Phase III Randomized, Placebo-Controlled Clinical Trial of Donepezil for Treatment of Cognitive Impairment in Breast Cancer Survivors After Adjuvant Chemotherapy (WF-97116).

PURPOSE: To test efficacy of donepezil, a cognitive enhancer, to improve memory in breast cancer survivors who report cancer-related cognitive impairment 1-5 years postchemotherapy. PATIENTS AND METHODS: Adult female BCS exposed to ≥4 cycles of adjuvant chemotherapy 1-5 years before enrollment who reported cancer-related cognitive impairment were eligible. Participants, enrolled at sites affiliated with the Wake Forest NCI Community Oncology Research Program (NCORP) Research Base, were randomly assigned to receive 5 mg of donepezil once daily for 6 weeks titrated to 10 mg once daily for 18 weeks or placebo. Cognition and self-report cognitive functioning was assessed at baseline, 12, 24 (end of intervention), and 36 (washout) weeks postrandomization. Mixed-effects repeated measures analysis of covariance models were used to assess treatment differences in immediate recall (primary outcome) on the Hopkins Verbal Learning Test-Revised (HVLT-R) and other cognitive domains (secondary outcomes) with covariates of treatment, time, time by treatment interaction, baseline outcome level, age stratification, and an unstructured covariance matrix to account for within participant correlation over time. RESULTS: Two hundred seventy-six BCS from 87 NCORP practices (mean age, 57.1, standard deviation [SD], 10.5) who were at a mean of 29.6 months (SD, 14.2) postchemotherapy were randomly assigned to donepezil (n = 140) or placebo (n = 136). At 24 weeks, treatment groups did not differ on HVLT-R scores (donepezil mean = 25.98, placebo = 26.50, P = .32). There were no statistically significant differences between treatments at 12, 24, or 36 weeks for attention, executive function, verbal fluency, processing speed, or self-reported cognitive functioning. Endocrine therapy and menopausal status did not affect results. CONCLUSION: BCS 1-5 years after completing chemotherapy with documented memory problems, randomly assigned to 24 weeks of 5-10 mg of donepezil once daily, did not perform differently at the end of treatment on tests of memory, other cognitive functions, or subjective functioning than those randomly assigned to placebo.

Development of a two-hit lethal liver injury model in swine.

PURPOSE: Noncompressible truncal hemorrhage remains a leading cause of preventable death in the prehospital setting. Standardized and reproducible large animal models are essential to test new therapeutic strategies. However, existing injury models vary significantly in consistency and clinical accuracy. This study aims to develop a lethal porcine model to test hemostatic agents targeting noncompressible abdominal hemorrhages. METHODS: We developed a two-hit injury model in Yorkshire swine, consisting of a grade IV liver injury combined with hemodilution. The hemodilution was induced by controlled exsanguination of 30% of the total blood volume and a 3:1 resuscitation with crystalloids. Subsequently, a grade IV liver injury was performed by sharp transection of both median lobes of the liver, resulting in major bleeding and severe hypotension. The abdominal incision was closed within 60 s from the injury. The endpoints included mortality, survival time, serum lab values, and blood loss within the abdomen. RESULTS: This model was lethal in all animals (5/5), with a mean survival time of 24.4 ± 3.8 min. The standardized liver resection was uniform at 14.4 ± 2.1% of the total liver weight. Following the injury, the MAP dropped by 27 ± 8mmHg within the first 10 min. The use of a mixed injury model (i.e., open injury, closed hemorrhage) was instrumental in creating a standardized injury while allowing for a clinically significant hemorrhage. CONCLUSION: This novel highly lethal, consistent, and clinically relevant translational model can be used to test and develop life-saving interventions for massive noncompressible abdominal hemorrhage.

Field method for preservation of total mercury in waters, including those associated with artisanal scale gold mining.

