Gestational exposure to organochlorine compounds and metals and infant birth weight: effect modification by maternal hardships.

BACKGROUND: Gestational exposure to toxic environmental chemicals and maternal social hardships are individually associated with impaired fetal growth, but it is unclear whether the effects of environmental chemical exposure on infant birth weight are modified by maternal hardships. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1982 pregnant females enrolled between 2008 and 2011. We quantified eleven environmental chemical concentrations from two chemical classes - six organochlorine compounds (OCs) and five metals - that were detected in ≥ 70% of blood samples collected during the first trimester. We examined fetal growth using birth weight adjusted for gestational age and assessed nine maternal hardships by questionnaire. Each maternal hardship variable was dichotomized to indicate whether the females experienced the hardship. In our analysis, we used elastic net to select the environmental chemicals, maternal hardships, and 2-way interactions between maternal hardships and environmental chemicals that were most predictive of birth weight. Next, we obtained effect estimates using multiple linear regression, and plotted the relationships by hardship status for visual interpretation. RESULTS: Elastic net selected trans-nonachlor, lead, low educational status, racially minoritized background, and low supplemental folic acid intake. All were inversely associated with birth weight. Elastic net also selected interaction terms. Among those with increasing environmental chemical exposures and reported hardships, we observed stronger negative associations and a few positive associations. For example, every two-fold increase in lead concentrations was more strongly associated with reduced infant birth weight among participants with low educational status (ß = -100 g (g); 95% confidence interval (CI): -215, 16), than those with higher educational status (ß = -34 g; 95% CI: -63, -3). In contrast, every two-fold increase in mercury concentrations was associated with slightly higher birth weight among participants with low educational status (ß = 23 g; 95% CI: -25, 71) compared to those with higher educational status (ß = -9 g; 95% CI: -24, 6). CONCLUSIONS: Our findings suggest that maternal hardships can modify the associations of gestational exposure to some OCs and metals with infant birth weight.

Effects of gestational exposures to chemical mixtures on birth weight using Bayesian factor analysis in the Health Outcome and Measures of Environment (HOME) Study.

Studying the effects of gestational exposures to chemical mixtures on infant birth weight is inconclusive due to several challenges. One of the challenges is which statistical methods to rely on. Bayesian factor analysis (BFA), which has not been utilized for chemical mixtures, has advantages in variance reduction and model interpretation. METHODS: We analyzed data from a cohort of 384 pregnant women and their newborns using urinary biomarkers of phthalates, phenols, and organophosphate pesticides (OPs) and serum biomarkers of polychlorinated biphenyls (PCBs), polybrominated diphenyl ethers (PBDEs), perfluoroalkyl substances (PFAS), and organochlorine pesticides (OCPs). We examined the association between exposure to chemical mixtures and birth weight using BFA and compared with multiple linear regression (MLR) and Bayesian kernel regression models (BKMR). RESULTS: For BFA, a 10-fold increase in the concentrations of PCB and PFAS mixtures was associated with an 81 g (95% confidence intervals [CI] = -132 to -31 g) and 57 g (95% CI = -105 to -10 g) reduction in birth weight, respectively. BKMR results confirmed the direction of effect. However, the 95% credible intervals all contained the null. For single-pollutant MLR, a 10-fold increases in the concentrations of multiple chemicals were associated with reduced birth weight, yet the 95% CI all contained the null. Variance inflation from MLR was apparent for models that adjusted for copollutants, resulting in less precise confidence intervals. CONCLUSION: We demonstrated the merits of BFA on mixture analysis in terms of precision and interpretation compared with MLR and BKMR. We also identified the association between exposure to PCBs and PFAS and lower birth weight.

Prenatal exposure to endocrine disrupting chemical mixtures and infant birth weight: A Bayesian analysis using kernel machine regression.

