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Introduction Antiretroviral therapy (ART) is very effective in preventing vertical transmission of HIV but some women on ART experience different virologic, immunologic, and safety profiles. While most pregnant women are closely monitored for short-term effects of ART during pregnancy, few women receive similar attention beyond pregnancy. We aimed to assess retention in care and clinical and laboratory-confirmed outcomes over 3 years after starting ART under Malawi’s Option B + program. Methods We conducted a prospective cohort study of pregnant women newly diagnosed with HIV who started tenofovir disoproxil fumarate/emtricitabine/efavirenz (TDF/3TC/EFV) for the first time at Bwaila Hospital in Lilongwe, Malawi between May 2015 and June 2016. Participants were followed for 3 years. We summarized demographic characteristics, pregnancy outcomes, and clinical and laboratory adverse events findings using proportions. Log-binomial regression models were used to estimate the overall risk ratios (RR) and the corresponding 95% confidence interval (CI) for the association between index pregnancy (i.e. index pregnancy vs. subsequent pregnancy) and preterm birth, and index pregnancy and low birthweight. Results Of the 299 pregnant women who were enrolled in the study, 255 (85.3%) were retained in care. There were 340 total pregnancies with known outcomes during the 36-month study period, 280 index pregnancies, and 60 subsequent pregnancies. The risks of delivering preterm (9.5% for index pregnancy and13.5% for subsequent pregnancy: RR = 0.70; 95% CI: 0.32–1.54), or low birth weight infant (9.8% for index pregnancy and 4.2% for subsequent pregnancy: RR = 2.36; 95% CI: 0.58–9.66) were similar between index and subsequent pregnancies. Perinatally acquired HIV was diagnosed in 6 (2.3%) infants from index pregnancies and none from subsequent pregnancies. A total of 50 (16.7%) women had at least one new clinical adverse event and 109 (36.5%) women had at least one incident abnormal laboratory finding. Twenty-two (7.3%) women switched to second line ART: of these 64.7% (8/17) had suppressed viral load and 54.9% (6/17) had undetectable viral load at 36 months. Conclusion Most of the women who started TDF/3TC/EFV were retained in care and few infants were diagnosed with perinatally acquired HIV. Despite switching, women who switched to second line therapy continued to have higher viral loads suggesting that additional factors beyond TDF/3TC/EFV failure may have contributed to the switch. Ongoing support during the postpartum period is necessary to ensure retention in care and prevention of vertical transmission.

Outcomes for patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) that have progression after treatment with hypomethylating agent (HMA) and venetoclax (VEN) are poor. However, data for chemotherapy and VEN (C+VEN) therapy after prior treatment with HMA+VEN are limited. We identified 18 patients with AML or MDS/AML who received C+VEN after prior HMA+VEN. Complete remission (CR) or CR with incomplete hematologic recovery (CRi) was achieved in 7 patients (39%) and 6 patients (33%) proceeded to allogeneic hematopoietic stem cell transplantation. This study shows suggests that C+VEN could be a viable option in a subset of patients after HMA+VEN.

Background Whole-genome-based comparative bacterial phylogenetics led to Enterobacter aerogenes being renamed Klebsiella aerogenes. It is unclear how infections with K. aerogenes differ from Enterobacter cloacae complex (Ecc) regarding clinical characteristics, antibiotic resistance, patient outcomes, and bacterial virulence genes. Methods Adult inpatients with K. aerogenes or Ecc bloodstream infection (BSI) were prospectively enrolled at Duke from 2002–2015. Whole-genome bacteria sequencing was performed. Chi-squared, Fisher’s exact, Mann–Whitney U, t-tests, and multivariable logistic regression models identified risk factors for infection and clinical outcomes. PanOCT algorithm identified flexible genomic islands (fgi). Multidrug resistance (MDR) was defined as resistance to ≥3 drug classes and poor clinical outcome as death before discharge and/or BSI complication (septic shock, acute kidney injury, acute lung injury/acute respiratory distress syndrome, disseminated intravascular coagulation). Results We identified 104 (69%) patients with Ecc BSI and 46 (31%) with K. aerogenes BSI (N = 150). Patients with Ecc BSI more often required hemodialysis (23% vs. 9%, P = 0.04). MDR was similar between Ecc and K. aerogenes (30% vs. 33%; P = 0.85). Total (21% vs. 28%; P = 0.3) and attributable in-hospital mortality (12% vs. 20%; P = 0.3) did not differ between the two genera. Poor clinical outcome was more common with K. aerogenes BSI (70% vs. 40%, P = 0.001) and remained significant after adjusting for age, source of BSI, site of acquisition (e.g., hospital), days to appropriate antibiotic, and chronic APACHE-II score (odds ratio 2.8, 95% CI 1.2–6.4, P = 0.001). Ecc and K. aerogenes isolates formed 14 and 3 phylogenetic clades, respectively (Fig 1A). K. aerogenes contained 983 core genes, grouped within 324 fgi, that were not present in Ecc (Fig 1B). These included homologs to virulence genes involved in iron acquisition, flagella synthesis, and fimbriae production. Conclusion Patients with BSI due to K. aerogenes had poor clinical outcomes relative to Ecc. Multiple unique K. aerogenes genes homologous to virulence factors may contribute to this difference. Disclosures All authors: No reported disclosures.