Analysis of mercury (Hg) in natural water samples has routinely been impractical in many environments, for example, artisanal and small-scale gold mines (ASGM), where difficult conditions make monitoring of harmful elements and chemicals used in the processes highly challenging. Current sampling methods require the use of hazardous or expensive materials, and so difficulties in sample collection and transport are elevated. To solve this problem, a solid-phase extraction-based method was developed for the sampling and preservation of dissolved Hg in natural water samples, particularly those found around ASGM sites. Recoveries of 85% ± 10% total Hg were obtained during 4 weeks of storage in refrigerated (4 °C, dark) and unrefrigerated (16 °C, dark) conditions, and from a representative river water spiked to 1 µg L-1 Hg2+, 94% ± 1% Hg recovery was obtained. Solid-phase extraction loading flow rates were tested at 2, 5, and 10 mL min-1 with no breakthrough of Hg, and sorbent stability showed no breakthrough of Hg up to 2 weeks after functionalisation. The method was deployed across five artisanal gold mines in Kakamega gold belt, Kenya, to assess Hg concentrations in mine shaft water, ore washing ponds, and river and stream water, including drinking water sources. In all waters, Hg concentrations were below the WHO guideline limit value of 6 µg L-1, but drinking water sources contained trace concentrations of up to 0.35 µg L-1 total Hg, which may result in negative health effects from long-term exposure. The SPE method developed and deployed here is a robust sampling method that can therefore be applied in future Hg monitoring, toxicology, and environmental work to provide improved data that is representative of total dissolved Hg in water samples.

Earth at risk: An urgent call to end the age of destruction and forge a just and sustainable future.

Human development has ushered in an era of converging crises: climate change, ecological destruction, disease, pollution, and socioeconomic inequality. This review synthesizes the breadth of these interwoven emergencies and underscores the urgent need for comprehensive, integrated action. Propelled by imperialism, extractive capitalism, and a surging population, we are speeding past Earth's material limits, destroying critical ecosystems, and triggering irreversible changes in biophysical systems that underpin the Holocene climatic stability which fostered human civilization. The consequences of these actions are disproportionately borne by vulnerable populations, further entrenching global inequities. Marine and terrestrial biomes face critical tipping points, while escalating challenges to food and water access foreshadow a bleak outlook for global security. Against this backdrop of Earth at risk, we call for a global response centered on urgent decarbonization, fostering reciprocity with nature, and implementing regenerative practices in natural resource management. We call for the elimination of detrimental subsidies, promotion of equitable human development, and transformative financial support for lower income nations. A critical paradigm shift must occur that replaces exploitative, wealth-oriented capitalism with an economic model that prioritizes sustainability, resilience, and justice. We advocate a global cultural shift that elevates kinship with nature and communal well-being, underpinned by the recognition of Earth's finite resources and the interconnectedness of its inhabitants. The imperative is clear: to navigate away from this precipice, we must collectively harness political will, economic resources, and societal values to steer toward a future where human progress does not come at the cost of ecological integrity and social equity.

In men with LUTS in primary care, a standardized intervention reduced symptoms by a small amount at 12 mo.

SOURCE CITATION: Drake MJ, Worthington J, Frost J, et al. Treatment of lower urinary tract symptoms in men in primary care using a conservative intervention: cluster randomised controlled trial. BMJ. 2023;383:e075219. 37967894.

Systematic Review of Literature Citing the ISCHEMIA Trial.

PURPOSE OF REVIEW: Optimal therapy for patients with chronic coronary artery disease (CCD) has long been a topic under investigation and a subject of debate. Seeking to clarify appropriate management, the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial compared medical management versus coronary angiography for patients with stable ischemic heart disease. Its reception in the medical community has been met with both acclaim and criticism. In light of such disparate views of this trial, a systematic review of the literature citing the ISCHEMIA trial was performed. RECENT FINDINGS: All articles citing the ISCHEMIA trial on PubMed as of July 21, 2023, were compiled and underwent qualitative analysis. A total of 430 articles were evaluated; 109 (25.3%) did not offer substantial commentary on ISCHEMIA and cite it as background evidence for further study. Of the commentary articles, the majority (224, 52.1%) gave balanced, honest appraisals of the ISCHEMIA trial. A total of 46 (10.7%) strongly praised the trial while another 39 (9.1%) were strongly critical of the results. Almost three-quarters of the literature citing the ISCHEMIA trial was commentary in nature, with roughly equal distribution across the spectrum of praise and criticism. Despite being one of the largest studies on CCD and coronary revascularization ever conducted, the impact of ISCHEMIA on the cardiology community appears to be mixed.

