Does type of antiretroviral therapy pick-up point influence 12-month virologic suppression in South Africa?

We assessed the impact of community- versus clinic-based medication pick-up on rates of virologic suppression in an observational cohort of adults on ART enrolled in a decentralized antiretroviral therapy program (CCMDD) in South Africa. Participants either attended clinics where they were given the choice to pick up ART in community venues or traditional clinics, or clinics where this pathway was assigned. Among 1856 participants, 977 (53%) opted for community ART pick-up at enrollment, and 1201 (86%) were virologically suppressed at one year. Because of missing data on virologic suppression, primary results are based on a model incorporating multiple imputation. In addition to age and gender, distance from clinic and year of HIV diagnosis were included in the multivariable model. There was no difference in opting for clinic- vs. community-based pick-up with regard to achieving 12-month virologic suppression (aRR 1.02, 95% CI 0.98-1.05) in clinics offering choice. There was no impact of assigning all participants to an external pick-up point (aRR 1.00, 95% CI 0.95-1.06), but virologic suppression was reduced in the clinic that assigned participants to clinic pick-up (aRR 0.87, 95% CI 0.81-0.92). These results suggest that provision of community-based ART has not reduced continued virologic suppression in the population enrolled in the CCMDD program.

Laparoscopy experience in East, Central, and Southern Africa: insights from operative case volume analysis.

BACKGROUND: With the primary objective of addressing the disparity in global surgical care access, the College of Surgeons of East, Central, and Southern Africa (COSECSA) trains surgeons. While sufficient operative experience is crucial for surgical training, the extent of utilization of minimally invasive techniques during COSECSA training remains understudied. METHODS: We conducted an extensive review of COSECSA general surgery trainees' operative case logs from January 1, 2015, to December 31, 2020, focusing on the utilization of minimally invasive surgical procedures. Our primary objective was to determine the prevalence of laparoscopic procedures and compare this to open procedures. We analyzed the distribution of laparoscopic cases across common indications such as cholecystectomy, appendicitis, and hernia operations. Additionally, we examined the impact of trainee autonomy, country development index, and hospital type on laparoscopy utilization. RESULTS: Among 68,659 total cases, only 616 (0.9%) were laparoscopic procedures. Notably, 34 cases were conducted during trainee external rotations in countries like the United Kingdom, Germany, and India. Gallbladder and appendix pathologies were most frequent among the 582 recorded laparoscopic cases performed in Africa. Laparoscopic cholecystectomy accounted for 29% (276 of 975 cases), laparoscopic appendectomy for 3% (76 of 2548 cases), and laparoscopic hernia repairs for 0.5% (26 of 5620 cases). Trainees self-reported lower autonomy for laparoscopic (22.5%) than open cases (61.5%). Laparoscopy usage was more prevalent in upper-middle-income (2.7%) and lower-middle-income countries (0.8%) compared with lower-income countries (0.5%) (p < 0.001). Private (1.6%) and faith-based hospitals (1.5%) showed greater laparoscopy utilization than public hospitals (0.5%) (p < 0.001). CONCLUSIONS: The study highlights the relatively low utilization of minimally invasive techniques in surgical training within the ECSA region. Laparoscopic cases remain a minority, with variations observed based on specific diagnoses. The findings suggest a need to enhance exposure to minimally invasive procedures to ensure well-rounded training and proficiency in these techniques.

A Brief Mind-body Intervention Is Feasible and May Prevent Persistent Pain After Acute Orthopaedic Traumas: A Randomized Controlled Trial.

