with r/r DLBCL, 5 pts had r/r HGBCL, and 2 pts had r/r tFL; 44% of all pts had "double-hit" lymphoma. Median age at CTL019 infusion was 68 years (range: 42-75 years); 7 pts (44%) were female. Twelve pts (75%) had advanced stage lymphoma at leukapheresis. Median prior therapies before leukapheresis was 3 (range: 2-5). Median ECOG performance status was 0 (range: 0-2). Median absolute lymphocyte count and CD3 count were 900/uL (range: 200-1300/uL) and 614/uL (range: 228-1343/uL), respectively. Median CTL019 dose was 1.3 x 108 CAR-positive viable T cells (range: 0.5 x 108 to 2.1 x 108). Median product viability was 78.4% (range: 70.8-87.4%). Thirteen of 16 pts (81%) were enrolled due to low viability products (viability < 80%). The median viability for pts enrolled due to low product viability was 78.0% (range: 70.8-79.8%). The remaining 3 pts' products did not meet release specifications due to T cell dose below 0.6 x 108 CAR-positive T cells (dose administered, 0.5 x 108; n=1), residual beads by microscopy (n=1), or IFN gamma release level above the upper range (>1000 fg/transduced cell; n=1). All pts with low viability products had CAR-positive T cell doses that were within the product dose specifications for tisa-cel (13 of 13 pts). Of 16 pts enrolled, 11 pts have at least 3 months follow-up; 3 pts were never treated due to progressive lymphoma and 2 pts have not had 3 month response assessments. Median follow-up is 3.4 months. There were 3 pts with CRS grades 1 or 2 by ASTCT criteria and no pts had neurotoxicity. Of 3 pts with CRS, one received a low dose of CTL019 (grade 2 CRS), one had higher levels of IFN gamma (grade 1 CRS), and one had low viability (grade 1 CRS). For all pts infused with OOS products, the 3-month overall response rate (ORR) was 64% including 6/11 (55%) CR and 1/11 (9%) PR. Progression-free survival (PFS) is 64% at 3 months (median not reached, 95%CI: 30-85%). For OOS products due to low viability, ORR was 4/8 (50%) CR and 4/8 (50%) PD; 3-month PFS was 50% (95%CI: 15-77%). Conclusions: We report the first experience with commercially produced CTL019 products that do not meet product release specifications, primarily due to low viability. Three-month ORRs appear similar to published tisa-cel outcomes for aggressive B-cell non-Hodgkin lymphomas. Our results suggest that other product release characteristics such as potency and replicative capacity should also be more carefully evaluated prior to establishing criteria for release. Disclosures Chong: Novartis: Consultancy; Merck: Research Funding; Tessa: Consultancy. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Landsburg:Takeda: Research Funding; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Triphase: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Speakers Bureau; Curis, INC: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dwivedy Nasta:Debiopharm: Research Funding; Rafael: Research Funding; Millenium/Takeda: Research Funding; Roche: Research Funding; 47 (Forty Seven): Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Aileron: Research Funding; ATARA: Research Funding; Pharmacyclics: Research Funding. Svoboda:AstraZeneca: Consultancy; Celgene: Research Funding; Incyte: Research Funding; Pharmacyclics: Consultancy, Research Funding; Kyowa: Consultancy; Merck: Research Funding; BMS: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding. Porter:Glenmark Pharm: Membership on an entity's Board of Directors or advisory committees; Immunovative: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Membership on an entity's Board of Directors or advisory committees; Genentech: Employment; Wiley and Sons: Honoraria; Kite: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees. Barta:Merck: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Mundipharma: Honoraria; Celgene: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Mundipharma: Honoraria. Levine:Incysus: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy; CRC Oncology: Consultancy; Cure Genetics: Consultancy; Vycellix: Membership on an entity's Board of Directors or advisory committees; Brammer Bio: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Equity Ownership; Avectas: Membership on an entity's Board of Directors or advisory committees. June:Tmunity: Other: scientific founder, for which he has founders stock but no income, Patents & Royalties; Novartis: Research Funding. Schuster:Novartis: Other: a patent (with royalties paid to Novartis) on combination therapies of CAR and PD-1 inhibitors.; Novartis, Nordic Nanovector, and Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis, Celgene, Genentech, Merck, Pharmacyclics, Acerta, and Gilead: Other: Grants, Research Funding; Nordic Nanovector, Pfizer, AstraZeneca, Loxo Oncology, Acerta, and Celgene: Honoraria. OffLabel Disclosure: Out of specificity product release of tisagenlecleucel

A quick review of the specification sheets for new technologically intensive diagnostic ultrasound systems reveals a substantial number of fairly impressive operational performance claims. In at least one manufacturer's published material, the system specifications boasts of a dynamic range of 180 dB. To put that number in perspective, a device capable of 180 dB of dynamic range of resolution would be able to detect the flutter of a butterfly's wing in the middle of a thermonuclear explosion. How does one verify such an astounding performance claim using currently available ultrasound testing devices such as a tissue-mimicking phantom and what is the explicit clinical significance of such dynamic range? Additionally, while most of us were focused with amazement in leapfrog advances in system technology, diagnostic ultrasound transducers were also undergoing radical changes in array material composition and design. Most modern composite transducer specifications claim fractional bandwidths of 85%, and more and element counts as high as 2500. While the great technological strides made in ultrasound system design have been impressive, all of the computational and processing power of the 'all-digital' ultrasound device is singularly dependent on the output and input characteristics of the ultrasound transducer. Published data shows that the ultrasound transducer is subject to degradation in performance, as well as element failure, potentially leading to patient misdiagnosis or under-diagnosis. The need to regularly test transducers for performance variances will be explored within this paper. Additionally, the key areas of transducer performance as they relate to image and Doppler quality will be defined.

Abstract Accurate and consistent sequence variant interpretation is critical to the correct diagnosis and appropriate clinical management and counseling of patients with inherited genetic disorders. To minimize discrepancies in variant curation and classification among different clinical laboratories, the American College of Medical Genetics and Genomics (ACMG), along with the Association for Molecular Pathology (AMP), published standards and guidelines for the interpretation of sequence variants in 2015. Because the rules are not universally applicable to different genes or disorders, the Clinical Genome Resource (ClinGen) Platelet Disorder Expert Panel (PD-EP) has been tasked to make ACMG/AMP rule specifications for inherited platelet disorders. ITGA2B and ITGB3, the genes underlying autosomal recessive Glanzmann thrombasthenia (GT), were selected as the pilot genes for specification. Eight types of evidence covering clinical phenotype, functional data, and computational/population data were evaluated in the context of GT by the ClinGen PD-EP. The preliminary specifications were validated with 70 pilot ITGA2B/ITGB3 variants and further refined. In the final adapted criteria, gene- or disease-based specifications were made to 16 rules, including 7 with adjustable strength; no modification was made to 5 rules; and 7 rules were deemed not applicable to GT. Employing the GT-specific ACMG/AMP criteria to the pilot variants resulted in a reduction of variants classified with unknown significance from 29% to 20%. The overall concordance with the initial expert assertions was 71%. These adapted criteria will serve as guidelines for GT-related variant interpretation to increase specificity and consistency across laboratories and allow for better clinical integration of genetic knowledge into patient care.

Safety measure development has focused on inpatient care despite outpatient visits far outnumbering inpatient admissions. Some measures are clearly identified as outpatient safety measures when published, yet outcomes from quality improvement studies also may be useful measures. The authors conducted a systematic review of the literature to identify published articles detailing safety measures applicable to adult primary care. A total of 21 articles were identified, providing specifications for 182 safety measures. Each measure was classified into one of 6 outpatient safety dimensions: medication management, sentinel events, care coordination, procedures and treatment, laboratory testing and monitoring, and facility structures/resources. Compared to the multitude of available inpatient safety measures, the number of existing adult primary care measures is low. The measures identified by this systematic review may yield further insight into the breadth of safety events causing harm in primary care, while also identifying areas of patient safety in primary care that may be understudied.

PURPOSE Because of expanding interoperability requirements, structured patient data are increasingly available in electronic health records. Many oncology data elements (eg, staging, biomarkers, documentation of adverse events and cancer outcomes) remain challenging. The Minimal Common Oncology Data Elements (mCODE) project is a consensus data standard created to facilitate transmission of data of patients with cancer. METHODS In 2018, mCODE was developed through a work group convened by ASCO, including oncologists, informaticians, researchers, and experts in terminologies and standards. The mCODE specification is organized by 6 high-level domains: patient, laboratory/vital, disease, genomics, treatment, and outcome. In total, 23 mCODE profiles are composed of 90 data elements. RESULTS A conceptual model was published for public comment in January 2019 and, after additional refinement, the first public version of the mCODE (version 0.9.1) Fast Healthcare Interoperability Resources (FHIR) implementation guide (IG) was presented at the ASCO Annual Meeting in June 2019. The specification was approved for balloting by Health Level 7 International (HL7) in August 2019. mCODE passed the HL7 ballot in September 2019 with 86.5% approval. The mCODE IG authors worked with HL7 reviewers to resolve all negative comments, leading to a modest expansion in the number of data elements and tighter alignment with FHIR and other HL7 conventions. The mCODE version 1.0 FHIR IG Standard for Trial Use was formally published on March 18, 2020. CONCLUSION The mCODE project has the potential to offer tremendous benefits to cancer care delivery and research by creating an infrastructure to better share patient data. mCODE is available free from www.mCODEinitiative.org . Pilot implementations are underway, and a robust community of stakeholders has been assembled across the oncology ecosystem.

The process of automatic evaluation of a structured C++ program has the first and foremost requirement of specifying the developed structural C++ program in a standard, generalized and unified format. This generalized and standard representation of the program needs to incorporate the specification in terms of semantics as per the language features used and also the contextual binding in regards of the program definition as perceived and desired by the subject expert. Hence an inter - lingua which can represent the semantic and contextual knowledge of the developed structured C++ program will be the first and foremost requirement towards the process of automated assessment and grading of a structured C++ program.The work presented here is published for patent at Patent Office Branch, Mumbai, India with the reference number E-12/215/2021/MUM and application number 202121000796.

Abstract Stability of a measurand in a specimen is a function of the property variation over time in specific storage conditions, which can be expressed as a stability equation, and is usually simplified to stability limits (SLs). Stability studies show differences or even inconsistent results due to the lack of standardized experimental designs and heterogeneity of the chosen specifications. Although guidelines for the validation of sample collection tubes have been published recently, the measurand stability evaluation is not addressed. This document provides an easy guideline for the development of a stability test protocol based on a two-step process. A preliminary test is proposed to evaluate the stability under laboratory habitual conditions. The loss of stability is assessed by comparing measurement values of two samples obtained from the same patient and analyzed at different time points. One of them is analyzed under optimal conditions (basal sample). The other is stored under specific stability conditions for a time set by the laboratory (test sample). Differences are expressed using percentage deviation (PD%) to facilitate comparison with specifications. When the preliminary test demonstrates instability, a comprehensive test is proposed in order to define the stability equation and to specify SLs. Several samples are collected from a set of patients. The basal sample is analyzed under optimal conditions, whereas analysis of test samples is delayed at time intervals. For each patient PD% is calculated as the difference between measurements for every test sample and its basal one and represented in a coordinate graph versus time.

Bioethics is currently witnessing unprecedented debate over the moral and legal norms governing the conduct of clinical research. At the center of this debate is the duty of care in clinical research, and its most widely accepted specification, clinical equipoise. In recent work, we have argued that equipoise and cognate concepts central to the ethics of clinical research have been left unnecessarily vulnerable to criticism. We have suggested that the vulnerability lies in the conspicuous absence of an articulated foundation in moral and legal theory of the physician-researcher's duty of care to the patient-subject. We have repeatedly suggested that the requisite foundation is in the ethics of trust and the law of fiduciaries.Curiously, despite the absence of a published thorough exposition of our position, some have preemptively criticized our suggestion that the relationship between physician-researcher and patient-subject is fiduciary. Others have offered their own accounts of the implications of fiduciary law for the relationship.

Virtual Reality (VR) can play a key role in automotive marketing research, lowering costs and shortening the time to launch a new product. However, few VR applications support automotive customers’ experiences during the early stages of product design. This study aims to identify and characterize into attributes the challenges and opportunities for the application of Virtual Reality in car clinics through a systematic review of the literature and patents. We searched PatentScout, ScienceDirect, Springer, and IEEEXplore for studies published between the databases’ inception and July 2020. Of the 77,383 patents and 336,785 articles identified, 72 and 13 were eligible, respectively. We discovered that patents are strongly concentrated by a few inventors, that the United States has the most records, and that the most prevalent applications relate to devices for automatically reading responders’ emotions in virtual environments. The articles revealed sixteen categories of challenges and opportunities: cost, location to customers, flexibility in interactions, model transportation, depth perception, haptic perception, motion, movement perception/physical collision, color and texture, sound feedback, product interaction/manipulation, visual–spatial, graphic quality, intuitiveness, cybersecurity, and cybersickness. Virtual Reality may be used for automotive marketing research but key factors such as hardware and software specification, stimulus quality, and survey objectives must be considered.

Background: Concerns have been raised over poor standards of hospital cleanliness and insufficient time for staff to clean reusable communal patient care equipment. These items may then act as vectors for the transmission of nosocomial pathogens between hospital patients. Aim: To evaluate the impact of cleaning duration on nosocomial infection rates and estimate the time required to clean care equipment in accordance with national specifications (i.e. a ‘time to clean’). Methods: A systematic review of the published literature on cleaning times and an observational study in which nine healthcare workers cleaned seven items of care equipment while the duration of time taken to clean each item was measured. Results: A limited volume of low-quality evidence indicates that increased cleaning times in hospitals can reduce the incidence of healthcare-associated infections (HCAIs). The mean ‘time to clean’ for care equipment ranged from 166.3 s (95% confidence interval [CI] = 117.8–214.7) for a bed frame to 29.0 s (95% CI = 13.4–44.6) for a blood pressure cuff. Discussion: ‘Time to clean’ estimates for care equipment provide an indication of how much protected time is necessary to ensure acceptable standards of cleanliness. Clinical trials are needed to further evaluate the impact of increased cleaning times on nosocomial infection rates.

Objective: To summarize the literature on cholesterol point-of-care tests (POCTs). This article would serve as a resource to assist community pharmacists in developing cholesterol point-of-care (POC) pharmacy services. Data Sources: A literature search was performed in MEDLINE Ovid, PubMed, EMBASE, and Cochrane database using the following medical subject headings (MeSH) terms: point-of-care test, cholesterol, blood chemical analysis, rapid testing, collaborative practice, community pharmacy, and ambulatory care. Additional resources including device manufacturer web sites were summarized to supplement the current literature. Study Selection and Data Extraction: All human research articles, review articles, meta-analyses, and abstracts published in English through September 1, 2014, were considered. Data Synthesis: A total of 36 articles were applicable for review. Information was divided into the following categories to be summarized: devices, pharmacists’ impact, and operational cost for the pharmacy. Conclusions: The current literature suggests that POCTs in community pharmacies assist with patient outcomes by providing screenings and referring patients with dyslipidemia for further evaluation. The majority of studies on cholesterol POC devices focused on accuracy, revealing the need for further studies to develop best practices and practice models with successful reimbursement. Accuracy, device specifications, required supplies, and patient preference should be considered when selecting a POC device for purchase.

