Faculty Bibliography

OBJECTIVES/OBJECTIVE:This study investigates the prevalence of the use of reusable menstrual materials in LMICs, examines differences in prevalence between countries and areas, and identifies individual and country-level factors associated with their use. METHODS:Data from Multiple Indicator Cluster surveys conducted between 2017 and 2020 in LMICs were used. Prevalence estimates and 95% CIs were calculated for overall, rural, and urban areas. Multivariable logistic regression was used to identify individual and country-level factors associated with the use of reusable menstrual materials. RESULTS:The study included 42 surveys from LMICs, with 1653850 weighted women and girls aged 15-49 years. The overall prevalence of the use of reusable menstrual materials was 12.1% (95% CI 12.1-12.2), with significant variation between and within countries, ranging from 0.5% (0.3-0.8) in Serbia to 97.2% (96.5-97.9) in Sao Tome and Principe. The prevalence was higher in rural areas (23.9% [23.8-24.0]) than in urban areas (6.2% [6.2-6.2]), with significant differences between most countries. Use of reusable menstrual materials was associated with lower education levels, being married, low economic status, living in Asia and Africa, living in countries with lower GDP, living in rural areas, and limited availability of private places to wash menstrual materials. The prevalence of the use of reusable menstrual materials had an inverse linear relationship with the country's GDP. CONCLUSIONS:The study found that the use of reusable menstrual materials is more prevalent among women and girls in rural areas, those with lower education levels, lower economic status, and those living in countries with lower GDP. Given these disparities, policies and initiatives targeted at improving menstrual health in LMICs should focus on socioeconomically disadvantaged groups to ensure they have access to safe and appropriate menstrual materials.

Magnetic resonance elastography (MRE) is a non-invasive method for determining the mechanical response of tissues using applied harmonic deformation and motion-sensitive MRI. MRE studies of the human brain are typically performed at conventional field strengths, with a few attempts at the ultra-high field strength, 7T, reporting increased spatial resolution with partial brain coverage. Achieving high-resolution human brain scans using 7T MRE presents unique challenges of decreased octahedral shear strain-based signal-to-noise ratio (OSS-SNR) and lower shear wave motion sensitivity. In this study, we establish high resolution MRE at 7T with a custom 2D multi-slice single-shot spin-echo echo-planar imaging sequence, using the Gadgetron advanced image reconstruction framework, applying Marchenko-Pastur Principal component analysis denoising, and using nonlinear viscoelastic inversion. These techniques allowed us to calculate the viscoelastic properties of the whole human brain at 1.1 mm isotropic imaging resolution with high OSS-SNR and repeatability. Using phantom models and 7T MRE data of eighteen healthy volunteers, we demonstrate the robustness and accuracy of our method at high-resolution while quantifying the feasible tradeoff between resolution, OSS-SNR, and scan time. Using these post-processing techniques, we significantly increased OSS-SNR at 1.1 mm resolution with whole-brain coverage by approximately 4-fold and generated elastograms with high anatomical detail. Performing high-resolution MRE at 7T on the human brain can provide information on different substructures within brain tissue based on their mechanical properties, which can then be used to diagnose pathologies (e.g. Alzheimer's disease), indicate disease progression, or better investigate neurodegeneration effects or other relevant brain disorders,in vivo.

In 2022, 1 in 8 people in the world were living with obesity, and lifestyle interventions that include diet, exercise, and behavioral modification have been the foundation for management of obesity. Recently, pharmacologic therapies have been developed for management of obesity, the newest of these being glucagon-like peptide 1 receptor agonists. With the development of new pharmacologic options, the American Gastroenterological Association developed a guideline in 2022 to provide evidence-based recommendations for the pharmacologic management of obesity in adults and recommended, for adults with obesity or overweight with weight-related complications who have had an inadequate response to lifestyle interventions, adding pharmacologic agents to lifestyle interventions over continuing lifestyle interventions alone. In this article, 2 experts review the available evidence to answer the following questions: How effective are lifestyle interventions for the treatment of obesity? How effective are pharmacologic interventions for the treatment of obesity? Given these options, how do you engage in a shared decision-making discussion to develop a mutually agreed-on treatment plan?

Treatment with the hypomethylating agent 5-azacytidine (AZA) increases survival in high-risk (HR) myelodysplastic syndrome (MDS) patients, but predicting patient response and overall survival remains challenging. To address these issues, we analyzed mutational and transcriptional profiles in CD34+ hematopoietic stem/progenitor cells (HSPCs) before and following AZA therapy in MDS patients. AZA treatment led to a greater reduction in the mutational burden in both blast and hematological responders than non-responders. Blast and hematological responders showed transcriptional evidence of pre-treatment enrichment for pathways such as oxidative phosphorylation, MYC targets, and mTORC1 signaling. While blast non-response was associated with TNFa signaling and leukemia stem cell signature, hematological non-response was associated with cell-cycle related pathways. AZA induced similar transcriptional responses in MDS patients regardless of response type. Comparison of blast responders and non-responders to normal controls, allowed us to generate a transcriptional classifier that could predict AZA response and survival. This classifier outperformed a previously developed gene signature in a second MDS patient cohort, but signatures of hematological responses were unable to predict survival. Overall, these studies characterize the molecular consequences of AZA treatment in MDS HSPCs and identify a potential tool for predicting AZA therapy responses and overall survival prior to initiation of therapy.

