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High-altitude (HA) exposure may stimulate significant physiological and molecular changes, resulting in HA-related illnesses. HA may impact oxidative stress, antioxidant capacity, and iron homeostasis, yet it is unclear how both repeated exposure and HA acclimatization may modulate such effects. Therefore, we assessed the effects of weeklong repeated daily HA exposure (2,900–5,050 m) in altitude-naïve individuals ( n = 21 individuals, 13 females, mean ± SD, 25.3 ± 3.7 yr) to mirror the working schedule of HA workers ( n = 19 individuals, all males, 41.1 ± 9.4 yr) at the Atacama Large Millimeter Array (ALMA) Observatory (San Pedro de Atacama, Chile). Markers of oxidative stress, antioxidant capacity, and iron homeostasis were measured in blood plasma. Levels of protein oxidation ( P < 0.001) and catalase activity ( P = 0.023) increased and serum iron ( P < 0.001), serum ferritin ( P < 0.001), and transferrin saturation ( P < 0.001) levels decreased with HA exposure in both groups. HA workers had lower levels of oxidative stress, and higher levels of antioxidant capacity, iron supply, and hemoglobin concentration as compared with altitude-naïve individuals. On a second week of daily HA exposure, changes in levels of protein oxidation, glutathione peroxidase, and nitric oxide metabolites were lower as compared with the first week in altitude-naïve individuals. These results indicate that repeated exposure to HA may significantly alter oxidative stress and iron homeostasis, and the degree of such changes may be dependent on if HA is visited naïvely or routinely. Further studies are required to fully elucidate differences in HA-induced changes in oxidative stress and iron homeostasis profiles among visitors of HA.

BACKGROUND The longer-term risks of statins on physical function among people with HIV are unclear. METHODS Longitudinal analysis of Multicenter AIDS Cohort Study men between 40 and 75 years of age with ≥2 measures of gait speed or grip strength. Generalized estimating equations with interaction terms between (1) statin use and age and (2) HIV serostatus, age, and statin use were considered to evaluate associations between statin use and physical function. Models were adjusted for demographics and cardiovascular risk factors. RESULTS Among 2021 men (1048 with HIV), baseline median age was 52 (interquartile range 46-58) years; 636 were consistent, 398 intermittent, and 987 never statin users. There was a significant interaction between age, statin, and HIV serostatus for gait speed. Among people with HIV, for every 5-year age increase, gait speed (m/s) decline was marginally greater among consistent versus never statin users {-0.008 [95% confidence interval (CI) -0.017 to -0.00007]; P = 0.048}, with more notable differences between intermittent and never users [-0.017 (95% CI -0.027 to -0.008); P < 0.001]. Similar results were observed among men without HIV. Significant differences in grip strength (kg) decline were seen between intermittent and never users [-0.53 (95% CI -0.98 to -0.07); P = 0.024] and differences between consistent and never users [-0.28 (95% CI -0.63 to 0.06); P = 0.11] were not statistically significant. CONCLUSIONS Among men with and without HIV, intermittent statin users had more pronounced declines in physical function compared with consistent and never users. Consistent statin use does not seem to have a major impact on physical function in men with or without HIV.

The study examined and compared the sensitivity of culture and a quantitative PCR assay for screening equine semen for the presence of Taylorella equigenitalis (CEMO). Chilled semen samples, both raw and treated with extender, from two stallions were spiked with the organism at seven or 23 days postejaculation and prepared in serial dilutions. Culture of the 7-day raw semen readily detected CEMO at all dilutions, but extended semen yielded counts that were two log cycles lower at equivalent dilutions, with the organism being nearly undetectable at the maximal dilutions. By contrast, PCR sensitivity was not affected by extender, but for 7-day-old raw semen, PCR detection declined abruptly three log dilutions earlier than detection by culture. The more aged 23-day-old semen proved less satisfactory for spiking, with detection of CEMO by culture failing in three of the four samples due to overgrowth with commensal organisms. However, PCR performance was similar in both the 23- and 7-day spiking series. The detection limit by PCR is estimated at between 10

Received 12th May 2021. Accepted 17th May 2021. Published online 28th May 2021. Issue published 1st August 2021.

OBJECTIVE People living with HIV (PLWH) are living longer and developing more non-AIDS comorbidities, which negatively impact antiretroviral therapy (ART) adherence. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a novel pharmacologic measure of cumulative ART adherence that is predictive of viral suppression and future viremia. However, the relationship between non-AIDS comorbidities and this adherence measure is unknown. We aimed to evaluate the association between 3 non-AIDS comorbidities (diabetes mellitus (DM), hypertension, and hyperlipidemia) and TFV-DP in DBS in PLWH. METHODS Blood for TFV-DP in DBS and HIV viral load was prospectively collected from PLWH on tenofovir disoproxil fumarate for up to 3 times over 48 weeks. Non-AIDS comorbidities were recorded. Mixed effect multivariable linear regression models were used to estimate the changes in TFV-DP concentrations in DBS according to the presence of comorbidities and to estimate the percent differences in TFV-DP concentrations between these groups. RESULTS A total of 1144 person-visits derived from 523 participants with available concentrations of TFV-DP in DBS were included in this analysis. In univariate analysis, no significant association between non-AIDS comorbidities (categorized as having 0, 1, 2, or 3 comorbidities) and the concentrations of TFV-DP in DBS was observed (P = 0.40). Participants who had DM had 25% lower (95% confidence interval: -36% to -12%; P < 0.001) TFV-DP in DBS than participants without DM after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4 T-cell count, hematocrit, ART class, patient-level medication regimen complexity index, and 3-month self-reported adherence. CONCLUSIONS Diabetic PLWH have lower concentrations of TFV-DP in DBS compared with those without DM. Further research is required to identify the clinical implications and biological mechanisms underlying these findings.

We examined the associations between pulmonary impairments and physical function and whether age, HIV serostatus, or smoking modified these relationships.Using Multicenter AIDS Cohort Study data, we examined associations between pulmonary function (diffusing capacity for carbon monoxide [DLOf 1,048 men, 55% were living with HIV, median age was 57(IQR=48,64) and median cumulative pack-years was 1.2(IQR = 0,18.1); 33% and 13% had impaired DLPulmonary impairment and decreased physical function were associated. Preserving pulmonary function may help preserve physical function in aging men with and without HIV.

Background Sofosbuvir is converted to its active form, 007 triphosphate (007-TP), within cells. To date, the association between treatment adherence and 007-TP in dried blood spots (DBS) and factors that influence this relationship remain unknown. Objectives To examine relationships between adherence and 007-TP concentrations in DBS and identify factors that influence 007-TP in DBS. Methods Persons with HCV or HIV/HCV coinfection and self-reported drug and/or alcohol use were randomized to one of two technology-based approaches for monitoring 12 week adherence to once-daily ledipasvir/sofosbuvir. Convenience blood samples were collected every 2 weeks during treatment. 007-TP in DBS was quantified using LC/MS and analysed using mixed-effects models. Results A total of 337 observations were available from 58 participants (78% male; 21% black; 22% Hispanic/Latino; 26% cirrhotic; 78% HIV-coinfected). The mean half-life of 007-TP in DBS was 142 h (95% CI 127–156) and concentrations increased by 7.3% (95% CI 2.2–12.6) for every 10% increase in between-visit adherence. Geometric mean (95% CI) 007-TP concentrations in DBS were 301 (247–368), 544 (462–639) and 647 (571–723) fmol/punch by adherence categories of ≤50%, >50 to ≤80%, and >80%. Adherence, time on therapy, increasing age and decreased estimated glomerular filtration rate were associated with higher 007-TP, whereas increased time since last dose, male sex, black race and higher BMI were associated with lower 007-TP. Conclusions 007-TP has an extended half-life in DBS and concentrations increased with adherence. Further research is needed to examine additional factors that affect 007-TP and the clinical utility of this measure.

