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Currently, there is limited knowledge regarding occupational exposure of traditional and emerging organophosphate esters (OPEs) from e-waste and automobile dismantling activities, and their distribution within the human blood. In the present study, we collected dust and urine samples from e-waste (ED) (n = 91 and 130, respectively) and automobile dismantling (AD) plants (n = 93 and 94, respectively), as well as serum-plasma-whole blood samples (sets from 128 participants) within ED areas for analyzing traditional and emerging organophosphate tri-esters (tri-OPEs) and organophosphate di-esters (di-OPEs). Median concentration of ∑tri-OPEs and ∑di-OPEs in dust (37,400 and 9,000 ng/g in ED, and 27,000 and 14,700 ng/g in AD areas, respectively) and urine samples (11.8 and 21.9 ng/mL in ED areas, and 17.2 and 15.0 ng/mL in AD areas, respectively) indicated that both e-waste and automobile dismantling activities served as important pollution source for OPEs. Dust ingestion has been evidenced to be the main exposure pathway compared to dermal absorption and inhalation. The median concentration (ng/mL) of OPEs in blood matrices descended order as follow: whole blood (13.1) > serum (11.6) > plasma (10.4) for ∑tri-OPEs, and plasma (3.51) > serum (0.36) > whole blood (0.23) for ∑di-OPEs. Concentration ratios of OPEs varied across blood matrices, depending on the compounds, suggesting that the essentiality of appropriate biomonitoring matrix for conducting comprehensive exposure assessments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: QUANTI-TAF aimed to establish tenofovir-diphosphate (TFV-DP)/emtricitabine-triphosphate (FTC-TP) adherence benchmarks in dried blood spots (DBS) for persons with human immunodeficiency virus (PWH) receiving tenofovir alafenamide/emtricitabine (TAF/FTC)-based antiretroviral therapy (ART)., Methods: For 16 weeks, PWH received TAF/FTC-based ART co-encapsulated with an ingestible sensor to directly measure cumulative (enrollment to final visit) and 10-day adherence. At monthly visits, intraerythrocytic concentrations of TFV-DP and FTC-TP in DBS were quantified and summarized at steady-state (week 12 or 16) as median (interquartile range). Linear mixed-effects models evaluated factors associated with TFV-DP/FTC-TP., Results: Eighty-four participants (11% female, 4% transgender) predominantly receiving bictegravir/TAF/FTC (73%) were enrolled. Ninety-two percent completed week 12 or 16 (94% unboosted ART). TFV-DP for <85% (7/72), 85%-<95% (9/72), and ≥95% (56/72) cumulative adherence was 2696 (2039-4108), 3117 (2332-3339), and 3344 (2605-4293) fmol/punches. Adjusting for cumulative adherence, TFV-DP was higher with boosted ART, lower body mass index, and in non-Black participants. FTC-TP for <85% (14/77), 85%-<95% (6/77), and ≥95% (57/77) 10-day adherence was 3.52 (2.64-4.48), 4.58 (4.39-5.06), and 4.96 (4.21-6.26) pmol/punches. All participants with ≥85% cumulative and 10-day adherence had TFV-DP ≥1800 fmol/punches and FTC-TP ≥2.5 pmol/punches, respectively. Low-level viremia (HIV-1 RNA 20-199 copies/mL) occurred at 18% of visits in 39% of participants with similar TFV-DP (3177 [2494-4149] fmol/punches) compared with suppressed visits (3279 [2580-4407] fmol/punches)., Conclusions: TFV-DP ≥1800 fmol/punches and FTC-TP ≥2.5 pmol/punches represent DBS benchmarks for ≥85% adherence to unboosted TAF/FTC-based ART. Among PWH with high adherence, low-level viremia was common., Clinical Trials Registration: NCT04065347., Competing Interests: Potential conflicts of interest. J. R. C.-M. is an employee of ViiV Healthcare and has received research support from Gilead Sciences, paid to his institution. P. L. A. has received consulting fees from Gilead Sciences, Merck, and ViiV Healthcare and research support from Gilead Sciences, paid to his institution. K. M. B. has received consulting fees from ViiV Healthcare. J. J. K. is an employee of Merck. S. C. M. has received research support from Gilead Sciences, paid to her institution. P. E. A., T. C. C., and D. E. B. are employees of etectRx. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Aims: Many transgender and gender diverse (TGD) individuals have expressed concerns about the potential for oral pre-exposure prophylaxis to affect hormonal concentrations achieved from taking gender-affirming hormone therapy (GAHT). The purpose of this study was to understand the bidirectional effects between hormone and intraerythrocytic tenofovir diphosphate concentrations when switching from tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) to tenofovir alafenamide/emtricitabine (TAF/FTC) in TGD users/nonusers of GAHT., Methods: The study evaluated stored blood samples and dried blood spot cards from TGD adults without HIV who took ≥12 weeks of TDF/FTC and then switched to ≥12 weeks of TAF/FTC for pre-exposure prophylaxis., Results: Thirty-nine individuals met the study inclusion criteria. Regardless of sex assigned at birth and the use of GAHT, there were no significant differences in hormone concentrations when individuals taking GAHT were taking TDF/FTC and then switched to TAF/FTC. Further, there was no significant difference in intraerythrocytic tenofovir diphosphate concentrations between users and nonusers of GAHT., Conclusion: There are no bidirectional effects between hormone and intraerythocytic tenofovir diphosphate concentrations when switching from TDF/FTC to TAF/FTC in TGD users/nonusers of GAHT., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Few studies have considered household interventions for reducing endocrine disrupting chemical (EDC) exposures. We conducted a secondary analysis of a randomized controlled trial, originally designed to reduce lead exposure, to evaluate if the intervention lowered EDC exposures in young children. Study participants were children from the Cincinnati, Ohio area (n = 250, HOME Study). Prenatally, families received a housing intervention that included paint stabilization and dust mitigation, or as a control, injury prevention measures. At 24-months, we measured organophosphate esters (OPEs) and phthalates or their metabolites in dust and urine. We measured perfluoroalkyl substances (PFAS) in dust and serum at 24- and 36-months, respectively. We assessed associations between dust and biomarker EDCs using Spearman correlations, characterized EDC mixtures via principal components analysis, and investigated treatment effects using linear regression. To mitigate selection bias, we fit statistical models using inverse probability of retention weights. Correlations between dust EDCs and analogous biomarkers were weak-to-moderate (ρ's ≤ 0.3). The intervention was associated with 23 % (95 % CI: -38, -3) lower urinary DEHP metabolites and, in a per-protocol analysis, 34 % lower (95 % CI: -55, -2) urinary MBZP. Additionally, among Black or African American children, the intervention was associated with lower serum concentrations of several PFAS (e.g., -42 %; 95 % CI: -63, -8 for PFNA). Household interventions that include paint stabilization and dust mitigation may reduce childhood exposures to some phthalates and PFAS in Blacks/African Americans. These findings highlight the need for larger studies with tailored and sustained housing interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The ability of organophosphate pesticides to disturb immune function has been demonstrated by in vivo and in vitro studies, but evidence of such effects on humans remains scarce. To assess the association between organophosphate pesticides exposure and cytokine levels in Mexican flower workers, a cross-sectional study was carried out. A questionnaire was provided to 121 male flower workers, and urine and blood samples were collected. Using gas chromatography, urinary concentrations of dialkylphosphate metabolites were determined. The serum cytokine levels, IL-4, IL-5, IL-6, IL-8, and IL-10, were measured using multiplex analysis, and levels of INF-γ and TNF-α by ELISA. We found that a higher dialkylphosphate concentration decreased the pro-inflammatory cytokines INF-γ (β = -0.63; 95 % CI: -1.22, -0.05), TNF-α (β= -1.18; 95 % CI: -2.38, 0.02), and IL-6 (β= -0.59; 95 % CI: -1.29, 0.12), and increased IL-10 (β=0.56; 95 % CI: 0.02, 1.09), the main anti-inflammatory cytokine, suggesting an imbalance of the immune response in flower workers., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Objectives: We measured the intracellular concentrations of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in dried blood spots (DBS) for pre-exposure prophylaxis (PrEP) adherence using sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS)., Methods: A total of 191 DBS were obtained from 85 participants who were receiving tenofovir disoproxil fumarate (TDF; 300 mg) and emtricitabine (FTC; 200 mg) as PrEP at the Sexual Health Clinic, National Center for Global Health and Medicine, Tokyo, Japan. DBS punch (3 mm) added to 25 μL of 50% methanol and 400 μL of internal standard solution was used for solid phase extraction. Chromatographic separation was achieved on an Atlantis Premier BEH C18 AX Column (50 mm × 2.1 mm i.d.; particle size 1.7 μm) using gradient elution (flow rate: 0.6 mL/min); injection volume: 7 μL and run time: 5.5 min. Calibration curves for the two drugs were linear in the range 0.05-12.5 ng/punch., Results: We determined the intracellular TFV-DP and FTC-TP concentrations in 191 DBS obtained from 85 patients administered with TDF and FTC as PrEP. The analytical performance data (calibration curve and QC samples) for all the analytical runs met the acceptance criteria. Intracellular concentrations of TFV-DP and FTC-TP in the DBS remained stable for at least 24 h after oral administration., Conclusions: A multiplex LC-MS/MS method was successfully developed for DBS, which can be useful for monitoring the levels of TFV-DP and FTC-TP in individuals receiving PrEP., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Organophosphate esters (OPEs) are widely used as flame retardants and plasticizers, which are of growing concern due to their endocrine-disrupting effects, developmental toxicity, and potential carcinogenicity. However, data on human exposure to OPEs is still scarce. In this study, a relatively simple and efficient method with less serum consumption for the detection of OPEs in human serum was developed and validated. Nine OPEs in 200 μL of human serum were extracted by an acetonitrile-formic acid system and analyzed using ultra-high-performance liquid chromatography-quadrupole tandem time-of-flight high-resolution mass spectrometry. Several experiments were conducted to optimize the chromatographic and mass spectrometric conditions as well as sample preparation to obtain a more sensitive and efficient analytical protocol. The proposed method was examined in terms of its linearity, accuracy, precision, detection limit, and matrix effect. The matrix-spiked recoveries of the target OPEs ranged from 83.3% to 111.1%, with relative standard deviations between 2.7% and 16.6%. The detection limits were within (0.002 to 0.029) ng mL -1 , while the quantification limits were within (0.007 to 0.098) ng mL -1 . The internal standard-corrected matrix effects varied from 82.7% to 113.9%. Finally, the method was applied to detect OPEs in actual human serum samples. All nine OPEs were detected in 269 serum samples to varying degrees, with the average concentrations ranging from (0.08 to 1.77) ng mL -1 . After validation, the method was found to be simple in pretreatment, high in sensitivity, good in practicality, and suitable for exposure evaluation of OPEs in populations.