Previously published evidence has established major clinical benefits from using computer-aided design, computer-aided manufacturing, and additive manufacturing to produce patient-specific devices. These include cutting guides, drilling guides, positioning guides, and implants. However, custom devices produced using these methods are still not in routine use, particularly by the UK National Health Service. Oft-cited reasons for this slow uptake include the following: a higher up-front cost than conventionally fabricated devices, material-choice uncertainty, and a lack of long-term follow-up due to their relatively recent introduction. This article identifies a further gap in current knowledge – that of design rules, or key specification considerations for complex computer-aided design/computer-aided manufacturing/additive manufacturing devices. This research begins to address the gap by combining a detailed review of the literature with first-hand experience of interdisciplinary collaboration on five craniofacial patient case studies. In each patient case, bony lesions in the orbito-temporal region were segmented, excised, and reconstructed in the virtual environment. Three cases translated these digital plans into theatre via polymer surgical guides. Four cases utilised additive manufacturing to fabricate titanium implants. One implant was machined from polyether ether ketone. From the literature, articles with relevant abstracts were analysed to extract design considerations. In all, 19 frequently recurring design considerations were extracted from previous publications. Nine new design considerations were extracted from the case studies – on the basis of subjective clinical evaluation. These were synthesised to produce a design considerations framework to assist clinicians with prescribing and design engineers with modelling. Promising avenues for further research are proposed.

Background: The multi-disciplinary tumor board (MTB) is essential to quality cancer care and currently recommended to offer the best personalized clinical approach, but little has been published regarding MTBs in neuro-oncology (nMTBs). The aim of the present paper is to describe our nMTB, to evaluate its impact on clinical management decisions, and to assess the role of neuroradiologists. Methods: The retrospective evaluation of the cases discussed at our nMTB from March 2017 to March 2020. From the electronic records, we extracted epidemiological, clinical and other specific data of nMTB. From the radiological records, we calculated data relating to the number, time for revision, and other specifications of MRI re-evaluation. Statistical analysis was performed. Results: a total of 447 discussions were analyzed, representing 342 patients. The requests for case evaluations came from radiation oncologists (58.8%) and neurosurgeons (40.5%), and were mainly addressed to the neuroradiologist (73.8%). The most frequent questions were about the treatment’s changes (64.4%). The change in patient treatment was reported in 40.5% of cases, 76.8% of these were based on the neuroradiologic assessment. A total of 1514 MRI examinations were re-evaluated, employing approximately 67 h overall. The median of the MRI exams reviewed per patient was 3 (min–max 1–12). Conclusions: Our study supported that the multidisciplinary approach to patient care can be particularly effective in managing brain tumors. A review by an expert neuroradiologist impacts patient management in the context of nMTBs, but has costs in terms of the time and effort spent preparing for it.

ABSTRACT Introduction Current thinking in healthcare education stipulates a holistic approach with a focus on patient management, bringing together technical skills, decision-making, and team performance. In parallel, training opportunities with actual patients have diminished, and the number of different interventions to master has increased. Training on simulators has become broadly accepted; however, requirements for such training devices have outpaced the development of new simulators. The Department of Defense (DoD) targeted this gap with a development challenge. This article introduces the Advanced Modular Manikin (AMM) platform and describes the path followed to address the challenge. Materials and Methods Under Contract # W81XWH-14-C-0101, our interdisciplinary team of healthcare providers, educators, engineers, and scientists, together with partners in industry and the government collaborated to establish a set of comprehensive requirements and develop an overarching system architecture and specifications to meet healthcare simulation needs. In order to instantiate the architecture and investigate usability of the platform, a demonstration modular manikin was created that incorporated physical and digital peripherals. Results The system architecture and corresponding data models have been completed and published as open source. A developer’s tool kit has been created, including instructional materials and required hardware and software for interested parties to develop AMM-compatible modules. A reference manikin was created based on the platform specifications and successfully supported a usability study that was performed by the American College of Surgeons, Education Division at the Naval Medical Center San Diego. Conclusions The formal release of a functional modular, interoperable open-source healthcare simulation platform is complete. Next steps involve a strategy for maintaining the open standards and verification of AMM-compatibility for modules. Increasing awareness of this powerful tool and prioritization of module-development to address the wide range of healthcare education needs could lead to a renaissance in military and civilian healthcare simulation-based training.

Extemporaneous compounding takes place in community and hospital pharmacies. There are usually specialist compounding pharmacies in major towns and cities, but any pharmacy may undertake compounding as long as they have appropriate facilities according to state-based legislation (e.g. allocated clean bench, specific compounding equipment). Although development is a continuous process, companies are customizing features to meet the majority of patient needs, but the very nature of the process cannot meet all patient needs. The risk-benefit ratio of using traditionally compounded medicines is favorable for patients who require specialized medications that are not commercially available, as they would otherwise not have access to suitable treatment. However, if an FDA-approved drug is commercially available, the use of an unapproved compounded drug confers additional risk with no commensurate benefit. Published reports of independent testing by the FDA, state agencies, and others consistently show that compounded drugs fail to meet specifications at a considerably higher rate than FDA-approved drugs. Compounded sterile preparations pose the additional risk of microbial contamination to patients. In the last 11 years, three separate meningitis outbreaks have been traced to purportedly ‘sterile’ steroid injections contaminated with fungus or bacteria, which were made by compounding pharmacies. The 2012 outbreak has resulted in intense scrutiny of pharmacy compounding practices and increased recognition of the need to ensure that compounding is limited to appropriate circumstances.
 
 Article Type: Review

This article presents an overview of contemporary risk assessment systems used in patients with myocardial infarction. The full range of risk scales, both recommended by the European Society of Cardiology and others published in recent years, is presented. Scales for assessing the risk of ischemia/death as well as for assessing the risk of bleeding are presented. A separate section is devoted to systems assessing the integrated risk associated with both ischemia and bleeding. In the first part of the work, each of the risk scales is described in detail, including the clinical trials/registers on the basis of which they were created, the statistical methods used to develop them, as well as the specification of their individual parameters. The next chapter presents the practical application of a given scale in the patient risk assessment process, the timing of its application on the timeline of myocardial infarction, as well as a critical assessment of its potential advantages and limitations. The last part of the work is devoted to the presentation of potential directions for the development of risk assessment systems in the future.

Background:Patients with long-term conditions (LTCs), including many RMDs, often require continuous management of care. Patient-generated health data (PGHD) collected between visits could inform ongoing care management and provide important insights into patient health and well-being. There is increasing interest in integrating PGHD in electronic health records (EHRs). However, integration is still largely aspirational with limited evidence of successful systems.Objectives:To map the landscape of EHR-integrated remote symptom monitoring systems in the field of LTCs. The objectives were to 1) characterise state of the art systems, 2) describe their clinical use, and 3) outline anticipated and realized benefits for clinical practice.Methods:A systematic search was conducted in three electronic databases up until November 2019. Titles and abstracts were independently screened by two reviewers. One reviewer screened full-text articles, identified those relevant for review and extracted data. Inclusion criteria included 1) symptom reporting systems in adult patients suffering a LTC, 2) integration of data into the EHR, 3) symptom data collected remotely, 4) evidence of use in clinical care. We did not exclude studies based on study design, quality, or sample size. Synthesis focused on describing system specifications and their use. For objective three we adopted a list of outcome indicators [1], which each of the studies were assessed against.Results:The initial search yielded 2040 articles. Only 12 studies reporting on ten unique systems were identified. Two systems were used in rheumatology, but the majority were used in oncology. Systems were highly heterogeneous in terms of technical and functional specifications. Nine systems were fully integrated (data viewable in the EHR) while the remaining system represented a partial integration (data viewable via link in the EHR). Five systems allowed repeated data collection at pre-defined intervals between visits with frequencies varying from daily to monthly. The remaining five made a single request before a scheduled clinic visit. The number of items requested from patients ranged from 9-48 per session. We identified three different clinical workflows: Simple (data only used during consultation, n=5), moderate (real-time alerts for providers when severe symptoms were reported, n=4) and on-demand (patient-initiated visits, n=1). Benefits of symptom reporting from each of the studies were categorised as anticipated, realized quantitative, and realized qualitative. We present summarised counts of these benefits in Figure 1. The most common anticipated benefits were better communication, changes to patient management and improved health outcomes. Most common realized benefits were detecting unrecognised problems and changes to patient management.Figure 1.Summarized counts of benefits from each included study assessed against Chen et al.’s 10 outcome indicators. Categorized in anticipated (orange), realized quantitative (light purple), and realized qualitative benefits (dark purple).Conclusion:There is growing interest and urge for integrating symptom data in the EHR and clinical care. Yet, this review has illustrated that there are limited published efforts to learn from. The heterogeneity in approaches underpins the need for a common framework. There is growing evidence from qualitative work in support of remote symptom-reporting in enabling better and patient-centred care in LTCs. The next step will be for robust, quantitative studies to provide evidence of benefits.References:[1]Chen J, Ou L, Hollis SJ. A systematic review of the impact of routine collection of patient reported outcome measures on patients, providers and health organisations in an oncologic setting. BMC Health Serv Res. 2013 Jun 11;13:211.Disclosure of Interests:Julie de Fonss Gandrup: None declared, Syed Mustafa Ali: None declared, Sabine van der Veer: None declared, John McBeth: None declared, William Dixon Consultant of: Bayer and Google

Introduction: Leukapheresis and adequate cell collection of patient derived T cells is critical in the successful manufacturing of chimeric antigen receptor T cell (CAR-T) therapy. There are limited published data on parameters that might affect quality of leukapheresis collection or collection efficiency (CE). The aim of this study is to identify patient characteristics or collection parameters that might affect leukapheresis CE and any potential impact on manufactured product characteristics. Methods: We retrospectively reviewed collection data from 23 consecutive patients with relapsed/refractory diffuse large B cell lymphoma (DLBCL) who underwent leukapheresis for Kymriah® (tisagenlecleucel) at our institution from May 1st, 2018 to July 1st, 2020. The study was approved by the Institutional Review Board. Non-stimulated mononuclear cell (MNC) collections were performed on the Spectra Optia, Terumo BCT, using the continuous MNC collection protocol. Acid citrate dextrose A (ACD-A) was used for anticoagulant. Inlet/AC ratio maintained at 15:1. Collection flow rates were targeted for 60-85 mL/min, with goal of processing 2-4 times the patient's total blood volume (TBV). Patients underwent peripheral collection if they had adequate venous access, otherwise central venous access was obtained. Peripheral blood (PB) flow cytometry was obtained prior to leukapheresis. Collection efficiency (CE) was calculated using the following formula: CE = Product CD3+ x106/ (PB CD3+ cells/μL x Total Volume Processed/ 1000). Descriptive summary statistics included median (range) for continuous variables and number (percentage) for categorical variables. Routine methods of continuous and categorical data analysis were performed using Statistica (version 7). Graph Pad Prism 8 was used to look for possible relations between variables. Results: Table 1 summarizes patient baseline characteristics (at time of leukapheresis) and pre-collection laboratory results. Table 2 summarizes the apheresis product. The median CE was 73% (with SD=13%). Baseline characteristics did not correlate significantly with collection efficiency. Collection by tunneled catheter or peripheral vein access did not significantly impact collection efficiency. PB absolute lymphocyte count (ALC) strongly correlated with PB CD3 cell and apheresis product CD3 counts (p<0.0001). PB CD3 cell count significantly correlated with apheresis product CD3 count (p<0.03; Figure 1). Notably, one patient with PB ALC of 0.0 K/uL and PB CD3+ of 0.204 K/uL was adequately collected, with successful product manufactured. All patients were able to receive manufactured product. Table 3 summarizes the tisagenlecleucel product information. Nine patients received out of specification (OOS) product due to low cell viability. All OOS products were due to cell viability below 80% threshold. When OOS products were compared to in specification products, OOS products were significantly associated with lower patient weight, less total volume processed, shorter collection run times, and smaller final collection product volumes. TBV processed was similar between groups. Conclusions: High CE is feasible in heavily pre-treated DLBCL patients, even with very low peripheral blood lymphocyte counts (ALC < 100). Our study confirms that pre-collection ALC and PB CD3 are strong indicators of CD3 yield in the leukapheresis collection product. OOS products were significantly associated with smaller volume processed, shorter run times, and smaller product volumes. This warrants further investigation. Disclosures Shah: NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; Moffitt Cancer Center: Current Employment; Kite/Gilead, Jazz, Incyte: Research Funding. Nishihori:Karyopharm: Other: Research support to institution; Novartis: Other: Research support to institution. Locke:Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Jain:Kite/Gilead: Consultancy; Novartis: Consultancy.

近年來，各種生技產物或方法無論於技術研發或實際應用上均快速成長，因此關於何種生技產物或方法得授予專利，以及生技產物或方法之專利權人行使該等專利的權利範圍是否應加以限制與如何限制所衍生之爭議也愈來愈多，而專利法制先進之國家或地區無不企圖藉由司法裁判或增修法規以解決此等問題。美國法制上與專利之申請及應用有關之規範涵蓋範圍甚廣，包括35 U. S. C. §101、§102及§103所訂有關得成為申請專利之標的之條件及其他申請專利之要件、35 U. S. C.§112所訂有關專利說明書之記載方式與內容、35 U. S. C. §287（c）所訂醫療從業人員及健康照護相關機構利用有關醫療的生技產物或方法之專利從事醫療活動得適用責任限制之條件及其範圍；美國專利商標局公布的「實用性審查基準」中有關基因之成分可授予專利的條件；美國專利商標局在2018年修正公布的「專利審查程序手冊」有關如何判斷「專利標的之適格性」與如何適用「標的適格性之兩部標準」所進行的說明；以及由美國聯邦最高法院與美國聯邦巡迴上訴法院之判決所建立的關於生技產物或方法是否能取得專利之判斷標準，此部分之內容將於本文第二部份詳加分析說明。歐洲相關公約與法制中為有效解決生技產物或方法是否能取得專利之問題，主要由歐洲專利公約與歐洲專利公約執行規則的相關規定；歐洲議會與理事會公布的相關指令；以及歐洲專利局與歐洲法院的相關案例建立其判斷標準，此部分之內容將於本文第三部分詳細說明。在台灣，有關生技產物或方法是否能作為申請專利之標的，以及生技產物或方法是否符合發明專利審查之要件，其主要規範為專利法第24條第2款及第3款、第22條第1項及第2項、第26條第1項；專利審查基準第2篇第2章及第14章；以及智慧財產法院的相關案例對於生技產物或方法是否符合專利要件之見解，此部分之內容將於本文第四部份詳細分析說明。本文之內容係綜合研究生技產物或方法之專利對於生技產業之研發誘因、改良發明之技術障礙、醫療倫理與醫療資源之妥適性等層面之影響，並檢討有關醫療的生技產物或方法是否應授予專利及其專利權人行使該等專利之權限應如何限制較為合理。最後，對於與生技產物或方法之專利有關的重要議題進行比較分析與彙整討論，並提出相關建議，作為台灣的專利相關規範適用與修訂之參考，以促進台灣有關生技產物與生技方法之專利法制能夠健全發展，期能有助於台灣的生技產業之成長與人民福祉之提升。 In recent years, various biotechnological products and processes all rapidly grow regardless of the technology research and development or the practical application, so are the issues which biotechnological products and processes can be granted patents, whether the fields of the patents should be limited and how it will be done; therefore, a number of the advanced countries or regions of the various patent legal system all attempt to resolve the issues by the judicial judgments or upgrading regulations. The scope covered by the provisions related to the application and use of patents in the U.S. legal system is very wide, including the conditions for being a patentable subject set by the United States Patent Law Article 101, Article 102 and Article 103, the manner and content recorded in the patent specification set by the United States Patent Law Article 112, the conditions and its scope of the limitation of liability for the medical practitioners and the products and processes in relation to medical therapy to practice medical activities set by the United States Patent Law Article 287 (c); the conditions for being patentable genetic components set by the “Utility Examination Guidelines” published by the United States Patent and Trademark Office; the interpretations with regard to how to determine “Patent Subject Matter Eligibility” and how to apply “Two Criteria for Subject Matter Eligibility” set by the “Manual of Patent Examining Procedure” amended and published by the United States Patent and Trademark Office in 2018; the criteria for the patentable biotechnological products and processes established by the decision of the Supreme Court and the Court of Appeals for the Federal Circuit in U.S. The previous provisions will be particularly analyzed and explained in the Part 2 of this Article. On the relevant European conventions and the legal system to effectively solve the problem of the patentable biotechnological products and processes, respectively, it relies on the provisions of the directive published by European Parliament and the Council of the European Union, the European Patent Convention, and the Implementing Regulations to the Convention on the Grant of European Patents; the criteria established by the related case of the European Patent Office and the Eurpean Court. The previous provisions will be particularly explain in the Part 3 of this Article. In Taiwan, the provisions related to whether the biotechnological products and processes are patentable and match the requirement of the examination of the inventions are mainly regulated in Taiwan's Patent Law Article 24, Item 2 and Item 3, Article 22, Item 1 and Item 2, Article 26, Item 1; the Patent Examination Guidelines in Chapter 2 and Chapter 14; the criteria for the patentable biotechnological products and processes established by the decision of the Court of the Intellectual Property. The previous provisions will be particularly analyzed and explained in the Part 4 of this Article. biotechnological products and processes for the effects on the R & D incentives of biotechnology industry, the technical barriers to the improvement of the inventions, the appropriation of medical ethics and health care resources, the review on whether the biotechnological products and processes in relation to medical therapy are patentable and how it is more reasonable to limit the exercise of such patent of patent holders. Finally, by comparing, analyzing and collectively discuss the important issues regarding the patents of the biotechnological products and processes and providing suggestions as the references for the application and the modification of Taiwan's patent-related legal provisions, in order to promote the sound development and the patent-related legal systems of the biotechnological products and processes, so as to look forward to assisting the growth of the Taiwan's biotechnology industry and the promotion of the public welfare.