BACKGROUND: Residual systemic inflammation, which is associated with non-AIDS clinical outcomes, may persist despite viral suppression. We assessed the effect of antiretroviral (ART) adherence interruptions on systemic inflammation among Ugandans living with HIV who were virally suppressed. SETTING: We evaluated adults initiating first-line ART at a regional referral hospital clinic in Mbarara, Uganda. METHODS: Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble sCD14, sCD163, the kynurenine/tryptophan (K/T) ratio, and CD8(+) T-cell activation (HLA-DR(+)/CD38(+) co-expression) were measured at baseline and 6 months following ART initiation among participants who achieved viral suppression (VL

The prediction of a difficult cholecystectomy has traditionally been based on certain pre-operative clinical and imaging factors. Most of the previous literature reported small patient cohorts and have not used an objective measure of operative difficulty. The aim of this study was to develop a pre-operative score to predict difficult cholecystectomy, as defined by a validated intra-operative difficulty grading scale. Two cohorts from prospectively maintained databases of patients who underwent laparoscopic cholecystectomy were analysed: the CholeS Study (8755 patients) and a single surgeon series (4089 patients). Factors potentially predictive of difficulty were correlated to the Nassar intra-operative difficulty scale. A multivariable binary logistic regression analysis was then used to identify factors that were independently associated with difficult laparoscopic cholecystectomy, defined as operative difficulty grades 3 to 5. The resulting model was then converted to a risk score, and validated on both internal and external datasets. Increasing age and ASA classification, male gender, diagnosis of CBD stone or cholecystitis, thick-walled gallbladders, CBD dilation, use of pre-operative ERCP and non-elective operations were found to be significant independent predictors of difficult cases. A risk score based on these factors returned an area under the ROC curve of 0.789 (95% CI 0.773–0.806, p

BackgroundTenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is associated with viral suppression in persons living with HIV (PLWH) taking tenofovir disoproxil fumarate (TDF). However, its value as a predictor of future viremia remained unknown.MethodsBlood for plasma viral load (VL) and TFV-DP in DBS were collected (up to 3 visits within 48 weeks) in PLWH on TDF. TFV-DP cut points were selected using logistic prediction models maximizing the area under the receiver operation characteristic curve, and estimated adjusted odds ratio (aOR) of future viremia (≥20 copies/mL) were compared to the highest TFV-DP category.ResultsAmong all 451 participants in the analysis, aOR of future viremia for participants with TFV-DP ConclusionsTFV-DP in DBS predicts future viremia in PLWH on TDF, even in those who are virologically suppressed. This highlights the utility of this biomarker to inform about adherence beyond VL.Clinical Trials Registration. NCT02012621.

Introduction Increased mortality has been demonstrated in older adults with coronavirus disease 2019 (COVID-19), but the effect of frailty has been unclear. Methods This multi-centre cohort study involved patients aged 18 years and older hospitalised with COVID-19, using routinely collected data. We used Cox regression analysis to assess the impact of age, frailty and delirium on the risk of inpatient mortality, adjusting for sex, illness severity, inflammation and co-morbidities. We used ordinal logistic regression analysis to assess the impact of age, Clinical Frailty Scale (CFS) and delirium on risk of increased care requirements on discharge, adjusting for the same variables. Results Data from 5,711 patients from 55 hospitals in 12 countries were included (median age 74, interquartile range [IQR] 54–83; 55.2% male). The risk of death increased independently with increasing age (>80 versus 18–49: hazard ratio [HR] 3.57, confidence interval [CI] 2.54–5.02), frailty (CFS 8 versus 1–3: HR 3.03, CI 2.29–4.00) inflammation, renal disease, cardiovascular disease and cancer, but not delirium. Age, frailty (CFS 7 versus 1–3: odds ratio 7.00, CI 5.27–9.32), delirium, dementia and mental health diagnoses were all associated with increased risk of higher care needs on discharge. The likelihood of adverse outcomes increased across all grades of CFS from 4 to 9. Conclusion Age and frailty are independently associated with adverse outcomes in COVID-19. Risk of increased care needs was also increased in survivors of COVID-19 with frailty or older age.

BACKGROUND People with HIV (PWH) are at an increased risk for adiposity and sarcopenia, despite effective antiretroviral therapy. Our objective was to compare the effects of prescribed exercise on body composition in older PWH and uninfected controls. SETTING Academic medical center. METHODS Sedentary PWH (n = 27) and uninfected controls (n = 28) aged 50-75 years completed 24 weeks of cardiovascular and resistance exercise. Participants completed 12 weeks of moderate-intensity exercise and then were randomized to moderate- or high-intensity exercise for 12 additional weeks. Total lean (LEAN) and fat mass (FAT), and visceral adipose tissue area (VAT) were measured using dual-energy x-ray absorptiometry at baseline and 24 weeks; baseline and intervention differences were compared by HIV serostatus using multivariable regression analyses adjusted for baseline values, age, and exercise adherence. RESULTS At baseline, PWH had significantly lower FAT (P = 0.003), but no significant differences in LEAN or VAT compared with controls (P > 0.20). Changes over 24 weeks were not significantly different by HIV serostatus, although controls tended to gain more LEAN (0.8 kg; range, 0-1.6 kg; P = 0.04] than PWH (0.6 kg; range, -0.2 to 1.4 kg; P = 0.12) and lose less FAT and VAT (controls: (-0.9 kg; range, -1.8 to 0.0 kg and -10.3 cm; range, -19.6, 1.0) cm; both P = 0.03 vs PWH: -2.0 kg; range, -2.9 to -1.1 kg and -17.7 cm; range, -27.1 to -8.2 cm; both P < 0.001). Exercise intensity differences were not apparent for LEAN, FAT, or VAT. CONCLUSIONS Exercise reduced total and visceral fat in older PWH and controls. Minimal gains in lean mass suggest that greater emphasis on resistance exercise may be needed to more effectively increase muscle in PWH.

Pre-exposure prophylaxis (PrEP) containing antiretrovirals tenofovir disoproxil fumarate (TDF) or tenofovir alafenamide (TAF) can reduce the risk of acquiring HIV. Concentrations of intracellular tenofovir-diphosphate (TFV-DP) measured in dried blood spots (DBS) have been used to quantify PrEP adherence; although even under directly observed dosing, unexplained between-subject variation remains. Here, we wish to identify patient-specific factors associated with TFV-DP levels. Data from the iPrEX Open Label Extension (OLE) study were used to compare multiple covariate selection methods for determining demographic and clinical covariates most important for drug concentration estimation. To allow for the possibility of non-linear relationships between drug concentration and explanatory variables, the component selection and smoothing operator (COSSO) was implemented. We compared COSSO to LASSO, a commonly used machine learning approach, and traditional forward and backward selection. Training (N = 387) and test (N = 166) datasets were utilized to compare prediction accuracy across methods. LASSO and COSSO had the best predictive ability for the test data. Both predicted increased drug concentration with increases in age and self-reported adherence, the latter with a steeper trajectory among Asians. TFV-DP reductions were associated with increasing eGFR, hemoglobin and transgender status. COSSO also predicted lower TFV-DP with increasing weight and South American countries. COSSO identified non-linear relationships between log(TFV-DP) and adherence, weight and eGFR, with differing trajectories for some races. COSSO identified non-linear log(TFV-DP) trajectories with a subset of covariates, which may better explain variation and enhance prediction. Future research is needed to examine differences identified in trajectories by race and country.

