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Transgender persons have an increased vulnerability to HIV infection yet have not been well-represented in past clinical trials for pre-exposure prophylaxis (PrEP). Because of this, there are few data available to understand whether gender-affirming hormone concentrations are influenced by PrEP agents in transgender men (TM) and transgender women (TW). The objective of this study was to compare gender-affirming hormone concentrations with versus without emtricitabine (F, FTC)-tenofovir disoproxil fumarate (TDF). TM and TW without HIV, aged 15-24 years, were enrolled for 1 month of directly observed daily F/TDF. Participants were required to be receiving a stable hormone dose (estradiol or testosterone) for at least 1 month or three consecutive doses, whichever was longer, before enrollment and willing to continue the same dose. Intensive pharmacokinetic (PK) sampling for gender-affirming hormones was collected before and 2-3 weeks after daily F/TDF. Serum estradiol and total testosterone were determined by liquid chromatography-tandem mass spectrometry; free testosterone by equilibrium dialysis. Maximum concentrations (Cmax) and area under the curve (AUClast) were log-transformed and compared between baseline and on F/TDF using geometric mean ratios (GMRs) with 95% confidence intervals (CIs). Twenty-five TW and 24 TM were enrolled (median age: 20 and 21 years, respectively). In TW, estradiol Cmax (GMR [95% CI]: 0.85 [0.65-1.11]) and AUClast (GMR [95% CI]: 0.87 [0.73-1.03]) were comparable on F/TDF versus baseline. In TM, similar comparability was observed for PrEP versus baseline including total testosterone Cmax (GMR [95% CI]: 0.91 [0.80-1.03]) and AUClast (GMR [95% CI]: 0.91 [0.81-1.04]) and free testosterone Cmax (GMR [95% CI]: 0.89 [0.74-1.07]) and AUClast (GMR [95% CI]: 0.88 [0.74-1.03]). Estradiol and testosterone exposures in young TW and TM did not significantly differ on F/TDF versus baseline. These findings should reassure patients and providers that F/TDF can be used as PrEP without concern for altering gender-affirming hormone PK. ClinicalTrials.gov (NCT03652623).

The transgender community has expressed concerns regarding drug-drug interactions between HIV-pre-exposure prophylaxis (PrEP) and gender-affirming hormones. In this study, we evaluated emtricitabine (F, FTC)/tenofovir (TFV) disoporoxil fumarate (TDF) pharmacokinetics (PK) among adolescent and young adult transgender persons receiving gender-affirming hormone therapy (GAHT). This was a prospective, observational study among transgender women (TW) and men (TM) without HIV, 15-24 years of age, receiving GAHT (estradiol with/without spironolactone, or testosterone). Participants received 1 month of directly observed daily F/TDF. Weekly convenience blood samples were collected for plasma TFV and FTC, and intracellular TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in peripheral blood mononuclear cells (PBMC) and dried blood spots (DBS). After 2-3 weeks of F/TDF dosing, intensive PK sampling was conducted. PK parameters were estimated using noncompartmental methods. Data were log-transformed and compared between TM and TW, and to historical data among cisgender adults. Plasma TFV exposures were similar between TM and TW [geometric mean ratio (GMR); confidence interval (95% CI): 1.06 (0.89-1.28)], whereas FTC plasma exposures were 21% higher in TM versus TW (95% CI: 1.07-1.38). TFV-DP in PBMC and DBS and FTC-TP in DBS did not differ between TM versus TW after controlling for creatinine clearance (CrCl), but FTC-TP in PBMC remained 46% (95% CI: 1.15-1.86) higher in TM versus TW. All PK exposures were within expected ranges based on historical studies. TM had higher FTC exposures compared with TW, but overall plasma and intracellular exposures for both drugs were within the range of historical studies, suggesting high PrEP efficacy will be retained in adolescent and young adult transgender persons. Registered at ClinicalTrials.gov (NCT03652623).

