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This case-control study explored cumulative tenofovir exposure among patients with human immunodeficiency virus/hepatis B virus (HIV/HBV) coinfection with HIV viral suppression. Among patients taking tenofovir disoproxil fumarate, median TFV-DP levels in dried blood spots were ∼3-fold lower among patients with incomplete HBV viral suppression (n = 4) compared to those with complete suppression (n = 5) (516 vs 1456 fmol/punch). [ABSTRACT FROM AUTHOR]

Background On-demand topical products could be an important tool for human immunodeficiency virus (HIV) prevention. We evaluated the safety, pharmacokinetics, and ex vivo pharmacodynamics of a tenofovir alafenamide/elvitegravir (TAF/EVG, 20 mg/16 mg) insert administered rectally. Methods MTN-039 was a phase 1, open-label, single-arm, 2-dose study. Blood, rectal fluid, and rectal tissue were collected over 72 hours following rectal administration of 1 and 2 TAF/EVG inserts for each participant. Results TAF/EVG inserts were safe and well tolerated. EVG and tenofovir (TFV) were detected in blood plasma at low concentrations: median peak concentrations after 2 inserts were EVG 2.4 ng/mL and TFV 4.4 ng/mL. Rectal tissue EVG peaked at 2 hours (median, 2 inserts = 9 ng/mg) but declined to below limit of quantification in the majority of samples at 24 hours, whereas tenofovir diphosphate (TFV-DP) remained high >2000 fmol/million cells for 72 hours with 2 inserts. Compared to baseline, median cumulative log10 HIV p24 antigen of ex vivo rectal tissue HIV infection was reduced at each time point for both 1 and 2 inserts (P <.065 and P <.039, respectively). Discussion Rectal administration of TAF/EVG inserts achieved high rectal tissue concentrations of EVG and TFV-DP with low systemic drug exposure and demonstrable ex vivo inhibition of HIV infection for 72 hours. Clinical Trials Registration. NCT04047420. [ABSTRACT FROM AUTHOR]

We evaluated hair tenofovir (TFV) concentrations as an adherence metric for HIV preexposure prophylaxis during pregnancy and postpartum and compared hair levels with TFV-diphosphate levels in dried blood spots (DBSs). Overall 152 hair samples from 102 women and 36 hair-DBS paired samples from 29 women were collected from a subset of women in a cluster-randomized trial. Having a partner with HIV was associated with higher hair TFV levels (P <.001). Hair TFV concentrations were strongly correlated with DBS TFV-diphosphate levels (r = 0.76, P <.001), indicating hair as a promising cumulative adherence metric for perinatal preexposure prophylaxis assessment. [ABSTRACT FROM AUTHOR]

Early life experiences can exert a significant influence on cortical and cognitive development. Very preterm birth exposes infants to several adverse environmental factors during hospital admission, which affect cortical architecture. However, the subsequent consequence of very preterm birth on cortical growth from infancy to adolescence has never been defined; despite knowledge of critical periods during childhood for establishment of cortical networks. Our aims were to: chart typical longitudinal cortical development and sex differences in cortical development from birth to adolescence in healthy term-born children; estimate differences in cortical development between children born at term and very preterm; and estimate differences in cortical development between children with normal and impaired cognition in adolescence. This longitudinal cohort study included children born at term (≥37 weeks' gestation) and very preterm (<30 weeks' gestation) with MRI scans at ages 0, 7 and 13 years (n = 66 term-born participants comprising 34 with one scan, 18 with two scans and 14 with three scans; n = 201 very preterm participants comprising 56 with one scan, 88 with two scans and 57 with three scans). Cognitive assessments were performed at age 13 years. Cortical surface reconstruction and parcellation were performed with state-of-the-art, equivalent MRI analysis pipelines for all time points, resulting in longitudinal cortical volume, surface area and thickness measurements for 62 cortical regions. Developmental trajectories for each region were modelled in term-born children, contrasted between children born at term and very preterm, and contrasted between all children with normal and impaired cognition. In typically developing term-born children, we documented anticipated patterns of rapidly increasing cortical volume, area and thickness in early childhood, followed by more subtle changes in later childhood, with smaller cortical size in females than males. In contrast, children born very preterm exhibited increasingly reduced cortical volumes, relative to term-born children, particularly during ages 0–7 years in temporal cortical regions. This reduction in cortical volume in children born very preterm was largely driven by increasingly reduced cortical thickness rather than area. This resulted in amplified cortical volume and thickness reductions by age 13 years in individuals born very preterm. Alterations in cortical thickness development were found in children with impaired language and memory. This study shows that the neurobiological impact of very preterm birth on cortical growth is amplified from infancy to adolescence. These data further inform the long-lasting impact on cortical development from very preterm birth, providing broader insights into neurodevelopmental consequences of early life experiences. [ABSTRACT FROM AUTHOR]

Brief alcohol advice offered to patients was shown to be a clinically- and cost-effective intervention to prevent and manage alcohol-related health harm. However, this intervention is not yet optimally implemented in practice. A suggested strategy to improve the implementation of brief alcohol advice is through community actions which would enhance the environment in which primary healthcare providers must deliver the intervention. However, there has been scarce research conducted to date regarding which community actions have most influence on the adoption and implementation of brief alcohol advice. The current protocol presents the development of a package of community actions to be implemented in three Latin American municipalities, in Colombia, Mexico and Peru. The community actions were based on the Institute for Health Care Improvement's framework for going to full scale, and include: (i) involvement of a Community Advisory Board, (ii) involvement of a project champion, (iii) adoption mechanisms, (iv) support systems and (v) a communication campaign. By presenting a protocol for developing community actions with input from local stakeholders, this article contributes to advancing the public health field of alcohol prevention by potentially stimulating the sustainable adoption and implementation of brief alcohol advice in routine practice. [ABSTRACT FROM AUTHOR]

Background Food insecurity has been linked to suboptimal antiretroviral therapy (ART) adherence in persons with HIV (PWH). This association has not been evaluated using tenofovir diphosphate (TFV-DP) in dried blood spots (DBSs), a biomarker of cumulative ART adherence and exposure. Methods Within a prospective South African cohort of treatment-naive PWH initiating ART, a subset of participants with measured TFV-DP in DBS values was assessed for food insecurity status. Bivariate and multivariate median-based regression analysis compared the association between food insecurity and TFV-DP concentrations in DBSs adjusting for age, sex, ethnicity, medication possession ratio (MPR), and estimated glomerular filtration rate. Results Drug concentrations were available for 285 study participants. Overall, 62 (22%) PWH reported worrying about food insecurity and 44 (15%) reported not having enough food to eat in the last month. The crude median concentrations of TFV-DP in DBSs differed significantly between those who expressed food insecurity worry versus those who did not (599 [interquartile range {IQR}, 417–783] fmol/punch vs 716 [IQR, 453–957] fmol/punch; P =.032). In adjusted median-based regression, those with food insecurity worry had concentrations of TFV-DP that were 155 (95% confidence interval, −275 to −35; P =.012) fmol/punch lower than those who did not report food insecurity worry. Age and MPR remained significantly associated with TFV-DP. Conclusions In this study, food insecurity worry is associated with lower TFV-DP concentrations in South African PWH. This highlights the role of food insecurity as a social determinant of HIV outcomes including ART failure and resistance. [ABSTRACT FROM AUTHOR]