Outcomes and complications of postoperative seroma cavities following soft-tissue sarcoma resection.

Introduction: Seroma development is a known complication following extremity and trunk soft-tissue sarcoma (STS) resection. The purpose of this study is to evaluate and characterize seroma outcomes and the development of associated complications. Methods: A retrospective review of 123 patients who developed postoperative seromas following STS resection at a single institution was performed. Various patient and surgical factors were analyzed to determine their effect on overall seroma outcomes. Results: 77/123 seromas (62.6%) were uncomplicated, 30/123 (24.4%) developed infection, and 16/123 (13.0%) were symptomatic and required aspiration or drainage for symptom relief at an average of 12.2 months postoperatively. 65/123 (52.8%) seromas resolved spontaneously at an average time of 12.41 months. Seromas in the lower extremity (p=0.028), surgical resection volume >864 cm3, (p=<0.001) and initial seroma volume >42 cm3 (p=<0.001) increased the likelihood of infection. 90% of infected seromas developed the infection within the first three months following initial resection. No seromas which were aspirated or drained ultimately developed an infection following these procedures, though 50% recurred. Discussion: Most seromas following STS resection are uncomplicated and do not require intervention, though a large resection cavity >864 cm3 and a large seroma volume >42 cm3 are risk factors for complications.

Ecological filtering shapes the impacts of agricultural deforestation on biodiversity.

The biodiversity impacts of agricultural deforestation vary widely across regions. Previous efforts to explain this variation have focused exclusively on the landscape features and management regimes of agricultural systems, neglecting the potentially critical role of ecological filtering in shaping deforestation tolerance of extant species assemblages at large geographical scales via selection for functional traits. Here we provide a large-scale test of this role using a global database of species abundance ratios between matched agricultural and native forest sites that comprises 71 avian assemblages reported in 44 primary studies, and a companion database of 10 functional traits for all 2,647 species involved. Using meta-analytic, phylogenetic and multivariate methods, we show that beyond agricultural features, filtering by the extent of natural environmental variability and the severity of historical anthropogenic deforestation shapes the varying deforestation impacts across species assemblages. For assemblages under greater environmental variability-proxied by drier and more seasonal climates under a greater disturbance regime-and longer deforestation histories, filtering has attenuated the negative impacts of current deforestation by selecting for functional traits linked to stronger deforestation tolerance. Our study provides a previously largely missing piece of knowledge in understanding and managing the biodiversity consequences of deforestation by agricultural deforestation.

A comprehensive analysis of clinical and polygenic germline influences on somatic mutational burden.

Tumor mutational burden (TMB), the total number of somatic mutations in the tumor, and copy number burden (CNB), the corresponding measure of aneuploidy, are established fundamental somatic features and emerging biomarkers for immunotherapy. However, the genetic and non-genetic influences on TMB/CNB and, critically, the manner by which they influence patient outcomes remain poorly understood. Here, we present a large germline-somatic study of TMB/CNB with >23,000 individuals across 17 cancer types, of which 12,000 also have extensive clinical, treatment, and overall survival (OS) measurements available. We report dozens of clinical associations with TMB/CNB, observing older age and male sex to have a strong effect on TMB and weaker impact on CNB. We additionally identified significant germline influences on TMB/CNB, including fine-scale European ancestry and germline polygenic risk scores (PRSs) for smoking, tanning, white blood cell counts, and educational attainment. We quantify the causal effect of exposures on somatic mutational processes using Mendelian randomization. Many of the identified features associated with TMB/CNB were additionally associated with OS for individuals treated at a single tertiary cancer center. For individuals receiving immunotherapy, we observed a complex relationship between PRSs for educational attainment, self-reported college attainment, TMB, and survival, suggesting that the influence of this biomarker may be substantially modified by socioeconomic status. While the accumulation of somatic alterations is a stochastic process, our work demonstrates that it can be shaped by host characteristics including germline genetics.