BACKGROUND: Pregnant women are regularly exposed to a multitude of endocrine disrupting chemicals (EDCs). EDC exposures, both individually and as mixtures, may affect fetal growth. The relationship of EDC mixtures with infant birth weight, however, remains poorly understood. We examined the relations between prenatal exposure to EDC mixtures and infant birth weight. METHODS: We used data from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1857 pregnant women enrolled between 2008 and 2011. We quantified twenty-one chemical concentrations from five EDC classes, including organochlorine compounds (OCs), metals, perfluoroalkyl substances (PFAS), phenols and phthalate metabolites that were detected in >70% of urine or blood samples collected during the first trimester. In our primary analysis, we used Bayesian kernel machine regression (BKMR) models to assess variable importance, explore EDC mixture effects, and identify any interactions among EDCs. Our secondary analysis used traditional linear regression to compare the results with those of BKMR and to quantify the changes in mean birth weight in relation to prenatal EDC exposures. RESULTS: We found evidence that mixtures of OCs and metals were associated with monotonic decreases in mean birth weight across the whole range of exposure. trans-Nonachlor from the OC mixture and lead (Pb) from the metal mixture had the greatest impact on birth weight. Our linear regression analysis corroborated the BKMR results and found that a 2-fold increase in trans-nonachlor and Pb concentrations reduced mean birth weight by -38 g (95% confidence interval (CI): -67, -10) and -39 g (95% CI: -69, -9), respectively. A sex-specific association for OC mixture was observed among female infants. PFAS, phenols and phthalates were not associated with birth weight. No interactions were observed among the EDCs. CONCLUSIONS: Using BKMR, we observed that both OC and metal mixtures were associated with decreased birth weight in the MIREC Study. trans-Nonachlor from the OC mixture and Pb from the metal mixture contributed most to the adverse effects.

Higher BMI, But Not Sarcopenia, Is Associated With Pembrolizumab-related Toxicity in Patients With Advanced Melanoma.

BACKGROUND/AIM: To determine whether BMI and sarcopenia were related to treatment-limiting toxicity or efficacy of pembrolizumab treatment in melanoma patients. PATIENTS AND METHODS: Medical records for melanoma patients undergoing pembrolizumab treatment at Duke University from January 2014 to September 2018 were reviewed. Pre-treatment measurements such as BMI were collected. Pre-treatment CT imaging was used to determine psoas muscle index (PMI). Patients in the lowest sex-specific tertile of PMI were sarcopenic. Logistic regression measured associations with treatment toxicity and response. Kaplan-Meier analysis assessed progression-free survival (PFS) and overall survival (OS). RESULTS: Among 156 patients, the overall objective response rate was 46.2% and 29 patients (18.6%) experienced treatment-limiting toxicity. Sarcopenia was not significantly associated with toxicity, response, or survival. However, obese patients (BMI >30) experienced higher rates of toxicity (p=0.0007). CONCLUSION: Sarcopenia did not appear to predict clinically relevant outcomes. Obesity, however, represents a readily available predictor of pembrolizumab toxicity.

Retreatment with talimogene laherparepvec for advanced melanoma.

Aim: Talimogene laherparepvec (T-VEC) is a genetically modified oncolytic herpesvirus approved for the treatment of unresectable, locoregionally advanced and recurrent melanoma. There is little relevant literature in the context of retreatment with T-VEC. Materials & methods: We reviewed four patients aged 71-87 years old with stage IIIB-IV melanoma at treatment who were rechallenged with T-VEC after experiencing recurrence of locoregional disease or prior treatment-limiting toxicity. Results: Cessation of initial treatment was due to one of the following reasons: severe adverse event (one case), mixed response (one case) or complete response (two cases). Three males and one female underwent T-VEC retreatment with a mean of 5.5 injection cycles. Three patients experienced a complete response to retreatment, while one experienced disease progression. Conclusion: Intralesional T-VEC may be effective and well-tolerated in patients who have completed prior T-VEC therapy.

Associations of prenatal urinary phthalate exposure with preterm birth: the Maternal-Infant Research on Environmental Chemicals (MIREC) Study.

