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Background: Most human immunodeficiency virus (HIV) point-of-care tests detect antibodies (Ab) but not p24 antigen (Ag) or RNA. In the absence of antibodies, p24 antigen and RNA typically indicate acute HIV infection. We conducted a field evaluation of the Determine® HIV-1/2 Ag/Ab Combo rapid test (Combo RT).Methods: The antigen portion of the Combo RT (for acute HIV infection) was compared with a Roche Monitor HIV RNA polymerase chain reaction assay. The antibody portion of Combo RT (for established HIV infection) was compared with rapid test algorithms. Participants were enrolled at a sexually transmitted infection clinic and HIV testing and counseling center in Lilongwe, Malawi. Rapid testing was conducted with parallel testing in the clinic and serial testing in the center. The Combo RT was performed in clinic participants with negative or discordant antibody results and in all center participants.Results: Of the participants 838 were HIV negative, 163 had established HIV infection, and 8 had acute HIV infection. For detecting acute HIV infection, the antigen portion had a sensitivity of 0.000 and a specificity of 0.983. For detecting established HIV infection, the antibody portion had a sensitivity of 0.994 and a specificity of 0.992.Conclusions: Combo RT displayed excellent performance for detecting established HIV infection and poor performance for detecting acute HIV infection. In this setting, Combo RT is no more useful than current algorithms. [ABSTRACT FROM AUTHOR]

This study examined the relationship between reading women's beauty and fashion magazines and the use of pathogenic dieting methods (laxatives, appetite suppressants/diet pills, skipping two meals a day, intentional vomiting, and restricting calories to 1,200 or less each day) among 502 high school females. Weak to moderate positive associations were found between reading frequency and each of these unhealthful practices except the use of laxatives. When controlling for anxiety about weight and frequency of regular exercise, however, the original bivariate relations between reading frequency and skipping two meals a day, and reading and intentional vomiting, disappeared. Replication and weak specification effects were found when examining the relationships between reading and taking appetite suppressant/weight control pills, and reading and restricting calories, under the control conditions. These findings suggest that two of the most common adolescent dieting methods--restricting calories and taking diet pills--appear to be influenced by the reading of women's beauty and fashion magazines. [ABSTRACT FROM AUTHOR]

Single-cell cytometry data are crucial for understanding the role of the immune system in diseases and responses to treatment. However, traditional methods for annotating cytometry data face challenges in scalability, robustness, and accuracy. We propose a cytometry masked autoencoder (cyMAE), which automates immunophenotyping tasks including cell type annotation. The model upholds user-defined cell type definitions, facilitating interpretability and cross-study comparisons. The training of cyMAE has a self-supervised phase, which leverages large amounts of unlabeled data, followed by fine-tuning on specialized tasks using smaller amounts of annotated data. The cost of training a new model is amortized over repeated inferences on new datasets using the same panel. Through validation across multiple studies using the same panel, we demonstrate that cyMAE delivers accurate and interpretable cellular immunophenotyping and improves the prediction of subject-level metadata. This proof of concept marks a significant step forward for large-scale immunology studies., Competing Interests: Declaration of interests E.J.W. is a member of the Parker Institute for Cancer Immunotherapy, which supports cancer immunotherapy research in his laboratory. E.J.W. is an advisor for Arsenal Biosciences, Coherus, Danger Bio, IpiNovyx, NewLimit, Marengo, Pluto Immunotherapeutics, Related Sciences, Santa Ana Bio, and Synthekine. E.J.W. is a founder of and holds stock in Coherus, Danger Bio, Prox Biosciences, and Arsenal Biosciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Background: Advances in surgical practices have decreased hospital length of stay (LOS) after surgery. This study aimed to determine the safety of short-stay (≤24-hour) left colectomy for colon cancer patients in the US., Study Design: Adult colon cancer patients who underwent elective left colectomies were identified using the American College of Surgeons NSQIP database (2012 to 2021). Patients were categorized into 4 LOS groups: LOS 1 day or less (≤24-hour short stay), 2 to 4, 5 to 6, and 7 or more. Primary outcomes were 30-day postoperative overall and serious morbidity. Secondary outcomes were 30-day mortality and readmission. Multivariable logistic regression was performed to explore the association between LOS and overall and serious morbidity., Results: A total of 15,745 patients who underwent left colectomies for colon cancer were identified with 294 (1.87%) patients undergoing short stay. Short-stay patients were generally younger and healthier with lower 30-day overall morbidity rates (LOS ≤1 day: 3.74%, 2 to 4: 7.38%, 5 to 6: 16.12%, and ≥7: 37.64%, p < 0.001). Compared with patients with LOS 2 to 4 days, no differences in mortality and readmission rates were observed. On adjusted analysis, there was no statistical difference in the odds of overall (LOS 2 to 4 days: odds ratio 1.90, 95% CI 1.01 to 3.60, p = 0.049) and serious morbidity (LOS 2 to 4 days: odds ratio 0.86, 95% CI 1.42 to 1.76, p = 0.672) between the short-stay and LOS 2 to 4 days groups., Conclusions: Although currently performed at low rates in the US, short-stay left colectomy is safe for a select group of patients. Attention to patient selection, refinement of clinical pathways, and close follow-up may enable short-stay colectomies to become a more feasible reality., (Copyright © 2023 by the American College of Surgeons. Published by Wolters Kluwer Health, Inc. All rights reserved.)