Sugar intake, particularly fructose, is implicated as a factor contributing to insulin resistance via hepatic de novo lipogenesis (DNL). A nine-day fructose reduction trial, controlling for other dietary factors and weight, in children with obesity and metabolic syndrome, decreased DNL and mitigated cardiometabolic risk (CMR) biomarkers. Ceramides are bioactive sphingolipids whose dysregulated metabolism contribute to lipotoxicity, insulin resistance, and CMR. We evaluated the effect of fructose reduction on ceramides and correlations between changes observed and changes in traditional CMR biomarkers in this cohort. Analyses were completed on data from 43 participants. Mean weight decreased (-0.9 ± 1.1 kg). The majority of total and subspecies ceramide levels also decreased significantly, including dihydroceramides, deoxyceramides and ceramide-1-phoshates. Change in each primary ceramide species correlated negatively with composite insulin sensitivity index (CISI). Change in deoxyceramides positively correlated with change in DNL. These results suggest that ceramides decrease in response to dietary fructose restriction, negatively correlate with insulin sensitivity, and may represent an intermediary link between hepatic DNL, insulin resistance, and CMR.

Elevated levels of triglyceride-rich lipoproteins (TRLs), both fasting and postprandial, are associated with increased risk for atherosclerosis. However, guidelines for treatment are defined solely by fasting lipid levels, even though postprandial lipids may be more informative. In the postprandial state, circulating lipids consist of dietary fat transported from the intestine in chylomicrons (CMs; containing ApoB48) and fat transported from the liver in VLDL (containing ApoB100). Research into the roles of endogenous versus dietary fat has been hindered because of the difficulty in separating these particles by ultracentrifugation. CM fractions have considerable contamination from VLDL (purity, 10%). To separate CMs from VLDL, we produced polyclonal antibodies against ApoB100 and generated immunoaffinity columns. TRLs isolated by ultracentrifugation of plasma were applied to these columns, and highly purified CMs were collected (purity, 90-94%). Overall eight healthy unmedicated adult volunteers (BMI, 27.2 ± 1.4 kg/m2; fasting triacylglycerol, 102.6 ± 19.5 mg/dl) participated in a feeding study, which contained an oral stable-isotope tracer (1-13C acetate). We then used this technique on plasma samples freshly collected during an 8 h human feeding study from a subset of four subjects. We analyzed fractionated lipoproteins by Western blot, isolated and derivatized triacylglycerols, and calculated fractional de novo lipogenesis. The results demonstrated effective separation of postprandial lipoproteins and substantially improved purity compared with ultracentrifugation protocols, using the immunoaffinity method. This method can be used to better delineate the role of dietary sugar and fat on postprandial lipids in cardiovascular risk and explore the potential role of CM remnants in atherosclerosis.

ObjectiveTo investigate the link between dietary sugar consumption and two separate pathogenetic mechanisms associated with metabolic syndrome: de novo lipogenesis (DNL) and nonenzymatic glycation.Design and participantsWe assessed changes in serum d-lactate (the detoxification end-product of methylglyoxal) concentration in response to 9 days of isocaloric fructose restriction in 20 children with obesity and metabolic syndrome, and examined correlations with changes in DNL, liver fat, insulin sensitivity, and other metrics of hepatic metabolism.InterventionsNine days of dietary sugar restriction, with substitution of equal amounts of refined starch.Main outcome measuresOn days 0 and 10, children had laboratory evaluation of d-lactate levels and other analytes, and underwent oral glucose tolerance testing, magnetic resonance spectroscopy to quantify fat depots, and 13C-acetate incorporation into triglyceride (TG) to measure DNL.Resultsd-Lactate was associated with baseline liver fat fraction (P < 0.001) and visceral adipose tissue (P < 0.001) but not with subcutaneous adipose tissue. At baseline, d-lactate was positively correlated with DNL-area under the curve (AUC) (P = 0.003), liver fat fraction (P = 0.02), TG (P = 0.004), and TG/high-density lipoprotein ratio (P = 0.002). After 9 days of isocaloric fructose restriction, serum d-lactate levels reduced by 50% (P < 0.0001), and changes in d-lactate correlated with both changes in DNL-AUC and measures of insulin sensitivity.ConclusionBaseline correlation of d-lactate with DNL and measures of insulin sensitivity and reduction in d-lactate after 9 days of isocaloric fructose restriction suggest that DNL and nonenzymatic glycation are functionally linked via intermediary glycolysis in the pathogenesis of metabolic syndrome and point to fructose as a key dietary substrate that drives both pathways.

