Journal articles: 'Trials (Illegal arms transfer)'

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Bastien Olvera, Gustavo Mauricio. "The security council and the illegal transfer of small arms and light weapons to non-state actors." Mexican Law Review 6, no. 2 (January 2014): 225–50. http://dx.doi.org/10.1016/s1870-0578(16)30013-0.

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Peterson, Carrie L., Lynn M. Rogers, Michael S. Bednar, Anne M. Bryden, Michael W. Keith, Eric J. Perreault, and Wendy M. Murray. "Posture-Dependent Corticomotor Excitability Differs Between the Transferred Biceps in Individuals With Tetraplegia and the Biceps of Nonimpaired Individuals." Neurorehabilitation and Neural Repair 31, no. 4 (December 8, 2016): 354–63. http://dx.doi.org/10.1177/1545968316680488.

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Background. Following biceps transfer to enable elbow extension in individuals with tetraplegia, motor re-education may be facilitated by greater corticomotor excitability. Arm posture modulates corticomotor excitability of the nonimpaired biceps. If arm posture also modulates excitability of the transferred biceps, posture may aid in motor re-education. Objective. Our objective was to determine whether multi-joint arm posture affects corticomotor excitability of the transferred biceps similar to the nonimpaired biceps. We also aimed to determine whether corticomotor excitability of the transferred biceps is related to elbow extension strength and muscle length. Methods. Corticomotor excitability was assessed in 7 arms of individuals with tetraplegia and biceps transfer using transcranial magnetic stimulation and compared to biceps excitability of nonimpaired individuals. Single-pulse transcranial magnetic stimulation was delivered to the motor cortex with the arm in functional postures at rest. Motor-evoked potential amplitude was recorded via surface electromyography. Elbow moment was recorded during maximum isometric extension trials, and muscle length was estimated using a biomechanical model. Results. Arm posture modulated corticomotor excitability of the transferred biceps differently than the nonimpaired biceps. Elbow extension strength was positively related and muscle length was unrelated, respectively, to motor-evoked potential amplitude across the arms with biceps transfer. Conclusions. Corticomotor excitability of the transferred biceps is modulated by arm posture and may contribute to strength outcomes after tendon transfer. Future work should determine whether modulating corticomotor excitability via posture promotes motor re-education during the rehabilitative period following surgery.

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Dercle, Laurent, Dana E. Connors, Ying Tang, Stacey J. Adam, Mithat Gönen, Patrick Hilden, Sanja Karovic, et al. "Vol-PACT: A Foundation for the NIH Public-Private Partnership That Supports Sharing of Clinical Trial Data for the Development of Improved Imaging Biomarkers in Oncology." JCO Clinical Cancer Informatics, no. 2 (December 2018): 1–12. http://dx.doi.org/10.1200/cci.17.00137.

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Purpose To develop a public-private partnership to study the feasibility of a new approach in collecting and analyzing clinically annotated imaging data from landmark phase III trials in advanced solid tumors. Patients and Methods The collection of clinical trials fulfilled the following inclusion criteria: completed randomized trials of > 300 patients, highly measurable solid tumors (non–small-cell lung cancer, colorectal cancer, renal cell cancer, and melanoma), and required sponsor and institutional review board sign-offs. The new approach in analyzing computed tomography scans was to transfer to an academic image analysis laboratory, draw contours semi-automatically by using in-house–developed algorithms integrated into the open source imaging platform Weasis, and perform serial volumetric measurement. Results The median duration of contracting with five sponsors was 12 months. Ten trials in 7,085 patients that covered 12 treatment regimens across 20 trial arms were collected. To date, four trials in 3,954 patients were analyzed. Source imaging data were transferred to the academic core from 97% of trial patients (n = 3,837). Tumor imaging measurements were extracted from 82% of transferred computed tomography scans (n = 3,162). Causes of extraction failure were nonmeasurable disease (n = 392), single imaging time point (n = 224), and secondary captured images (n = 59). Overall, clinically annotated imaging data were extracted in 79% of patients (n = 3,055), and the primary trial end point analysis in each trial remained representative of each original trial end point. Conclusion The sharing and analysis of source imaging data from large randomized trials is feasible and offer a rich and reusable, but largely untapped, resource for future research on novel trial-level response and progression imaging metrics.

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Hoddinott, John, Akhter Ahmed, and Shalini Roy. "Randomized control trials demonstrate that nutrition-sensitive social protection interventions increase the use of multiple-micronutrient powders and iron supplements in rural pre-school Bangladeshi children." Public Health Nutrition 21, no. 9 (February 22, 2018): 1753–61. http://dx.doi.org/10.1017/s1368980017004232.

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AbstractObjectiveTo examine the impact of a nutrition-sensitive social protection intervention on mothers’ knowledge of Fe deficiency, awareness of multiple-micronutrient powders (MMP) and the consumption of MMP and other Fe supplements by their children aged 6–59 months.DesignTwo randomized controlled trials with treatment arms including cash transfers, food transfers, cash and food transfers, cash and nutrition behaviour change communication (BCC), and food and nutrition BCC were implemented over two years. Both included a control group that received no transfer or BCC. Transfer recipients were mothers living in poor households with at least one child aged less than 2 years at baseline. Probit models were used to analyse endline data.SettingRural areas in north-west and south Bangladesh.SubjectsMothers (n 4840) and children 6–59 months (n 4840).ResultsA transfer accompanied by nutrition BCC increased the share of mothers with knowledge of Fe deficiency (11·9 and 9·2 percentage points for North and South, respectively, P≤0·01), maternal awareness of MMP (29·0 and 22·2 percentage points, P≤0·01), the likelihood that their children 6–59 months had ever consumed MMP (32 and 11·9 percentage points, P≤0·01), consumed MMP in the preceding week (16·9 and 3·9 percentage points, P≤0·01) and consumed either MMP or an Fe supplement in the preceding week (22·3 and 7·1 percentage points, P≤0·01). Improvements were statistically significant relative to groups that received a transfer only.ConclusionsNutrition-sensitive social protection (transfers with BCC added) may be a promising way to advance progress on micronutrient deficiencies.

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Suit, Herman, Thomas F. Delaney, and Alexei Trofimov. "Physical and Biological Basis of Proton and of Carbon Ion Radiation Therapy and Clinical Outcome Data." Reviews of Accelerator Science and Technology 02, no. 01 (January 2009): 1–15. http://dx.doi.org/10.1142/s179362680900017x.

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There is a clear basis in physics for the clinical use of proton and carbon beams in radiation therapy, namely, the finite range of the particle beam. The range is dependent on the beam initial energy, density and atomic composition of tissues along the beam path. Beams can be designed that penetrate to the required depth and deliver a uniform biologically effective dose across the depth of interest. The yield is a superior dose distribution relative to photon beams. There is a potential clinical advantage from the high linear energy transfer (LET) characteristics of carbon beams. This is based on a lower oxygen enhancement ratio (OER) and a flatter age response function. However, due to uncertainties relating OER with relative biological effectiveness (RBE), there is no clinical evidence to date that carbon ion beams have an advantage over proton beams. We strongly support performance Phase III clinical trials of protons vs carbon ion beams designed to feature a single variable, LET. Dose fractionation would be identical in both arms and dose distribution would be similar for the sites to be tested. For sites for which the carbon beam has a demonstrated important advantage in comparative treatment planning due to the narrower penumbra would not be selected for the clinical trials.

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Santos-Ribeiro, Samuel, Shari Mackens, Biljana Popovic-Todorovic, Annalisa Racca, Nikolaos P. Polyzos, Lisbet Van Landuyt, Panagiotis Drakopoulos, Michel de Vos, Herman Tournaye, and Christophe Blockeel. "The freeze-all strategy versus agonist triggering with low-dose hCG for luteal phase support in IVF/ICSI for high responders: a randomized controlled trial." Human Reproduction 35, no. 12 (September 23, 2020): 2808–18. http://dx.doi.org/10.1093/humrep/deaa226.

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Abstract STUDY QUESTION Does the freeze-all strategy in high-responders increase pregnancy rates and improve safety outcomes when compared with GnRH agonist triggering followed by low-dose hCG intensified luteal support with a fresh embryo transfer? SUMMARY ANSWER Pregnancy rates after either fresh embryo transfer with intensified luteal phase support using low-dose hCG or the freeze-all strategy did not vary significantly; however, moderate-to-severe ovarian hyperstimulation syndrome (OHSS) occurred more frequently in the women who attempted a fresh embryo transfer. WHAT IS KNOWN ALREADY Two strategies following GnRH agonist triggering (the freeze-all approach and a fresh embryo transfer attempt using a low-dose of hCG for intensified luteal phase support) are safer alternatives when compared with conventional hCG triggering with similar pregnancy outcomes. However, these two strategies have never been compared head-to-head in an unrestricted predicted hyper-responder population. STUDY DESIGN, SIZE, DURATION This study included women with an excessive response to ovarian stimulation (≥18 follicles measuring ≥11 mm) undergoing IVF/ICSI in a GnRH antagonist suppressed cycle between 2014 and 2017. Our primary outcome was clinical pregnancy at 7 weeks after the first embryo transfer. Secondary outcomes included live birth and the development of moderate-to-severe OHSS. PARTICIPANTS/MATERIALS, SETTING, METHODS Following GnRH agonist triggering, women were randomized either to cryopreserve all good-quality embryos followed by a frozen embryo transfer in an subsequent artificial cycle or to perform a fresh embryo transfer with intensified luteal phase support (1500 IU hCG on the day of oocyte retrieval, plus oral estradiol 2 mg two times a day, plus 200 mg of micronized vaginal progesterone three times a day). MAIN RESULTS AND THE ROLE OF CHANCE A total of 212 patients (106 in each arm) were recruited in the study, with three patients (one in the fresh embryo transfer group and two in the freeze-all group) later withdrawing their consent to participate in the study. One patient in the freeze-all group became pregnant naturally (clinical pregnancy diagnosed 38 days after randomization) prior to the first frozen embryo transfer. The study arms did not vary significantly in terms of the number of oocytes retrieved and embryos produced/transferred. The intention to treat clinical pregnancy and live birth rates (with the latter excluding four cases lost to follow-up: one in the fresh transfer and three in the freeze-all arms, respectively) after the first embryo transfer did not vary significantly among the fresh embryo transfer and freeze-all study arms: 51/105 (48.6%) versus 57/104 (54.8%) and 41/104 (39.4%) versus 42/101 (41.6%), respectively (relative risk for clinical pregnancy 1.13, 95% CI 0.87–1.47; P = 0.41). However, moderate-to-severe OHSS occurred solely in the group that received low-dose hCG (9/105, 8.6%, 95% CI 3.2% to 13.9% vs 0/104, 95% CI 0 to 3.7, P < 0.01). LIMITATIONS, REASONS FOR CAUTION The sample size calculation was based on a 19% absolute difference in terms of clinical pregnancy rates, therefore smaller differences, as observed in the trial, cannot be reliably excluded as non-significant. WIDER IMPLICATIONS OF THE FINDINGS This study offers the first comparative analysis of two common strategies applied to women performing IVF/ICSI with a high risk to develop OHSS. While pregnancy rates did not vary significantly, a fresh embryo transfer with intensified luteal phase support may still not avoid the risk of moderate-to-severe OHSS and serious consideration should be made before recommending it as a routine first-line treatment. Future trials may allow us to confirm these findings. STUDY FUNDING/COMPETING INTEREST(S) The authors have no conflicts of interest to disclose. No external funding was obtained for this study. TRIAL REGISTRATION NUMBER ClinicalTrials.gov identifier NCT02148393. TRIAL REGISTRATION DATE 28 May 2014 DATE OF FIRST PATIENT’S ENROLMENT 30 May 2014

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Allen, Angier, Anna Siefkas, Emily Pellegrini, Hoyt Burdick, Gina Barnes, Jacob Calvert, Qingqing Mao, and Ritankar Das. "A Digital Twins Machine Learning Model for Forecasting Disease Progression in Stroke Patients." Applied Sciences 11, no. 12 (June 16, 2021): 5576. http://dx.doi.org/10.3390/app11125576.

