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Abstract Background The use of gastrointestinal disease multiplex polymerase chain reaction (GI PCR) testing has become common for suspected gastrointestinal infection. Patients often test positive for multiple pathogens simultaneously through GI PCR, although the clinical significance of this is uncertain. Methods This retrospective cohort study investigated risk factors and clinical outcomes associated with detection of multiple (as opposed to single) pathogens on GI PCR. We included adult patients who underwent GI PCR testing from 2020 to 2023 and had one or more pathogens detected. We compared patients with multiple versus those with single pathogens and hypothesized that immunosuppression would be a risk factor for detection of multiple pathogens. We further hypothesized that, during the 90 days after GI PCR testing, patients with multiple pathogens would have worse clinical outcomes such as increased rates of emergency department (ED) visits, death, hospitalization, or ambulatory care visits. Results GI PCR was positive in 1341 (29%) of tested patients; 356 patients had multiple pathogens and 985 had one pathogen. The most common pathogens included Enteropathogenic Escherichia coli (EPEC, 27%), norovirus (17%), and Enteroaggregative E. coli (EAEC, 14%) in both multi- and singly positive patients. Immunosuppression was not associated with multiple pathogens (adjusted odds ratio [aOR] 1.35, 95% CI 0.96, 1.86). The factors most associated with multiple pathogens were Hispanic ethnicity (OR 1.86, 95% CI 1.42, 2.45) and chronic kidney disease (OR 1.69, 95% CI 1.13, 2.49). Patients with multiple pathogens were more likely to have ED visits during the 90 days after GI PCR testing (40% vs. 32%, p

Abstract Background In the US, 1.2 million people live with HIV (PWH). Despite having near-normal life expectancies due to antiretroviral therapy (ART), many PWH seek an HIV cure, even if it means risking their lives. This willingness to take risks for a cure raises questions about “affective forecasting biases,” where people tend to overestimate the positive impact of future events on their well-being. We conducted a study to test two interventions to mitigate affective forecasting in the decisions of PWH about taking HIV cure medication. Methods We recruited PWH to complete a 30-minute survey about their current quality of life (QoL) and the QoL they anticipate after being cured of HIV, and assigned them to either no additional intervention, to one of two interventions intended to reduce affective forecasting bias, or to both interventions: (1) a defocusing intervention designed to broaden the number of life domains people consider when imagining life changes associated with new circumstances (e.g. HIV cure); and (2) an adaptation intervention to help them gauge fading of strong emotions over time. The study design included a 2 × 2 design: defocusing (yes/no) x adaptation (yes/no) intervention. We assessed PWH’s willingness to take hypothetical HIV sterilizing cure medication using the Time Trade-Off (TTO) and their quality of life predictions with WHOQOL-HIV. Results 296 PWH participated. Counter to what we had hypothesized, neither intervention significantly reduced PWH’s willingness to trade time for a cure. Instead, the defocusing intervention increased their willingness to trade time (IRR 1.77, p = 0.03). Exploratory analysis revealed that PWH with lower current quality of life who received the defocusing intervention were more willing to trade time for a cure. Conclusion These negative findings suggest that either these biases are difficult to overcome in the settings of HIV curative medication or other factors beyond affective forecasting biases influence willingness to participate in HIV curative studies, such as respondents’ current quality of life.

Abstract Background Implementation research generally assumes established evidence-based practices and prior piloting of implementation strategies, which may not be feasible during a public health emergency. We describe the use of a simulation model of the effectiveness of COVID-19 mitigation strategies to inform a stakeholder-engaged process of rapidly designing a tailored intervention and implementation strategy for individuals with serious mental illness (SMI) and intellectual/developmental disabilities (ID/DD) in group homes in a hybrid effectiveness-implementation randomized trial. Methods We used a validated dynamic microsimulation model of COVID-19 transmission and disease in late 2020/early 2021 to determine the most effective strategies to mitigate infections among Massachusetts group home staff and residents. Model inputs were informed by data from stakeholders, public records, and published literature. We assessed different prevention strategies, iterated over time with input from multidisciplinary stakeholders and pandemic evolution, including varying symptom screening, testing frequency, isolation, contact-time, use of personal protective equipment, and vaccination. Model outcomes included new infections in group home residents, new infections in group home staff, and resident hospital days. Sensitivity analyses were performed to account for parameter uncertainty. Results of the simulations informed a stakeholder-engaged process to select components of a tailored best practice intervention and implementation strategy. Results The largest projected decrease in infections was with initial vaccination, with minimal benefit for additional routine testing. The initial level of actual vaccination in the group homes was estimated to reduce resident infections by 72.4% and staff infections by 55.9% over the 90-day time horizon. Increasing resident and staff vaccination uptake to a target goal of 90% further decreased resident infections by 45.2% and staff infections by 51.3%. Subsequent simulated removal of masking led to a 6.5% increase in infections among residents and 3.2% among staff. The simulation model results were presented to multidisciplinary stakeholders and policymakers to inform the “Tailored Best Practice” package for the hybrid effectiveness-implementation trial. Conclusions Vaccination and decreasing vaccine hesitancy among staff were predicted to have the greatest impact in mitigating COVID-19 risk in vulnerable populations of group home residents and staff. Simulation modeling was effective in rapidly informing the selection of the prevention and implementation strategy in a hybrid effectiveness-implementation trial. Future implementation may benefit from this approach when rapid deployment is necessary in the absence of data on tailored interventions. Trial registration ClinicalTrials.gov NCT04726371

