Risk factors for toxoplasmosis in people living with HIV in the Asia-Pacific region.

INTRODUCTION: Toxoplasma gondii can cause symptomatic toxoplasmosis in immunodeficient hosts, including in people living with human immunodeficiency virus (PLWH), mainly because of the reactivation of latent infection. We assessed the prevalence of toxoplasmosis and its associated risk factors in PLWH in the Asia-Pacific region using data from the TREAT Asia Human Immunodeficiency Virus (HIV) Observational Database (TAHOD) of the International Epidemiology Databases to Evaluate AIDS (IeDEA) Asia-Pacific. METHODS: This study included both retrospective and prospective cases of toxoplasmosis reported between 1997 and 2020. A matched case-control method was employed, where PLWH diagnosed with toxoplasmosis (cases) were each matched to two PLWH without a toxoplasmosis diagnosis (controls) from the same site. Sites without toxoplasmosis were excluded. Risk factors for toxoplasmosis were analyzed using conditional logistic regression. RESULTS: A total of 269/9576 (2.8%) PLWH were diagnosed with toxoplasmosis in 19 TAHOD sites. Of these, 227 (84%) were reported retrospectively and 42 (16%) were prospective diagnoses after cohort enrollment. At the time of toxoplasmosis diagnosis, the median age was 33 years (interquartile range 28-38), and 80% participants were male, 75% were not on antiretroviral therapy (ART). Excluding 63 out of 269 people without CD4 values, 192 (93.2%) had CD4 ≤200 cells/µL and 162 (78.6%) had CD4 ≤100 cells/µL. By employing 538 matched controls, we found that factors associated with toxoplasmosis included abstaining from ART (odds ratio [OR] 3.62, 95% CI 1.81-7.24), in comparison to receiving nucleoside reverse transcriptase inhibitors plus non-nucleoside reverse transcriptase inhibitors, HIV exposure through injection drug use (OR 2.27, 95% CI 1.15-4.47) as opposed to engaging in heterosexual intercourse and testing positive for hepatitis B virus surface antigen (OR 3.19, 95% CI 1.41-7.21). Toxoplasmosis was less likely with increasing CD4 counts (51-100 cells/µL: OR 0.41, 95% CI 0.18-0.96; 101-200 cells/µL: OR 0.14, 95% CI 0.06-0.34; >200 cells/µL: OR 0.02, 95% CI 0.01-0.06), when compared to CD4 ≤50 cells/µL. Moreover, the use of prophylactic cotrimoxazole was not associated with toxoplasmosis. CONCLUSIONS: Symptomatic toxoplasmosis is rare but still occurs in PLWH in the Asia-Pacific region, especially in the context of delayed diagnosis, causing advanced HIV disease. Immune reconstitution through early diagnosis and ART administration remains a priority in Asian PLWH.

Quantitative pupillometry as a biomarker for prediction of return to play in mild traumatic brain injury: a Military Traumatic Brain Injury Initiative study.

OBJECTIVE: This study aimed to determine the validity of quantitative pupillometry to predict the length of time for return to full activity/duty after a mild traumatic brain injury (mTBI) in a cohort of injured cadets at West Point. METHODS: Each subject received baseline (T0) quantitative pupillometry, in addition to evaluation with the Balance Error Scoring System (BESS), Standardized Assessment of Concussion (SAC), and Sport Concussion Assessment Tool 5th Edition Symptom Survey (SCAT5). Repeat assessments using the same parameters were conducted within 48 hours of injury (T1), at the beginning of progressive return to activity (T2), and at the completion of progressive return to activity protocols (T3). Pupillary metrics were compared on the basis of length of time to return to full play/duty and the clinical scores. RESULTS: The authors' statistical analyses found correlations between pupillometry measures at T1, including end-initial diameter and maximum constriction velocity, with larger change and faster constriction predicting earlier return to play. There was also an association with maximum constriction velocity at baseline (T0), predicting faster return to play. CONCLUSIONS: The authors conclude that that pupillometry may be a valuable tool for assessing time to return to duty from mTBI by providing a measure of baseline resiliency to mTBI and/or autonomic dysfunction in the acute phase after mTBI.

HIV-1 subtype-specific drug resistance on dolutegravir-based antiretroviral therapy: protocol for a multicentre longitudinal study (DTG RESIST).