BACKGROUND: Approximately 20% to 50% of patients develop persistent pain after traumatic orthopaedic injuries. Psychosocial factors are an important predictor of persistent pain; however, there are no evidence-based, mind-body interventions to prevent persistent pain for this patient population. QUESTIONS/PURPOSES: (1) Does the Toolkit for Optimal Recovery after Injury (TOR) achieve a priori feasibility benchmarks in a multisite randomized control trial (RCT)? (2) Does TOR demonstrate a preliminary effect in improving pain, as well as physical and emotional function? METHODS: This pilot RCT of TOR versus a minimally enhanced usual care comparison group (MEUC) was conducted among 195 adults with an acute orthopaedic traumatic injury at risk for persistent pain at four geographically diverse Level 1 trauma centers between October 2021 to August 2023. Fifty percent (97 of 195) of participants were randomized to TOR (mean age 43 ± 17 years; 67% [65 of 97] women) and 50% (98) to MEUC (mean age 45 ± 16 years; 67% [66 of 98] women). In TOR, 24% (23 of 97) of patients were lost to follow-up, whereas in the MEUC, 17% (17 of 98) were lost. At 4 weeks, 78% (76 of 97) of patients in TOR and 95% (93 of 98) in the MEUC completed the assessments; by 12 weeks, 76% (74 of 97) of patients in TOR and 83% (81 of 98) in the MEUC completed the assessments (all participants were still included in the analysis consistent with an intention-to-treat approach). The TOR has four weekly video-administered sessions that teach pain coping skills. The MEUC is an educational pamphlet. Both were delivered in addition to usual care. Primary outcomes were feasibility of recruitment (the percentage of patients who met study criteria and enrolled) and data collection, appropriateness of treatment (the percent of participants in TOR who score above the midpoint on the Credibility and Expectancy Scale), acceptability (the percentage of patients in TOR who attend at least three of four sessions), and treatment satisfaction (the percent of participants in TOR who score above the midpoint on the Client Satisfaction Scale). Secondary outcomes included additional feasibility (including collecting data on narcotics and rescue medications and adverse events), fidelity (whether the intervention was delivered as planned) and acceptability metrics (patients and staff), pain (numeric rating scale), physical function (Short Musculoskeletal Function Assessment questionnaire [SMFA], PROMIS), emotional function (PTSD [PTSD Checklist], depression [Center for Epidemiologic Study of Depression]), and intervention targets (pain catastrophizing, pain anxiety, coping, and mindfulness). Assessments occurred at baseline, 4 and 12 weeks. RESULTS: Several outcomes exceeded a priori benchmarks: feasibility of recruitment (89% [210 of 235] of eligible participants consented), appropriateness (TOR: 73% [66 of 90] scored > midpoint on the Credibility and Expectancy Scale), data collection (79% [154 of 195] completed all surveys), satisfaction (TOR: 99% [75 of 76] > midpoint on the Client Satisfaction Scale), and acceptability (TOR: 73% [71 of 97] attended all four sessions). Participation in TOR, compared with the MEUC, was associated with improvement from baseline to postintervention and from baseline to follow-up in physical function (SMFA, baseline to post: -7 [95% CI -11 to -4]; p < 0.001; baseline to follow-up: -6 [95% CI -11 to -1]; p = 0.02), PROMIS (PROMIS-PF, baseline to follow-up: 2 [95% CI 0 to 4]; p = 0.045), pain at rest (baseline to post: -1.2 [95% CI -1.7 to -0.6]; p < 0.001; baseline to follow-up: -1 [95% CI -1.7 to -0.3]; p = 0.003), activity (baseline to post: -0.7 [95% CI -1.3 to -0.1]; p = 0.03; baseline to follow-up: -0.8 [95% CI -1.6 to -0.1]; p = 0.04), depressive symptoms (baseline to post: -6 [95% CI -9 to -3]; p < 0.001; baseline to follow-up: -5 [95% CI -9 to -2]; p < 0.002), and posttraumatic symptoms (baseline to post: -4 [95% CI -7 to 0]; p = 0.03; baseline to follow-up: -5 [95% CI -9 to -1]; p = 0.01). Improvements were generally clinically important and sustained or continued through the 3 months of follow-up (that is, above the minimum clinically important different [MCID] of 7 for the SMFA, the MCID of 3.6 for PROMIS, the MCID of 2 for pain at rest and pain during activity, the MCID of more than 10% change in depressive symptoms, and the MCID of 10 for posttraumatic symptoms). There were treatment-dependent improvements in pain catastrophizing, pain anxiety, coping, and mindfulness. CONCLUSION: TOR was feasible and potentially efficacious in preventing persistent pain among patients with an acute orthopaedic traumatic injury. Using TOR in clinical practice may prevent persistent pain after orthopaedic traumatic injury. LEVEL OF EVIDENCE: Level I, therapeutic study.

The impact of civil commitment laws for substance use disorder on opioid overdose deaths.

Objective: Our study analyzed the impact of civil commitment (CC) laws for substance use disorder (SUD) on opioid overdose death rates (OODR) in the U.S. from 2010-21. Methods: We used a retrospective study design using the CDC Wide-ranging Online Data for Epidemiologic Research (WONDER) dataset to analyze overdose death rates from any opioid during 2010-21 using ICD-10 codes. We used t-tests and two-way ANOVA to compare the OODR between the U.S. states with the law as compared to those without by using GraphPad Prism 10.0. Results: We found no significant difference in the annual mean age-adjusted OODR from 2010-21 between U.S. states with and without CC SUD laws. During the pre-COVID era (2010-19), the presence or absence of CC SUD law had no difference in age-adjusted OODR. However, in the post-COVID era (2020-21), there was a significant increase in OODR in states with a CC SUD law compared to states without the law (p = 0.032). We also found that OODR increased at a faster rate post-COVID among both the states with CC SUD laws (p < 0.001) and the states without the law (p = 0.019). Conclusion: We found higher age-adjusted OODR in states with a CC SUD law which could be due to the laws being enacted in response to the opioid crisis or physicians' opposition to or unawareness of the law's existence leading to underutilization. Recent enactment of CC SUD law(s), a lack of a central database for recording relapse rates, and disparities in opioid overdose rate reductions uncovers multiple variables potentially influencing OODR. Thus, further investigation is needed to analyze the factors influencing OODRs and long-term effects of the CC SUD laws.