Background: Travel-related strategies to reduce the spread of COVID-19 evolved rapidly in response to changes in the understanding of SARS-CoV-2 and newly available tools for prevention, diagnosis, and treatment. Modeling is an important methodology to investigate the range of outcomes that could occur from different disease containment strategies. Methods: We examined 43 articles published from December 2019 through September 2022 that used modeling to evaluate travel-related COVID-19 containment strategies. We extracted and synthesized data regarding study objectives, methods, outcomes, populations, settings, strategies, and costs. We used a standardized approach to evaluate each analysis according to 26 criteria for modeling quality and rigor. Results: The most frequent approaches included compartmental modeling to examine quarantine, isolation, or testing. Early in the pandemic, the goal was to prevent travel-related COVID-19 cases with a focus on individual-level outcomes and assessing strategies such as travel restrictions, quarantine without testing, social distancing, and on-arrival PCR testing. After the development of diagnostic tests and vaccines, modeling studies projected population-level outcomes and investigated these tools to limit COVID-19 spread. Very few published studies included rapid antigen screening strategies, costs, explicit model calibration, or critical evaluation of the modeling approaches. Conclusion: Future modeling analyses should leverage open-source data, improve the transparency of modeling methods, incorporate newly available prevention, diagnostics, and treatments, and include costs and cost-effectiveness so that modeling analyses can be informative to address future SARS-CoV-2 variants of concern and other emerging infectious diseases (e.g., mpox and Ebola) for travel-related health policies.

Abstract Direct oral anticoagulants (DOACs) targeting activated factor Xa (FXa) are used to prevent or treat thromboembolic disorders. DOACs reversibly bind to FXa and inhibit its enzymatic activity. However, DOAC treatment carries the risk of anticoagulant-associated bleeding. Currently, only one specific agent, andexanet alfa, is approved to reverse the anticoagulant effects of FXa-targeting DOACs (FXaDOACs) and control life-threatening bleeding. However, because of its mechanism of action, andexanet alfa requires a cumbersome dosing schedule, and its use is associated with the risk of thrombosis. Here, we present the computational design, engineering, and evaluation of FXa-variants that exhibit anticoagulation reversal activity in the presence of FXaDOACs. Our designs demonstrate low DOAC binding affinity, retain FXa-enzymatic activity and reduce the DOAC-associated bleeding by restoring hemostasis in mice treated with apixaban. Importantly, the FXaDOACs reversal agents we designed, unlike andexanet alfa, do not inhibit TFPI, and consequently, may have a safer thrombogenic profile.

IntroductionInfant HIV prophylaxis with broadly neutralizing anti-HIV antibodies (bNAbs) could provide long-acting protection against vertical transmission. We sought to estimate the potential clinical impact and cost-effectiveness of hypothetical bNAb prophylaxis programmes for children known to be HIV exposed at birth in three sub-Saharan African settings.MethodsWe conducted a cost-effectiveness analysis using the CEPAC-Pediatric model, simulating cohorts of infants from birth through death in Côte d'Ivoire, South Africa and Zimbabwe. These settings were selected to reflect a broad range of HIV care cascade characteristics, antenatal HIV prevalence and budgetary constraints. We modelled strategies targeting bNAbs to only WHO-designated "high-risk" HIV-exposed infants (HR-HIVE) or to all HIV-exposed infants (HIVE). We compared four prophylaxis approaches within each target population: standard of care oral antiretroviral prophylaxis (SOC), and SOC plus bNAbs at birth (1-dose), at birth and 3 months (2-doses), or every 3 months throughout breastfeeding (Extended). Base-case model inputs included bNAb efficacy (60%/dose), effect duration (3 months/dose) and costs ($60/dose), based on published literature. Outcomes included paediatric HIV incidence and incremental cost-effectiveness ratios (ICERs) calculated from discounted life expectancy and lifetime HIV-related costs.ResultsThe model projects that bNAbs would reduce absolute infant HIV incidence by 0.3-2.2% (9.6-34.9% relative reduction), varying by country, prophylaxis approach and target population. In all three settings, HR-HIVE-1-dose would be cost-saving compared to SOC. Using a 50% GDP per capita ICER threshold, HIVE-Extended would be cost-effective in all three settings with ICERs of $497/YLS in Côte d'Ivoire, $464/YLS in South Africa and $455/YLS in Zimbabwe. In all three settings, bNAb strategies would remain cost-effective at costs up to $200/dose if efficacy is ≥30%. If the bNAb effect duration were reduced to 1 month, the cost-effective strategy would become HR-HIVE-1-dose in Côte d'Ivoire and Zimbabwe and HR-HIVE-2-doses in South Africa. Findings regarding the cost-effectiveness of bNAb implementation strategies remained robust in sensitivity analyses regarding breastfeeding duration, maternal engagement in postpartum care, early infant diagnosis uptake and antiretroviral treatment costs.ConclusionsAt current efficacy and cost estimates, bNAb prophylaxis for HIV-exposed children in sub-Saharan African settings would be a cost-effective intervention to reduce vertical HIV transmission.