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Background: Machine learning methods have been developed to predict the likelihood of a given event or classify patients into two or more diagnostic categories. Digital twin models, which forecast entire trajectories of patient health data, have potential applications in clinical trials and patient management. Methods: In this study, we apply a digital twin model based on a variational autoencoder to a population of patients who went on to experience an ischemic stroke. The digital twin’s ability to model patient clinical features was assessed with regard to its ability to forecast clinical measurement trajectories leading up to the onset of the acute medical event and beyond using International Classification of Diseases (ICD) codes for ischemic stroke and lab values as inputs. Results: The simulated patient trajectories were virtually indistinguishable from real patient data, with similar feature means, standard deviations, inter-feature correlations, and covariance structures on a withheld test set. A logistic regression adversary model was unable to distinguish between the real and simulated data area under the receiver operating characteristic (ROC) curve (AUCadversary = 0.51). Conclusion: Through accurate projection of patient trajectories, this model may help inform clinical decision making or provide virtual control arms for efficient clinical trials.

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Dawson, Ellen A., Mark A. Black, Jennifer Pybis, N. Timothy Cable, and Daniel J. Green. "The impact of exercise on derived measures of central pressure and augmentation index obtained from the SphygmoCor device." Journal of Applied Physiology 106, no. 6 (June 2009): 1896–901. http://dx.doi.org/10.1152/japplphysiol.91564.2008.

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The purpose of this study was to investigate whether measures derived from the SphygmoCor device and its associated transfer function are influenced by exercise-induced alterations in vascular tone. Measurements were taken from either the exercised or the contralateral nonexercised limb during repeated and identical incremental hand-grip protocols. Eight male subjects performed three 3-min bouts of hand-grip exercise on two occasions. The exercise intensities were set at 3 kg, 5 kg, with a final 1.5-kg bout performed during cuff ischemia (1.5Isch). Blood pressure waveforms were recorded from the radial artery of either the exercised or nonexercised limb using applanation tonometry (SphygmoCor) during a 90-s rest period immediately after each exercise bout. Central blood pressures and augmentation indexes (AIx), an index of arterial stiffness, were derived using the peripheral waveform and the inbuilt SphygmoCor transfer function (TF). AIx was consistently ∼10% higher in the exercised arm during all trials compared with the nonexercised limb. Similarly, there was a consistent and significant difference (∼3 mmHg; P < 0.05) between exercised and nonexercised arms for the derived central systolic and mean arterial blood pressures. Despite identical bouts of exercise, AIx and central systolic and mean arterial blood pressures derived from applanation tonometry at the peripheral radial artery were statistically different when assessed at the exercising arm vs. the nonexercising arm. Changes in vascular tone with exercise may modify the intrinsic characteristics of the vessel wall and could compromise the assumptions underlying transfer functions used to derive central measures using applanation tonometry.

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Wagner, Anjuli D., Irene N. Njuguna, Jillian Neary, Vincent O. Omondi, Verlinda A. Otieno, Joseph Babigumira, Elizabeth Maleche-Obimbo, Dalton C. Wamalwa, Grace C. John-Stewart, and Jennifer A. Slyker. "Financial Incentives to Increase Uptake of Pediatric HIV Testing (FIT): study protocol for a randomised controlled trial in Kenya." BMJ Open 8, no. 10 (October 2018): e024310. http://dx.doi.org/10.1136/bmjopen-2018-024310.

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IntroductionIndex case testing (ICT) to identify HIV-infected children is efficient but has suboptimal uptake. Financial incentives (FI) have overcome financial barriers in other populations by offsetting direct and indirect costs. A pilot study found FI to be feasible for motivating paediatric ICT among HIV-infected female caregivers. This randomised trial will determine the effectiveness of FI to increase uptake of paediatric ICT.Methods and analysisThe Financial Incentives to Increase Uptake of Pediatric HIV Testing trial is a five-arm, unblinded, randomised controlled trial that determines whether FI increases timely uptake of paediatric ICT. The trial will be conducted in multiple public health facilities in western Kenya. Each HIV-infected adult enrolled in HIV care will be screened for eligibility: primary caregiver to one or more children of unknown HIV status aged 0–12 years. Eligible caregivers will be individually randomised at the time of recruitment in equal 1:1:1:1:1 allocation to one of five arms (US$0 (control), US$1.25, US$2.50, US$5.00 and US$10.00). The trial aims to randomise 800 caregivers. Incentives will be disbursed at the time of child HIV testing using mobile money transfer or cash. Arms will be compared in terms of the proportion of adults who complete testing for at least one child within 2 months of randomisation and time to testing. A cost-effectiveness analysis of FI for paediatric ICT will also be conducted.Ethics and disseminationThis study was reviewed and approved by the University of Washington Institutional Review Board and the Kenyatta National Hospital Ethics and Research Committee. Trial results will be disseminated to healthcare workers at study sites, regional and national policymakers, and with patient populations at study sites (regardless of enrolment in the trial). Randomised trials of caregiver-child FI interventions pose unique study design, ethical and operational challenges, detailed here as a resource for future investigations.Trial registration numberNCT03049917; Pre-results.

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Baizer, Joan S., Ines Kralj-Hans, and Mitchell Glickstein. "Cerebellar Lesions and Prism Adaptation in Macaque Monkeys." Journal of Neurophysiology 81, no. 4 (April 1, 1999): 1960–65. http://dx.doi.org/10.1152/jn.1999.81.4.1960.

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Cerebellar lesions and prism adaptation in Macaque monkeys. If a laterally displacing prism is placed in front of one eye of a person or monkey with the other eye occluded, they initially will point to one side of a target that is located directly in front of them. Normally, people and monkeys adapt easily to the displaced vision and correct their aim after a few trials. If the prism then is removed, there is a postadaptation shift in which the subject misses the target and points in the opposite direction for a few trials. We tested five Macaque monkeys for their ability to adapt to a laterally displacing prism and to show the expected postadaptation shift. When tested as normals, all five animals showed the typical pattern of adaptation and postadaptation shift. Like human subjects, the monkeys also showed complete interocular transfer of the adaptation but no transfer of the adaptation between the two arms. When preoperative training and testing was complete, we made lesions of various target areas on the cerebellar cortex. A cerebellar lesion that included the dorsal paraflocculus and uvula abolished completely the normal prism adaptation for the arm ipsilateral to the lesion in one of the five monkeys. The other four animals retained the ability to prism-adapt normally and showed the expected postadaptation shift. In the one case in which the lesion abolished prism adaptation, the damage included Crus I and II, paramedian lobule and the dorsal paraflocculus of the cerebellar hemispheres as well as lobule IX, of the vermis. Thus in this case, the lesion included virtually all the cerebellar cortex that receives mossy-fiber visual information relayed via the pontine nuclei from the cerebral cortex. The other four animals had damage to lobule V, the classical anterior lobe arm area and/or vermian lobules VI/VII, the oculomotor region. When tested postoperatively, some of these animals showed a degree of ataxia equivalent to that of the case in which prism adaptation was affected, but prism adaptation and the postadaptation shift remained normal. We conclude that in addition to its role in long-term motor learning and reflex adaptation, the region of the cerebellum that was ablated also may be a critical site for a short-term motor memory. Prism adaptation seems to involve a region of the cerebellum that receives a mossy-fiber visual error signal and probably a corollary discharge of the movement.

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Poppendieck, Wigand, Oliver Faude, Melissa Wegmann, and Tim Meyer. "Cooling and Performance Recovery of Trained Athletes: A Meta-Analytical Review." International Journal of Sports Physiology and Performance 8, no. 3 (May 2013): 227–42. http://dx.doi.org/10.1123/ijspp.8.3.227.

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Purpose:Cooling after exercise has been investigated as a method to improve recovery during intensive training or competition periods. As many studies have included untrained subjects, the transfer of those results to trained athletes is questionable.Methods:Therefore, the authors conducted a literature search and located 21 peer-reviewed randomized controlled trials addressing the effects of cooling on performance recovery in trained athletes.Results:For all studies, the effect of cooling on performance was determined and effect sizes (Hedges’ g) were calculated. Regarding performance measurement, the largest average effect size was found for sprint performance (2.6%, g = 0.69), while for endurance parameters (2.6%, g = 0.19), jump (3.0%, g = 0.15), and strength (1.8%, g = 0.10), effect sizes were smaller. The effects were most pronounced when performance was evaluated 96 h after exercise (4.3%, g = 1.03). Regarding the exercise used to induce fatigue, effects after endurance training (2.4%, g = 0.35) were larger than after strength-based exercise (2.4%, g = 0.11). Cold-water immersion (2.9%, g = 0.34) and cryogenic chambers (3.8%, g = 0.25) seem to be more beneficial with respect to performance than cooling packs (−1.4%, g= −0.07). For cold-water application, whole-body immersion (5.1%, g = 0.62) was significantly more effective than immersing only the legs or arms (1.1%, g = 0.10).Conclusions:In summary, the average effects of cooling on recovery of trained athletes were rather small (2.4%, g = 0.28). However, under appropriate conditions (whole-body cooling, recovery from sprint exercise), postexercise cooling seems to have positive effects that are large enough to be relevant for competitive athletes.

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Giannarelli, D., E. Bria, F. Cuppone, M. Ciccarese, C. Nisticò, P. Carlini, M. Milella, V. Lorusso, E. Terzoli, and F. Cognetti. "Three-year disease-free survival (DFS) as surrogate end-point for predicting five-year overall survival (OS) benefit in adjuvant taxane-based chemotherapy for breast cancer (BC): Analysis of 10 randomized clinical trials (RCTs)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 584. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.584.