Introduction: HIV drug resistance poses a challenge to the United Nation's goal of ending the HIV/AIDS epidemic. The integrase strand transfer inhibitor (InSTI) dolutegravir, which has a higher resistance barrier, was endorsed by the World Health Organization in 2019 for first-, second-, and third-line antiretroviral therapy (ART). This multiplicity of roles of dolutegravir in ART may facilitate the emergence of dolutegravir resistance. Methods and analysis: DTG RESIST is a multicentre longitudinal study of adults and adolescents living with HIV in sub-Saharan Africa, Asia, and South and Central America who experienced virologic failure on dolutegravir-based ART. At the time of virologic failure whole blood will be collected and processed to prepare plasma or dried blood spots. Laboratories in Durban, Mexico City and Bangkok will perform genotyping. Analyses will focus on (i) individuals who experienced virologic failure on dolutegravir, and (ii) on those who started or switched to such a regimen and were at risk of virologic failure. For population (i), the outcome will be any InSTI drug resistance mutations, and for population (ii) virologic failure defined as a viral load >1000 copies/mL. Phenotypic testing will focus on non-B subtype viruses with major InSTI resistance mutations. Bayesian evolutionary models will explore and predict treatment failure genotypes. The study will have intermediate statistical power to detect differences in resistance mutation prevalence between major HIV-1 subtypes; ample power to identify risk factors for virologic failure and limited power for analysing factors associated with individual InSTI drug resistance mutations. Ethics and dissemination: The research protocol was approved by the Biomedical Research Ethics Committee at the University of KwaZulu-Natal, South Africa, and the Ethics Committee of the Canton of Bern, Switzerland. All sites participate in IeDEA and have obtained ethics approval from their local ethics committee to conduct the additional data collection. Registration: NCT06285110. Strengths and limitations of this study: - DTG RESIST is a large international study to prospectively examine emergent dolutegravir resistance in diverse settings characterised by different HIV-1 subtypes, provision of ART, and guidelines on resistance testing. - Embedded within the International epidemiology Databases to Evaluate AIDS (IeDEA), DTG RESIST will benefit from harmonized clinical data across participating sites and expertise in clinical, epidemiological, biological, and computational fields. - Procedures for sequencing and assembling genomes from different HIV-1 strains will be developed at the heart of the HIV epidemic, by the KwaZulu-Natal Research Innovation and Sequencing Platform (KRISP), in Durban, South Africa. Phenotypic testing, Genome Wide Association Study (GWAS) methods and Bayesian evolutionary models will explore and predict treatment failure genotypes. - A significant limitation is the absence of genotypic resistance data from participants before they started dolutegravir treatment, as collecting and bio-banking pre-treatment samples was not feasible at most IeDEA sites. Consistent and harmonized data on adherence to treatment are also lacking. - The distribution of HIV-1 subtypes across different sites is uncertain, which may limit the statistical power of the study in analysing patterns and risk factors for dolutegravir resistance. The results from GWAS and Bayesian modelling analyses will be preliminary and hypothesis-generating.

Quantitative Pupillometry Predicts Return to Play and Tracks the Clinical Evolution of Mild Traumatic Brain Injury in US Military Academy Cadets: A Military Traumatic Brain Injury Initiative Study.

BACKGROUND AND OBJECTIVES: The objective of this study was to determine the utility of the pupillary light reflex use as a biomarker of mild traumatic brain injury (mTBI). METHODS: This prospective cohort study was conducted at The US Military Academy at West Point. Cadets underwent a standard battery of tests including Balance Error Scoring System, Sports Concussion Assessment Tool Fifth Edition Symptom Survey, Standard Assessment of Concussion, and measure of pupillary responses. Cadets who sustained an mTBI during training events or sports were evaluated with the same battery of tests and pupillometry within 48 hours of the injury (T1), at the initiation of a graded return to activity protocol (T2), and at unrestricted return to activity (T3). RESULTS: Pupillary light reflex metrics were obtained in 1300 cadets at baseline. During the study period, 68 cadets sustained mTBIs. At T1 (<48 hours), cadets manifested significant postconcussion symptoms (Sports Concussion Assessment Tool Fifth Edition P < .001), and they had decreased cognitive performance (Standardized Assessment of Concussion P < .001) and higher balance error scores (Balance Error Scoring System P < .001) in comparison with their baseline assessment (T0). The clinical parameters showed normalization at time points T2 and T3. The pupillary responses demonstrated a pattern of significant change that returned to normal for several measures, including the difference between the constricted and initial pupillary diameter (T1 P < .001, T2 P < .05), dilation velocity (T1 P < .01, T2 P < .001), and percent of pupillary constriction (T1 P < .05). In addition, a combination of dilation velocity and maximum constriction velocity demonstrates moderate prediction ability regarding who can return to duty before or after 21 days (area under the curve = 0.71, 95% CI [0.56-0.86]). CONCLUSION: This study's findings indicate that quantitative pupillometry has the potential to assist with injury identification and prediction of symptom severity and duration.