BACKGROUND Frailty and physical function impairments occur at an earlier than expected age in people with HIV (PWH). The goal of this study was to determine which tools or combination of tools assessing frailty/physical function were most predictive of mortality in a middle-aged population of PWH. METHODS Using electronic health records, we determined survival, death, or loss to follow-up for 359 PWH, aged 45-65 years originally enrolled in a 2009-2010 cross-sectional cohort study. The predictive accuracy of various physical function measures [frailty score, Veterans Aging Cohort Study (VACS) index, 400-m walk, Short Physical Performance Battery (SPPB), grip strength, and falls] were compared using integrated time-dependent receiver operating characteristic area under the curve (AUC) in single variable models. Two-variable models were compared with the best single-variable model to determine if AUC improved with additional physical function variables. RESULTS At 8-year follow-up, frailty, 400-m walk pace, SPPB, chair rise pace, VACS score, and falls were associated with increased hazard of mortality; grip strength was only predictive in sex-adjusted models. The VACS index and 400-m walk pace were the best individual predictors of mortality with time-dependent receiver operating characteristic AUC scores of 0.82, followed by SPPB (0.73), chair-rise pace (0.68), falls (0.65), frailty (0.63), and grip strength (0.55). Addition of the 400-m walk to VACS index yielded the only significant improvement in the prediction of survival compared with the VACS index alone (P = 0.04). CONCLUSION Our study highlights several clinically applicable physical function measures predictive of mortality in middle-aged PWH that can be tailored to specific patient subpopulations and clinical or research encounters.

A 41-year-old man with no significant medical history presented with acute behavioural disruption on the background of a 1-day history of severe headache and a 10-day history of dry cough and fever. He was sexually disinhibited with pressured speech and grandiose ideas. His behaviour worsened, necessitating heavy sedation and transfer to intensive care for mechanical ventilation despite no respiratory indication. Investigations confirmed that he was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Neuroimaging and a lumbar puncture were normal. Initial screening for SARS-CoV-2 in the cerebrospinal fluid was negative although no validated assay was available. The patient’s mental state remained abnormal following stepdown from intensive care. Psychiatric assessment found features consistent with acute mania, and he was detained under the Mental Health Act. This case indicates the need to consider COVID-19 in a wider series of clinical presentations and to develop a validated assay for SARS-CoV-2 in the cerebrospinal fluid.

Tenofovir alafenamide (TAF), in combination with FTC, was recently approved for PrEP in the United States. The objective of this study was to assess the relationship between tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) with adherence to TAF/FTC.TAF-DBS was a randomized, crossover clinical study of TFV-DP in DBS, following directly observed dosing of 33%, 67%, or 100% of daily TAF (25 mg)/FTC (200 mg). Healthy volunteers were randomized to 2 different, 12-week dosing regimens, separated by a 12-week washout. DBS were collected weekly. TFV-DP and FTC-TP were extracted from two 7-mm punches and assayed with LC-MS/MS.Thirty-seven participants (17 female, 7 African American, and 6 Hispanic) were included. TFV-DP exhibited a mean half-life of 20.8 days (95% confidence interval: 19.3 to 21.3). The slope for TFV-DP versus dosing arm was 1.14 (90% confidence interval: 1.07 to 1.21). The mean (SD) TFV-DP after 12 weeks was 657 (186), 1451 (501), and 2381 (601) fmol/2 7-mm punches for the 33%, 67%, and 100% arms. The following adherence interpretations are proposed:450 fmol/punches,2 doses/wk; 450-949 fmol/punches, 2-3 doses/wk; 950-1799 fmol/punches, 4-6 doses/wk; and ≥1800 fmol/punches, 7 doses/wk. FTC-TP was quantifiable for 1 week after drug cessation in 50%, 92%, and 100% of participants in the 33%, 67%, and 100% arms, respectively.TFV-DP in DBS after TAF/FTC exhibited a long half-life and was linearly associated with dosing, similar to its predecessor tenofovir disoproxil fumarate. FTC-TP was quantifiable for up to 1 week after drug cessation. Together, these moieties provide complementary measures of cumulative adherence and recent dosing for TAF/FTC.

BACKGROUND: Emtricitabine triphosphate (FTC-TP), the phosphorylated anabolite of emtricitabine, can be quantified in dried blood spots (DBS). We evaluated FTC-TP in DBS as a predictor of viral suppression and evaluated self-reported adherence as a predictor of FTC-TP. METHODS: Persons living with HIV (PLWH) on an FTC-containing regimen were prospectively recruited. A DBS and HIV viral load were obtained during routine clinical visits. Self-reported adherence for 3 days, 30 days and 3 months was captured. Generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression for quantifiable FTC-TP versus below the limit of quantification (BLQ). The utility of self-reported adherence to predict quantifiable FTC-TP was assessed by calculating the area under receiver operating characteristic (ROC) curve. RESULTS: One thousand one hundred and fifty-four person-visits from 514 participants who had DBS assayed for FTC-TP were included in the analysis. After adjusting for age, gender, race, BMI, ART class, ART duration, estimated glomerular filtration rate and CD4+ T cell count, the aOR (95% CI) for viral suppression for quantifiable FTC-TP versus BLQ was 7.2 (4.3–12.0; P

ObjectivesTo determine factors associated with interindividual variability in tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBSs) among persons living with HIV (PLWH).MethodsPLWH who were at least 18 years old and taking tenofovir disoproxil fumarate-containing ART were prospectively recruited and enrolled from a clinical cohort and followed longitudinally (up to three visits over 48 weeks). With log-transformed TFV-DP concentrations in DBSs as the outcome, mixed-model regression analyses were used to assess associations between self-reported 3 month ART adherence, race and other clinical covariates (gender, age, BMI, CD4+ T cell count, estimated glomerular filtration rate, haematocrit, duration on current ART and anchor drug class) on TFV-DP in DBSs.ResultsFive hundred and twenty-seven participants (1150 person-visits) were analysed. Adjusting for race and other clinical covariates, every 10% increase in self-reported 3 month ART adherence was associated with an average TFV-DP concentration increase in DBSs of 28% (95% CI: 24%–32%; P ConclusionsIndividual patient characteristics were predictive of TFV-DP concentration in DBSs in PLWH receiving tenofovir disoproxil fumarate-based ART. Future research to incorporate these predictors into the interpretation of this ART adherence biomarker, and to establish whether these associations extend to PLWH taking tenofovir alafenamide-containing ART, is needed.

People with HIV (PWH) often experience social isolation, loss of friends or partners, and estranged family relationships, creating challenges in selecting medical decision makers or clarifying end-of-life wishes. Whether advanced directive (AD) completion rates or informal proxy or medical power assignment (MPOA) differ by ultimate cause of death is unknown. We conducted a retrospective study of deceased PWH from a single clinic to examine factors associated with AD completion (47%) or MPOA assignment (73%) prior to death. AD completers were older at death (54.3[10.9] vs. 50.3[11.1] years, p = .04) than non-completers, and cancer death was more prevalent (23[54%] vs. 9[22%], p = .014). Patients with an MPOA had lower CD4 count (48% vs. 21%) and greater prevalence of cancer death (48% vs. 15%), but were of similar age at death (51.9[11.2] vs. 52.9[11.2] years, p = .66). This research identifies target populations for AD or MPOA education and assistance.