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584 Background: The issue regarding the eventual correlation between DFS at earlier follow-up (i.e. 3-yrs) with 5-yrs OS has not actually been explored in trials addressing the role of taxanes in BC. All RCTs in which patients were randomized to receive a standard or a taxane-based regimen for early BC were analyzed to evaluate this topic. Methods: All phase III trials with at least 60 month follow-up were considered eligible. The correlation has been explored according to a linear regression model considering both each single outcome pair (DFS/OS) for all arms (extracted by curves), their differences, and each outcome Hazard Ratio (HR) or calculated Relative Risk (RRs), following 2 steps: 1) correlation between 5-yrs DFS and OS (to confirm the evidence); 2) correlation between 3-yrs DFS and 5-yrs OS (predictive role). The correlation was estimated according to Pearson (r) and R2 coefficients (parametric) and Spearman (Rho) coefficient (non- parametric). A model to calculate the target sample size to determine 5-yrs OS benefit of 3%, 5% and 7%, respectively, was calculated as well. Results: Ten RCTs (17,067 patients) with available data for outcomes were gathered. For 5-yrs DFS/OS, a linear correlation was found between rates (r=0.74, R2=0.55; p<0.0001; Rho=0.83; p<0.0001), and HRs (r=0.90, R2=0.81; p<0.0001; Rho=0.91; p<0.0001). Three-yrs DFS correlates with 5-yrs OS, with both rates (r=0.81, R2=0.66; p<0.0001; Rho=0.92; p<0.0001), and RRs (r=0.84, R2=0.71; p=0.002; Rho=0.85; p=0.002). Three-yrs DFS and 5-yrs OS absolute differences strongly correlate (r=0.86, R2=0.74; p=0.001; Rho=0.84; p=0.002). The sample size model (on the basis of the r-coefficient=0.81), calculates 2,733, 863, and 389 pts to improve 3-yrs DFS of 4%, 7% and 10%, which means to improve 5-yrs OS of 3.2%, 5.7% and 8.1%, respectively. Conclusions: By these data, 3-yrs DFS is a reliable surrogate end-point for OS when testing new drugs in early BC, and is able to predict a late survival benefit. Thanks to the smaller patient sample size, RCTs with this design will provide early results in a shorter time period, allowing a faster data transfer to clinical practice. No significant financial relationships to disclose.

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Levi Setti, P. E., F. Cirillo, E. Morenghi, V. Immediata, V. Caccavari, A. Baggiani, E. Albani, and P. Patrizio. "One step further: randomised single-centre trial comparing the direct and afterload techniques of embryo transfer." Human Reproduction 36, no. 9 (July 29, 2021): 2484–92. http://dx.doi.org/10.1093/humrep/deab178.

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Abstract STUDY QUESTION What are the differences in ease of use between two different embryo transfer (ET) techniques: the preload direct approach and the afterload approach. SUMMARY ANSWER The afterload technique seems to reduce the rate of difficult ETs. WHAT IS KNOWN ALREADY Numerous published trials now document that the ET procedure has an impact on pregnancy and delivery rates after IVF. Difficult transfers should be avoided, as they reduce implantation and pregnancy rates. Preload direct ETs with soft catheters under ultrasound guidance is currently considered the best procedure. However, when using soft catheters, it is not known which technique is preferable or which one should be implemented to reduce the operator factor. STUDY DESIGN, SIZE, DURATION This prospective randomised unblinded controlled clinical trial, included 352 ultrasound-guided ETs assigned to either direct ET or afterload ET, between September 2017 and March 2019. The sample size was calculated based on the historical rate of difficult ETs encountered between 2014 and 2015 with a direct ET procedure. PARTICIPANTS/MATERIALS, SETTING, METHODS The inclusion criteria were women 18–38 years old, with BMI between 18 and 28, receiving a single-thawed blastocyst transfer. The exclusion criteria were use of testicular sperm and preimplantation genetic testing (PGT) cycles. The primary outcome was the rate of difficult or suboptimal transfers defined as: advancement of the outer sheath (specific for the direct transfer), multiple attempts, use of force, required manipulation, use of a stylet or tenaculum, dilatation, or use of a different catheter. The secondary outcome was clinical pregnancy rate. MAIN RESULTS AND THE ROLE OF CHANCE A total of 352 frozen ETs were randomised, with 176 patients in each group. The two arms were homogeneous for female and male age, female BMI, duration of infertility, secondary infertility, previous deliveries or miscarriages, myomas, previous surgery to the uterine cavity, cycle day at ovulation trigger, freeze all cycles, first transfers, indication for treatment, endometrial preparation protocol and duration, endometrial thickness, and blastocyst grade at vitrification. Across the entire population, 85 (24.1%) ETs were defined as difficult. The rate of difficult transfers was significantly higher in the direct ET group than in the afterload group: 68 (38.6%) versus 17 (9.7%), respectively (OR 0.17, 95% CI 0.09–0.30, P < 0.001). The mean percentage in the rate of difficult transfers per operator was 22.5% (SD ± 14.5%), of which 36.1% (SD ± 23.4%) were in the direct group compared with 8.6% (± 8.2%) in the afterload group (P < 0.001). The difficult transfer rate among operators varied from 0 to 43.8% (0–77.8% in the direct group and 0 to 25.0% in the afterload group). The clinical pregnancy rates (42.0% vs 48.3%, P = 0.239 in the direct and afterload groups, respectively) were not significantly different between the groups. LIMITATIONS, REASONS FOR CAUTION There were 18 experienced operators who participated in the trial. Conclusions about the pregnancy rate should not be generalised, since the sample analysis was not performed on this outcome and, although clinically relevant, the difference was not significantly different. WIDER IMPLICATIONS OF THE FINDINGS The rate of difficult transfers was significantly higher in the direct ET group compared with the afterload ET group, although a wide variation was observed among operators. Further studies regarding the association between transfer technique and ART outcomes are required. STUDY FUNDING/COMPETING INTEREST(S) No specific funding was sought and there are no competing interests. TRIAL REGISTRATION NUMBER NCT03161119. TRIAL REGISTRATION DATE 5 April 2017. DATE OF FIRST PATIENT'S ENROLMENT 26 September 2017.

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Samuelson, Clare, Olivier Humbert, Stefan Radtke, Haiying Zhu, Mallory J. Llewellyn, Emily Fields, Savannah Cook, et al. "Multiplex CRISPR/Cas9 Genome Editing Targeting the BCL11A/HBG Axis Maximizes Fetal Hemoglobin Reinduction but Generates Chromosomal Translocations Which Persist In Vivo." Blood 136, Supplement 1 (November 5, 2020): 47–48. http://dx.doi.org/10.1182/blood-2020-138539.

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Sickle cell disease and β-thalassemia are among the most common monogenic disorders globally, causing significant morbidity and early mortality. The only curative option available is allogeneic hematopoietic stem cell transplantation, which is limited by a lack of matched donors and risks, including graft versus host disease and secondary malignancy. Retroviral gene transfer is being explored in clinical trials, but an alternative approach is more targeted CRISPR/Cas9 genome editing, to recapitulate naturally occurring hereditary persistence of fetal hemoglobin (HPFH) which ameliorates disease. HbF reinduction is achieved by disrupting either transcription factor binding sites within the HBG promoter, or an erythroid enhancer sequence within the HbF repressor, BCL11A. Results from preclinical studies have suggested that HbF levels may remain suboptimal when each locus is targeted individually. We thus investigated the feasibility of a dual editing approach, targeting both loci simultaneously or sequentially, to maximize HbF production. G-CSF-mobilized human peripheral blood hematopoietic stem and progenitor cells (HSPCs) underwent CRISPR/Cas9 genome editing at either HBG promoter, BCL11A erythroid enhancer, or both loci targeted either simultaneously or sequentially. Immunodeficient mice were transplanted with edited cells. HSPCs cultured in differentiation media demonstrated comparable levels of editing at each locus in the single edited arms (by TIDE).The dual editing approach did not impair editing efficiency at each site when conducted sequentially and only slightly reduced efficiency in the simultaneously-edited reactions. HbF reinduction was also greatest in sequentially double-edited reactions, with HbF/HbA ratio as high as 3.9 times that seen in mock reactions by flow cytometry and 4.1 times by HPLC. In single-edited arms, HbF reinduction was slightly greater with HBG promotor than BCL11A erythroid enhancer editing. Two separate chromosomal translocation events encompassing both loci were detected in each double-edited arm and quantified using digital droplet PCR. Both were more frequent in simultaneous (mean of 1.0% and 0.6%) than sequential reactions (means <0.2%, n=3, p=0.0420 and p=0.0296). Analysis of single BFU-E colonies grown on methocult media revealed markedly different indel patterns at the 2 target loci. Concurrent hemoglobin fraction analysis of these clonal populations by HPLC demonstrated greatest HbF proportion in double-edited colonies. Where ≥60% editing was reported at both loci mean HbF was 71.3%, compared to 47.1% with ≥60% editing at HBG only, and 29.6% with ≥60% editing at BCL11A only (p=0.0373). Following transplant into mice, engraftment and lineage differentiation were comparable among all experimental arms. At necropsy, bone marrow populations of human CD45+ cells, CD34+CD38low HSPCs and, within these, HSC-enriched CD90+CD45RA- subpopulation, were present at comparable levels indicating that the dual editing approach did not impair engraftment. Translocation events were detected, albeit at frequencies of less than 0.25%, in the bone marrows of all 4 mice transplanted with simultaneously dual-edited cells and in 5 of 6 mice transplanted with sequentially dual-edited cells. Bone marrow cells cultured ex vivo demonstrated greatest HbF from mice transplanted with sequentially double-edited cells. In summary, we present evidence of maximized HbF reinduction with sequentially applied multiplex genome editing at BCL11A erythroid enhancer and HBG promoter, with no impairment of engraftment or differentiation. However, chromosomal translocation events were consistently seen in double-edited reactions, even when edits at each locus were applied sequentially, and persisted in vivo after engraftment, thus rendering this approach inappropriate for clinical applications. However, multiplex editing and targeting both the BCL11A erythroid enhancer and HBG promoter to maximize fetal hemoglobin induction may be a promising strategy for alternative platforms such as base editors which are expected to greatly reduce or completely eliminate the occurrence of translocations. Disclosures Radtke: Forty Seven INC: Consultancy. Kiem:Enochian: Membership on an entity's Board of Directors or advisory committees; Umoja: Membership on an entity's Board of Directors or advisory committees; Magenta Therapeutics: Consultancy; Homology Medicines: Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy; Vor Biopharma: Membership on an entity's Board of Directors or advisory committees; Rocket Pharma: Membership on an entity's Board of Directors or advisory committees.

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Lecky, Fiona, Wanda Russell, Gordon Fuller, Graham McClelland, Elspeth Pennington, Steve Goodacre, Kyee Han, et al. "The Head Injury Transportation Straight to Neurosurgery (HITS-NS) randomised trial: a feasibility study." Health Technology Assessment 20, no. 1 (January 2016): 1–198. http://dx.doi.org/10.3310/hta20010.