BACKGROUND:Cigarette smoking affects fracture repair, leading to delayed healing or nonunion. PURPOSE/OBJECTIVE:We sought to investigate if cigarette smoke differentially affects intramembranous and endochondral ossification in healing fractures, focusing on whether endochondral ossification is particularly impaired. METHODS:This study utilized a bilateral femur fracture model in Sprague Dawley rats to examine the impact of cigarette smoke exposure on healing of femur fractures, treated with either a custom-locked intramedullary nail or compression plating to induce endochondral and membranous ossification, respectively. Animals were exposed to tobacco smoke 30 days before and after surgery, with evaluations including radiographs, histomorphometry, and microCT at 10 days, 1, 3, and 6-months post-operation, and biomechanical testing at 3, 6 months. RESULTS:Sixty-eight animals were randomized to control or exposure groups (two died perioperatively), and 89% of the femora achieved union when harvested at 3 and 6 months. Smoke exposure delayed cartilaginous callus formation and bone maturation in nailed fractures compared to plated fractures and controls in same animals. Plated fractures in exposed animals exhibited little cartilage callus and healed like control animals. At 3 months, plated fractures were stiffer and stronger than nailed fractures in both groups, but these differences vanished by 6 months. CONCLUSIONS:Plated fractures healed more rapidly and more completely than nailed fractures under both control and smoke-exposed conditions. CLINICAL RELEVANCE/CONCLUSIONS:Using compression plating instead of IM nailing for closed long bone fractures may lead to better outcomes in patients who smoke compared to current results with nailing.

BACKGROUND:rVSVΔG-ZEBOV-GP is the first approved vaccine with clinical efficacy against Ebola virus disease. Although a seroprotective threshold has not been defined for those at occupational risk of exposure, the current vaccine strategy is to attain a sustained high level of antibody titres. The aim of this trial was to explore the effects of delayed boosting upon both the height and duration of antibody titres following primary immunisation. METHODS:plaque-forming unit per mL of VSVΔG-ZEBOV-GP. 18 months later, individuals who consented and were still eligible were randomly assigned 1:1 to receive either a homologous booster dose or no booster. Study visits for safety and serial blood collections for antibody titres were done on enrolled participants at months 0, 1, 3, 6, 12, 18, 19, 24, 30, and 36. Through July, 2021, a web-based application was used for randomisation, including assignments with schedules for each of the five sites using mixed permuted blocks. The trial was not masked to participants or site staff. The primary endpoint was a comparison of geometric mean titres (GMTs) of anti-Ebola virus glycoprotein IgG antibody at month 36 (ie, 18 months after randomisation) for all randomly assigned participants who completed the 36 months of follow-up (primary analysis cohort). Investigators were aware of antibody titres from baseline (enrolment) through month 18 but were masked to summary data by randomisation group after month 18. This study is registered with ClinicalTrials.gov (NCT02788227). FINDINGS/RESULTS:Of the 248 participants who enrolled and received their primary immunisation, 114 proceeded to the randomisation step at month 18. The two randomisation groups were balanced: 57 participants (24 [42%] of whom were female; median age was 42 years [IQR 35-50]) were randomly assigned to the booster group and 57 (24 [42%] of whom were female; median age was 42 years [IQR 36-51]) to the no-booster group. Of those randomly assigned, 92 participants (45 in the booster group and 47 in the no-booster group) completed 36 months of follow-up. At 18 months after primary immunisation, GMTs in the no-booster group increased from a baseline of 10 ELISA units (EU)/mL (95% CI 7-14) to 1451 EU/mL (1118-1882); GMTs in the booster group increased from 9 EU/mL (6-16) to 1769 EU/mL (1348-2321). At month 19, GMTs were 31 408 EU/mL (23 181-42 554) for the booster group and 1406 EU/mL (1078-1833) for the no-booster group; at month 36, GMTs were 10 146 EU/mL (7960-12 933) for the booster group and 1240 EU/mL (984-1563) for the no-booster group. Accordingly, the geometric mean ratio (GMR) of antibody titres had increased almost 21-fold more in the booster versus no-booster group at 1 month after booster administration (GMR 20·6; 95% CI 18·2-23·0; p<0·0001) and was still over 7-fold higher at month 36 (GMR 7·8; 95% CI 5·5-10·2; p<0·0001). Consistent with previous reports of this vaccine's side-effects, transient mono-articular or oligo-articular arthritis was diagnosed in 18 (9%) of 207 primary vaccination recipients; after randomisation, arthritis was diagnosed in one (2%) of 57 participants in the no-booster group. No new cases of arthritis developed after booster administration. Four serious adverse events occurred following randomisation: one (epistaxis) in the booster group and three (gastrointestinal haemorrhage, prostate cancer, and tachyarrhythmia) in the no-booster group. None of the serious adverse events was judged attributable to the booster vaccination assignment. INTERPRETATION/CONCLUSIONS:In addition to no new safety concerns and in marked contrast to earlier trials evaluating short-term boosting, delaying a rVSVΔG-ZEBOV-GP booster until month 18 resulted in an increase in GMT that remained several-fold above the no-booster group GMT for at least 18 months. These findings could have implications for defining the optimal timing of booster doses as pre-exposure prophylaxis in populations at ongoing risk for Ebola virus exposure. FUNDING/BACKGROUND:The Division of Intramural Research and the Division of Clinical Research of the National Institute of Allergy and Infectious Diseases at the US National Institutes of Health, Canadian Immunization Research Network through the Public Health Agency of Canada, Canadian Institutes of Health Research, and the US Defense Threat Reduction Agency.