Organophosphate flame retardants (OPFRs) are extensively used as flame retardants and plasticizers, but their endocrine disrupting potentials have raised concerns. However, the impacts of OPFR exposures on reproductive and thyroid hormones in females remains unclear. In this study, serum concentrations of OPFRs were investigated, and levels of reproductive and thyroid hormones, including follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, anti-Müllerian hormone, prolactin (PRL), testosterone (T), and thyroid stimulating hormone, were analyzed in childbearing-age females undergoing in-vitro fertilization treatment from Tianjin, a coastal city in China (n = 319). Tris (2-chloroethyl) phosphate (TCEP) was the predominant OPFR, with a median concentration of 0.33 ng/mL and a detection frequency of 96.6%. In the whole population, tris(1,3-dichloro-2-propyl) phosphate (TDCIPP) and tris(2-chloroisopropyl) phosphate (TCIPP) were positively associated with T (p < 0.05), while triethyl phosphate (TEP) was negatively associated with LH (p < 0.05) and LH/FSH (p < 0.01). Particularly, TCIPP was negatively associated with PRL in the younger subgroup (age≤30, p < 0.05). Moreover, TCIPP was negatively associated with diagnostic antral follicle counting (AFC) in the mediation analysis by a dominating direct effect (p < 0.01). In conclusion, serum levels of OPFRs were significantly associated with reproductive and thyroid hormone levels and a risk of decreased ovarian reserve in childbearing-age females, with age and body mass index being significant influencing factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Nutritional status plays a major role in determining the possible adverse health outcomes due to pesticide toxicity. The objective of the present study was to assess the organophosphorus pesticide residue levels among farm women (FW) (24-45years) and farm children (FC) (9-12 and 13-15years) belonging to the Rangareddy district (Telangana, India) along with their micronutrient status, inhibition of acetylcholinesterase activity, and oxidative stress levels. Residues of Chlorpyrifos, Diazinon, Malathion, Monocrotophos and Phosalone were found in the serum samples of FW and FC along with significantly low levels of vitamins and minerals. Inhibition of AChE activity was observed in FW and FC and altered oxidative stress parameters among FW. Correlation studies have found significant associations between the pesticide residues, micronutrients and antioxidant enzymes. The study suggests an association between pesticide exposure coupled with micronutrient deficiency, induced AChE inhibition, and oxidative stress.

In analogy to the fluoride-induced regeneration of butyrylcholinesterase (BChE) inhibited by nerve agents a method was developed and optimized for whole blood samples. Compared to the plasma method, regeneration grade was found to be higher for cyclosarin (GF), i-butylsarin from VR, and n-butylsarin from CVX, but lower for sarin (GB), fluorotabun from tabun (GA), and ethylsarin from VX. Regeneration grade of soman (GD) is the same for both matrices because it is released from serum albumin and not from cholinesterases. The method was fully validated for GB and GF to prove selectivity, linearity (n = 6), limit of determination (LOD1), reproducibility (within day (n = 8) and from day to day (n = 8)), effectiveness of extraction, matrix effect, and sample stability (after sample preparation and during three freeze/thaw cycles). The other agents were tested for selectivity, linearity (n = 2), limit of determination, and stability after sample preparation. The method showed high selectivity, good linearity up to the protein's saturation concentration (GB: R 2  = 0.9995, GF: 0.9968), and high reproducibility (GB: C.V. 5.9-13.7%, GF: 4.9-10.3%). The limits of determination (calculated from the spiked amount of the original agent) were found with 0.3 ng/mL VX, 0.5 ng/mL GB, 1 ng/mL VR, 0.5 ng/mL GA, 1 ng/mL CVX, and 8 ng/mL GD. In the case of GF, it was found with 4 ng/mL using Isolute ENV + SPE cartridges as for the other analytes and with 2.5 ng/mL using Isolute C8 EC SPE cartridges instead. This method was then applied to a denatured whole blood sample obtained from an individual exposed to GB. While previously only the GB metabolite isopropyl methylphosphonic acid (IMPA) could be detected in this blood sample it was now possible to successfully release GB from the blood proteins by excess fluoride., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study., Methods and Findings: HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV-negative women ages 16-25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted., Conclusions: In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population., Trial Registration: ClinicalTrials.gov NCT02732730., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: PLA reports grants from NIH, during the conduct of the study; grants and personal fees from Gilead Sciences, outside the submitted work; JMB reports grants from NIH, during the conduct of the study; personal fees from Gilead Science, Janssen, Merck, outside the submitted work; CC reports grants from NIH and has served as a scientific advisor to Merck and Gilead Sciences; JR reports salary from Gilead Sciences, outside the submitted work.

Measurement of organophosphate esters (OPEs) in human body fluids is important for understanding human internal exposure to OPEs and for assessing related health risks. Most of the current studies have focused on the determination of OPE metabolites in human urine, as OPEs are readily metabolized into their diester or hydroxylated forms in the human body. However, given the existence of one metabolite across multiple OPEs or multiple metabolites of one OPE, as well as the low metabolic rates of several OPEs in in vitro studies, the reliability of urinary OPE metabolites as biomarkers for specific OPEs is needs to be treated with caution.Human blood is a matrix that is in contact with all body organs and tissues, and the blood levels of compounds may better represent the doses that reach target tissues. Currently, only a few studies have investigated the occurrence of OPEs in human blood by different analytical methods, and the variety of OPEs considered is limited. In this study, a method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed for the simultaneous determination of 16 OPEs in human blood, and the extraction efficiency of the solid phase extraction (SPE) column for OPEs was verified. To human blood samples, 10 ng of an internal standard was added, followed by mixing and aging for 30 min. The samples were extracted three times with acetonitrile using a shaker, and then purified on ENVI-18 cartridges with acetonitrile containing 25% dichloromethane as the eluent. Finally, the OPEs were analyzed by high performance liquid chromatography-tandem mass spectrometry. After optimization of the analytical column and mobile phases, the analytes were separated on a BEH C18 column (100 mm×2.1 mm, 1.7 μm) by gradient elution using methanol and 5 mmol/L ammonium acetate in water as the mobile phase. Then, the analytes were ionized in electrospray ionization positive (ESI + ) mode and detected in the multiple reaction monitoring (MRM) mode. The mass spectral parameters, including the precursor ion, product ion, declustering potential, entrance potential, and collision cell exit potential, were optimized. The results were quantified by the internal standard method. The limits of detection (LOD, S/N =3) of the OPEs were in the range of 0.0038-0.882 ng/mL. The calibration curves for the 16 OPEs showed good linear relationships in the range of 0.1-50 ng/mL, and the correlation coefficients were >0.995. The extraction efficiency of the ENVI-18 column for the 16 OPEs was validated, and the average recoveries of the target compounds were 54.6%-104%. The average recoveries ( n =3) of 15 OPEs, except trimethyl phosphate (TMP), in whole blood at three spiked levels were in the range of 53.1%-126%, and the relative standard deviations (RSDs) were in the range of 0.15%-12.6%. The average recoveries of six internal standards were in the range of 66.8%-91.6% except for TMP-d9 (39.1%), with RSDs of 3.52%-6.85%. The average matrix effects of the OPEs in whole blood were 56.4%-103.0%. Significant matrix effects were found for resorcinol bis(diphenyl phosphate) (RDP) (75.8%±1.4%), trimethylphenyl phosphate (TMPP) (68.4%±1.0%), 2-ethylhexyl di-phenyl phosphate (EHDPP) (56.4%±12.4%), and bisphenol-A bis(diphenyl phosphate) (BABP) (58.5%±0.4%). However, these effects could be corrected by similar signal suppressions of the corresponding internal standard (TPHP-d15, 77.4%±7.5%). This method is simple, highly sensitive, and suitable for the determination of OPEs in human blood. Fifteen human whole blood samples were collected to quantify the 16 OPEs using the developed method. The total concentrations of the OPEs ranged from 1.50 to 7.99 ng/mL. The detection frequencies of eight OPEs were higher than 50%. Tri-iso-butyl phosphate (TiBP), tri(2-chloroethyl) phosphate (TCEP), and tri(1-chloro-2-propyl) phosphate (TCIPP) were the dominant OPEs, with median concentrations of 0.813, 0.764, and 0.690 ng/mL, respectively. These results indicated widespread human exposure to OPEs, which should be of concern.