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BackgroundReconfiguration of trauma services, with direct transport of traumatic brain injury (TBI) patients to neuroscience centres (NCs), bypassing non-specialist acute hospitals (NSAHs), could potentially improve outcomes. However, delays in stabilisation of airway, breathing and circulation (ABC) and the difficulties in reliably identifying TBI at scene may make this practice deleterious compared with selective secondary transfer from nearest NSAH to NC. National Institute for Health and Care Excellence guidance and systematic reviews suggested equipoise and poor-quality evidence – with regard to ‘early neurosurgery’ in this cohort – which we sought to address.MethodsPilot cluster randomised controlled trial of bypass to NC conducted in two ambulance services with the ambulance station (n = 74) as unit of cluster [Lancashire/Cumbria in the North West Ambulance Service (NWAS) and the North East Ambulance Service (NEAS)]. Adult patients with signs of isolated TBI [Glasgow Coma Scale (GCS) score of < 13 in NWAS, GCS score of < 14 in NEAS] and stable ABC, injured nearest to a NSAH were transported either to that hospital (control clusters) or bypassed to the nearest NC (intervention clusters). Primary outcomes: recruitment rate, protocol compliance, selection bias as a result of non-compliance, accuracy of paramedic TBI identification (overtriage of study inclusion criteria) and pathway acceptability to patients, families and staff. ‘Open-label’ secondary outcomes: 30-day mortality, 6-month Extended Glasgow Outcome Scale (GOSE) and European Quality of Life-5 Dimensions.ResultsOverall, 56 clusters recruited 293 (169 intervention, 124 control) patients in 12 months, demonstrating cluster randomised pre-hospital trials as viable for heath service evaluations. Overall compliance was 62%, but 90% was achieved in the control arm and when face-to-face paramedic training was possible. Non-compliance appeared to be driven by proximity of the nearest hospital and perceptions of injury severity and so occurred more frequently in the intervention arm, in which the perceived time to the NC was greater and severity of injury was lower. Fewer than 25% of recruited patients had TBI on computed tomography scan (n = 70), with 7% (n = 20) requiring neurosurgery (craniotomy, craniectomy or intracranial pressure monitoring) but a further 18 requiring admission to an intensive care unit. An intention-to-treat analysis revealed the two trial arms to be equivalent in terms of age, GCS and severity of injury. No significant 30-day mortality differences were found (8.8% vs. 9.1/%;p > 0.05) in the 273 (159/113) patients with data available. There were no apparent differences in staff and patient preferences for either pathway, with satisfaction high with both. Very low responses to invitations to consent for follow-up in the large number of mild head injury-enrolled patients meant that only 20% of patients had 6-month outcomes. The trial-based economic evaluation could not focus on early neurosurgery because of these low numbers but instead investigated the comparative cost-effectiveness of bypass compared with selective secondary transfer for eligible patients at the scene of injury.ConclusionsCurrent NHS England practice of bypassing patients with suspected TBI to neuroscience centres gives overtriage ratios of 13 : 1 for neurosurgery and 4 : 1 for TBI. This important finding makes studying the impact of bypass to facilitate early neurosurgery not plausible using this study design. Future research should explore an efficient comparative effectiveness design for evaluating ‘early neurosurgery through bypass’ and address the challenge of reliable TBI diagnosis at the scene of injury.Trial registrationCurrent Controlled Trials ISRCTN68087745.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 1. See the NIHR Journals Library website for further project information.

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Thomas, Mike, Anne Bruton, Paul Little, Stephen Holgate, Amanda Lee, Lucy Yardley, Steve George, et al. "A randomised controlled study of the effectiveness of breathing retraining exercises taught by a physiotherapist either by instructional DVD or in face-to-face sessions in the management of asthma in adults." Health Technology Assessment 21, no. 53 (September 2017): 1–162. http://dx.doi.org/10.3310/hta21530.

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BackgroundAsthma control is suboptimal, resulting in quality of life (QoL) impairment and costs. Breathing retraining exercises have evidence of effectiveness as adjuvant treatment, but are infrequently used.ObjectivesTo transfer the contents of a brief (three-session) physiotherapist-delivered breathing retraining programme to a digital versatile disc (DVD) and booklet format; to compare the effectiveness of the self-guided intervention with that of ‘face-to-face’ physiotherapy and usual care for QoL and other asthma-related outcomes; to perform a health economic assessment of both interventions; and to perform a process evaluation using quantitative and qualitative methods.DesignParallel-group three-arm randomised controlled trial.SettingGeneral practice surgeries in the UK.ParticipantsIn total, 655 adults currently receiving asthma treatment with impaired asthma-related QoL were randomly allocated to the DVD (n = 261), physiotherapist (n = 132) and control (usual care) (n = 262) arms in a 2 : 1 : 2 ratio. It was not possible to blind participants but data collection and analysis were performed blinded.InterventionsPhysiotherapy-based breathing retraining delivered through three ‘face-to-face’ respiratory physiotherapist sessions or a self-guided programme (DVD plus our theory-based behaviour change booklet) developed by the research team, with a control of usual care.Main outcome measuresThe primary outcome measure was asthma-specific QoL, measured using the Asthma Quality of Life Questionnaire (AQLQ). Secondary outcomes included asthma symptom control [Asthma Control Questionnaire (ACQ)], psychological state [Hospital Anxiety and Depression Scale (HADS)], hyperventilation symptoms (Nijmegen questionnaire), generic QoL [EuroQol-5 Dimensions (EQ-5D)], assessments of airway physiology (spirometry) and inflammation (exhaled nitric oxide) and health resource use and costs. Assessments were carried out at baseline and at 3, 6 and 12 months post randomisation. Patient engagement and experience were also assessed using quantitative and qualitative methods.ResultsPrimary efficacy analysis was between-group comparison of changes in AQLQ scores from baseline to 12 months in the intention-to-treat population with adjustments for prespecified covariates. Significant improvements occurred in the DVD group compared with the control group [adjusted mean difference 0.28, 95% confidence interval (CI) 0.11 to 0.44;p < 0.001] and in the face-to-face physiotherapy group compared with the control group (adjusted mean difference 0.24, 95% CI 0.04 to 0.44;p < 0.05), with equivalence between the DVD and the face-to-face physiotherapy groups (adjusted mean difference 0.04, 95% CI –0.16 to 0.24). In all sensitivity analyses, both interventions remained significantly superior to the control and equivalence between the interventions was maintained. In other questionnaire outcome measures and in the physiological measures assessed, there were no significant between-group differences. Process evaluations showed that participants engaged well with both of the active interventions, but that some participants in the DVD arm would have liked to receive tuition from a professional. Asthma health-care costs were lower in both intervention arms than in the control group, indicating ‘dominance’ for both of the interventions compared with the control, with lowest costs in the DVD arm. The rate of adverse events was lower in the DVD and face-to-face physiotherapy groups than in the control group.ConclusionsOnly 10% of the potentially eligible population responded to the study invitation. However, breathing retraining exercises improved QoL and reduced health-care costs in adults with asthma whose condition remains uncontrolled despite standard pharmacological therapy, were engaged with well by patients and can be delivered effectively as a self-guided intervention. The intervention should now be transferred to an internet-based platform and implementation studies performed. Interventions for younger patients should be developed and trialled.Trial registrationCurrent Controlled Trials ISRCTN88318003.FundingThis project was primarily funded by the NIHR Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 53. See the NIHR Journals Library website for further project information. Additional financial support was received from Comprehensive Local Research Networks.

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Barrington, Sally F., Michael J. O’Doherty, Jane MacKewn, Paul Schleyer, Wendi Qian, Philippa Patrick, Timothy Illidge, et al. "Quality Control of PET Imaging in a Multicentre Phase III Trial (RAPID) Involving Randomisation of Patients with Stages IA and IIA Hodgkin Lymphoma Who Are PET ‘negative’ after 3 Cycles of ABVD Chemotherapy." Blood 112, no. 11 (November 16, 2008): 1449. http://dx.doi.org/10.1182/blood.v112.11.1449.1449.

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Abstract Prospective randomised trials are required to evaluate response adapted treatment algorithms in lymphoma featuring decision making based on positron emission tomography (PET). Trial recruitment is likely to be optimised if patients can be scanned close to home but consistency in quality control (QC), scan acquisition and interpretation is needed for results to be comparable when scans are performed at different locations and to validate the eventual clinical results of the trial. We describe the arrangements for QC of PET imaging in an ongoing randomised controlled trial (RAPID) involving patients with clinical stages IA/IIA HL and 13 PET Centres across the UK. The aim of the trial is to test whether 18F-fluorodeoxyglucose PET can identify patients cured by chemotherapy who can therefore avoid consolidation radiotherapy (RT) and involves a randomisation between involved field RT and no further treatment in pts who are PET ‘negative’ (-ve) after 3 cycles ABVD. When 400 PET -ve patients have been randomised the trial is powered to reliably exclude a 7% difference in progression free survival between the trial arms. All PET Centres wishing to take part in RAPID had to have a fixed-installation PET scanner and were visited by a physicist from the ‘core lab’ in London who performed a phantom acquisition, validated data anonymisation and transfer, and confirmed adherence to a specific QC protocol. Phantom data were assessed to ensure consistency of image quality and reconstruction across all scanners. Scans are reviewed at the core lab by the same two nuclear medicine specialists using visual assessment and scored according to a 5 point scale (1, no disease; 2, probably no disease; 3, possibly disease; 4, probably disease; 5, definitely disease). For the purposes of the trial, centrally reviewed scores of 1 and 2 are considered ‘negative’ and these patients are randomised. Scores of 3, 4 and 5 are considered ‘positive’ and these patients receive a 4th cycle of ABVD and involved field RT. 331 patients who have completed initial chemotherapy have had PET scans centrally reviewed with central review scores returned to the clinical centre and trial office within 72 hours of receipt of images at the core lab. Scans have been acquired 7–15 days after day 15 of cycle 3 ABVD in 69.5% pts, 1–6 days after in 14.5% and 16 or more days after in 16%. One scan was unsatisfactory and had to be repeated because a site of original disease in the olecranon fossa was not included. The proportion of scans scored as ‘negative’ has been consistent over successive 6 month periods, varying between 72% and 85%. We conclude that central review of PET imaging can be successfully co-ordinated across multiple centres in real time using a central Core Lab featuring agreed methods for QC and image interpretation. This methodology, which can easily be applied to other clinical trial settings, provides quality assured PET data and ultimately allows robust conclusions to be drawn from trial results.

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Knop, Stefan, Peter Liebisch, Holger Hebart, Ernst Holler, Monika Engelhardt, Ralf C. Bargou, Bernd Metzner, et al. "Allogeneic Stem Cell Transplant Versus Tandem High-Dose Melphalan for Front-Line Treatment of Deletion 13q14 Myeloma – An Interim Analysis of the German DSMM V Trial." Blood 114, no. 22 (November 20, 2009): 51. http://dx.doi.org/10.1182/blood.v114.22.51.51.

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Abstract Abstract 51 Background Allogeneic stem cell transplantation (allo SCT), a treatment modality based on transfer of immunocompetent donor lymphocytes offers curative potential to subjects with a variety of hematological cancers. In multiple myeloma (MM), high-dose melphalan followed by autologous stem cell transplantation (auto SCT) is adopted as a standard of care. However, it remains palliative since virtually all patients (pts) relapse and renders allo SCT an option of interest. Deletion of chromosome 13q14 (13q-) in MM has been shown to negatively impact prognosis. Therefore, improvement of therapy for 13q- pts is highly desirable. Patients and methods A prospective two-arm multi-center trial (DSMM V) was set up by our group to compare tandem high-dose melphalan 200 mg/m2 (HD Mel) with a reduced intensity conditioning allo-SCT after one cycle of HD Mel for 13q- MM. Eligibility criteria were 13q- on bone marrow FISH analysis; age up to 60 years; newly diagnosed MM in Salmon and Durie stages II and III; and measurable disease. Allocation to either treatment arm was by availability of an HLA-matched (one mismatch allowed) volunteer related (VRD) or unrelated donor (VUD). Initially, all pts received four cycles of anthracycline/dexamethasone-based induction followed by chemomobilization of peripheral blood stem cells (PBSCT) and one cycle of HD Mel. Allogeneic SCT was performed after preparation with fludarabine (30 mg/m2 for 3 consecutive days) and melphalan 140 mg/m2. ATG was administered for VUD transplants. Results 199 pts with a median age of 53 (range, 30 – 60) years were enrolled between October 2002 and March 2007 and included in this interim analysis. Sixty-seven percent had stage III disease. Allo SCT was performed in 126 of 199 pts (63%), 76 of whom (60%) received VUD allografts. The remaining 73 subjects uniformely received tandem HD Mel. Pts following allo SCT were more likely to achieve CR (59%) when compared to tandem HD Mel (32%; p=.003) within one year after end of therapy. Similarly, overall response rate was significantly higher with allo SCT (91% versus 86%; p=.003). Of note, depth of response to allo SCT was not associated with presence of acute graft-versus-host disease (GVHD): 62% CR with grades II to IV GVHD vs 58% CR with grades 0 and I (p=.75). Treatment-related mortality (TRM) at 2 years from allo SCT was 16/126 (12.7%). At a median follow up of 25 months for tandem HD Mel and 34 months for allo SCT, projected 3-year overall survival is 72% (auto) and 60% (auto/allo SCT; p=0.22), respectively. Conclusions This is the largest trial on first-line allogeneic stem cell transplant in MM so far. Our interim results show a higher CR rate in FISH 13q- subjects undergoing allo SCT when compared to tandem HD Mel. Despite a majority of allografts in our study being delivered from unrelated donors, TRM was comparable to trials confined to sibling transplants. At a relatively short follow-up, there is not yet a difference between both arms regarding OS, albeit longer follow-up may be important as previously described. This as well as analysis of the impact of donor type and chronic GVHD on outcome will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

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Nishihori, Taiga, Jonathan L. Kaufman, James E. Hoffman, Kristin Blouch, Sunil Pandit, Emily Butler, Amit Jain, et al. "Open-Label Pilot Study of Genetically Engineered NY-ESO-1 Specific T Cells (GSK3377794) Alone or in Combination with Pembrolizumab in Relapsed and Refractory Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 3134. http://dx.doi.org/10.1182/blood-2019-128059.