Validation of a Pseudovirus Neutralization Assay for Severe Acute Respiratory Syndrome Coronavirus 2: A High-Throughput Method for the Evaluation of Vaccine Immunogenicity.

The evaluation of coronavirus disease 2019 (COVID-19) vaccine immunogenicity remains essential as the severe acute respiratory syncytial virus 2 (SARS-CoV-2) pandemic continues to evolve and as additional variants emerge. Neutralizing antibodies are a known correlate of protection for SARS-CoV-2 vaccines. A pseudovirus neutralization (PNT) assay was developed and validated at Novavax Clinical Immunology Laboratories to allow for the detection of neutralizing antibodies in vaccine clinical trial sera. The PNT assay was precise, accurate, linear, and specific in measuring SARS-CoV-2 neutralization titers in human serum for ancestral strain and the Omicron subvariants BA.5 and XBB.1.5, with an overall geometric coefficient of variation of ≤43.4%, a percent relative bias within the expected range of -60% to 150%, and a linearity value of R2 > 0.98 for all three strains. This pseudovirus assay will be useful for the analysis of vaccine clinical trial samples to assess vaccine immunogenicity. Future work will focus on modifying the assay for emerging variants, including XBB.1.16, EG.5.1, BA.2.86, and any other variants that emerge in the ongoing pandemic.

EVIDENCE meta-analysis: evaluating minimal residual disease as an intermediate clinical endpoint for multiple myeloma.

Estimating progression-free survival (PFS) and overall survival (OS) superiority during clinical trials of multiple myeloma (MM) has become increasingly challenging as novel therapeutics have improved patient outcomes. Thus, it is imperative to identify earlier endpoint surrogates that are predictive of long-term clinical benefit to expedite development of more effective therapies. Minimal residual disease (MRD)-negativity is a common intermediate endpoint that has shown prognostic value for clinical benefit in trials of patients with multiple myeloma (MM). This meta-analysis was based on the FDA guidance for considerations for a meta-analysis of MRD as a clinical endpoint and evaluates MRD-negativity as an early endpoint reasonably likely to predict long-term clinical benefit. Eligible studies were phase 2 or 3 randomized controlled clinical trials measuring MRD negativity as an endpoint in patients with MM, with follow-up of ≥6 months following an a priori defined time point of 12±3 months post-randomization. Eight newly diagnosed MM-(NDMM)-studies evaluating 4,907 patients were included. Trial-level associations between MRD-negativity and PFS were R2WLSiv (95% CI) 0.67 (0.43-0.91) and R2copula 0.84 (0.64->0.99) at the 12-month timepoint. The individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 4.02 (95% CI: 2.57-5.46). For relapse/refractory MM-(RRMM), there were four studies included, and the individual-level association between 12-month MRD negativity and PFS resulted in a global odds ratio of 7.67 (4.24-11.10). A clinical trial demonstrating a treatment effect on MRD is reasonably likely to eventually demonstrate a treatment effect on PFS, suggesting that MRD may be an early clinical endpoint reasonably likely to predict clinical benefit in MM, that may be used to support accelerated approval and thereby expedite the availability of new drugs to patients with MM.

Metabolic causes of liver disease among adults living with HIV from low- and middle-income countries: a cross-sectional study.

INTRODUCTION: Liver disease is a leading cause of morbidity and mortality among persons living with HIV (PLHIV). While chronic viral hepatitis has been extensively studied in low- and middle-income countries (LMICs), there is limited information about the burden of metabolic disorders on liver disease in PLHIV. METHODS: We conducted a cross-sectional analysis of baseline data collected between October 2020 and July 2022 from the IeDEA-Sentinel Research Network, a prospective cohort enrolling PLHIV ≥40 years on antiretroviral treatment (ART) for ≥6 months from eight clinics in Asia, Americas, and central, East, southern and West Africa. Clinical assessments, laboratory testing on fasting blood samples and liver stiffness measurement (LSM)/controlled attenuation parameter (CAP) by vibration-controlled transient elastography were performed. Multivariable logistic regression models assessed factors associated with liver fibrosis (LSM ≥7.1 kPa) and steatosis (CAP ≥248 dB/m). Population attributable fraction (PAF) of each variable associated with significant liver fibrosis was estimated using Levin's formula. RESULTS: Overall, 2120 PLHIV (56% female, median age 50 [interquartile range: 45-56] years) were included. The prevalence of obesity was 19%, 12% had type 2 diabetes mellitus (T2DM), 29% had hypertension and 53% had dyslipidaemia. The overall prevalence of liver fibrosis and steatosis was 7.6% (95% confidence interval [CI] 6.1-8.4) and 28.4% (95% CI 26.5-30.7), respectively, with regional variability. Male sex at birth (odds ratio [OR] 1.62, CI 1.10-2.40), overweight/obesity (OR = 2.50, 95% CI 1.69-3.75), T2DM (OR 2.26, 95% CI 1.46-3.47) and prolonged exposure to didanosine (OR 3.13, 95% CI 1.46-6.49) were associated with liver fibrosis. Overweight/obesity and T2DM accounted for 42% and 11% of the PAF for liver fibrosis, while HBsAg and anti-HCV accounted for 3% and 1%, respectively. Factors associated with steatosis included overweight/obesity (OR 4.25, 95% CI 3.29-5.51), T2DM (OR 2.06, 95% CI 1.47-2.88), prolonged exposure to stavudine (OR 1.69, 95% CI 1.27-2.26) and dyslipidaemia (OR 1.68, 95% CI 1.31-2.16). CONCLUSIONS: Metabolic disorders were significant risk factors for liver disease among PLHIV in LMICs. Early recognition of metabolic disorders risk factors might be helpful to guide clinical and lifestyle interventions. Further prospective studies are needed to determine the causative natures of these findings.