Pre-exposure prophylaxis (PrEP) with tenofovir disoproxil fumarate-emtricitabine (TDF-FTC) reduces bone mineral density in HIV-uninfected men who have sex with men (MSM). We hypothesized that PrEP with TDF-FTC would increase bone turnover markers (BTMs) at week 24 and that vitamin D supplementation from weeks 24 to 48 would blunt this increase. Participants were from a cohort of 398 MSM and transgender women who received daily TDF-FTC for PrEP. At week 24, a prospective intervention group initiated vitamin D3 4,000 IU daily. Concurrent controls were selected from the cohort who took ≤400 IU/day of vitamin D3 matched by age, race, and body mass index. The primary endpoint was the change in procollagen-I N-terminal propeptide (P1NP) from weeks 24 to 48. Paired t-tests were used to compare changes in BTMs between intervention and controls. Among 48 intervention-control pairs, median age was 33 years. At baseline, 68.9% of the intervention group and 77.3% of controls were vitamin D sufficient (≥20 ng/mL, p = .94). P1NP, C-telopeptide, parathyroid hormone (PTH), and 25-OH vitamin D3 did not increase significantly at week 24. P1NP fell by a mean ± SD of -27.6 ± 49.9 pg/mL from weeks 24 to 48 with vitamin D and -2.5 ± 40.2 pg/mL in controls (p = .01). There were no significant between-group differences in the weeks 24-48 change in C-telopeptide, PTH, or 25-OH vitamin D3. Vitamin D3 supplementation with 4,000 IU/day resulted in a significant reduction in the BTM P1NP compared with controls, suggesting that this intervention has potential to improve bone health during PrEP.

ContextBariatric surgery results in reduced muscle mass as weight is lost, but postoperative changes in muscle strength and performance are incompletely understood.ObjectiveTo examine changes in body composition, strength, physical activity, and physical performance following Roux-en-Y gastric bypass (RYGB).Design, participants, outcomesIn a prospective cohort of 47 adults (37 women, 10 men) aged 45 ± 12 years (mean ± SD) with body mass index (BMI) 44 ± 8 kg/m2, we measured body composition by dual-energy X-ray absorptiometry, handgrip strength, physical activity, and physical performance (chair stand time, gait speed, 400-m walk time) before and 6 and 12 months after RYGB. Relative strength was calculated as absolute handgrip strength/BMI and as absolute strength/appendicular lean mass (ALM).ResultsParticipants experienced substantial 12-month decreases in weight (-37 ± 10 kg or 30% ± 7%), fat mass (-48% ± 12%), and total lean mass (-13% ± 6%). Mean absolute strength declined by 9% ± 17% (P < 0.01). In contrast, relative strength increased by 32% ± 25% (strength/BMI) and 9% ± 20% (strength/ALM) (P < 0.01 for both). There were clinically significant postoperative improvements in all physical performance measures, including mean improvement in gait speed of >0.1 m/s (P < 0.01) and decrease in 400-m walk time of nearly a full minute.ConclusionsIn the setting of dramatic weight loss, lean mass and absolute grip strength declined after RYGB. However, relative muscle strength and physical function improved meaningfully and are thus noteworthy positive outcomes of gastric bypass.

We examined associations of 25-hydroxy vitamin D (25-OHD), tenofovir disoproxil fumarate (TDF), and bone toxicity. We studied TDF/emtricitabine (FTC) HIV pre-exposure prophylaxis (PrEP) in young men who have sex with men (YMSM). Bone toxicity was predefined using bone mineral density/content change from baseline to week 48. Baseline serum 25-OHD was dichotomized as 700 fmol/punch (protective against HIV acquisition) versus ≤700. Associations were examined by univariate and multivariable logistic regression, reporting crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs). Of 101 enrolled, 69 had complete bone assessments and 25-OHD; of these, 59 had week 48 TFV-DP data. Median (Q1-Q3) age was 20 (18-21) years; 54% were black/African American. In univariate analysis, participants with baseline 25-OHD 700 (OR = 11.5; 95% CI = 1.4-169.6), 25-OHD 700 (OR = 32.3; 95% CI = 3.3-653.6) had greater odds of bone toxicity after adjusting for race. In multivariable models, 25-OHD insufficiency, protective TFV-DP concentrations, and black race were significantly associated with bone toxicity after 48 weeks of TDF/FTC PrEP in YMSM. Clinical Trials Registration: NCT01769469.

BackgroundAntiretroviral 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.MethodsWe 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.ResultsLean 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.ConclusionsTDF/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 registrationNCT00458393.