Introduction: HIV incidence remains high among African adolescent girls and young women (AGYW), who would benefit from pre-exposure prophylaxis (PrEP). Strategies to increase PrEP adherence and persistence need to be evaluated in African AGY, including incentives conditional on high adherence., Methods: The 3Ps for Prevention Study was a 12-month prospective cohort of 200 women ages 16 to 25 initiating PrEP in South Africa from 2017 to 2018. Participants received retrospective feedback about drug levels at Months 1, 2 and 3; half was randomized to receive a 200 Rand shopping voucher ($13 US) at Months 2, 3 and 4, conditioned on high intracellular tenofovir diphosphate (TFV-DP) levels in dried blood spots (≥500 fmol/punch at Month 1, ≥700 fmol/punch at Months 2 and 3). The primary analysis was intention-to-treat, comparing the proportion with high PrEP adherence (≥700 fmol/punch) at Month 3 by randomized group, based on 100% efficacy among men who have sex with men., Results: Median age of the 200 women was 19 years (interquartile range [IQR] 17, 21); 86% had a primary sexual partner. At Month 3, the mean TFV-DP level was 822 fmol/punch (SD 522) in the incentive group and 689 fmol/punch (SD 546) in the control group (p = 0.11). Forty-five (56%) of 85 women in the incentive group and 35 (41%) of 85 women in the control group had TFV-DP levels ≥700 fmol/punch (RR 1.35; 95% CI 0.98, 1.86; p = 0.067), which declined to 8% and 5% in the incentive and control groups at Month 12 (no significant difference by arm). 44% refilled PrEP without gaps, 14% had a gap of ≥3 weeks in coverage subsequently restarted PrEP and 54% accepted at the final dispensing visit at Month 9. No new HIV infections were observed after PrEP initiation., Conclusions: Among South African AGYW initiating PrEP, drug levels indicated high PrEP adherence in almost half of women at Month 3, with a non-statistically significant higher proportion with high adherence among those in the incentive group. Over half persisted with the 12-month PrEP programme although high adherence declined after Month 3. Strategies to support PrEP adherence and persistence and longer-acting PrEP formulations are needed., (© 2020 The Authors. Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Aims: In last few decades, the prevalence of diabetes and vascular diseases has intensified concurrently with increased use of synthetic chemicals in agriculture. This study is aimed to evaluate the association of co-accumulation of arsenic and organophosphate (OP) insecticides with diabetes and atherosclerosis prevalence in a rural Indian population., Methods: This study included observations from KMCH-NNCD-I (2015) cross-sectional study (n = 865) from an Indian farming village. The participants had assessment of clinical parameters including HbA 1c and carotid intima-media thickness and urinary heavy metals. Serum OP residues were extracted and quantified by GC-MS. Statistical analyses were performed to unravel the co-association of arsenic and OPs on prevalence of diabetes and atherosclerosis., Results: On multivariate regression analyses, total organophosphate level and arsenic accumulation showed association with diabetes and atherosclerosis. Higher odds ratio with significant trends were observed for the sub-quartiles formed by the combination of higher quartiles of arsenic and total organophosphates in association with diabetes and atherosclerosis., Conclusions: We observed evidence of possible synergism between arsenic and OPs in association with prevalence of diabetes, pre-diabetes and atherosclerosis in the study population. Our findings highlight the importance of understanding health effects of mixed exposures and raises vital questions on the role of these agrochemicals in the etiology of diabetes and vascular diseases.

As kinds of endocrine disruptors, organophosphate esters (OPEs) pollution in the environment had received increasing attention recently. Food and water intake were two important exposure pathways for OPEs. However, the studies about the potential association between OPEs and gastrointestinal cancer were limited. This study investigated the possible association between OPEs and gastrointestinal cancer. All cancer patients were diagnosed with gastrointestinal cancer from a Grade 3 A hospital in Wuhan, China, while the control group was non-cancer healthy persons. The results showed that 6 OPEs were found in the control samples, while 8 in the samples from patients with gastrointestinal cancer. The detection frequencies of OPEs in gastrointestinal cancer patients were significantly higher than those in the control group (p < 0.05 or p < 0.01), except for triethyl phosphate (TEP) and tris (methylphenyl) phosphate (TMPP) in the gastric cancer group. The concentrations of OPEs in the control group were significantly lower than those in the gastric cancer group and colorectal cancer group (p < 0.01). In the control group and gastrointestinal cancer group, TEP was the dominant pollutant. Correlation analysis found that concentrations of TEP, tris(2-chloroisopropyl) phosphate (TCIPP), triphenyl phosphate (TPHP), TMPP, tris(2-ethylhexyl) phosphate (TEHP), and 2-ethylhexyl diphenyl phosphate (EHDPP) were associated with gastric cancer (p < 0.01), and concentrations of TEP, TCIPP, TPHP, TMPP and TEHP were associated with colorectal cancer (p < 0.01). A cluster analysis divided the 34 patients with gastric cancer and 40 patients with colorectal cancer in four groups. The results showed that the elderly male patients with gastric cancer were more sensitive to the exposure of EHDPP, while the TEP exposure was more sensitive to the relatively young gastrointestinal cancer patients. These findings indicated that OPEs might play a role in developing gastrointestinal cancer., Competing Interests: Declaration of competing interest The authors declared that they have no conflicts of interest to this work. We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Electronic waste recycling (e-recycling) exposes workers to substances such as flame retardants and metals. Some of them are known or suspected endocrine disruptors that could affect hormonal homeostasis and eventually result in adverse health outcomes. Our aim was to measure biological concentrations of organophosphate ester (OPE) metabolites, polybrominated diphenyl ethers (PBDEs), mercury, lead and cadmium in e-recycling workers, and to explore associations with thyroid and sexual hormones. In a cross-sectional study, end-of-shift blood and urine spot samples were collected from 23 women and 77 men in six e-recycling facilities and one commercial recycling facility. Urinary concentrations of 15 OPE metabolites and mercury, and blood concentrations of 12 PBDE congeners, lead, cadmium, and thyroid (thyroxine [T4], triiodothyronine [T3], thyroid stimulating hormone [TSH]) and sexual (testosterone [T], estradiol, Follicle Stimulating Hormone [FSH], Luteinizing hormone [LH]) hormones were measured. E-recycling workers had higher concentrations of BDE209, all OPE metabolites, and lead than commercial recycling workers. In e-recycling workers, plasma geometric mean concentration of BDE209 was 18 ng/g lipids (geometric standard deviation [GSD]: 2.8) vs.1.7 ng/g lipids (GSD: 2.8) in commercial recycling, and urinary geometric mean concentration of diphenyl phosphate (DPhP), a major metabolite of triphenyl phosphate, was 1.7 ng/ml (GSD: 2.5), vs. 0.95 ng/ml (GSD: 2.0). In men, a two-fold increase in BDE209 was associated with 3.1% (95% Confidence interval: 0.07, 6.1) higher levels of total T4, and a two-fold increase in tert-butyl diphenyl phosphate (tb-DPhP) was associated with 18% (-29, -4.7) lower total T, 18% (-27, -6.9) lower free T and 13% (-25, 0.70) lower free T/estradiol ratio. In women, a two-fold increase in BDE153 was associated with 10% (-17, -3.2) lower free T3. To our knowledge, this is the first study to show associations between OPE metabolites and sex hormones in adults. Although some of our results are not conclusive and need replication, they suggest that prudent avoidance should be applied in risk management of flame retardants., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2019 Elsevier GmbH. All rights reserved.)

Inadequate adherence to chronic medications is a far-reaching problem with financial and human health consequences. By a wide margin, non-adherence is the leading cause of therapeutic failures of HIV pre-exposure chemoprophylaxis (PrEP) and antiretroviral therapy (ART). It has been proven that HIV infection can be prevented by daily dosing of emtricitabine and tenofovir disoproxil fumarate. Measurement of intracellular tenofovir diphosphate in red blood cells has been established as an effective way to assess cumulative adherence, however, the LC-MS-based analytical method developed for the purpose is both complicated and expensive. Here, we report a simple method for adherence monitoring based on direct MS quantification of intracellular tenofovir diphosphate in human whole blood. The method requires only microliters of whole blood, employs special membranes to perform plasma separation and concomitant desalting during blood collection, and uses nanoelectrospray on a triple quadrupole instrument. Quantitative performance in this proof-of-concept study includes RSDs of < 15% and successful analysis of a small number of patient samples with medium to high adherence levels. The results correlate with those of a validated LC-MS/MS method, and an R 2 value of 0.9962 is achieved. This methodology has promise for extension to point-of-care testing using miniature mass spectrometers. Graphical abstract.