The incorporation of the nonstandard amino acid para-nitro-L-phenylalanine (pN-Phe) within proteins has been used for diverse applications, including the termination of immune self-tolerance. However, the requirement for the provision of chemically synthesized pN-Phe to cells limits the contexts where this technology can be harnessed. Here we report the construction of a live bacterial producer of synthetic nitrated proteins by coupling metabolic engineering and genetic code expansion. We achieved the biosynthesis of pN-Phe in Escherichia coli by creating a pathway that features a previously uncharacterized nonheme diiron N-monooxygenase, which resulted in pN-Phe titers of 820 ± 130 µM after optimization. After we identified an orthogonal translation system that exhibited selectivity toward pN-Phe rather than a precursor metabolite, we constructed a single strain that incorporated biosynthesized pN-Phe within a specific site of a reporter protein. Overall, our study has created a foundational technology platform for distributed and autonomous production of nitrated proteins., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Several studies have shown that various anticoagulants used for collection of blood samples produce varying effects on haematological analyses. Tripotassium ethylenediamine tetra-acetic acid (K 3 EDTA), sodium citrate and lithium heparin remain the most used anticoagulants employed in hematological analysis. There is paucity of data on the effect of these anticoagulants on haematological parameters in humans in Ghana. We assessed the suitability of K 3 EDTA, sodium citrate and lithium heparin for routine Full Blood Count (FBC) investigation., Method: A laboratory-based analytical cross-sectional study was conducted using blood samples from 55 conveniently sampled apparently healthy tertiary students from January 2021 to October 2021. Blood samples were taken from each participant into 3 anticoagulant tubes: K 3 EDTA, sodium citrate and lithium heparin and FBC parameters estimated using the Mindray automated haematology analyzer. One-way ANOVA Kruskal-Wallis test, Mann-Whitney U, Intra-class correlation coefficient (ICC) analysis, Bland-Altman's plot and Lin's concordance correlation coefficient were used where appropriate to ascertain the level of variation, consistency, and agreements among and between results. Normality testing using Shapiro-Wilk test statistic revealed non-Gaussian distribution of data, hence, were presented as median, minimum, and maximum. Data generated were analyzed using STATA v15 and MedCalc v20 where appropriate for statistical analysis. P -values <0.05 were considered statistically significant., Results: The study comprised 34 males and 21 females. The median age for males (23 years: min = 20, max = 34) was statistically comparable (p = 0.2652) to that of females (22 years: min = 18, max = 34). We observed excellent consistency in the estimation of MCV (ICC = 0.94), MCH (ICC = 0.98), MCHC (ICC = 0.91), GRAN# (ICC = 0.92) and LYMPH% (ICC = 0.91) across the three anticoagulants. Heparin and K 3 EDTA largely agreed on most of the FBC parameters, 50.0% (7/14) including HGB, MCV, MCH, PLT, LYMPH#, GRAN# and GRAN%. Meanwhile using K 3 EDTA as a standard, heparin produced almost perfect agreement only in the assessment of RBC (CCC = 0.992) while a substantial agreement was observed in the assessment of HGB (0.971), HCT (0.958) and MCH (0.987). Citrate agreed substantially with K 3 EDTA in the assessment of LYMPH% (CCC = 0.964) and moderately in