OBJECTIVE Whether older people living with HIV (PLWH) can achieve similar functional benefits with exercise as their uninfected peers and the ideal intensity of exercise needed for these benefits are not known. DESIGN Sedentary adults (50-75 years) with or without HIV were recruited for 24 weeks of supervised endurance/resistance exercise. After 12 weeks of moderate-intensity exercise, participants were randomized to continue moderate-intensity or advance to high-intensity exercise for an additional 12 weeks. METHODS Outcomes by serostatus and exercise intensity (moderate, high) were compared using linear and mixed effects regression models and controlled for baseline values or week 12 values. RESULTS A total of 32 PLWH and 37 controls were enrolled; 27 PLWH (12 moderate/15 high) and 29 controls (15 moderate/14 high) completed 24 weeks. PLWH had significantly poorer physical function across nearly all baseline measures. Both groups had significant improvements in all functional measures. From 0 to 12 weeks, PLWH had significantly greater percentage improvements (mean, 95% confidence interval) than controls on VO2 max [5 (0, 10)%]; from 13 to 24 weeks, PLWH had significantly greater percentage improvements on stair climb [-5 (-10, -1)%], and the time to complete a 400-m walk [-3 (-5, -0)%]; all P less than 0.05. An interaction between exercise intensity and HIV serostatus was significant for measures of strength: PLWH randomized to high-intensity gained significantly more strength than moderate-intensity in bench and leg press [6 (0, 12)% and 10 (2, 17)% greater; both P

BackgroundAlthough tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a predictor of adherence and pre-exposure prophylaxis efficacy, its utility in human immunodeficiency virus (HIV) treatment remains unknown.MethodsDBS for TFV-DP were collected up to 3 times over 48 weeks in persons living with HIV (PLWH) who were receiving TFV disoproxil fumarate (TDF)-based therapy. Log-transformed baseline TFV-DP was compared using t-tests or analyses of variance; generalized estimating equations were used to estimate the adjusted odds ratio (aOR) of viral suppression (ResultsWe analyzed 1199 DBS from 532 participants (76 female; 101 Black, 101 Hispanic). Among the virologically-suppressed participants at baseline (n = 347), TFV-DP was lower in Blacks (geometric mean 1453, 95% confidence interval [CI] 1291–1635) vs Whites (1793, 95% CI 1678–1916; P = .002) and Hispanics (1760, 95% CI 1563–1982; P = .025); in non-boosted (1610, 95% CI 1505–1723) vs. boosted (1888, 95% CI 1749–2037; P = .002) regimens; and in non-nucleoside reverse transcription inhibitor–based (1563, 95% CI 1432–1707) vs. boosted protease inhibitor–based (1890, 95% CI 1704–2095; P = .006) and multiclass-based (1927, 95% CI 1650–2252; P = .022) regimens. The aOR of virologic suppression, after adjusting for age, gender, race, body mass index, estimated glomerular filtration rate, CD4+ T-cell count, antiretroviral drug class and duration of therapy, was 73.5 (95% CI 25.7–210.5; P < .0001) for a TFV-DP concentration ≥1850 fmol/punch compared to ConclusionsTFV-DP in DBS is strongly associated with virologic suppression in PLWH on TDF-based therapy and is associated with certain participant characteristics. Further research is required to evaluate this drug adherence and exposure measure in clinical practice.Clinical Trials RegistrationNCT02012621.

Background: Sets of genital swabs are routinely taken from horses to screen for the presence of Taylorella equigenitalis, the cause of contagious equine metritis. Typically, two to four different sites are swabbed at a time and tested by culture or PCR. Objectives: This study explored the feasibility of pooling these swabs for a single PCR test per animal instead of testing each swab individually. Study design: In vitro. Methods: PCR signal strengths (Ct values) from 149 historical PCR positive genital swabs, together with historical data on the number of swabs in a set expected to be positive, were used to assess the suitability of pooling for screening horses for T. equigenitalis infection in the population at large. Twenty-four sets of four equine genital swabs were tested. The sets were prepared in the laboratory using one or more swabs positive for T. equigenitalis from naturally infected cases. Positive and negative swabs were selected to reflect a typical range of PCR Ct values expected in field cases of T. equigenitalis infection. These pools were tested by an established PCR to assess the impact and suitability of a PCR test on pooled swabs compared to individual swab testing, by comparing the Ct values. Results: Pooling one positive swab with three negative swabs produced a small drop in Ct value but all pools were still clearly positive. Main limitations: Large numbers of field positive horses are not available, but the proof of concept approach with laboratory prepared pools shows the method is applicable to field cases. Conclusions: It was concluded that pooling of swabs would confer no appreciable drop in the ability to detect a positive animal compared to individual swab testing; pooling is therefore a suitable alternative to individual swab testing with reduced costs. The Summary is available in Spanish – see Supporting Information.

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p p Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty.

Background Dolutegravir, an HIV integrase strand-transfer inhibitor, and simeprevir, an HCV NS3/4A PI, have the potential to interact as dolutegravir is a P-glycoprotein, uridine glucuronosyl transferase 1A1 and cytochrome P4503A substrate and simeprevir has been shown to mildly inhibit these. Objectives To compare dolutegravir and simeprevir pharmacokinetics (PK) when given separately versus in combination. Methods Healthy volunteers received: (i) 150 mg of simeprevir once daily for 7 days; (ii) 50 mg of dolutegravir once daily for 7 days; and (iii) 150 mg of simeprevir once daily plus 50 mg of dolutegravir once daily for 7 days, with randomization to treatment sequence. Twenty-four hour intensive PK sampling was performed on day 7 of each sequence following observed dosing and a standardized meal. PK parameters were determined using non-compartmental methods and compared using paired t-tests. Bioequivalence for area under the curve (AUCtau) and maximum concentration (Cmax) were also assessed. NCT02404805. Results Twenty-four subjects completed all three sequences. Dolutegravir trough was increased 24% (P = 0.0003) with simeprevir. Dolutegravir AUCtau was increased 15% (P = 0.002), but was deemed bioequivalent as the 90% CI for the geometric mean ratio was 107%-123%. Dolutegravir Cmax was bioequivalent. Simeprevir PK was unaffected by dolutegravir. There were no discontinuations due to adverse events and all adverse events were mild to moderate in severity. Conclusions Dolutegravir trough was increased slightly with simeprevir, but AUCtau was bioequivalent. Despite the increase in trough, dolutegravir concentrations were well within the range with established safety data. Suggesting that simeprevir and dolutegravir can be safely co-administered.

