Academic literature on the topic 'GARG-39'

ABSTRACT The evolution of orthopedic implants has witnessed a great evolution and allowed insights into the various metals and alloys compatible with the human body. However, some recent reports have raised concerns regarding hypersensitivity to several metals used in orthopedic implants. These cases are mostly documented in the field of arthroplasty. Metal ion release following hip or knee arthroplasty is a known phenomenon and associated immune reactions to these metal ions have been implicated in the causation of these hypersensitivity reactions. These reactions frequently lead to poor outcome following these implant surgeries. We here present two rare cases of metal induced hypersensitivity reactions following orthopedic surgeries. We have also reviewed the literature in this context to look into the various causes of metal reactions, types of implant involved in hypersensitivity, methods of testing and management options in these cases. How to cite this article Kanojia R, Kumar V, Garg B, Dhillon MS. Implant-related Metal Hypersensitivity—A Cause for Concern: A Report of Two Cases and Literature Review. J Postgrad Med Edu Res 2014;48(1):37-39.

ABSTRACT Introduction Eclampsia is one of the leading causes of maternal mortality. Magnesium sulfate (MgSO4) can be a drug for its management. Objectives To study the safety and efficacy of low-dose MgSO4 for control of convulsions in case of eclampsia and to compare it with Pritchard regimen in terms of its effects and perinatal outcome. Materials and methods This study was conducted in Department of Obstetrics and Gynecology. It was a prospective study and included 78 cases of eclampsia. Thirty-nine cases were given low-dose regime and remaining 39 were given Pritchard regimen. Low-dose regime for eclampsia: Loading dose 4 gm MgSO4 IV diluted in 20 cc of 5% dextrose, slowly over 5 to 8 minutes. Maintenance dose 2 gm IV similarly diluted was given 3 hourly till 24 hours after delivery or after convulsion which ever was later. If recurrence of convulsions occurs, then additional dose 2 gm IV was given and previous dose schedule continued as such. Results Eclamptic convulsions were controlled in 94.87% of cases with low-dose regime, and in the remaining cases were controlled with additional 2 gm IV dose MgSO4 compared to 37.14% with Pritchard regimen. Conclusion Low-dose magnesium regime is highly suitable for women in our setup, and it is as effective as Pritchard regimen for controlling convulsions in eclampsia along with better perinatal outcome and with less MgSO4 toxicity. How to cite this article Garg R, Agrawal N, Kumari SS, Agrawal P. Low-dose Magnesium Sulfate Regime for Eclampsia in India. J South Asian Feder Obst Gynae 2017;9(1):5-8.

ABSTRACT Objectives (1) To investigate the association between term elective cesarean sections and neonatal respiratory morbidity and the importance of timing of the cesarean. (2) To assess the maternal morbidity when emergency lower segment cesarean section (LSCS) was required. Participants All women with singleton term (37—41 + 6 weeks) pregnancies and planned for elective cesarean section in Christian Medical College, Vellore, India. Outcome measures The primary outcome measures were neonatal morbidities such as transient tachypnea of newborn (TTN) and respiratory distress syndrome (RDS). The secondary outcome measures were emergency cesarean section and maternal morbidities such as scar dehiscence, urinary tract infection (UTI), endometritis, peritonitis, and hemoperitoneum in the mother. Results The percentage of TTN in the infants in group I was 1.3% while there were none in group II. No infants were diagnosed to have RDS. Out of the 150 women who were planned for elective cesarean section, 55 women underwent emergency cesarean section. Among this, 19 (25.3%) of women were from group I as compared with 36 (48.0%) in group II. The difference in proportion between the two groups was –22.7 [95% confidence interval (CI): –37.7, –7.7], which was statistically significant (p < 0.01). The incidence of scar dehiscence, UTI, endometritis, and hemoperitoneum in the mothers of group II was marginally higher than that in the mothers of group I. There was one woman with peritonitis in group I while none was reported in the other group. All the maternal morbidities occurred to women who underwent emergency cesarean section. Out of the 19 women in group I and 36 women in group II who underwent emergency cesarean section, 1 (5.3%) and 6 (16.7%) women had morbidities. Conclusion Women requiring elective cesarean section can safely be done between 37 and 39 weeks with no further significant increase in the rates of neonatal morbidity such as TTN and RDS. How to cite this article Roy P, Jeyaseelan L, Ruby J, Garg R. Respiratory Morbidity in Term Infants delivered by Elective Cesarean Section at a Tertiary Care Hospital in India: A Randomized Controlled Trial. J South Asian Feder Obst Gynae 2017;9(4):312-317.