Strategies and Challenges of a Safe Fireplace Program in Rural Kenya: A Qualitative Study.

There is a lack of information on effective burn prevention strategies. The objective of this study was to examine a safe fireplace program, as a method of burn prevention, in a resource-limited setting. We conducted a qualitative, phenomenological study at a community health and development program for a rural population in Kenya. Semi-structured, in-depth interviews were conducted with a purposive sample of community health workers involved with the safe fireplace program. Data were reviewed iteratively and coded independently by two researchers using NVivo 12. The study included five participants. Reflections from participants fell into three main domains: (1) effective methods of education, (2) strategies to incorporate stakeholders, and (3) implementation challenges. The results of this study emphasize the importance of community engagement in implementing a successful burn injury prevention program in a resource-limited setting. The participants involved in this study reported that rather than focusing on resources outside the community, effective methods of education and strategies for incorporating stakeholders depended on involving peers and community leaders. The challenges to the program were similarly specific to community concerns about resources and maintenance. These findings provide information to guide future community health programs in creating successful models for burn prevention strategies in resource-limited areas.

Impact of planned delivery mode on neonatal outcomes and costs in twin pregnancies in Kenya.

Background: Twin pregnancies are associated with higher risks of adverse neonatal outcomes compared to singleton pregnancies. The choice of delivery mode, when twin A presents cephalic, remains a subject of debate. In low- and middle-income countries, where healthcare resources are limited, the decision on the mode of delivery is even more critical. Objective: To evaluate the neonatal outcomes and the hospital costs of planned vaginal delivery compared to cesarean section (CS) in twin pregnancies with twin A presenting cephalic at Tenwek Hospital, Kenya. Study Design: This retrospective cohort study analyzed data from all twin deliveries at Tenwek Hospital, Kenya from, April 1, 2017, to March 30, 2023. Maternal data, mode of delivery, and neonatal data were collected from delivery logs, electronic health records, and neonatal records. Neonatal outcomes were a composite of either Appearance, Pulse, Grimace, Activity, and Respiration score less than seven at 5 minutes, neonatal intensive care unit admission, resuscitation, birth trauma, or neonatal complications, including death before discharge from the hospital. A logistic regression model was created to assess the impact of the planned mode of delivery on neonatal outcomes, controlling for antenatal care clinic visits, noncephalic presentation of twin B, and birth weight category. Results: The study included 177 twin deliveries: 129 (72.9%) were planned as vaginal deliveries and 48 (27.1%) were planned for CS. Among the planned vaginal deliveries, 66 (51.2%) experienced adverse outcomes, compared to 14 (29.2%) in the CS group (P=.009). Logistic regression showed that the odds of adverse outcomes were 0.35 times lower in the CS group compared to the planned vaginal delivery group (95% CI: 0.15-0.83; P=.017). The average total hospital costs for planned vaginal delivery were 104,608 Kenya Shillings (standard deviation 111,761) compared to 100,708 Kenya Shillings (standard deviation 75,468) for CS (P=.82). Conclusion: Planned cesarean deliveries in twin pregnancies with twin A presenting cephalic at Tenwek Hospital were associated with fewer adverse neonatal outcomes compared to planned vaginal deliveries. There was no significant difference in hospital costs. These findings raise the question of the safest mode of delivery for patients in a resource-constrained setting.

A Mind-Body Intervention to Improve Physical Activity for Patients with Chronic Hip-Related Pain: Protocol for a Mixed Methods Study.

BACKGROUND: Pain and dysfunction persist for most patients following hip-related pain treatment. Additionally, individuals with hip-related pain are typically less physically active than individuals without hip pain, despite evidence that regular physical activity reduces chronic musculoskeletal pain. Poor psychological health is common in patients with hip-related pain and further reinforces low physical activity. Mind-body interventions can improve psychological health and activity levels but have yet to be integrated to provide comprehensive, psychologically informed care for patients with hip-related pain. Thus, we are using the NCCIH intervention development framework to develop Helping Improve PSychological Health (HIPS), a novel, multimodal mind-body intervention to improve physical activity for individuals with hip-related pain and poor psychological health. METHODS: We will recruit physical therapists (N = 20) and patients with hip-related pain (N = 20) to participate in 60 min qualitative interviews (focus groups with therapists; one-on-one interviews with patients). Using these data, we will develop the initial HIPS intervention and provider training materials. One physical therapist will be trained to deliver the HIPS intervention to five participants in an open pilot trial. Participants will attend six 30 min HIPS intervention sessions. We will collect quantitative data on satisfaction, improvement, and physical activity, alongside qualitative exit interviews with participants and the physical therapist in order to refine the HIPS intervention and provider training materials. RESULTS: This study has been approved by the MGB IRB. We aim to develop and test the initial feasibility of the HIPS intervention in an open pilot trial. The findings from this project will inform a subsequent feasibility RCT.

MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.

Understanding the nature and extent of non-canonical human leukocyte antigen (HLA) presentation in tumour cells is a priority for target antigen discovery for the development of next generation immunotherapies in cancer. We here employ a de novo mass spectrometric sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical MHC-associated peptides specific to cancer without any prior knowledge of the target sequence from genomic or RNA sequencing data. Our strategy integrates MHC binding rank, Average local confidence scores, and peptide Retention time prediction for improved de novo candidate Selection; culminating in the machine learning model MARS. We benchmark our model on a large synthetic peptide library dataset and reanalysis of a published dataset of high-quality non-canonical MHC-associated peptide identifications in human cancer. We achieve almost 2-fold improvement for high quality spectral assignments in comparison to de novo sequencing alone with an estimated accuracy of above 85.7% when integrated with a stepwise peptide sequence mapping strategy. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, immunogenic, non-canonical peptide sequences in primary tumour tissue.

Improving multimodal physical function in adults with heterogeneous chronic pain; Protocol for a multisite feasibility RCT.

BACKGROUND: Chronic pain is associated with substantial impairment in physical function, which has been identified as a top concern among persons with pain. GetActive-Fitbit, a mind-body activity program, is feasible, acceptable, and associated with improvement in physical function among primarily White, sedentary individuals with pain. In preparation for a multisite efficacy trial, we must examine feasibility across multiple sites with diverse patient populations. Here we describe the protocol of a multisite, feasibility RCT comparing GetActive-Fitbit with a time- and attention-matched educational comparison (Healthy Living for Pain). We aim to 1) test multisite fidelity of clinician training; 2) evaluate multisite feasibility benchmarks, including recruitment of chronic pain patients taking <5000 steps/day and racial and ethnic minorities; and 3) optimize fidelity and study protocol in preparation for a future multisite efficacy trial. METHODS: Clinician training fidelity was assessed via roleplays and mock group sessions. Feasibility (i.e., recruitment, acceptability, credibility, adherence, satisfaction), multimodal physical function (e.g., self-report, 6-Minute Walk Test, step-count), and other psychosocial outcomes are assessed at baseline, posttest, and 6 months. Protocol optimization will be assessed using exit interviews and cross-site meetings. RESULTS: The trial is ongoing. Clinician training is complete. 87 participants have been recruited. 54 completed baseline assessments and randomization, 44 are mid-intervention, and 9 have completed the intervention and posttest. CONCLUSIONS: This study addresses the critical need for feasible, acceptable mind-body-activity interventions for chronic pain that follow evidence-based guidelines and improve all aspects of physical function across diverse populations. Results will inform a future fully-powered multisite efficacy trial. CLINICAL TRIAL REGISTRATION: NCT05700383.

Shieldin and CST co-orchestrate DNA polymerase-dependent tailed-end joining reactions independently of 53BP1-governed repair pathway choice.

53BP1 regulates DNA end-joining in lymphocytes, diversifying immune antigen receptors. This involves nucleosome-bound 53BP1 at DNA double-stranded breaks (DSBs) recruiting RIF1 and shieldin, a poorly understood DNA-binding complex. The 53BP1-RIF1-shieldin axis is pathological in BRCA1-mutated cancers, blocking homologous recombination (HR) and driving illegitimate non-homologous end-joining (NHEJ). However, how this axis regulates DNA end-joining and HR suppression remains unresolved. We investigated shieldin and its interplay with CST, a complex recently implicated in 53BP1-dependent activities. Immunophenotypically, mice lacking shieldin or CST are equivalent, with class-switch recombination co-reliant on both complexes. ATM-dependent DNA damage signalling underpins this cooperation, inducing physical interactions between these complexes that reveal shieldin as a DSB-responsive CST adaptor. Furthermore, DNA polymerase ζ functions downstream of shieldin, establishing DNA fill-in synthesis as the physiological function of shieldin-CST. Lastly, 53BP1 suppresses HR and promotes NHEJ in BRCA1-deficient mice and cells independently of shieldin. These findings showcase the resilience of the 53BP1 pathway, achieved through the collaboration of chromatin-bound 53BP1 complexes and DNA end-processing effector proteins.