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Background: Emerging clinical data demonstrate that adoptive cellular therapy has potential to be practice-changing in the management of relapsed/refractory multiple myeloma (MM). NY-ESO-1 TCR T (GSK3377794) are autologous polyclonal T cells transduced by a self-inactivating lentiviral vector to express an affinity-enhanced TCR capable of recognizing NY-ESO-1 or LAGE-1a antigenic peptides in complex with HLA-A2. In prior studies, encouraging clinical activity has been observed with GSK3377794 treatment in patients with synovial sarcoma, melanoma, myxoid/round cell liposarcoma, and in MM patients receiving GSK3377794 after autologous stem cell transplant (ASCT). NY-ESO-1 and LAGE-1a are immunogenic cancer/testis antigens frequently overexpressed in MM and are linked to poor clinical outcome. While a number of phase 1 and 2 trials are evaluating GSK3377794 in solid tumors, this abstract presents a trial in progress aiming to evaluate safety and efficacy of GSK3377794 alone or in combination with the anti-PD1 inhibitor, pembrolizumab, in patients with MM. PD-1 expression on CD8 T cells has been observed in MM patients previously treated with GSK3377794 and can limit adaptive immune response. This has also been described as a mechanism of resistance and relapse in CD19 CAR T-cell trials (Fraietta et al, Nat Med 2018). Thus, we hypothesize that combining GSK3377794 and pembrolizumab may result in a synergistic antitumor effect. Study design and methods: This is an open-label, pilot study (NCT03168438) of GSK3377794 in patients who are HLA-A*02:01, HLA-A*02:05, and/or HLA-A*02:06 positive and have NY-ESO-1/LAGE-1a positive relapsed/refractory MM. Twenty patients who have received at least three prior therapies containing at least one of the following drug classes as separate or combined lines of therapy (including ASCT): an immunomodulatory imide, proteasome inhibitor, alkylator, CD38 monoclonal antibody, and glucocorticoid, will be assigned to one of two arms: GSK3377794 alone as a single infusion (Arm 1, n=10) or GSK3377794 as a single infusion in combination with pembrolizumab 200 mg IV every 3 weeks (Arm 2, n=10). Enrollment of Arm 1 will be completed before enrolling subjects to Arm 2. Administration of pembrolizumab will start from Week 3 (or Week 6 if toxicities preclude Week 3 treatment). Patients will undergo leukapheresis to obtain cells for the manufacture of autologous NY-ESO-1-specific T cells. Each patient will then undergo lymphodepleting chemotherapy with fludarabine and cyclophosphamide followed by GSK3377794 infusion of 1−8x109 transduced T cells. Primary and secondary objectives are to assess safety and tolerability, and antitumor activity, respectively, of GSK3377794 treatment (with and without pembrolizumab). Patients will be monitored for adverse events and combination-related treatment-limiting toxicities; efficacy will be assessed using International Myeloma Working Group Response Criteria (Rajkumar et al, Blood 2011). In Arm 2, enrollment will be temporarily paused for a 3-week safety review period after the first 3 patients have received their first dose of pembrolizumab. Efficacy, safety, and biomarker assessments will be conducted at each visit. Patients will complete the treatment phase upon progression of disease or 108 weeks after GSK3377794 infusion. After completion of the treatment phase, patients will transfer to the long-term follow-up study (NCT03391778) to continue safety and survival monitoring for up to 15 years. As of January 27, 2019, 50 patients have undergone screening for HLA status and NY-ESO-1/LAGE-1a antigen expression. Among 50 patients screened for HLA, 25 (50%) tested positive for HLA-A*02:01, 05, and/or 06. Of these patients, bone marrow samples from 12/21 (57%) tested positive for NY-ESO-1, LAGE-1a, or both, illustrating high expression of this antigen in MM. To date, 3 patients have been treated with GSK3377794, demonstrating feasibility of identifying and treating HLA/antigen-positive patients with relapsed/refractory MM. Further work is underway towards introducing flexibility in screening procedures in order to permit wider screening of patients and to minimize time between screening and leukapheresis and for cell manufacturing, which will enhance patient eligibility. Acknowledgment: Medical writing support by O Conn PhD of Fishawack Indicia Ltd, funded by GSK. This study (NCT03168438) is funded by GSK. Disclosures Nishihori: Karyopharm: Research Funding; Novartis: Research Funding. Kaufman:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; AbbVie: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Winship Cancer Institute of Emory University: Employment; TG Therapeutics: Consultancy; Bristol-Myers Squibb: Consultancy; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Blouch:GSK: Employment, Equity Ownership. Pandit:GSK: Employment, Equity Ownership. Butler:GSK: Employment, Equity Ownership. Jain:GSK: Employment. Wu:GSK: Employment, Equity Ownership. DeYoung:GSK: Employment, Equity Ownership. Hasan:GSK: Employment, Equity Ownership; Atara Biotherapeutics: Patents & Royalties; Merck: Equity Ownership.

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Meyer, Everett H., Rasmus Hoeg, Anna Moroz, Bryan Xei, Hsin-Hsu Wu, Rahul Pawar, Kartoosh Heydari, et al. "Orca-T, a Precision Treg-Engineered Donor Product, Prevents Acute Gvhd with Less Immunosuppression in an Early Multicenter Experience with Myeloablative HLA-Matched Transplants." Blood 136, Supplement 1 (November 5, 2020): 47–48. http://dx.doi.org/10.1182/blood-2020-142974.

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BACKGROUND GVHD remains a frequent and serious complication of HSCT despite the decades-long use of standard immunosuppression, such as tacrolimus and methotrexate, as prophylaxis against GVHD. Preclinical models have shown that the timed infusion of donor-derived high-purity CD4+CD25+FOXP3+ regulatory T cells (Treg) preceding adoptive transfer of conventional T cells (Tcon) prevents GVHD and maintains anti-cancer immunity without the need of pharmacologic agents. Early clinical trials using purified Treg-engineered graft showed safety and feasibility, but more extensive clinical studies are needed to test scalability and efficacy. Orca-T is an industry-manufactured, precision-engineered CD34-selected, Treg-engineered graft made in a central GMP laboratory and distributed to multiple centers in the U.S. We present our early patient experience with Orca-T in an ongoing single center phase 2 trial and a multicenter Phase Ib trial and report a pre-planned evaluation of patients randomized to receive Orca-T plus single-agent GVHD prophylaxis (PPX) or Orca-T and no PPX. METHODS 51 patients with high risk or active hematologic malignancies undergoing myeloablative conditioning were enrolled on two trials: a single-center Phase I/II (n=40, NCT01660607) and a multicenter Phase Ib (n=11; NCT04013685) study. Patients received CD34-selected cells infused with highly purified Treg (target dose: 3.0 x 106 cells/kg) followed 2 days later by the infusion of Tcon (3.0 x 106 cells/kg). Initial GMP manufacturing was demonstrated at Stanford (n=9 grafts; 2016 - 2019) and then transferred to Orca Bio in 2019 for scaled production. We evaluated the 34 patients beyond dose escalation since July 2016 who received Orca-T grafts from either matched related (n=25) or unrelated (n=9) donors and single agent GVHD PPX with either tacrolimus (n=28) or sirolimus (n=6). For comparative analysis, we identified a contemporaneous SOC cohort at Stanford (n=138) with both matched related (n=79) and unrelated (n=59) transplant recipients who received unmanipulated PBSC products (median f/u 546 days) and methotrexate plus tacrolimus. In April 2019, enrollment on a phase 2, stage 1 pre-planned subgroup of 24 patients were randomized to test whether all GVHD PPX could be removed: Orca-T plus either single-agent PPX (Arm 1, n=12) or no PPX (Arm2, n=12). RESULTS The Orca-T drug products were manufactured reliably with high Treg purity (93.8% +/- 3.1%) and a dose of 2.6 +/- 0.4 x 106 per kg (equivalent between arms and trials). Central lab turn-around times were 25.3 +/- 3.0 hours and all vein-to-vein times were less than 72 hrs (Table 1). For trial participants, there were no manufacturing failures, engraftment failures or treatment related mortality. Orca-T patients vs. SOC showed earlier neutrophil (median of 11 days vs. 14 days, p<0.0001 by Mann-Whitney U) and platelet engraftment (11 vs 17 days, p<0.0001) and a shorter hospital stay (15 vs 19 days, p=0.0002). Patients across 4 clinical sites received Orca-T plus single agent GVHD PPX (n=34; median f/u 261 days) had an acute GVHD grade 2-4 incidence of 0% as compared to 33% in the SoC cohort (n=138, p=0.0018 by Log-rank Mantel-Cox test, Fig. 1). The rate of moderate to severe chronic GVHD for Orca-T patients was 4% vs. 44% in the SoC cohort (p=0.016). In a preliminary subset of evaluable Orca- T patients, GVHD & relapse free survival (GRFS) at one year was higher for Orca-T patients vs SoC (69% versus 33%, p=0.006) while relapse and overall survival did not appear to differ. We observed no differences in infectious complications. In patients randomized to PPX vs. no PPX, the incidence of aGVHD grade 2-4 was 0% in Arm 1 and 58% in Arm 2 (p <0.0001, Log-rank Mantel-Cox test), with 17% of these events being Grade 3-4. All GVHD in Arm 2 responded to steroids with no GVHD-related deaths. CONCLUSIONS Manufacture of high precision Orca-T Treg-engineered donor products were successfully scaled in a central GMP with reliable distribution to centers. Patients who received Orca-T and single agent PPX had no grade 2 or greater acute GVHD acute and very little chronic GVHD when compared to SOC. Patients randomized to Orca-T and no PPX showed an increased incidence of acute GVHD vs. those with Orca-T and single agent PPX. Engineered Treg grafts show promise to improve GFRS and other transplant outcomes. Orca-T has been granted RMAT status by the FDA and evaluation continues in an ongoing multicenter clinical trial. Disclosures Meyer: Orca Bio: Research Funding. Moroz:Orca Bio: Research Funding. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding. Shiraz:Kite, a Gilead Company: Research Funding; ORCA BioSystems: Research Funding. Muffly:Servier: Research Funding; Adaptive: Research Funding; Amgen: Consultancy. Rezvani:Pharmacyclics: Research Funding. Shizuru:Jasper Therapeutics, Inc: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Fernhoff:Orca Bio: Current Employment, Current equity holder in private company. Putnam:Orca Bio: Current Employment, Current equity holder in private company. McClellan:Orca Bio: Current Employment, Current equity holder in private company. Shaw:Orca Bio: Consultancy. McGuirk:Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Fresenius Biotech: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Allo Vir: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Pluristem Ltd: Research Funding. Abedi:BMS, Gilead Sciences: Research Funding; AbbVie, BMS, Gilead Sciences, Seattle Genetics, Takeda: Speakers Bureau. Negrin:Magenta Therapeutics: Consultancy, Current equity holder in publicly-traded company; KUUR Therapeutics: Consultancy; Biosource: Current equity holder in private company; UpToDate: Honoraria; Amgen: Consultancy; BioEclipse Therapeutics: Current equity holder in private company.