Background:Infectious diseases are increased in patients with rheumatic disorders; vaccination improves morbidity and mortalityObjectives:The aim of this study was to describe the frequency of vaccination in patients with rheumatic disorders and to compare the results with those obtained in 2009 and 2013 in a similar population. We also identified factors leading to lack of vaccination and patients beliefs on vaccines.Methods:Multicentric cross sectional study in patients with autoinmune diseases from external rheumatology offices. Evaluation of vaccination status and patients´ knowledge about vaccines were studied. A comparative analysis was carried out with the series registered in 2009 and 2013 in a similar population.Results:179 patients (158 female, 88.3% and 21 male, 11.7%) were evaluated. Median age was 52 years. Main pathologies were: Rheumatoid Arthritis 65.9% (n:118), Systemic Lupus Erythematosus 11.7% (n:21), Systemic Sclerosis 3.9% (7), Sjogren Syndrome n = 3.4% (n:6), other diseases 15% (n: 27). Median disease duration: 8.87 years. Ninety three percent of patients (n:167) were taking inmunomodulators and 36.8% (n: 66) were using oral corticosteroids (20mg/day or less); 26,8% patients (n: 48) were receiving biological therapies. Vaccination frequency in the population was: Influenza 82% (147); 13-valent conjugate pneumococcal 69.3% (124), 23-valent pneumococcal 64.2% (115) and hepatitis B 62% (111). Comparative with 2009 and 2013 series there was an increase in the rate of vaccinated patients: influenza (82% vs. 39,1% and 74,2% respectively), antineumococcal (64% vs. 17% and 29%) and hepatitis B (62% vs. 6,7% and 26,7%).Reasons for non-vaccination were absence of medical indication (41% of patients for hepatitis B; 32% for 23-valent pneumococcal; 38% for 13-valent pneumococcal and 34% for influenza).139 patients (77, 7%) knew the benefits of vaccines, 164 (91, 6%) thought vaccines are useful; 134 (74,9%) reported that vaccines may decrease dying probability, 155 (86,5%) thought that vaccines are effective to prevent diseases and 149 patients (83,2%) believed that they prevent serious infections. 71 patients (39%) believed that vaccines can lead to serious consequences and 99 (55,3%) that they are more likely to acquire infections than the rest of the population.Conclusion:Frequency of vaccination has increased since 2009 but there is still misinformation regarding vaccines risks and benefits. Promotion and information is essential to improve adherence.References:[1]2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases. Furer V, et al. Ann Rheum Dis 2020;79:39–52[2] Vaccines and Disease-Modifying Antirheumatic Drugs: Practical Implications for the Rheumatologist. Friedman MA et al. Rheum Dis Clin North Am. 2017 Feb; 43 (1):1-13.[3] Recommendations and barriers to vaccination in systemic lupus erythematosus. Garg M et al. Autoimmun Rev. 2018 Oct; 17 (10):990-1001.[4] Comparison of national clinical practice guidelines and recommendations on vaccination of adult patients with autoimmune rheumatic diseases. Papadopoulou D. et al. Rheumatol Int. 2014 Feb;34 (2):151-63.[5] Guías de recomendaciones de prevención de infecciones en pacientes que reciben modificadores de la respuesta biológica. Jordán R. Et al. Rev Arg Reumatol. 2014; 25 (2): 08-26.Disclosure of Interests:Malena Viola: None declared, Alejandro Benitez: None declared, Cecilia Garbarino: None declared, Gonzalo Rodriguez: None declared, Federico Benavidez: None declared, Claudia Peon: None declared, Eliana Soledad Blanco: None declared, Hernan Molina: None declared, Gimena Gómez: None declared, griselda redondo: None declared, Maria DeLaVega: None declared, Dario Mata: None declared, Augusto Riopedre: None declared, Osvaldo Messina Speakers bureau: Amgen; Americas Health Foundation; Pfizer

Background:Patients with rheumatoid arthritis (RA) have a higher risk of developing a cardiovascular (CV) event than the general population, due to an accelerated process of atherosclerosis (1), which has been documented to begin in early stages of the disease and is directly associated with systemic inflammation (2).Objectives:The aim of this study was to compare the prevalence of subclinical atherosclerosis detected by carotid ultrasound (US) in patients with RA in the first five years of diagnosis and healthy controls.Methods:This was a cross-sectional, observational, and comparative study. A total of 53 patients aged 40-75 years old, with RA diagnosis, in the previous five years, according to the 2010 ACR/EULAR classification criteria, and 53 controls matched by age (±5 years), gender and comorbidities were included in this study. Subjects with a previous CV event, such as myocardial infarction, cerebrovascular event and peripheral arterial disease, another connective tissue disease and pregnant women were excluded from this study. A high-resolution B-mode carotid US was performed in all study subjects. Subclinical atherosclerosis was evaluated as the presence of carotid plaque (CP) or an increased carotid intima media thickness (cIMT). CP was defined as a cIMT ≥1.2mm or a focal narrowing ≥0.5mm of the surrounding lumen, and an increased cIMT was defined as a value ≥0.8mm. Distribution was evaluated with the Kolmogorov-Smirnov test. Comparisons were done with χ2 test and Fisher’s exact test for qualitative variables, and Student’s t test and Mann-Whitney’s U test for quantitative variables. A p-value <0.05 was considered statistically significant.Results:Comparisons of demographic characteristics showed no differences between the RA group and the control group (Table 1). When comparing carotid US findings there was a difference in the presence of CP, being more prevalent in RA patients (26.4% vs 11.3%, p=0.047), in the presence of an increased cIMT, being