BackgroundTenofovir disoproxil fumarate (TDF) decreases bone mineral density (BMD). We hypothesized that vitamin D3 (VITD3) would increase BMD in youth receiving TDF.MethodsThis was a randomized, double-blind, placebo-controlled trial of directly observed VITD3 vs placebo every 4 weeks for 48 weeks in youth aged 16-24 years with HIV, RNA load

BackgroundHIV-infected (HIV-pos) male children/youth showed lower bone mineral density at sexual maturity than HIV-uninfected (HIV-neg) females. It is not known whether complications of HIV disease, including abnormal body fat distribution, contribute to lower bone accrual in male HIV-pos adolescents.MethodsIn a cross-sectional study, we evaluated the relationship between body composition (fat and lean mass) and bone mass in HIV-pos and HIV-neg children/youth and determined if it is modified by HIV status and sex. We used generalized estimating equations to simultaneously model the effect of fat/lean mass on multiple bone outcomes, including total body bone mineral density and bone mineral content and spine bone mineral density. We evaluated effect modification by HIV and sex.ResultsThe analysis cohort consisted of 143 HIV-neg and 236 HIV-pos, of whom 55% were black non-Hispanic and 53% were male. Ages ranged from 7 to < 25 years. Half of the children/youth were at Tanner stage 1 and 20% at Tanner 5. Fat mass was more strongly positively correlated with bone mass in HIV-neg than HIV-pos children/youth and these relationships were more evident for total body bone than spine outcomes. Within HIV strata, fat mass and bone were more correlated in female than male children/youth. The relationship between lean mass and bone varied by sex, but not by HIV status.ConclusionsHIV disease diminishes the positive relationship of greater fat mass on bone mass in children/youth. Disruptions in body fat distribution, which are common in HIV disease, may have an impact on bone accretion during pubertal development.

ImportanceAdolescents represent a key population for implementing preexposure prophylaxis (PrEP) interventions worldwide, yet tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) for PrEP is only licensed for adults.ObjectiveTo examine the safety of and adherence to PrEP along with changes in sexual risk behavior among adolescent men who have sex with men (MSM).Design, setting, and participantsAdolescent Medicine Trials Network for HIV/AIDS Interventions 113 (Project PrEPare) was a PrEP demonstration project that evaluated the safety, tolerability, and acceptability of TDF/FTC and patterns of use, rates of adherence, and patterns of sexual risk behavior among healthy young MSM aged 15 to 17 years. Participants were recruited from adolescent medicine clinics and their community partners in 6 US cities, had negative test results for human immunodeficiency virus (HIV) but were at high risk for acquiring an infection, and were willing to participate in a behavioral intervention and accept TDF/FTC as PrEP.ExposuresAll participants completed an individualized evidence-based behavioral intervention and were provided with daily TDF/FTC as PrEP for 48 weeks.Main outcomes and measuresThe main objectives were to: (1) provide additional safety data regarding TDF/FTC use among young MSM who had negative test results for HIV; (2) examine the acceptability, patterns of use, rates of adherence, and measured levels of tenofovir diphosphate in dried blood spots; and (3) examine patterns of risk behavior when young MSM were provided with a behavioral intervention in conjunction with open-label TDF/FTC.ResultsAmong 2864 individuals screened (from August 2013 to September 2014), 260 were eligible and 78 were enrolled (mean [SD] age, 16.5 [0.73] years), of whom 2 (3%) were Asian/Pacific Islander, 23 (29%) were black/African American, 11 (14%) were white, 16 (21%) were white Hispanic, and 26 (33%) were other/mixed race/ethnicity. Over 48 weeks of PrEP use, 23 sexually transmitted infections were diagnosed in 12 participants. The HIV seroconversion rate was 6.4 (95% CI: 1.3-18.7) per 100 person-years. Tenofovir diphosphate levels consistent with a high degree of anti-HIV protection (>700 fmol/punch) were found in 42 (54%), 37 (47%), 38 (49%), 22 (28%), 13 (17%), and 17 (22%) participants at weeks 4, 8, 12, 24, 36, and 48, respectively.Conclusions and relevanceAdolescent Medicine Trials Network for HIV/AIDS Interventions 113 enrolled a diverse sample of adolescent MSM at risk for HIV who consented to study participation. Approximately half achieved protective drug levels during the monthly visits, but adherence decreased with quarterly visits. Youth may need additional contact with clinical staff members to maintain high adherence.Trial registrationclinicaltrials.gov Identifier: NCT01769456.