Moving toward point-of-care surgery in Ukraine: testing an ultra-portable operating room in an active war zone.

PURPOSE: In conflict zones, providers may have to decide between delaying time-sensitive surgeries or performing operative interventions in the field, potentially subjecting patients to significant infection risks. We conducted a single-arm crossover study to assess the feasibility of using an ultraportable operating room (U-OR) for surgical procedures on a porcine cadaver abdominal traumatic injury model in an active war zone. METHODS: We enrolled participants from an ASSET-type course designed to train Ukrainian surgeons before deployment to active conflict zones. They performed three standardized consecutive abdominal surgical procedures (liver, kidney, and small bowel injury repair) with and without the U-OR. Primary outcomes included surgical procedure completion rate, procedure time, and airborne particle count at the start of surgery. Secondary survey-based outcomes assessed surgery task load index (SURG-TLX) and perceived operative factors. RESULTS: Fourteen surgeons performed 76 surgical procedures (38 with the U-OR, 38 without the U-OR). The completion rate for each surgical procedure was 100% in both groups. While the procedure time for the liver injury repair did not differ significantly between the two groups, the use of the U-OR was associated with a longer time for kidney (155 vs. 56 s, p = 0.002), and small bowel (220 vs. 103 s, p = 0.004) injury repair. The average airborne particle count within the U-OR was substantially lower compared to outside the U-OR (6,753,852 vs. 232,282 n/m3, p < 0.001). There was no statistically significant difference in SURG-TLX for procedures performed with and without the U-OR. CONCLUSION: The use of the U-OR did not affect the procedure completion rate or SURG-TLX. However, there was a marked difference in airborne particle counts between inside and outside the U-OR during surgery. These preliminary findings indicate the potential feasibility of using a U-OR to perform abdominal damage-control surgical procedures in austere settings.

Factors affecting the nesting success of Swainson's Thrush (Catharus ustulatus) along an elevational gradient.

Montane birds experience a range of challenges that may limit their breeding success, including nest predation and severe climactic conditions. The continuing effects of climate change are causing shifts in biotic and abiotic factors that may compound these threats to montane bird species. In northeastern montane forests, many bird species are shifting downslope, potentially as the result of increased precipitation and temperature at higher elevations. Although lower elevations might be more favorable in terms of climactic conditions, nest predation is higher at lower elevations. Thus, montane birds might be faced with the opposing pressures of adverse climactic conditions at higher elevations and increased predation at lower elevations. We monitored nests of Swainson's Thrush (Catharus ustulatus) along an elevation gradient in the White Mountain National Forest in New Hampshire in 2016, 2018, 2019, and 2021 to examine the effect of biotic and abiotic factors on daily nest survival rate (DSR). Linear time explained the most variation of DSR in AICc model comparison, indicating that DSR decreases across the breeding season. Rain intensity (mm/h) had a weak negative effect on DSR, indicating that heavier rain per hour decreases Swainson's Thrush DSR. Moreover, we found some support for a negative interaction effect of elevation in conjunction with minimum daily temperature: DSR of Swainson's Thrush nests at low elevations (281 m) increased with increasing minimum daily temperatures and decreased at high elevations with increasing minimum daily temperatures. Our results suggest nesting survival of montane breeding birds may be at risk as heavier precipitation events become more frequent and intense due to the changing climate and raises the possibility that other passerine species could be at risk in this system.

GC-MS analysis, molecular docking, and pharmacokinetic studies of Multidentia crassa extracts' compounds for analgesic and anti-inflammatory activities in dentistry.

