Walter Reed Army Institute of Research

Kenyan guidelines recommend syndromic management for sexually transmitted infections (STIs), which may miss many infections. We used nucleic acid amplification testing to screen for Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) at 3 anatomic sites among adolescents and adults with behavioral risk factors in Western Kenya. From December 2021 to April 2023, we enrolled participants without HIV who were aged 14 to 55 years and reported a recent history of an STI, transactional sex, condomless sex with multiple partners, injection drug use, and/or anal sex with male partners. Urine, oropharyngeal swabs, and anorectal swabs were tested using Xpert CT/NG (Cepheid). Multivariable robust Poisson regression models were used to estimate prevalence ratios and 95% confidence intervals for factors potentially associated with the prevalence of both STIs combined. Among 405 participants tested for CT/NG at enrollment, 324 (80.0%) were females, and 324 (80.0%) were aged 14 to 24 years. CT and/or NG was diagnosed in 143 participants (35.3%), including CT in 111 (27.4%) and NG in 76 (18.8%). Infections were most prevalent at the urogenital site, with 124 (30.6%) participants diagnosed with urogenital CT and/or NG. Anorectal CT/NG was observed in 117 (28.9%) and oropharyngeal CT/NG in 14 (3.5%). Females had higher prevalences than males of both urogenital (33.6% vs. 18.5%, P = 0.012) and anorectal CT/NG (31.8% vs. 17.3%, P = 0.015). A theoretical screening approach that only tested for urogenital infections would have missed 18.0% of CT cases and 18.4% of NG cases. In multivariable analyses, there were no statistically significant associations between sociodemographic variables and CT/NG prevalence. Urogenital and anorectal CT/NG infections were common in 2 communities in Western Kenya with behavioral vulnerability but difficult to predict based on sociodemographic variables. Nucleic acid amplification testing-based urogenital and anorectal screening of sexually active adolescents and young adults could reduce CT/NG burden in this population.

Plasmodium falciparum is responsible for what appears to be a never-ending public health issue in the developing world. With repeated infections, a gradual semi-immunity to severe malaria can be acquired but this is disrupted when women become pregnant as the parasite cytoadheres in the placenta to prevent splenic clearance. This change in tissue tropism is due to specific transcription of the antigenically variable adhesin VAR2CSA. To better understand the molecular mechanisms activating var2csa and antigenic variation overall, we used a combination of phenotypic and systems biology assays. We first established phenotypically homogenous populations of VAR2CSA expressing and placenta binding parasites that were shown to exclusively transcribe var2csa while all other var genes remained silenced. We also confirmed that the transcriptional activation was strongly associated with distinct depletion of repressive H3K9me3 marks. Further, we used chromatin conformation capture as a high-resolution approach to determine interchromosomal interactions and established that transcriptional activation is linked to a small yet significant repositioning of var2csa relative to heterochromatic telomeric clusters. Lastly, we demonstrated that occupancy of 5-methylcytosine was present in all var genes but independent of transcriptional repression and switching. All together, these findings provide insights at high resolution into the potential role of 5-methylcytosine in P. falciparum and increase our understanding of the mechanisms regulating antigenic variation at the epigenetics and chromatin structure level.

Deep brain stimulation (DBS) has increasingly been pursued as a treatment for obesity over the past couple of decades. This has occurred despite limited scientific justification or a serious ethical analysis of the concerns it raises. These interventions have relied on an “obese brain” model, which treats fatness as a neurological defect that can and should be corrected—reflecting and reinforcing stigmatizing, racialized assumptions about self-control, deviance, and bodily normalcy. To show this, we situate DBS for obesity within the broader and ethically troubling history of psychosurgery. We critique the scientific basis of the obese brain model and argue that its moral justification ultimately collapses. In this narrative framing, we argue that DBS for obesity is not a therapeutic innovation; instead it is a continuation of medicine’s role in pathologizing nonconformity.

Immune imprinting, in which prior antigenic exposures biases recall toward dominant epitopes, constrains the breadth and durability of influenza vaccine protection. Here we show that targeted variation across multiple hemagglutinin (HA) head sites (A, B, and D) between sequential A(H3N2) vaccines reprograms epitope hierarchy-redirecting recall toward conserved, subdominant head and stem epitopes. In a controlled ferret model mimicking imprinting-like recall in humans, antigenically distant priming accelerates neutralizing antibody induction, broadens reactivity, enhances cross-protection, and reduces viral shedding after drifted virus challenge. Epitope mapping and structural analysis confirms redirection toward conserved epitopes; single-cell transcriptomics and ELISpot assays reveal amplified germinal center B cell and Th1 responses. This "epitope hierarchy reshaping" links targeted antigenic variation to enhanced B cell competition, amplified T cell help, and improved viral control. This principle is likely applicable to vaccines against other rapidly evolving viruses where strong imprinting effects similarly limit immune breadth.