Background Online health care services effectively supplement traditional medical treatment. The development of online health care services depends on sustained interactions between health care professionals (HCPs) and patients. Therefore, it is necessary to understand the demands and gains of health care stakeholders in HCP-patient online interactions and determine an agenda for future work. Objective This study aims to present a systematic review of the antecedents and consequences of HCP-patient online interactions. It seeks to reach a better understanding of why HCPs and patients are willing to interact with each other online and what the consequences of HCP-patient online interactions are for health care stakeholders. Based on this, we intend to identify the gaps in existing studies and make recommendations for future research. Methods In accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, a systematic retrieval was carried out from the Web of Science, PubMed, and Scopus electronic databases. The search results were confined to those papers published in English between January 1, 2000 and June 30, 2018. Selected studies were then evaluated for quality; studies that did not meet quality criteria were excluded from further analysis. Findings of the reviewed studies related to our research questions were extracted and synthesized through inductive thematic analysis. Results A total of 8440 records were found after the initial search, 28 papers of which were selected for analysis. Accessibility to HCPs, self-management, and unmet needs were the main triggers for patients to participate in online interaction. For HCPs, patient education, career needs, and self-promotion were the major reasons why they took the online approach. There were several aspects of the consequences of HCP-patient online interactions on health care stakeholders. Consequences for patients included patient empowerment, health promotion, and acquisition of uncertain answers. Consequences for HCPs included social and economic returns, lack of control over their role, and gaining more appointments. HCP-patient online interactions also improved communication efficiency in offline settings and helped managers of online health care settings get a better understanding of patients’ needs. Health care stakeholders have also encountered ethical and legal issues during online interaction. Conclusions Through a systematic review, we sought out the antecedents and consequences of HCP-patient online interactions to understand the triggers for HCPs and patients to participate and the consequences of participating. Potential future research topics are the influences on the chain of online interaction, specifications and principles of privacy design within online health care settings, and roles that sociodemographic and psychological characteristics play. Longitudinal studies and the adoption of text-mining method are worth encouraging. This paper is expected to contribute to the sustained progress of online health care settings.

Aim: To develop a nursing early warning system in children’s hospital during the outbreak of the novel coronavirus pneumonia, and to accomplish the construction and application of this system, so as to provide decision-support of the prevention and control for COVID-19 in children’s medical institutions. Method: Children’s hospital nursing early warning system was divided into three modules: hospital nursing early warning platform includes internal and external early warning platform, nursing staff early warning program includes protection, human resources early warning plan and patient early warning program includes outpatient, emergency and ward early warning plan. The data of epidemic training, assessment, prevention and control screening from January to June 2020 were collected from the nursing early warning system to evaluate the application effect of the system. Results: A total of 18 procedures and specifications were formulated, nine hospital-level trainings and about 1000 department-level trainings were organized, two hospital-level assessments (pass rate 95.6% and 98.2%), and 78 nurses were reserved, and 10 popular science articles, five popular science videos were published during the application of the nursing early warning system. A total of 583,435 children and 139,308 caregivers were screened in outpatient, emergency and wards during pre-checks, 2385 suspected cases of novel coronavirus pneumonia were confirmed (0.41%) after the screening and 1 case (0.0002%) was finally confirmed. Conclusion: The nursing early warning system of children’s hospital can prevent and control the novel coronavirus pneumonia epidemic from each module, ensure early warning and triage of suspected infected patients, reduce the risk of cross-infection in hospital and improve the safety of the children’s hospital medical environment.

ABSTRACT
 
 The Femur the longest bone of the body. The bone is a pipe bone and has a stem and two ends, with an indication of examination for the presence of congenital abnormalities in the bone, the occurrence of a fracture or fissure and several other cases sich as spiral fractures that cause shortening of overlapping fragment, or communal fracture (broken into pieces) an resulting in changes in size, shape and length of the bone. Orthorontgenografi method is a method that provides certainty in measuring the length of the bone in moral detail, accurate and specifications on the bone to be measured. The purpose of this study is know the measurement results os femur by using orthorontgenografi method.
 The type of research is using research quantitative with the experimental method is being done to get results conclusion, place and time study published in May 2019 at the Ropanosuri Padang Special Surgical Hospital. This study was conducted on one male patient, 18 years old and 172 cm tall with clinical post orif on the femur.
 The results of the study of measurement of femoral bone with orthoroentgenography method were obtained at length in the medial part of the femur is 28 cm, in the distal part of the femur is 11.9 cm, in the proximal part of the femur is 4,6 cm. The overall results of the measurements obtained 44.5 cm. From the discussion above, it can be seen that the method of orthoroentgenography is a method that can accurately prove the correct and accurate measurement of the femur on the examination of the femoral bone.
 
 Keywords : Os Femoralis, Radiographic, Orthoroentgenografi Method

Analysis of patient-derived DNA samples has identified hundreds of variants that are likely involved in neuropsychiatric diseases such as autism spectrum disorder (ASD) and schizophrenia (SCZ). While these studies couple behavioral phenotypes to individual genotypes, the number and diversity of candidate genes implicated in these disorders highlights the fact that the mechanistic underpinnings of these disorders are largely unknown. Here, we describe a RNAi-based screening platform that uses C. elegans to screen candidate neuropsychiatric risk genes (NRGs) for roles in controlling dendritic arborization. To benchmark this approach, we queried published lists of NRGs whose variants in ASD and SCZ are predicted to result in complete or partial loss of gene function. We found that a significant fraction (>16%) of these candidate NRGs are essential for dendritic development. Furthermore, these gene sets are enriched for dendritic arbor phenotypes (>14 fold) when compared to control RNAi datasets of over 500 human orthologs. The diversity of PVD structural abnormalities observed in these assays suggests that the functions of diverse NRGs (encoding transcription factors, chromatin remodelers, molecular chaperones and cytoskeleton-related proteins) converge to regulate neuronal morphology and that individual NRGs may play distinct roles in dendritic branching. We also demonstrate that the experimental value of this platform by providing additional insights into the molecular frameworks of candidate NRGs. Specifically, we show that ANK2/UNC-44 function is directly integrated with known regulators of dendritic arborization and suggest that altering the dosage of ARID1B/LET-526 expression during development affects neuronal morphology without diminishing aspects of cell fate specification.

Background Pressure ulcers (PUs) are a burden to patients, carers and health-care providers. Specialist mattresses minimise the intensity and duration of pressure on vulnerable skin sites in at-risk patients. Primary objective Time to developing a new PU of category ≥ 2 in patients using an alternating pressure mattress (APM) compared with a high-specification foam mattress (HSFM). Design A multicentre, Phase III, open, prospective, planned as an adaptive double-triangular group sequential, parallel-group, randomised controlled trial with an a priori sample size of 2954 participants. Randomisation used minimisation (incorporating a random element). Setting The trial was set in 42 secondary and community inpatient facilities in the UK. Participants Adult inpatients with evidence of acute illness and at a high risk of PU development. Interventions and follow-up APM or HSFM – the treatment phase lasted a maximum of 60 days; the final 30 days were post-treatment follow-up. Main outcome measures Time to event. Results From August 2013 to November 2016, 2029 participants were randomised to receive either APM (n = 1016) or HSFM (n = 1013). Primary end point – 30-day final follow-up: of the 2029 participants in the intention-to-treat population, 160 (7.9%) developed a new PU of category ≥ 2. There was insufficient evidence of a difference between groups for time to new PU of category ≥ 2 [Fine and Gray model HR 0.76, 95% confidence interval (CI) 0.56 to 1.04; exact p-value of 0.0890 and 2% absolute difference]. Treatment phase sensitivity analysis: 132 (6.5%) participants developed a new PU of category ≥ 2 between randomisation and end of treatment phase. There was a statistically significant difference in the treatment phase time-to-event sensitivity analysis (Fine and Gray model HR 0.66, 95% CI 0.46 to 0.93; p = 0.0176 and 2.6% absolute difference). Secondary end points – 30-day final follow-up: new PUs of category ≥ 1 developed in 350 (17.2%) participants, with no evidence of a difference between mattress groups in time to PU development, (Fine and Gray model HR 0.83, 95% CI 0.67 to 1.02; p-value = 0.0733 and absolute difference 3.1%). New PUs of category ≥ 3 developed in 32 (1.6%) participants with insufficient evidence of a difference between mattress groups in time to PU development (Fine and Gray model HR 0.81, 95% CI 0.40 to 1.62; p = 0.5530 and absolute difference 0.4%). Of the 145 pre-existing PUs of category 2, 89 (61.4%) healed – there was insufficient evidence of a difference in time to healing (Fine and Gray model HR 1.12, 95% CI 0.74 to 1.68; p = 0.6122 and absolute difference 2.9%). Health economics – the within-trial and long-term analysis showed APM to be cost-effective compared with HSFM; however, the difference in costs models are small and the quality-adjusted life-year gains are very small. There were no safety concerns. Blinded photography substudy – the reliability of central blinded review compared with clinical assessment for PUs of category ≥ 2 was ‘very good’ (kappa statistic 0.82, prevalence- and bias-adjusted kappa 0.82). Quality-of-life substudy – the Pressure Ulcer Quality of Life – Prevention (PU-QoL-P) instrument meets the established criteria for reliability, construct validity and responsiveness. Limitations A lower than anticipated event rate. Conclusions In acutely ill inpatients who are bedfast/chairfast and/or have a category 1 PU and/or localised skin pain, APMs confer a small treatment phase benefit that is diminished over time. Overall, the APM patient compliance, very low PU incidence rate observed and small differences between mattresses indicate the need for improved indicators for targeting of APMs and individualised decision-making. Decisions should take into account skin status, patient preferences (movement ability and rehabilitation needs) and the presence of factors that may be potentially modifiable through APM allocation, including being completely immobile, having nutritional deficits, lacking capacity and/or having altered skin/category 1 PU. Future work Explore the relationship between mental capacity, levels of independent movement, repositioning and PU development. Explore ‘what works for whom and in what circumstances’. Trial registration Current Controlled Trials ISRCTN01151335. Funding This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 52. See the NIHR Journals Library website for further project information.

Pharmacists are only knowledgeable and skilled healthcare professionals dedicated to compounding and preparing medications to meet the unique needs of patients. The safe and effective extemporaneous compounding of prescription products for patients require in special care is fundamental to the pharmacy profession. But there are much to do for secundum artem. It is not at all economical for a pharmaceutical company to marketize a product in 10 different probable doses or in 5 different dosage forms to meet the needs of the entire range of individuals receiving therapy. Although development is a continuous process, companies are customizing features to meet the majority of patient needs, but the very nature of the process cannot meet all patient needs. The risk-benefit ratio of using traditionally compounded medicines is favorable for patients who require specialized medications that are not commercially available, as they would otherwise not have access to suitable treatment. However, if an FDA-approved drug is commercially available, the use of an unapproved compounded drug confers additional risk with no commensurate benefit. Published reports of independent testing by the FDA, state agencies, and others consistently show that compounded drugs fail to meet specifications at a considerably higher rate than FDA-approved drugs. Compounded sterile preparations pose the additional risk of microbial contamination to patients. In the last 11 years, three separate meningitis outbreaks have been traced to purportedly ‘sterile’ steroid injections contaminated with fungus or bacteria, which were made by compounding pharmacies. The 2012 outbreak has resulted in intense scrutiny of pharmacy compounding practices and increased recognition of the need to ensure that compounding is limited to appropriate circumstances. Purpose of The Study: The article aims to physico-chemical and economic considerations before compounding; factors and quality control issues; compounding support, training, chemical supplies, types of compounding (specially in hospital and ambulatory care compounding). It should aid to practice the extemporaneous preparation of basic and advanced formulations including pharmacopoeial and non-pharmacopoeial formulations encountered in pharmacy practice, together with requisite documentation, labeling, packaging and counseling requirements. Along with this, they have to study the analysis of formulations and their components and relate these to the clinical performance of medicines. This will help them to investigate, evaluate and report the physical characteristics of formulations including release kinetics and relate these to quality control and preformulation requirements; relate the application of quality control, quality assurance and the principles of good manufacturing practice to regulation of medicine production in home and abroad. Outline: Background; Introduction; Compounding Factors; Types of Compounding; Identifying Errors and Cause

106 Background: Addressing utilization near the end of life (EOL) for cancer patients is critical to enhance the value of cancer care. Cancer EOL utilization measures have been widely endorsed, including by the National Quality Forum (chemotherapy in the last 14 days; ICU in the last 30 days; not admitted to hospice; admitted to hospice for < 3 days). However, efforts to use these measures to assess hospital quality and value have been constrained, in part because currently endorsed specifications do not provide a claims-based approach to cohort identification, and do not include a hospital attribution methodology. Methods: Using Medicare fee-for-service claims for adults ≥65 years, and through an iterative process informed by an expert panel, we developed extensible claims-based algorithms to a) identify patients who were deceased from cancer; b) attribute each patient to a responsible hospital; and c) derive hospital-level performance measures. We sought to ensure that these algorithms had strong face validity and were consistent with standard practices for claims-based analyses. Results: We identified 347,452 cancer decedents as those who had a cancer diagnosis associated with ≥2 hospital inpatient (IP), hospital outpatient (OP), or hospice claims, and died between 2011-2014. A decedent’s care was attributed to a hospital if there were ≥2 claims from that institution during the 6 months before death (N = 221,102). If this identified multiple hospitals, one was selected using the following sequence: total majority of all claims; most OP claims; most IP claims; last IP claim before death. Measure performance reflected national published data: 6% received chemotherapy in the last 14 days; 28% admitted to ICU in the last 30 days; and 34% not admitted to hospice. There was significant variation in hospital performance for all measures. Conclusions: Claims-based EOL measures do not define ‘ideal’ performance, but they do provide hospitals with broad utilization data that can help inform value-based cancer care delivery. These methods addressed gaps hindering the application of endorsed cancer EOL measures to hospitals. Companion quality measures to assess goal-concordant care are also needed.