more prevalent in RA patients (34.0% vs 3.8%, p=<0.001), in the cIMT as a quantitative variable, being higher in RA patients (0.70mm vs 0.59mm, p=<0.001 in the right carotid artery, and 0.75mm vs 0.60mm, p=0.001 in the left carotid artery), and in the presence of subclinical atherosclerosis overall, being more prevalent in RA patients (52.8% vs 18.9%, p=<0.001) (Figure 1).Table 1.Demographic and clinical characteristicsRAControlsp(n=53)(n=53)Age years, mean ± SD54.48 ± 9.0954.86 ± 6.83NSWomen, n (%)49 (92.5)49 (92.5)NST2DM, n (%)8 (15.1)7 (13.2)NSHTN, n (%)17 (32.1)17 (32.1)NSDyslipidemia, n (%)19 (35.8)19 (35.8)NSObesity, n (%)21 (39.6)20 (37.7)NSActive smoking, n (%)3 (5.7)4 (7.5)NSBMI kg/m2, median (p25-p75)28.78 (25.92-33.21)27.59 (24.55-33.34)NSDisease duration, mean ± SD2.48 ± 1.31--DAS28-CRP, median (p25-p75)3.21 (1.89-4.12)--MTX, n (%)39 (73.6)--Glucocorticoids, n (%)29 (54.7)--Conclusion:Patients with RA in the first five years of diagnosis have a higher prevalence of subclinical atherosclerosis than the general population. CV evaluation including a carotid US should be done at the time of diagnosis of RA patients, and subsequently it must be individualized according to the CV risk of each patient, with a maximum of five years to identify those patients who would benefit from an opportune treatment.References:[1]Geraldino-Pardilla L, Russo C, Sokolove J, et al. Association of anti-citrullinated protein or peptide antibodies with left ventricular structure and function in rheumatoid arthritis. Rheumatology (Oxford) 2017;56(4):534-40. doi: 10.1093/rheumatology/kew436[2]Ahmad S, Garg S, Dhar M, et al. Predictors of atherosclerosis in rheumatoid arthritis. Vasa 2012;41(5):353-9. doi: 10.1024/0301-1526/a000221Disclosure of Interests:None declared

BackgroundObesity and sarcopenia have been associated with higher disease activity, poor response to disease modifying agents and lower remission achievement in rheumatoid arthritis (RA) patients [1, 2]. Weight loss has been associated with increased chances of remission [1]. The prevalence of obesity in the Asian population is 64% but the relationship between fat distribution and disease activity is not explored in the Indian population [3].ObjectivesTo describe fat mass, lean mass, fat mass index, lean mass index, fat mass percentage, fat-to-lean mass ratio, android-gynoid ratio and trunk-leg fat ratio measured using dual energy x-ray absorptiometry (DEXA) in patients with rheumatoid arthritis and assess their relationship with DAS28, patient global assessment of disease activity (PtGA), and Indian health assessment questionnaire (IHAQ) disability index.MethodsA hospital based cross-sectional study was initiated after Ethics Committee approval in patients with RA at our rheumatology clinic from March 2022 onwards, at Jodhpur, India. Demographic, clinical, anthropometric and treatment details of the patients were collected after informed written consent. Whole body DEXA was done using a DEXA scanner Hologic Corp, model no - Horizon A S/N 303237M). Correlation of fat mass, lean mass, fat mass index, lean mass index, fat mass percentage, fat-to-lean mass ratio, android-gynoid ratio and trunk-leg fat ratio with DAS28, PtGA, and IHAQ was determined using Spearman correlation. Multivariable logistic regression was done to see if fat distribution indices could predict disease activity and IHAQ disability index. This is an ongoing study, with a calculated sample size of 104.ResultsSixty patients have been enrolled so far with a mean age of 46 ± 11 years, 78.3% were females. Mean body mass index was 23.7 ± 5.1 kg/m2and 51.7% (n = 31) patients were overweight. Mean waist-hip ratio was 0.88 ± 0.07 among females and 0.98 ± 0.08 among males. The mean fat mass percentage, lean mass index, fat lean mass index, android-gynoid ratio and fat trunk-leg ratio were 39.87 ± 6.13%, 14.46 ± 2.31 kg/m2, 67.19 ± 19.26, 0.92 ± 0.14 and 0.81 ± 0.12 respectively. The median fat mass, lean mass and fat mass index in the study population were 22.98 ± 10.42 kg, 33.53 ± 10.42 kg and 10.05 ± 4.19 kg/m2respectively (Table 1). The fat mass percentage had significant correlation with previous history of steroid use for more than 21 days (r = 0.347, p = 0.008). None of the fat distribution indices evaluated could reliably predict DAS28, PtGA, and IHAQ disability index using multivariable logistic regression models.ConclusionThe proportion of patients who were overweight was less in our patients with RA compared to the general population [3]. In this ongoing study, body fat composition and distribution did not exhibit any relationship with disease severity, or disability. However, prolonged steroid use increased fat mass percentage. Further studies are needed to evaluate the changes in fat and lean mass distribution and their relationship to disease activity.References[1] Moroni L, Farina N, Dagna L. Obesity and its role in the management of rheumatoid and psoriatic arthritis. Clin Rheumatol. 2020 Apr;39(4):1039–47.[2] Son KM, Kang SH, Seo YI, Kim HA. Association of body composition with disease activity and disability in rheumatoid arthritis. Korean J Intern Med. 2021 Jan;36(1):214–22.[3] Marwaha RK, Tandon N, Garg MK, Narang A, Mehan N, Bhadra K. Normative Data of Body Fat Mass and Its Distribution as Assessed by DXA in Indian Adult Population. J Clin Densitom. 2014 Jan 1;17(1):136–42.Table 1.Fat distribution indices in patients with rheumatoid arthritis.Fat distribution indicesMean ± SD or Median ± IQRFat mass (kg)22.98 ± 10.42⃰Lean mass (kg)33.53 ± 10.42Fat mass %39.87 ± 6.13Fat mass index (kg/m2)10.05 ± 4.19Lean mass index (kg/m2)14.46 ± 2.31Fat to lean mass ratio67.18 ± 19.26Android - gynoid ratio0.92 ± 0.14Trunk - leg fat ratio0.81 ± 0.12AcknowledgementsNone.Disclosure of InterestsNone Declared.