OBJECTIVES: To examine the relation between prenatal urinary phthalate metabolite concentrations and preterm birth (PTB). METHODS: The data were drawn from the Maternal-Infant Research on Environmental Chemicals (MIREC) Study, a pan-Canadian cohort of 1857 pregnant women enrolled between 2008 and 2011. We quantified urinary concentrations of 7 phthalate metabolites that were detected in > 70% of urine samples collected during the first trimester. Gestational age was obtained from either the last menstrual period or early ultrasound. We used Cox proportional hazard models to examine the associations of urinary phthalate metabolite concentrations, plus the molar sum of di-2-ethylhexyl phthalate metabolites (∑DEHP), with time to delivery before 37 weeks of gestation. We also examined PTB by clinical presentation. PTBs presented with either spontaneous labour or premature rupture of the membrane were considered spontaneous PTB (sPTB). Additionally, we used multiple linear regression to model changes in mean gestational age in relation to phthalate exposure. RESULTS: We found no evidence of an association between first trimester phthalate metabolite concentrations and PTB among the MIREC study participants. For example, each 2-fold increase in any of the 7 phthalate concentrations or ∑DEHP was associated with hazard ratios (HRs) for PTB ranging from 0.95 to 1.07 with 95% confidence intervals including the null. An assessment of non-linear trends showed some evidence of non-monotonic dose-response relationships between phthalates and PTB. Furthermore, male infants exposed to MCPP showed higher sPTB risk compared with female infants. CONCLUSION: Phthalate exposure during early pregnancy is not clearly associated with the risk of PTB among this Canadian population.

Efficacy of Talimogene Laherparepvec (T-VEC) Therapy in Patients with In-Transit Melanoma Metastasis Decreases with Increasing Lesion Size.

BACKGROUND: Talimogene laherparepvec (T-VEC) is the first injectable oncolytic viral therapy approved for in-transit melanoma metastasis, with a reported overall response rate (ORR) of 25% and complete response rate (CRR) of 10%. To ascertain the role of patient selection on outcomes in routine practice, we evaluated the impact of patient, lesion, and treatment factors on clinical response. METHODS: Medical records were extracted for patients with recurrent stage IIIB-IV melanoma completing T-VEC at Duke University Medical Center between 1 January 2016 and 1 September 2018. Kaplan-Meier analysis assessed time to response and survival, while logistic regression measured associations of clinicopathologic status, lesion burden, T-VEC dosing, and use of prior and concurrent therapy with ORR and CRR. RESULTS: Of 27 patients, an objective response was observed in 11 (40.7%), including one patient with partial response (3.7%) and 10 with complete response (37.0%). Time to complete response and overall response was a median 22 weeks (95% confidence interval [CI] 2.0-41.9 weeks and 15.8-28.2 weeks, respectively), and median progression-free survival was 17 weeks (95% CI 0-36 weeks). Logistic regression demonstrated each millimeter increase in maximum lesion diameter predicted decreased ORR (odds ratio [OR] 0.866, 95% CI 0.753-0.995; p = 0.04). Stage IV disease (OR 0.04, 95% CI 0.00-0.74; p = 0.031) and programmed death-1 inhibitor treatment (OR 0.06, 95% CI 0.01-0.74; p = 0.028) also predicted reduced clinical response. CONCLUSIONS: This study corroborates recent data suggesting response rates to T-VEC may be higher than reported in clinical trials, arising in part from patient selection. T-VEC lesion diameter was persistently associated with clinical response and is a readily assessed predictor of successful T-VEC therapy.

The impact of lay counselors on HIV testing rates: quasi-experimental evidence from lay counselor redeployment in KwaZulu-Natal, South Africa.