We aimed to understand drivers of HIV-infection in pregnant women in Malawi. The study was conducted in antenatal and labor and delivery wards. HIV-infected women and their partners (cases) were frequency matched in a 1:2 ratio based on age and screening location to HIV-uninfected women and their partners (controls) in a prevalent case–control study. Characteristics associated with female HIV infection were assessed using logistic regression modeling. At screening, HIV-infected women were more likely to have partners outside Lilongwe than HIV-uninfected women (24% vs. 0%, p < 0.0001). Case females were more likely to have HIV-infected study partners than control females (75% vs. 4%, p < 0.0001). The odds of female HIV-infection were higher if either couple member reported ≥ 2 lifetime marriages (OR 9.0, CI 2.6–30.9) or ≥ 3 lifetime partners (OR 18.0, CI 3.1–103.6) and lower if either reported past couple HIV testing and counseling (OR 0.1, CI 0.04–0.3). Targeting women with migrating partners, promoting couple HIV testing and counseling, and limiting partners could slow HIV transmission.

Policy changes are needed to ensure that Cooperative Research and Development Agreements and patent applications filed by the US National Institutes of Health are aligned with the interests of the American public.

Trex2 is a 3′ → 5′ exonuclease that removes 3′-mismatched sequences in a biochemical assay; however, its biological function remains unclear. To address biology we previously generated trex2null mouse embryonic stem (ES) cells and expressed in these cells wild-type human TREX2 cDNA (Trex2hTX2) or cDNA with a single-amino-acid change in the catalytic domain (Trex2H188A) or in the DNA-binding domain (Trex2R167A). We found the trex2null and Trex2H188A cells exhibited spontaneous broken chromosomes and trex2null cells exhibited spontaneous chromosomal rearrangements. We also found ectopically expressed human TREX2 was active at the 3′ ends of I-SceI–induced chromosomal double-strand breaks (DSBs). Therefore, we hypothesized Trex2 participates in DNA DSB repair by modifying 3′ ends. This may be especially important for ends with damaged nucleotides. Here we present data that are unexpected and prompt a new model. We found Trex2-altered cells (null, H188A, and R167A) were not hypersensitive to camptothecin, a type-1 topoisomerase inhibitor that induces DSBs at replication forks. In addition, Trex2-altered cells were not hypersensitive to γ-radiation, an agent that causes DSBs throughout the cell cycle. This observation held true even in cells compromised for one of the two major DSB repair pathways: homology-directed repair (HDR) or nonhomologous end joining (NHEJ). Trex2 deletion also enhanced repair of an I-SceI–induced DSB by both HDR and NHEJ without affecting pathway choice. Interestingly, however, trex2null cells exhibited reduced spontaneous sister chromatid exchanges (SCEs) but this was not due to a defect in HDR-mediated crossing over. Therefore, reduced spontaneous SCE could be a manifestation of the same defect that caused spontaneous broken chromosomes and spontaneous chromosomal rearrangements. These unexpected data suggest Trex2 does not enable DSB repair and prompt a new model that posits Trex2 suppresses the formation of broken chromosomes.

Immune checkpoint inhibitors (ICIs) activate the immune system against cancer and have become standard of care for many cancers. With increased ICI use, their toxicities known as immune-related adverse events (irAEs) are becoming more common, but it is unclear how prepared relevant clinicians feel to diagnose and treat irAEs. The objective of this study was to assess irAE knowledge, confidence, and experience among generalists and oncology clinicians to guide future curricular interventions related to irAEs. A 25-item survey with questions assessing knowledge, experience level, confidence, and resource utilization regarding irAE diagnosis and management was sent to University of Chicago-affiliated (UChicago) internal medicine residents and hospitalists (inpatient irAE management) along with UChicago oncology fellows, attendings, nurse practitioners (NPs), and physician assistants (PAs) (inpatient and outpatient) as well as Chicago community oncologists (outpatient) in June 2022. Overall response rate was 37% (171/467). Knowledge scores averaged below 70% for all clinicians. “No idea” responses were most common with knowledge questions on steroid-sparing agent use and ICI use for patients with preexisting autoimmune disease. IrAE experience correlated with higher knowledge for oncology attendings (p = 0.015) and hematology/oncology NPs/PAs (p = 0.031). IrAE experience correlated with higher confidence for residents (p = 0.026), oncology fellows (p = 0.047), and hematology/oncology NPs/PAs (p = 0.042). Most commonly utilized resources were colleagues and UpToDate, and most clinicians were very likely to use online resources in the future. Knowledge and confidence gaps exist, and they were somewhat mitigated by experience. Future irAE curricula can fill these needs through online role-specific resources: irAE identification for generalists versus irAE identification and management for oncologists.