: Introduction: As access to effective antiretroviral therapy (ART) has improved globally, tobacco‐related illnesses, including cardiovascular disease, cancer and chronic respiratory conditions, account for a growing proportion of deaths among people with HIV (PWH). We estimated the impact of tobacco smoking and smoking cessation on life expectancy among PWH in South Africa. Methods: In a microsimulation model, we simulated 18 cohorts of PWH with virologic suppression, each homogenous by sex, initial age (35y/45y/55y) and smoking status (current/former/never). Input parameters were from data sources published between 2008 and 2022. We used South African data to estimate age‐stratified mortality hazard ratios: 1.2−2.3 (females)/1.1−1.9 (males) for people with current versus never smoking status; and 1.0−1.3 (females)/1.0−1.5 (males) for people with former versus never smoking status, depending on age at cessation. We assumed smoking status remains unchanged during the simulation; people who formerly smoked quit at model start. Simulated PWH face a monthly probability of disengagement from care and virologic non‐suppression. In sensitivity analysis, we varied smoking‐associated and HIV‐associated mortality risks. Additionally, we estimated the total life‐years gained if a proportion of all virologically suppressed PWH stopped smoking. Results: Forty‐five‐year‐old females/males with HIV with virologic suppression who smoke lose 5.3/3.7 life‐years compared to PWH who never smoke. Smoking cessation at age 45y adds 3.4/2.4 life‐years. Simulated PWH who continue smoking lose more life‐years from smoking than from HIV (females, 5.3 vs. 3.0 life‐years; males, 3.7 vs. 2.6 life‐years). The impact of smoking and smoking cessation increase as smoking‐associated mortality risks increase and HIV‐associated mortality risks, including disengagement from care, decrease. Model results are most sensitive to the smoking‐associated mortality hazard ratio; varying this parameter results in 1.0−5.1 life‐years gained from cessation at age 45y. If 10−25% of virologically suppressed PWH aged 30−59y in South Africa stopped smoking now, 190,000−460,000 life‐years would be gained. Conclusions: Among virologically suppressed PWH in South Africa, tobacco smoking decreases life expectancy more than HIV. Integrating tobacco cessation interventions into HIV care, as endorsed by the World Health Organization, could substantially improve life expectancy., INTRODUCTION South Africa is home to over seven million people with HIV (PWH), more than any other country [1]. Improved access to antiretroviral therapy (ART) has increased life expectancy among [...]

Acute care surgery (ACS) encompasses five major pillars - trauma, surgical critical care, emergency general surgery, elective general surgery and surgical rescue. The specialty continues to evolve and due to high-acuity, high-volume and around-the-clock care, the workload can be significant leading to workforce challenges such as rightsizing of staff, work-life imbalance, surgeon burnout and more. To address these challenges and ensure a stable workforce, ACS as a specialty must be deliberate and thoughtful about how it manages workload and workforce going forward. In this article, we address the importance, benefits and challenges of defining full-time equivalence for ACS as a method to establish a stable ACS workforce for the future.