BackgroundOral tenofovir disoproxil fumarate (TDF) for HIV prevention and treatment is associated with decreases in bone mineral density (BMD). Previous reports suggest that these changes may be reversible after discontinuation of TDF.SettingA metabolic substudy of 498 participants in a randomized, placebo-controlled HIV prevention trial of oral coformulated TDF with emtricitabine (TDF/FTC, Truvada) for HIV pre-exposure prophylaxis (PrEP) enrolling a global sample of men who have sex with men and trans women.MethodsParticipants underwent dual X-ray absorptiometry to quantify bone mineral density (BMD) in the hip and spine during PrEP and at 2 visits after stopping (median of 23 and 79 weeks post-PrEP, respectively). Results are stratified by pharmacologic measure of TDF/FTC adherence.ResultsThere was no significant difference in change in hip/spine BMD at any time point between placebo and those with low adherence. Adherent participants had a mean (standard error) BMD change at TDF/FTC discontinuation of -1.02% (0.24) in the hip and -1.84% (0.36) in the spine. After stop, annualized BMD increases of 1.13% per year (0.27) in hip and 1.81% per year (0.36) in spine BMD were observed in adherent participants compared with 0.19% (0.16) and 0.74% (0.21) in the placebo group, respectively (P = 0.003, both comparisons). On average, BMD returned to baseline levels by 1 year after PrEP stop. Recovery was consistent across age, baseline BMD z-score, and treatment duration.ConclusionsMean BMD returns to baseline levels within 12-18 months after TDF-based PrEP discontinuation in both hip and spine with consistency across participant subgroups.Clinical trials registrationclinicaltrials.gov NCT00458393.

Background & aimsConsumption of sugar is associated with obesity, type 2 diabetes mellitus, nonalcoholic fatty liver disease, and cardiovascular disease. The conversion of fructose to fat in liver (de novo lipogenesis [DNL]) may be a modifiable pathogenetic pathway. We determined the effect of 9 days of isocaloric fructose restriction on DNL, liver fat, visceral fat (VAT), subcutaneous fat, and insulin kinetics in obese Latino and African American children with habitual high sugar consumption (fructose intake >50 g/d).MethodsChildren (9-18 years old; n = 41) had all meals provided for 9 days with the same energy and macronutrient composition as their standard diet, but with starch substituted for sugar, yielding a final fructose content of 4% of total kilocalories. Metabolic assessments were performed before and after fructose restriction. Liver fat, VAT, and subcutaneous fat were determined by magnetic resonance spectroscopy and imaging. The fractional DNL area under the curve value was measured using stable isotope tracers and gas chromatography/mass spectrometry. Insulin kinetics were calculated from oral glucose tolerance tests. Paired analyses compared change from day 0 to day 10 within each child.ResultsCompared with baseline, on day 10, liver fat decreased from a median of 7.2% (interquartile range [IQR], 2.5%-14.8%) to 3.8% (IQR, 1.7%-15.5%) (P < .001) and VAT decreased from 123 cm3 (IQR, 85-145 cm3) to 110 cm3 (IQR, 84-134 cm3) (P < .001). The DNL area under the curve decreased from 68% (IQR, 46%-83%) to 26% (IQR, 16%-37%) (P < .001). Insulin kinetics improved (P < .001). These changes occurred irrespective of baseline liver fat.ConclusionsShort-term (9 days) isocaloric fructose restriction decreased liver fat, VAT, and DNL, and improved insulin kinetics in children with obesity. These findings support efforts to reduce sugar consumption. ClinicalTrials.gov Number: NCT01200043.