the assessment of MCV (CCC = 0.948) and MCH (0.913). Overall, compared to K 3 EDTA, heparin was highly precise and accurate in the estimation of HGB, RBC, HCT and MCH while citrate determined MCV and MCH more accurately and precisely., Conclusion: Citrated blood consistently produced lower FBC values compared to heparin and K 3 EDTA and hence suggests not reliable in the assessment of FBC among humans. Heparin agreed largely with K 3 EDTA in the estimation of FBC parameters and may be used as a better alternative anticoagulant in the absence of K 3 EDTA however with great caution., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Aggressive breast cancers portend a poor prognosis, but current polygenic risk scores (PRSs) for breast cancer do not reliably predict aggressive cancers. Aggressiveness can be effectively recapitulated using tumor gene expression profiling. Thus, we sought to develop a PRS for the risk of recurrence score weighted on proliferation (ROR-P), an established prognostic signature. Using 2363 breast cancers with tumor gene expression data and single nucleotide polymorphism (SNP) genotypes, we examined the associations between ROR-P and known breast cancer susceptibility SNPs using linear regression models. We constructed PRSs based on varying p-value thresholds and selected the optimal PRS based on model r 2 in 5-fold cross-validation. We then used Cox proportional hazards regression to test the ROR-P PRS's association with breast cancer-specific survival in two independent cohorts totaling 10,196 breast cancers and 785 events. In meta-analysis of these cohorts, higher ROR-P PRS was associated with worse survival, HR per SD = 1.13 (95% CI 1.06-1.21, p = 4.0 × 10 -4 ). The ROR-P PRS had a similar magnitude of effect on survival as a comparator PRS for estrogen receptor (ER)-negative versus positive cancer risk (PRS ER-/ER+ ) . Furthermore, its effect was minimally attenuated when adjusted for PRS ER-/ER+ , suggesting that the ROR-P PRS provides additional prognostic information beyond ER status. In summary, we used integrated analysis of germline SNP and tumor gene expression data to construct a PRS associated with aggressive tumor biology and worse survival. These findings could potentially enhance risk stratification for breast cancer screening and prevention., (© 2023. The Author(s).)

Germ-line hypomorphism of the pleiotropic transcription factor Myc in mice, either through Myc gene haploinsufficiency or deletion of Myc enhancers, delays onset of various cancers while mice remain viable and exhibit only relatively mild pathologies. Using a genetically engineered mouse model in which Myc expression may be systemically and reversibly hypomorphed at will, we asked whether this resistance to tumour progression is also emplaced when Myc hypomorphism is acutely imposed in adult mice. Indeed, adult Myc hypomorphism profoundly blocked KRas G12D -driven lung and pancreatic cancers, arresting their evolution at the early transition from indolent pre-tumour to invasive cancer. We show that such arrest is due to the incapacity of hypomorphic levels of Myc to drive release of signals that instruct the microenvironmental remodelling necessary to support invasive cancer. The cancer protection afforded by long-term adult imposition of Myc hypomorphism is accompanied by only mild collateral side effects, principally in haematopoiesis, but even these are circumvented if Myc hypomorphism is imposed metronomically whereas potent cancer protection is retained., (© 2022. The Author(s).)