OBJECTIVES: This study aimed to determine the causal effect of the number of lay counselors removed from a primary care clinic in rural South Africa on the number of clinic-based HIV tests performed. DESIGN: Fixed-effects panel analysis. METHODS: We collected monthly data on the number of lay counselors employed and HIV tests performed at nine primary care clinics in rural KwaZulu-Natal from January 2014 to December 2015. Using clinic-level and month-level fixed-effects regressions, we exploited the fact that lay counselors were removed from clinics at two quasi-random time points by a redeployment policy. RESULTS: A total of 24 526 HIV tests were conducted over the study period. Twenty-one of 27 lay counselors were removed across the nine clinics in the two redeployment waves. A 10% reduction in the number of lay counselors at a clinic was associated with a 4.9% [95% confidence interval (CI) 2.8-7.0, P < 0.001] decrease in the number of HIV tests performed. In absolute terms, losing one lay counselor from a clinic was associated with a mean of 29.7 (95% CI 21.2-38.2, P < 0.001) fewer HIV tests carried out at the clinic per month. CONCLUSION: This study provides some evidence that lay counselors play an important role in the HIV response in rural South Africa. More broadly, this analysis adds some empirical support to plans to increase the involvement of lay health workers in the HIV response.

Implementation of personalized music listening for assisted living residents with dementia.

Personalized music listening (PML) has been touted as a safe and inexpensive means of improving the quality of life, mood, and behavior of persons with dementia. A PML program was implemented in an assisted living facility and evaluated across the five dimensions of the RE-AIM framework: reach, effectiveness, adoption, implementation, and maintenance. The first 17 residents invited to participate were enrolled and followed over eight months. Effectiveness was evident in staff-reported mood improvement in 62% of encounters. Adoption was evident in qualitative feedback collected from medication technicians. Implementation was facilitated by low costs, engagement of external volunteers, highlighting outcomes that are relevant to staff, and attention to playlists over time. Maintenance required continued engagement of volunteers, ongoing fundraising, attention to facility staff engagement, and iterative adjustments to the program framework as staffing changes occurred. PML was found to be a meaningful intervention that is possible at a reasonable cost.

The impact of community health worker-led home delivery of antiretroviral therapy on virological suppression: a non-inferiority cluster-randomized health systems trial in Dar es Salaam, Tanzania.

BACKGROUND: Home delivery of antiretroviral therapy (ART) by community health workers (CHWs) may improve ART retention by reducing the time burden and out-of-pocket expenditures to regularly attend an ART clinic. In addition, ART home delivery may shorten waiting times and improve quality of care for those in facility-based care by decongesting ART clinics. This trial aims to determine whether ART home delivery for patients who are clinically stable on ART combined with facility-based care for those who are not stable on ART is non-inferior to the standard of care (facility-based care for all ART patients) in achieving and maintaining virological suppression. METHODS: This is a non-inferiority cluster-randomized trial set in Dar es Salaam, Tanzania. A cluster is one of 48 healthcare facilities with its surrounding catchment area. 24 clusters were randomized to ART home delivery and 24 to the standard of care. The intervention consists of home visits by CHWs to provide counseling and deliver ART to patients who are stable on ART, while the control is the standard of care (facility-based ART and CHW home visits without ART home delivery). In addition, half of the healthcare facilities in each study arm were randomized to standard counseling during home visits (covering family planning, prevention of HIV transmission, and ART adherence), and half to standard plus nutrition counseling (covering food production and dietary advice). The non-inferiority design applies to the endpoints of the ART home delivery trial; the primary endpoint is the proportion of ART patients at a healthcare facility who are virally suppressed at the end of the study period. The margin of non-inferiority for this primary endpoint was set at nine percentage points. DISCUSSION: As the number of ART patients in sub-Saharan Africa is expected to rise, this trial provides causal evidence on the effectiveness of a home-based care model that could decongest ART clinics and reduce patients' healthcare expenditures. More broadly, this trial will inform the increasing policy interest in task-shifting of chronic disease care from facility- to community-based healthcare workers. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02711293 . Registration date: 16 March 2016.

Community-Based Financing of Family Planning in Developing Countries: A Systematic Review.