Plant extracts have been useful for oral health or dentistry. However, only a few evidence-based justifications exist. This study evaluated Multidentia crassa (Hiern) Bridson & Verdc, one of the oral health-used plants in Malawi. Gas chromatography-mass spectrometry (GC-MS) and Fourier transform infrared (FT-IR) identified the extracts' compounds. The pharmacokinetics of the identified compounds were studied using pkCSM and SwissADME, and molecular docking studies were used to identify potential drug candidates for oral health by predicting the binding affinity of the compounds to cyclooxygenases, interleukin-1 beta receptors, odontoblast cold sensor proteins, and purinergic receptor P2X3. FT-IR analysis showed characteristic peaks of phenols, carboxylic acids, alkenes, alkyl halides, amines, esters, ethers, aromatics, and lipids. GC-MS results showed the presence of 58 bioactive phytocompounds, some of which have various pharmacological activities relevant to oral health. Molecular docking further validated stigmastan-3,5-diene's potency for analgesic and anti-inflammatory purposes. Based on a literature review, this is the first report on the bioactive compounds of M. crassa extracts showing analgesic and anti-inflammatory effects. This study's results can lead to new herbal and conventional medicines. Therefore, we recommend in vivo and in vitro studies to elucidate the pharmacological effects of the plant extracts.

Mutation protocols share with sexual reproduction the physiological role of producing genetic variation within 'constraints that deconstrain'.

Because the universe of possible DNA sequences is inconceivably vast, organisms have evolved mechanisms for exploring DNA sequence space while substantially reducing the hazard that would otherwise accrue to any process of random, accidental mutation. One such mechanism is meiotic recombination. Although sexual reproduction imposes a seemingly paradoxical 50% cost to fitness, sex evidently prevails because this cost is outweighed by the advantage of equipping offspring with genetic variation to accommodate environmental vicissitudes. The potential adaptive utility of additional mechanisms for producing genetic variation has long been obscured by a presumption that the vast majority of mutations are deleterious. Perhaps surprisingly, the probability for adaptive variation can be increased by several mechanisms that generate mutations abundantly. Such mechanisms, here called 'mutation protocols', implement implicit 'constraints that deconstrain'. Like meiotic recombination, they produce genetic variation in forms that minimize potential for harm while providing a reasonably high probability for benefit. One example is replication slippage of simple sequence repeats (SSRs); this process yields abundant, reversible mutations, typically with small quantitative effect on phenotype. This enables SSRs to function as adjustable 'tuning knobs'. There exists a clear pathway for SSRs to be shaped through indirect selection favouring their implicit tuning-knob protocol. Several other molecular mechanisms comprise probable components of additional mutation protocols. Biologists might plausibly regard such mechanisms of mutation not primarily as sources of deleterious genetic mistakes but also as potentially adaptive processes for 'exploring' DNA sequence space.

A Double-Blind, Randomized, Placebo-Controlled Pilot Study examining an Oxygen Nanobubble Beverage for 16.1-km Time Trial and Repeated Sprint Cycling Performance.

There is growing interest of ergogenic aids that deliver supplemental oxygen during exercise and recovery, however, breathing supplemental oxygen via specialist facemasks is often not feasible. Therefore, this study investigated the effect of an oxygen-nanobubble beverage during submaximal and repeated sprint cycling. In a double-blind, randomized, placebo-controlled study, 10 male cyclists (peak aerobic capacity, 56.9 ± 6.1 mL·kg-1·min-1; maximal aerobic power, 385 ± 25 W) completed submaximal or maximal exercise after consuming an oxygen-nanobubble (O2) or placebo (PLA) beverage. Submaximal trials comprised 30-min of steady-state cycling at 60% peak aerobic capacity and 16.1-km time-trial (TT). Maximal trials involved 4 × 30 s Wingate tests interspersed by 4-min recovery. Time-to-completion during the 16.1-km TT was 2.4% faster after O2 compared with PLA (95% CI = 0.7-4.0%, p = 0.010, d = 0.41). Average power for the 16.1-km TT was 4.1% higher for O2 vs. PLA (95% CI = 2.1-7.3%, p = 0.006, d = 0.28). Average peak power during the repeated Wingate tests increased by 7.1% for O2 compared with PLA (p = 0.002, d = 0.58). An oxygen-nanobubble beverage improves performance during submaximal and repeated sprint cycling, therefore may provide a practical and effective ergogenic aid for competitive cyclists.