Background: Skin and soft tissue infections (SSTIs) are commonly caused by group A Streptococcus (GAS). Rapid molecular assays for detecting GAS in wounds would help with clinical management. This study assessed a point-of-care system for the detection of GAS in non-severe SSTIs in a Native American community in the Southwest., Methods: Patients presenting with a new non-severe SSTI were eligible if a swab was collected. The swab was tested by traditional culture methods and using the cobas® Liat® point-of-care (POC) system and results were compared., Results: 399 samples were included. The final result from the POC assay was positive for 52.0% of samples. Compared to culture, the POC assay had a sensitivity of 100% and specificity of 99.5%., Conclusions: The cobas® Liat® system accurately and efficiently identified GAS in non-severe SSTIs. Having a POC test available to rapidly identify or rule out GAS could help to minimize overuse of antibiotics., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

To assess SARS-CoV-2 outcomes, we matched a municipal COVID-19 registry and clinic rosters from a municipal primary care network containing a large HIV clinic and assessed clinical outcomes by HIV status. The risk of severe COVID-19 was higher among people with HIV (PWH, adjusted relative risk = 1.84, 95% confidence interval = 1.05-3.25), while SARS-CoV-2 incidence was lower despite higher testing rates. SARS-CoV-2 vaccination campaigns should prioritize PWH to prevent severe COVID-19 disease given potentially higher risk., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Most cohorts show similar or lower COVID-19 incidence among people living with HIV compared with the general population. However, incidence might be affected by lower testing rates among vulnerable populations. We aimed to compare SARS-CoV-2 IgG seroprevalence, disease severity, and neutralising antibody activity after infection among people with and without HIV receiving care in a county hospital system over a 3-month period., Methods: In this matched case-control observational study, remnant serum samples were collected between Aug 1 and Oct 31, 2020, from all people living with HIV who underwent routine outpatient laboratory testing in a municipal health-care system (San Francisco General Hospital, CA, USA). Samples from people living with HIV were date of collection-matched (same day) and age-matched (±5 years) to samples from randomly selected adults (aged 18 years or older) without HIV receiving care for chronic conditions at the same hospital. We compared seroprevalence by HIV status via mixed-effects logistic regression models, accounting for the matched structure of the data (random effects for the matched group), adjusting for age, sex, race or ethnicity, and clinical factors (ie, history of cardiovascular or pulmonary disease, and type 2 diabetes). Severe COVID-19 was assessed in participants with past SARS-CoV-2 (IgG or PCR) infection by chart review and compared with multivariable mixed-effects logistic regression, adjusting for age and sex. SARS-CoV-2 IgG, neutralising antibody titres, and antibody avidity were measured in serum of participants with previous positive PCR tests and compared with multivariable mixed-effects models, adjusting for age, sex, and time since PCR-confirmed SARS-CoV-2 infection., Findings: 1138 samples from 955 people living with HIV and 1118 samples from 1062 people without HIV were tested. SARS-CoV-2 IgG seroprevalence was 3·7% (95% CI 2·4 to 5·0) among people with HIV compared with 7·4% (5·7 to 9·2) among people without HIV (adjusted odds ratio 0·50, 95% CI 0·30 to 0·83). Among 31 people with HIV and 70 people without HIV who had evidence of past infection, the odds of severe COVID-19 were 5·52 (95% CI 1·01 to 64·48) times higher among people living with HIV. Adjusting for time since PCR-confirmed infection, SARS-CoV-2 IgG concentrations were lower (percentage change -53%, 95% CI -4 to -76), pseudovirus neutralising antibody titres were lower (-67%, -25 to -86), and avidity was similar (7%, -73 to 87) among people living with HIV compared with those without HIV., Interpretation: Although fewer infections were detected by SARS-CoV-2 IgG testing among people living with HIV than among those without HIV, people with HIV had more cases of severe COVID-19. Among people living with HIV with past SARS-CoV-2 infection, lower IgG concentrations and pseudovirus neutralising antibody titres might reflect a diminished serological response to infection, and the similar avidity could be driven by similar time since infection., Funding: US National Institute of Allergy and Infectious Diseases, US National Institutes of Health., Competing Interests: Declaration of interests MAS, DVG, TJH, MG, and LBB report funding from the US National Institutes of Health during conduct of the study. DVG reports personal fees from Gilead Sciences outside the submitted work. All other authors declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objective: Sub-Saharan Africa faces twin epidemics of HIV and noncommunicable diseases including hypertension. Integrating hypertension care into chronic HIV care is a global priority, but cost estimates are