Abstract Background: Successful vaccination against SARS-CoV2 is highly effective in preventing serious COVID-19 illness and is particularly recommended for at risk populations including patients with multiple myeloma (MM). However, there is uncertainty to which extent modern intensified therapies targeting plasma cell features might attenuate vaccination responses; some early vaccination recommendations for MM have proposed extended treatment breaks of several weeks to maximise vaccination success. Such an approach can be challenging in UHiR MM and pPCL, where maintaining treatment intensity is hallmark for preventing rapid relapse of the aggressive tumor. To address this uncertainty, we measured post-vaccination serological responses in patients treated uniformly with intensified Dara-VR consolidation and Dara-R maintenance post-ASCT for UHiR NDMM or pPCL in the UK OPTIMUM/MUKnine trial (NCT03188172). Methods: Between Sep 2017 and Jul 2019, 107 patients with UHiR NDMM or pPCL were recruited to OPTIMUM and received intensified post-ASCT consolidation with Dara-VR(d) for 18 cycles followed by maintenance with Dara-R until progression. In an exploratory analysis, centrally stored serum samples available for patients with a completed and documented vaccination history of two doses of an anti-SARS-CoV2 vaccine were analyzed for serological vaccine responses Total IgG/IgA/IgM Anti-SARS-CoV-2 spike glycoprotein was measured by ELISA (MK654; The Binding Site). As per UK national guidance and local availability, patients received two vaccine doses 12 weeks apart of either tozinameran (Pfizer/Biontech) or vaxzevria (AstraZeneca); serum taken at least 3 weeks after patients received their second dose was analyzed. Results were correlated with baseline characteristics and annotated with treatment and response data. Patient with available matched serological and vaccination status data at time of data cut-off (09 JUL 2021) were included. Collection of vaccination status data is ongoing and updated results comprising additional patients enrolled in OPTIMUM, as well as antigen levels, will be presented. Data will also comprise longitudinal antibody level measurements for patient with available sequential material. Results: Serological vaccine response data was available for 40 OPTIMUM patients with documented completed double vaccination status. Median patient age was 58.5 years (range 39-70) and clinical and molecular tumor features were similar to the overall trial safety population. All patients had received their second dose before June 2021. Of the 40 patients, 42.5% had received tozinameran and 57.5% vaxzevria. Baseline characteristics of the two groups were comparable. At time of second vaccine dose, 55% of patients were receiving Dara-VR consolidation treatment and 45% Dara-R maintenance. There was no recommendation to pause trial treatment for purposes of vaccination and no extended times off treatment for this reason were reported. Overall, 72.5% of patients had a positive vaccine antibody level as per manufacturer cut-point for high specificity evidence of antigen exposure (infection or vaccine). The response rate was nominally higher for vaxzevria (91.3%) than for tozinameran (47.1%), a dysbalance that will be further investigated with ongoing extension of the cohort. Of note, 90% of patients analyzed had reached a complete response (CR) of their MM prior to being vaccinated, and the majority of patients not in CR had a positive vaccine response. Response rates were nominally slightly higher in patients in receipt of Dara-R maintenance at time of second dose with 77.8% compared to Dara-VR consolidation with 68.2%. Conclusions: These results show a high serological response rate to COVID-19 vaccination in UHiR MM patients receiving intensified post-ASCT consolidation and maintenance therapy in remission. Findings suggest that continuation of intensified post-ASCT therapy for patients with aggressive tumors and a high risk of relapse are compatible with serological responses to commonly used COVID-19 vaccines. Disclosures Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy; Pfizer: Consultancy. Hall: BMS/Celgene: Research Funding; Janssen: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Pratt: Binding Site: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Cook: Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS/Celgene: Consultancy, Research Funding; Amgen: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy.