Using intraerythrocytic tenofovir-diphosphate data from the emtricitabine/tenofovir disoproxil fumarate arms of HIV Prevention Trials Network (HPTN) 083 (men) and HPTN 084 (women), approximately 99% efficacy was achieved at a lower adherence threshold in HPTN 083 (≥2 doses/week) compared with HPTN 084 (daily), suggesting higher adherence is necessary for women vs men. [ABSTRACT FROM AUTHOR]

Objectives To investigate the longitudinal associations between parental mental health symptoms within 4 weeks of birth, parenting behaviors at 1 year, and child general cognitive ability at 4.5–5 years in a sample of children born very preterm (VP). This study also examined whether these associations differed based on level of family social risk. Methods Participants were 143 children born <30 weeks' gestation and their parents. Within 4 weeks of birth, mothers' and fathers' depressive and anxiety symptoms were assessed using the Center for Epidemiologic Studies Depression Scale and Hospital Anxiety Depression Scale-Anxiety Subscale. Parents' sensitive and structuring parenting behaviors were assessed at 1 year using the Emotional Availability Scales. Child general cognitive ability was assessed at 4.5–5 years using the Wechsler Preschool & Primary Scale of Intelligence–Fourth Edition. Results Higher maternal depressive symptoms were associated with lower levels of sensitive and structuring parenting behavior, while higher maternal anxiety symptoms were associated with higher levels of structuring parenting behavior. There was weak evidence for positive associations between mothers' sensitive parenting behavior and fathers' structuring parenting behavior and child general cognitive ability. There was also weak evidence for stronger associations between mothers' mental health symptoms, parenting behaviors, and child general cognitive ability, in families of higher compared with lower social risk. Conclusions Depressive and anxiety symptoms experienced by mothers in the initial weeks following VP birth can have long-term effects on their parenting behaviors. Enquiring about parents' mental health during their child's hospitalization in the neonatal intensive care unit is crucial. [ABSTRACT FROM AUTHOR]

Background Lowering the strength of alcohol products could lead to less alcohol being bought and drunk. In its prevention White Paper, the UK Government aims to promote a significant increase in the availability of alcohol-free and low-alcohol products by 2025. Methods Through descriptive analysis and ARIMA modelling of >4 million alcohol purchases from 69 803 British households, we study the potential impact of lower strength alcohol products in reducing household purchases of grams of alcohol over 2015–2019. Households are divided into predominantly beer, wine or spirits purchasers. Results Over 5 years, there were decreases in purchases of grams of alcohol within beer amongst beer-purchasing households and increases in purchases of grams of alcohol within wine and spirits amongst, respectively, wine- and spirits-purchasing households. Almost all the changes were due to beer-purchasing households buying less regular strength beer, and wine and spirits-purchasing households buying, respectively, more regular strength wine and spirits, rather than increases in purchases of no- and low-alcohol products. Conclusions In general, lower strength alcohol products have not contributed to British households buying fewer grams of alcohol over the 5-year follow-up period during 2015–2019. [ABSTRACT FROM AUTHOR]

Background: Tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is a reliable pharmacokinetics biomarker of adherence to tenofovir disoproxil fumarate (TDF). We aimed to use DBSs to estimate pill intake among participants using on-demand pre-exposure prophylaxis (PrEP) and to identify predictive factors associated with higher TFV-DP concentrations.Methods: DBSs were collected at the last study visit of the open-label phase of the ANRS IPERGAY study, assessing on-demand oral TDF/emtricitabine for PrEP among MSM and transgender female participants. We quantified TFV-DP in DBSs centrally. We assessed correlation between pill count and TFV-DP concentration by Spearman correlation and explored associations between participant demographics, sexual behaviour and PrEP use during sexual intercourse (SI) with TFV-DP concentrations by univariate and multivariate logistic regression models.Results: The median age of the 245 participants included in this study was 40 years, with a median body weight of 73 kg. Median (IQR) TFV-DP concentration reached 517 (128-868) fmol/punch, corresponding to an estimated intake of 8-12 tablets per month (2-3 doses per week). Only 39% of participants had a TFV-DP concentration above 700 fmol/punch. TFV-DP concentrations were moderately correlated with pill count (r: 0.59; P < 0.001). In multivariate analysis, only systematic use of PrEP during SI and more frequent episodes of SI in the past 4 weeks were significantly associated with higher TFV-DP levels [OR (95% CI): 11.30 (3.62-35.33) and 1.46 (1.19-1.79), respectively; P < 0.001].Conclusions: Among participants using on-demand PrEP, estimated pill intake reached 8-12 tablets per month and was correlated with frequency and systematic use of PrEP for SI. [ABSTRACT FROM AUTHOR]

Objectives: Potential interactions between feminizing hormone therapy (FHT) and pre-exposure prophylaxis (PrEP) may be a barrier to PrEP use among transgender women (TGW). We aimed to assess the impact of FHT on PrEP plasma pharmacokinetics (PK) among TGW.Methods: This was a PK substudy of the effects of FHT on tenofovir disoproxil fumarate/emtricitabine nested to a trans-specific PrEP demonstration study (NCT03220152). Participants were assigned to receive PrEP only (noFHT) or standardized FHT (sFHT; oestradiol valerate 2-6 mg plus spironolactone 100-300 mg) plus PrEP for 12 weeks, after which they could start any FHT (aFHT). Short- and long-term PK assessment occurred at Weeks 12 and 30-48, respectively (plasma samples prior and 0.5, 1, 2, 4, 6, 8 and 24 h after dose). Non-compartmental PK parameters of tenofovir and emtricitabine were compared as geometric mean ratios (GMRs) between noFHT and PrEP and FHT (sFHT at short-term PK; aFHT at long-term PK) participants.Results: No differences in tenofovir and emtricitabine plasma PK parameters were observed between the short-term PK of noFHT (n = 12) and sFHT participants (n = 18), except for emtricitabine Cmax [GMR: 1.15 (95% CI: 1.01-1.32)], or between noFHT short-term PK and aFHT long-term PK (n = 13). Most participants were on oestradiol valerate 2 mg at the short-term PK (56%) and 4 mg at the long-term PK (54%). Median (IQR) oestradiol levels were 56.8 (43.2-65.4) pg/mL at short-term PK (sFHT) and 44.8 (24.70-57.30) pg/mL at long-term PK (aFHT). No participants in this analysis seroconverted during the study.Conclusions: Our results indicate no interaction of FHT on tenofovir levels, further supporting PrEP use among TGW using FHT. [ABSTRACT FROM AUTHOR]