INTRODUCTION/BACKGROUND:Approximately 50 % of resected stage II-IV melanoma patients develop recurrent disease by 5 years despite adjuvant anti-PD-1 therapy. Data to define best management of recurrences is lacking. METHODS:This was a multicentre, international, retrospective cohort study. Patients with resected stage II-IV melanoma who commenced adjuvant anti-PD-1-based therapy before January 2022 and later recurred were identified. Data on demographics, disease characteristics, recurrence patterns, management and outcomes were collected. RESULTS:711 patients from 17 sites were included. Median age was 60 [range 16-92], 64 % were male, 2 % stage II, 91 % were stage III, 7 % stage IV. Median time to recurrence was 6.2 months (0-68.5) and median follow up time from recurrence was 19.8 months (range 0.2-73.1). 63 % recurred on anti-PD-1 therapy, 36 % off therapy [3 % < 6 months, 33 % > 6 months]. Initial recurrences were locoregional (LR) alone in 44 %, distant alone (DR) in 43 %, and 11 % in both sites. LR recurrences were managed with local therapy, alone (62 %) or with "second adjuvant" anti-PD-1 (14 %) or BRAF/MEK therapy (23 %); 12 m RFS2 was 25 %, 29 % and 69 % respectively (p = 0.0045). Definitive systemic therapy at first recurrence was given in 16 % LR and 86 % DR, with best outcomes for anti-CTLA4 + anti-PD-1 and trial combinations (24 m PFS 63 % and 69 %, respectively). The 24 m OS for the entire cohort was 65 %. CONCLUSION/CONCLUSIONS:Most recurrences following adjuvant anti-PD-1 based therapy occur early and while still on drug. Outcomes are poor, regardless of site, timing of recurrence, and subsequent treatment.

The astrocyte, a major glial cell type in the central nervous system (CNS), is widely regarded as a functionally diverse mediator of homeostasis. During development and throughout adulthood, astrocytes have essential roles, such as providing neuron metabolic support, modulating synaptic function, and maintaining the blood-brain barrier (BBB). Recent evidence continues to underscore their functional heterogeneity and importance for CNS maintenance, as well as how these cells ensure optimal CNS and immune responses to disease, acute trauma, and infection. Advances in our understanding of neuroimmune interactions complement our knowledge of astrocyte functional heterogeneity, where astrocytes are now regarded as key effectors and propagators of immune signaling. This shift in perspective highlights the role of astrocytes not merely as support cells, but as active participants in CNS immune responses.

From the perspective of developing relevant interventions for treating HIV and controlling its spread, it is particularly important to comprehensively understand the underlying diversity of the virus, especially in countries where the virus has been present and evolving since the cross-species transmission event that triggered the global pandemic. Here, we generate and phylogenetically analyse sequences derived from the gag-protease (2010 bp; n = 115), partial integrase (345 bp; n = 36), and nef (719 bp; n = 321) genes of HIV-1 group M (HIV-1M) isolates sampled between 2000 and 2022 from two cosmopolitan cities and 40 remote villages of Cameroon. While 52.4% of all sequenced viruses belonged to circulating recombinant form (CRF) 02_AG (CRF02_AG), the remainder were highly diverse, collectively representing seven subtypes and sub-subtypes, eight CRFs, and 36 highly divergent lineages that fall outside the established HIV-1M classification. Additionally, in 77 samples for which at least two genes were typed, 31% of the studied viruses apparently had fragments from viruses belonging to different clades. Furthermore, we found that the distribution of HIV-1M populations is similar between different regions of Cameroon. In contrast, HIV-1M demographics in Cameroon differ significantly from those in its neighbouring countries in the Congo Basin (CB). In phylogenetic trees, viral sequences cluster according to the countries where they were sampled, suggesting that while there are minimal geographical or social barriers to viral dissemination throughout Cameroon, there is strongly impeded dispersal of HIV-1M lineages between Cameroon and other locations of the CB. This suggests that the apparent stability of highly diverse Cameroonian HIV-1M populations may be attributable to the extensive mixing of human populations within the country and the concomitant trans-national movements of major lineages with very similar degrees of fitness; coupled with the relatively infrequent inter-national transmission of these lineages from neighbouring countries in the CB.