Background The incidence of anterior cruciate ligament (ACL) injury is steadily increasing in skeletally immature patients [1-7]. As a result, surgical approaches to reconstruction of the ACL without compromising the physis have been developed [6, 8, 9]. It is essential to understand how the native ACL changes with patient growth and age, in order to better understand how grafts might serve patients as they continue to grow. The purpose of this study is to characterize the morphological change over time of different ACL parameters in the pediatric and adolescent population based on serial magnetic resonance imaging (MRI). Methods After receiving Institutional Review Board approval, the patient cohort was identified retrospectively from a database of all patients who had a routine magnetic resonance imaging (MRI) of the knee between July 2005 and February 2017. Patients aged 0 to 18 years at the time of their initial MRI, who had undergone at least two serial MRI examinations of the same knee at least 4 months apart for reasons other than ACL tear were included. Patients were excluded if they had a fracture of the distal femur or proximal tibia, congenital condition that affects the knee, deformity of the femur or tibia, or if they have a pathologic process (e.g. tumor) that disrupts the anatomy of the distal femur or proximal tibia. The parameters measured included physeal status, length of the ACL, diameter of the ACL in the sagittal and coronal plane, ACL-tibial inclination angle, notch width index, the midpoint of the ACL tibial attachment, anterior to posterior dimension of the tibia, and tibial epiphyseal height. A Pearson correlation coefficient was calculated to determine the strength of correlation of each parameter relative to age. Growth curves were calculated for individual parameters, which produced a predictive model for the rate of growth of the ACL at different ages. Results 162 knees in 147 patients (365 MRI studies) were identified to have had serial MRI of their knee. 50.3% of patients were female. Ages at time of MRI ranged from 1.3 to 21.7 years (average 13.5 years, SD 3.60). The Pearson correlation coefficient for each parameter showed statistically significant relationship relative to age. The ACL grows in length and diameter with age. Younger patients had more oblique, anteriorly attached ACLs compared to older patients. The growth model for ACL length shows three distinct phases of growth: patients age 1.5 to 5.75 years average 2.25 mm of growth per year; patients aged 6 to 11.5 average 1.46 mm of growth per year; growth begins to plateau at age 11.75, stopping by age 18.5 years. The growth model for ACL sagittal diameter shows an average of 0.45 mm of growth per year between 1.5 and 14.5 years old, after which growth slows until it stops at age 18.75. The ACL coronal diameter model shows an average of 0.22 mm of growth per year between 1.5 and 18.75 years old, with growth completion by age 18.75. ANCOVA was used to assess the difference in growth rates between men and women. Growth rates for ACL length, ACL diameter in the coronal plane, transcondylar width, posterior border, center, and width of ACL-tibial attachment, and anterior-to-posterior dimension of the tibia are significantly different in men and women. Namely, for all significant differences, men had faster growth rates than women. Conclusions/Significance In the skeletally immature patient, the ACL grows in length and diameter in a predictable fashion until age 18. This model aids clinicians in predicting normal ACL parameters for reconstruction procedures in the skeletally immature patient. It may have important implications for ACL reconstruction in very young patients. [Table: see text][Table: see text][Figure: see text][Figure: see text][Figure: see text] References Mizuta, H., et al., The conservative treatment of complete tears of the anterior cruciate ligament in skeletally immature patients. J Bone Joint Surg Br, 1995. 77(6): p. 890-4. Angel, K.R. and D.J. Hall, Anterior cruciate ligament injury in children and adolescents. Arthroscopy, 1989. 5(3): p. 197-200. Lawrence, J.T., N. Argawal, and T.J. Ganley, Degeneration of the knee joint in skeletally immature patients with a diagnosis of an anterior cruciate ligament tear: is there harm in delay of treatment? Am J Sports Med, 2011. 39(12): p. 2582-7. Dumont, G.D., et al., Meniscal and chondral injuries associated with pediatric anterior cruciate ligament tears: relationship of treatment time and patient-specific factors. Am J Sports Med, 2012. 40(9): p. 2128-33. Newman, J.T., et al., Factors predictive of concomitant injuries among children and adolescents undergoing anterior cruciate ligament surgery. Am J Sports Med, 2015. 43(2): p. 282-8. Kocher, M.S., S. Garg, and L.J. Micheli, Physeal sparing reconstruction of the anterior cruciate ligament in skeletally immature prepubescent children and adolescents. J Bone Joint Surg Am, 2005. 87(11): p. 2371-9. Cruz, A.I., Jr., et al., All-Epiphyseal ACL Reconstruction in Children: Review of Safety and Early Complications. J Pediatr Orthop, 2017. 37(3): p. 204-209.