Aims Buying and consuming no- (per cent alcohol by volume, ABV = 0.0%) and low- (ABV = >0.0% and ≤ 3.5%) alcohol beers could reduce alcohol consumption but only if they replace buying and drinking higher-strength beers. We assess whether buying new no- and low-alcohol beers increases or decreases British household purchases of same-branded higher strength beers. Methods Generalized linear models and interrupted time series analyses, using purchase data of 64,280 British households from Kantar Worldpanel's household shopping panel, 2015–2018. We investigate the extent to which the launch of six new no- and low-alcohol beers affected the likelihood and volume of purchases of same-branded higher-strength beers. Results Households that had never previously bought a same-branded higher-strength beer but bought a new same-branded no- or low-alcohol beer were less than one-third as likely to go on and newly buy the same-branded higher-strength product. When they did later buy the higher-strength product, they bought half as much volume as households that had not bought a new same-branded no- or low-alcohol beer. For households that had previously purchased a higher-strength beer, the introduction of the new same-branded no- or low-alcohol beer was associated with decreased purchases of the volume of the higher-strength beer by, on average, one-fifth. Conclusions The increased availability of new no- and low-alcohol beers does not seem to be a gateway to purchasing same-branded higher-strength beers but rather seems to replace purchases of these higher-strength products. Thus, introduction of new no- and low-alcohol beers could contribute to reducing alcohol consumption. [ABSTRACT FROM AUTHOR]

Background: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding.Methods: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry.Results: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V.Conclusions: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Mothers of children born very preterm (VP) are at increased risk of developing postnatal depression, anxiety, and post-traumatic stress symptoms. However, mental health disorder rates are rarely assessed in this population compared with full-term peers, and it is unclear if postnatal distress symptoms precede higher rates of maternal mental health disorders at 5 years post-birth in both birth groups.Methods: Mothers of children born VP (n = 65; mean [SD] age at birth, 33.9 [5.0]; 72.1% tertiary educated) and full-term (n = 90; mean [SD] age at birth, 33.4 [4.0]; 88.2% tertiary educated) completed questionnaires assessing symptoms of depression, anxiety, and trauma within 4 weeks of birth. At 5 years post-birth, they participated in a structured diagnostic interview assessing mood, anxiety, and trauma-related mental health disorders, both current and over the lifetime.Results: There was little evidence for differences between mothers in the VP and full-term groups in rates of any mental health disorder at 5 years (VP = 14%, full-term = 14%) or lifetime (VP = 41%, full-term = 37%). In mothers of children born VP, elevated postnatal post-traumatic stress symptoms were associated with higher rates of mental health disorders at 5 years (odds ratio = 21.5, 95% confidence interval = 1.35-342).Conclusions: Findings suggest that preterm birth may not lead to increased odds of later developing maternal mental health disorders, despite known risks of elevated postnatal distress following a VP birth. However, those with post-traumatic stress symptoms following a VP birth could be more vulnerable, and assessment and monitoring is recommended. [ABSTRACT FROM AUTHOR]

Background. Intracellular tenofovir diphosphate (TFV-DP) concentration in dried blood spots (DBSs) is used to monitor cumulative pre-exposure prophylaxis (PrEP) adherence. We evaluated TFV-DP in DBSs following daily oral PrEP (emtricitabine 200 mg/tenofovir diphosphate 300 mg) among pregnant and postpartum adolescent girls and young women (AGYW). Methods. Directly observed PrEP was administered for 12 weeks in a pregnancy (14–24 weeks’ gestation, n = 20) and postpartum (6–12 weeks postpartum, n = 20) group of AGYW aged 16–24 years in sub-Saharan Africa. Weekly DBS TFV-DP was measured by validated liquid chromatography–tandem mass spectrometry assay. Week 12 TFV-DP distributions were compared between groups with Wilcoxon test. Population pharmacokinetic models were fit to estimate steady-state concentrations and create benchmarks for adherence categories. Baseline correlates of TFV-DP were evaluated. Results. Median age was 20 (IQR, 19–22) years. Of 3360 doses, 3352 (>99%) were directly observed. TFV-DP median (IQR) half-life was 10 (7–12) days in pregnancy and 17 (14–21) days postpartum, with steady state achieved by 5 and 8 weeks, respectively. Observed median (IQR) steady-state TFV-DP was 965 fmol/punch (691–1166) in pregnancy versus 1406 fmol/punch (1053–1859) postpartum (P = .006). Modeled median steady-state TFV-DP was 881 fmol/punch (667–1105) in pregnancy versus 1438 fmol/punch (1178–1919) postpartum. In pooled analysis, baseline creatinine clearance was associated with observed TFV-DP concentrations. Conclusions. TFV-DP in African AGYW was approximately one-third lower in pregnancy than postpartum. These Populationspecific benchmarks can be used to guide PrEP adherence support in pregnant/postpartum African women. [ABSTRACT FROM AUTHOR]

Background Sex hormone and preexposure prophylaxis (PrEP) drug interactions among transgender women (TGW), transgender men (TGM), and cisgender men (CGM) are not fully understood. Methods TGM and TGW on at least 6 months of stable sex hormone therapy containing testosterone or estradiol (respectively) were enrolled in a 4-week study of directly observed dosing of daily oral coformulated emtricitabine and tenofovir disoproxil fumarate (FTC/TDF). TFV-DP in dried blood spots and sex hormones in serum were measured at weekly intervals. TFV-DP was compared with 2- and 4-week samples from Directly Observed Therapy Dried Blood Spots (DOT-DBS) Study (NCT02022657). Results From May 2017 to June 2018, 24 TGM and 24 TGW were enrolled. Testosterone (total and free) and estradiol concentrations were comparable before and after 4 weeks of PrEP use in TGM and TGW, respectively. Historical controls included 17 cisgender women (CGW) and 15 CGM. TFV-DP concentrations at week 4 were comparable between TGW and TGM (mean difference, −6%; 95% confidence interval [CI], −21% to 12%; P  = .47), comparable between TGW and CGM (mean difference, −12%; 95% CI, −27% to 7%; P  = .21) and were lower among TGM compared with CGW (mean difference, −23%; 95% CI, −36% to −7%; P  = .007). All persons in all groups were projected to reach the TFV-DP threshold that has been associated with high protection from human immunodeficiency virus. Conclusions CGM, TGM, and TGW had comparable TFV-DP concentrations in dried blood spots after 4 weeks of directly observed daily FTC/TDF PrEP use. Serum hormone concentrations were not affected by FTC/TDF PrEP use. Clinical Trials Registration NCT04050371. [ABSTRACT FROM AUTHOR]