Organophosphate esters (OPEs), as a class of emerging flame retardant and plasticizers, have attracted particular attention due to their ubiquitous existence in the environment and potential effects on human health. Here, we investigated the levels of OPEs in human serum and examined the role of demographic variables on the body burden of such compounds. Of 11 OPEs screened, 8 were detected in human serum samples collected from a population (n = 89) in Bohai Bay, North China. The ∑OPE concentrations ranged from 4.7 to 948 ng/g lipid weight (lw), with a median concentration of 243 ng/g lw. Tris(2-chloroethyl)phosphate (TCEP) was identified as the most abundant OPEs with a median concentration of 214 ng/g lw. The concentrations of the triphenyl phosphate (TPhP) in older adults were higher than those in young adults (p < 0.05), and lower concentrations of tri-iso-butyl phosphate (TIBP) were observed in female samples compared to males. Furthermore, significant differences were observed in tri-n-propyl phosphate (TPrP) concentrations between urban and rural residence groups (p < 0.05). This study provides important information on the accumulation potential of OPEs in human bodies and suggests the need for further investigation to understand the potential human health risk.

Mental health (MH) disorders are more prevalent among persons living with HIV compared to the general population, and may contribute to suboptimal adherence to antiretroviral therapy (ART). Tenofovir-diphosphate (TFV-DP), the phosphorylated anabolite of tenofovir (TFV), is a biomarker with a 17-day half-life in red blood cells. TFV-DP can be measured in dried blood spots (DBS) using liquid chromatography/tandem mass spectrometry (LC-MS/MS) to assess adherence and cumulative drug exposure to tenofovir disoproxil fumarate (TDF)-based ART. From a larger clinical cohort (N = 807), TFV-DP concentrations and a paired HIV viral load were available from 521 participants at their enrollment visit. We used multivariable linear regression to evaluate the association between TFV-DP in DBS and engagement in MH care. After adjusting for clinical covariates, participants with MH disorders who were engaged in MH care had 40% higher TFV-DP compared to participants with MH disorders who were not engaged in MH care (p < 0.001), and similar TFV-DP to participants without MH disorders (p = 0.219). Further research is needed to identify the mechanism(s) for these findings, with the goal of optimizing engagement and retention in MH care strategies to improve ART adherence and clinical outcomes in PLWH with MH disorders.

Since organophosphate (OP) triesters are ubiquitous in environmental matrices, there is an increasing concern regarding human exposure to OP triesters or their metabolites. In this study, we measured levels of 16 OP triesters and 4 OP diesters in n = 99 human blood samples of non-occupationally exposed adults (aged 18-87) from Jiangsu Province, eastern China. Based on the measured concentrations, statistical difference and correlativity were calculated to characterize the population diversity and potential sources of OP triester and diester. Di (2-ethylhexyl) phosphate (DEHP) and 2-ethylhexyl diphenyl phosphate (EHDPP) were found in many participants' blood, with median concentrations of 1.2 (range: n.d. - 44.7, detection frequency: 99%) and 0.85 (n.d. - 28.8, 68%) ng mL - 1 , respectively. Blood samples of older participants contained significantly lower concentrations of OP diesters or triesters than their younger counterparts (p < 0.01). Regional- and age-specific differences in the blood concentrations of OP triesters and diesters were attributed to disparities in environmental exposure intensity. EHDPP and tris (phenyl) phosphate (TPHP), the predominant OP triesters, exhibited significant positive correlation (p < 0.01, r = 0.84) suggestive of analogous transport behavior from similar exposure sources to humans. The increased correlations between diphenyl phosphate (DPHP) and TPHP as well as with EHDPP as observed from the multivariate regression suggests that DPHP could be derived from the metabolism of both TPHP (the crucial precursor) and EHDPP. When the blood samples were subsequently screened using high-resolution spectrometry, we detected five novel OP metabolites: glucuronide conjugates of hydroxylated DEHP (OH-DEHP glucuronide conjugate), 2-ethylhexyl monophenyl phosphate (EHMPP), hydroxylated EHMPP (OH-EHMPP), dihydroxylated bis(2-butoxyethyl) phosphate (di-OH-BBOEP), and dihydroxylated tris(butyl) phosphate (di-OH-TNBP). Overall, this study provides novel information regarding the occurrence of OP triesters and diesters, and further suggested several novel OP metabolites in human blood., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Partners Demonstration Project was a prospective, open-label, implementation science-driven study of preexposure prophylaxis (PrEP) among heterosexual HIV serodiscordant couples in Kenya and Uganda. Adherence data were collected using the Medication Event Monitoring System (MEMS), and time of sexual activity was collected using the mobile phone short message service (SMS). Two plasma samples were collected at a single study visit. We integrated adherence, pharmacokinetics, and SMS data using a population pharmacokinetic (PopPK) model to simulate tenofovir plasma concentrations from PrEP at the time of sexual activity. In the first stage of this analysis, we used data from the current study to update a prior PopPK model of tenofovir (TFV) developed with data from the Partners PrEP Study (a phase III clinical trial). The second stage involved simulating plasma concentrations at the time of sexual activity using empirical Bayes estimates (EBEs) derived from the final model. In addition, EBEs from a previously published parent metabolite model of TFV (MTN-001, an open-label 3-way crossover study in healthy women) was used to simulate tenofovir diphosphate (TFV-DP) concentrations. We estimated percent PrEP "coverage" as the number of reported sexual events during which simulated concentrations were above an a priori threshold concentrations associated with a high degree of protection from HIV infection: plasma TFV of >40 ng/ml and peripheral blood mononuclear cell (PBMC) TFV-DP concentration of >36 fmol/million cells. The levels of coverage were 72% for TFV and 81% for TFV-DP. These levels are consistent with a high degree of protection against HIV acquisition in this study of a pragmatic delivery model for antiretroviral-based HIV prevention., (Copyright © 2019 American Society for Microbiology.)

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., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) is an objective long-term adherence measure, but data are limited on its ability to predict virologic suppression (VS) in people on antiretroviral (ARV) treatment. There are also no data comparing DBS TFV-DP with plasma ARV concentrations as predictors of VS., Methods: Women who were on a first-line regimen of tenofovir, emtricitabine, and efavirenz (EFV) were enrolled in a cross-sectional study. Plasma EFV and tenofovir (TFV), DBS TFV-DP assays, and 30-day self-reported adherence were evaluated as predictors of VS (<50 copies/mL) with the area under the curve of receiver operating characteristics and logistic regression., Results: We enrolled 137 women; mean age of 33 years; median 4 years on antiretroviral therapy; 88 (64%) had VS. In receiver operating characteristics analyses: DBS TFV-DP [0.926 (95% CI: 0.876 to 0.976)] had a higher area under the curve than plasma TFV [0.864 (0.797 to 0.932); P = 0.006], whereas plasma EFV [0.903 (0.839-0.967)] was not significantly different from DBS TFV-DP (P = 0.138) or plasma TFV (P = 0.140); all ARV assays performed better than self-report. The association of TFV-DP in DBS with VS strengthened with increasing concentrations [reference <350 fmol/punch: 350-699 fmol/punch aOR 37 (8-178); 700-1249 fmol/punch aOR 47 (13-175); ≥1250 fmol/punch aOR 175 (20-1539)]. "White coat adherence" (defined as DBS TFV-DP <350 fmol/punch with detectable plasma TFV) was only detected in 4 women., Conclusions: Plasma EFV, TFV, and DBS TFV-DP were all strong predictors of VS. EFV or TFV assays have potential for development as point-of-care assays for use as objective adherence measures in resource-limited settings.

Triclofos sodium (TCS) and chloral hydrate (CH) are widely used as sedatives for children, but no analytical method to simultaneously monitor concentrations of blood TCS, CH and their metabolites, trichloroacetic acid (TCA) and trichloroethanol (TCEOH), has been reported. The present study aimed to develop a simple analytical method for TCS and its metabolites (TCA, TCEOH and CH) in small-volume plasma from children. After acidification of specimens, TCS formic acid adduct or the metabolites derivatized using water/sulfuric acid/methanol (6:5:1, v/v) were measured by combined use of liquid chromatography tandem-mass spectrometry and gas chromatography mass-spectrometry. The limits of detection and quantification levels (µg/ml) were 0.10 and 0.29 for TCS, 0.24 and 0.72 for TCA, 0.10 and 0.31 for TCEOH, and 0.25 and 0.76 for CH, respectively. The mean recoveries were 82.8-107% for TCS, 85.4-101% for TCA, 91.6-107% for TCEOH, and 88.9-109% for CH. Within-run and between-run precision (percent of relative standard deviation, %RSD) using this method ranged from 1.1 to 15.7% and 3.6 to 13.5%, respectively, for TCS and all of its metabolites. The calibration curves were obtained with standard spiked plasma, and all of the coefficients of determination were more than 0.975. Subsequently, we applied the present method to plasma taken from five children after sedation induced by CH and TCS. In addition to TCS and CH, elevated TCA and TCEOH concentrations were detected. This new method can be applied for the pharmacokinetic analysis of TCS and its metabolites and the determination of the optimal TCS dosage in children.