Abstract Background: Outcomes for patients with ultra-high risk (UHiR) newly diagnosed multiple myeloma (NDMM) and patients with primary plasma cell leukemia (pPCL) remain unsatisfactory with current standard therapies. Traditional comparative trials randomising against a standard of care control arm are thus challenging for patients with UHiR NDMM or pPCL, and novel approaches to address their high unmet need are required. OPTIMUM/MUKnine (NCT03188172) is a 'digital comparator arm' trial for UHiR NDMM and pPCL patients with protocol defined outcome comparison against fully molecularly matched UHiR patients from the near-concurrent NCRI Myeloma XI/XI+ trial, the 'MyXI prior'. We report final analysis of the primary endpoint progression free survival (PFS) at 18 months for patients treated in OPTIMUM with Dara-CVRd induction, V-augmented ASCT and Dara-VRd consolidation, compared to the MyXI prior. Methods: Between Sep 2017 and Jul 2019, 472 patients from 39 UK hospitals with suspected NDMM or pPCL were screened. 107 patients with UHiR NDMM by central trial genetic (≥2 high risk lesions: t(4;14), t(14;16), t(14;20), gain(1q), del(1p), del(17p)) or gene expression SKY92 (SkylineDx) profiling, or with pPCL (circulating plasmablasts &gt;20%) were identified and recruited to OPTIMUM. Patients received up to 6 cycles of Dara-CVRd induction, V-ASCT, followed by Dara-VRd consolidation 1 for 6 cycles (Cons1), Dara-VR consolidation 2 for 12 cycles and monthly Dara-R maintenance until progression. This is the final analysis of the primary trial endpoint progression-free survival (PFS) at 18 months comparing OPTIMUM with the MyXI prior of patients treated with CRd or carfilzomib-CRd (KCRd) induction, ASCT and R maintenance or observation, using a Bayesian framework. Secondary endpoints include PFS, OS, safety and quality of life. Results: At median follow-up of 27.1 months (95% CI 25.1-29.3), median PFS was not reached for OPTIMUM patients. PFS was superior at the pre-specified time point of 18 months for OPTIMUM patients with an estimate of 81.7% (95% CI: 74.2-89.1) versus 65.9% (95% CI: 57.3-74.4) for the MyXI prior (Figure 1). PFS at 18 months was consistently shorter for both CRd (64.5%; 95% CI: 53.8-75.3) and KCRd (68.3%; 95% CI: 54.0-82.5) treated patients compared with OPTIMUM. There was a 99.5% chance of superior PFS outcome with OPTIMUM therapy compared to the MyXI prior within the Bayesian framework; easily surpassing the 85% pre-specified threshold of sufficient evidence of activity. The difference between trial treatments increased over time: 6 month estimates were similar across all treatment arms with OPTIMUM 95.3% (95% CI: 91.3-99.3), MyXI KCRd 95.1% (95% CI: 88.5-100.0), MyXI CRd 93.5% (95% CI: 88.0-99.0), while 12 month estimates were similar for OPTIMUM with 87.5% (95% CI: 81.2-93.9) and MyXI KCRd 87.8% (77.8-97.8), but lower in CRd 81.7% (95% CI: 73.0-90.3). The majority (94%) of patients who started OPTIMUM Cons1 completed all 6 cycles of therapy. Most frequent grade 3/4 adverse events (AEs) during Cons1 included thrombocytopenia (27.9%), neutropenia (21%) and infection (19.8%), however, grade 4 events were rare (&lt;5%) for all categories, consistent with previously presented data on induction. We previously reported high MRD-negativity rates of 61% at day +100 post V-ASCT for OPTIMUM, with a lower rate of 40% of patients showing both complete response (CR) and MRD-neg. With further follow-up, CR rate increased to 68.2% (95% CI: 58.5-76.9) at end of Cons1, including virtually all patients with MRD-neg finding post V-ASCT. Conclusions: OPTIMUM demonstrated a clear PFS benefit at 18 months for intensified Dara combination therapy pre- and post-ASCT for UHiR NDMM and pPCL over the MyXI prior. Improvement of comparative benefit over time suggests particular efficacy of Dara-VRd in maintaining responses post ASCT, a key challenge in UHiR MM. This is, to our knowledge, the first prospective digital comparator trial for MM; central screening of an all-comer population combined with robust, detailed molecular matching maintained reliability and limited biases. These results demonstrate a novel framework for accelerated comparative evidence generation for patients with high unmet clinical need. Figure 1 Figure 1. Disclosures Kaiser: BMS/Celgene: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Educational support, Research Funding; GSK: Consultancy; Karyopharm: Consultancy, Research Funding; Pfizer: Consultancy; Amgen: Honoraria; Seattle Genetics: Consultancy; Takeda: Consultancy, Other: Educational support; AbbVie: Consultancy. Hall: Janssen: Research Funding; BMS/Celgene: Research Funding. Garg: University Hospital Leicester: Current Employment; Takeda Janssen Novartis Sanofi: Other: Travel Accommodations, Expenses; Amgen Janssen Novartis Sanofi Takeda: Honoraria. Jackson: J and J: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; amgen: Consultancy, Honoraria, Speakers Bureau; celgene BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; oncopeptides: Consultancy; Sanofi: Honoraria, Speakers Bureau. Cook: BMS/Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Karyopharm: Consultancy; Amgen: Consultancy. Pratt: Binding Site: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy; BMS/Celgene: Consultancy; Gilead: Consultancy. Drayson: Abingdon Health: Current holder of individual stocks in a privately-held company. Jenner: Janssen: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy; Takeda: Consultancy.

One of the key events in a virus-infected host cell is the activation and repression of a large number of host genes. In recent years, such differentially expressed host genes have been identified for several viruses, bacteria and parasites. Such studies indicate that reprogramming of host transcriptome during infection by a pathogen is a major component of host response and many of the reprogrammed genes may promote or prevent pathogen infection or may contribute to pathogen-induced pathological changes. Host gene expression changes have been studied for a number of viruses in cell lines. However, in case of neurotropic viruses which infect nonrenewable populations of central nervous system (CNS), changes in the host gene expression need to be studied in the intact host rather than cells grown in culture. Since such studies are reported only for a few neurotropic viruses, an attempt has been made in this thesis to identify and characterize genes that are differentially expressed in the mouse brain during infection by Japanese encephalitis virus (JEV) and rabies virus. Using subtraction hybridization technique, subtraction cDNA libraries were generated representing mRNAs that are induced or repressed in the mouse brain during JEV infection. Sequence analysis of the 350 isolated clones resulted in the identification of 73 unique genes. Out of these, 66 were of forward library clones (upregulated