We studied 156 individuals of Native American descent from the city of Tlapa in the state of Guerrero in western Mexico. Most individuals' ethnicity was either Nahua, Mixtec, or Tlapanec, but self-identified Mestizos and individuals of mixed ethnicities were also included in the sample. We typed 24 autosomal, one Y-chromosome, and four mitochondrial ancestry-informative markers (AIMs) to estimate group and individual admixture proportions, and determine whether the admixture process involved directional gene flow between parental groups. When genetically defined (GD) Mestizos were excluded from the analysis, Native American ancestry represented approximately 98% of the population's gene pool, while European and West African ancestry represented approximately 1% each. Maternally inherited markers also showed an exceptionally high Native American contribution (98.5%), as did the paternally inherited marker, DYS199 (90.7%). We did not detect genetic structure in this population using these AIMs, which appears consistent with the homogeneity of the sample in terms of admixture proportions. The addition of GD Mestizos to the sample did not produce a considerable change in admixture estimates, but it had a major effect on population structure. These results show that the population of Tlapa in Guerrero, Mexico, has experienced little admixture with Europeans and/or West Africans. They also show that the impact of a small number of admixed individuals on an otherwise homogeneous population might have profound implications on subsequent ancestry/phenotype analysis and mapping strategies. We suggest that heterogeneity is a major characteristic of Mexican populations and, as a consequence, should not be disregarded when designing epidemiological studies of Mexican and Mexican American populations.

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As a long-acting formulation of the nonnucleoside reverse transcriptase inhibitor rilpivirine (RPV LA) has been proposed for use as preexposure prophylaxis (PrEP) and the prevalence of transmitted RPV-resistant viruses can be relatively high, we evaluated the efficacy of RPV LA to inhibit vaginal transmission of RPV-resistant HIV-1 in humanized mice. Vaginal challenges of wild-type (WT), Y181C, and Y181V HIV-1 were performed in mice left untreated or after RPV PrEP. Plasma viremia was measured for 7 to 10 weeks, and single-genome sequencing was performed on plasma HIV-1 RNA in mice infected during PrEP. RPV LA significantly prevented vaginal transmission of WT HIV-1 and Y181C HIV-1, which is 3-fold resistant to RPV. However, it did not prevent transmission of Y181V HIV-1, which has 30-fold RPV resistance in the viruses used for this study. RPV LA did delay WT HIV-1 dissemination in infected animals until genital and plasma RPV concentrations waned. Animals that became infected despite RPV LA PrEP did not acquire new RPV-resistant mutations above frequencies in untreated mice or untreated people living with HIV-1, and the mutations detected conferred low-level resistance. These data suggest that high, sustained concentrations of RPV were required to inhibit vaginal transmission of HIV-1 with little or no resistance to RPV but could not inhibit virus with high resistance. HIV-1 did not develop high-level or high-frequency RPV resistance in the majority of mice infected after RPV LA treatment. However, the impact of low-frequency RPV resistance on virologic outcome during subsequent antiretroviral therapy still is unclear. IMPORTANCE The antiretroviral drug rilpivirine was developed into a long-acting formulation (RPV LA) to improve adherence for preexposure prophylaxis (PrEP) to prevent HIV-1 transmission. A concern is that RPV LA will not inhibit transmission of drug-resistant HIV-1 and may select for drug-resistant virus. In female humanized mice, we found that RPV LA inhibited vaginal transmission of WT or 3-fold RPV-resistant HIV-1 but not virus with 30-fold RPV resistance. In animals that became infected despite RPV LA PrEP, WT HIV-1 dissemination was delayed until genital and plasma RPV concentrations waned. RPV resistance was detected at similar low frequencies in untreated and PrEP-treated mice that became infected. These results indicate the importance of maintaining RPV at a sustained threshold after virus exposure to prevent dissemination of HIV-1 after vaginal infection and low-frequency resistance mutations conferred low-level resistance, suggesting that RPV resistance is difficult to develop after HIV-1 infection during RPV LA PrEP.