Purpose: Cold-water immersion (CWI) and whole body cryotherapy (WBC) are widely used recovery methods in an attempt to limit exercise-induced muscle damage, soreness and functional deficits after strenuous exercise. The aim of this study was to compare the effects of ecologically-valid CWI and WBC protocols on post-exercise lower limb thermoregulatory, femoral artery and cutaneous blood flow responses.Methods: Ten males completed a continuous cycle exercise protocol at 70% maximal oxygen uptake until a rectal temperature of 38°C was attained. Participants were then exposed to lower-body CWI (8°C) for 10 min, or WBC (-110°C) for 2 min, in a randomized cross-over design. Rectal and thigh skin, deep and superficial muscle temperatures, thigh and calf skin blood flow (laser Doppler flowmetry), superficial femoral artery blood flow (duplex ultrasound) and arterial blood pressure were measured prior to, and for 40 min post, cooling interventions.Results: Greater reductions in thigh skin (CWI, -5.9±1.8°C; WBC, 0.2±0.5°C; P < 0.001) and superficial (CWI, -4.4±1.3°C; WBC, -1.8±1.1°C; P < 0.001) and deep (CWI, -2.9±0.8°C; WBC, -1.3±0.6°C; P < 0.001) muscle temperatures occurred immediately after CWI. Decreases in femoral artery conductance were greater after CWI (CWI, -84±11%; WBC, -59±21%, P < 0.02) and thigh (CWI, -80±5%; WBC, -59±14%, P < 0.001) and calf (CWI, -73±13%; WBC, -45±17%, P < 0.001) cutaneous vasoconstriction was greater following CWI. Reductions in rectal temperature were similar between conditions after cooling (CWI, -0.6±0.4°C; WBC, -0.6±0.3°C; P = 0.98).Conclusion: Greater reductions in blood flow and tissue temperature were observed after CWI in comparison to WBC. These novel findings have practical and clinical implications for the use of cooling in the recovery from exercise and injury.

Chronic sleep disruption can have significant negative health effects and prior studies suggest that people with HIV (PWH) have disproportionately higher rates of sleep problems. We evaluated baseline sleep of sedentary, older adults (50–75 years) with (n = 28) and without HIV (n = 29) recruited into a 24-week exercise study. Subjective sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI); objective sleep parameters were assessed using wrist-worn actigraphy. Regression models were used to investigate changes in outcomes. Fifty-seven participants completed the intervention. At baseline, PWH had significantly lower sleep efficiency (88.7 [95% CI 86, 91]%) compared to controls (91.8 [95% CI 91, 93]%; p = 0.02); other sleep measures indicated poorer sleep among PWH but did not reach statistical significance (p ≥ 0.12). Overall, sleep outcomes did not significantly change with the exercise intervention (all p > 0.05). In adjusted analyses, PWH demonstrated a decrease in total sleep time (–22.1 [–43.7, –0.05] p = 0.045) and sleep efficiency (–1.3 [–2.5, –.01], p = 0.03) during the 24 weeks of exercise; these differences were attenuated and no longer significant after adjusting for exercise intensity. At the completion of the intervention, compared to controls, PWH had significantly poorer sleep by PSQI score (2.2 [0.6, 3.8]; p = 0.006) and sleep efficiency (–2.8 [–5.4,–0.2]%; p = 0.04). In this study, sleep disturbance was more prevalent in sedentary older PWH compared to uninfected controls. An exercise intervention had minimal effect on sleep impairments among PWH nor controls. Among older adults, interventions beyond cardiovascular and resistance exercise may be needed to significantly alter subjective and objective sleep outcomes.

Adherence to tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, Truvada(®)) is the primary determinant of HIV pre-exposure prophylaxis (PrEP) efficacy. Despite its importance, limitations exist in current methods of adherence quantification, restricting their implementation in the clinic. Proteus Discover (Proteus Digital Health(®)) can measure the time of each dose using an ingestible sensor that is coencapsulated with medication. In this study, the bioequivalence of coencapsulated TDF/FTC with the Proteus sensor was compared relative to unencapsulated drug. This was a 1:1 randomized cross-over study in which healthy participants received a single dose of unencapsulated and coencapsulated TDF/FTC. A 14-day washout separated each period. Blood was collected at predose and at 0.25, 0.5, 1, 2, 4, 6, 10, 24, 48, and 72 h postdose. Plasma concentrations were determined by LC-MS/MS methods, with a 10 ng/mL lower limit of quantitation (LLOQ) for both tenofovir (TFV) and FTC. Noncompartmental analysis was carried out with Phoenix(®) WinNonlin(®) for maximum concentrations (C(max)), area under the concentration–time curve from time 0 to the last measured time point (AUC(last)) and AUC extrapolated to infinity (AUC(inf)). Geometric mean ratios were calculated for each parameter and bioequivalence was defined as the 90% confidence interval (CI) of each ratio being within 80%–125%. Twenty-four participants (11 males; 19 white, 3 African American, and 2 Hispanic) completed both visits. Mean ± SD age was 28 ± 4 years and weight was 74 ± 14 kg. The 90% CIs for TFV C(max), AUC(last), and AUC(inf) were 89%–119%, 94%–111%, and 96%–111%, respectively. The 90% CIs for FTC C(max), AUC(last), and AUC(inf) were 96%–120%, 96%–108%, and 96%–108%, respectively. Bioequivalence was observed for the coencapsulation of TDF/FTC with the Proteus ingestible sensor, as assessed by a rigorously conducted pharmacokinetic study. Future studies will evaluate the utility and effectiveness of the sensor system as a tool to monitor PrEP adherence in clinical settings.

Mortality for people living with HIV (PLWH) has dramatically decreased since the mid-1990s and the proportion of deaths attributable to non-AIDS-related conditions has increased. Deceased PLWH were identified from a single academic medical center through provider survey and electronic medical record query. Cause of death was determined using the Coding Causes of Death in HIV tool following review of available medical records. Chart review of comorbidities, demographics, laboratory values, and previous completion of screening tests for malignancies was conducted for deaths during the period of 2013–2017. The proportion of AIDS-related deaths decreased markedly between 1995 and 2017, while the proportion of deaths from non-AIDS malignancies increased. From 2013 to 2017, 30 of 121 deaths were attributed to AIDS-related conditions, 32 to non-AIDS malignancies, 14 to suicide/homicide or sudden death, 10 to cardiac causes, 28 to other non-HIV causes, and 7 to unknown causes. Those who died of non-AIDS-related malignancies were older than AIDS-related deaths [mean age 55.8 (7.6) vs. 47.3 (13.5), p value = .003]. Less than half of potentially eligible patients had documented colon cancer screening. The number of individuals dying from AIDS-related conditions has decreased significantly and non-AIDS-related causes, particularly non-AIDS-related malignancies, have become more prominent causes of death. As our patients age, a greater focus needs to be placed on management of comorbid illnesses and screening and prevention of malignancy.

ObjectivesThe British Association of Spinal Surgeons recently called for updates in consenting practice. This study investigates the utility and acceptability of a personalised video consent tool to enhance patient satisfaction in the preoperative consent giving process.DesignA single-centre, prospective pilot study using questionnaires to assess acceptability of video consent and its impacts on preoperative patient satisfaction.SettingA single National Health Service centre with individuals undergoing surgery at a regional spinal centre in the UK.Outcome measureAs part of preoperative planning, study participants completed a self-administered questionnaire (CSQ-8), which measured their satisfaction with the use of a video consent tool as an adjunct to traditional consenting methods.Participants20 participants with a mean age of 56 years (SD=16.26) undergoing spinal surgery.ResultsMean patient satisfaction (CSQ-8) score was 30.2/32. Median number of video views were 2–3 times. Eighty-five per cent of patients watched the video with family and friends. Eighty per cent of participants reported that the video consent tool helped to their address preoperative concerns. All participants stated they would use the video consent service again. All would recommend the service to others requiring surgery. Implementing the video consent tool did not endure any significant time or costs.ConclusionsIntroduction of a video consent tool was found to be a positive adjunct to traditional consenting methods. Patient–clinician consent dialogue can now be documented. A randomised controlled study to further evaluate the effects of video consent on patients’ retention of information, preoperative and postoperative anxiety, patient reported outcome measures as well as length of stay may be beneficial.