Background: Efficacy of HIV pre-exposure prophylaxis (PrEP) among men who have sex with men is well documented in randomized trials. After trial completion, participants are challenged with acquiring PrEP on their own and remaining adherent., Methods: This was a follow-up study of the TAPIR randomized controlled multicenter PrEP trial. Participants were contacted after their last TAPIR visit (ie, after study-provided PrEP was discontinued) to attend observational posttrial visits 24 and 48 weeks later. Adherence during TAPIR and posttrial visits was estimated by dried blood spot intracellular tenofovir diphosphate levels (adequate adherence defined as tenofovir diphosphate levels >719 fmol/punch). Binary logistic regression analysis assessed predictors of completing posttrial visits and PrEP adherence among participants completing ≥1 visit., Results: Of 395 TAPIR participants who were on PrEP as part of the TAPIR trial for a median of 597 days (range 3-757 days), 122 (31%) completed ≥1 posttrial visit (57% of University of California San Diego participants completed posttrial visits, whereas this was 13% or lower for other study sites). Among participants who completed ≥1 posttrial visit, 57% had adequate adherence posttrial. Significant predictors of adequate adherence posttrial were less problematic substance use, higher risk behavior, and adequate adherence in year 1 of TAPIR., Conclusion: More than half of PrEP users followed after trial completion had successfully acquired PrEP and showed adequate adherence. Additional adherence monitoring and intervention measures may be needed for those with low PrEP adherence and problematic substance use during the first year of trial.

Background: Objective adherence metrics for tenofovir (TFV) disoproxil fumarate/emtricitabine (FTC)-based pre-exposure prophylaxis (PrEP) were critical for interpretation of efficacy in PrEP clinical trials, and there is increasing interest in using drug levels to tailor interventions for reengagement and adherence. Point-of-care immunoassays for TFV, which examine short-term adherence, are in development. However, the ability of poor short-term and long-term adherence to predict future PrEP nonretention is unknown., Setting: Secondary data analysis of a large, prospective multi-site U.S. PrEP demonstration project., Methods: An adjusted Cox-proportional hazards model examined the relationship of dried blood spot (DBS) levels of FTC-triphosphate (FTC-TP) or TFV-diphosphate (TFV-DP), measures of short-term and long-term PrEP adherence, respectively, with future study nonretention., Results: Overall, 294 individuals (median age 33 years) contributed drug levels within the U.S. PrEP demonstration project. By the end of study, 27% were lost to follow-up, 25% had at least one undetectable FTC-TP level indicating poor short-term adherence, and 29% had a drug level indicating suboptimal long-term adherence (TFV-DP <700 fmol/punch). The strongest factor associated with future study nonretention using a binary drug-level cut-off was an undetectable DBS FTC-TP level (adjusted hazard ratio 6.3; 95% confidence interval 3.8 to 10.2). The suboptimal long-term adherence based on low DBS TFV-DP levels was also associated with nonretention (adjusted hazard ratio 4.3; 95% confidence interval: 2.4 to 7.6)., Conclusions: Both short- and long-term metrics of PrEP adherence are strongly associated with future loss to follow-up in a U.S. demonstration project study. Short-term metrics of adherence, once available at the point-of-care, could be used to direct real-time tailored retention and adherence interventions.

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., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a strong predictor of viral suppression in persons living with HIV (PLWH). Its association with antiretroviral therapy (ART) resistance remains unknown., Methods: Blood was collected in PLWH receiving TDF-containing ART enrolled in a 48-week study. Tenofovir diphosphate/emtricitabine triphosphate (FTC-TP) were quantified from the same sample as HIV viral load (VL) in PLWH who developed resistance within ≤12 months., Results: The study enrolled 807 participants, of whom 10 had new resistance-conferring mutations. Among these, median (interquartile range) TFV-DP and HIV VL were 956 (407-1510) fmol/punch and 9840 (513-68,200) copies/mL, respectively. Five had quantifiable FTC-TP in DBS. Based on previously published data, a TFV-DP concentration of 956 fmol/punch would have an adjusted odds of virologic suppression of 32.8 versus TFV-DP <350 fmol/punch, making viremia of ∼10,000 copies/mL an unexpected outcome., Conclusion: Moderately high TFV-DP in DBS (700-1249 fmol/punch) in PLWH with high viremia suggest that antiretroviral drug resistance might be present.

Tris(chloropropyl)phosphate (TCPP) is an organophosphorus flame retardant (OPFR) and plasticizer increasingly used in consumer products and as a replacement for brominated flame retardants. Commercially available TCPP is a mixture of four structural isomers the most abundant of which is tris(1-chloro-2-propyl)phosphate (TCPP-1). Although there is a widespread use of TCPP and potential for human exposure, there is limited data on the safety or toxicity of TCPP. The National Toxicology Program is conducting long-term studies to examine the toxicity of the TCPP in rats after lifetime exposure, including perinatal oral exposure. Quantitative estimates of internal dose are essential to interpret toxicological findings in rodents. To aid in this, a method was fully validated to quantitate the most abundant isomer, TCPP-1, in female Harlan Sprague Dawley (HSD) rat and B6C3F1 mouse plasma with partial validation in male rat plasma, and male and female mouse plasma. The method used protein precipitation using trichloroacetic acid followed by the extraction with toluene, and analysis by gas chromatography with flame photometric detection. The performance of the method was evaluated over 5-70 ng TCPP-1/mL plasma. The method was linear (r ≥ 0.99), accurate (inter-day relative error: ≤ ± -7.2) and precise (inter-batch relative standard deviation: ≤27.5%). The validated method has lower limits of quantitation and detection of ~5 and 0.9 ng/mL, respectively, in female HSD rat plasma and can be used on samples as small as 50 μL demonstrating the applicability to plasma samples from toxicology studies.

Pre-exposure prophylaxis (PrEP) with antiretroviral (ARV) drugs are effective at preventing human immunodeficiency virus (HIV) transmission. However, implementation of PrEP presents significant challenges due to poor user adherence, low accessibility to ARVs and multiple routes of HIV exposure. To address these challenges, we developed the nanochannel delivery implant (NDI), a subcutaneously implantable device for sustained and constant delivery of tenofovir alafenamide (TAF) and emtricitabine (FTC) for HIV PrEP. Unlike existing drug delivery platforms with finite depots, the NDI incorporates ports allowing for transcutaneous refilling upon drug exhaustion. NDI-mediated drug delivery in rhesus macaques resulted in sustained release of both TAF and FTC for 83 days, as indicated by concentrations of TAF, FTC and their respectively metabolites in plasma, PBMCs, rectal mononuclear cells and tissues associated with HIV transmission. Notably, clinically relevant preventative levels of tenofovir diphosphate were achieved as early as 3 days after NDI implantation. We also demonstrated the feasibility of transcutaneous drug refilling to extend the duration of PrEP drug delivery in NHPs. Overall, the NDI represents an innovative strategy for long-term HIV PrEP administration in both developed and developing countries., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Over the past decade, the prevalence of infections involving methicillin-resistant Staphylococcus aureus (MRSA) in patients with cystic fibrosis (CF) has increased significantly. Tedizolid (TZD) demonstrates excellent activity against MRSA and a favorable safety profile. The pharmacokinetics of several antibiotics have been shown to be altered in CF patients. The purpose of this study was to characterize the pharmacokinetics of tedizolid in this population. Eleven patients with CF were randomized to receive tedizolid phosphate at 200 mg orally or intravenously once daily for 3 doses with a minimum 2-day washout, followed by crossover to the remaining dosage form. Plasma and expectorated sputum were collected following the third dose of each dosage form for analysis. Population pharmacokinetic analysis was performed using the maximum likelihood expectation maximization method, and the disposition of TZD was described by a two-compartment model. The sputum concentrations exceeded the unbound plasma concentrations with an estimated mean sputum-to-unbound plasma penetration ratio of 2.88 (coefficient of variation, 50.3%). The estimated population mean ± standard deviation of total clearance, central volume of distribution, and bioavailability were 9.72 ± 1.62 liters/h, 61.6 ± 6.94 liters, and 1.04 ± 0.232, respectively. The total clearance was higher in CF patients than in healthy volunteers; however, it was similar to published data for patients with complicated skin and skin structure infections (cSSSIs). This study demonstrates that the oral bioavailability of tedizolid is excellent in patients with CF and that the plasma pharmacokinetics are similar to those reported for patients with cSSSIs., (Copyright © 2018 American Society for Microbiology.)

Objectives: Pregnancy is a time of increased HIV acquisition risk and pregnancy reduces concentrations of antiretrovirals used for treatment. We assessed whether pregnancy lowers concentrations of tenofovir (TFV) and tenofovir-diphosphate (TFV-DP) among HIV-uninfected women using oral preexposure prophylaxis (PrEP)., Methods: We analyzed data from an open-label PrEP study, comparing concentrations of TFV in plasma and TFV-DP in dried blood spots (DBS) among 37 pregnant women and 97 nonpregnant women. Analyses controlled for adherence from daily electronic monitoring., Results: The average plasma concentration of TFV among pregnant women was 34.7 ng/ml with 22.2 average recorded doses over the prior month versus 86.5 ng/ml with 23.1 doses among nonpregnant women. After controlling for adherence, TFV concentrations were 58% lower among pregnant women, a statistically significant difference of -50.4 ng/ml (95% CI -68.3 to -32.5). The average TFV-DP concentration was 450.3 fmol/punch among pregnant women and 636.7 fmol/punch among nonpregnant women. This difference was not statistically significant after adjusting for adherence; however, among those with quantifiable TFV-DP, concentrations were 27% lower during pregnancy [-202 fmol/punch (95% CI -384 to -19)]. Among participants with samples before and during pregnancy, there were significant decreases during pregnancy, controlling for adherence: -28.1 ng/ml TFV (95% CI -52.3 to -4.0) and -289.2 fmol/punch TFV-DP (95% CI -439.0 to -139.3)., Conclusion: Consistent with studies among HIV-infected women on ART, we found TFV and TFV-DP concentrations were lower during pregnancy. There is no established TFV concentration threshold to achieve HIV prevention. Additional pharmacokinetic studies and studies of PrEP efficacy in pregnancy are needed.