The drivers of low-level viremia (LLV) between 20 and 200 copies/mL remain unclear. In 1042 person-visits from 497 persons with HIV on tenofovir disoproxil fumarate–containing antiretroviral therapy (ART), the association between LLV and cumulative antiretroviral adherence (quantified using tenofovir diphosphate [TFV-DP] in dried blood spots) was assessed. Lower TFV-DP levels were associated with higher odds of LLV. As TFV-DP (fmol/punch) categories decreased from >1650 to 800–1650; 800–1650 to <800; and >1650 to <800, the adjusted odds ratios for LLV vs HIV VL <20 copies/mL were 2.0 (95% CI, 1.2–3.1), 2.4 (95% CI, 1.1–5.0), and 4.6 (95% CI, 2.2–9.9), respectively. This suggests that adherence could impact LLV. [ABSTRACT FROM AUTHOR]

From directly observed therapy studies, urine tenofovir (TFV) levels were 74% lower when taking tenofovir alafenamide (TAF) vs tenofovir disoproxil fumarate. Urine TFV remains quantifiable across a range of TAF adherence patterns, but a separate point-of-care lateral flow immunoassay with a lower TFV threshold will be needed to support TAF adherence monitoring. [ABSTRACT FROM AUTHOR]

Cases of seroconversion on pre-exposure prophylaxis (PrEP) should be carefully investigated, given their public health implications and rarity. We report a case of transmitted drug resistance causing seroconversion on PrEP in spite of high adherence, confirmed with dried blood spot and segmental hair drug-level testing and single-genome sequencing. [ABSTRACT FROM AUTHOR]

Aims To investigate if COVID-19 confinement led to excess alcohol purchases by British households. Methods We undertake controlled interrupted time series analysis of the impact of COVID-19 confinement introduced on 26 March 2020, using purchase data from Kantar Worldpanel's of 23,833 British households during January to early July 2020, compared with 53,428 British households for the same time period during 2015–2018. Results Excess purchases due to confinement during 2020 were 178 g of alcohol per 100 households per day (adjusted for numbers of adults in each household) above an expected base of 438 g based on averaged 2015–2018 data, representing a 40.6% increase. However, when adjusting for expected normal purchases from on-licenced premises (i.e. bars, restaurants, etc.), there was evidence for no excess purchases of grams of alcohol (a 0.7% increase). With these adjustments, beer purchases dropped by 40%, wine purchases increased by 15% and spirits purchases by 22%. Excess purchases increased the richer the household and the lower the age of the main shopper. Confinement was associated with a shift in purchases from lower to higher strength beers. Conclusion During the COVID-19 confinement, the evidence suggests that households did not buy more alcohol for the expected time of the year, when adjusting for what they normally would have purchased from on-licenced premises. [ABSTRACT FROM AUTHOR]

The objective of this study was to evaluate the ruminal fermentation characteristics of ruminally fistulated beef steers consuming a steam-flaked corn (SFC) or dry-rolled corn (DRC) based diet containing either Rumensin 90 (RUM ; Elanco, Greenfield, IN), or Monovet 90 (MV ; Huvepharma, Peachtree City, GA). Six ruminally fistulated steers (657.7 kg ± 72.6) housed individually were used in a 6 × 6 Latin square design with 2 × 3 factorial treatment arrangement. Each of the 6 periods were 15 d with 14 d for diet adaptation and 1 d of rumen fluid collections. Dietary treatments were DRC without monensin sodium (DRC-C), SFC without monensin sodium (SFC-C), DRC with Rumensin 90 (DRC-R), DRC with Monovet 90 (DRC-MV), SFC with Rumensin 90 (SFC-R), and SFC with Monovet 90 (SFC-MV). Rumen contents and fluid were collected through the fistula of each animal at 0, 3, 6, 12, and 24 h on d 15 of each period. Rumen fluid collected at 6 h post-feeding each period was used for in vitro analyses. Steer was the experimental unit and the model included fixed effects of grain processing, additive, and grain processing × additive. Total gas produced was composited from each in vitro bottle into a gas collection bag for the 48-h determination of methane concentration. No differences were detected for DMI (P = 0.81). Ruminal pH did not differ for the control or additive treatments (P = 0.33). However, ruminal pH was lower (P < 0.01) with SFC compared to DRC. There was a significant difference in acetate to propionate ratio for grain type (P = 0.01) and a tendency for additive inclusion (P = 0.06). Additive inclusion reduced methane proportion of total gas compared to control treatments (P ≤ 0.01). Overall, monensin sodium reduced methane concentration though source had no effect on DMI or ruminal pH. [ABSTRACT FROM AUTHOR]

Background In this study, we evaluate associations between cumulative antiretroviral adherence/exposure, quantified using tenofovir diphosphate (TFV-DP) in dried blood spots (DBS), and human immunodeficiency virus (HIV)-related aging factors. Methods This is a cross-sectional analysis of younger (ages 18–35) and older (ages ≥60) persons with HIV (PWH) taking TFV disoproxil fumarate. Tenofovir diphosphate concentrations were quantified in DBS. Linear and logistic regression models were used to evaluate associations between TFV-DP and bone mineral density (BMD), physical function, frailty, and falls. Results Forty-five PWH were enrolled (23 younger, 22 older). Every 500 fmol/punch (equivalent to an increase in ~2 doses/week) increase in TFV-DP was associated with decreased hip BMD (−0.021 g/cm2; 95% confidence interval [CI], −0.040 to −0.002; P  = .03). Adjusting for total fat mass, every 500 fmol/punch increase in TFV-DP was associated with higher odds of Short Physical Performance Battery impairment (score ≤10; adjusted odds ratio [OR], 1.6; 95% CI, 1.0–2.5; P  = .04). Every 500 fmol/punch increase in TFV-DP was associated with slower 400-meter walk time (14.8 seconds; 95% CI, 3.8–25.8; P  = .01) and remained significant after adjusting for age, lean body mass, body mass index (BMI), and fat mass (all P  ≤ .01). Every 500 fmol/punch increase in TFV-DP was associated with higher odds of reporting a fall in the prior 6 months (OR, 1.8; 95% CI, 1.1–2.8; P  = .02); this remained significant after adjusting for age, lean body mass, BMI, and total fat mass (all P  < .05). Conclusions Higher TFV-DP levels were associated with lower hip BMD, poorer physical function, and greater risk for falls, a concerning combination for increased fracture risk. [ABSTRACT FROM AUTHOR]