Abstract Introduction: Sickle cell disease (SCD) is a recessively inherited anemia caused by a single gene mutation leading to sickle hemoglobin production. Sickle cell trait (SCT) is the carrier state. Abnormal hemoglobin polymerization and resultant red blood cell (RBC) sickling, decreased deformability and increased adhesion, are well-known features of homozygous SCD. However, the overall pathophysiological impact of SCT on the RBC remains incompletely characterized. Here we use microfluidic techniques designed by us, the OcclusionChip and SCD Biochip (previously published), and commercially available ektacytometry to investigate hypoxia impact on RBC biophysical properties in SCT. Methods: Venous blood samples were collected in EDTA from subjects with homozygous HbSS, SCT (HbAS), and non-anemic controls (HbAA) under an IRB-approved protocol. OcclusionChip devices were fabricated using standard soft lithography protocols [1]. RBCs were isolated from whole blood, re-suspended in PBS at 20% hematocrit, and passed through the OcclusionChip device with a constant inlet pressure. Following a wash step, the OcclusionChip microchannel was imaged, and Occlusion Index (OI), a standardized generalizable parameter we developed, representing the overall microcapillary network occlusion, was quantified. SCD Biochip microchannels were fabricated by lamination and were functionalized with human laminin (LN-511) [2]. Undiluted whole blood was injected into the microchannel at 1 dyne/cm 2, a shear stress value typically observed in the post-capillary venules. Following a wash step, the SCD Biochip microchannel was imaged, and the number of adherent RBCs in a 32-mm 2 window was quantified. For hypoxia experiments, a hypoxic setup was fabricated for blood deoxygenation (pO 2 ~45 mmHg) [3, 4]. Ektacytometry measurements were performed according to the manufacturers' specifications (Lorrca Maxsis). Data are reported as mean ± standard deviation (SD). Results: We initially analyzed RBC-mediated microvascular occlusion under normoxia or hypoxia using the OcclusionChip (Figure 1A). Under normoxia, HbSS-containing RBCs had relatively greater OI values compared to HbAA- and HbAS-containing RBCs (Figure 1B, P = 0.057 for HbSS vs HbAA and P = 0.060 for HbSS vs HbAS). However, exposure to hypoxia led to significantly elevated OI values in the HbAS- and HbSS-containing RBCs (Figure 1B, 0.05 ± 0.02% vs 33.62 ± 18.31%, P = 0.015 for HbAS, and 0.27 ± 0.24% vs 49.37 ± 24.47%, P = 0.001 for HbSS, normoxia vs hypoxia). Negligible occlusion was observed in HbAA-containing RBCs (Figure 1B). We then analyzed RBC adhesion to LN under normoxia or hypoxia using the SCD Biochip (Figure 1C). Hypoxia led to greater number of adherent RBCs on LN in the HbSS-containing RBCs (Figure 1D, 141 ± 91 vs 497 ± 392, P = 0.089, normoxia vs hypoxia), but this effect was not present in HbAA- or HbAS-containing RBCs (Figure 1B, 2 ± 1 vs 3 ± 1, P > 0.05 for HbAA, and 10 ± 7 vs 12 ± 3, P > 0.05 for HbAS, normoxia vs hypoxia). Further, under normoxia, we found that the HbAS-containing RBCs had slightly greater number of adherent RBCs on LN compared to the HbAA-containing RBCs (Figure 1D, P = 0.057 for HbAA vs HbAS). As previously reported, HbSS-containing RBCs showed greatest adhesion to LN under normoxia compared to the HbAA- and HbAS-containing RBCs (Figure 1D, P = 0.027 for HbSS vs HbAA and P = 0.033 for HbSS vs HbAS)., Finally, we preformed Lorrca oxyscan and found that ektacytometry is less sensitive to RBC deformability change under hypoxia in SCT (Figure 1E). Conclusions: Findings in this study suggest that although RBCs from subjects with SCT are deformable under normoxia and are able to clear narrow capillaries similar to normal RBCs, hypoxia changes deformability, presumably due to hypoxic polymer formation, and could contribute to microvascular occlusion in SCT. The OcclusionChip is a single cell-based technology, and may be more sensitive to single RBC deformability. Future studies will prospectively focus on analyzing RBC adhesion on activated microvascular endothelial cells in physiologic flow to further interrogate the impact of hypoxia on pathophysiology in SCT. References: [1] Man et al., LabChip, 2020, 20, 2086-2099. [2] Kim et al., Microcirculation, 2017, 24, e12374. Figure 1 Figure 1. Disclosures An: Hemex Health, Inc.: Patents & Royalties. Kucukal: BioChip Labs: Current Employment, Patents & Royalties. Nayak: BioChip Labs: Patents & Royalties. Little: Biochip Labs: Patents & Royalties; Hemex Health, Inc.: Patents & Royalties. Gurkan: Dx Now Inc.: Patents & Royalties; Hemex Health, Inc.: Current Employment, Patents & Royalties; Biochip Labs: Patents & Royalties; Xatek Inc.: Patents & Royalties.

Abstract Clinical Genome Resource (ClinGen) is an NIH/NHGRI-funded effort dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for use in precision medicine and research. ClinGen has developed both gene and variant expert panels to adapt the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for consistent and accurate variant classification of specific genes and diseases. Here, we describe a new effort initiated in 2018 and supported by the American Society of Hematology (ASH) in collaboration with ClinGen to develop expert panels. This effort was motivated by the increasing use of genomics in clinical hematology and the lack of resources containing expert interpretation of germline variation. This panel, named the ClinGen Myeloid Malignancy Variant Curation Expert Panel is focused on the curation and annotation of variants in genes associated with familial/inherited risk for myeloid malignancies. Our team consists of expert clinicians, clinical laboratory diagnosticians, and researchers interested in developing and implementing standardized protocols for sequence variant specific annotations of genes in inherited myeloid malignancies. The optimization of the ACMG/AMP guidelines encompasses disease-/gene-informed specifications or strength adjustments of existing rules, including defining gene-specific population frequency cutoffs, and specifying recommendations for the use of computational/predictive data, as supported by published functional and clinical data in addition to guidance on ACMG/AMP variant interpretation provided by the ClinGen effort. Our initial focus has been to organize sub-groups of teams to develop approaches for evaluating ACMG/AMP codes to interpret germline variants of the RUNX1 gene. Once the curation of RUNX1 variants is underway, we will extend our focus to include CEBPA, DDX41, ETV6, and GATA2. These efforts will be bolstered by encouraging submission of existing variant interpretations to ClinVar or other public variant databases by the Hematology community. In summary, the ClinGen Myeloid Malignancy Variant Curation Expert Panel aims to develop recommendations to optimize ACMG/AMP criteria for standardization of variant interpretation in myeloid leukemia genes and make expert-reviewed and interpreted variants available to the hematology community through ClinVar and the ClinGen website (www.clinicalgenome.org) to support patient care and research. Disclosures DiNardo: Karyopharm: Honoraria; Agios: Consultancy; Medimmune: Honoraria; Celgene: Honoraria; Bayer: Honoraria; Abbvie: Honoraria. Nichols:Incyte: Research Funding; Alpine Immune Sciences: Research Funding. Plon:Baylor Genetics: Membership on an entity's Board of Directors or advisory committees.

Background Young children’s vision screening, as part of a preventative health care service, produces great value for developing regions. Besides yielding a high return on investment from forestalling surgeries using a low-cost intervention at a young age, it improves school performance and thus boosts future labor force quality. Leveraging low-skilled health care workers with smartphones and automated diagnosis to offer such programs can be a scalable model in resource-limited areas. Objective This study aimed to develop and evaluate an effective, efficient, and comprehensive vision screening solution for school children in resource-limited areas. First, such an exam would need to cover the major risk factors of amblyopia and myopia, 2 major sources of vision impairment effectively preventable at a young age. Second, the solution must be integrated with digital patient record-keeping for long-term monitoring and popular statistical analysis. Last, it should utilize low-skilled technicians and only low-cost tools that are available in a typical school in developing regions, without compromising quality or efficiency. Methods A workflow for the screening program was designed and a smartphone app was developed to implement it. In the standardized screening procedure, a young child went through the smartphone-based photoscreening in a dark room. The child held a smartphone in front of their forehead, displaying pre-entered personal information as a quick response code that duplexed as a reference of scale. In one 10-second procedure, the child’s personal information and interpupillary distance, relative visual axis alignment, and refractive error ranges were measured and analyzed automatically using image processing and artificial intelligence algorithms. The child’s risk for strabismus, myopia, and anisometropia was then derived and consultation given. Results A preliminary evaluation of the solution was conducted alongside yearly physical exams in Luoyang, Henan, People’s Republic of China. It covered 20 students with suspected strabismus and 80 randomly selected students, aged evenly between 8 and 10. Each examinee took about 1 minute, and a streamlined workflow allowed 3 exams to run in parallel. The 1-shot and 2-shot measurement success rates were 87% and 100%, respectively. The sensitivity and specificity of strabismus detection were 0.80 and 0.98, respectively. The sensitivity and specificity of myopia detection were 0.83 and 1.00, respectively. The sensitivity and specificity of anisometropia detection were 0.80 and 1.00, respectively. Conclusions The proposed vision screening program is effective, efficient, and scalable. Compared with previously published studies on utilizing a smartphone for an automated Hirschberg test and photorefraction screening, this comprehensive solution is optimized for practicality and robustness, and is thus better ready-to-deploy. Our evaluation validated the achievement of the program’s design specifications.

Introduction: Repair of Tetralogy of Fallot up until recent decades involved aggressive resection and annular enlargement through a right ventriculotomy. This resulted in ventricular scarring and pulmonary incompetence, with an increased risk of ventricular tachyarrhythmia and sudden death in young adulthood. Following the NICE guidelines, implantation of ICDs as primary prevention in patients with repaired Tetralogy is ever increasing. This study aims to determine the rate of appropriate and inappropriate discharges, the success rate of ICD therapy and the impact of ICD implantation on the use of anti-arrhythmic medication in this population of patients. Materials and Methods: This is a retrospective review of patients with repaired Tetralogy of Fallot (n = 18) and pulmonary stenosis (n = 2) with implantable cardioverter defibrillators managed at our tertiary centre. Patients were identified from our outpatient database, their notes and charts were examined and details regarding indication for ICD implantation, device specifications and complications following implantation were collected. Data was also collected on the incidence of appropriate and inappropriate therapies and the success rate of ICD therapy along with the impact of implantation on the usage of anti-arrhythmic medication in these patients. Results: Of the 20 patients, 18 had previous repair of Tetralogy of Fallot and 2 had pulmonary valvotomy and infundibular resection for pulmonary stenosis between 1969 and 1989. 70% (n = 14) of these patients required reoperation with 10 patients having pulmonary valve replacements (PVR), 3 having redo infundibular resections and 1 requiring aortic valve replacement. At the time of consideration for ICD implantation 80% had moderate to severe pulmonary incompetence and 60% had more than mild right ventricular dilatation on echocardiography. Indications for ICD implantation were symptomatic ventricular tachycardia requiring cardioversion (n = 8), ventricular tachycardia on 24 hr tape/Reveal or electrophysiological study (n = 8), ventricular fibrillation (VF)/pulseless ventricular tachycardia (VT) (n = 2) and syncope with an abnormal EPS other than VT (n = 2, high grade ventricular ectopics, sinus node dysfunction).The median age at implantation was 22 years (16.4–43 years). All our patients had dual chamber devices implanted with either dual (n = 13) or single coil (n = 6) ventricular leads. GEM3 AT (n = 5), Marquis DR (n = 8) and Maximo DR (n = 7) generators (Medtronic Inc.) were implanted in sub pectoral position and both anti-tachycardia pacing and cardioversion modes were programmed as part of individualised VT and VF protocols. Early post procedural complications included atrial lead displacement (n = 1) and pneumothorax requiring drainage (n = 1).During a median follow up of 1.6 years (0.03– 4.5 years) several episodes of inappropriate therapies were noted in 6 patients (30%) especially early after implantation. This was found to be mainly due to atrial tachyarrhythmia, double counting of T waves or inaccurate interpretation of varying PR intervals as AV dyssynchrony which were effectively dealt with by changes in device programming. There were 33 episodes of inappropriate anti-tachycardia pacing (ATP) in 4 patients and 19 episodes of inappropriate cardioversion in 5 patients. Appropriate ATP was instituted in 4 patients (25%) with successful termination of all 20 episodes (100% success rate) of ventricular tachycardia. One patient required cardioversion with successful termination of VF. One patient (5%) with troublesome tachyarrhythmia died suddenly of unknown cause, 10 months after AICD implantation having had no detections or therapies on his device.Prior to ICD implantation 8 patients were on amiodarone therapy. At the time of last follow up after AICD implantation all patients were established on anti-arrhythmic agents and of these 6 patients were on amiodarone with the others being effectively managed on beta-blockers and/or flecainide.Late complications of ICD implantation included lead failure in 1 patient requiring replacement 3.3 years after implantation and generator replacement in a patient who was pacemaker dependent a year after implantation due to an advisory issued by the manufacturer regarding the risk of sudden battery depletion. Conclusions: In our study we found a rate of 0.6 appropriate and 1.4 inappropriate therapies (0.9 episodes of inappropriate ATP and 0.5 episodes of inappropriate cardioversion) per patient-year of follow up following ICD implantation which is in keeping with published literature. The mortality in our study group was 5% which is acceptable given the high risk population. Implantation of an ICD allowed switching over from amiodarone to less toxic anti arrhythmic therapy in a proportion of patients. Anti-tachycardia pacing was very successful in terminating tachyarrhythmia in our population with 100% success in terminating ventricular tachycardia.

Abstract Myelodysplastic syndrome (MDS) caused by monosomy 7 or del(7q) is a frequent clonal abnormality that arises in the context of inherited bone marrow failure syndromes, such as Shwachman Diamond Syndrome (SDS). Monosomy 7/del(7q) also develops in a subset of patients with acquired aplastic anemia or de novo MDS in the general population. Monosomy 7/del(7q) is associated with high grade MDS and a high risk of malignant transformation, most frequently to acute myelogenous leukemia (AML). Bone marrow failure and clonal evolution to MDS and AML remain major causes of morbidity and mortality for individuals with SDS. Currently, the only curative therapy for these hematological complications is a hematopoietic stem cell transplant. Prognosis is extremely poor once SDS patients develop leukemia. The basis for this propensity to develop monosomy 7 clones remains unclear. The longterm aim of this study is to understand the molecular mechanisms underlying leukemia predisposition and develop more effective treatments. Whether monosomy 7/del(7q) functions as a driver of MDS, or is merely an associated marker of clonal progression in bone marrow failure remains a critical question. The lack of synteny between murine versus human chromosome 7 has posed a major barrier to the development of mouse models of monosomy 7/del(7q). To study the biological and molecular consequences of monosomy 7/del(7q) in SDS, induced pluripotent stem cells (iPSCs) were generated from bone marrow mononuclear cells of two patients with SDS. Each patient harbored homozygous c.258+2 T>C mutations in the canonical splice donor site of intron 2 in the SBDS gene. The SDS-iPSCs retained the pathogenic homozygous IVS2+2 T>C SBDS mutations, expressed stem cell markers, formed teratomas, and expressed reduced levels of SBDS protein similar to levels noted in the primary patient samples. Proliferation of 4 distinct SDS-iPSC clones derived from two different patients was reduced relative to wild type controls without an increase in cell death. SDS-iPSC formed smaller embryoid bodies with reduced production of CD34+ hematopoietic stem/progenitor cells. Hematopoietic differentiation from CD34+ to CD45+ cells was also impaired. Preliminary data suggest that SDS-iPSCs retain the capacity to give rise to hematopoietic stem/progenitor cells and early myeloid progenitor cells in vitro. These populations were also observed in primary SDS patient-derived bone marrow samples. Because the number of CD34+ cells derived from SDS-iPSCs are limiting, a previously reported 5 transcrition factor re-specification system was used to expand multilineage hematopietic progenitors for further characterization. SDS iPSCs were able to differentiate into an expandable CD34+ population in vitro. Further studies to characterize the hematopoietic impairment in SDS iPSC and primary marrow samples are ongoing. To model del(7q) in SDS iPSCs, a deletion of the MDS-associated long arm of chromosome 7 was genomically engineered using a previously published modified Cre-Lox approach. The deletion of 7q at locus (11.2) was confirmed by karyotyping and by qPCR across chromosome 7. The SDS (del7q) iPSCs retained the SBDS pathogenic mutations, expressed stem cell markers, and formed teratomas. Proliferation of the SDS del(7q) iPSC was markedly impaired compared to isogenic SDS iPSCs. No increase in cell death was observed in the SDS del7q iPSCs. Studies are in progress to determine the effects of del7q on hematopoiesis. Investigation is ongoing to determine the molecular consequences of deleting 7q. These isogenic SDS+/- del(7q) iPS models provide a platform to study the role of 7q loss in clonal evolution from bone marrow failure and to screen for novel therapeutic compounds or pathways to treat bone marrow failure and MDS. Disclosures No relevant conflicts of interest to declare.