The aim of our work was to develop a method for the determination of six organophosphorous pesticides (Ops) (azynphos-ethyl (AZP), diazinon (DZN), chlorpyrifos (CLP), chlorfenvinfos (CLF), parathion-ethyl (PRT) and quinalphos (QLP)) in whole blood using microextraction by packed sorbent (MEPS) and analysis by gas chromatography-tandem mass spectrometry (GC-MS/MS). The optimization of the MEPS procedure was performed using a design of experiments (DOE) approach, assessing different factors that significantly affected the extraction efficiency. Ultimately, the number of sample strokes, wash volume, percentage of 2-propanol in the wash solvent and the number of elution strokes were successfully optimized using a response surface methodology (RSM). The developed and optimized method was fully validated according to international guidelines. Linearity was established from 2.5 to 50 μg/mL for AZP and from 0.5 to 50 μg/mL for the remaining compounds, with coefficients of determination (R2) higher than 0.99 in all cases. The lower limit of quantification were 2.5 μg/mL (AZP) and 0.5 μg/mL (remaining compounds). Recoveries ranged from 61% to 77%. Intra- and inter-day precision and accuracy were considered adequate according to the guidelines. This is the first method employing MEPS as a sample preparation procedure for the analysis of these OPs in whole blood.

Background: Adherence is critical for efficacy of tenofovir disoproxil fumarate/emtricitabine (FTC) as preexposure prophylaxis (PrEP)., Methods: Between February 2013 and February 2016, 398 men who have sex with men and transgender women were randomized 1:1 to receive individualized texting for adherence building (iTAB) or standard care (SoC) for 48 weeks. The primary endpoint was dried blood spot (DBS) tenofovir diphosphate (TFV-DP) concentrations at both week 12 and the last on-drug visit of >719 fmol/punch (ie, adequate adherence). Secondary outcomes included DBS TFV-DP concentrations of >1246 fmol/punch (ie, near-perfect adherence) and plasma FTC >350 ng/mL (consistent with dosing within the past 24 hours)., Results: Concentrations >719 fmol/punch of TFV-DP were found in 88.6% of participants at week 12 and 82.5% at week 48. For the primary endpoint, the study arms did not differ (72.0% in iTAB and 69.2% in SoC; P > .05). For the secondary composite endpoint of >1246 fmol/punch the iTAB arm was superior to SoC (33.5% vs 24.8%; P = .06), reaching statistical significance when adjusting for age (odds ratio, 1.56 [95% confidence interval, 1.00-2.42]; P < .05). At week 48, iTAB was superior to SoC for near-perfect adherence (51.0% vs 37.4%; P = .02). At week 12, iTAB was superior to SoC for dosing in past 24 hours by plasma FTC (47.5% vs 33.3%; P = .007), but not at weeks 24, 36, and 48 (all P > .05)., Conclusions: Automated text messaging is a low-burden tool that improves durability of near-perfect PrEP adherence., Clinical Trials Registration: NCT01761643.

Studies of daily emtricitabine-tenofovir disoproxil fumarate (FTC-TDF) for HIV preexposure prophylaxis (PrEP) in men who have sex with men (MSM) modeled intracellular tenofovir-diphosphate (TFV-DP) in dried blood spots (DBS) to assess adherence and corresponding PrEP outcomes. We conducted a prospective, randomized, crossover pharmacokinetic study of TFV-DP in DBS during 33%, 67%, or 100% of daily dosing under directly observed therapy (DOT). Participants were assigned to two 12-week dosing regimens, separated by a 12-week washout. Forty-eight adults (25 women) from Denver and San Francisco were included. TFV-DP exhibited a median half-life of 17 days, reaching steady state in 8 weeks. TFV-DP was dose proportional with mean (SD) steady-state concentrations of 530 (159), 997 (267), and 1,605 (405) fmol/punch for the 33%, 67%, and 100% arms, respectively. Prior work in MSM demonstrated clinically meaningful TFV-DP thresholds of 350, 700, and 1,250 fmol/punch, which were estimated 25th percentiles for 2, 4, and 7 doses/week. In the present study, corresponding TFV-DP was within 3% of the prior estimates, and subgroups by site, race, and sex were within 14% of prior estimates, although males had 17.6% (95% confidence intervals [CIs], 6.5, 27.4%) lower TFV-DP than females. The thresholds of 350, 700, and 1,250 fmol/punch were achieved by 75% of men taking ≥1.2, 3.2, and 6 doses/week and 75% of women taking ≥0.6, 2.0, and 5.3 doses/week, indicating that lower dosing reached these thresholds for both sexes. In conclusion, TFV-DP arising from DOT was similar to previous estimates and is useful for interpreting PrEP adherence and study outcomes. (This study has been registered at ClinicalTrials.gov under identifier NCT02022657.)., (Copyright © 2017 American Society for Microbiology.)

Human external exposure (i.e. intake) of organophosphate flame retardants (PFRs) has recently been quantified, but no link has yet been established between external and internal exposure. In this study, we used a pharmacokinetic (PK) model to probe the relationship between external and internal exposure data for three PFRs (EHDPHP, TNBP and TPHP) available for a Norwegian cohort of 61 individuals from 61 different households. Using current literature on metabolism of PFRs, we predicted the metabolite serum/urine concentrations and compared it to measured data from the study population. Unavailable parameters were estimated using a model fitting approach (least squares method) after assigning reasonable constraints on the ranges of fitted parameters. Results showed an acceptable comparison between PK model estimates and measurements (<10-fold deviation) for EHDPHP. However, a deviation of 10-1000 was observed between PK model estimates and measurements for TNBP and TPHP. Sensitivity and uncertainty analysis on the PK model revealed that EHDPHP results showed higher uncertainty than TNBP or TPHP. However, there are indications that (1) current biomarkers of exposure (i.e. assumed metabolites) for TNBP and TPHP chemicals might not be specific and ultimately affecting the outcome of the modelling and (2) some exposure pathways might be missing. Further research, such as in vivo laboratory metabolism experiments of PFRs including identification of better biomarkers will reduce uncertainties in human exposure assessment., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Pre-exposure prophylaxis (PrEP) with emtricitabine and tenofovir disoproxil fumarate is highly effective against acquisition of HIV infection, and only two cases of infection with a multidrug-resistant virus have been reported under adequate long-term adherence, as evidenced by tenofovir diphosphate concentrations in dried blood spots. We report a case of wild-type HIV-1 infection despite consistent use of emtricitabine and tenofovir disoproxil fumarate., Methods: The patient participated in the Amsterdam PrEP project, a demonstration project of daily and event-driven PrEP. We did extensive testing for HIV, including plasma HIV RNA and nested PCR on bulk peripheral blood mononuclear cells (PBMCs) and sigmoid biopsies after seroconversion., Findings: A 50-year-old man who has sex with men and had been on daily emtricitabine and tenofovir disoproxil fumarate for 8 months presented with fever, urinary tract infection caused by Escherichia coli, anal lymphogranuloma venereum infection, and a positive fourth-generation HIV test. We found an atypical seroconversion pattern, with initially only gp160 antibodies detected in the western blot. HIV RNA could not be detected in plasma, and nested PCR for HIV RNA and DNA on bulk PBMCs and sigmoid biopsies were negative. PrEP was discontinued; 3 weeks later HIV RNA was detected in plasma. No drug-resistant mutations were detected. Tenofovir diphosphate concentrations in dried blood spots were stable and high., Interpretation: To our knowledge, this is the first detailed case report suggesting wild-type HIV-1 infection despite good adherence, evidenced by repeatedly high concentrations of tenofovir diphosphate in dried blood spots. PrEP providers need to be aware that infection can occur despite good adherence. Regular HIV testing and awareness of atypical patterns of seroconversion is highly recommended., Funding: ZonMw, National Institute for Public Health and the Environment, Internal GGD research funds, Aidsfonds, Stichting AmsterdamDiner Foundation, Gilead Sciences, Janssen Pharmaceutica, M A C AIDS Fund, and ViiV Healthcare., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: Tedizolid phosphate is a next-generation oxazolidinone prodrug that is transformed into the active moiety tedizolid. Its indication is acute bacterial skin and skin structure infections caused by gram-positive species, including methicillin-resistant Staphylococcus aureus. Although tedizolid phosphate has been marketed in Korea, no data on the pharmacokinetic (PK) properties or tolerability of tedizolid phosphate in Korean subjects are available. This study was designed to evaluate the PK properties, oral bioavailability, and tolerability with a single-dose oral and intravenous administration of tedizolid phosphate in healthy Korean male subjects., Methods: A block-randomized, double-blind, placebo-controlled, single-dose study was conducted in 3 groups (200, 400, and 600 mg; 10 subjects in each group). In the second part of the study, subjects from the 200-mg group received administration orally and intravenously (1-hour infusion) via 2-way crossover for the evaluation of absolute bioavailability. There was a 7-day washout period between treatments in the absolute bioavailability part of the study. Serial blood samples for PK analysis were collected for up to 72 hours. Tolerability was assessed by analysis of adverse events., Findings: Thirty healthy Korean subjects completed the study and were included in the PK and tolerability analyses. Tedizolid phosphate was rapidly converted into tedizolid. After a single oral dose, the T max of tedizolid was observed to be 1.5 to 2.5 hours, and the plasma concentration-time curve of tedizolid showed a 2-phase elimination pattern, with a half-life of ~11 hours. Dose-dependent increases were observed in the AUC last value (29,441-78,062 μg · h/L) and in the C max value ( 2679-6980 μg/L) with the administration of tedizolid phosphate 200 to 600 mg PO. The absolute bioavailability of tedizolid was 95.2% (90% CI, 92.7%-97.8%) in the 200-mg administration group. There were no serious adverse events or clinically significant changes in the tolerability assessment., Implications: Tedizolid phosphate at doses of up to 600 mg was well-tolerated in these healthy Korean male subjects. Tedizolid shows dose linearity with oral administration, and no dose adjustment of tedizolid phosphate 200 mg would be needed when switching administration routes. ClinicalTrials.gov identifier: NCT02097043., (Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.)