Background Hepatitis C virus treatment in persons who use drugs (PWUD) is often withheld due to adherence and reinfection concerns. In this study, we report treatment outcomes, technology-based adherence data, and adherence predictors in PWUD and/or alcohol. Methods INCLUD was a prospective, open-label study of ledipasvir/sofosbuvir for 12 weeks in PWUD aged 18–70 years. Participants were randomized to wireless (wirelessly observed therapy) or video-based directly observed therapy (vDOT). Drug use was assessed every 2 weeks. Sustained virologic response (SVR) was examined by intention-to-treat and as-treated. Factors associated with missing ≥1 dose(s) between visits were examined using generalized linear models. Results Sixty participants received ≥1 ledipasvir/sofosbuvir dose (47 human immunodeficiency virus [HIV]/hepatitis C virus [HCV], 13 HCV only; 78% male; 22% black; 25% cirrhotic). Substance use occurred at 94% of person-visits: 60% marijuana, 56% alcohol, 37% methamphetamine, 22% opioids, 17% cocaine, and 20% injection drug use. The SVR by intention-to-treat was 86.7% (52 of 60) and as-treated was 94.5% (52 of 55). Confirmed failures included 1 relapse, 1 reinfection, and 1 unknown (suspected reinfection). Median total adherence was 96% (interquartile range [IQR], 85%–100%; range, 30%–101%), and between-visit adherence was 100% (IQR, 86%–100%; range, 0%–107%). The odds of missing ≥1 dose between visits increased with HIV coinfection (2.94; 95% confidence interval [CI], 1.37–6.32; P  = .006), black race (4.09; 95% CI, 1.42–11.74; P  = .009), methamphetamine use (2.51; 95% CI, 1.44–4.37; P  = .0.001), and cocaine use (2.12; 95% CI, 1.08–4.18; P  = .03) and decreased with marijuana use (0.34; 95% CI, 0.17–0.70; P  = .003) and vDOT (0.43; 95% CI, 0.21–0.87; P  = .02). Conclusions Persons who use drugs achieved high SVR rates with high, but variable, ledipasvir/sofosbuvir adherence using technology-based methods. These findings support efforts to expand HCV treatment in PWUD. [ABSTRACT FROM AUTHOR]

Background: Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir.Objectives: To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs.Methods: Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and β2 microglobulin (β2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit.Results: Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and β2M:creatinine improved following the switch to TAF.Conclusions: Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations. [ABSTRACT FROM AUTHOR]

In a pre-exposure prophylaxis program for Kenyan women, we detected tenofovir-diphosphate in 61% (125/201) of randomly selected dried blood spots collected at the first follow-up visit. Tenofovir-diphosphate was detected more frequently among women who had partners living with human immunodeficiency virus, who were not pregnant, and who were ≥24 years. [ABSTRACT FROM AUTHOR]

Background The adherence biomarker tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is associated with viral suppression and predicts future viremia. However, its association with social determinants of health (SDoH) in people with human immunodeficiency virus (PWH) remains unknown. Methods Dried blood spots for TFV-DP were longitudinally collected from a clinical cohort of PWH receiving tenofovir disoproxil fumarate-based therapy (up to 3 visits over 48 weeks) residing in 5 Colorado counties. To assign SDoH, zip codes at enrollment were matched with SDoH data from AIDSVu (https://aidsvu.org/). The SDoH included household income, percentage living in poverty, education level, and income inequality (quantified using Gini coefficient, where 0 and 1 represent perfect income equality and inequality, respectively). Log-transformed TFV-DP concentrations were analyzed using a mixed-effects model to estimate percentage change (95% confidence interval) in TFV-DP for every significant change in the SDoH and adjusted for relevant covariates including age, gender, race, estimated glomerular filtration rate, body mass index, hematocrit, CD4+ T-cell count, antiretroviral drug class, and 3-month self-reported adherence. Results Data from 430 PWH totaling 950 person-visits were analyzed. In an adjusted analysis, income inequality was inversely associated with TFV-DP in DBS. For every 0.1 increase in the Gini coefficient, TFV-DP concentrations decreased by 9.2% (−0.5 to −17.1; P  = .039). This remained significant after adjusting for human immunodeficiency virus viral suppression, where a 0.1 increase in Gini was associated with a decrease of 8.7% (−0.3 to −17.9; P  = .042) in TFV-DP. Conclusions Higher income inequality was associated with lower cumulative antiretroviral adherence. These findings support the need for further research on how SDoH impact adherence and clinical care. [ABSTRACT FROM AUTHOR]

Objective: Mothers of infants born very preterm (VPT) are at high risk of mental health difficulties. However, less is known about the course of fathers' depressive and anxiety symptoms over time, and the implications this may have for early parenting behaviors.Methods: In total, 100 fathers of 125 infants born VPT (<30 weeks' gestation) completed questionnaires assessing depressive and anxiety symptoms shortly after their infant's birth, and when their infant reached term-equivalent age, 3 months, 6 months, and 12 months' corrected age. At 12 months' corrected age, fathers' parenting behaviors were assessed using the Emotional Availability Scales. Longitudinal latent class analysis was used to identify trajectories of fathers' depressive and anxiety symptoms, and linear regression equations examined relationships between these trajectories and fathers' parenting behaviors.Results: For both depressive and anxiety symptoms, two distinct trajectories were identified. For depression, most fathers were assigned to the persistently low symptom trajectory (82%), while the remainder were assigned to the persistently high symptom trajectory (18%). For anxiety, 49% of fathers were assigned to the persistently low symptom trajectory, while 51% were assigned to the trajectory characterized by moderate symptoms over the first postnatal year. There were no significant differences in parenting behaviors between fathers assigned to the different depressive and anxiety symptom trajectories.Conclusions: Fathers of infants born VPT are at risk of chronic depressive and anxiety symptoms over the first postnatal year, highlighting the need for screening and ongoing support. [ABSTRACT FROM AUTHOR]

Aims To describe a case study in the British market of one of the global beer-producing companies that has set a target to increase the proportion of its products with an alcohol by volume (ABV) of 3.5% or less, and to reduce the mean ABV of its beer products. Methods Descriptive statistics and time-series analyses using Kantar Worldpanel's British household purchase data for 2015–2018. Results As assessed by British household purchase data, 15.7% of the company's beer products had an ABV of 3.5% or less in 2018, compared with 8.8% in 2015. The mean ABV of its beer products dropped from 4.69 in 2015 to 4.55 in 2018. Associated with these changes, the increase in purchased grams of alcohol in all beer that occurred during 2015–2016 (standardized coefficient = 0.007), plateaued during 2017 (standardized coefficient = −0.006) and decreased during 2018 (standardized coefficient = −0.034). Similar findings applied to the purchased grams of alcohol in beer other than ABI beer, suggesting some switching from other beer products to ABI products; and in all alcohol, suggesting, on balance, no overall switching to higher strength products. Greater decreases in purchases were found in the younger age groups, the highest purchasing households in terms of grams of alcohol, class groups D and E, and Scotland; there was no clear pattern by household income. Conclusions The proportion of the company's beer purchased in Great Britain that had an ABV of 3.5% or less increased since the launch of the target, and the mean ABV of its beer products decreased. The changes were associated with reduced purchases of grams of alcohol within its beer products. The associated reductions in purchases of alcohol in all beer and in all alcohol products suggest no evidence of overall switching to other higher strength beer or alcohol products. Other beer-producing companies should undertake similar initiatives. A regulatory tax environment should be introduced to ensure a level-playing field favouring lower alcohol concentration across all beer and other alcohol products. [ABSTRACT FROM AUTHOR]