Safety of the injectable expanding biopolymer foam for non-compressible truncal bleeding in swine.

BACKGROUND: A novel hydrophobically modified chitosan (hm-chitosan) polymer has been previously shown to improve survival in a non-compressible intra-abdominal bleeding model in swine. We performed a 28-day survival study to evaluate the safety of the hm-chitosan polymer in swine. METHODS: Female Yorkshire swine (40-50 kg) were used. A mild, non-compressible, closed-cavity bleeding model was created with splenic transection. The hm-chitosan polymer was applied intra-abdominally through an umbilical nozzle in the same composition and dose previously shown to improve survival. Animals were monitored intraoperatively and followed 28 days postoperatively for survival, signs of pain, and end-organ function. Gross pathological and microscopic evaluations were performed at the conclusion of the experiment. RESULTS: A total of 10 animals were included (hm-chitosan = 8; control = 2). The 2 control animals survived through 28 days, and 7 of the 8 animals from the hm-chitosan group survived without any adverse events. One animal from the hm-chitosan group required early termination of the study for signs of pain, and superficial colonic ulcers were found on autopsy. Laboratory tests showed no signs of end-organ dysfunction after exposure to hm-chitosan after 28 days. On gross pathological examination, small (<0.5 cm) peritoneal nodules were noticed in the hm-chitosan group, which were consistent with giant-cell foreign body reaction in microscopy, presumably related to polymer remnants. Microscopically, no signs of systemic polymer embolization or thrombosis were noticed. CONCLUSION: Prolonged intraperitoneal exposure to the hm-chitosan polymer was tolerated without any adverse event in the majority of animals. In the single animal that required early termination, the material did not appear to be associated with end-organ dysfunction in swine. Superficial colonic ulcers that would require surgical repair were identified in 1 out of 8 animals exposed to hm-chitosan.

Cough in Children and Adults: Diagnosis, Assessment and Management (CICADA). Summary of an updated position statement on chronic cough in Australia.

INTRODUCTION: Cough is the most common symptom leading to medical consultation. Chronic cough results in significant health care costs, impairs quality of life, and may indicate the presence of a serious underlying condition. Here, we present a summary of an updated position statement on cough management in the clinical consultation. MAIN RECOMMENDATIONS: Assessment of children and adults requires a focused history of chronic cough to identify any red flag cough pointers that may indicate an underlying disease. Further assessment with examination should include a chest x-ray and spirometry (when age > 6 years). Separate paediatric and adult diagnostic management algorithms should be followed. Management of the underlying condition(s) should follow specific disease guidelines, as well as address adverse environmental exposures and patient/carer concerns. First Nations adults and children should be considered a high risk group. The full statement from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia for managing chronic cough is available at https://lungfoundation.com.au/resources/cicada-full-position-statement. CHANGES IN MANAGEMENT AS A RESULT OF THIS STATEMENT: Algorithms for assessment and diagnosis of adult and paediatric chronic cough are recommended. High quality evidence supports the use of child-specific chronic cough management algorithms to improve clinical outcomes, but none exist in adults. Red flags that indicate serious underlying conditions requiring investigation or referral should be identified. Early and effective treatment of chronic wet/productive cough in children is critical. Culturally specific strategies for facilitating the management of chronic cough in First Nations populations should be adopted. If the chronic cough does not resolve or is unexplained, the patient should be referred to a respiratory specialist or cough clinic.