33 Background: Historically, PSA DT can be prognostic for metastasis free survival in BCR (as defined on computed tomography (CT) and bone scan). PSA DT is also an important tool in risk stratification in BCR to identify which patients (pts) require therapy (e.g. pts with a PSA DT>6 months). The emerging use of PSMA imaging creates another tool to assess BCR pts, but there is no data on the association of PSA DT and PSMA findings. Methods: NCT05588128 enrolls BCR pts after definitive +/- salvage therapies. Pts must have a PSA>0.5 ng/ml, testosterone >100 ng/dL, and negative CT/bone scans. Lymph nodes (LNs) up to 1.5 cm and prior therapies are permitted. All patients undergo a baseline PSMA PET scan, along with measurement of PSA and PSA DT. Here we describe the relationship between baseline PSA metrics and baseline PSMA imaging findings in patients with BCR. Results: 130 patients are currently evaluable with a median age= 71 years, baseline PSA of 1.95 ng/dL (range: 0.5 to 71) and PSA DT of 10.6 months (range 1.2 to 132) off therapy. Of all participants, 16.9% (n=22) had findings limited to the prostate bed and 34.6% (n=45) had PSMA+ avidity in the prostate bed with other findings. 42.3% (n=55) had PSMA + LNs, and 13.8% (n=18) had PSMA+ bone lesions. Four patients had serosal deposits with PSMA avidity, and one patient had a PSMA+ lung nodule. Conclusions: These data are the first to compare PSMA imaging results with corresponding PSA levels and PSA DT in a large cohort of patients with BCR. Results show that pts with historically favorable/long PSA DT may have high volume/bone+ findings on PSMA. There is no data to suggest treatment escalation is required in BCR pts with high volume PSMA findings, but long/favorable PSA DT. These results highlight the caveats of using PSMA imaging alone to drive treatment decisions in BCR without further data for how baseline PSMA imaging corresponds with long-term outcomes. Clinical trial information: NCT05588128 . PSMA PET+ lesion locations by PSA doubling time in patients with BCR prostate cancer (total n=130). PSA DT # Pts Median PSA PSMA Neg Prostate+ only Lymph Nodes+ ≥ 4 Lymph Nodes+ Bone+ ≥12 mo 52 3.55 9 (17.3%) 16 (30.8%) 24 (46.2%) 12 (23%) 6 (11.5%) 9 to <12 mo 20 1.56 2 (10%) 4 (20%) 11 (55%) 3 (15%) 3 (15%) 6 to <9 mo 17 0.9 5 (29.4%) 0 (0%) 12 (70%) 8 (47.1%) 2 (11.8*) <6 mo 41 2.1 5 (12.2%) 2 (4.9%) 28 (68.3) 15 (36.6) 7 (17.1)

We evaluated the incidence of anxiety, depression, and suicidality amongst TC survivors and the impact of chemotherapy on these outcomes. We conducted a retrospective cohort study of men diagnosed with TC in the United States Veterans Affairs Health System from 1990 to 2016. De novo anxiety or depression was a composite endpoint comprised of diagnosis codes for anxiety, depression, or medications used to treat these diagnoses. Incident suicidality was defined as a diagnosis code for suicidal ideation. 2022 TC patients were compared in a 1:3 ratio to 6375 controls. Cox proportional hazards models were employed for statistical analysis. Mean age at diagnosis was 42.6 years. 5-year cumulative incidence of anxiety or depression was 53.4% in TC patients and 35% for controls (p < 0.001). TC patients were more likely to develop anxiety or depression (HR 1.66, 95% CI 1.56-1.78, p < 0.001) and suicidality (HR 22.99, 95% CI 17.52-30.17, p < 0.001). In the TC cohort, factors associated with a higher risk of anxiety or depression were divorce (HR 1.15, 95% CI 1.00-1.32, p = 0.044), unemployment (HR 1.68, 95% CI 1.47-1.9, p < 0.001), and receipt of chemotherapy (HR 1.20, 95% CI 1.06-1.35, p < 0.001). Psychological morbidity due to depression, anxiety, and suicidality is high among TC survivors. In our analysis chemotherapy increases the rates of psychosocial morbidity. Clinicians should be proactive in screening and intervening for these diagnoses in TC survivors to provide early intervention and improve health comes.

Human conflicts are associated with increased prevalence of multi-drug-resistant organisms (MDROs). Here, we investigate a collection of extensively drug resistant (XDR) bacteria recovered from foreign combatants wounded in Ukraine and evacuated to a U.S. military treatment facility in Germany between November 2022 and March 2024. As part of routine surveillance, perirectal swabs were collected upon admission from all patients arriving from outside Germany. Whole genome sequencing, antimicrobial resistance gene (AMR) carriage, and antimicrobial susceptibility testing (AST) was determined for all isolates. Genetic relatedness to a set of isolates from soldiers treated at Ukrainian hospitals was assessed. Eighty-six deduplicated clinically significant MDROs were cultured from 32 combatants from 10 countries injured in Ukraine and subsequently treated in Germany. Twenty-three (72%) patients carried isolates from well-established global lineages of Enterococcus faecium (ST117), Klebsiella pneumoniae (ST147, 395), Acinetobacter baumannii (ST78) and Pseudomonas aeruginosa (ST235, ST773) that harbored carbapenemase (IMP, NDM, OXA), a 16S rRNA methyltransferase (ArmA, RmtB, RmtC), and/or the van operon, with 14 patients having >1 of these organisms. Sixteen combatants carried isolates genetically related to those from Ukrainian patients, suggesting acquisition occurred in Ukraine. AST revealed multiple isolates non-susceptible to cefiderocol (n = 8) or aztreonam-avibactam (n = 6), further complicating treatment options for carbapenemase-producing organisms. This is the first study describing the epidemiology of MDROs collected from a population of foreign combatants injured in Ukraine. The findings forecast challenges to clinicians and infection prevention and control both in Ukraine and foreign healthcare systems as combatants are repatriated.