Abstract Introduction As access to effective antiretroviral therapy (ART) has improved globally, tobacco‐related illnesses, including cardiovascular disease, cancer and chronic respiratory conditions, account for a growing proportion of deaths among people with HIV (PWH). We estimated the impact of tobacco smoking and smoking cessation on life expectancy among PWH in South Africa. Methods In a microsimulation model, we simulated 18 cohorts of PWH with virologic suppression, each homogenous by sex, initial age (35y/45y/55y) and smoking status (current/former/never). Input parameters were from data sources published between 2008 and 2022. We used South African data to estimate age‐stratified mortality hazard ratios: 1.2−2.3 (females)/1.1−1.9 (males) for people with current versus never smoking status; and 1.0−1.3 (females)/1.0−1.5 (males) for people with former versus never smoking status, depending on age at cessation. We assumed smoking status remains unchanged during the simulation; people who formerly smoked quit at model start. Simulated PWH face a monthly probability of disengagement from care and virologic non‐suppression. In sensitivity analysis, we varied smoking‐associated and HIV‐associated mortality risks. Additionally, we estimated the total life‐years gained if a proportion of all virologically suppressed PWH stopped smoking. Results Forty‐five‐year‐old females/males with HIV with virologic suppression who smoke lose 5.3/3.7 life‐years compared to PWH who never smoke. Smoking cessation at age 45y adds 3.4/2.4 life‐years. Simulated PWH who continue smoking lose more life‐years from smoking than from HIV (females, 5.3 vs. 3.0 life‐years; males, 3.7 vs. 2.6 life‐years). The impact of smoking and smoking cessation increase as smoking‐associated mortality risks increase and HIV‐associated mortality risks, including disengagement from care, decrease. Model results are most sensitive to the smoking‐associated mortality hazard ratio; varying this parameter results in 1.0−5.1 life‐years gained from cessation at age 45y. If 10−25% of virologically suppressed PWH aged 30−59y in South Africa stopped smoking now, 190,000−460,000 life‐years would be gained. Conclusions Among virologically suppressed PWH in South Africa, tobacco smoking decreases life expectancy more than HIV. Integrating tobacco cessation interventions into HIV care, as endorsed by the World Health Organization, could substantially improve life expectancy.

INTRODUCTION: An estimated 15%-29% of patients report new gastrointestinal (GI) symptoms after coronavirus-19 disease (COVID-19) while 4%-31% report new depressive symptoms. These symptoms may be secondary to gut microbiome tryptophan metabolism and 5-hydroxytryptamine (5-HT)-based signaling. METHODS: This study used specimens from 2 patient cohorts: (i) fecal samples from patients with acute COVID-19 who participated in a randomized controlled trial testing prebiotic fiber and (ii) blood samples from patients with acute COVID-19. Six months after recovering from COVID-19, both cohorts answered questions related to GI symptoms and anxiety or depression. Microbiome composition and function, focusing on tryptophan metabolism-associated pathways, and plasma 5-HT were assessed. RESULTS: In the first cohort (n = 13), gut microbiome L-tryptophan biosynthesis during acute COVID-19 was decreased among those who developed more severe GI symptoms (2.0-fold lower log activity comparing those with the most severe GI symptoms vs those with no symptoms, P = 0.06). All tryptophan pathways showed decreased activity among those with more GI symptoms. The same pathways were also decreased in those with the most severe mental health symptoms after COVID-19. In an untargeted analysis, 5 additional metabolic pathways significantly differed based on subsequent development of GI symptoms. In the second cohort (n = 39), plasma 5-HT concentration at the time of COVID-19 was increased 5.1-fold in those with GI symptoms alone compared with those with mental health symptoms alone ( P = 0.02). DISCUSSION: Acute gut microbiome-mediated reduction in 5-HT signaling may contribute to long-term GI and mental health symptoms after COVID-19. Future studies should explore modification of 5-HT signaling to reduce post-COVID symptoms.

Abstract Background Microbiome restitution therapies are being developed to prevent gut pathogen colonization among patients in the intensive care unit (ICU) and in other select populations. If preventive therapies are to be effective, they must be administered prior to pathogen acquisition. The timing and risk factors for early acquisition of gut pathogen colonization (within 72 h) are currently unknown and could be helpful to guide ICU trial design. Methods This was a prospective cohort study. Patients in the ICU had deep rectal swabs performed within 4 h of ICU admission and exactly 72 h later. Early gut pathogen colonization was classified as the new presence (based on culture of rectal swabs) of one or more of the following organisms of interest: methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant (VRE), and Gram-negative bacteria that showed multidrug resistance (MDR) or third generation Cephalosporin resistance (Ceph-R). Clinical risk factors for early acquisition of gut pathogen colonization were captured using the Acute Physiology and Chronic Health Evaluation IV (APACHE IV) scoring system. Findings Among 131 patients who were swabbed at ICU admission and 72 h later, the rates of gut pathogen colonization at ICU admission were 11.4%, 10.6%, 38.6%, and 8.3% for MRSA, VRE, MDR and Ceph-R Gram-negatives respectively. Among the patients who were negative for a given pathogen at ICU admission, the rates of early acquisition of gut pathogen colonization were 7.8% for MRSA (95% CI 3.6 to 14.2%), 7.7% for VRE (95% CI 3.6 to 14.1%), 11.3% for MDR Gram-negatives (95% CI 4.4 to 18.8%), and 4.2% for Ceph-R Gram-negatives (95% CI 1.4 to 9.5%). There were no clinical risk factors which independently predicted early acquisition of gut pathogen colonization. Interpretation Early gut pathogen colonization was common in the ICU, but our single-center study could not identify any clinical risk factors which were significantly associated with acquisition of gut pathogens.