Management of DOAC-related bleeding in cancer patients: a single center-case series.

Venous thromboembolism (VTE) and stroke carry significant mortality and morbidity in cancer patients. Direct oral anticoagulants (DOACs) have been demonstrated to be effective for the treatment of VTE and prevention of stroke in atrial fibrillation (AF). Bleeding rates are variable and are based on the cancer type and the patient's specific risk factors. There are approved specific antidotes for DOAC-associated bleeding. Other strategies are available for bleeding reversal, including the use of prothrombin complex concentrate (PCC). No randomized studies have compared head-to-head the efficacy and safety of reversal agents. We aim to examine the safety and effectiveness of hemostatic agents in cancer patients with DOAC-related major bleeding. A retrospective chart review study of patients at MD Anderson Cancer Center with DOAC-related major bleeding between 2014 and 2019. Bleeding severity and clinical hemostasis were described based on ISTH guidelines and the Sarode criteria, respectively. The rates of thrombotic complications and mortality at 30-day from the index bleeding event were described. We identified 23 patients with DOAC-related major bleeding; 14 patients received PCC and 9 patients received andexanet alfa. The most common sites of bleeding were the gastrointestinal tract and intracranial. Effective hemostasis and 30-day mortality were similar to reported results from other reports of outcomes of reversal agents for DOAC related-bleeding in non-cancer patients. One patient in each treatment group experienced a thrombotic event. Further larger scale studies are needed to confirm our findings in cancer patients.

High mortality in adolescents and young adults with perinatally-acquired HIV in Thailand during the transition to adulthood.

Transitioning from pediatric to adult care remains a challenge for adolescents and young adults with perinatally-acquired HIV (AYA-PHIV). We assessed treatment outcomes and mortality among Thai AYA-PHIV. The study included AYA-PHIV who reached age 18-24 years who started antiretroviral treatment during childhood at five pediatric HIV clinics across Thailand. From November 2020-July 2021, data were gathered from a cohort database, medical records, and the Thai National AIDS Program. Of 811 eligible AYA-PHIV, 93% were alive; median age 22.3 years (IQR 20.6-23.7), treatment duration 16.1 years (IQR 13.4-18.0). Current HIV care was provided in adults (71%) and pediatric clinics (29%). Treatment regimens included non-nucleoside reverse transcriptase inhibitors (55%), protease inhibitors (36%), and integrase inhibitors (8%); 78% had HIV RNA <200 copies/ml. Of the 7.0% who died, median age at death was 20.8 years (IQR 20.6-22.1); 88% were AIDS-related death. Mortality after age 18 was 1.76 per 100-person years (95% confidence interval 1.36-2.28). Those with CD4 <200 cell/mm3 at age 15 had higher risk of mortality (adjusted hazard ratio 6.16, 95% CI 2.37-16.02). In conclusion, the high mortality among Thai AYA-PHIV indicated the need for better systems to support AYA-PHIV during the transition to adulthood.

Changes in atherosclerotic cardiovascular disease risk over time among people living with HIV.