lacking. In the SEARCH Study, we performed population-level HIV/hypertension testing, and offered integrated streamlined chronic care. Here, we estimate costs for integrated hypertension/HIV care for HIV-positive individuals, and costs for hypertension care for HIV-negative individuals in the same clinics., Design: Microcosting analysis of healthcare expenditures within Ugandan HIV clinics., Methods: SEARCH (NCT: 01864603) conducted community health campaigns for diagnosis and linkage to care for both HIV and hypertension. HIV-positive patients received hypertension/HIV care jointly including blood pressure monitoring and medications; HIV-negative patients received hypertension care at the same clinics. Within 10 Ugandan study communities during 2015-2016, we estimated incremental annual per-patient hypertension care costs using micro-costing techniques, time-and-motion personnel studies, and administrative/clinical records review., Results: Overall, 70 HIV-positive and 2355 HIV-negative participants received hypertension care. For HIV-positive participants, average incremental cost of hypertension care was $6.29 per person per year, a 2.1% marginal increase over prior estimates for HIV care alone. For HIV-negative participants, hypertension care cost $11.39 per person per year, a 3.8% marginal increase over HIV care costs. Key costs for HIV-positive patients included hypertension medications ($6.19 per patient per year; 98% of total) and laboratory testing ($0.10 per patient per year; 2%). Key costs for HIV-negative patients included medications ($5.09 per patient per year; 45%) and clinic staff salaries ($3.66 per patient per year; 32%)., Conclusion: For only 2-4% estimated additional costs, hypertension care was added to HIV care, and also expanded to all HIV-negative patients in prototypic Ugandan clinics, demonstrating substantial synergy. Our results should encourage accelerated scale-up of hypertension care into existing clinics., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We investigated whether serial measurements of circulating tumor DNA (ctDNA) and functional tumor volume (FTV) by magnetic resonance imaging (MRI) can be combined to improve prediction of pathologic complete response (pCR) and estimation of recurrence risk in early breast cancer patients treated with neoadjuvant chemotherapy (NAC). We examined correlations between ctDNA and FTV, evaluated the additive value of ctDNA to FTV-based predictors of pCR using area under the curve (AUC) analysis, and analyzed the impact of FTV and ctDNA on distant recurrence-free survival (DRFS) using Cox regressions. The levels of ctDNA (mean tumor molecules/mL plasma) were significantly correlated with FTV at all time points (p < 0.05). Median FTV in ctDNA-positive patients was significantly higher compared to those who were ctDNA-negative (p < 0.05). FTV and ctDNA trajectories in individual patients showed a general decrease during NAC. Exploratory analysis showed that adding ctDNA information early during treatment to FTV-based predictors resulted in numerical but not statistically significant improvements in performance for pCR prediction (e.g., AUC 0.59 vs. 0.69, p = 0.25). In contrast, ctDNA-positivity after NAC provided significant additive value to FTV in identifying patients with increased risk of metastatic recurrence and death (p = 0.004). In this pilot study, we demonstrate that ctDNA and FTV were correlated measures of tumor burden. Our preliminary findings based on a limited cohort suggest that ctDNA at surgery improves FTV as a predictor of metastatic recurrence and death. Validation in larger studies is warranted.

Background: Oral pre-exposure prophylaxis (PrEP) is highly effective for HIV prevention, but data are limited on HIV incidence among PrEP users in generalized epidemic settings, particularly outside of selected risk groups. We performed a population-based PrEP study in rural Kenya and Uganda and sought to evaluate both changes in HIV incidence and clinical and virologic outcomes following seroconversion on PrEP., Methods and Findings: During population-level HIV testing of individuals ≥15 years in 16 communities in the Sustainable East Africa Research in Community Health (SEARCH) study (NCT01864603), we offered universal access to PrEP with enhanced counseling for persons at elevated HIV risk (based on serodifferent partnership, machine learning-based risk score, or self-identified HIV risk). We offered rapid or same-day PrEP initiation and flexible service delivery with follow-up visits at facilities or community-based sites at 4, 12, and every 12 weeks up to week 144. Among participants with incident HIV infection after PrEP initiation, we offered same-day antiretroviral therapy (ART) initiation and analyzed HIV RNA, tenofovir hair concentrations, drug resistance, and viral suppression (<1,000 c/ml based on available assays) after ART start. Using Poisson regression with cluster-robust standard errors, we compared HIV incidence among PrEP initiators to incidence among propensity score-matched recent historical controls (from the year before PrEP availability) in 8 of the 16 communities, adjusted for risk group. Among 74,541 individuals who tested negative