OBJECTIVE: MSM in India are at a high risk for HIV infection given psychosocial challenges, sexual orientation stress, and stigma. We examined the cost-effectiveness of a novel resilience-based psychosocial intervention for MSM in India. DESIGN: We parameterized a validated microsimulation model (CEPAC) with India-specific data and results from a randomized trial and examined two strategies for MSM: status quo HIV care ( SQ ), and a trial-based psychosocial intervention ( INT ) focused on building resilience to stress, improving mental health, and reducing condomless anal sex (CAS). METHODS: We projected lifetime clinical and economic outcomes for MSM without HIV initially. Intervention effectiveness, defined as reduction in self-reported CAS, was estimated at 38%; cost was $49.37/participant. We used a willingness-to-pay threshold of US$2100 (2019 Indian per capita GDP) per year of life saved (YLS) to define cost-effectiveness. We also assessed the 5-year budget impact of offering this intervention to 20% of Indian MSM. RESULTS: Model projections showed the intervention would avert 2940 HIV infections among MSM over 10 years. Over a lifetime horizon, the intervention was cost-effective (ICER = $900/YLS). Results were most sensitive to intervention effectiveness and cost; the intervention remained cost-effective under plausible ranges of these parameters. Offering this intervention in the public sector would require an additional US$28 M over 5 years compared with SQ . CONCLUSION: A resilience-based psychosocial intervention integrated with HIV risk reduction counseling among MSM in India would reduce HIV infections and be cost-effective. Programs using this approach should be expanded as a part of comprehensive HIV prevention in India.

Abstract Introduction The HIV and hepatitis B virus (HBV) epidemics are interconnected with shared routes of transmission and specific antiviral drugs that are effective against both viruses. Nearly, 300 million people around the world live with chronic HBV, many of whom are from priority populations who could benefit from HIV prevention services. Oral pre‐exposure prophylaxis (PrEP) for HIV has implications in the prevention and treatment of HBV infection, but many people at increased risk of HIV acquisition may instead prefer long‐acting formulations of PrEP, which are currently not active against HBV. Discussion People at increased risk for HIV acquisition may also be at risk for or already be living with HBV infection. Oral PrEP with tenofovir is effective in preventing both HIV and HBV, and tenofovir is also the recommended treatment for chronic HBV infection. Although implementation of oral PrEP has been challenging in sub‐Saharan Africa, investments in its scale‐up could secondarily reduce the clinical impact of HBV. Long‐acting PrEP, including injectable medicines and implantable rings, may overcome some of the implementation challenges associated with oral PrEP, such as daily pill burden, adherence challenges and stigma; however, current formulations of long‐acting PrEP do not have activity against HBV replication. Ideally, PrEP programmes would offer both oral and long‐acting formulations with HBV screening to optimize HIV prevention services and HBV prevention and care, when appropriate. People who are not immune to HBV would benefit from being vaccinated against HBV before initiating long‐acting PrEP. People who remain non‐immune to HBV despite vaccination may benefit from being offered oral, tenofovir‐based PrEP given its potential for HBV PrEP. People using PrEP and living with HBV who are not linked to dedicated HBV care would also benefit from laboratory monitoring at PrEP sites to ensure safety when using and after stopping tenofovir. PrEP programmes are ideal venues to offer HBV screening, HBV vaccination for people who are non‐immune and treatment with tenofovir‐based PrEP for people with indications for HBV therapy. Conclusions Long‐acting PrEP holds promise for reducing HIV incidence, but its implications for the HBV epidemic, particularly in sub‐Saharan Africa, should not be overlooked.