Objectives: Tenofovir alafenamide, a prodrug of tenofovir, produces higher PBMC concentrations of tenofovir diphosphate (tenofovir-dp) than tenofovir disoproxil fumarate. To understand tenofovir alafenamide's mucosal tissue distribution and its implications for pre-exposure prophylaxis, we characterized tenofovir-dp in female genital tract (FGT) and lower gastrointestinal (GI) tissues., Methods: Healthy seronegative women were given 5, 10 or 25 mg of tenofovir alafenamide ( n  =   8/group). Each participant provided plasma, PBMC and cervical, vaginal and rectal tissue samples over 14 days. Plasma, cell lysate and tissue homogenate concentrations were analysed by LC-MS/MS. Dose proportionality was declared in plasma and PBMCs if the natural log AUC versus natural log dose regression line 90% CI was within 0.57-1.43. In vitro tenofovir-dp formation was assessed in PBMCs and ectocervical (Ect1/E6E7) and vaginal (VK2/E6E7) cells incubated in 0.5 and 10 μM tenofovir alafenamide or tenofovir. clinicaltrials.gov: NCT02357602., Results: Following single doses of 5, 10 and 25 mg, median (IQR) tenofovir plasma AUC 0-14 days was 52.8 (49.5-59.6), 78.1 (68.2-86.9) and 169.7 (131.2-211.4) ng·h/mL and tenofovir-dp PBMC AUC 0-14 days was 2268 (1519-4090), 4584 (3113-5734) and 9306 (6891-10785) fmol·h/10 6 cells, respectively. Tenofovir was quantifiable in 52% and 92% of FGT and GI tissues, whereas tenofovir-dp was quantifiable in only 5% and 19% of FGT and GI tissues, respectively. Plasma tenofovir and PBMC tenofovir-dp were dose proportional (90% CI = 0.87-1.15 and 0.62-1.02, respectively). In vitro tenofovir-dp was 1.7-17-fold higher in epithelial cells than PBMCs., Conclusions: After tenofovir alafenamide dosing in vivo , tenofovir-dp was unquantifiable in most tissues (91%) although cervical and vaginal epithelial cells efficiently formed tenofovir-dp from tenofovir alafenamide in vitro . These findings warrant further investigation of tenofovir alafenamide's pharmacology., (© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Triphenyl phosphate (TPHP) is a commonly used organophosphate flame retardant and plasticizer with widespread human exposure. Data on health effects of TPHP are limited. Recent toxicological studies suggest TPHP may alter thyroid function. We used repeated measures to assess the temporal variability in urinary concentrations of the TPHP metabolite, diphenyl phosphate (DPHP), and to examine relationships between DPHP concentrations and thyroid hormones. We sampled 51 adults at months 1, 6, and 12 from 2010 to 2011. Urine samples were analyzed for DPHP. Serum samples were analyzed for free and total thyroxine (fT 4 , TT 4 ), total triiodothyronine (TT 3 ), and thyroid stimulating hormone (TSH). We assessed variability in DPHP using intraclass correlation coefficients (ICCs) and kappa statistics. We used linear mixed-effects models to examine associations between DPHP and thyroid hormones. DPHP was detected in 95% of urine samples. Mean DPHP concentrations were 43% higher in women than men. DPHP showed high within-subject variability (ICC range, 0.13-0.39; kappa range, 0.16-0.39). High versus low (≥2.65 vs. <2.65ng/mL) DPHP in all participants was associated with a 0.43μg/dL (95% confidence interval: 0.15, 0.72) increase in mean TT 4 levels. In sex-stratified analyses, high versus low DPHP was associated with a 0.91μg/dL (95% CI: 0.47, 1.36) increase in mean TT 4 in women. The association was attenuated in men (βeta=0.19; 95% CI: -0.15, 0.52). We found no significant associations between DPHP and fT 4 , TT 3 , or TSH. We found evidence that TPHP exposure may be associated with increased TT 4 levels, especially in women., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objectives: This study aims to determine (1) total dialkylphosphate (ΣDAP) levels, occupational knowledge and practice, DNA damage, AChE activity, and health symptoms in rice, corn, and double-crop farmers; (2) the association of health symptoms with ΣDAP levels, occupational knowledge and practice, DNA damage, and AChE activity in farmers; and (3) the prevalence of health symptoms between farmers and non-farmers., Methods: A cross-sectional study was conducted by interviewing as well as analyzing urine and blood samples during July to August 2014., Results: There were no differences in ΣDAP levels, AChE activity, and occupational knowledge and practice scores among all farmer groups. In terms of health symptoms related to ΣDAP, AChE activity, DNA damage, and occupational knowledge and practice, pesticide-related symptoms were determined, including breathlessness, chest pain, dry throat, numbness, muscle weakness, cramp, headache, dizziness, eye irritation, white/red rash, and white/red pimple, which were classified as respiratory, muscle, nervous, and epithelial symptoms. A remarkable finding was that farmers had a significantly higher prevalence of muscle weakness (odds ratio (OR)=3.79) and numbness (OR=3.45) as compared with non-farmers., Conclusion: Our findings, therefore, suggest that a long-term low-level exposure to organophosphates (OPs) may be associated with an increasing prevalence of muscle symptoms. However, a further cohort study incorporating sensitive health outcomes and measurement of multiple pesticides monitoring on a larger scale is warranted.

The production and use of brominated flame retardants have been increasingly restricted. Organophosphate esters (OPEs) have been widely used as substitutes for brominated flame retardants. However, little is yet known about human exposure to OPEs. The potential health risks posed by OPEs were assessed by determining the concentrations of 6 OPEs in pooled serum samples from residents of Shandong, China. The mean ∑ 6 OPE concentrations in 2011 and 2015 were 680 ng/g lipid and 709 ng/g lipid, respectively. The most abundant OPE was tri(2-chloroethyl) phosphate, contributing a mean of 82% of the ∑ 6 OPE concentration. A significant correlation was found between the tri(2-chloroethyl) phosphate and tri-n-butylphosphate concentrations, possibly indicating that these OPEs are used in similar applications and have similar human exposure pathways in the study area. The mean tri(2-chloroethyl) phosphate concentration increased from 536 ng/g lipid in 2011 to 605 ng/g lipid in 2015, but the concentrations of tri-n-butylphosphate, triphenyl phosphate, and tris(methylphenyl) esters decreased between 2011 and 2015. This could indicate that chlorinated OPEs bioaccumulate in humans more strongly than nonchlorinated OPEs do. Environ Toxicol Chem 2017;36:414-421. © 2016 SETAC., (© 2016 SETAC.)

Given that tedizolid exhibits substantial lung penetration, we hypothesize that it could achieve good efficacy against Streptococcus pneumoniae lung infections. We evaluated the pharmacodynamics of tedizolid for treatment of S. pneumoniae lung infections and compared the efficacies of tedizolid human-simulated epithelial lining fluid (ELF) exposures in immunocompetent and neutropenic murine lung infection models. ICR mice were rendered neutropenic via intraperitoneal cyclophosphamide injections and then inoculated intranasally with S. pneumoniae suspensions. Immunocompetent CBA/J mice were inoculated similarly. Single daily tedizolid doses were administered 4 h postinoculation (termed 0 h). Changes in log 10 CFU at 24 h compared with 0-h controls were estimated. Ratios of area under the free-drug concentration-time curve to MIC (fAUC 0-24 /MIC) required to achieve various efficacy endpoints against each isolate were estimated using the Hill equation. Tedizolid doses in neutropenic and immunocompetent mice that mimic the human-simulated ELF exposure were examined. Stasis, 1-log reduction, and 2-log reduction were achieved at fAUC 0-24 /MIC of 8.96, 24.62, and 48.34, respectively, in immunocompetent mice and 19.21, 48.29, and 103.95, respectively, in neutropenic mice. Tedizolid at 40 mg/kg of body weight/day and 55 mg/kg/day in immunocompetent and neutropenic mice, respectively, resulted in ELF AUC 0-24 comparable to that achieved in humans following a 200-mg once-daily clinical dose. These human-simulated ELF exposures were adequate to attain >2-log reduction in bacterial burden at 24 h in 3 out of 4 isolates in both models and 1.58- and 0.74-log reductions with the fourth isolate in immunocompetent and neutropenic mice, respectively. Tedizolid showed potent in vivo efficacy against S. pneumoniae in both immunocompetent and neutropenic lung infection models, which support its consideration for S. pneumoniae lung infections., (Copyright © 2016 American Society for Microbiology.)