BackgroundImproving Access to Psychological Therapies (IAPT) is a National Institute for Health and Care Excellence-approved approach to intervention for depression and/or anxiety. This exploratory study sets the groundwork for comparing psychological therapies for Deaf sign language users experiencing anxiety and/or depression, delivered in British Sign Language (BSL) by a Deaf therapist with usual access through an interpreter within the IAPT national programme.Objectives(1) To explore the following questions: (a) is BSL-IAPT more effective than standard IAPT for Deaf people with anxiety and/or depression? and (b) is any additional benefit from BSL-IAPT worth any additional cost to provide it? (2) To establish relevant BSL versions of assessment tools and methods to answer research questions (a) and (b). (3) To gauge the feasibility of a larger-scale definitive study and to inform its future design.DesignA mixed-methods exploratory study combing an economic model to synthesise data from multiple sources; a qualitative study of understanding and acceptability of randomisation and trial terminology; statistical determination of clinical cut-off points of standardised assessments in BSL; secondary data analysis of anonymised IAPT client records; realist inquiry incorporating interviews with service providers and survey results.SettingsIAPT service providers (NHS and private); the Deaf community.ParticipantsDeaf people who use BSL and who are clients of IAPT services (n = 502); healthy Deaf volunteers (n = 104); IAPT service providers (NHS and private) (n = 118).InterventionsIAPT at steps 2 and 3.Main outcome measuresReliable recovery and reliable improvement defined by IAPT; Deaf community views on the acceptability of randomisation; BSL terminology for trial-related language; clinical cut-off measurements for the BSL versions of the Patient Health Questionnaire-9 items (PHQ-9) and the Generalised Anxiety Disorder-7 (GAD-7); a valid BSL version of the EuroQol-5 Dimensions five-level version (EQ-5D-5L); costs, quality-adjusted life-years and incremental cost-effectiveness ratios.Data sourcesIAPT service provider anonymised records of the characteristics and clinical outcomes of Deaf BSL users of BSL-IAPT and of standard IAPT; published literature.ResultsRandomisation may be acceptable to Deaf people who use IAPT if linguistic and cultural requirements are addressed. Specifications for effective information in BSL for recruitment have been established. A valid EQ-5D-5L in BSL has been produced. The clinical cut-off point for the GAD-7 BSL is 6 and for the PHQ-9 BSL is 8. No significant difference in rates of reliable recovery and reliable improvement between Deaf users of standard IAPT or BSL-IAPT has been found. Whether or not BSL-IAPT is more cost-effective than standard IAPT is uncertain.LimitationsThe small number of participating standard IAPT services who have seen Deaf clients means that there is statistical uncertainty in the comparable clinical outcome result. Clinical cut-off scores have not been verified through gold standard clinical interview methodology. Limited data availability means that whether or not BSL-IAPT is more cost-effective than standard IAPT is uncertain.ConclusionsThere is a lack of evidence to definitively compare reliable recovery and reliable improvement between Deaf users of standard IAPT and BSL-IAPT. Instrumentation and prerequisites for a larger-scale study have been established.Future workA prospective observational study for definitive results is justified.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

Abstract Background: Pediatric venous thromboembolism (VTE) is a rare but serious medical condition resulting in significant morbidity, mortality and healthcare costs. In the recent decade, the rate of general pediatric VTE has dramatically increased across all age ranges, from neonates to adolescents. This increase is likely multi-factorial, including more aggressive management of critically ill patients, improved survival of children with chronic disease and the increased use of central venous catheters (CVCs). Cystic fibrosis (CF) is a chronic, inflammatory disease process often managed with courses of intravenous antibiotics administered through CVCs, both peripherally inserted central catheters (PICC) and implantable venous ports. There are limited data documenting an increased risk of VTE in CF patients with ports. However, there are no published data on PICC line-associated VTE or overall VTE incidence specifically in the pediatric CF population. Methods: A retrospective cohort study was conducted in CF patients, ages 0 to 21 years, followed at the CF Care Center at Children's Hospital Colorado between 2003 and 2016, who were enrolled in the national CF Foundation Patient Registry. VTE cases were identified by informatics, including anticoagulation administration, documentation of VTE in radiographic reports and nursing flowsheets, and use of VTE ICD-9 and ICD-10 codes. All identified cases were confirmed by manual chart review and data including personal and family history of VTE, use of prophylaxis and VTE type, diagnosis date, diagnostic modality and line-association were entered into a secured REDCap longitudinal database. Data including CF mutation, CF co-morbidities, microbiology history, pulmonary function testing, disease modifying medications, thrombophilia testing and central line specifications and duration were collected for every admission on all study participants to allow for future risk factor analysis. Results: The cohort consisted of 488 participants with a total of 2,590 admissions (mean 5.34 per participant, range 1-56). Two hundred and forty-nine individuals were male (51%) and the majority were Caucasian (463, 95.3%) with a normal BMI (average 19.7, range 14.8-25.4). A total of 1,157 CVCs were placed over the study period including 981 PICCs (84.8%), 93 ports (8%) and 83 unspecified (7.2%). Thirty-one VTEs were diagnosed in 23 participants (4.3%) on 29 admissions (1.12%). Twelve of the 23 participants with VTE were male (52%) and the average age of those with VTE was 15.3 years (range 4-21). Twenty-two of the VTEs were deep vein thromboses, including 4 pulmonary emboli, and 9 were in superficial veins. The average day of VTE diagnosis was hospital day 4.9 (range 0-14). At the time of diagnosis, 11 had ports, 15 had PICCs and 5 had no CVC. The majority of VTEs were associated with the CVC (19, 61.3%) and of those CVC-associated VTEs, the majority were seen with PICCs (14, 73.7%). On average, PICC-associated VTE occurred on line day 5.2 (range 2-14) and port-associated VTE occurred on line day 897.5 (range 37-1496). Of the 23 participants with VTE, 14 were tested for Factor V Leiden mutation and 2 were heterozygous. Similarly, for the prothrombin mutation, 13 were tested and two were heterozygous. While the majority of participants had minimal to no thrombophilia evaluation, notably, an elevated factor VIII was associated with 11 of 12 VTE diagnoses (91.7%, average 215.47, range 61-341.3). Conclusion: In this large pediatric cohort of patients with CF, there was an increased number of VTE when compared to previously published general pediatric populations. Consistent with known risk factors, the average participant with VTE was in their teenage years and had a CVC, although 16% occurred without a line in place. Gender and obesity did not appear to contribute dramatically as the male/female distribution was roughly equal and the average BMI was within normal range. If a CVC was placed, the vast majority of CF patients received PICCs. PICCs also made up the majority of CVC-associated VTE with the average thrombosis occurring on day 5 following line placement. Few participants with VTE had complete thrombophilia evaluations but of those that did, factor VIII was elevated in all but one individual. Disclosures Wang: HEMA Biologics: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Membership on an entity's Board of Directors or advisory committees; Baxalta: Membership on an entity's Board of Directors or advisory committees; LFB: Membership on an entity's Board of Directors or advisory committees; Biogen: Membership on an entity's Board of Directors or advisory committees; Novo Nordisk: Membership on an entity's Board of Directors or advisory committees.

Abstract Long-term hematopoietic stem cells (HSCs) are capable of self-renewal and differentiation into all mature hematopoietic lineages. This process is regulated by transcription factors interact with co-factors to orchestrate chromatin structure and facilitate gene expression. To generate a compendium of factors that establish the epigenetic code in HSCs, we have undertaken the first large-scale in vivo reverse genetic screen targeting chromatin factors. We have designed and injected antisense morpholinos to knockdown expression of 488 zebrafish orthologs of conserved human chromatin factors. The resultant morphants were analyzed by whole embryo in situ hybridization at 36 hours post fertilization for expression of two HSC marker genes, c-myb and runx1, which are expressed in the developing blood stem cells. Morphants were categorized into five groups based on HSC marker expression, ranging from no change to mild, intermediate, or strong reduction in expression or an increase in expression. 29 morpholinos caused a complete or near complete knockdown of HSC marker expression, while 4 were found to increase HSC marker expression. As ubiquitous knockdown of chromatin factors could interfere with vascular development and the establishment of proper arterial identity, a crucial upstream event for HSC formation, we subsequently analyzed morphants with the most robust HSC phenotypes using two vascular markers: kdr for overall vasculogenesis and ephrinb2a for arterial formation. We found that of the 29 morpholinos that caused reduced marker expression, only 9 showed reduced overall vascular or arterial marker staining, suggesting that the majority of morphants with HSC phenotypes are specific to HSC formation. For the 4 morphants with increased HSC marker expression, vasculature appeared normal. These factors likely function as potent negative regulators of HSC development. Several genes known to be essential for HSC self-renewal and maintenance were identified in the screen. For example, knockdown of Mll or Dot1, which are also present in leukemia fusion proteins, fail to specify HSCs, as indicated by a nearly complete reduction in expression of the HSC markers in embryos tested. Of the remaining hits, many represent factors with no previous function ascribed in hematopoiesis. By incorporating protein interaction data, we have defined a handful of complexes necessary for HSC specification, including the SWI/SNF, ISWI, SET1/MLL, CBP/P300/HBO1/NuA4, HDAC/NuRD, and Polycomb complexes. As chromatin factors associated with the same complex likely share target binding sites, we analyzed 34 published ChIP-seq datasets in K562 erythroleukemia cells of chromatin factors tested in the screen, including hits from our screen: SIN3A, CHD4, HDAC1, TAF1, and JARID1C associated with the HDAC/NuRD complex and RNF2, SUZ12, CBX2, and CBX8 from the Polycomb complexes. We ranked triplet combinations of these factors together with all other groups of three factors based on the percent overlap of target genes. The HDAC/NuRD and PRC1/2 complex combinations predicted from our screen fell within the top 20% of all possible combinations of 3 factors, suggesting that our screen has identified chromatin factors that function in distinct complexes to regulate hematopoietic development. Our work has been compiled into a web-based database that will be made publicly available upon publication. Within this database, users can search by gene names and aliases, chromatin domain names and human or zebrafish genes. All experimental data, including experimental design, materials, protocols, images, and all further analyses of the 33 most robust morphants is included. Our large-scale genetic analysis of chromatin factors involved in HSC development provides a comprehensive view of the programs involved in epigenetic regulation of the blood program, offering new avenues to pursue in the study of histone modifications in HSCs and for therapeutic alternatives for patients with blood disorders and leukemia. Disclosures: Zon: FATE Therapeutics, Inc: Consultancy, Equity Ownership, Founder Other, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties; Stemgent, Inc: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Stocks, Stocks Other; Scholar Rock: Consultancy, Equity Ownership, Founder, Founder Other, Membership on an entity’s Board of Directors or advisory committees, Patents & Royalties.

Little is known about the disease-specific factors that predict responsiveness to CAR-T cell therapy, other the direct presence of the CAR-T target. Clinical outcomes at our center have demonstrated that durable responses to CD19-directed CAR-T therapy in pediatric pre-B-ALL (acute lymphoblastic leukemia) are associated with persistence of CAR-T cells in the peripheral blood, antigenic load (percent CD19-positive cells in marrow prior to CAR-T infusion), and apheresis product T-cell quality (Finney O, et al., 2019). However, in a small number of cases where both antigenic load and T-cell quality predicted a good response, the treatment failed rapidly. This led us to undertake a detailed investigation of the leukemia itself in order to discover potential disease-associated factors that correlate with resistance to CAR-T therapy. We employed advanced exomic, and single-cell genomic and epigenomic analysis techniques to define signatures present in four CD19-CAR-T resistant bone marrow biopsy specimens, in comparison to five specimens from CD19-CAR-T responsive disease, from patients enrolled in a phase I clinical trial at Seattle Children's Hospital (PLAT-02, NCT02028455). Current cytogenic approaches to identify high risks markers (Ph+, Ph-like, MLL) were not informative as to CAR-T susceptibility, as high risk leukemias were CAR-T responsive; while a CAR-T resistant leukemia contained a marker (ETV6-RUNX1 fusion) previously associated with a good prognosis. Thus, we performed bulk whole-exome sequencing and RNAseq, single cell (sc) RNAseq, sc B-cell receptor (BCR)-seq, methylation array, H3K27ac ChIPseq, and ATACseq on these marrow samples. Initial genomic analysis revealed a total of 5 previously described hotspot mutations in ABL1, IKZF1, EP300, and 2 in KRAS. RNAseq analyses identified actionable fusions for ABL1, ETV6, ETV5, and KMT2A. Interestingly, a therapy-sensitive leukemia harbored a KMT2A-AFF1 fusion that was shown to predispose patients to leukemic plasticity and lineage switching when treated with blinatumomab. Importantly, we identified CREBBP-fusions in leukemias that failed to achieve CD19-CAR-T cell induced B cell aplasia. CREBBP perturbations have previously been associated with relapsed and refractory ALL, but not with resistance to CAR-T therapy. Single cell RNAseq and scBCRseq data are being analyzed for the existence of mixed lineage and gene expression-based heterogeneity that may predict clonal selection under CAR-T pressure. RNASeq analysis identified upregulation of JUN and JUND transcripts in CAR-T resistant disease, a finding which is complemented by the hypermethylation of JUND in CAR-T sensitive disease. Similarly, ATACseq and methylation data is being analyzed for lineage specification in CAR-T resistant leukemia. In comparing dysfunctional to functional CAR-T responders by ATACseq, > 10,000 unique open chromatin regions were identified in dysfunctional responders, as opposed to <500 open chromatin regions in the functional responders, indicating that CAR-T resistant disease had more open chromatin. A recent published analysis of cancer cell lines identified EP300 and CREBBP mutations that were proposed to increase substrate acetylation, and which "…may represent the first cancer-associated gain of function mutations for p300 and CBP…" (Ghandi M, et al, 2019). Our study represents one of the most comprehensive approaches to genomic profiling for B-ALL patient samples to date. The immune evasion we have described is not due to overt CD19 antigen loss, or to a long-term process of genetic alteration or drift. We propose that continued analysis of our data may reveal that epigenetic plasticity is a component of CAR-T resistance. The presence of CREBBP fusion genes or mutations, methylation array-based identification of altered JUND/JUN regulation, and ATAC Seq identification of multiple open regions of the genome in leukemias from dysfunctional responders lend support to this hypothesis. Although our analysis is preliminary and the sample number is small, we believe these in-depth analyses will highlight crucial differences in leukemia that predict responsiveness to CAR T therapy Disclosures Gardner: Novartis: Honoraria. Jensen:Bluebird Bio: Research Funding; Juno Therapeutics, a Celgene Company: Research Funding. Orentas:Lentigen Technology Inc., a Miltenyi Biotec Company: Consultancy, Research Funding.