BackgroundThe HIV Prevention Trials Network (HPTN) 083 trial demonstrated the superiority of long-acting injectable cabotegravir (CAB-LA) compared with oral emtricitabine-tenofovir disoproxil fumarate (F/TDF) for HIV preexposure prophylaxis (PrEP).ObjectiveTo identify the maximum price premium (that is, greatest possible price differential) that society should be willing to accept for the additional benefits of CAB-LA over tenofovir-based PrEP among men who have sex with men and transgender women (MSM/TGW) in the United States.DesignSimulation, cost-effectiveness analysis.Data sourcesTrial and published data, including estimated HIV incidence (5.32, 1.33, and 0.26 per 100 person-years for off PrEP, generic F/TDF and branded emtricitabine-tenofovir alafenamide (F/TAF), and CAB-LA, respectively); 28% 6-year PrEP retention. Annual base-case drug costs: $360 and $16 800 for generic F/TDF and branded F/TAF. Fewer side effects with branded F/TAF versus generic F/TDF were assumed.Target population476 700 MSM/TGW at very high risk for HIV (VHR).Time horizon10 years.PerspectiveHealth care system.InterventionCAB-LA versus generic F/TDF or branded F/TAF for HIV PrEP.Outcome measuresPrimary transmissions, quality-adjusted life-years (QALYs), costs (2020 U.S. dollars), incremental cost-effectiveness ratios (ICERs; U.S. dollars per QALY), maximum price premium for CAB-LA versus tenofovir-based PrEP.Results of base-case analysisCompared with generic F/TDF (or branded F/TAF), CAB-LA increased life expectancy by 28 000 QALYs (26 000 QALYs) among those at VHR. Branded F/TAF cost more per QALY gained than generic F/TDF compared with no PrEP. At 10 years, CAB-LA could achieve an ICER of at most $100 000 per QALY compared with generic F/TDF at a maximum price premium of $3700 per year over generic F/TDF (CAB-LA price

: Introduction: The HIV and hepatitis B virus (HBV) epidemics are interconnected with shared routes of transmission and specific antiviral drugs that are effective against both viruses. Nearly, 300 million people around the world live with chronic HBV, many of whom are from priority populations who could benefit from HIV prevention services. Oral pre‐exposure prophylaxis (PrEP) for HIV has implications in the prevention and treatment of HBV infection, but many people at increased risk of HIV acquisition may instead prefer long‐acting formulations of PrEP, which are currently not active against HBV. Discussion: People at increased risk for HIV acquisition may also be at risk for or already be living with HBV infection. Oral PrEP with tenofovir is effective in preventing both HIV and HBV, and tenofovir is also the recommended treatment for chronic HBV infection. Although implementation of oral PrEP has been challenging in sub‐Saharan Africa, investments in its scale‐up could secondarily reduce the clinical impact of HBV. Long‐acting PrEP, including injectable medicines and implantable rings, may overcome some of the implementation challenges associated with oral PrEP, such as daily pill burden, adherence challenges and stigma; however, current formulations of long‐acting PrEP do not have activity against HBV replication. Ideally, PrEP programmes would offer both oral and long‐acting formulations with HBV screening to optimize HIV prevention services and HBV prevention and care, when appropriate. People who are not immune to HBV would benefit from being vaccinated against HBV before initiating long‐acting PrEP. People who remain non‐immune to HBV despite vaccination may benefit from being offered oral, tenofovir‐based PrEP given its potential for HBV PrEP. People using PrEP and living with HBV who are not linked to dedicated HBV care would also benefit from laboratory monitoring at PrEP sites to ensure safety when using and after stopping tenofovir. PrEP programmes are ideal venues to offer HBV screening, HBV vaccination for people who are non‐immune and treatment with tenofovir‐based PrEP for people with indications for HBV therapy. Conclusions: Long‐acting PrEP holds promise for reducing HIV incidence, but its implications for the HBV epidemic, particularly in sub‐Saharan Africa, should not be overlooked., INTRODUCTION The HIV and hepatitis B virus (HBV) epidemics are interconnected [1]. The two viruses share many of the same routes of transmission and both benefit from focused prevention efforts [...]

O-Acetylation is a common naturally occurring modification of carbohydrates and is especially widespread in sialic acids, a family of nine-carbon acidic monosaccharides. O-Acetyl migration within the exocyclic glycerol-like side chain of mono-O-acetylated sialic acid reported previously was from the C7- to C9-hydroxyl group with or without an 8-O-acetyl intermediate, which resulted in an equilibrium that favors the formation of the 9-O-acetyl sialic acid. Herein, we provide direct experimental evidence demonstrating that O-acetyl migration is bidirectional, and the rate of equilibration is influenced predominantly by the pH of the sample. While the O-acetyl group on sialic acids and sialoglycans is stable under mildly acidic conditions (pH < 5, the rate of O-acetyl migration is extremely low), reversible O-acetyl migration is observed readily at neutral pH and becomes more significant when the pH increases to slightly basic. Sialoglycan microarray studies showed that esterase-inactivated porcine torovirus hemagglutinin-esterase bound strongly to sialoglycans containing a more stable 9-N-acetylated sialic acid analog, but these compounds were less resistant to periodate oxidation treatment compared to their 9-O-acetyl counterparts. Together with prior studies, the results support the possible influence of sialic acid O-acetylation and O-acetyl migration to host-microbe interactions and potential application of the more stable synthetic N-acetyl mimics.