for HIV, 15,632/74,541 (21%) were assessed to be at elevated HIV risk; 5,447/15,632 (35%) initiated PrEP (49% female; 29% 15-24 years; 19% in serodifferent partnerships), of whom 79% engaged in ≥1 follow-up visit and 61% self-reported PrEP adherence at ≥1 visit. Over 7,150 person-years of follow-up, HIV incidence was 0.35 per 100 person-years (95% confidence interval [CI] 0.22-0.49) among PrEP initiators. Among matched controls, HIV incidence was 0.92 per 100 person-years (95% CI 0.49-1.41), corresponding to 74% lower incidence among PrEP initiators compared to matched controls (adjusted incidence rate ratio [aIRR] 0.26, 95% CI 0.09-0.75; p = 0.013). Among women, HIV incidence was 76% lower among PrEP initiators versus matched controls (aIRR 0.24, 95% CI 0.07-0.79; p = 0.019); among men, HIV incidence was 40% lower, but not significantly so (aIRR 0.60, 95% CI 0.12-3.05; p = 0.54). Of 25 participants with incident HIV infection (68% women), 7/25 (28%) reported taking PrEP ≤30 days before HIV diagnosis, and 24/25 (96%) started ART. Of those with repeat HIV RNA after ART start, 18/19 (95%) had <1,000 c/ml. One participant with viral non-suppression was found to have transmitted viral resistance, as well as emtricitabine resistance possibly related to PrEP use. Limitations include the lack of contemporaneous controls to assess HIV incidence without PrEP and that plasma samples were not archived to assess for baseline acute infection., Conclusions: Population-level offer of PrEP with rapid start and flexible service delivery was associated with 74% lower HIV incidence among PrEP initiators compared to matched recent controls prior to PrEP availability. HIV infections were significantly lower among women who started PrEP. Universal HIV testing with linkage to treatment and prevention, including PrEP, is a promising approach to accelerate reductions in new infections in generalized epidemic settings., Trial Registration: ClinicalTrials.gov NCT01864603., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: CAK has received grant support to institution from the US National Institutes of Health and Gilead Research Scholars Program in HIV. DVH has received grant support from the US National Institutes of Health and study drug donation from Gilead Sciences. CM has received grant support from the US National Institutes of Health, the Stupski Foundation, and the Chan-Zuckerberg Biohub Foundation. LiBB has received grant support from the US National Institutes of Health. VJ has received grant support from the US Centers for Disease Control and Prevention/PEPFAR.

Purpose of Review: We examine the interplay between the HIV and COVID-19 epidemics, including the impact of HIV on COVID-19 susceptibility and severe disease, the effect of the COVID-19 epidemic on HIV prevention and treatment, and the influence of the HIV epidemic on responses to COVID-19., Recent Findings: Evidence to date does not suggest that people living with HIV (PLWH) have a markedly higher susceptibility to SARS-CoV-2 infection, with disparities in the social determinants of health and comorbidities likely having a greater influence. The majority of literature has not supported a higher risk for severe disease among PLWH in Europe and the United States, although a large, population-based study in South Africa reported a higher rate of death due to COVID-19. Higher rates of comorbidities associated with COVID-19 disease severity among PLWH is an urgent concern. COVID-19 is leading to decreased access to HIV prevention services and HIV testing, and worsening HIV treatment access and virologic suppression, which could lead to worsening HIV epidemic control., Conclusion: COVID-19 is threatening gains against the HIV epidemic, including the U.S. Ending the HIV Epidemic goals. The ongoing collision of these two global pandemics will continue to need both study and interventions to mitigate the effects of COVID-19 on HIV efforts worldwide.

Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jtd-19-2267). SHB reports grants from Steris and Medtronic, outside the submitted work. These funds are only used to fund research. The other authors have no conflicts of interest to declare.

Competing Interests: Disclosure Dr. Brown has nothing to disclose. Dr. Streiff is/was co-investigator of contracts from PCORI (CE-12-11-4489 and DI-1603-34596), from the AHRQ (1R01HS024547) and the NIH/NHLBI (R21HL129028). Dr. Streiff has received research funding from Boehringer-Ingelheim, Janssen, Portola and Roche , consulted for Bayer, CSL Behring, Daiichi-Sankyo, Janssen and Pfizer. Dr. Haut is/was primary investigator of contracts from PCORI (CE-12-11-4489 and DI-1603-34596) and co-investigator of another contract (PCS-1511-32745). Dr. Haut is primary investigator of a grant from the AHRQ (1R01HS024547) and is a co-investigator on a grant from the NIH/NHLBI (R21HL129028). Dr. Haut receives research grant support from the DOD/Army Medical Research Acquisition Activity and has received grant support from Henry M. Jackson Foundation. Dr. Haut receives book royalties from Lippincott, Williams, Wilkins and is a paid consultant to Vizient for their HIIN Venous Thromboembolism (VTE) Prevention Action Network.