OBJECTIVE: To describe changes in atherosclerotic cardiovascular disease (ASCVD) risk over time among people living with HIV (PLHIV). METHODS: We used data from the TREAT Asia HIV Observational Database (TAHOD) and the Australian HIV Observational Database (AHOD). Five-year ASCVD risk was calculated using the D:A:D equation. Individuals were eligible for inclusion if they were aged ≥18 years, had started ART, had no previous history of ASCVD and had complete ASCVD risk factor data available within the first 5 years of ART initiation. RESULTS: A total of 3368 adults contributed data, 3221 were from TAHOD and 147 were from AHOD. The median age at ART initiation was 36 [IQR 31-43] years for TAHOD participants, and 42 [IQR 35-50] years for AHOD participants. Most TAHOD (70.4%) and AHOD (91.8%) participants were male. Overall, ASCVD risk increased from 0.84% (95% CI 0.81%-0.87%) at ART initiation to 1.34% (95% CI 1.29%-1.39%) after 5 years on ART. After adjusting for traditional and HIV-associated ASCVD risk factors, ASCVD risk increased at a similar rate among sub-populations defined by HIV exposure (heterosexuals, men who have sex with men, people who inject drugs), race/ethnicity (Caucasian and Asian) and nadir CD4 at ART initiation (<200 and ≥200 cells/mm3). CONCLUSIONS: These findings emphasize the growing burden of ASCVD risk among PLHIV and the need to develop interventions that are effective across a broad range of HIV sub-populations.

The Tuberculosis Sentinel Research Network (TB-SRN) of the International epidemiology Databases to Evaluate AIDS (IeDEA): protocol for a prospective cohort study in Africa, Southeast Asia and Latin America.

INTRODUCTION: Tuberculosis (TB) is a leading infectious cause of death globally. It is the most common opportunistic infection in people living with HIV, and the most common cause of their morbidity and mortality. Following TB treatment, surviving individuals may be at risk for post-TB lung disease. The TB Sentinel Research Network (TB-SRN) provides a platform for coordinated observational TB research within the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS AND ANALYSIS: This prospective, observational cohort study will assess treatment and post-treatment outcomes of pulmonary TB (microbiologically confirmed or clinically diagnosed) among 2600 people aged ≥15 years, with and without HIV coinfection, consecutively enrolled at 16 sites in 11 countries, across 6 of IeDEA's global regions. Data regarding clinical and sociodemographic factors, mental health, health-related quality of life, pulmonary function, and laboratory and radiographic findings will be collected using standardised questionnaires and data collection tools, beginning from the initiation of TB treatment and through 12 months after the end of treatment. Data will be aggregated for proposed analyses. ETHICS AND DISSEMINATION: Ethics approval was obtained at all implementing study sites, including the Vanderbilt University Medical Center Human Research Protections Programme. Participants will provide informed consent; for minors, this includes both adolescent assent and the consent of their parent or primary caregiver. Protections for vulnerable groups are included, in alignment with local standards and considerations at sites. Procedures for requesting use and analysis of TB-SRN data are publicly available. Findings from TB-SRN analyses will be shared with national TB programmes to inform TB programming and policy, and disseminated at regional and global conferences and other venues.

Phase 2 study of ibrutinib plus venetoclax in Japanese patients with relapsed/refractory mantle cell lymphoma.

BACKGROUND: Despite high response rates to initial therapy, most patients with mantle cell lymphoma (MCL) experience relapsed or refractory (R/R) disease. Here, we report the efficacy, safety, and pharmacokinetics of the Phase 2, single-arm M20-075 study (NCT04477486) of ibrutinib and venetoclax combination therapy in Japanese patients with R/R MCL. METHODS: Patients received 560 mg ibrutinib and 400 mg venetoclax (after a 5-week ramp-up from 20 mg) once daily for up to 104 weeks. Primary endpoint was complete response (CR) rate by independent review committee (IRC). Secondary endpoints included overall response rate (ORR), duration of response (DOR), undetectable minimal residual disease (uMRD) rate, progression-free survival (PFS), overall survival (OS), safety including dose-limiting toxicity (DLT) assessment in the first six patients, and pharmacokinetic parameters. Full analysis set (FAS) comprised all treated patients. Per protocol set (PPS) excluded treated patients with non-evaluable disease at baseline by IRC. RESULTS: Thirteen patients were treated (FAS n = 13; PPS, n = 12). Median age was 71 years, patients had a median of two prior treatments. After a median follow-up of 9.6 months, IRC-assessed CR rate and ORR were both 83% (PPS). All six MRD-evaluable patients had uMRD. Median DOR, PFS, and OS were unreached. The most common Grade ≥ 3 treatment-emergent adverse event (TEAE) was neutropenia (23%); 1 patient discontinued due to squamous cell carcinoma of the lung. No DLTs, tumor lysis syndrome, or deaths related to TEAEs were observed. CONCLUSION: Ibrutinib plus venetoclax exhibited high response rates and a well-tolerated safety profile in Japanese patients with R/R MCL.

Measurement of Head Kinematics Using Instrumented Mouthguards During Introductory Boxing Courses in U.S. Military Academy Cadets.