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Li, Hojun, Virginia Haurigot, Yannick Doyon, James Li, Anand Bhagwat, Sunnie Wong, Xavier Anguela, et al. "Phenotypic Correction of a Mouse Model of Hemophilia B by In Vivo Genetic Correction of the F9 Gene." Blood 116, no. 21 (November 19, 2010): LBA—5—LBA—5. http://dx.doi.org/10.1182/blood.v116.21.lba-5.lba-5.

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Abstract Abstract LBA-5 Inherited hematologic disorders have the potential to be effectively treated by gene therapy, with recent successes reported for several genetic disorders using viral vector-mediated gene transfer (ADA-SCID, NEJM 2009; β-thalassemia, Nature 2010). However, these trials and others illustrate some of the disadvantages and risks of using viral vector-based gene addition strategies, including loss of endogenous gene regulation and random insertion leading to potential for insertional mutagenesis. An alternative approach is gene correction, where in situ correction of a gene mutation allows endogenous gene regulation and decreases risks related to random integration. Gene correction is based on gene targeting, the therapeutic utility of which has historically been limited to mouse embryonic stem cells due to low homologous recombination rates in other cell types. However, a recently developed class of fusion proteins, zinc finger nucleases (ZFNs), have been shown to increase targeting efficiency 2–3 logs by inducing site-specific DNA double strand breaks at the intended targeting site. ZFNs have permitted high efficiency therapeutic gene targeting in a variety of cultured cells previously thought intractable to these processes, but ZFN-mediated gene correction has yet to be successfully achieved in vivo in an animal model of disease. Here we show ZFN-mediated therapeutic gene targeting of a mutated F9 gene in vivo, resulting in phenotypic correction of a mouse model of hemophilia B (HB). We first generated ZFNs targeting intron 1 of the human F9 gene (F9 ZFNs). We hypothesized the F9 ZFNs would mediate insertion of a wild-type F9 exons 2–8 minigene into intron 1 via gene targeting, thus bypassing the 95% of F9 mutations that occur in exons 2–8. We next generated a humanized HB mouse model with a deletion of the mouse F9 gene and knock-in (at the ROSA 26 locus) of a catalytic domain-deleted human F9 mini-gene (hF9mut) transgene. Adeno-associated viral (AAV) vector delivery of the F9 ZFNs to hF9mut mouse liver resulted in cleavage of the intron 1 target site in 45% of hepatocytes. We then generated an AAV donor vector containing a w.t. exons 2–8 insert flanked by arms of homology. Co-delivery of the AAV-ZFN and AAV-donor vectors to neonatal hF9mut mice (n=16) resulted in circulating F.IX levels of 120–350 ng/mL (2-7% of normal), whereas mice receiving AAV-ZFN alone (n=17) or AAV-mock & AAV-donor (n=15) had no detectable F.IX expression (detection limit 15 ng/mL), or <25 ng/mL F.IX, respectively. PCR analysis of liver DNA from ZFN+donor mice demonstrated genomic evidence of gene targeting at a rate of 2–7% of alleles. F.IX expression in ZFN+donor mice was shown to be stable after 5 months, with follow-up ongoing. In addition, there was no loss of expression following partial hepatectomy, which causes loss of expression from non-integrated episomes upon subsequent hepatocyte proliferation. F.IX expression was also shown to be specific, as opposed to resulting from random integration, as mice lacking the hF9mut gene averaged less than 30 ng/mL after receiving AAV-ZFN and AAV-donor. hF.IX RT-PCR on 10 different tissues confirmed liver-specific expression. To assess phenotypic correction, we performed aPTTs on mice that received ZFN+donor or mock+donor, as well as wild-type (WT) mice and HB mice. WT mice averaged 36 seconds, ZFN+donor mice averaged 44 seconds, mock+donor mice averaged 60 seconds, and HB mice averaged 67 seconds. There was no significant difference in aPTT between WT and ZFN+donor, or mock+donor and HB (p = 0.086 and 0.11, respectively). However, the aPTT for ZFN+donor mice was significantly shortened compared to mock+donor mice (p=0.0014), demonstrating phenotypic correction of the defect in clot formation in HB mice. To our knowledge this is the first demonstration of ZFN-driven gene correction in vivo, and the first demonstration of the in vivo use of ZFNs to correct an animal model of human disease. These results establish a novel paradigm for in vivo gene correction as a method for treating inherited hematologic diseases. Disclosures: Doyon: Sangamo Biosciences: Employment. Li:Sangamo Biosciences: Employment. Wong:Sangamo Biosciences: Employment. Paschon:Sangamo Biosciences: Employment. Rebar:Sangamo Biosciences: Employment. Gregory:Sangamo Biosciences: Employment. Holmes:Sangamo: Employment. High:Sangamo Biosciences: Consultancy; Children's Hospital of Philadelphia: Patents & Royalties.

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Sadowski, Jerzy, Tomasz Niźnikowski, Andrzej Mastalerz, Weronika Łuba-Arnista, and Michał Biegajło. "THE EFFECT OF SELF-CONTROLLED AND EXPERIMENTER-CONTROLLED FREQUENCY OF MODEL DEMONSTRATION ON LEARNING A COMPLEX GYMNASTIC ROUTINE." Acta kinesiologica, S1 2021 (2021). http://dx.doi.org/10.51371/issn.1840-2976.2021.15.s1.8.

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The purpose of the present study was to examine the effectiveness of learning a complex gymnastic routine with different frequencies of model demonstration controlled by the experimenter or self-controlled by learners. Fifty undergraduate physical education (PE) students were randomly assigned to 5 training groups: GF100 (100% frequency), GF20 (20% frequency), GFF (faded frequency), GSF (self-controlled frequency) and GYF (yoked group). All five groups followed the same experimental design, with one difference: groups GF100, GF20 and GFF observed model demonstration under externally controlled frequency, whereas group GSF self-controlled that condition. Participants were asked to perform a complex gymnastic routine (maximum vertical jump) with swinging the arms forwards and upwards, pulling the knees up to the chest while grabbing the shins followed by a half-squat landing with arms extended sidewards. During the acquisition phase, all the participants completed a total of 150 trials, with 15 trials completed in three blocks during each of the ten practice sessions. In the present study, we used expert ratings based on the FIG-COP to evaluate movement quality. For each trial, three gymnastic judges assessed the performance. To assess the differences between the five groups, a repeated measures ANOVA was conducted on the last factor for retention and transfer (Group x Test) and practice (Group x Practice). Partial eta squared (ηp2) effect sizes were calculated for multiple comparisons and Cohen’s d effect sizes were calculated for pairwise comparisons. Post-hoc Fisher’s LSD test was used for pairwise comparison. No significant Group x Test interaction or Group main effect was found, indicating that no group performed better than another in retention immediate, delayed and transfer tests. For each group, a significant improvement compared to baseline was observed in the retention and transfer tests (d > 0.8). The most important finding from the current study was that groups under self-controlled and experimenter-controlled frequency of model observing appeared similarly effective in learning a complex gymnastic routine. No significant differences were observed between the five groups in retention and transfer tests.

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Stamp, Elizabeth, Holly Schofield, Victoria Laurina Roberts, Wendy Burton, Michelle Collinson, June Stevens, Amanda Farrin, Harry Rutter, and Maria Bryant. "Contamination within trials of community-based public health interventions: lessons from the HENRY feasibility study." Pilot and Feasibility Studies 7, no. 1 (March 26, 2021). http://dx.doi.org/10.1186/s40814-021-00805-3.

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Abstract Introduction Contamination occurs when participants allocated to trial control arms receive elements of the active intervention. Randomisation at cluster level, rather than individual level, may reduce or eliminate contamination, avoiding the dilution of intervention effectiveness that it may cause. However, cluster randomisation can result in selection bias and may not be feasible to deliver. We explored the extent of contamination in a qualitative study nested within a feasibility study of HENRY (Health, Exercise and Nutrition for the Really Young); a UK community-based child obesity prevention programme. We aimed to determine the nature and impact of contamination to inform a larger planned trial and other trials in community based public health settings. Method We invited participants to take part in the nested qualitative study who were already involved in the HENRY feasibility study. Semi-structured interviews/focus groups were conducted with children’s centre managers (n=7), children’s centre staff (n=15), and parents (n=29). Data were transcribed and analysed using an integrative approach. First, deductively organised using a framework guided by the topic guide and then organised using inductive thematic analysis. Results Potential for contamination between treatment arms was recognised by all stakeholder groups. Staff within the intervention centres presented the greatest risk of contamination, predominantly because they were often asked to work in other children centre’s (including control group centres). ‘Sharing of best practice’ by staff was reported to be a common and desirable phenomenon within community based settings. Parental sharing of HENRY messages was reported inconsistently; though some parents indicated a high degree of knowledge transfer within their immediate circles. Conclusions The extent of contamination identified has influenced the design of a future effectiveness trial of HENRY which will be clustered at the centre level (with geographically distinct clusters). The common practice of knowledge sharing amongst community teams means that this clustering approach is also likely to be most suitable for other trials based within these settings. We provide recommendations (e.g. cluster randomisation, training intervention facilitators on implications of contamination) to help reduce the impact of contamination in public health intervention trials with or without clustering, whilst enabling transfer of knowledge where appropriate. Trial registration ClinicalTrials.gov Identifier NCT03333733 registered 6th November 2017

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Rychert, Marta, Machel Anthony Emanuel, and Chris Wilkins. "Foreign investment in emerging legal medicinal cannabis markets: the Jamaica case study." Globalization and Health 17, no. 1 (April 1, 2021). http://dx.doi.org/10.1186/s12992-021-00687-3.