The signature features of pancreatic ductal adenocarcinoma (PDAC) are its fibroinflammatory stroma, poor immune activity, and dismal prognosis. We show that acute activation of Myc in indolent pancreatic intraepithelial neoplasm (PanIN) epithelial cells in vivo is, alone, sufficient to trigger immediate release of instructive signals that together coordinate changes in multiple stromal and immune-cell types and drive transition to pancreatic adenocarcinomas that share all the characteristic stromal features of their spontaneous human counterpart. We also demonstrate that this Myc -driven PDAC switch is completely and immediately reversible: Myc deactivation/inhibition triggers meticulous disassembly of advanced PDAC tumor and stroma and concomitant death of tumor cells. Hence, both the formation and deconstruction of the complex PDAC phenotype are continuously dependent on a single, reversible Myc switch. SIGNIFICANCE: We show that Myc activation in indolent Kras G12D -induced PanIN epithelium acts as an immediate pleiotropic switch, triggering tissue-specific signals that instruct all the diverse signature stromal features of spontaneous human PDAC. Subsequent Myc deactivation or inhibition immediately triggers a program that coordinately disassembles PDAC back to PanIN. See related commentary by English and Sears, p. 495 ., (©2020 American Association for Cancer Research.)

Background: Optimal strategies for pre-exposure prophylaxis (PrEP) engagement in generalised HIV epidemics are unknown. We aimed to assess PrEP uptake and engagement after population-level HIV testing and universal PrEP access to characterise gaps in the PrEP cascade in rural Kenya and Uganda., Methods: We did a 72-week interim analysis of observational data from the ongoing SEARCH (Sustainable East Africa Research in Community Health) study. Following community sensitisation and PrEP education, we did HIV testing and offered PrEP at health fairs and facilities in 16 rural communities in western Kenya, eastern Uganda, and western Uganda. We provided enhanced PrEP counselling to individuals 15 years and older who were assessed as having an elevated HIV risk on the basis of serodifferent partnership or empirical risk score, or who otherwise self-identified as being at high risk but were not in serodifferent partnerships or identified by the risk score. PrEP follow-up visits were done at facilities, homes, or community locations. We assessed PrEP uptake within 90 days of HIV testing, programme engagement (follow-up visit attendance at week 4, week 12, and every 12 weeks thereafter), refills, self-reported adherence up to 72 weeks, and concentrations of tenofovir in hair samples from individuals reporting HIV risk and adherence during follow-up, and analysed factors associated with uptake and adherence. This study is registered with ClinicalTrials.gov, NCT01864603., Findings: Between June 6, 2016, and June 23, 2017, 70 379 community residents 15 years or older who had not previously been diagnosed with HIV were tested during population-level HIV testing. Of these individuals, 69 121 tested HIV-negative, 12 935 of whom had elevated HIV risk (1353 [10%] serodifferent partnership, 6938 [54%] risk score, 4644 [36%] otherwise self-identified risk). 3489 (27%) initiated PrEP, 2865 (82%) of whom did so on the same day as HIV testing and 1733 (50%) of whom were men. PrEP uptake was lower among individuals aged 15-24 years (adjusted odds ratio 0·55, 95% CI 0·45-0·68) and mobile individuals (0·61, 0·41-0·91). At week 4, among 3466 individuals who initiated PrEP and did not withdraw or die before the first visit, 2215 (64%) were engaged in the programme, 1701 (49%) received medication refills, and 1388 (40%) self-reported adherence. At week 72, 1832 (56%) of 3274 were engaged, 1070 (33%) received a refill, and 900 (27%) self-reported adherence. Among participants reporting HIV risk at weeks 4-72, refills (89-93%) and self-reported adherence (70-76%) were high. Among sampled participants self-reporting adherence at week 24, the proportion with tenofovir concentrations in the hair reflecting at least four doses taken per week was 66%, and reflecting seven doses per week was 44%. Participants who stopped PrEP accepted HIV testing at 4274 (83%) of 5140 subsequent visits; half of these participants later restarted PrEP. 29 participants of 3489 who initiated PrEP had serious adverse events, including seven deaths. Five adverse events (all grade 3) were assessed as being possibly related to the study drug., Interpretation: During population-level HIV testing, inclusive risk assessment (combining serodifferent partnership, an empirical risk score, and self-identification of HIV risk) was feasible and identified individuals who could benefit from PrEP. The biggest gap in the PrEP cascade was PrEP uptake, particularly for young and mobile individuals. Participants who initiated PrEP and had perceived HIV risk during follow-up reported taking PrEP, but one-third had drug concentrations consistent with poor