Objectives: To determine factors associated with interindividual variability in tenofovir diphosphate (TFV-DP) concentrations in dried blood spots (DBSs) among persons living with HIV (PLWH).Methods: PLWH 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.Results: Five 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 < 0.0001). In the same model, female participants had 20% (95% CI: 3%-40%; P = 0.02) higher TFV-DP concentrations in DBSs, compared with male participants, and every 1 kg/m2 increase in BMI was associated with a decrease in TFV-DP concentration in DBSs by 2% (95% CI: -3% to -1%; P < 0.0001).Conclusions: Individual 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. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus–seronegative men aged 15–22 years who lost bone mineral density (BMD) during tenofovir disoproxil fumarate/emtricitabine preexposure prophylaxis (PrEP) showed BMD recovery 48 weeks following PrEP discontinuation. Lumbar spine and whole body BMD z -scores remained below baseline 48 weeks off PrEP in participants aged 15–19 years. Clinical Trials Registration. NCT01772823 (ATN 110) and NCT01769456 (ATN 113). [ABSTRACT FROM AUTHOR]

Background Metronidazole is traditionally dosed every 6–8 hours even though in adults it has a long half-life, concentration-dependent killing, and 3-hour postantibiotic effect. Based on this logic, some pediatric hospitals adopted once-daily dosing for appendicitis, despite limited pharmacokinetics-pharmacodynamics (PK/PD) in children. We studied pediatric patients with appendicitis given metronidazole once daily to determine whether this dosing would meet target area under the curve (AUC)/minimum inhibitory concentration (MIC) ratio of ≥70 for Bacteroides fragilis. Methods One hundred pediatric patients aged 4–17 years had an average of 3 blood draws per patient during the first 24 hours after a 30 mg/kg per dose of intravenous metronidazole. Concentrations of drug were determined using validated liquid chromatography and tandem mass spectrometry. A NONMEM model was constructed for determining PK, followed by Monte Carlo simulations to generate a population of plasma concentration-time AUC of metronidazole and hydroxy-metronidazole. Results Simulated AUC values met target attainment (AUC/MIC ratio of ≥70 to B fragilis MICs) for 96%–100% of all patients for an MIC of 2 mcg/mL. For MICs of 4 and 8 mcg/mL, target attainment ranged from 61% to 97% and 9% to 71%, respectively. Areas under the curve were similar to that of adults receiving 1000 mg and 1500 mg q24, or 500 mg q8 hours. Conclusions Metronidazole, 30 mg/kg per dose, once daily achieved AUC target attainment for B fragilis with an MIC of 2 mcg/mL or less in pediatric appendicitis patients. Based on this and studies in adults, there does not seem to be any PK/PD advantage of more frequent dosing in this population. [ABSTRACT FROM AUTHOR]

Background: Tenofovir 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.Methods: Blood 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.Results: Among all 451 participants in the analysis, aOR of future viremia for participants with TFV-DP <800 and 800 to <1650 fmol/punch were 4.7 (95% CI, 2.6-8.7; P < .0001) and 2.1 (95% CI, 1.3-3.3; P = .002) versus ≥1650 fmol/punch, respectively. These remained significant for participants who were virologically suppressed at the time of the study visit (4.2; 95% CI, 1.5-12.0; P = .007 and 2.2; 95% CI, 1.2-4.0; P = .01).Conclusions: TFV-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. [ABSTRACT FROM AUTHOR]

Background: Intracellular 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.Methods: HIV/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.Results: Ten 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 < 0.0001), respectively, after 4 weeks of ledipasvir/sofosbuvir.Conclusions: Tenofovir 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: To examine trajectories of psychological distress in mothers of children born very preterm (VPT, <30 weeks gestation) and full term from 2 to 13 years after the birth, and examine predictors of maternal psychological distress over time within the VPT group.Methods: Mothers of children born VPT (n = 159) and full term (n = 71) completed questionnaires assessing their psychological distress when their child was 2, 7, and 13 years of age. Mixed models were used to examine differences between groups in maternal psychological distress over time. Family social risk, child neonatal medial risk, child sex, multiple pregnancy, and child's neurodevelopmental impairment in early childhood were examined as potential predictors of maternal psychological distress within the VPT group.Results: Mothers of children born VPT displayed elevated psychological distress compared with mothers of full-term children, and this difference was consistent over time. Higher family social risk was associated with elevated maternal psychological distress throughout childhood across all time-points. There was evidence that mothers of children at higher neonatal medical risk displayed increasing psychological distress over time.Conclusions: Mothers of children born VPT show prolonged psychological distress. Mothers from socially disadvantaged background and those whose child has neonatal medical complications may require extensive support to prevent prolonged psychological distress and promote optimal outcomes for children and families. [ABSTRACT FROM AUTHOR]

Background Young men who have sex with men are among the most vulnerable to human immunodeficiency virus (HIV) infection. Although preexposure prophylaxis (PrEP) has demonstrated effectiveness, adherence and retention have been low among youth. Methods We conducted a randomized controlled trial to evaluate the impact of a youth-tailored, bidirectional text-messaging intervention (PrEPmate) on study retention and PrEP adherence. Young individuals at risk for HIV initiating PrEP within Chicago's safety-net system were randomized 2:1 to receive PrEPmate or standard of care (SoC) for 36 weeks. The primary retention outcome was study-visit completion, and the primary adherence outcome was tenofovir diphosphate (TFV-DP) concentrations ≥700 fmol/punch (consistent with ≥4 doses/week) assessed at 4, 12, 24, and 36 weeks. The impact of PrEPmate on retention and adherence was evaluated using generalized estimating equation logistic models with robust standard errors. Results From April 2015 to March 2016, 121 participants enrolled (mean age 24; 27% black, 36% Latino). Participants who received PrEPmate were more likely to attend study visits (86% PrEPmate vs. 71% SoC, odds ratio [OR] = 2.62, 95% confidence interval [CI] 1.24–5.54) and have TFV-DP levels consistent with ≥4 doses/week (72% PrEPmate vs. 57% SoC, OR = 2.05, 95% CI 1.06–3.94). PrEPmate efficacy did not differ significantly by age, race/ethnicity, education, or insurance. Overall, 88% reported PrEPmate to be very/somewhat helpful, and 92% would recommend PrEPmate to others. Conclusions An interactive text-messaging intervention had high acceptability and significantly increased study-visit retention and PrEP adherence among young individuals at risk for HIV acquisition. Clinical Trials Registration NCT02371525. [ABSTRACT FROM AUTHOR]

Background Public sector bodies have called for policies and programmes to shift collective social norms in disfavour of the harmful use of alcohol. This article aims to identify and summarize the evidence and propose how policies and programmes to shift social norms could be implemented and evaluated. Design Review of reviews for all years to July 2017. Data sources Searches on OVID Medline, Healthstar, Embase, PsycINFO, AMED, Social Work Abstracts, CAB Abstracts, Mental Measurements Yearbook, Joanna Briggs Institute EBP, Health and Psychosocial Instruments, International Pharmaceutical Abstracts, International Political Science Abstracts, NASW Clinical Register and Epub Ahead of Print databases. Eligibility All reviews, without language or date restrictions resulting from combining the terms ((review or literature review or review literature or data pooling or comparative study or systematic review or meta-analysis or pooled analysis) and (social norms or culture) and (alcohol drinking)). Results Two relevant reviews were identified. One review of community-based interventions found one study that demonstrated small changes in parental disapproval of under-age drinking. One review stressed that collective social norms about drinking are malleable and not uniform in any one country. Three factors are proposed to inform programmes: provide information about the consequences of the harmful use of alcohol, and their causes and distribution; act on groups, not individuals; and strengthen environmental laws, regulations and approaches. Conclusions Purposeful policies and programmes could be implemented to change collective social norms in disfavour of the harmful use of alcohol; they should be evidence-based and fully evaluated for their impact. [ABSTRACT FROM AUTHOR]