INTRODUCTION: Use of wearable impact sensor devices to quantitatively measure head impact exposure remains largely unstudied in military-style martial arts training and combat sports, particularly at the beginner levels. The baseline frequency and severity of head impact exposure during introductory military-style martial arts trainings, such as combatives training, is valuable information for developing future programs of instruction and exposure monitoring programs. The purpose of this study was to describe head impact exposures experienced during introductory combatives training (a boxing course) at U.S. Military Academy. METHODS: This study used instrumented mouthguards to measure head impact exposure in U.S. Military Academy cadets during a compulsory boxing course. Summary exposures from a preliminary dataset are presented. RESULTS: Twenty-two male subjects (19.9 ± 1.1 years, 86.6 ± 11.7 kg) participated in 205 analyzed player-bouts (full contact sparring sessions) with 809 video verified impacts (average 3.9 impacts per player-bout). The mean peak linear acceleration was 16.5 ±7.1 G, with a maximum of 70.8 G. There was a right-skewed distribution, with 640/809 (79.1%) events falling between 10 and 20 G. The mean peak angular acceleration was 1.52 ± 0.96 krad/s2, with a maximum of 8.85 krad/s2. CONCLUSIONS: Compared to other high-risk sports at Service Academies, head impacts from beginner boxing were of similar magnitude to those reported for Service Academy football and slightly lower than those reported for Service Academy rugby. Based on these preliminary data, the risk profile for introductory military-style martial arts training, such as boxing or combatives, may be similar to other contact sports like football and rugby, but further research is required to confirm these findings and understand the effects of the exposures in a shorter duration.

t(11;14) status is stable between diagnosis and relapse, and concordant between detection methodologies based on fluorescence in situ hybridization and next-generation sequencing in patients with multiple myeloma.

Multiple myeloma (MM) is associated with a wide variety of recurrent genomic alterations. The most common translocation in MM is t(11;14). In this retrospective, single-center, non-interventional study, patient bone marrow samples were examined at diagnosis and at relapse(s) following treatment with anti-myeloma regimens to determine whether t(11;14) status was stable over time. This Stability Cohort consisted of 272 patients, of whom 118 were t(11;14)-positive at diagnosis and 154 were negative. All patients in the Stability Cohort retained the same t(11;14) status at relapse that they had at diagnosis of MM. Sixteen patients who had t(11;14)-positive MM at diagnosis had multiple longitudinal FISH assessments at relapse events, which remained t(11;14)-positive across all time points. Patients who had t(11;14)-positive disease at diagnosis of monoclonal gammopathy of unknown significance (MGUS) or smoldering multiple myeloma (SMM) also retained t(11;14) positivity through MM diagnosis and relapse. The t(11;14) fusion patterns also remained constant for 90% of patients. For detection of t(11;14), results from fluorescence in situ hybridization (FISH) and next generation sequencing (NGS) were compared to determine the rate of concordance between these 2 methods. This Concordance Cohort contained 130 patients, of whom 66 had t(11;14)-positive disease and 64 were t(11;14)-negative. In this sample set, the concordance between FISH and NGS-based detection of t(11;14) was 100%. These results strongly suggest that the t(11;14) rearrangement remains stable during the full disease course in patients with multiple myeloma and can be detected by FISH- and NGS-based methodologies.

Evaluation of a semi-automated approach for FDG PET image analysis for routine clinical application in patients with multiple myeloma.

BACKGROUND: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/CT images in patients with multiple myeloma (MM) to standardize FDG PET application. METHODS: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD). RESULTS: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. CONCLUSIONS: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

Association Between Symptom Cluster Endorsement at Initiation of a Graduated Return-to-Activity Protocol and Time to Return to Unrestricted Activity After Concussion in United States Service Academy Cadets.