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Abstract Introduction The establishment of a legal market for medicinal cannabis under the Dangerous Drugs Amendment Act 2015 has positioned Jamaica at the forefront of cannabis law reform in the developing world. Many local cannabis businesses have attracted investment from overseas, including from Canada, US and Europe. Aim To explore the opportunities and risks of foreign investment in an emerging domestic legal cannabis market in a developing country. Methods Thematic analysis of semi-structured face-to-face interviews with 22 key informants (KIs) from the Jamaican government, local cannabis industry, academia and civil society, and field observations of legal and illegal cannabis cultivators. Results KIs from the Jamaican public agencies and domestic cannabis entrepreneurs saw foreign investment as an essential source of capital to finance the start-up costs of legal cannabis businesses. Local cannabis entrepreneurs prioritised investors with the greatest financial resources, brand reputation and export networks. They also considered how allied an investor was with their business vision (e.g., organic cultivation, medical vs. recreational). The key benefits of partnering with a foreign investor included transfer of technical knowledge and financial capital, which enhanced production, quality assurance and seed-to-sale tracking. Some KIs expressed concern over investors’ focus on increasing production efficiency and scale at the expense of funding research and development (R&D) and clinical trials. KIs from the local industry, government agencies and civil society highlighted the risks of ‘predatory’ shareholder agreements and domestic political interference. Concerns were raised about the impact of foreign investment on the diversity of the domestic cannabis sector in Jamaica, including the commitment to transition traditional illegal small-scale cannabis cultivators to the legal sector. Conclusion While foreign investment has facilitated the commercialisation of the cannabis sector in Jamaica, regulatory measures are also needed to protect the domestic industry and support the transition of small-scale illegal cultivators to the legal regime. Foreign investments may alter the economic, social and political determinants of health in transitioning from illegal to legal cannabis market economy.

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Dey, Amrita. "Changing Face of Sea Piracy in the Eastern Indian Ocean Region: Examining India’s Role in Maritime Cooperation." Journal of International Studies, January 6, 2020. http://dx.doi.org/10.32890/jis.6.2010.7908.

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There is hardly any dispute that the Eastern Indian Ocean like its historical past is once again emerging into a ‘cosmopolitan’ maritime arena underpinned by long stretches of peaceful exchange of commodities, energy and other maritime accessories. It has witnessed a new constellation of ‘inward-looking’ regional powers with a ‘bazaar nexus’ (for mercantile goods and energy supply) with Asian and non-Asian powers. Economically, small and middle powers of this region do share and accommodate all to draw the benefits of a highly globalised ‘closely-knit’ mercantile system. Problems relating to trade hazards—‘maritime mugging,’ ‘sea piracy,’ ‘illegal transfer of arms and ammunition, maritime terrorism, has already been addressed adequately by the collective effort of member nations under the aegis of ASEAN. This goodwill effort in the maritime zone awaits response from the cultural domain as well, which still lacks its frequency and luster of the glorious past. Although loads have been talked about, there has been little in action. The present paper is an attempt to study the community building efforts of ASEAN in connivance with emerging powers like India and China; and efforts at building up an Indian Ocean community as it existed in its past—sans feuds, sans fight—but unhindered exchange of culture and trade

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Ziaei, Ava, Parivash Davoodian, Habib Dadvand, Omid Safa, Soheil Hassanipour, Mahmoud Omidi, Moein Masjedi, Fahime Mahmoudikia, Bahareh Rafiee, and Mohammad Fathalipour. "Evaluation of the efficacy and safety of Melatonin in moderately ill patients with COVID-19: A structured summary of a study protocol for a randomized controlled trial." Trials 21, no. 1 (October 26, 2020). http://dx.doi.org/10.1186/s13063-020-04737-w.

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Abstract Objectives We will evaluate the efficacy and safety of Melatonin, compared to the standard therapeutic regimen on clinical symptoms and serum inflammatory parameters in patients with confirmed COVID-19, who are moderately ill. Trial design This is a single-center, randomized, double-blind, placebo-controlled clinical trial with a parallel-group design conducted at Shahid Mohammadi Hospital, Bandar Abbas, Iran. Participants All patients admitted to Severe Acute Respiratory Syndrome Departments of Shahid Mohammadi Hospital, Bandar Abbas, Iran will be screened for the following criteria. Inclusion criteria: 1. Age ≥20 years 2. Confirmed SARS-CoV-2 diagnosis (positive polymerase chain reaction). 3. Moderate COVID-19 pneumonia (via computed tomography and or X-ray imaging), requiring hospitalization. 4. Hospitalized ≤48 hours. 5. Signing informed consent and willingness of the participant to accept randomization to any assigned treatment arm. Exclusion criteria: 1. Underlying diseases, including chronic hypertension, diabetes mellitus, seizure, depression, chronic hepatitis, cirrhosis, and cholestatic liver diseases. 2. Severe and critical COVID-19 pneumonia. 3. Use of warfarin, corticosteroids, hormonal drugs, alcohol, other antiviral and investigational medicines, and illegal drugs (during the last 30 days). 4. History of known allergy to Melatonin. 5. Pregnancy and breastfeeding. Intervention and comparator Intervention group: The standard treatment regimen for COVID-19, according to the Iranian Ministry of Health and Medical Education's protocol, along with Melatonin capsules at a dose of 50 mg daily for a period of seven days. Control group: The standard therapeutic regimen for COVID-19 along with Melatonin-like placebo capsules at a dose of one capsule daily for a period of seven days. Both Melatonin and placebo capsules were prepared at the Faculty of Pharmacy and Pharmaceutical Sciences, Hormozgan University of Medical Sciences, Bandar Abbas, Iran. Main outcomes The primary outcomes are the recovery rate of clinical symptoms and oxygen saturation as well as improvement of serum inflammatory parameters, including C-reactive protein, tumor necrosis factor-alpha (TNF-ɑ), interleukin-1β (IL-1β), and IL-6 within seven days of randomization. The secondary outcomes are the time to improve clinical and paraclinical features along with the incidence of serious adverse drug reactions within seven days of randomization. Randomization Included patients will be allocated to one of the study arms using block randomization in a 1:1 ratio (each block consists of 10 patients). This randomization method ensures a balanced allocation between the arms during the study. A web-based system will generate random numbers for the allocation sequence and concealment of participants. Each number relates to one of the study arms. Blinding (masking) All study participants, clinicians, nurses, research coordinators, and those analyzing the data are blinded to the group assignment. Numbers to be randomized (sample size) A total of 60 patients randomized into two groups (30 in each group). Trial Status The trial protocol is Version 1.0, August 14, 2020. Recruitment began August 22, 2020, and is anticipated to be completed by November 30, 2020. Trial registration The trial protocol has been registered in the Iranian Registry of Clinical Trials (IRCT). The registration number is “IRCT20200506047323N5”. The registration date was 14 August 2020. Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting the dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

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Sato, Shigeru, Riku Yoshida, Ryosuke Kiyono, Kaoru Yahata, Koki Yasaka, Kazunori Nosaka, and Masatoshi Nakamura. "Cross-education and detraining effects of eccentric vs. concentric resistance training of the elbow flexors." BMC Sports Science, Medicine and Rehabilitation 13, no. 1 (September 6, 2021). http://dx.doi.org/10.1186/s13102-021-00298-w.

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Abstract Background Unilateral resistance training increases the strength of the contralateral non-trained homologous muscles known as the cross-education effect. We tested the hypothesis that unilateral eccentric resistance training (ET) would induce greater and longer-lasting cross-education effect when compared with concentric resistance training (CT). Methods Young (20–23 y) participants were allocated to ET (5 males, 4 females) or CT (5 males, 4 females) group that performed unilateral progressive ET or CT of the elbow flexors, twice a week for 5 weeks (10 sessions) followed by a 5-week detraining, and control group (7 males, 6 females) that did not perform any training. Maximum voluntary isometric contraction torque of the elbow flexors (MVIC), one-repetition maximum of concentric dumbbell curl (1-RM), and biceps brachii and brachialis muscle thickness (MT) were measured from the trained and non-trained arms before, several days after the last training session, and 5 weeks later. A ratio between the trained and non-trained arms for the change in MVIC or 1-RM from pre- to post-training (cross-body transfer ratio) was compared between ET and CT groups. Results The control group did not show significant changes in any variables. Both ET and CT increased (P < 0.05) MVIC (22.5 ± 12.3 % vs. 26.0 ± 11.9 %) and 1-RM (28.8 ± 6.6 % vs. 35.4 ± 12.9 %) of the trained arm without a significant difference between groups. MVIC was maintained after detraining for ET but returned to the baseline for CT, and 1-RM was maintained after detraining for both ET and CT. For the non-trained arm, MVIC (22.7 ± 17.9 % vs. 12.2 ± 10.2 %) and 1-RM (19.9 ± 14.6 % vs. 24.0 ± 10.6 %) increased similarly (P > 0.05) after ET and CT, and MVIC returned to the baseline after detraining, but 1-RM was maintained for both groups. An increase (P < 0.05) in MT was found only after ET for the trained arm (7.1 ± 6.1 %). The cross-body transfer ratio for MVIC was greater (P < 0.05) for ET (90.9 ± 46.7 %) than CT (49.0 ± 30.0 %). Conclusions These results did not support the hypothesis and showed similar changes in the most of the variables between ET and CT for the trained and non-trained arms, and strong cross-education effects on MVIC and 1-RM, but less detraining effect after ET than CT on MVIC of the trained arm. Trial registration University Hospital Medical Information Network Clinical Trials Registry (UMIN000044477; Jun 09, 2021).

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Packel, Laura, Carolyn Fahey, Atuganile Kalinjila, Agatha Mnyippembe, Prosper Njau, and Sandra I. McCoy. "Preparing a financial incentive program to improve retention in HIV care and viral suppression for scale: using an implementation science framework to evaluate an mHealth system in Tanzania." Implementation Science Communications 2, no. 1 (September 23, 2021). http://dx.doi.org/10.1186/s43058-021-00214-w.

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Abstract Background Viral suppression is key to ending the HIV epidemic, yet only 58% of people living with HIV (PLHIV) in sub-Saharan Africa are suppressed. Cash transfers are an effective strategy to improve retention in care, but little is known about optimization of implementation; for example, designing effective programs that integrate into existing clinic workflows. We studied implementation of an mHealth system to deliver cash transfers to support retention. Methods We conducted a mixed-methods study assessing implementation of an mHealth cash transfer study. This was part of a larger, hybrid implementation-effectiveness randomized controlled trial evaluating cash transfers conditional on visit attendance for viral suppression among Tanzanian PLHIV initiating ART. An mHealth system using fingerprint identification and mobile payments was used to automatically disburse mobile money to eligible PLHIV. We used Proctor’s framework, assessing implementation of the mHealth system from the perspectives of PLHIV and clinicians. We analyzed mHealth system data and conducted surveys (n = 530) and in-depth interviews (n = 25) with PLHIV, clinic and pharmacy staff (n = 10), and structured clinic observations (n = 2293 visits). Results One thousand six hundred fifty-one cash transfers were delivered to 346 PLHIV in the cash arms, 78% through mobile money. Among those in the cash arms, 81% registered their mobile money account with the mHealth system by study end, signaling high adoption. While acceptability for fingerprinting and mobile payments was high among PLHIV, interviews revealed mixed views: some had privacy concerns while others felt the system was secure and accurate, and provided some legitimacy to the clinical visits. Pharmacists praised system efficiency, but concerns about duplicative recordkeeping and added work arose. Clinic staff voiced excitement for the system’s potential to bring the cash program to all patients and simplify workflows; yet concerns about multiple systems, staffing, and intermittent connectivity tempered enthusiasm, highlighting structural issues beyond program scope. Structured observations revealed a steep learning curve; repeat fingerprint scans and manual entry declined as the system improved. Conclusions Biometric identification and mobile payments were acceptable to most patients and staff. Fingerprinting encountered some feasibility limitations in the first months of testing; however, mobile payments were highly successful. Biometric identification and mobile payments may provide a scalable mechanism to improve patient tracking and efficiently implement financial incentives in low-resource settings. Trial registration Name of the registry: clinicaltrials.gov Trial registration number: NCT03351556 Date of registration: 11/24/2017 Checklists: StaRI (included with submission). Note CONSORT for cluster-randomized trials was used for the main trial but is not directly applicable to this manuscript.