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 < 0.0001). After further adjusting for tenofovir diphosphate, the aOR was 2.1 (1.2-4.0; P < 0.015). The area under the ROC curve for 3 day self-reported adherence was 0.82 (95% CI 0.75-0.88) compared with 0.70 (95% CI 0.62-0.77, P = 0.004) and 0.79 (95% CI 0.71-0.86, P = 0.32) for 3 month and 30 day self-reported adherence, respectively.Conclusions: In PLWH, FTC-TP from DBS is a strong predictor of viral suppression, even after adjusting for tenofovir diphosphate, and was best predicted by 3 day self-reported adherence. [ABSTRACT FROM AUTHOR]

Background Although 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. Methods DBS 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 (<20 copies/mL) based on the TFV-DP concentration at the study visit. Results We 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 <350 fmol/punch. Conclusions TFV-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 Registration NCT02012621. [ABSTRACT FROM AUTHOR]

Background Screening and brief interventions (SBIs) for heavy drinking are an effective and cost-effective approach to reducing alcohol-related harm, yet delivery rates remain low. This study uses trial data to estimate the cost-effectiveness of alternative strategies to increase SBI delivery. Methods Data from a large cluster-randomized trial were combined with the Sheffield Alcohol Policy Model, a policy appraisal tool, to estimate the cost-effectiveness of eight strategies to increase SBI delivery in primary care in England, Poland and the Netherlands: care as usual (control), training and support (TS), financial reimbursement (FR), referral of patients to an online brief intervention (eBI) and all combinations of TS, FR and eBI. cost-effectiveness was assessed from a healthcare perspective by comparing health benefits (measured in Quality-Adjusted Life Years) with total implementation costs and downstream healthcare savings for each strategy over a 30-year horizon and calculating Incremental cost-effectiveness ratios (ICERs). Results All trialled strategies were cost-effective compared to control. TS combined with FR was the most cost-effective approach in England (more effective and less costly than control) and Poland (ICER €4632 vs. next-best strategy). This combination is not cost-effective in the Netherlands, where TS alone is the most cost-effective approach (ICER €3386 vs. next-best strategy). Conclusions Structured TS, financial incentives and access to online interventions are all estimated to be cost-effective methods of improving delivery of alcohol brief interventions. TS and FR together may be the most cost-effective approach, however this is sensitive to country characteristics and alternative BI effect assumptions. Trial registration ClinicalTrials.gov trial identifier: NCT01501552 [ABSTRACT FROM AUTHOR]

Background Vaginal rings (VRs) are a promising approach for sustained delivery of antiretroviral (ARV) medication to prevent human immunodeficiency virus (HIV) infection in women. Combination ARV VRs could increase efficacy. Methods MTN-028, a phase 1 trial in 19 HIV-uninfected women, evaluated 2 VRs containing vicriviroc (VCV) and MK-2048. Participants were randomized 2:1 to a low-dose (VCV, 91 mg; MK-2048, 10 mg) or original-dose (VCV, 182 mg; MK-2048, 30 mg) ring used for 28 days. Safety was assessed by documenting adverse events (AEs). Drug concentrations were evaluated in plasma, cervicovaginal fluid (CVF), and cervical tissue samples. Results All AEs reported were grade 1 or 2, with no statistically significant differences in related genitourinary AEs or grade ≥2 AEs observed between arms (P = >.99). VCV/MK-2048 concentrations rose rapidly, with higher plasma area under the concentration-time curve (AUC) in the original-dose arm (geometric mean ratio, 3.29 for VCV and 1.49 for MK-2048) and similar AUCs across arms for CVF samples. Cervical tissue concentrations were higher in the original-dose arm (geometric mean ratio, 7.94 for VCV and 6.45 for MK-2048), with greater drug released based on residual drug levels. Plasma and CVF concentrations for both drugs fell rapidly after ring removal. Conclusions In this first study evaluating 2 doses of a combination VCV/MK-2048 VR, both rings were found to be safe and well tolerated. VCV and MK-2048 were detectable in plasma, CVF, and cervical tissue samples, and drug release and plasma drug exposure were higher for the original-dose than for the low-dose ring. [ABSTRACT FROM AUTHOR]

Background Vaginal rings (VR) containing antiretroviral (ARV) drugs can be utilized for prevention of human immunodeficiency virus (HIV) with potential for improved adherence compared to daily pills. Combination ARV VRs could improve efficacy. Methods MTN-027, a single-blind, randomized, placebo-controlled trial in 48 women, evaluated VRs containing MK-2048 (30 mg) and vicriviroc (VCV, 182 mg), alone or in combination, and placebo used continuously for 28 days. Safety was assessed by recording adverse events. Drug concentrations were quantified in plasma, vaginal fluid, cervical tissue, and rectal fluid. Cervical tissue was utilized for ex vivo HIV inhibition analysis. Results There was no difference in related genitourinary adverse events between treatment arms compared to placebo. VCV and MK-2048 released from single or combination VRs both achieved peak concentrations in vaginal fluids, which were substantially higher compared to plasma (200× for VCV, 30× for MK-2048) and rectal fluid. In an ex vivo challenge assay, the antiviral activity of VCV and/or MK-2048 was not correlated with tissue-associated drug concentrations. Most women (77%) were fully adherent to 28 days of continuous VR use and found the VR acceptable. Conclusions VCV and/or MK-2048 containing VRs were safe and acceptable. Both VCV and MK-2048 were quantifiable in all matrixes tested with peak compartmental drug concentrations similar for single and combination drug VRs. Tissue-associated VCV and/or MK-2048 did not correlate with inhibition of HIV infection. These data highlight the need to assess adequacy of drug dosing in the VR and measuring genital tissue drug concentrations to develop more precise concentration-response relationships. [ABSTRACT FROM AUTHOR]