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Introduction: Lifestyle interventions, with physical activity (PA) as a key component, are important to reducing cardiometabolic disease risk. In our work in both efficacy and effectiveness clinical trials, we have shown that season has a significant impact on subjectively determined moderate-vigorous (MV) PA levels, both at baseline and during the intervention. However, the effect of season in these lifestyle interventions has not yet been examined utilizing objective measurements of PA so that time spent in all PA intensities and sedentary behavior(SB) can be quantified. Hypothesis: Our hypothesis is that PA would increase and SB would decrease due to the intervention but that season would have an additional effect on both. Methods: We enrolled 150 overweight/obese adults (51.1±10.2 y; 79% Caucasian; 91% female) in a 12-month lifestyle intervention for weight loss that provided regular feedback to participants on diet and PA goal achievement. Six cohorts were recruited from 2012-2014. The PA goal was to achieve and maintain 150 minutes/week of MVPA. ActiGraph GT3x accelerometers, worn on the waist, were used to assess average daily step counts and time spent in PA and SB. Accelerometer recordings with 10 hours/day of wear time on ≥4 days were considered a valid assessment of typical PA and SB. Changes in activity variables at 6 months and 12 months were examined using linear mixed models. We also examined the season (winter, spring, summer, or autumn) when the intervention was implemented and if this affected changes in PA and SB. Results: Baseline accelerometer data were valid for 149 participants. Mean (SD) baseline values were 6132 (1873) steps counts/day, 11 (11) MVPA min/day, 245 (64) light intensity (L)PA min/day, 635 (85) SB min/day. Season was significantly related to step counts, LPA, MVPA, and SB with significantly lower PA and higher SB in the winter (p<0.05). Changes in LPA and SB were not significant over the entire follow-up (p>0.05). When adjusted (for monitor wear time/day and season) mean (SD) increases in step counts from baseline were 1128 (208) and 742(209) steps/day at 6 and 12 months, respectively (both p<0.0001). For MVPA adjusted mean (SD) increases from baseline were 7(1) and 6(1) min/day at 6 and 12 months, respectively (both p<0.0001). Conclusions: Relevant improvements in steps counts and MVPA were recorded at 6 and 12 months. This was true even after controlling for the effect of differences in the season of implementation. When considering the effect of lifestyle interventions on activity, future studies should consider the effect of seasonal changes on PA levels.

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Previous findings of time-of-day differences in athletic performance could be confounded by diurnal fluctuations in environmental and behavioral "masking" factors (e.g., sleep, ambient temperature, and energy intake). The purpose of this study was to examine whether there is a circadian rhythm in swim performance that is independent of these masking factors. Experienced swimmers (n ϭ 25) were assessed for 50 -55 consecutive hours in the laboratory. The swimmers followed a 3-h "ultra-short" sleep-wake cycle, involving 1 h of sleep in darkness and 2 h of wakefulness in dim light, that was repeated throughout the observation. The protocol distributes behavioral and environmental masking factors equally across the 24-h period. Each swimmer was scheduled to perform six maximal-effort 200-m swim trials that were distributed equally across eight times of day (n ϭ 147 trials). Each trial was separated by 9 h. A cosine fit of intra-aural temperature data established the time of the lowest body temperature (T min). Swim performances were z-transformed and compared across the eight times of day and across twelve 2-h intervals relative to Tmin. Analysis of covariance, controlling for trial number, revealed a significant (P Ͻ 0.001) pattern in swim performance relative to environmental and circadian times of day. Performance peaked 5-7 h before Tmin (ϳ2300) and was worst from 1 h before to 1 h after Tmin (ϳ0500). Mean swim performance was 169.5 s; circadian variation from peak to worst performance was 5.8 s. These data suggest a circadian rhythm in athletic performance independent of environmental and behavioral masking effects. body temperature rhythm; swimming; ultra-short sleep-wake cycle CIRCADIAN RHYTHMS ARE INTERNALLY generated phenomena with periodicity of ϳ24 h (3). Most mammalian circadian rhythms originate from an endogenous pacemaker located in the suprachiasmatic nucleus (SCN) of the anterior hypothalamus (37). Neural and humoral outputs from the SCN communicate with other centers in the hypothalamus and the endocrine system. These centers drive a multitude of behavioral and physiological rhythms (17).Demonstration of circadian rhythms requires chronobiological techniques that separate the measurement of circadian rhythms from environmental and behavioral factors that might "mask" the measurement (e.g., energy intake, activity, posture, sleep, ambient temperature, and light) (21). These "unmasking" techniques have included the constant routine (21), data purification (51), forced desynchrony (19), and ultra-short sleep-wake protocols (15).There has been speculation that there may be a circadian rhythm in athletic performance. The theoretical rationale for