Aryl phosphate flame retardants (aryl-PFRs), such as triphenyl phosphate (TPHP) and 2-ethylhexyl diphenyl phosphate (EHDPHP), are emerging contaminants that can exhibit toxic properties, including severe aquatic toxicity and endocrine disruptive effects. Monitoring exposure to aryl-PFRs through specific biomarkers is necessary to assess the health risk associated with chronic exposure. Hydrolytic serum enzymes could play an important role in the formation of the hydrolysis product diphenyl phosphate (DPHP), the seemingly most abundant in vivo biomarker of TPHP in urine. Here, we assess whether serum enzymes have an impact on the toxicokinetics of TPHP and EHDPHP and on the contribution of both aryl-PFRs to in vivo DPHP levels. TPHP and EHDPHP were incubated separately with pooled human serum to measure the formation of hydrolysis products DPHP and 2-ethylhexyl phenyl phosphate (EHPHP) by liquid chromatography-tandem mass spectrometry. Clearance of TPHP and EHDPHP was 70 and 8.6 mL/min/L serum (as measured by formation of DPHP and EHPHP, respectively). No discernible amount of DPHP was produced from EHDPHP by serum hydrolases. Our results suggest that serum hydrolases can significantly contribute to the in vivo levels of DPHP formed from TPHP and can play an important role in the toxicokinetics, toxicity, and selection of biomarkers for aryl-PFRs.

Tedizolid (TDZ) is a novel oxazolidinone class antibiotic, indicated for the treatment of acute bacterial skin and skin structure infections in adults. In this study a highly sensitive UPLC-MS/MS assay was developed and validated for the determination of TDZ in rat plasma using rivaroxaban as an internal standard (IS). Both TDZ and IS were separated on an Acquity UPLC BEH™ C 18 column using an isocratic mobile phase comprising of acetonitrile-20 mm ammonium acetate (85:15, v/v), eluted at 0.3 mL/min flow rate. The plasma sample was processed by liquid liquid extraction technique using ethyl acetate as an extracting agent. The analyte and IS were detected in positive mode using electrospray ionization source. The precursor to product ion transitions at m/z 371.09 > 343.10 for TDZ and m/z 435.97 > 144.94 for IS were used for the quantification in multiple reaction monitoring mode. The calibration curve was linear in the concentration range of 0.74-1500 ng/mL and the lower limit of quantification was 0.74 ng/mL only. The developed assay was validated following standard guidelines for bioanalytical method validation (US Food and Drug Administration) and all the validation results were within the acceptable limits. The developed assay was successfully applied into a pharmacokinetic study in rats. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

We compared tedizolid alone and tedizolid with rifampin to rifampin and vancomycin plus rifampin in a rat model of methicillin-resistant Staphylococcus aureus (MRSA) foreign body-associated osteomyelitis. The study strain was a prosthetic joint infection-associated isolate. Steady-state pharmacokinetics for intraperitoneal administration of tedizolid, vancomycin, and rifampin were determined in uninfected rats. MRSA was inoculated into the proximal tibia, and a wire was implanted. Four weeks later, the rats were treated intraperitoneally for 21 days with tedizolid (n = 14), tedizolid plus rifampin (n = 11), rifampin (n = 16), or vancomycin plus rifampin (n = 13). Seventeen rats received no treatment. After treatment, quantitative bone cultures were performed. Blood was obtained for determination of drug trough concentrations in the tedizolid and tedizolid plus rifampin groups. The mean peak plasma concentration and mean area under the concentration-time curve from time zero to 24 h for tedizolid were 12 μg/ml and 60 μg · h/ml, respectively. The bacterial loads in all treatment groups were significantly lower than those in the control group; those in the tedizolid- plus rifampin-treated animals were not significantly different from those in the vancomycin- plus rifampin-treated animals. The range of mean plasma trough concentrations in the tedizolid group was 0.44 to 0.73 μg/ml. Although neither tedizolid nor vancomycin resistance was detected in isolates recovered from bones, rifampin resistance was detected in 10 animals (63%) in the rifampin group, 8 animals (73%) in the tedizolid plus rifampin group, and a single animal (8%) in the vancomycin plus rifampin group. Tedizolid alone or tedizolid combined with rifampin was active in a rat model of MRSA foreign body-associated osteomyelitis. The emergence of rifampin resistance was noted in animals receiving tedizolid plus rifampin., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

This study analyzed the associations of farmers' exposure to organophosphates (OPs), organosulfurs (OSs), organonitrogens (ONs) and pyrethroids (PYRs) with parameters of the blood complete counts (CBC), a blood chemistry panel (BCP) and the conventional nerve conduction studies among 224 farmers in China in 2012. Two health examinations and a series of follow-up field surveys were conducted. Multiple linear regression analyses were used to evaluate the associations. The results show considerable associations between multiple groups of pesticides and several CBC parameters, but it was not enough to provide evidence of hematological disorders. The short- and medium-term OPs exposures were mainly associated with liver damage and peripheral nerve impairment, respectively, while OSs exposure might induce liver damage and renal dysfunction. The neurotoxicity of ONs was second only to OPs in addition to its potential liver damage and the induced alterations in glucose. In comparison, the estimated results show that PYRs would be the least toxic in terms of the low-dose application. In conclusion, occupational exposures to pesticides with heterogeneous chemical structures are associated with farmer health in different patterns, and the association between a specific group of pesticides and farmer health also differs between the short- and medium-term exposures.

After the phase-out of polybrominated diphenyl ethers (PBDEs), the use of alternative flame retardants (AFRs), such as FireMaster 550, and of organophosphate esters (OPEs) has increased. However, little is known about human exposure to these chemicals. This lack of biomonitoring studies is partially due to the absence of reliable noninvasive biomarkers of exposure. Human hair and nails can provide integrated exposure measurements, and as such, these matrices can potentially be used as noninvasive biomarkers of exposure to these flame retardants. Paired human hair, fingernail, toenail, and serum samples obtained from 50 adult participants recruited at Indiana University Bloomington campus were analyzed by gas chromatographic mass spectrometry for 36 PBDEs, 9 AFRs, and 12 OPEs. BDE-47, BDE-99, 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), di(2-ethylhexyl) tetrabromophthalate (TBPH), tris(1,3-dichloro-2-propyl)phosphate (TDCIPP), and triphenyl phosphate (TPHP) were the most abundant compounds detected in almost all hair, fingernail, and toenail samples. The concentrations followed the order OPEs > TBB+TBPH > Σpenta-BDE. PBDE levels in the hair and nail samples were significantly correlated with their levels in serum (P < 0.05), suggesting that human hair and nails can be used as biomarkers to assess human exposure to PBDEs.

Importance: Several randomized clinical trials have demonstrated the efficacy of preexposure prophylaxis (PrEP) in preventing human immunodeficiency virus (HIV) acquisition. Little is known about adherence to the regimen, sexual practices, and overall effectiveness when PrEP is implemented in clinics that treat sexually transmitted infections (STIs) and community-based clinics serving men who have sex with men (MSM)., Objective: To assess PrEP adherence, sexual behaviors, and the incidence of STIs and HIV infection in a cohort of MSM and transgender women initiating PrEP in the United States., Design, Setting, and Participants: Demonstration project conducted from October 1, 2012, through February 10, 2015 (last date of follow-up), among 557 MSM and transgender women in 2 STI clinics in San Francisco, California, and Miami, Florida, and a community health center in Washington, DC. Data were analyzed from December 18, 2014, through August 8, 2015., Interventions: A combination of daily, oral tenofovir disoproxil fumarate and emtricitabine was provided free of charge for 48 weeks. All participants received HIV testing, brief client-centered counseling, and clinical monitoring., Main Outcomes and Measures: Concentrations of tenofovir diphosphate in dried blood spot samples, self-reported numbers of anal sex partners and episodes of condomless receptive anal sex, and incidence of STI and HIV acquisition., Results: Overall, 557 participants initiated PrEP, and 437 of these (78.5%) were retained through 48 weeks. Based on the findings from the 294 participants who underwent measurement of tenofovir diphosphate levels, 80.0% to 85.6% had protective levels (consistent with ≥4 doses/wk) at follow-up visits. African American participants (56.8% of visits; P = .003) and those from the Miami site (65.1% of visits; P < .001) were less likely to have protective levels, whereas those with stable housing (86.8%; P = .02) and those reporting at least 2 condomless anal sex partners in the past 3 months (88.6%; P = .01) were more likely to have protective levels. The mean number of anal sex partners declined during follow-up from 10.9 to 9.3, whereas the proportion engaging in condomless receptive anal sex remained stable at 65.5% to 65.6%. Overall STI incidence was high (90 per 100 person-years) but did not increase over time. Two individuals became HIV infected during follow-up (HIV incidence, 0.43 [95% CI, 0.05-1.54] infections per 100 person-years); both had tenofovir diphosphate levels consistent with fewer than 2 doses/wk at seroconversion., Conclusions and Relevance: The incidence of HIV acquisition was extremely low despite a high incidence of STIs in a large US PrEP demonstration project. Adherence was higher among those participants who reported more risk behaviors. Interventions that address racial and geographic disparities and housing instability may increase the impact of PrEP.