genes) and 7 of reverse library clones (downregulated genes). The forward library clones was clustered in different functional groups such as, proteins involved in immune response and interferon-inducible proteins, GTPase and GTP binding proteins, transcriptional regulators, enzymes, ribosomal proteins, neuronal proteins, carrier proteins, DNA-binding proteins, miscellaneous and proteins of unknown function. The differential expression of all these genes was further validated by northern blot analysis of brain RNA isolated from normal and JEV-infected mice, which indicate that out of 66 forward library clones 33 were genuinely upregulated in JEV-infected mouse brain, whereas all 7 reverse library clones were repressed in JEV infection. Since vaccination is known to prevent virus replication in the brain, host gene expression changes in mice immunized with BIKEN JE vaccine was also examined. There was a good correlation between inhibition of JEV replication and reduced expression of JEV-inducible CNS genes in the vaccinated mice. To check whether JEV-induced CNS genes identified in this study are specific to JEV or can be induced by any other neurotropic virus, expression patterns of 15 randomly chosen genes were checked in RV infected mouse brain. Results indicated that all the chosen genes are modulated in the same way during RV infection as well. Comparison of JEV-induced gene expression changes with those induced by other neurotropic viruses indicated that 83% of the JEV-inducible mouse CNS genes are also induced by Sindbis virus, a neurotropic virus of the family alphaviridae, indicating that despite diverse life cycles, these two viruses may activate common host signaling pathways. This study also led to the identification of 9 unique JEV-inducible genes (LRG-21, VHSV induced gene1, Tpt1, SLC25A3, Olfm1, Ina/NF-66, Dst/Bpag1, Mdm2 and Gbp5) which are not reported to be activated by any other neurotropic virus. Since it is beyond the scope of this study to characterize all the JEV-induced and repressed genes, two genes were chosen for a detailed analysis. These are: JEV-inducible gene encoding GARG-39 protein which is a member of the glucocorticoid attenuated response gene family and an unannotated, JEV-repressible gene designated in this study as clone # 137. The gene encoding GARG-39 identified as a JEV-inducible gene in this study was originally discovered as lipopolysaccharide- and interferon-inducible gene in macrophages. This protein contains tetratricopeptide repeat (TPR) motifs that are known to be involved in protein-protein interactions. However, the function of this protein remains unknown till date. Therefore the gene was cloned and over-expressed in E. coli and antibodies were raised against the recombinant protein. Western blot analysis revealed that GARG-39 protein is detectable only in JEV-infected but not in the normal mouse brain. Surprisingly, immunoflourescence studies carried out in NIH3T3 cells revealed that GARG-39 is localized in the cytosol of normal cells and it colocalizes with α-tubulin in the mitotic spindle in a small fraction of cells which are in the mitotic stage. Further, in an in vitro assay, GARG-39 was found to interact with taxol-stabilized tubulin polymers. Since microtubules are known to play an important role in virus assembly, it is possible that GARG-39 may have a role in virus assembly and maturation. Alternatively, microtubule-associated proteins are implicated in several neurodegenerative disorders including Parkinson’s, Alzheimer’s and mental retardation and therefore, a role for GARG-39 in virus-induced neuropathogenesis cannot be ruled out. In addition, the expression of GARG-39 in normal dividing cells in the culture indicates a role for this protein in mitosis. In a normal mouse brain, mitotically active cells are very low in number and hence GARG-39 expression (both at the RNA and protein levels) is below the detection limits. JEV infection may trigger mitotic activity in brain leading to increased expression of GARG-39. One of the cDNA clones identified in this study, designated as clone # 137, hybridized to a ~2.6 kb transcript which was found to be down regulated in the mouse brain by JEV as well as rabies virus. A series of investigations led to the conclusion that clone #137 corresponds to the 3′ end of a ~2.6 kb transcript encoding mouse calcium calmodulin kinase inhibitor II α (mCaMKIINα). Interestingly, only the α isoform but not the β isoform of mCaMKIINα mRNA is down regulated in the mouse brain during JEV infection. Since the physiological function of mCaMKIINα is not known, the gene encoding 8 kDa mouse mCaMKIINα open reading frame was cloned into an E. coli expression vector and antibodies were raised against the purified recombinant protein. Surprisingly, antibodies raised against the ~8 kDa recombinant mouse CaMKIINα reacted with a ∼37 kDa mouse brain protein. This protein designated as CaMKIINα-immunoreactive protein (CaMKIINα-IRP) is also down regulated during JEV infection and is localized in the post synaptic density (PSD) of normal mouse brain. In addition, distinct changes are also observed in the subcellular localization and phosphorylation of CaMKIIα leading to an increase in cytosolic CaMKII activity in JEV-infected mouse brain. The differential regulation of CaMKIIα and CaMKIINα during JEV infection suggests a possible role for CaMKII signaling pathway in JEV infection and/or JEV-induced neuropathogenesis in the CNS. Conclusions: • A number of host genes whose expression is modulated in the mouse brain during JEV and/or rabies virus infection have been identified. • One of the JEV-inducible genes encoding the GARG-39 protein was shown to be a microtubule-associated protein with a possible role in mitosis. • One of the JEV-repressible genes was found to encode the mouse CaMKIINα mRNA. • A novel JEV-repressible ∼37 kDa protein immunoreactive to antibodies raised against the recombinant CaMKIINα was identified in the post synaptic density of the mouse brain.