There are limited and inconsistent data suggesting that mild iodine deficiency in pregnancy might be associated with poorer developmental outcomes in children. Between 2011 and 2015, we conducted a prospective cohort study in Australia examining the relationship between maternal iodine intake in pregnancy and childhood neurodevelopment, assessed using Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III), in 699 children at 18 months. Maternal iodine intake and urinary iodine concentration (UIC) were assessed at study entry (<20 weeks' gestation) and at 28 weeks' gestation. Maternal iodine intake in the lowest (<220 μg/day) or highest (≥391 μg/day) quartile was associated with lower cognitive, language, and motor scores (mean differences ranged from 2.4 (95% confidence interval (CI): 0.01, 4.8) to 7.0 (95% CI: 2.8, 11.1) points lower) and higher odds (odds ratios ranged from 2.7 (95% CI: 1.3, 5.6) to 2.8 (95% CI: 1.3, 5.7)) of cognitive developmental delay (Bayley-III score <85) compared with mothers with an iodine intake in the middle quartiles. There was no association between UIC in pregnancy and Bayley-III outcomes regardless of whether UIC and the outcomes were analyzed as continuous or categorical variables. Both low and high iodine intakes in pregnancy were associated with poorer childhood neurodevelopment in this iodine-sufficient population. [ABSTRACT FROM AUTHOR]

Inadequate cold tolerance of Eucalyptus spp. has limited a broader deployment beyond subtropical regions of the United States. We examined growth, photosynthetic rate, and cold tolerance of a cold-hardy Eucalypt (Eucalyptus benthamii) planted in North Carolina and compared the results with native Pinus taeda. After two growing seasons, E. benthamii surpassed P. taeda in both height (5.06 m, 1.34 m) and diameter (5.0 cm, 0.7 cm) growth, respectively. From April through November, E. benthamii's mean photosynthetic rate (Ps) (13.82 µmol CO2 m-2s-1) was more than twice that of P. taeda (6.21 µmol CO2 m-2s-1). Similarly, mean Ps during winter months was 6.09 µmol CO2 m-2s-1 for E. benthamii compared to 2.73 µmol CO2 m-2s-1 for P. taeda. Laboratory assessments of cold tolerance demonstrated that, unlike P. taeda, E. benthamii had a limited ability to acclimate to seasonal temperature changes. The coldest temperature (Tm) where >50% of the tissue was damaged and recovery unlikely for E. benthamii was -13.4°C for leaves and -14.3°C for stems, whereas for P. taeda it was -29.9°C for leaves and -36.5°C for stems. The exceptional productivity of E. benthamii was not without trade-offs as all trees died after experiencing air temperatures of -12.8°C on January 7, 2014. [ABSTRACT FROM AUTHOR]

Background: The nucleotide analogues tenofovir and sofosbuvir are considered to have low potential for drug interactions.Objectives: To determine the effect of sofosbuvir-based HCV treatment on plasma concentrations of tenofovir and cellular concentrations of tenofovir diphosphate.Methods: HIV-infected participants with acute HCV were treated for 12 weeks with sofosbuvir + ribavirin in Cohort 1 or 8 weeks with ledipasvir/sofosbuvir in Cohort 2 of AIDS Clinical Trials Group study 5327. Only participants taking tenofovir disoproxil fumarate were included in this analysis. Tenofovir in plasma, tenofovir diphosphate in dried blood spots and tenofovir diphosphate in PBMCs were measured pre-HCV therapy and longitudinally during the study using validated LC/MS-MS.Results: Fifteen and 22 men completed Cohorts 1 and 2, respectively. In Cohort 1, tenofovir diphosphate was 4.3-fold higher (95% CI geometric mean ratio 2.46-7.67; P = 0.0001) in dried blood spots and 2.3-fold higher (95% CI 1.09-4.92; P = 0.03) in PBMCs following 12 weeks of sofosbuvir + ribavirin versus study entry. Tenofovir in the plasma was unchanged. In Cohort 2, tenofovir diphosphate was 17.8-fold higher (95% CI 12.77-24.86; P < 0.0001) in dried blood spots after 8 weeks of ledipasvir/sofosbuvir versus study entry. Tenofovir plasma concentrations were 2.1-fold higher (95% CI 1.44-2.91; P = 0.0005). Despite the increase in cellular tenofovir diphosphate concentrations, only a small decline in CLCR (6%-7%) was observed in both cohorts between study entry and end of treatment.Conclusions: These data indicate an unexpected drug interaction with tenofovir disoproxil fumarate and sofosbuvir at the cellular level. Additional studies are needed to determine the mechanism and clinical significance. [ABSTRACT FROM AUTHOR]

Background Most cost of illness studies are based on models where information on exposure is combined with risk information from meta-analyses, and the resulting attributable fractions are applied to the number of cases. Methods This study presents data on alcohol and tobacco use for 2011 and 2012 obtained from a routine medical practice in Catalonia of 606 947 patients, 18 years of age and older, as compared with health care costs for 2013 (all costs from the public health care system: primary health care visits, hospital admissions, laboratory and medical tests, outpatient visits to specialists, emergency department visits and pharmacy expenses). Quasi-Poisson regressions were used to assess the association between alcohol consumption and smoking status and health care costs (adjusted for age and socio-economic status). Results Resulting health care costs per person per year amounted to 1290 Euros in 2013, and were 20.1% higher for men than for women. Sex, alcohol consumption, tobacco use and socio-economic status were all associated with health care costs. In particular, alcohol consumption had a positive dose–response association with health care costs. Similarly, both smokers and former smokers had higher health care costs than did people who never smoked. Conclusions Alcohol and tobacco use had modest and large impacts respectively on health care costs, confirming the results of previous ecological modelling analyses. Reductions of alcohol consumption and smoking through public policies and via early identification and brief interventions would likely be associated with reductions in health care costs. [ABSTRACT FROM AUTHOR]

Background Antiretroviral drugs have been associated with changes in lipids, fat mass and dat distribution. Tenofovir disoproxil fumarate (TDF) has been shown to have a more favorable metabolic profile than other drugs in its class. However, the metabolic effects of TDF in preexposure prophylaxis (PrEP) are unknown. Methods We evaluated the effects of TDF/emtricitabine (FTC) on lipids and body composition in a blinded, placebo-controlled PrEP trial. Participants enrolled in a metabolic subcohort (N = 251, TDF/FTC; N = 247, placebo) consented to fasting lipid panels, dual-energy X-ray absorptiometry scans for body composition, and pharmacologic testing of drug metabolites at baseline and every 24 weeks thereafter. Results Lean body mass was stable and unaffected by TDF/FTC. Body weight increased in both groups but was lower on TDF/FTC through week 72. This difference was explained by lower fat accumulation on TDF/FTC. The net median percent difference (standard error, P value) for TDF/FTC vs placebo at week 24 was −0.8% (0.4%, P =.02), +0.3% (0.4%, P =.46), and −3.8% (1.4%, P =.009) for total, lean, and fat mass, respectively. There was no apparent differential regional fat accumulation on TDF/FTC. Decreases in cholesterol, but not triglycerides, were seen in TDF/FTC participants, with detectable drug levels compared to placebo. Conclusions TDF/FTC for PrEP showed cholesterol reductions and appeared to transiently suppress the accumulation of weight and body fat compared to placebo. There was no evidence of altered fat distribution or lipodystrophy during daily oral TDF/FTC PrEP. Clinical Trials Registration NCT00458393. [ABSTRACT FROM AUTHOR]