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Huda, Tanvir M., Ashraful Alam, Tazeen Tahsina, Mohammad Mehedi Hasan, Afrin Iqbal, Jasmin Khan, Gulshan Ara, et al. "Shonjibon cash and counselling: a community-based cluster randomised controlled trial to measure the effectiveness of unconditional cash transfers and mobile behaviour change communications to reduce child undernutrition in rural Bangladesh." BMC Public Health 20, no. 1 (November 25, 2020). http://dx.doi.org/10.1186/s12889-020-09780-5.

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Abstract Background Undernutrition is strongly associated with poverty - levels of undernutrition are higher in poor countries than in better-off countries. Social protection especially cash transfer is increasingly recognized as an important strategy to accelerate progress in improving maternal and child nutrition. A critical method to improve nutrition knowledge and influence feeding practices is through behaviour change communication intervention. The Shonjibon Cash and Counselling study aims to assess the effectiveness of unconditional cash transfers combined with a mobile application on nutrition counselling and direct counselling through mobile phone in reducing the prevalence of stunting in children at 18 months. Method The study is a longitudinal cluster randomised controlled trial, with two parallel groups, and cluster assignment by groups of villages. The cohort of mother-child dyads will be followed-up over the intervention period of approximately 24 months, starting from recruitment to 18 months of the child’s age. The study will take place in north-central Bangladesh. The primary trial outcome will be the percentage of stunted children at 18 m as measured in follow up assessments starting from birth. The secondary trial outcomes will include differences between treatment arms in (1) Mean birthweight, percentage with low birthweight and small for gestational age (2) Mean child length-for age, weight for age and weight-for-length Z scores (3) Prevalence of child wasting (4) Percentage of women exclusively breastfeeding and mean duration of exclusive breastfeeding (5) Percentage of children consuming > 4 food groups (6) Mean child intake of energy, protein, carbohydrate, fat and micronutrients (7) Percentage of women at risk of inadequate nutrient intakes in all three trimesters (8) Maternal weight gain (9) Household food security (10) Number of events for child suffering from diarrhoea, acute respiratory illness and fever (11) Average costs of mobile phone BCC and cash transfer, and benefit-cost ratio for primary and secondary outcomes. Discussion The proposed trial will provide high-level evidence of the efficacy and cost-effectiveness of mobile phone nutrition behavior change communication, combined with unconditional cash transfers in reducing child undernutrition in rural Bangladesh. Trial registration The study has been registered in the Australian New Zealand Clinical Trials Registry (ACTRN12618001975280).

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Rosa, Mário Fabrício Fleury, Everton Nunes da Silva, Christina Pacheco, Marcos Vinícius Pereira Diógenes, Christopher Millett, Carlos Augusto Grabois Gadelha, and Leonor Maria Pacheco Santos. "Direct from the COVID-19 crisis: research and innovation sparks in Brazil." Health Research Policy and Systems 19, no. 1 (January 21, 2021). http://dx.doi.org/10.1186/s12961-020-00674-x.

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Abstract Background The coronavirus disease 2019 (COVID-19) pandemic has spread throughout more than 160 countries, infecting millions of people worldwide. To address this health emergency, countries have organized the flow of production and innovation to reduce the impact on health. This article shows the response of the Brazilian scientific community to meet the urgent needs of the public unified health system [SUS], aiming to guarantee universal access to an estimated population of 211 million. By December 2020, Brazil had recorded more than six million cases and approximately 175,000 deaths. Methods We collected data on research, development and innovation projects carried out by 114 public universities (plus Oswaldo Cruz Foundation [Fiocruz] and Butantan Institute), as reported on their websites. Additionally, we examined the studies on COVID-19 approved by the National Comission for Research Ethics, as well as those reported on the Ministry of Education website as of May 15, 2020. Results The 789 identified projects were classified according to research categories as follows: development and innovation (n = 280), other types of projects (n = 226), epidemiologic research (n = 211), and basic research on disease mechanisms (n = 72). Most proposals focused on the development and innovation of personal protective equipment, medical devices, diagnostic tests, medicines and vaccines, which were rapidly identified as research priorities by the scientific community. Some promising results have been observed from phase III vaccine trials, one of which is conducted in partnership with Oxford University and another of which is performed with Sinovac Biotech. Both trials involve thousands of volunteers in their Brazilian arms and include technology transfer agreements with Fiocruz and the Butantan Institute, respectively. These vaccines proved to be safe and effective and were immediately licensed for emergency use. The provision of doses for the public health system, and vaccination, started on January 17, 2021. Conclusions The mobilized Brazilian scientific community has generated comprehensive research, development and innovation proposals to meet the most urgent needs. It is important to emphasize that this response was only possible due to decades of investment in research, development and innovation in Brazil. We need to reinforce and protect the Brazilian science, technology and innovation system from austerity policies that disregard health and knowledge as crucial investments for Brazilian society, in line with the constitutional right of universal health access and universal health coverage.

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Dushianthan, Ahilanandan, Howard Clark, Jens Madsen, Robin Mogg, Lewis Matthews, Lee Berry, Jorge Bernardino de la Serna, et al. "Nebulised surfactant for the treatment of severe COVID-19 in adults (COV-Surf): A structured summary of a study protocol for a randomized controlled trial." Trials 21, no. 1 (December 2020). http://dx.doi.org/10.1186/s13063-020-04944-5.

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Abstract Objectives SARS-Cov-2 virus preferentially binds to the Angiotensin Converting Enzyme 2 (ACE2) on alveolar epithelial type II cells, initiating an inflammatory response and tissue damage which may impair surfactant synthesis contributing to alveolar collapse, worsening hypoxia and leading to respiratory failure. The objective of this study is to evaluate the feasibility, safety and efficacy of nebulised surfactant in COVID-19 adult patients requiring mechanical ventilation for respiratory failure. Trial design This study is a dose-escalating randomized open-label clinical trial of 20 COVID-19 patients. Participants This study is conducted in two centres: University Hospital Southampton and University College London Hospitals. Eligible participants are aged ≥18, hospitalised with COVID-19 (confirmed by PCR), who require endotracheal intubation and are enrolled within 24 hours of mechanical ventilation. For patients unable to consent, assent is obtained from a personal legal representative (PerLR) or professional legal representative (ProfLR) prior to enrolment. The following are exclusion criteria: imminent expected death within 24 hours; specific contraindications to surfactant administration (e.g. known allergy, pneumothorax, pulmonary hemorrhage); known or suspected pregnancy; stage 4 chronic kidney disease or requiring dialysis (i.e., eGFR < 30); liver failure (Child-Pugh Class C); anticipated transfer to another hospital, which is not a study site, within 72 hours; current or recent (within 1 month) participation in another study that, in the opinion of the investigator, would prevent enrollment for safety reasons; and declined consent or assent. Intervention and comparator Intervention: The study is based on an investigational drug/device combination product. The surfactant product is Bovactant (Alveofact®), a natural animal derived (bovine) lung surfactant formulated as a lyophilized powder in 108 mg vials and reconstituted to 45 mg/mL in buffer supplied in a prefilled syringe. It is isolated by lung lavage and, by weight, is a mixture of: phospholipid (75% phosphatidylcholine, 13% phosphatidylglycerol, 3% phosphatidylethanolamine, 1% phosphatidylinositol and 1% sphingomyelin), 5% cholesterol, 1% lipid-soluble surfactant-associated proteins (SP-B and SP-C), very low levels of free fatty acid, lyso-phosphatidylcholine, water and 0.3% calcium. The Drug Delivery Device is the AeroFact-COVID™ nebulizer, an investigational device based on the Aerogen® Solo vibrating mesh nebulizer. The timing and escalation dosing plans for the surfactant are as follows. Cohort 1: Three patients will receive 10 vials (1080 mg) each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 2: Three patients will receive 10 vials (1080 mg) of surfactant at dosing times of 0 hours and 8 hours, and 30 vials (3240 mg) at a dosing time of 24 hours. 2 controls with no placebo intervention. Cohort 3: Three patients will receive 10 vials (1080 mg) of surfactant at a dosing time of 0 hours, and 30 vials (3240 mg) at dosing times of 8 hours and 24 hours. 2 controls with no placebo intervention. Cohort 4: Three patients will receive 30 (3240 mg) vials each of surfactant at dosing times of 0 hours, 8 hours and 24 hours. 2 controls. 2 controls with no placebo intervention. The trial steering committee, advised by the data monitoring committee, will review trial progression and dose escalation/maintenance/reduction after each cohort is completed (48-hour primary outcome timepoint reached) based on available feasibility, adverse event, safety and efficacy data. The trial will not be discontinued on the basis of lack of efficacy. The trial may be stopped early on the basis of safety or feasibility concerns. Comparator: No placebo intervention. All participants will receive usual standard of care in accordance with the local policies for mechanically ventilated patients and all other treatments will be left to the discretion of the attending physician. Main outcomes The co-primary outcome is the improvement in oxygenation (PaO2/FiO2 ratio) and pulmonary ventilation (Ventilation Index (VI), where VI = [RR x (PIP − PEEP) × PaCO2]/1000) at 48 hours after study initiation. The secondary outcomes include frequency and severity of adverse events (AEs), Adverse Device Effects (ADEs), Serious Adverse Events (SAEs) and Serious Adverse Device Events (SADEs), change in pulmonary compliance, change in positive end-expiratory pressure (PEEP) requirement of ventilatory support at 24 and 48 hours after study initiation, clinical improvement defined by time to one improvement point on the ordinal scale described in the WHO master protocol (2020) recorded while hospitalised, days of mechanical ventilation, mechanical ventilator free days (VFD) at day 21, length of intensive care unit stay, number of days hospitalised and mortality at day 28. Exploratory end points will include quantification of SARS-CoV-2 viral load from tracheal aspirates using PCR, surfactant dynamics (synthesis and turnover) and function (surface tension reduction) from deep tracheal aspirate samples (DTAS), surfactant phospholipid concentrations in plasma and DTAS, inflammatory markers (cellular and cytokine) in plasma and DTAS, and blood oxidative stress markers. Randomisation After informed assent, patients fulfilling inclusion criteria will be randomised to 3:2 for the treatment and control arms using an internet-based block randomization service (ALEA tool for clinical trials, FormsVision BV) in combination with electronic data collection. Randomisation will be done by the recruiting centre with a unique subject identifier specific to that centre. Blinding (masking) This is an open-labelled unblinded study. Numbers to be randomised (sample size) The total sample size is 20 COVID-19 mechanically ventilated patients (12 intervention; 8 control). Trial Status Current protocol version is V2 dated 5th of June 2020. The recruitment is currently ongoing and started on the 14th of October 2020. The anticipated study completion date is November 2021. Trial registration ClinicalTrials.gov: NCT04362059 (Registered 24 April 2020), EUDAMED number: CIV-GB-20-06-033328, EudraCT number: 2020-001886-35 (Registered 11 May 2020) Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

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