Radical prostatectomy is the most commonly performed treatment option for localised prostate cancer. In the last decades the surgical technique has been improved and modified in order to satisfy both oncological safety and postoperative functional results. Urinary incontinence and erectile dysfunction (ED) are the main postoperative functional impairments in patients that undergo radical prostatectomy (RP). [1] According to the EAU Guidelines erectile dysfunction is defined as “the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance”. To this moment it is estimated that 25-75% of the patients who underwent RP develop ED with major implications in postoperative quality of life. [2] Various risk factors can be related to post-prostatectomy ED, among which the most important are the patient’s age, comorbidities, preoperative erectile function, but also surgical approach (robot-assisted, laparoscopic, open) and nerve-sparing technique (inter/intrafascial). [2, 3] Among physiopathological modifications that concur to ED, the nerve damage (neuropraxia) appears to be the main domino piece that triggers other alterations like structural changes of the smooth muscle, arterial damage and veno-oclusive dysfunction which lead to cavernosal oxygenation impairments. [4–6] The clinical results of physiopathological alterations are shortening of penile size, impairment of orgasm and ejaculation achievement which have tremendous impact on psychological and mental health. [5] Various treatment options include oral medication with phosphodiesterase 5 inhibitors (PDE5i), intracavernosal injections or intraurethral applications of prostaglandin E1 (PGE1), vacuum or vibratory treatments. Though there are many options for ED treatment, to this date there is no definitive protocol for penile rehabilitation (PR) after prostatectomy. [5, 7] In this regard we have made a literature review and meta-analysis of the most important randomised trials published in the last 5 years in order to find the best strategies of penile rehabilitation after radical prostatectomy. MATERIALS AND METHODS We have systematically reviewed and collected data from randomised trials published in the last 5 years involving patients diagnosed with prostate cancer who experienced ED after radical prostatectomy. In order to find the necessary trials we have searched PubMed and ScienceDirect databases and used several key words like: erectile dysfunction, penile rehabilitation, phosphodiesterase 5 inhibitors, erectile functional recovery, prostate cancer, prostatectomy and nerve sparing – in various combinations. The first aspect for our meta-analysis inclusion criteria was to identify randomized (prospective or retrospective) placebo-controlled trials involving patients with localised prostate cancer that benefited of nerve sparing radical prostatectomy and developed postoperative ED. The key aspect of our research was the penile rehabilitation strategy which included the therapeutic means used for erectile 1 Dimitrie Gerota Emergency Hospital, Bucharest, Romania 2 Dr. Carol Davila University Central Emergency Military Hospital, Bucharest, Romania 3 Carol Davila University of Medicine and Pharmacy, Bucharest, Romania 10 function recovery and the treatment duration. Other aspects followed by us regarded the means of ED assessment, the surgical means and invasiveness and the rate of treatment success reported to ED severity. In this regard we have conducted our research for each year between January 2014 and December 2018 and reviewed a total of 631 articles published on this theme collected from both search engines. For a time-efficient assessment we have read the title and abstract of each article and included only those articles that matched our criteria. We have excluded the reviews and meta-analyses and also the trials of ED that was not related to prostate cancer surgery. That left us 194 publications from which to select. We have also excluded the trials withdrawn from database for various reasons and articles that didn’t followed the therapeutic means of ED recovery. Finally we have selected 15 articles matching our criteria for meta-analysis that were thoroughly full text reviewed. Seven out of the 15 were prospective randomised trials, 2 of them being double-blind, placebo-controlled. Another 2 were nonrandomised prospective trials and the rest of 6 articles were retrospective review. Although some studies included by us followed-up both the ED and postoperative incontinence problem, we have concerned strictly on erectile dysfunction issue and collected the necessary data. For statistical analysis we have used ReviewManager 5.3 and Microsoft Excel software with data of treatment strategies and drug dosages collected from the studies. Although there was less heterogeneity between the study designs of the included articles we found important data about postoperative EF recovery. These data allowed us to include the studies in subgroups in order to analyse them. Table 1. Distribution of included studies Trial author Design Patient no. Mean age Cardiovascular comorbidities Diabetes Vickers et al. [8] Randomised prospective 2162 64.2 NoS NoS Montorsi et al. [9] Randomised double-blind placebo-control 423 58 NoS NoS Seo et al. [10] Retrospective review 92 67.9 40 (43.5%) 14 (15.2%) Nakano et al. [11] Retrospective review 103 63.4 NoS NoS Fode et al. [12] Randomised prospective control 68 62 NoS NoS Stolzenburg et al. [13] Randomised double-blind 422 59 NoS NoS Canat et al. [14] Randomised prospective 112 63 42 (37.5%) 18 (16.07%) Yiou et al. [15] Retrospective review 75 59.4 30 (40%) 6 (8%) Haglind et al. [16] Prospective controlled nonrandomised 2625 63 NoS NoS Kim D. et al. [17] Randomised prospective placebo-control 97 54 NoS NoS Capogrosso et al. [18] Retrospective review 2364 61 NoS NoS Sooriakumaran et al. [19] Prospective non-randomised 2545 63.3 556 (35.2%) 99 (6.2%) RESULTS A total of 11,831 patients were enlisted in the 15 studies we have included for analysis. Mean age of all patients was 61.91 years with a range between 54 and 67.9 years. (Table 1) Although not all the studies specifically mentioned the most encountered comorbidity was the cardiovascular disease (37.5% - 100%) followed by diabetes mellitus (6.2% – 16.07%). For most ED patients the presence of cardiovascular comorbidities creates the premises of disease trigger, followed by diabetes and obesity. [] All patients were Vol. CXXII • No. 3/2019 • December • Romanian Journal of Military Medicine 11 diagnosed (by means of PSA, prostate biopsy and pelvic MRI) with localised prostate cancer mainly T1c - T2c, with Gleason score ranging between 6 and 7 and PSA values below 10 ng/ml. (Table 2) These data were correlated with the postoperative pathology findings which in some cases changed the actual diagnostic stage according to d’Amico criteria. As it can be seen in Table 2 in some cases based on the degree of invasion the cancer stage was changed from localised to locally-advanced (T3b-T4) and based on Gleason score from low or intermediate risk to high risk (Gleason 8). All patients were proposed for radical prostatectomy using various approaches: open surgery (n = 4,460), conventional laparoscopy (n = 1,371) or robot assisted laparoscopic prostatectomy (n = 4,929). (Table 2) Most patients benefited of bilateral nerve sparing (BNS) dissection of the nerve bundles (n = 6,852) by al known technical procedures (interfascial/intrafascial), which represented 63.68% of the operated patients. When case did not impose BNS dissection, unilateral nerve sparing technique was attempted (n = 3,209) which was performed in 29.82% of the operated patients. The rest of 6.5% of the patients either had not benefited of NS dissection either the information about the NS status was not mentioned. [16, 18, 19] The NS status at the end of the surgery was crucial because it ensured the premises for postoperative ED recovery although most of the patients experienced postoperative neuropraxia. Table 2. PCa status and surgical approach for each study Trial author PCa clinical stage Gleason Score Surgical approach Nerve sparing OP CLP RALP BNS UNS Vickers et al. [8] T2a – T3 6 - 8 859 (40%) 546 (25%) 757 (35%) 657 (30%) 1498 (70%) Montorsi et al. [9] T1c – T2c 6 - 7 68 (48.9%) 29 (20.9%) 31 (22.3%) 423 (100%) - Seo et al. [10] T2a – T2c 4 - 8 - - 92 (100%) 57 (62%) 35 (38%) Nakano et al. [11] T2 – T3 6 - 7 NoS NoS NoS 24 (23.3%) 79 (76.7%) Fode et al. [12] T2 – T3 NoS 7 (10.3%) - 61 (89.7%) 37 (54.41%) 31 (45.58%) Stolzenburg et al. [13] T2-T3 ≤ 7 189 (44.78%) 88 (20.85%) 115 (27.25%) 422 (100%) - Canat et al. [14] T2a-T2c 5 - 8 NoS NoS NoS 112 - Yiou et al. [15] T2 - T3 6 - 8 - 75 (100%) - 75 (100%) - Haglind et al. [16] T1 - T3 6 - 8 778 - 1847 1318 750 Kim D. et al. [17] T1c – T3 6 - 8 58 (61.7%) - 36 (38.3%) 96 (98.96%) 1 (1.04%) Capogrosso et al. [18] T2 - T4 NoS 614 (26%) 633 (27%) 1117 (47%) 2253 (95%) 78 (3%) Sooriakumaran et al. [19] T2 – T4 NoS 1792 (70.41%) - 753 (29.58%) 1283 (50.41%) 737 (28.95%) Kim S. et al. [20] T2a – T2c 4 - 8 95 (100%) - - 95 (100%) - Kwon et al. [21] NoS NoS NoS NoS NoS NoS NoS Jo et al. [22] T2a – T2c 5 - 7 - - 120 (100%) NoS NoS NoS – no specification; OS – open surgery; CLP – conventional laparoscopic prostatectomy; RALP – robot assisted laparoscopic prostatectomy; BNS – bilateral nerve-sparing; UNS – unilateral nerve-sparing. 12 Table 3. Preoperative EF assessment and postoperative EF recovery means and results Trial author Type of EF questionnaire Preop. mean EF score Means of penile recovery Subgroups Trial duration Recovery rates Vickers et al. [8] IIEF-6 ³22 - 937 (59%) PDE5i (NoS) PGE1 ICI - 2 years 36% (NoS) Montorsi et al. [9] IIEF-EF ³22 - 423 (100%) PDE5i Tadalafil 5 mg – OaD – 139 (32.86%) Tadalafil 20 mg – PRN – 143 (33.8%) Placebo – 141 (33.3%) 9 months Tadalafil 5 mg – 25.2% Tadalafil 20 mg – 19.7% Placebo – 14.2% Seo et al. [10] IIEF-5 ³22 - 92 (100%) PDE5i Tadalafil 5 mg – OaD Non-Tadalafil 1 year Tadalafil 5 mg – 13.2% Non-Tadalafil – 7.7% Nakano et al. [11] IIEF-5 17.7 PDE5i Vardenafil 10 mg – OD – 30 (29.12%) Vardenafil 20 mg – PRN – 5 (4.85%) No treat – 68 (66.01%) 1 year Vardenafil 10 mg + Vardenafil 20 mg – 21 (60%) No treat – 26 (38.2%) Fode et al. [12] IIEF-5 25 PDE5i PVS PDE5i + PVS - 30 PDE5i - 38 1 year PDE5i + PVS – 16 (53%) PDE5i – 12 (32%) Stolzenburg et al. [13] IIEF-5 ³22 – 422 (100%) PDE5i Tadalafil 5 mg – OaD - 102 Tadalafil 20 mg – PRN - 112 Placebo - 106 9 months Tadalafil 5 mg – OaD – 29 (28.43%) Tadalafil 20 mg – PRN – 24 (21.42%) Placebo – 27 (25.4%) Canat et al. [14] IIEF-6 ³ 22 PDE5i Tadalafil 5 mg – OpW - 38 Tadalafil 20 mg – PRN - 40 Non-Tadalafil - 34 1 year Tadalafil 5 mg – OpW – 19.89 (mean IIEF) Tadalafil 20 mg – PRN – 15.8 (mean IIEF) Non-Tadalafil – 13.47 (mean IIEF) Yiou et al. [15] IIEF-EF EHS ³ 24 ³ 2 PDE5i PGE1 ICI PDE5i + PGE1 ICI – NoS No treatment - NoS 2 years M12 – 19.6 (mean IIEF – treat.) M12 – 18.07 (mean IIEF – no treat.) M24 – 4.63 (mean IIEF – treat.) M24 – 4.92 (mean IIEF – no treat.) Haglind et al. [16] IIEF-5 ³ 21 - RRP RALP 1 year RRP – 124 (15.93%) IIEF-5 ³ 21 RALP – 339 (18.35%) Kim D. et al. [17] IIEF-EF ³ 21 (100%) (Mean 28.1) PDE5i Sildenafil 50 mg - OaD + Sildenafil 100 mg - PRN Placebo + Sildenafil 100 mg - PRN 13 months Sildenafil 50 mg - OaD + Sildenafil 100 mg – PRN – 15 (32.4%) Placebo + Sildenafil 100 mg – PRN – 13 (29%) Capogrosso et al. [18] IIEF-6 ³ 24 (Mean 27) PDE5i PGE1 ICI 12 months - 1779 24 months - 1095 2 years 12 mo – 483 (27%) 24 mo – 377 (34%) Sooriakumaran et al. [19] Penile stiffness Morning erection 1702 (66.9%) PPP. PGE1 ICI PGE1 IUr RARP RRP 2 years RARP – 377 (21%) RRP – 106 (14%) Kim S. et al. [20] IIEF-5 22.4 PDE5i Tadalafil 5 mg – OaD – 2 years Tadalafil 5 mg – OaD – 1 year No Tadalafil 2 years Tadalafil 5 mg OaD – 2 yr. – 16.1 (mean IIEF) Tadalafil 5 mg OaD – 1 yr. – 13.5 (mean IIEF) No Tadalafil – 9.4 (mean IIEF) Vol. CXXII • No. 3/2019 • December • Romanian Journal of Military Medicine 13 Kwon et al. [21] Penile lenght SHIM NoS PDE5i (Sildenafil, Vardenafil, Tadalafil) Complete recovery Incomplete recovery 1 year CR – 318 (60.2%) IR – 210 (39.8%) Jo et al. [22] IIEF - 5 ³ 17 PDE5i (Sildenafil 100 mg) Early treatment - 58 (3 wk. postop.) Delayed treatment - 62 (3 mo. postop.) 1 year ET – 24 (41.4%) DT – 11 (17.7%) PPP – preoperative potent patients; IIEF – International Index of Erectile Function; OaD – oance a day; PRN – pro re nata (on demand); ICI – intracavernosal injections; IUr – intrauretral; For pre and postoperative EF assessment the IIEF questionnaire was preferred in most of the studies in different forms: the classical 15 questions IIEF-EF or the shorter IIEF-5/IIEF-6 questionnaires. Most authors preferred the IIEF-5 questionnaire due to its reliability and rapid way of determining the EF status. (Table 3) In most of the studies that used the IIEF questionnaire a cut-of value of 22 points was established for preoperative potent men [8–10, 13, 14] while others established close cut-of values. [16, 20] Only two studies used other means of EF assessment. Sooriakumaran et al. used two questions about penile stiffness and morning erections, both having single choice answer from 5 possible variants. [19] In a particular case Kim et al. compared the penile length both pre and postoperative and additionally used the SHIM questionnaire for ED appraisal. [20] The most frequently used treatment method for penile recovery was the administration of PDE5i which was tested with various ways of administration and dosages and compared with placebo or no treatment control groups. The most commonly used drug in the included trials was Tadalafil [9, 10, 13, 14, 20], followed by Sildenafil [17, 22] and Vardenafil. [11] Some trials studied the single use treatment of PDE5i compared with combinations of PDE5 with PGE1 ICI [8, 15, 18] or penile vibratory stimulation (PVS) devices. [12] There were also particular studies that did not compare the method of PDE5i administration but rather the rate of EF recovery [8, 21], the moment of treatment initiation [22] or the length of treatment administration. [18] Haglid et al. compared the EF recovery based only on the surgical approach type (open vs. RALP) and not interfering with any medication in this regard while Sooriakumaran et al. compared the same surgical approaches using PGE1 treatment setting. [16] Figure 1: Multivariate comparison of PDE5i OaD and PRN treatment compared to control group Although the articles included in our meta-analysis had dichotomous criteria of study design we could find similarities between some of them, which allowed us to organise subgroups of trials. On multivariate analysis we have included trials in which PDE5i was administered as OaD and PRN treatment compared to a pacebo control group. The variables included in analysis were the mean IIEF scores recorded at the end of the trial for each group (OaD, PRN and control). As it can be observed in fig. 1 the higher rates of recovery are in favour of PDE5i OaD group compared to control group (CI 95%, P < 0.0001). On a lower scale, the same result could be observed when PDE5i OaD treatment was compared to PDE5i PRN although in this analysis only 2 studies had the necessary data to be included (CI 95%, P = 14 0.48). In a univariate analysis we also compared the trials were only the percentage of recovered patients after PDE5i treatment was given. (Fig 2) As in previous assessment the PDE5i OaD group had higher recovery rates compared to control group (CI 95% P = 0.40). Also when we have compared PDE5i OaD with PRN group the better results were slightly higher in favour of OaD group thus resulting that the benefit of PDE5i OaD compared to PRN treatment was minor (CI 95%, P = 0.95). Figure 2: Recovery rates in trials using PDE5i OaD and PRN treatment compared to control group DISCUSSION Erectile dysfunction is a major postoperative complication for men who undergo radical prostatectomy, alongside urinary incontinence. At this moment prostate cancer is the second most diagnosed neoplasia in men due to the systematic determination of PSA. [23] Radical prostatectomy remains the most important therapeutic procedure for localised PCa having a postoperative life-expectancy of 10 years. [2] Although the technical enhancements of prostatectomy reduced the rates of postoperative complication, ED still remains one of the most complex problem for PCa patient’s quality of life. Even if the nerve sparing dissection technique of the prostate bundles partially improved the ED rates, there are still problems regarding the postoperative penile rehabilitation. Neuropraxia is the main pathological alteration that leads to major structural changes of the penile tissue. This can also lead to veno-oclusive dysfunctions of blood drainage. Due to the constant state of hypo-oxygenation the penile smooth muscles suffers a process of apoptosis and fibrosis which in time are producing irreversible penile malformations such as penile shortening of 2-3 cm and Peyronie disease. [5, 24] In this regard it is advisable that urologists should discuss with their patients about the possibility of postoperative ED in various rates – from temporary to permanent. [25] Two trials included in our meta-analysis studied the rate of ED occurrence and penile recovery degree after RALP compared to RRP in high volume centres from Sweden. In a 2015 prospective study, Haglid et al. found a slightly higher rate of penile recovery for RALP, but the differences were not significant for these two surgical approaches. [16] In a recently conducted prospective trial, Sooriakumaran et al. (2018) found earlier recovery rates of EF for RALP (21%) compared to RRP (14%) due to a more precise identification and preservation of nerve bundles during RALP. Also the rates of post-surgical positive margins were similar to open surgery which is an important aspect for oncological radicality. [19] Both studies were prospective non-randomised. One key aspect of ED diagnosis is the use of pre and postoperative EF assessment questionnaires. As we have shown above the most frequently used questionnaire was IIEF-5 which is the short version of the IIEF-EF questionnaire. Other questionnaires like Sexual Health Inventory for Men (SHIM) or Expanded Prostate Cancer Index Composite (EHGS) have similar predictive results to IIEF and should be routinely used for postoperative ED diagnosis. [25, 26] It is a known fact that older age, cardiovascular comorbidities and diabetes mellitus are the most important predictive factors for ED onset. [27, 28] On the other hand the younger age and the lower body mass index are Vol. CXXII • No. 3/2019 • December • Romanian Journal of Military Medicine 15 demonstrated protective factors for ED recovery. [2] Even though not all the studies included in our meta-analysis reported the rate of cardiovascular disease and diabetes mellitus we could emphasize that in the post prostatectomy setting these two comorbidities could have significant impact on ED onset and the subsequent penile recovery. [10, 14, 15, 19, 20, 21] Penile rehabilitation is the cumulus of therapeutically means which includes medication, medical devices or actions, simple or in various combination recommended for erectile function recovery. [5] PDE5i are the most frequently used drugs in clinical practice for penile rehabilitation and to this date is the most studied therapeutic method administered to ED patients. The main advantage of PDE5i therapy is that there are quick and easy to administer but it requires the integrity of at least 1 cavernosal nerve bundle. Also the treatment cost and side effects (headache, flushing and palpitations) are not negletable. [24] In their common trial Montorsi et al. (2014) and Stolzenburg et al. (2015) studied the effect of Tadalafil administered once a day (OaD) and on demand (PRN) compared to a placebo-controlled group and found that the OaD administration of Tadalafil 5 mg has the best results for penile recovery after prostatectomy. [9, 13] Similar results for Tadalafil OaD administration were also found by Seo et al. (2014), Canat et al. (2015) and Kim S. et al. (2018) based on the mean IIEF score at the end of the trial. [14, 20] Nakano et al. (2014) and Kim D. et al. (2016) found similar results at the end of their trials although they have studied the effect of Vardenafil respectively Sildenafil. [11, 17] In our multivariate analysis the PDE5i OaD treatment has evident advantages over placebo and on demand PDE5i administration for postoperative penile recovery rate. Regarding the choice of PDE5i treatment there are no specific trials that compare the efficiency of currently available substances in postoperative ED. In a 2005 open-label randomised trial Eardley et al. emphasized that Tadalafil is the preferred PDE5i used for ED treatment because of long-lasting effect in time compared to Sildenafil that allowed patients to have less concerns about spontaneity of erection. [29] Further more Hyndman et al. demonstrated in their randomised trial that Sildenafil could have major impact over urinary continence, thus impairing the overall recovery of PCa operated patients. [30] Prostaglandin E1 intracavernosal injection (PGE1 ICI) was the first type of treatment for postoperative EF recovery, introduced and studied by Prof. Montorsi et al. [31] The most important advantage of PGE1 ICI is that is very effective in any type of surgical approach even if nerve sparing was not indicated, though the cost, the need to refrigerate the product, the invasiveness of the treatment and the side effects are a majos counterbalance for treatment initiation. [24] In our meta-analysis, Vickers et al., Yiou et al. and Capogrosso et al. have used PGE1 ICI in combination with PDE5i treatment for penile recovery. The results achieved by Yiou at 12 respectively 24 months of combined treatment were very similar in both drug-administered and control group. [15] On the other hand Capogrosso et al. found that at 24 months of combined PGE1 ICI and PDE5i treatment the rates of recovery were higher than at 12 months (34% vs. 27%). [18] Vacuum and vibratory devices are non-invasive and very effective in EF recovery especially when combined with PDE5i treatment. Fode et al. demonstrated in their randomised prospective trial that EF recovery could be very effective when penile vibratory stimulation devices are used in conjunction with PDE5i (53% recovery rate) compared to PDE5i only group (32%). [12] Regarding treatment initiation Jo et al. demonstrated that early penile rehabilitation commencement (at 3 weeks after surgery – immediately after urinary catheter removal) has better recovery results than delayed treatment initiation (at 3 months postoperative). [22] CONCLUSIONS The postoperative EF recovery of PCa patients can be achieved using a multitude of penile recovery strategies. For this purpose a preoperative assessment is very important, by using erectile function questionnaires. Patients should be informed about the postoperative ED risk and should be counselled in this area. Nerve-sparing robot assisted laparoscopic prostatectomy is the most protective surgical approach for EF preservation. PDE5i is the main therapeutic approach for postoperative penile recovery. Tadalafil 5 mg once a day was the most effective long term therapy for ED treatment both single use or in combination with PGE1 and other devices (vacuum or vibratory stimulation). Penile prosthesis implants should be regarded as last resort treatment option for cases when no penile recovery strategy has been successful.