BackgroundWe aimed to define the relative importance of renal and endocrine changes in tenofovir disoproxil fumarate (TDF)-related bone toxicity.MethodsIn a study of daily TDF/emtricitabine (FTC) preexposure prophylaxis (PrEP) in human immunodeficiency virus (HIV)-uninfected young men who have sex with men, we measured changes from baseline in blood and urine markers of the parathyroid hormone (PTH)-vitamin D-fibroblast growth factor 23 (FGF23) axis, creatinine, and renal tubular reabsorption of phosphate (TRP). We explored the relationship of those variables to changes in bone mineral density (BMD). Tenofovir-diphosphate (TFV-DP) in red blood cells was used to categorize participants into high and low drug exposure groups.ResultsThere were 101 participants, median age 20 years (range 15 to 22). Compared with low drug exposure, high-exposure participants showed increase from baseline in PTH and decline in FGF23 by study week 4, with no differences in creatinine, phosphate, or TRP. At 48 weeks, the median (interquartile range) percent decline in total hip BMD was greater in those with high- compared to low- exposure (-1.59 [2.77] vs +1.54 [3.34] %, respectively; P = .001); in high-exposure participants, this correlated with week 4 TFV-DP (inversely; r = -0.60, P = .002) and FGF23 (directly; r = 0.42; P = .039) but not other variables.ConclusionsThese findings support the short-term renal safety of TDF/FTC PrEP in HIV-seronegative young men and suggest that endocrine disruption (PTH-FGF23) is a primary contributor to TDF-associated BMD decline in this age group.Clinical trials registrationNCT01769469.

BackgroundYoung men who have sex with men (YMSM) are a key population for implementation of preexposure prophylaxis (PrEP) interventions. This open-label study examined adherence to PrEP and assessed sexual behavior among a diverse sample of YMSM in 12 US cities.MethodsEligible participants were 18- to 22-year-old HIV-uninfected MSM who reported HIV transmission risk behavior in the previous 6 months. Participants were provided daily tenofovir disoproxil fumarate/emtricitabine (Truvada). Study visits occurred at baseline, monthly through week 12, and then quarterly through week 48. Dried blood spots were serially collected for the quantification of tenofovir diphosphate (TFV-DP).ResultsBetween March and September 2013, 2186 individuals were approached and 400 were found to be preliminarily eligible. Of those 400, 277 were scheduled for an in-person screening visit and 200 were enrolled (mean age = 20.2; 54.5% black, 26.5% Latino). Diagnosis of sexually transmitted infections, including urethral and rectal chlamydial/gonococcal infection and syphilis, at baseline was 22% and remained high across visits. At week 4, 56% of participants had TFV-DP levels consistent with ≥4 pills per week. By week 48, 34% of participants had TFV-DP levels consistent with ≥4 pills per week, with a noticeable drop-off occurring at week 24. Four HIV seroconversions occurred on study (3.29/100 person-years). Condomless sex was reported by >80% of participants, and condomless anal sex with last partner was associated with higher TFV-DP levels.ConclusionsAcceptability of PrEP was high, and most participants achieved protective drug levels during monthly visits. As visit frequency decreased, so did adherence. YMSM in the United States may need PrEP access in youth-friendly settings with tailored adherence support and potentially augmented visit schedules.

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism.  Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men.  Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily.  Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Background and aimsDietary fructose may play a role in the pathogenesis of metabolic syndrome (MetS). In a recently published study of obese children with MetS, we showed that isocaloric fructose restriction reduced fasting triglyceride (TG) and LDL-cholesterol (LDL-C). In these ancillary analyses, we tested the hypothesis that these effects were also accompanied by improved quantitative and qualitative changes in LDL and HDL subclasses and their apolipoproteins; as well as change in VLDL, particularly apoC-III.MethodsObese children with MetS (n = 37) consumed a diet that matched self-reported macronutrient composition for nine days, with the exception that dietary fructose was reduced from 11.7 ± 4.0% to 3.8 ± 0.5% of daily calories and substituted with glucose (in starch). Participants underwent fasting biochemical analyses on Days 0 and 10. HDL and LDL subclasses were analyzed using the Lipoprint HDL and LDL subfraction analysis systems from Quantimetrix.ResultsSignificant reductions in apoB (78 ± 24 vs. 66 ± 24 mg/dl) apoC-III (8.7 ± 3.5 vs. 6.5 ± 2.6 mg/dl) and apoE (4.6 ± 2.3 vs. 3.6 ± 1.1 mg/dl), all p

Accumulating evidence suggests that rates of low bone mass are greater in HIV-infected males than females. Of 11 biomarkers assessed by sex and HIV-status, HIV-infected males had increased levels of soluble CD14 which inversely correlated with bone mineral content and bone mineral density measures, suggesting macrophage activation as a possible mechanism of differential bone loss.

Accumulating evidence suggests that rates of low bone mass are greater in HIV-infected males than females. Of 11 biomarkers assessed by sex and HIV-status, HIV-infected males had increased levels of soluble CD14 which inversely correlated with bone mineral content and bone mineral density measures, suggesting macrophage activation as a possible mechanism of differential bone loss.