BACKGROUND: The endorsement of symptoms upon initiation of a graduated return-to-activity (GRTA) protocol has been associated with prolonged protocols. It is unclear whether there are specific symptom clusters affecting protocol durations. PURPOSE: To describe the endorsement of specific concussion symptom clusters at GRTA protocol initiation and examine the association between symptom cluster endorsement and GRTA protocol duration. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: This study was conducted among cadets enrolled at 3 US service academies. Participants completed an evaluation upon GRTA protocol initiation. Participants endorsing symptoms were binarized based on 6 symptom clusters (cognitive, emotional, insomnia, physical, sensitivity, and ungrouped). The primary outcome of interest was GRTA protocol duration based on symptom cluster endorsement severity. Prevalence rates were calculated to describe symptom cluster endorsement. Kaplan-Meier survival estimates and univariate and multivariable Cox proportional hazards regression models were calculated for all 6 symptom clusters to estimate GRTA protocol duration while controlling for significant covariates. RESULTS: Data from 961 concussed participants were analyzed. Of these, 636 participants were asymptomatic upon GRTA protocol initiation. Among the 325 symptomatic participants, the physical symptom cluster (80%) was most endorsed, followed by the cognitive (29%), insomnia (23%), ungrouped (19%), sensitivity (15%), and emotional (9%) clusters. Univariate results revealed a significant association between endorsing cognitive (hazard ratio [HR], 0.79; p = .001), physical (HR, 0.84; p < .001), insomnia (HR, 0.83; p = .013), sensitivity (HR, 0.70; p < .001), and ungrouped (HR, 0.75; p = .005) symptom clusters and GRTA protocol duration. Endorsing physical (HR, 0.84; p < .001) and sensitivity (HR, 0.81; p = .036) clusters maintained a significant association with GRTA protocol duration in the multivariable models. CONCLUSION: Participants endorsing physical or sensitivity symptom clusters displayed GRTA protocols prolonged by 16% to 19% compared with participants not endorsing that respective cluster after controlling for significant covariates.

Availability of screening and treatment for common mental disorders in HIV clinic settings: data from the global International epidemiology Databases to Evaluate AIDS (IeDEA) Consortium, 2016-2017 and 2020.

INTRODUCTION: Common mental disorders (CMDs) are highly prevalent among people with HIV. Integrating mental healthcare into HIV care may improve mental health and HIV treatment outcomes. We describe the reported availability of screening and treatment for depression, anxiety and post-traumatic stress disorder (PTSD) at global HIV treatment centres participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) Consortium in 2020 and changes in availability at sites in low- or middle-income countries (LMICs) between 2016/2017 and 2020. METHODS: In 2020, 238 sites contributing individual-level data to the IeDEA Consortium and in 2016/2017 a stratified random sample of IeDEA sites in LMICs were eligible to participate in site surveys on the availability of screening and treatment for CMDs. We assessed trends over time for 68 sites across 27 LMICs that participated in both surveys. RESULTS: Among the 238 sites eligible to participate in the 2020 site survey, 227 (95%) participated, and mental health screening and treatment data were available for 223 (98%) sites across 41 countries. A total of 95 sites across 29 LMICs completed the 2016/2017 survey. In 2020, 68% of sites were in urban settings, and 77% were in LMICs. Overall, 50%, 14% and 12% of sites reported screening with a validated instrument for depression, anxiety and PTSD, respectively. Screening plus treatment in the form of counselling was available for depression, anxiety and PTSD at 46%, 13% and 11% of sites, respectively. Screening plus treatment in the form of medication was available for depression, anxiety and PTSD at 36%, 11% and 8% of sites, respectively. Among sites that participated in both surveys, screening for depression was more commonly available in 2020 than 2016/2017 (75% vs. 59%, respectively, p = 0.048). CONCLUSIONS: Reported availability of screening for depression increased among this group of IeDEA sites in LMICs between 2016/2017 and 2020. However, substantial gaps persist in the availability of mental healthcare at HIV treatment sites across global settings, particularly in resource-constrained settings. Implementation of sustainable strategies to integrate mental health services into HIV care is needed.

JAK3 Y841 Autophosphorylation Is Critical for STAT5B Activation, Kinase Domain Stability and Dimer Formation.

Janus tyrosine kinase 3 (JAK3) is primarily expressed in immune cells and is needed for signaling by the common gamma chain (γc) family of cytokines. Abnormal JAK3 signal transduction can manifest as hematological disorders, e.g., leukemia, severe combined immunodeficiency (SCID) and autoimmune disease states. While regulatory JAK3 phosphosites have been well studied, here a functional proteomics approach coupling a JAK3 autokinase assay to mass spectrometry revealed ten previously unreported autophosphorylation sites (Y105, Y190, Y238, Y399, Y633, Y637, Y738, Y762, Y824, and Y841). Of interest, Y841 was determined to be evolutionarily conserved across multiple species and JAK family members, suggesting a broader role for this residue. Phospho-substitution mutants confirmed that Y841 is also required for STAT5 tyrosine phosphorylation. The homologous JAK1 residue Y894 elicited a similar response to mutagenesis, indicating the shared importance for this site in JAK family members. Phospho-specific Y841-JAK3 antibodies recognized activated kinase from various T-cell lines and transforming JAK3 mutants. Computational biophysics analysis linked Y841 phosphorylation to enhanced JAK3 JH1 domain stability across pH environments, as well as to facilitated complementary electrostatic JH1 dimer formation. Interestingly, Y841 is not limited to tyrosine kinases, suggesting it represents a conserved ubiquitous enzymatic function that may hold therapeutic potential across multiple kinase families.