Risk of sexually transmitted infections among U.S. military service members in the setting of HIV pre-exposure prophylaxis use.

BACKGROUND: The evidence for an increased incidence of sexually transmitted infections (STIs) among patients utilizing HIV pre-exposure prophylaxis (PrEP) has been inconsistent. We assessed the risk of incident STI while on PrEP compared to periods off PrEP among military service members starting PrEP. METHODS: Incidence rates of chlamydia, gonorrhea, syphilis, hepatitis C virus, and HIV were determined among military service members without HIV prescribed daily oral tenofovir disoproxil fumarate and emtricitabine for HIV PrEP from February 1, 2014 through June 10, 2016. Hazard ratios for incident STIs were calculated using an Anderson-Gill recurrent event proportional hazard regression model. RESULTS: Among 755 male service members, 477 (63%) were diagnosed with incident STIs (overall incidence 21.4 per 100 person-years). Male service members had a significantly lower risk of any STIs (adjusted hazard ratio (aHR) 0.21, 95% CI 0.11-0.40) while using PrEP compared to periods off PrEP after adjustment for socio-demographic characteristics, reasons for initiating PrEP, surveillance period prior to PrEP initiation, and the effect of PrEP on site and type of infection in multivariate analysis. However, when stratifying for anatomical site and type of infection, the risk of extragenital gonorrhea infection (pharyngeal NG: aHR 1.84, 95% CI 0.82-4.13, p = 0.30; rectal NG: aHR 1.23, 95% CI 0.60-2.51, p = 1.00) and extragenital CT infection (pharyngeal CT: aHR 2.30, 95% CI 0.46-11.46, p = 0.81; rectal CT: aHR 1.36, 95% CI 0.81-2.31, p = 0.66) was greater on PrEP compared to off PrEP although these values did not reach statistical significance. CONCLUSIONS: The data suggest entry into PrEP care reduced the overall risk of STIs following adjustment for anatomical site of STI and treatment. Service members engaged in PrEP services also receive more STI prevention counseling, which might contribute to decreases in STI risk while on PrEP.

Tracking coreceptor switch of the transmitted/founder HIV-1 identifies co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting: the RV217 acute infection cohort study.

BACKGROUND: The CCR5 (R5) to CXCR4 (X4) coreceptor switch in natural HIV-1 infection is associated with faster progression to AIDS, but the mechanisms remain unclear. The difficulty in elucidating the evolutionary origin of the earliest X4 viruses limits our understanding of this phenomenon. METHODS: We tracked the evolution of the transmitted/founder (T/F) HIV-1 in RV217 participants identified in acute infection. The origin of the X4 viruses was elucidated by single genome amplification, deep sequencing and coreceptor assay. Mutations responsible for coreceptor switch were confirmed by mutagenesis. Viral susceptibility to neutralization was determined by neutralization assay. Virus CD4 subset preference was demonstrated by sequencing HIV-1 RNA in sorted CD4 subsets. FINDINGS: We demonstrated that the earliest X4 viruses evolved de novo from the T/F strains. Strong X4 usage can be conferred by a single mutation. The mutations responsible for coreceptor switch can confer escape to neutralization and drive the X4 variants to replicate mainly in the central memory (CM) and naïve CD4 subsets. Likely due to the smaller viral burst size of the CM and naïve subsets, the X4 variants existed at low frequency in plasma. The origin of the X4 viruses preceded accelerated CD4 decline. All except one X4 virus identified in the current study lost the conserved V3 N301 glycan site. INTERPRETATIONS: The findings demonstrate co-evolution of HIV-1 antigenicity, coreceptor usage and CD4 subset targeting which have implications for HIV-1 therapeutics and functional cure. The observations provide evidence that coreceptor switch can function as an evolutionary mechanism of immune evasion. FUNDING: Institute of Human Virology, National Institutes of Health, Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Thai Red Cross AIDS Research Centre, Gilead Sciences, Merck, and ViiV Healthcare.