Introduction: Rural populations, particularly in Africa, suffer worse health outcomes from poor health services access. Community health workers (CHWs) effectively improve health outcomes, but the best means for CHWs reaching rural populations is unknown. Since Zambia is predominantly Christian, this study explored the use of CHWs through churches as an existing community structure for promoting preventive health behaviors, specifically rotavirus vaccine uptake. Methods: A noncontrolled cross-sectional study of 32 churches receiving a packaged intervention of diarrhea prevention and treatment messaging was conducted with repeated time points of data collection over 13 months (2013-2014) in the Kafue District of Zambia. Two churches were selected for each of the 17 catchment areas, and CHWs were identified and trained in the intervention of promoting 4 key messages related to diarrhea prevention and treatment: hand washing with soap, exclusive breast-feeding, rotavirus vaccination, and treating diarrhea with oral rehydration solution and zinc. The intervention was conducted within existing church’s women’s groups, and data was collected on attendance and the distribution of Rota Cards for tracking rotavirus immunizations. Results: Nineteen (59%) churches completed the study, and CHWs delivered health messages at a total of 890 women’s group meetings. The overall reach of the intervention was to 37.0% of church-attending women, and the efficacy was 67.7% (317 of 468 Rota Cards collected at health centers). Discussion: Implementing community health programs is often expensive and unsustainable, but the reach and efficacy levels achieved through existing structures like churches are encouraging in resource-constrained countries. Churches can be effective channels for delivering health prevention strategies to often difficult-to-reach rural populations. Further research is needed to investigate the impact of the intervention on health outcomes.

BackgroundFragmented communication with patients and families during hospitalizations often leaves patients confused about the daily plan.ObjectiveTo pilot a supplemental text message–based platform for improving bidirectional communication about the clinical plan and patients’ goals.DesignRandomized controlled trialParticipantsThirty adult patients, thirty caregivers of pediatric patients, and the interns caring for them on inpatient general medicine and pediatric services.InterventionsPatients and caregivers were texted or emailed daily to report their personal goal and assess their understanding of the team’s clinical plan. Interns were texted daily to report the team’s clinical plan and to assess their understanding of the patient’s personal goal.Main MeasuresPrimary outcomes were feasibility, defined as survey response rates, and acceptability. Secondary outcomes were patient comprehension of the clinical plan, trainee comprehension of the patient’s goal, patient-centered communication scores, and educational satisfaction scores.Key ResultsThirty adult patients, thirty caregivers of pediatric patients, fourteen general medicine interns, and six general pediatric interns enrolled. Intervention feasibility was met, with survey response rates of 80% for general medicine trainees, 67% for general pediatric trainees, 58% for adult patients, and 70% for caregivers. Patients and caregivers in the intervention arm had higher understanding of medication changes (76% vs 50%, p = 0.02) and new consultations (90% vs 61%, p = 0.002). Interns had higher understanding of patients’ goals in the intervention arm (93% vs 40%, p < 0.001), particularly for adult patients (97% vs 17%, p < 0.001). Caregivers rated communication higher regarding information to help make decisions (p = 0.04). Interviews demonstrated high acceptability.ConclusionsOur text message–based communication intervention was feasible and acceptable to all involved participants, with preliminary signals of efficacy. The intervention may contribute to improved understanding of medication changes and new consultations, as well as help in making decisions. A large, randomized efficacy trial of this intervention is warranted.

Immune checkpoint inhibitors (ICIs) are approved for the treatment of a variety of cancer types. The doses of these drugs, though approved by the Food and Drug Administration (FDA), have never been optimised, likely leading to significantly higher doses than required for optimal efficacy. Dose optimisation would hypothetically decrease the risk, severity, and duration of immune-related adverse events, as well as provide an opportunity to reduce costs through interventional pharmacoeconomic strategies such as off-label dose reductions or less frequent dosing. We summarise existing evidence for ICI dose optimisation to advocate for the role of interventional pharmacoeconomics.