One of the key events in a virus-infected host cell is the activation and repression of a large number of host genes. In recent years, such differentially expressed host genes have been identified for several viruses, bacteria and parasites. Such studies indicate that reprogramming of host transcriptome during infection by a pathogen is a major component of host response and many of the reprogrammed genes may promote or prevent pathogen infection or may contribute to pathogen-induced pathological changes. Host gene expression changes have been studied for a number of viruses in cell lines. However, in case of neurotropic viruses which infect nonrenewable populations of central nervous system (CNS), changes in the host gene expression need to be studied in the intact host rather than cells grown in culture. Since such studies are reported only for a few neurotropic viruses, an attempt has been made in this thesis to identify and characterize genes that are differentially expressed in the mouse brain during infection by Japanese encephalitis virus (JEV) and rabies virus. Using subtraction hybridization technique, subtraction cDNA libraries were generated representing mRNAs that are induced or repressed in the mouse brain during JEV infection. Sequence analysis of the 350 isolated clones resulted in the identification of 73 unique genes. Out of these, 66 were of forward library clones (upregulated genes) and 7 of reverse library clones (downregulated genes). The forward library clones was clustered in different functional groups such as, proteins involved in immune response and interferon-inducible proteins, GTPase and GTP binding proteins, transcriptional regulators, enzymes, ribosomal proteins, neuronal proteins, carrier proteins, DNA-binding proteins, miscellaneous and proteins of unknown function. The differential expression of all these genes was further validated by northern blot analysis of brain RNA isolated from normal and JEV-infected mice, which indicate that out of 66 forward library clones 33 were genuinely upregulated in JEV-infected mouse brain, whereas all 7 reverse library clones were repressed in JEV infection. Since vaccination is known to prevent virus replication in the brain, host gene expression changes in mice immunized with BIKEN JE vaccine was also examined. There was a good correlation between inhibition of JEV replication and reduced expression of JEV-inducible CNS genes in the vaccinated mice. To check whether JEV-induced CNS genes identified in this study are specific to JEV or can be induced by any other neurotropic virus, expression patterns of 15 randomly chosen genes were checked in RV infected mouse brain. Results indicated that all the chosen genes are modulated in the same way during RV infection as well. Comparison of JEV-induced gene expression changes with those induced by other neurotropic viruses indicated that 83% of the JEV-inducible mouse CNS genes are also induced by Sindbis virus, a neurotropic virus of the family alphaviridae, indicating that despite diverse life cycles, these two viruses may activate common host signaling pathways. This study also led to the identification of 9 unique JEV-inducible genes (LRG-21, VHSV induced gene1, Tpt1, SLC25A3, Olfm1, Ina/NF-66, Dst/Bpag1, Mdm2 and Gbp5) which are not reported to be activated by any other neurotropic virus. Since it is beyond the scope of this study to characterize all the JEV-induced and repressed genes, two genes were chosen for a detailed analysis. These are: JEV-inducible gene encoding GARG-39 protein which is a member of the glucocorticoid attenuated response gene family and an unannotated, JEV-repressible gene designated in this study as clone # 137. The gene encoding GARG-39 identified as a JEV-inducible gene in this study was originally discovered as lipopolysaccharide- and interferon-inducible gene in macrophages. This protein contains tetratricopeptide repeat (TPR) motifs that are known to be involved in protein-protein interactions. However, the function of this protein remains unknown till date. Therefore the gene was cloned and over-expressed in E. coli and antibodies were raised against the recombinant protein. Western blot analysis revealed that GARG-39 protein is detectable only in JEV-infected but not in the normal mouse brain. Surprisingly, immunoflourescence studies carried out in NIH3T3 cells revealed that GARG-39 is localized in the cytosol of normal cells and it colocalizes with α-tubulin in the mitotic spindle in a small fraction of cells which are in the mitotic stage. Further, in an in vitro assay, GARG-39 was found to interact with taxol-stabilized tubulin polymers. Since microtubules are known to play an important role in virus assembly, it is possible that GARG-39 may have a role in virus assembly and maturation. Alternatively, microtubule-associated proteins are implicated in several neurodegenerative disorders including Parkinson’s, Alzheimer’s and mental retardation and therefore, a role for GARG-39 in virus-induced neuropathogenesis cannot be ruled out. In addition, the expression of GARG-39 in normal dividing cells in the culture indicates a role for this protein in mitosis. In a normal mouse brain, mitotically active cells are very low in number and hence GARG-39 expression (both at the RNA and protein levels) is below the detection limits. JEV infection may trigger mitotic activity in brain leading to increased expression of GARG-39. One of the cDNA clones identified in this study, designated as clone # 137, hybridized to a ~2.6 kb transcript which was found to be down regulated in the mouse brain by JEV as well as rabies virus. A series of investigations led to the conclusion that clone #137 corresponds to the 3′ end of a ~2.6 kb transcript encoding mouse calcium calmodulin kinase inhibitor II α (mCaMKIINα). Interestingly, only the α isoform but not the β isoform of mCaMKIINα mRNA is down regulated in the mouse brain during JEV infection. Since the physiological function of mCaMKIINα is not known, the gene encoding 8 kDa mouse mCaMKIINα open reading frame was cloned into an E. coli expression vector and antibodies were raised against the purified recombinant protein. Surprisingly, antibodies raised against the ~8 kDa recombinant mouse CaMKIINα reacted with a ∼37 kDa mouse brain protein. This protein designated as CaMKIINα-immunoreactive protein (CaMKIINα-IRP) is also down regulated during JEV infection and is localized in the post synaptic density (PSD) of normal mouse brain. In addition, distinct changes are also observed in the subcellular localization and phosphorylation of CaMKIIα leading to an increase in cytosolic CaMKII activity in JEV-infected mouse brain. The differential regulation of CaMKIIα and CaMKIINα during JEV infection suggests a possible role for CaMKII signaling pathway in JEV infection and/or JEV-induced neuropathogenesis in the CNS. Conclusions: • A number of host genes whose expression is modulated in the mouse brain during JEV and/or rabies virus infection have been identified. • One of the JEV-inducible genes encoding the GARG-39 protein was shown to be a microtubule-associated protein with a possible role in mitosis. • One of the JEV-repressible genes was found to encode the mouse CaMKIINα mRNA. • A novel JEV-repressible ∼37 kDa protein immunoreactive to antibodies raised against the recombinant CaMKIINα was identified in the post synaptic density of the mouse brain.