Normative Values for Pupillary Light Reflex Metrics Among Healthy Service Academy Cadets.

INTRODUCTION: Assessments of the pupil's response to light have long been an integral part of neurologic examinations. More recently, the pupillary light reflex (PLR) has shown promise as a potential biomarker for the diagnosis of mild traumatic brain injury. However, to date, few large-scale normative data are available for comparison and reference, particularly, in military service members. The purpose of this study was to report normative values for eight PLR measurements among healthy service academy cadets based on sex, age, sleep, race, ethnicity, anisocoria, and concussion history. METHODS: Freshmen entering a U.S. Service Academy completed a quantitative pupillometric assessment in conjunction with baseline concussion testing. PLR measurements were conducted using a Neuroptics PLR-3000 with a 121 µW light stimulus. The device measured maximum and minimum pupil diameter (mm), latency (time to maximum pupil constriction post-light stimulus [s]), peak and average constriction velocity (mm/s), average dilation velocity (mm/s), percentage pupil constriction, and T75 (time for pupil re-dilation from minimum pupil diameter to 75% maximum diameter [s]). During baseline testing, cadets also reported concussion history (yes and no) and hours slept the night before (<5.5 and ≥5.5). Normative values for each PLR measurement were calculated as mean ± SD, percentiles, and interquartile range. Mann-Whitney U tests were used to assess differences based on sex, concussion history, ethnicity, and hours slept for each PLR measurement. Kruskall-Wallis testing was used to assess differences based on age, race, and anisocoria. Alpha was set at .05 and nonparametric effect sizes (r) were calculated for statistically significant results. Effect sizes were interpreted as no effect (r < .1), small (r ≥.1-<.3), medium (r ≥.3-<.5), or large (r ≥ .5). All procedures were reviewed and approved by the local institutional review board and the U.S. Army Human Research Protection Office before the study was conducted. Each subject provided informed consent to participate in the study before data collection. RESULTS: Of the 1,197 participants baselined, 514 cadets (131 female; 18.91 ± 0.96 years) consented and completed a valid baseline pupillometric assessment. Eighty participants reported at least one previous concussion and participants reported an average of 5.88 ± 1.63 h slept the previous night. Mann-Whitney U results suggest females had larger initial (z = -3.240; P = .001; r = .10) and end pupil diameter (z = -3.080; P = .002; r = .10), slower average dilation velocity (z = 3.254; P = .001; r = .11) and faster T75 values (z = -3.342; P = .001; r = .11). Age, sleep, and race stratified by sex, also displayed a significant impact on specific PLR metrics with effect sizes ranging from small to medium, while ethnicity, anisocoria, and concussion history did not display an impact on PLR metrics. CONCLUSION: This study provides the largest population-specific normative values for eight PLR measurements. Initial and end pupil diameter, dilation velocity, and the T75 metrics differed by sex; however, these differences may not be clinically significant as small effect size was detected for all metrics. Sex, age, sleep, and race may impact specific PLR metrics and are worth consideration when performing PLR assessments for mild traumatic brain injury management.

The effect of extended shift work on autonomic function in occupational settings: A systematic review and meta-analysis.

OBJECTIVE: To examine the effect of 24-h shift work on autonomic nervous system function via heart rate variability (HRV) methodologies. METHODS: Electronic databases (indexed in either PubMed, MEDLINE, CINAHL, SPORTDiscus, or OpenDissertations) were searched from January 1964 to March 2023. A modified Downs and Black checklist was used for assessing methodological quality and the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the quality of evidence. Study design, study population, study sample, shift work description, and assessment of HRV metrics and methods were extracted from each study. FINDINGS: A total of 58 478 study articles were identified, of which 12 articles met inclusion criteria. Sample sizes varied from eight to 60 participants, with the ratio of low- to high-frequency HRV (LF/HF) as the most common frequency-domain variable reported. Of the nine included studies that observed LF/HF, three (33.3%) demonstrated a significant increase after 24-h shift work. Moreover, of the five studies that reported HF, two (40%) noted a significant decrease after 24-h shift work. When observing risk of bias, two (16.6%) studies were low quality, five (41.7%) were moderate quality, and five (41.7%) were high quality. INTERPRETATION: There were inconsistent findings demonstrating an effect of 24-h shift work on autonomic function, with a suggested shift away from parasympathetic dominance. Discrepancies in HRV methodologies, such as the duration of recordings and hardware used for measurement, may have contributed to the disparity in findings. In addition, differences in roles and responsibilities across occupations may explain the incongruence in findings across studies.