BACKGROUND: Recently, the first report of lung ultrasound (LUS) guided recruitment during open lung ventilation in neonates has been published. LUS guided recruitment can change the approach to open lung ventilation, which is currently performed without any measure of lung function/lung expansion in the neonatal population. METHODS: We included all the newborn infants that underwent a LUS-guided recruitment maneuver during mechanical ventilation as a rescue attempt for an extremely severe respiratory condition with oxygen saturation/fraction of inspired oxygen (SpO2/FIO2) ratio below 130 or the inability to wean off mechanical ventilation. RESULTS: We report a case series describing 4 LUS guided recruitment maneuvers, underlying crucial aspects of this technique that can improve the effectiveness of the procedure. In particular, we describe a novel pattern (the S-pattern) that allows us to distinguish the recruitable from the unrecruitable lung and guide the pressure titration phase. Additionally, we describe the optimal LUS-guided patient positioning. CONCLUSIONS: We believe that the inclusion of specifications regarding patient positioning and the S-pattern in the LUS-guided protocol may be beneficial for the success of the procedure.

The accuracy of pharmacokinetic (PK)-guided dosing depends on the clinical and laboratory data used to construct a population PK model, as well as the patient's individual PK profile. This review provides a detailed overview of data used for published population PK models for factor VIII (FVIII) and factor IX (FIX) concentrates, to support physicians in their choices which model best suits each patient. Furthermore, to enhance detailed data collection and documentation, we do suggestions for best practice. A literature search was performed; publications describing prophylactic population PK models for FVIII and FIX concentrates based on original patient data and constructed using non-linear mixed-effect modeling were included. The following data were collected: detailed demographics, type of product, assessed and included covariates, laboratory specifications and validation of models. Included models were scored according to our recommendations for best practice, specifically scoring the quality of data documentation as reported. Respectively, twenty models for FVIII and seven for FIX concentrates were retrieved. Although most models (22/27) included pediatric patients, only four reported detailed demographics. The wide range of body weights suggested that overweight and obese adults were represented. Twenty-six models reported the assay applied to measure factor levels, whereas only 16 models named reagents used. Eight models were internally validated using a data subset. This overview presents detailed information on clinical and laboratory data used for published population PK models. We provide recommendations on data collection and documentation to increase the reliability of PK-guided prophylactic dosing of factor concentrates in hemophilia A and B.

Background: The number of spinal cord stimulator (SCS) units sold in the United States (US) for the treatment of chronic pain has increased with a corresponding expansion in the number of different SCS platforms available. Each marketed stimulator has several unique features, indications, and limitations, which distinguish one from the other and makes the selection of appropriate hardware possible for optimal patient care. There are an even greater number of similar and overlapping features between SCS.Measures: We used market analysis techniques to survey the currently available SCS technology. We then reviewed published device specifications and manuals for comparison of features.Outcomes: As of 2020, there are nine commonly used SCS platforms made by four manufacturers including four SCS units from Abbott, three from Boston Scientific, and one each from Medtronic and Nevro.Conclusions: A working understanding of each SCS product's nuances is needed for selecting the most appropriate device with which to manage chronic pain patients. Here we present a brief survey of currently available SCS hardware in the US and the features that make each product unique.

The new Sars-Cov-2 (COVID-19) is causing thousands of deaths worldwide and has caused a global pandemic, one of the biggest health challenges ever faced in history. in the most severe cases, Sars-Cov-2 infection can cause fatal lung injuries. In this context, it is essential to recognise effective therapeutic agents against the virus. There are currently no direct and effective vaccines and antivirals available. People with pre-existing conditions, such as diabetes, and with chronic drug therapies in place may represent complex patients difficult to manage clinically during COVID-19 infection and at high risk of major complications. The regulation of blood glucose and the adoption of appropriate measures are critical aspects to consider for the diabetic patient in this pandemic period, especially in the patient with ongoing infection. In this article we describe the current evidence in the literature on the possible risks of side effects caused by taking antidiabetic drugs in the COVID-19 patient and the data on extra homeostasis glycemic activity useful to fight viral infection.
 Peer Review History: 
 Received 25 May 2020; Revised 8 June; Accepted 3 July, Available online 15 July 2020
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.
 Received file 
 
 Average Peer review marks at initial stage: 5.5/10
 Average Peer review marks at publication stage: 7.0/10
 Reviewer(s) detail:
 Name: Dr. Heba M. Abd El-Azim
 Affiliation: Damanhour University, Egypt
 E-mail: h_m_abdelazim@hotmail.com
 
 Name: Dr. George Zhu 
 Affiliation: Tehran University of Medical Sciences, Tehran, Iran
 E-mail: sansan4240732@163.com
 
 Comments of reviewer(s): 
 
 Similar Articles:
 THE RELATIONSHIP BETWEEN DIABETES MELLITUS AND TUBERCULOSIS IN REVIEW OF PREVALENCE, DIAGNOSTICS AND PREVENTION

BackgroundNon-medical devices such as the handheld fan (fan), mobility aids (wheeled walkers with seats) and inspiratory muscle training (IMT) devices offer benefits for patient management of chronic breathlessness. We examined the published evidence regarding patient, carer and clinician use of the fan, mobility aids and IMT devices for chronic breathlessness management, and the potential barriers and facilitators to day-to-day use in a range of settings.MethodsMEDLINE, Embase, Scopus, EBSCO and the Cochrane Database of Systematic Reviews were searched. Papers were imported into EndNote and Rayyan for review against a priori eligibility criteria. Outcome data relevant to use were extracted and categorised as potential barriers and facilitators, and a narrative synthesis exploring reasons for similarities and differences conducted.ResultsSeven studies met the inclusion criteria (n=5 fan, n=2 mobility aids and n=0 IMT devices). All of the studies presented patient use of non-medical devices only. Patients found the fan easy to use at home. Mobility aids were used mainly for outdoor activities. Outdoor use for both devices were associated with embarrassment. Key barriers included: appearance; credibility; self-stigma; technical specifications. Common facilitators were ease of use, clinical benefit and feeling safe with the device.ConclusionThe efforts of patients, carers and clinicians to adopt and use non-medical devices for the management of chronic breathlessness is impeded by lack of implementation research. Future research should improve knowledge of the barriers and facilitators to use. This would enhance understanding of how decision-making in patient–carer–clinician triads impacts on non-medical devices use for breathlessness management.

Abstract Background The purpose of a medical laboratory test is to provide information on the pathophysiologic condition of an individual patient as an aid in diagnosis, therapy, or assessment of risk for a disease. For optimal laboratory service, results from different measurement procedures (MPs) for the same measurand should be equivalent (harmonized) within stated specifications, enabling the results to be used reliably for medical decisions. The term “harmonization” refers to any process that enables establishing equivalence of reported values among different end-user MPs. The term “standardization” refers to achieving harmonization by metrological traceability of patients’ results to higher order reference materials and/or reference measurement procedures. Content New procedures for harmonization and standardization were published in 2020 by the International Organization for Standardization (ISO) and by the IFCC. ISO 17511:2020 provides revised requirements for establishing metrologically traceable calibration hierarchies for end-user MPs used in clinical laboratories. ISO 21151:2020 provides new requirements to implement a harmonization protocol to address the situation when there are no fit-for-purpose certified reference materials or reference MPs available for a measurand. The IFCC Working Group on Commutability published recommendations for applying a correction for noncommutability of a certified reference material to enable using that material in a metrologically traceable calibration hierarchy for an end-user MP. Summary We review metrological traceability and how these new approaches will improve the capability to achieve harmonized results for clinical samples.

Severe acute respiratory syndrome coronavirus-2(SARAS-COV-2) was reported firstly in China by the end of 2019 then disseminated vigorously worldwide and in 2020 reported by WHO as pandemic disease. It is associated by many symptoms, however; high incidence of thrombotic events was strongly correlated with SARAS-COV-2. Exploring anticoagulants to be added as thromboprophylaxis for Covid 19 patients become a must. Many options for thromboprophylaxis are available including anticoagulants, antiplatelets and fibrinolytics which were illustrated in this mini review.
 
 Peer Review History: 
 Received 19 January 2021; Revised 3 February; Accepted 24 February, Available online 15 March 2021
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. 
 Received file: Reviewer's Comments:
 Average Peer review marks at initial stage: 5.0/10
 Average Peer review marks at publication stage: 7.0/10
 Reviewer(s) detail:
 Dr. Cecilia Nwadiuto Amadi, University of Port Harcourt, Port Harcourt Rivers State, Nigeria, cnamadi@rocketmail.com
 Dr. A.A. Mgbahurike, University of Port Harcourt, Nigeria, amaka_mgbahurike@yahoo.com
 
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 COVID-19: PHARMACOLOGICAL AND THERAPEUTIC APPROACHES
 USE OF COLCHICINE TO COUNTERACT THE STRONG HYPERINFLAMMATORY STATE INDUCED BY SARS-COV-2
 THE RISKS AND ADVANTAGES OF ANTI-DIABETES THERAPY IN THE POSITIVE COVID-19 PATIENT
 EUCALYPTUS ESSENTIAL OIL; AN OFF-LABEL USE TO PROTECT THE WORLD FROM COVID-19 PANDEMIC: REVIEW-BASED HYPOTHESES
 SUDANESE EXPERIENCE OF HERBAL FORMULAS USED DURING COVID-19 INFECTION
 TRADITIONAL TO RECENT APPROACHES IN HERBAL MEDICINE THERAPY OF COVID-19

Background: Previous research indicates that the physical environment of healthcare facilities plays an important role in the health, well-being, and recovery outcomes of patients. However, prior works on mental healthcare facilities have incorporated physical environment effects from general healthcare settings and patient groups, which cannot be readily transferred to mental healthcare settings or its patients. There appears to be a specific need for evidence synthesis of physical environmental effects in mental healthcare settings by psychopathology.Purpose: This review evaluates the state (in terms of extent, nature and quality) of the current empirical evidence of physical environmental on mental health, well-being, and recovery outcomes in mental healthcare inpatients by psychopathology.Method: A systematic review (PRISMA guidelines) was performed of studies published in English, German, Dutch, Swedish, and Spanish, of all available years until September 2020, searched in Cochrane, Ovid Index, PsycINFO, PubMed, and Web of Science and identified through extensive hand-picking. Inclusion criteria were: Adult patients being treated for mental ill-health (common mental health and mood disorders, Cochrane frame); inpatient mental health care facilities; specifications of the physical and socio-physical environment (e.g., design features, ambient conditions, privacy); all types of empirical study designs. Quality assessment and data synthesis were undertaken.Results: The search retrieved 1,068 titles of which 26 met the inclusion criteria. Findings suggest that there is only indicative evidence of the impact of the physical healthcare environment on patients' mental health, well-being, and recovery outcomes. There is significant lack of pathology-specific evidence. Methodological shortcomings and empirical scarcity account for the poor evidence.Conclusion: This review highlights the need for more research using advanced study designs.