ObjectiveDietary fructose is implicated in metabolic syndrome, but intervention studies are confounded by positive caloric balance, changes in adiposity, or artifactually high amounts. This study determined whether isocaloric substitution of starch for sugar would improve metabolic parameters in Latino (n = 27) and African-American (n = 16) children with obesity and metabolic syndrome.MethodsParticipants consumed a diet for 9 days to deliver comparable percentages of protein, fat, and carbohydrate as their self-reported diet; however, dietary sugar was reduced from 28% to 10% and substituted with starch. Participants recorded daily weights, with calories adjusted for weight maintenance. Participants underwent dual-energy X-ray absorptiometry and oral glucose tolerance testing on Days 0 and 10. Biochemical analyses were controlled for weight change by repeated measures ANCOVA.ResultsReductions in diastolic blood pressure (-5 mmHg; P = 0.002), lactate (-0.3 mmol/L; P

BackgroundDaily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women.MethodsDual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF.ResultsIn 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, -0.91% [95% confidence interval {CI}, -1.44% to -.38%]; P = .001) and hip (-0.61% [95% CI, -.96% to -.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged -1.42% ± 29% and -0.85% ± 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD.ConclusionsIn HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter.Clinical trials registrationNCT00458393.

BackgroundTenofovir (TDF) is associated with phosphaturia and elevated 1,25 dihydroxy vitamin D (1,25-OH(2)D). Fibroblast growth factor 23 (FGF23) causes phosphaturia and increases in response to elevated 1,25-OH(2)D. Vitamin D-binding protein (VDBP) binds to 1,25-OH(2)D, decreasing its biological activity, and is elevated in individuals with higher plasma tenofovir concentrations. We compared FGF23 and VDBP before and after vitamin D3 (VITD) supplementation in youths treated with combination antiretroviral therapy (cART) containing or not containing TDF.MethodsA randomized controlled trial in HIV-positive youths aged 18-25 years enrolled participants based on cART treatment with TDF (TDF; n=118) or without TDF (no-TDF; n=85), and randomized within those groups to VITD (50,000 IU every 4 weeks) or placebo (PL). We measured FGF23 and VDBP and calculated free 1,25-OH(2)D at baseline and week 12, and compared changes by TDF treatment and VITD randomized group.ResultsAt baseline, serum FGF23 concentration showed a quadratic relationship with 1,25-OH(2)D most pronounced in the TDF group. At week 12, total and free 1,25-OH(2)D increased in the VITD but not PL groups, independent of TDF use. FGF23 increased in the TDF group receiving VITD, but there was no FGF23 change in the no-TDF group receiving VITD or the PL groups. The adjusted mean change in FGF23 from baseline to week 12 was 7.7 pg/ml in the TDF/VITD group, compared with -1.7 (no-TDF/VITD, P=0.010), -1.3 (TDF/PL, P=0.006) and 1.1 (no-TDF/PL, P=0.035).ConclusionsThese results suggest that TDF-containing cART may alter the FGF23 response to vitamin D supplementation in HIV-infected youths. Clinical trials number: NCT00490412.

ObjectiveTenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.Design and methodsThe Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft-Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.ResultsThere was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: -2.4 vs. -1.1 ml/min; P=0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P=0.02), and resolved after stopping pre-exposure prophylaxis (mean change: -0.1 vs. 0.0 ml/min; P=0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.ConclusionsIn HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.

Objective: Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons. Design and methods: The Iniciativa Profilaxis Pre-Exposición (iP