BackgroundOf new HIV infections in the US, 20% occur among young men who have sex with men (YMSM, ages 13-24), but >50% of YMSM with HIV are unaware of their status. Using Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) data, we projected the clinical benefit and cost-effectiveness of frequent HIV screening among high-risk YMSM from age 15.MethodsUsing a mathematical simulation, we examined 3 screening strategies: Yearly, 6-monthly, and 3-monthly, each in addition to the Status quo (SQ, 0.7-10.3% screened/year, stratified by age). We used published data (YMSM-specific when available) including: HIV incidences (0.91-6.41/100PY); screen acceptance (80%), linkage-to-care/antiretroviral therapy (ART) initiation (76%), HIV transmission (0.3-86.1/100PY, by HIV RNA), monthly ART costs ($2290-$3780), and HIV per-screen costs ($38). Projected outcomes included CD4 count at diagnosis, primary HIV transmissions from ages 15-30, quality-adjusted life expectancy, costs, and incremental cost-effectiveness ratios (ICERs, $/quality-adjusted life-year saved [QALY]; threshold ≤$100 000/QALY).ResultsCompared to SQ, all strategies increased projected CD4 at diagnosis (296 to 477-515 cells/µL) and quality-adjusted life expectancy from age 15 (44.4 to 48.3-48.7 years) among YMSM acquiring HIV. Compared to SQ, all strategies increased discounted lifetime cost for the entire population ($170 800 to $178 100-$185 000/person). Screening 3-monthly was cost-effective (ICER: $4500/QALY) compared to SQ and reduced primary transmissions through age 30 by 40%. Results were most sensitive to transmission rates; excluding the impact of transmissions, screening Yearly was ≤$100 000/QALY (ICER: $70 900/QALY).ConclusionsFor high-risk YMSM in the US, HIV screening 3-monthly compared to less frequent screening will improve clinical outcomes and be cost-effective.

Abstract Background Men who have sex with men (MSM) in Brazil remain disproportionately affected by HIV. We estimated the potential incidence reduction by five years with increased uptake of publicly-funded, daily, oral tenofovir/emtricitabine (TDF/FTC) for HIV pre-exposure prophylaxis (PrEP) among MSM using the Cost Effectiveness of Preventing AIDS Complications microsimulation model. We used national data, local studies, and literature to inform model parameters for three cities: Rio de Janeiro, Salvador, and Manaus. Results In Rio de Janero, a PrEP intervention achieving 10% uptake within 60 months would decrease incidence by 2.3% whereas achieving 60% uptake within 24 months would decrease incidence by 29.7%; results were similar for Salvador and Manaus. In sensitivity analyses, decreasing mean age at PrEP initiation from 33 to 21 years increased incidence reduction by 34%; a discontinuation rate of 25% per year decreased it by 12%. Conclusion Targeting PrEP to young MSM and minimizing discontinuation could substantially increase PrEP’s impact.

Introduction: In Brazil, though Antiretroviral Therapy (ART) is available to all, the benefits may not be experienced uniformly. We projected Life Expectancy (LE) for People Living with HIV (PLHIV) in care as currently observed and estimated the impact of guideline-concordant care. Methods: Using a microsimulation model, we projected LE for a cohort of PLHIV and for four population groups: cisgender Men who have Sex with Men (MSM), cisgender Men who have Sex with Women (MSW), Cisgender Women (CGW), and Transgender Women (TGW). Cohort data from Evandro Chagas National Institute of Infectious Diseases/Oswaldo Cruz Foundation (INI/Fiocruz) informed model parameters. We modeled five scenarios: 1) Current care: ART initiation, adherence, and retention in care as currently observed, 2) Guideline-concordant care: immediate ART initiation, full adherence to treatment, and consistent retention in care, 3) Immediate ART initiation with observed adherence to treatment and retention in care, 4) Full adherence to treatment with observed timing of ART initiation and retention in care, and 5) Consistent retention in care with observed timing of ART initiation and adherence. Results: With current care, LE from age 15 would be 45.9, 44.4, 54.2, and 42.3 years, for MSM, MSW, CGW, and TGW. With guideline-concordant care, LE would be 54.2, 54.4, 63.1, and 53.2 years, for MSM, MSW, CGW and TGW, with TGW experiencing the greatest potential increase in LE (10.9 years). When investigating the components of care separately, MSW and CGW would gain most LE with immediate ART initiation, whereas for MSM and TGW consistent retention in care would be most impactful. Conclusions: In settings like INI/Fiocruz, MSW and CGW would benefit most from interventions focused on earlier diagnosis and linkage to care, whereas TGW and MSM would benefit from interventions to sustain engagement in care. Assessment of the HIV care continuum for specific populations should inform care priorities.