Objectives: Corona virus disease 2019 (COVID-19) outbreak is recent worldwide disaster which is considered by the WHO as Public Health Emergency of International Concern (PHEIC).
 Method: A quick survey was done in Khartoum state for the commonly utilize herbs and the succeeded formulas, 652 people participated in this survey either they use these herbs for themselves or their relative use it during the symptoms of COVID-19.
 Results: A 652 people participated in the quick survey for the commonly utilized herbs & the succeeded formulas either they use these herbs for themselves or their relative use it during the symptoms of COVID-19. Other products used as additives include (honey,vinegar,sesame oil, olive oil and salt).
 Conclusion: Sudanese experience that various traditional herbs, usage and different route of administration can effectively alleviate primary symptoms e.g. fever, cough, fatigue and reduce probability of developing severe Conditions.
 Peer Review History: 
 Received: 8 September 2020; Revised: 7 October; Accepted: 20 October, Available online: 15 November 2020
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.
 Received file 
 
 Average Peer review marks at initial stage: 5.0/10
 Average Peer review marks at publication stage: 7.0/10
 Reviewer(s) detail:
 Dr. Hebatalla Ibrahim Ahmed Abdel Hameed, Al-Azhar University, Faculty of Pharmacy (Girls), Nasr City, Cairo, Egypt hebatalla123@yahoo.com
 Dr. Mohamed Derbali, Faculty of Pharmacy, Monastir, Tunisia, mohamed.edderbali@gmail.com
 Comments of reviewer(s): 
 
 Similar Articles:
 THE RISKS AND ADVANTAGES OF ANTI-DIABETES THERAPY IN THE POSITIVE COVID-19 PATIENT
 EUCALYPTUS ESSENTIAL OIL; AN OFF-LABEL USE TO PROTECT THE WORLD FROM COVID-19 PANDEMIC: REVIEW-BASED HYPOTHESES

Objective: Severe Acute Respiratory Syndrome Coronavirus 2 causes both health and economic crises and up till now no drug or vaccine has yet been approved. There is an increased demand to explore other complementary methods to protect the world. Eucalyptus essential oil; a popular off-label drug used to relieve nasal congestion via inhalation with promising effects on the upper respiratory diseases including viral infections.
 Methods: In order to provide review-based hypotheses demonstrating eucalyptus essential oil beneficial role; several published studies were retrieved from different databases and websites till June 2020. The retrieved data declared the antiviral potentials against viruses of same subgenus or with same pattern and the beneficial effects on respiratory system, immunity and overall health improvement, along with declaring the application methods and safety.
 Results: Off-label use of Eucalyptus essential oil by inhaling 12drops /150mL or 1.5% v/v solution boiling water may relief COVID-19 mild and moderate symptoms as pain, cough, respiratory inflammation, cytokine storm and dyspnea.
 Conclusions: Experimental and clinical data proved that inhalation of eucalyptus essential oil may provide the ability to reduce COVID-19 patients symptoms and morbidity risk factors and may play a role as a preventative technique complementary to WHO guidance for beating COVID-19 virulence and transmission spread.
 Peer Review History: 
 Received 28 June 2020; Revised 20 July; Accepted 10 August, Available online 15 September 2020
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.
 Received file 
 
 Average Peer review marks at initial stage: 6.5/10
 Average Peer review marks at publication stage: 8.5/10
 Reviewer(s) detail:
 Name: Dr. Dalia Kamal Zaffar Ali
 Affiliation: Modern University for technology and information, Egypt
 E-mail: dr.moda88@gmail.com
 
 Name: Prof. Dr. Mahadeva Rao US
 Affiliation: Universiti Sultan Zainal Abidin, Malaysia
 E-mail: raousm@gmail.com
 
 Name: Francesco Ferrara
 Affiliation: USL Umbria 1, Perugia, Italy
 E-mail: francesco.ferrara@uslumbria1.it
 
 Comments of reviewer(s): 
 
 Similar Articles:
 THE RISKS AND ADVANTAGES OF ANTI-DIABETES THERAPY IN THE POSITIVE COVID-19 PATIENT

By the end of 2019, SARS-CoV-2, a new virus from Coronaviruses family, has been detected in China and was responsible for COVID-19 disease. This disease has been suddenly and vigorously disseminated among individuals all over the world. Based on genetic vicinity, this novel virus is similar to SARS-CoV and MERS-CoV; it can spread from an unknown animal host to individuals. Till now, there is no specific therapy or vaccine for the treatment of COVID-19 patients. However, published clinical data and in vitro studies may offer treatment strategies of some effective antiviral and repurposed drugs, including remdesivir, favipiravir, lopinavir/ritonavir, corticosteroids, etc. This narrative review describes current pharmacological proposed treatments for COVID-19 patients and available experimental and clinical studies for these drugs. Eventually, these data may help to explain the most preferable way to treat COVID-19 and lessen symptoms and complications accompanied with it.
 
 Peer Review History: 
 Received 6 November 2020; Revised 25 Decembe; Accepted 4 January, Available online 15 January 2021
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency.
 Received file: Comments of reviewer(s): 
 Average Peer review marks at initial stage: 5.5/10
 Average Peer review marks at publication stage: 7.5/10
 Reviewer(s) detail:
 Dr. DANIYAN Oluwatoyin Michael, Obafemi Awolowo University, ILE-IFE, Nigeria, toyinpharm@gmail.com
 Dr. George Zhu, Tehran University of Medical Sciences, Tehran, Iran, sansan4240732@163.com
 Dr. Nuray Arı, Ankara University, Turkiye, ari@ankara.edu.tr
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 EUCALYPTUS ESSENTIAL OIL; AN OFF-LABEL USE TO PROTECT THE WORLD FROM COVID-19 PANDEMIC: REVIEW-BASED HYPOTHESES 
 SUDANESE EXPERIENCE OF HERBAL FORMULAS USED DURING COVID-19 INFECTION 
 TRADITIONAL TO RECENT APPROACHES IN HERBAL MEDICINE THERAPY OF COVID-19 

The world is now facing one of the most devastating public health concern where the 2019 novel coronavirus (2019-nCoV) or the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is spreading all over the world initiating from Wuhan, China, started from December, 2019. The World Health Organization (WHO) already announced the situation as pandemic all over the world. According to the webpage of WHO, this SARS-CoV-2 has been spreading all over the world (223 countries, areas or territories) with 126,890,643 of confirmed cases and 2,778,619 of confirmed deaths(as time of March 30, 2021). Accumulated published documents indicate that the SARS-CoV-2 virus primarily affects the lungs causing hypoxia which is the leading cause of death. There are many reports describing that with the progress of this disease, many other organs (such as heart, kidney, liver, brain) of the affected person start to malfunction. Though SARS-CoV-2 uses the cell surface receptor angiotensin-converting enzyme 2 (ACE-2) expressed by lungs, cardiovascular system, kidneys but it is still not clear except lungs all these other organs are directly affected by this virus or not. Therefore, the aim of this review is to gather information about the affected/damaged organs or tissues and the consequences of this damage in the COVID-19 patients.
 
 Peer Review History: 
 Received 11 March 2021; Revised 8 April; Accepted 23 April, Available online 15 May 2021
 UJPR follows the most transparent and toughest ‘Advanced OPEN peer review’ system. The identity of the authors and, reviewers will be known to each other. This transparent process will help to eradicate any possible malicious/purposeful interference by any person (publishing staff, reviewer, editor, author, etc) during peer review. As a result of this unique system, all reviewers will get their due recognition and respect, once their names are published in the papers. We expect that, by publishing peer review reports with published papers, will be helpful to many authors for drafting their article according to the specifications. Auhors will remove any error of their article and they will improve their article(s) according to the previous reports displayed with published article(s). The main purpose of it is ‘to improve the quality of a candidate manuscript’. Our reviewers check the ‘strength and weakness of a manuscript honestly’. There will increase in the perfection, and transparency. 
 Received file: Reviewer's Comments:
 Average Peer review marks at initial stage: 6.0/10
 Average Peer review marks at publication stage: 7.0/10
 Reviewer(s) detail:
 Dr. Vanina Doris Edo’o, 
 University of Yaounde I, Yaounde, Cameroun, vanina_edoo@yahoo.com
 Idoko Alexander,
 Caritas University, Enugu, Nigeria, idokoalexander1@gmail.com
 Similar Articles:
 COVID-19: PHARMACOLOGICAL AND THERAPEUTIC APPROACHES
 USE OF COLCHICINE TO COUNTERACT THE STRONG HYPERINFLAMMATORY STATE INDUCED BY SARS-COV-2 
 THE RISKS AND ADVANTAGES OF ANTI-DIABETES THERAPY IN THE POSITIVE COVID-19 PATIENT

Objective: To provide a forum to engage key stakeholders to discuss the process for updating and revising the Implementation Guide (IG) for Syndromic Surveillance (formerly the PHIN Message Guide for Syndromic Surveillance) and underscore the critically of community and stakeholder involvement as the Implementation Guide is vetted through the formal Health Level Seven (Hl7) balloting process in 2018.Introduction: Syndromic surveillance seeks to systematically leverage health-related data in near "real-time" to understand the health of communities at the local, state, and federal level. The product of this process provides statistical insight on disease trends and healthcare utilization behaviors at the community level which can be used to support essential surveillance functions in governmental public health authorities (PHAs). Syndromic surveillance is particularly useful in supporting public health situational awareness, emergency response management, and outbreak recognition and characterization. Patient encounter data from healthcare settings are a critical inputs for syndromic surveillance; such clinical data provided by hospitals and urgent care centers to PHAs are authorized applicable local and state laws. The capture, transformation, and messaging of these data in a standardized and systematic manner is critical to this entire enterprise.In August 2015, a collaborative effort was initiated between the CDC, ISDS, the Syndromic Surveillance Community, ONC and NIST to update the national electronic messaging standard which enables disparate healthcare systems to capture, structure, and transmit administrative and clinical data for public health surveillance and response. The PHIN Messaging Guide for Syndromic Surveillance -Release 2.0 (2015) provided an HL7 messaging and content reference standard for national, syndromic surveillance electronic health record technology certification as well as a basis for local and state syndromic surveillance messaging implementation guides. This standard was further amended with the release of the PHIN Messaging Guide for Syndromic Surveillance - Release 2.0, Erratum (2015) and theHL7 Version 2.5.1 PHIN Messaging Guide for Syndromic Surveillance- Release 2.0, NIST Clarifications and Validation Guidelines, Version 1.5(2016). ISDS is now engaged in a process, supported by a CDC Cooperative Agreement, to formally revise the existing guide and generate an HL7 V 2.5.1 Implementation Guide (IG) for Syndromic Surveillance v2.5 for HL7 balloting in 2018.This roundtable will provide a forum to present and discuss the HL7 Balloting process and the outstanding activities in which the Syndromic Surveillance community must participate during the coming months for this activity to be successful. Description: The scope of this project is to provide an updated and consolidated version of the IG v2.5 that includes issues identified in the previously published Erratum and Clarification documents as well as concerns expressed via a community commenting.How the Moderator Intends to Engage the Audience in Discussions on the Topic: Moderator Engagement on Topic:Through this Roundtable moderators will provide an overview of 1.) Recent accomplishments on this project, 2.) Pending deliverables for 2018, 3.) Critical milestones and dates, and 4.) How to participate in the review and balloting process through narrative, handouts, and visual aids.Recent accomplishments: To date this review process has identified and updated a wide-range of specification and requirements described within the IG 2.0. These include: specifications for persistent patient ID across venues of service, inclusion of the ICD-10-CM value set for diagnosis, removal of the ICD-9-CM requirement for testing and messaging, modification of values such as pregnancy status, travel history, and medication lists, and update of value sets and PHIN VADS references for FIPS, SNOmed, ICD-10-CM.Deliverables Include:Completion of the Project Documents as required by Project Insight as described in the 2018 Balloting Calendar (figure 1).Provide a copy of the IG to the Public Health and Emergency Response HL7 Workgroups prior to the ballotSubmit the final version of the IG for ballotingReconcile (with the HL7 Public Health Workgroup and other co-sponsoring workgroups) any comments submitted during the balloting processFinalize the IG for submission as a Standard for Trial Use. This IG v2.5 will replace or supersede all previous guide releases and related documentation and will no longer be a CDC or PHIN artifact.CONCLUSIONS: The results of this multi-agency comment and review process will be synthesized and compiled by ISDS. The updated version of the IG v2.5 will be made available to the Public Health community following the completion of the HL7 Balloting in May 2018. Future revisions of the IG v2.5 will be vettedthrough HL7 Public Health Workgroup.This systematic and structured review and documentation process has allowed for the synthetization and reconciliation of a wide range of disparate specifications, historical hold-overs, and requirements via the perspectives of a diverse range of public health partners. As we continue to move through this review process we believe that the final HL7 balloted “Standard for Trial Use” IG v2.5 will be a stronger more extensible product in supporting syndromic surveillance activities across a wider and more diverse range of clinical venues, EHR implementations, and PHAs.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19) whose pandemic was declared on March 11 2021 (1). Spectrum of COVID-19 clinical manifestations is very wide. Most patients report to ambulance with mild or moderate symptoms, but some of them rapidly develops acute respiratory distress syndrome (ARDS), respiratory failure, acute cardiac injury, multiple organ failure and death (2). Older age, diabetes mellitus and cardiovascular disease are reported as high predictors of morbidity and mortality.
 Aim: To determine correlation between diabetes mellitus and severity of clinical picture in patients with COVID-19.
 Methods: Current study involve retrospective analysis of 1513 patients with Real Time PCR confirmed COVID-19 hospitalized in Clinic for infectious disease, University Clinical Center, Sarajevo, Bosnia and Herzegovina, in a period of June 2020 to December 2020.
 Results: Among them 417 had previously diagnosed of diabetes mellitus. Results show that patients with diabetes mellitus are likely to require treatment in Intensive care unit, and oxygenic support with invasive ventilation. There was no statistically significant difference in outcome of the disease.
 Conclusion: Even this study didn’t find increased mortality in patients with COVID-19 and diabetes mellitus, further studies should be done to determine risk for patients with DM to develop severe form of disease.
 
 Peer Review History: 
 Received 23 March 2021; Revised 17 April; Accepted 5 May, Available online 15 May 2021
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 Received file: Reviewer's Comments:
 Average Peer review marks at initial stage: 6.0/10
 Average Peer review marks at publication stage: 7.5/10
 Reviewer(s) detail:
 Dr. Branislav Ranković,
 University of Kragujevac, Serbia, rankovic@kg.ac.rs
 Dr. Poualeu Kamani Sylviane Laure,
 University of Dschang, Cameroon, poualeusylviane@yahoo.fr
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