BackgroundChanges in the multiple mechanisms that regulate glucose metabolism after gastric bypass (RYGB) are still being unveiled. The objective of this study was to compare the changes of glucose and pancreatic hormones [C-peptide, glucagon, and pancreatic polypeptide (PP)] during a meal tolerance test (MTT) and steady-state insulin and free fatty acid (FFA) concentrations during euglycemic-hyperinsulinemic clamp 14 days and 6 months after RYGB in morbidly obese nondiabetic patients.MethodsTwo groups were studied at baseline and at 14 days: the RYGB followed by caloric restriction group (RYGB, n = 12) and the equivalent caloric restriction alone group (Diet, n = 10), to control for energy intake and weight loss. The RYGB group was studied again at 6 months to assess the changes after substantial weight loss. During MTT, the early and overall changes in glucose and pancreatic hormone concentrations were determined, and during the clamp, steady-state insulin and FFA concentrations were assessed.ResultsAfter 14 days, RYGB patients had enhanced postprandial glucose, C-peptide, and glucagon responses, and decreased postprandial PP concentrations. Steady-state insulin concentrations were decreased at 14 days only in RYGB patients, and FFA increased in both groups. Six months after RYGB and substantial weight loss, the decrease in insulin concentrations during clamp persisted, and there were further changes in postprandial glucose and glucagon responses. FFA concentrations during clamp were significantly lower at 6 months, relative to presurgical values.ConclusionsIn morbidly obese nondiabetic patients, RYGB produces early changes in postmeal glucose, C-peptide, glucagon, and PP responses, and it appears to enhance insulin clearance early after RYGB and improve insulin sensitivity in adipose tissue at 6 months postsurgery. The early changes cannot be explained by caloric restriction alone.

We conducted cross-sectional, multicenter studies in HIV-positive young women and men to assess metabolic and morphologic complications from tobacco smoking in 372 behaviorally infected HIV-positive youth, aged 14-25 years. Measurements included self-repor

Background: The COVID‐19 pandemic and response changed clinical service delivery and practice for speech and language therapists (SLTs) in the United Kingdom. SLTs work with children with neurodisability regarding both difficulties with their communication and eating and drinking skills (oropharyngeal dysphagia). This survey aimed to specifically explore the impact of the COVID‐19 pandemic on SLT practice for school‐aged children with dysphagia. Methods: UK‐based SLTs working with school‐aged children with neurodisability and oropharyngeal dysphagia were recruited to share their perceptions on the impact of COVID‐19 on practice. Four questions focusing on COVID‐19 impact were part of a larger online survey exploring SLT clinical practice regarding mealtime management of children with neurodisability and oropharyngeal dysphagia, which included demographic information, service delivery, assessment and intervention practices. COVID‐19 impact questions were a mixture of multiple choice and free text responses. The survey was disseminated using professional networks and social media, between 14 May and 30 July 2021. Data were analysed using descriptive statistics and qualitative content analysis. Results: One hundred and two participants answered at least one of the four COVID‐19 questions. Eighty‐two per cent of SLTs either agreed or strongly agreed that COVID‐19 impacted on service delivery to children and families. Negative impacts on service delivery included school absences/closures, home visiting restrictions, families declining input and/or having barriers to telehealth use and the impact of mask wearing on interactions. Positive impacts included increased telehealth access and skills, increased contact with families and focus on children's eating and drinking function within the home environment. Participants aimed to maintain the increased contact with families alongside a hybrid service delivery approach of in‐person and virtual appointments. Conclusions: This survey provides novel information capturing SLT practice change across two waves of COVID‐19 and return to in‐person practice for UK children with neurodisability. [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to characterize Medicare reimbursement trends for laryngology procedures over the last two decades. Methods: This analysis used CMS' Physician Fee Schedule (PFS) Look‐Up Tool to determine the reimbursement rate of 48 common laryngology procedures, which were divided into four groups based on their practice setting and clinical use: office‐based, airway, voice disorders, and dysphagia. The PFS reports the physician service reimbursement for "facilities" and global reimbursement for "non‐facilities". The annual reimbursement rate for each procedure was averaged across all localities and adjusted for inflation. The compound annual growth rate (CAGR) of each procedure's reimbursement was determined, and a weighted average of the CAGR for each group of procedures was calculated using each procedure's 2020 Medicare Part B utilization. Results: Reimbursement for laryngology procedure (CPT) codes has declined over the last two decades. In facilities, the weighted average CAGR for office‐based procedures was −2.0%, for airway procedures was −2.2%, for voice disorders procedures was −1.4%, and for dysphagia procedures was −1.7%. In non‐facilities, the weighted average CAGR for office‐based procedures was −0.9%. The procedures in the other procedure groups did not have a corresponding non‐facility reimbursement rate. Conclusion: Like other otolaryngology subspecialties, inflation‐adjusted reimbursements for common laryngology procedures have decreased substantially over the past two decades. Because of the large number of physician participants and patient enrollees in the Medicare programs, increased awareness and further research into the implications of these trends on patient care is necessary to ensure quality in the delivery of laryngology care. Level of Evidence: NA Laryngoscope, 134:247–256, 2024 [ABSTRACT FROM AUTHOR]