adherence, highlighting the need for novel approaches and long-acting formulations as PrEP roll-out expands., Funding: National Institutes of Health, President's Emergency Plan for AIDS Relief, Bill & Melinda Gates Foundation, and Gilead Sciences., (Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: This study was done to determine the burden of invasive Staphylococcus aureus on the White Mountain Apache Tribal lands., Methods: Active population and laboratory-based surveillance for invasive S aureus infections was conducted from May 2016 to April 2018. A case was defined as a Native American individual living on or around the White Mountain Apache Tribal lands with S aureus isolated from a normally sterile body site., Results: Fifty-three cases were identified. Most cases were adults (90.6%) and had ≥1 underlying medical condition (86.8%), the most common of which were diabetes (49.1%) and obesity (41.5%). A total of 26.4% cases were categorized as community acquired. Most infections were methicillin-resistant (75.5%). A total of 7.5% of cases required amputation, and 7.7% of cases died within 30 days of initial culture. The incidence of invasive S aureus was 156.3 per 100 000 persons. The age-adjusted incidence of invasive methicillin-resistant S aureus was 138.2 per 100 000 persons., Conclusions: This community has a disproportionately high burden of invasive methicillin-resistant S aureus compared with the general US population. Interventions are urgently needed to reduce the morbidity and mortality associated with these infections., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: HIV-infected youth in sub-Saharan Africa are less likely to initiate antiretroviral therapy (ART) than older adults., Setting and Methods: Adult (≥15 years) residents enumerated during a census in 32 communities in rural Kenya and Uganda named social contacts in 5 domains: health, money, emotional support, food, and free time. Named contacts were matched to other enumerated residents to build social networks among 150,395 adults; 90% were tested for HIV at baseline. Among youth (15-24 years) who were ART naive at baseline (2013-2014), we evaluated whether having ≥1 network contact who was HIV infected predicted ART initiation within 3 years and modification of this association by age and strength of contact, using logistic regression with robust standard errors., Results: Among 1120 HIV-infected youth who were ART naive at baseline, 805 remained alive and community residents after 3 years. Of these, 270 (33.5%) named at least one baseline HIV-infected contact; 70% (569/805) subsequently initiated ART. Youth with ≥1 HIV-infected same-age baseline contact were more likely to initiate ART [adjusted odds ratio (aOR), 2.95; 95% confidence interval (CI): 1.49 to 5.86] than those with no HIV-infected contact, particularly if the contact was a strong tie (named in >1 domain; aOR, 5.33; 95% CI: 3.34 to 8.52). When nonhousehold contacts were excluded, having an HIV-infected same age contact who was a strong tie remained associated with ART initiation (aOR, 2.81; 95% CI: 1.76 to 4.49)., Conclusions: Interventions that increase and strengthen existing social connections to other HIV-infected peers at the time of HIV diagnosis may increase ART initiation among HIV-infected youth.

Background: Pulmonary resection can concurrently diagnose and treat known or suspected lung cancer, but is not without risk. Benign resection rates range widely (9% to 40%). We evaluated the impact of an Interventional Pulmonology (IP) program and dedicated Pulmonary Nodule Clinic on surgical benign resection rates at a single institution., Methods: An IP program was initiated in August 2010 that offered advanced diagnostic techniques and a dedicated Pulmonary Nodule Clinic was opened in August 2013. We retrospectively reviewed all patients who underwent resection for known or suspected lung cancer between 2005 and 2015 at our tertiary referral hospital. Demographics, preoperative tissue diagnoses, surgical procedure, final pathology, and staging were collected. Quarterly benign resection rates were calculated and plotted on a statistical quality control chart (P-Chart) to determine the impact of the IP program and Pulmonary Nodule Clinic on benign resection rates over time., Results: Of 1112 resections, 209 (19%) were benign. Variation in quarterly benign resection rates decreased after introduction of the IP program in 2010, and a significant (P<0.05) sustained decrease in the quarterly benign resection rate occurred after introduction of the pulmonary nodule clinic in 2013 to a new baseline of 12% compared with 24% before 2010. After introduction of the IP program, mean quarterly preoperative tissue diagnostic rates increased from 45% to 58% (P<0.01)., Conclusion: Integration of an IP program employing advanced diagnostic bronchoscopic techniques has improved preoperative diagnostic rates of suspicious pulmonary nodules and in combination with a pulmonary nodule clinic has resulted in fewer benign resections.