Although prostate cancer is the leading cause of cancer mortality for African men, the vast majority of known disease associations have been detected in European study cohorts. Furthermore, most genome-wide association studies have used genotyping arrays that are hindered by SNP ascertainment bias. To overcome these disparities in genomic medicine, the Men of African Descent and Carcinoma of the Prostate (MADCaP) Network has developed a genotyping array that is optimized for African populations. The MADCaP Array contains more than 1.5 million markers and an imputation backbone that successfully tags over 94% of common genetic variants in African populations. This array also has a high density of markers in genomic regions associated with cancer susceptibility, including 8q24. We assessed the effectiveness of the MADCaP Array by genotyping 399 prostate cancer cases and 403 controls from seven urban study sites in sub-Saharan Africa. Samples from Ghana and Nigeria clustered together, whereas samples from Senegal and South Africa yielded distinct ancestry clusters. Using the MADCaP array, we identified cancer-associated loci that have large allele frequency differences across African populations. Polygenic risk scores for prostate cancer were higher in Nigeria than in Senegal. In summary, individual and population-level differences in prostate cancer risk were revealed using a novel genotyping array. Significance: This study presents an Africa-specific genotyping array, which enables investigators to identify novel disease associations and to fine-map genetic loci that are associated with prostate and other cancers.

Older people living with HIV (PLWH) experience multimorbidity that can negatively impact quality of life (QoL). Exercise can improve physical function, but effects on QoL are not well understood. 32 PLWH and 37 controls aged 50-75 completed 12-weeks of moderate-intensity exercise, then were randomized to moderate or high-intensity for 12 additional weeks. Depressive symptoms (CES-D scores) were significantly greater and QOL (SF-36 mental and physical summary scores) significantly lower among PLWH at baseline (all p

We assessed the effects of post‐exercise cold‐water immersion (CWI) in modulating PGC‐1α mRNA expression in response to exercise commenced with low muscle glycogen availability. In a randomized repeated‐measures design, nine recreationally active males completed an acute two‐legged high‐intensity cycling protocol (8 × 5 min at 82.5% peak power output) followed by 10 min of two‐legged post‐exercise CWI (8°C) or control conditions (CON). During each trial, one limb commenced exercise with low (LOW

OBJECTIVE: To test the hypothesis that APOE ε4 status and cerebrospinal fluid (CSF) Aβ42, T-tau and P-tau would independently predict the risk of postoperative delirium.BACKGROUND: Delirium following surgery is common and associated with adverse outcomes. Age and cognitive impairment are consistent risk factors for postoperative delirium.METHODS: This observational cohort study recruited 282 participants aged 65 years or older, without a diagnosis of dementia, admitted for primary elective hip or knee arthroplasty. Cognitive tests were undertaken preoperatively, blood and CSF were sampled at the time of spinal anesthesia, and participants were assessed daily postoperatively for delirium.RESULTS: Increasing age (P = 0.04), preoperative comorbidity (P = 0.03), type of surgery (P = 0.05), intravenous opioid usage (P = 0.04), and low CSF Aβ42 (P < 0.01) were independent predictors of postoperative delirium.CONCLUSIONS: This study is the first to show an independent association between CSF Aβ42 and delirium incidence in an elective surgical population, suggesting that postoperative delirium may indicate incipient Alzheimer disease.

Objectives Administrative databases with dedicated coding systems in healthcare systems where providers are funded based on services recorded have been shown to be useful for clinical research, although their reliability is still questioned. We devised a custom classification of procedures and algorithms based on OPCS, enabling us to identify open heart surgeries from the English administrative database, Hospital Episode Statistics, with the objective of comparing the incidence of cardiac procedures in administrative and clinical databases. Design A comparative study of the incidence of cardiac procedures in administrative and clinical databases. Setting Data from all National Health Service Trusts in England, performing cardiac surgery. Participants Patients classified as having cardiac surgery across England between 2004 and 2015, using a combination of procedure codes, age >18 and consultant specialty, where the classification was validated against internal and external benchmarks. Results We identified a total of 296 426 cardiac surgery procedures, of which majority of the procedures were coronary artery bypass grafting (CABG), aortic valve replacement (AVR), mitral repair and aortic surgery. The matching at local level was 100% for CABG and transplant, >90% for aortic valve and major aortic procedures and >80% for mitral. At national level, results were similar for CABG (IQR 98.6%–104%), AVR (IQR 105%–118%) and mitral valve replacement (IQR 86.2%–111%). Conclusions We set up a process which can identify cardiac surgeries in England from administrative data. This will lead to the development of a risk model to predict early and late postoperative mortality, useful for risk stratification, risk prediction, benchmarking and real-time monitoring. Once appropriately adjusted, the system can be applied to other specialties, proving especially useful in those areas where clinical databases are not fully established.

Delirium is a marker of brain vulnerability, associated with increasing age, pre-existing cognitive impairment and, recently, cerebrospinal fluid (CSF) biomarkers of Alzheimer’s disease. This nested case-control study used a targeted quantitative metabolomic methodology to profile the preoperative CSF of patients (n = 54) who developed delirium following arthroplasty (n = 28) and those who did not (n = 26). The aim was to identify novel preoperative markers of delirium, and to assess potential correlations with clinical data. Participants without a diagnosis of dementia (≥65 years) undergoing elective primary hip or knee arthroplasty were postoperatively assessed for delirium once-daily for three days. Groups were compared using multivariate, univariate and receiving operator characteristic (ROC) methods. Multivariate modelling using Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) of metabolomic data readily distinguished between delirium and control groups (R2 ≤ 0.56; Q2 ≤ 0.10). Three metabolites (spermidine, putrescine and glutamine) significantly differed between groups (P 0.75). The biomarker performance of the two polyamines (spermidine/putrescine) was enhanced by ratio with CSF Aβ42 (ROC > 0.8), and spermidine significantly correlated with Aβ42 (pearson r = −0.32; P = 0.018). These findings suggest that spermidine and putrescine levels could be useful markers of postoperative delirium risk, particularly when combined with Aβ42, and this requires further investigation.