Objectives Detailed simulation models are needed to assess strategies for prevention and treatment of hepatitis B virus (HBV) infection, the world’s leading cause of liver disease. We sought to develop and validate a simulation model of chronic HBV that incorporates virological, serological and clinical outcomes.Methods We developed a novel Monte Carlo simulation model (the HEPA-B Model) detailing the natural history of chronic HBV. We parameterised the model with epidemiological data from the Western Pacific and sub-Saharan Africa. We simulated the evolution of HBV DNA, ‘e’ antigen (HBeAg) and surface antigen (HBsAg). We projected incidence of HBeAg loss, HBsAg loss, cirrhosis, hepatocellular carcinoma (HCC) and death over 10-year and lifetime horizons. We stratified outcomes by five HBV DNA categories at the time of HBeAg loss, ranging from HBV DNA106 copies/mL. We tested goodness of fit using intraclass coefficients (ICC).Results Model-projected incidence of HBeAg loss was 5.18% per year over lifetime (ICC, 0.969 (95% CI: 0.728 to 0.990)). For people in HBeAg-negative phases of infection, model-projected HBsAg loss ranged from 0.78% to 3.34% per year depending on HBV DNA level (ICC, 0.889 (95% CI: 0.542 to 0.959)). Model-projected incidence of cirrhosis was 0.29–2.09% per year (ICC, 0.965 (95% CI: 0.942 to 0.979)) and HCC incidence was 0.06–1.65% per year (ICC, 0.977 (95% CI: 0.962 to 0.986)). Over a lifetime simulation of HBV disease, mortality rates were higher for people with older age, higher HBV DNA level and liver-related complications, consistent with observational studies.Conclusions We simulated HBV DNA-stratified clinical outcomes with the novel HEPA-B Model and validated them to observational data. This model can be used to examine strategies of HBV prevention and management.

Objectives. Conventional value-of-information (VOI) analysis assumes complete uptake of an optimal decision. We employed an extended framework that includes value-of-implementation (VOM)—the benefit of encouraging adoption of an optimal strategy—and estimated how future trials of diagnostic tests for HIV-associated tuberculosis could improve public health decision making and clinical and economic outcomes. Methods. We evaluated the clinical outcomes and costs, given current information, of 3 tuberculosis screening strategies among hospitalized people with HIV in South Africa: sputum Xpert ( Xpert ), sputum Xpert plus urine AlereLAM ( Xpert+AlereLAM ), and sputum Xpert plus the newer, more sensitive, and costlier urine FujiLAM ( Xpert+FujiLAM ). We projected the incremental net monetary benefit (INMB) of decision making based on results of a trial comparing mortality with each strategy, rather than decision making based solely on current knowledge of FujiLAM’s improved diagnostic performance. We used a validated microsimulation to estimate VOI (the INMB of reducing parameter uncertainty before decision making) and VOM (the INMB of encouraging adoption of an optimal strategy). Results. With current information, adopting Xpert+FujiLAM yields 0.4 additional life-years/person compared with current practices (assumed 50% Xpert and 50% Xpert+AlereLAM ). While the decision to adopt this optimal strategy is unaffected by information from the clinical trial (VOI = $ 0 at $3,000/year-of-life saved willingness-to-pay threshold), there is value in scaling up implementation of Xpert+FujiLAM , which results in an INMB (representing VOM) of $650 million over 5 y. Conclusions. Conventional VOI methods account for the value of switching to a new optimal strategy based on trial data but fail to account for the persuasive value of trials in increasing uptake of the optimal strategy. Evaluation of trials should include a focus on their value in reducing barriers to implementation. Highlights In conventional VOI analysis, it is assumed that the optimal decision will always be adopted even without a trial. This can potentially lead to an underestimation of the value of trials when adoption requires new clinical trial evidence. To capture the influence that a trial may have on decision makers’ willingness to adopt the optimal decision, we also consider value-of-implementation (VOM), a metric quantifying the benefit of new study information in promoting wider adoption of the optimal strategy. The overall value-of-a-trial (VOT) includes both VOI and VOM. Our model-based analysis suggests that the information obtained from a trial of screening strategies for HIV-associated tuberculosis in South Africa would have no value, when measured using traditional methods of VOI assessment. A novel strategy, which includes the urine FujiLAM test, is optimal from a health economic standpoint but is underutilized. A trial would reduce uncertainties around downstream health outcomes but likely would not change the optimal decision. The high VOT (nearly $700 million over 5 y) lies solely in promoting uptake of FujiLAM, represented as VOM. Our results highlight the importance of employing a more comprehensive approach for evaluating prospective trials, as conventional VOI methods can vastly underestimate their value. Trialists and funders can and should assess the VOT metric instead when considering trial designs and costs. If VOI is low, the VOM and cost of a trial can be compared with the benefits and costs of other outreach programs to determine the most cost-effective way to improve uptake.