Mental health (MH) disorders are more prevalent among persons living with HIV (PLWH) compared to the general population, and may contribute to suboptimal adherence to antiretroviral therapy (ART). Tenofovir-diphosphate (TFV-DP), the phosphorylated anabolite of tenofovir (TFV), is a biomarker with a 17-day half-life in red blood cells (RBCs). TFV-DP can be measured in dried blood spots (DBS) using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to assess adherence and cumulative drug exposure to tenofovir disoproxil fumarate (TDF)-based ART. From a larger clinical cohort (N=807), TFV-DP concentrations and a paired HIV viral load (VL) were available from 521 participants at their enrollment visit. We used multivariable linear regression to evaluate the association between TFV-DP in DBS and engagement in MH care. After adjusting for clinical covariates, participants with MH disorders who were engaged in MH care had 40% higher TFV-DP compared to participants with MH disorders who were not engaged in MH care (p

New objective measures of antiretroviral adherence are needed. We determined if emtricitabine triphosphate (FTC-TP) in dried blood spots (DBS) can be used as a marker of recent dosing with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC). The half-life of FTC-TP was estimated in DBS samples obtained from an intensive pharmacokinetic (PK) study of coformulated TDF-FTC in HIV-negative and HIV-infected participants. The concordance of quantifiable FTC-TP in DBS with tenofovir (TFV)/FTC in plasma was evaluated by utilizing paired plasma-DBS samples from participants enrolled in 2 large preexposure prophylaxis (PrEP) open-label trials. The time to FTC-TP nondetectability after TDF-FTC dosing was evaluated utilizing DBS from HIV-negative participants enrolled in a directly observed therapy study of variable adherence to TDF-FTC. The mean (95% confidence interval [CI]) terminal half-life of FTC-TP in the PK study was 35 (23 to 47) h. A total of 143/163 (88%) samples obtained 0 to 48 h post-TDF-FTC dose had quantifiable FTC-TP in DBS, compared with 2/93 (2%) and 0/87 (0%) obtained >48 and >96 h postdose. In 746 paired plasma-DBS samples from 445 participants enrolled in PrEP trials, when both TFV/FTC in plasma were below the limit of quantification, FTC-TP was as well in 98.9% of the samples, and when either TFV or FTC in plasma was quantifiable, FTC-TP was as well in 90.5% of the samples. The half-life of FTC-TP in DBS is short relative to that of TFV-diphosphate (TFV-DP), making it a surrogate for TFV-FTC detection in plasma. FTC-TP can be quantified in DBS simultaneously with TFV-DP, which quantifies cumulative adherence to TDF-FTC. (The clinical trials discussed in this article have been registered at ClinicalTrials.gov under identifiers NCT01040091, NCT02022657, NCT00458393, NCT01772823, and NCT02012621.)

The pharmacokinetics (PK) of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP), the active anabolites of tenofovir disoproxil fumarate (TDF), and emtricitabine (FTC) in blood, genital, and rectal compartments was determined in HIV-positive and seronegative adults who undertook a 60-day intensive PK study of daily TDF/FTC (plus efavirenz in HIV positives). Lymphocyte cell sorting, genital, and rectal sampling occurred once per subject, at staggered visits. Among 19 HIV-positive (3 female) and 21 seronegative (10 female) adults, TFV-DP in peripheral blood mononuclear cells (PBMC) accumulated 8.6-fold [95% confidence interval (CI): 7.2–10] from first-dose to steady-state concentration (Css) versus 1.7-fold (95% CI: 1.5–1.9) for FTC-TP. Css was reached in ∼11 and 3 days, respectively. Css values were similar between HIV-negative and HIV-positive individuals. Css TFV-DP in rectal mononuclear cells (1,450 fmol/106 cells, 898–2,340) was achieved in 5 days and was >10 times higher than PBMC (95 fmol/106 cells, 85–106), seminal cells (22 fmol/106 cells, 6–79), and cervical cells (111 fmol/106 cells, 64–194). FTC-TP Css was highest in PBMC (5.7 pmol/106 cells, 5.2–6.1) and cervical cells (7 pmol/106 cells, 2–19) versus rectal (0.8 pmol/106 cells, 0.6–1.1) and seminal cells (0.3 pmol/106 cells, 0.2–0.5). Genital drug concentrations on days 1–7 overlapped with estimated Css, but accumulation characteristics were based on limited data. TFV-DP and FTC-TP in cell sorted samples were highest and achieved most rapidly in CD14+ compared with CD4+, CD8+, and CD19+ cells. Together, these findings demonstrate cell-type and tissue-dependent cellular pharmacology, preferential accumulation of TFV-DP in rectal mononuclear cells, and rapid distribution into rectal and genital compartments.

Tenofovir (TFV) disoproxil fumarate (TDF) and emtricitabine (FTC), two nucleos(t)ide analogs (NA), are coformulated as an anti-HIV combination tablet for treatment and preexposure prophylaxis (PrEP). TDF/FTC may have effects on the deoxynucleoside triphosphate (dNTP) pool due to their similar structures and similar metabolic pathways. We carried out a comprehensive clinical study to characterize the effects of TDF/FTC on the endogenous dNTP pool, from baseline to 30 days of TDF/FTC therapy, in both treatment-naive HIV-positive and HIV-negative individuals. dATP, dCTP, dGTP, and TTP were quantified in peripheral blood mononuclear cells (PBMC) with a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology. Forty individuals (19 HIV-positive) were enrolled and underwent a baseline visit and then received TDF/FTC for at least 30 days. Longitudinal measurements were analyzed using mixed-model segmented linear regression analysis. The dNTPs were reduced by 14% to 37% relative to the baseline level within 3 days in both HIV-negative and HIV-positive individuals (P≤ 0.003). These reductions persisted to various degrees at day 30. These findings indicate that dNTP pools are influenced by TDF/FTC therapy. This may alter cellular homeostasis and could increase the antiviral effect through a more favorable analog/dNTP ratio. Further work is needed to elucidate mechanisms, to evaluate the clinical significance of these findings, and to further probe differences between HIV-negative and HIV-positive individuals. (This study has been registered at ClinicalTrials.gov under identifier NCT01040091.)

Peripheral neuropathy is a rare but important complication of total hip arthroplasty (THA) and has previously been reported in the ipsilateral arm and associated with inflammatory arthritis. The results of 7004 primary hip arthroplasties performed between January 1993 and February 2009 were retrospectively reviewed to identify patients who reported ulnar neuropathy symptoms, with ten patients identified at mean follow-up of 57 months (range = 3-195 months). Eight patients experienced unilateral ulnar nerve symptoms in the contralateral upper limb post-surgery, one patient experienced symptoms in the ipsilateral upper limb and one patient experienced symptoms in both upper limbs. The incidence of post-THA ulnar neuropathy was 0.14%. All patients had a pre-operative diagnosis of osteoarthritis and none had diabetes, a previous history of neuropathy or inflammatory arthritis. All operations were primary arthroplasties and were performed under the care of a single surgeon in a single centre. Two of the ten patients (20%) had a general anaesthetic. The pattern of symptoms reported, i.e. mainly unilateral affecting the contralateral side with variable resolution, contrasts with previous studies and suggests that intraoperative patient positioning may be an important factor influencing ulnar neuropathy following THA. Attention to support and positioning of the contralateral arm may help reduce the incidence of this complication.

Objectives The multinational PEARLS (ACTG A5175) study, conducted mainly in resource-limited settings, identified an increased treatment failure rate among HIV-infected individuals randomized to once-daily unboosted atazanavir, didanosine-EC, and emtricitabine compared with efavirenz-based regimens. We evaluated associations between selected human genetic polymorphisms and atazanavir pharmacokinetics in PEARLS. Methods Polymorphisms in CYP3A5, ABCB1, SLCO1B1 and NR1I2 were genotyped in PEARLS participants randomized to atazanavir plus didanosine-EC plus emtricitabine in Peru, South Africa and the USA, who also consented to genetic analysis. Non-linear mixed-effects population pharmacokinetic modelling was used to predict atazanavir oral clearance (CL/F) and concentration at 24 h (C24). Atazanavir mono-oxidation metabolites M1 and M2 were quantified from the same single-point plasma sample used to quantify the parent drug. Data were log10 transformed for statistical analysis using unpaired t-tests and one-way ANOVA and are presented as geometric mean (95% CI). Results Eighty-four HIV-infected participants were genotyped, including 44 Black Africans or African Americans and 28 women. Median age was 34 years. We identified 56 CYP3A5 expressers and 28 non-expressers. Atazanavir CL/F and C24 did not differ between CYP3A5 expressers and non-expressers: 13.2 (12.1-14.4) versus 12.7 L/h (11.7-13.9), P = 0.61, and 75.3 (46.1-123.0) versus 130.9 ng/mL (86.9-197.2), P = 0.14, respectively. M1/atazanavir and M2/atazanavir ratios were higher in expressers than in non-expressers: 0.0083 (0.0074-0.0094) versus 0.0063 (0.0053-0.0075), P = 0.008, and 0.0065 (0.0057-0.0073) versus 0.0050 (0.0042-0.0061), P = 0.02, respectively. Conclusions Expression of CYP3A5 appears to be associated with increased M1 and M2 atazanavir metabolite formation, without significantly affecting parent compound pharmacokinetics.

BackgroundIntracellular tenofovir diphosphate concentrations are markedly increased in HIV/HCV coinfected individuals receiving tenofovir disoproxil fumarate (TDF) with sofosbuvir-containing treatment. Sofosbuvir may inhibit the hydrolysis of TDF to tenofovir, resulting in increased concentrations of the disoproxil or monoester forms, which may augment cell loading. We sought to quantify tenofovir disoproxil and monoester concentrations in individuals receiving TDF with and without ledipasvir/sofosbuvir.MethodsHIV/HCV coinfected participants receiving TDF-based therapy were sampled pre-dose and 1 and 4 h post-dose prior to and 4 weeks after initiating ledipasvir/sofosbuvir. Tenofovir disoproxil was not detectable. Tenofovir monoester in plasma and tenofovir diphosphate in PBMC and dried blood spots (DBS) were quantified using LC-MS/MS. Geometric mean ratios (week 4 versus baseline) and 95% CIs were generated for the pharmacokinetic parameters. P values reflect paired t-tests.ResultsTen participants had complete data. At baseline, geometric mean (95% CI) tenofovir monoester plasma concentrations at 1 and 4 h post-dose were 97.4 ng/mL (33.0–287.5) and 0.74 ng/mL (0.27–2.06), respectively. With ledipasvir/sofosbuvir, tenofovir monoester concentrations at 4 h post-dose were 5.02-fold higher (95% CI 1.40–18.05; P = 0.019), but did not significantly differ at 1 h post-dose (1.72-fold higher, 95% CI 0.25–11.78; P = 0.54), possibly due to absorption variability. Tenofovir diphosphate in PBMC and DBS were increased 2.80-fold (95% CI 1.71–4.57; P = 0.001) and 7.31-fold (95% CI 4.47–11.95; P ConclusionsTenofovir monoester concentrations were increased in individuals receiving TDF with ledipasvir/sofosbuvir, consistent with inhibition of TDF hydrolysis. Additional studies are needed to determine the clinical relevance of this interaction.

Background Tenofovir monoester is a relatively lipophilic intermediate formed during the hydrolysis of tenofovir disoproxil to tenofovir. Its clinical pharmacokinetic profile and influence on the cellular pharmacology of tenofovir diphosphate have not been reported. Methods Plasma, PBMC and dried blood spots (DBS) were obtained from HIV-uninfected adults participating in a randomized, cross-over bioequivalence study of single-dose tenofovir disoproxil fumarate (TDF)/emtricitabine unencapsulated or encapsulated with a Proteus® ingestible sensor. Plasma pharmacokinetics of tenofovir monoester and tenofovir were characterized using non-compartmental methods. Relationships with tenofovir diphosphate in DBS and PBMC were examined using mixed-effects models. Results Samples were available from 24 participants (13 female; 19 white, 3 black, 2 Hispanic). Tenofovir monoester appeared rapidly with a median (range) Tmax of 0.5 h (0.25–2) followed by a rapid monophasic decline with a geometric mean (coefficient of variation) t½ of 26 min (31.0%). Tenofovir monoester Cmax was 131.6 ng/mL (69.8%) and AUC0–4 was 93.3 ng·h/mL (47.9%). The corresponding values for plasma tenofovir were 222.2 ng/mL (37.1%) and 448.1 ng·h/mL (30.0%). Tenofovir monoester AUC0–∞ (but not tenofovir AUC0–∞) was a significant predictor of tenofovir diphosphate in both PBMC (P = 0.015) and DBS (P = 0.005), increasing by 3.8% (95% CI 0.8%–6.8%) and 4.3% (95% CI 1.5%–7.2%), respectively, for every 10 ng·h/mL increase in tenofovir monoester. Conclusions Tenofovir monoester Cmax and AUC0–4 were 59.2% and 20.6% of corresponding plasma tenofovir concentrations. Tenofovir monoester was significantly associated with intracellular tenofovir diphosphate concentrations in PBMC and DBS, whereas tenofovir concentrations were not. Tenofovir monoester likely facilitates cell loading, thereby increasing tenofovir diphosphate exposures in vivo.

OBJECTIVES: Women likely require higher adherence than men to pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) for similar efficacy. Pharmacologic metrics of adherence predict efficacy better than self-report, but expected drug levels (adherence benchmarks) must be established using directly-observed therapy. We sought to evaluate whether tenofovir hair concentrations differ between women and men receiving directly-observed TDF/FTC. METHODS: We assessed tenofovir hair concentrations in HIV-uninfected volunteers randomized to receive 100%, 67%, or 33% of daily dosing of TDF/FTC for 12 weeks (DOT-DBS, NCT02022657). Hair samples were collected at dosing weeks 4, 8, and 12 and weeks 3 and 6 during a 12-week washout. Tenofovir concentrations in the proximal 1.5 centimeters of hair (representing ~6 weeks of exposure) were analyzed using liquid chromatography/tandem mass spectrometry. Linear regression was used to model tenofovir hair concentrations in terms of sex, doses over the prior 6 weeks, and number of days since last dose. RESULTS: A total of 264 hair samples were analyzed from 23 female and 24 male participants. Female participants had similar tenofovir hair concentrations to males (estimated fold-difference 0.92, 95% CI 0.75-1.13, p=0.43). The estimated fold-difference in tenofovir levels for female versus male participants did not appreciably change when age (0.93, CI 0.76-1.15), weight (0.89, CI 0.71-1.11), or race/ethnicity (0.95, CI 0.77-1.17) were added to the model. CONCLUSIONS: Women and men have similar adherence benchmarks for tenofovir in hair samples. As pharmacokinetic metrics are increasingly used for PrEP monitoring, these findings provide guidance for assessing adherence via hair concentrations.

A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets.Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall's tau for dichotomous variables, or Jonckheere-Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis.A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p 0.001).We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty.

BackgroundResidual systemic inflammation persists despite suppressive antiretroviral therapy (ART) and is associated with non-AIDS clinical outcomes. We aimed to evaluate the association between ART adherence and inflammation in Ugandans living with HIV who were predominantly receiving nevirapine-based ART with a thymidine analog backbone and were virologically suppressed by conventional assays.MethodsPlasma concentrations of interleukin-6 (IL-6), D-dimer, soluble (s)CD14, sCD163, and the kynurenine/tryptophan ratio, in addition to CD8 T-cell activation, were measured at baseline and 6 months after ART initiation in treatment-naive adults who achieved an undetectable plasma HIV RNA (