In this systematic review, we gather evidence on community financing schemes and insurance programs for family planning in developing countries, and we assess the impact of these programs on primary outcomes related to contraceptive use. To identify and evaluate the research findings, we adopt a four-stage review process that employs a weight-of-evidence and risk-of-bias analytic approach. Out of 19,138 references that were identified, only four studies were included in our final analysis, and only one study was determined to be of high quality. In the four studies, the evidence on the impact of community-based financing on family planning and fertility outcomes is inconclusive. These limited and mixed findings suggest that either: 1) more high-quality evidence on community-based financing for family planning is needed before any conclusions can be made; or 2) community-based financing for family planning may, in fact, have little or no effect on family planning outcomes.

Combined MTOR and autophagy inhibition: phase I trial of hydroxychloroquine and temsirolimus in patients with advanced solid tumors and melanoma.

The combination of temsirolimus (TEM), an MTOR inhibitor, and hydroxychloroquine (HCQ), an autophagy inhibitor, augments cell death in preclinical models. This phase 1 dose-escalation study evaluated the maximum tolerated dose (MTD), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of HCQ in combination with TEM in cancer patients. In the dose escalation portion, 27 patients with advanced solid malignancies were enrolled, followed by a cohort expansion at the top dose level in 12 patients with metastatic melanoma. The combination of HCQ and TEM was well tolerated, and grade 3 or 4 toxicity was limited to anorexia (7%), fatigue (7%), and nausea (7%). An MTD was not reached for HCQ, and the recommended phase II dose was HCQ 600 mg twice daily in combination with TEM 25 mg weekly. Other common grade 1 or 2 toxicities included fatigue, anorexia, nausea, stomatitis, rash, and weight loss. No responses were observed; however, 14/21 (67%) patients in the dose escalation and 14/19 (74%) patients with melanoma achieved stable disease. The median progression-free survival in 13 melanoma patients treated with HCQ 1200mg/d in combination with TEM was 3.5 mo. Novel 18-fluorodeoxyglucose positron emission tomography (FDG-PET) measurements predicted clinical outcome and provided further evidence that the addition of HCQ to TEM produced metabolic stress on tumors in patients that experienced clinical benefit. Pharmacodynamic evidence of autophagy inhibition was evident in serial PBMC and tumor biopsies only in patients treated with 1200 mg daily HCQ. This study indicates that TEM and HCQ is safe and tolerable, modulates autophagy in patients, and has significant antitumor activity. Further studies combining MTOR and autophagy inhibitors in cancer patients are warranted.

A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme.

Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.

Targeting ER stress-induced autophagy overcomes BRAF inhibitor resistance in melanoma.

Melanomas that result from mutations in the gene encoding BRAF often become resistant to BRAF inhibition (BRAFi), with multiple mechanisms contributing to resistance. While therapy-induced autophagy promotes resistance to a number of therapies, especially those that target PI3K/mTOR signaling, its role as an adaptive resistance mechanism to BRAFi is not well characterized. Using tumor biopsies from BRAF(V600E) melanoma patients treated either with BRAFi or with combined BRAF and MEK inhibition, we found that BRAFi-resistant tumors had increased levels of autophagy compared with baseline. Patients with higher levels of therapy-induced autophagy had drastically lower response rates to BRAFi and a shorter duration of progression-free survival. In BRAF(V600E) melanoma cell lines, BRAFi or BRAF/MEK inhibition induced cytoprotective autophagy, and autophagy inhibition enhanced BRAFi-induced cell death. Shortly after BRAF inhibitor treatment in melanoma cell lines, mutant BRAF bound the ER stress gatekeeper GRP78, which rapidly expanded the ER. Disassociation of GRP78 from the PKR-like ER-kinase (PERK) promoted a PERK-dependent ER stress response that subsequently activated cytoprotective autophagy. Combined BRAF and autophagy inhibition promoted tumor regression in BRAFi-resistant xenografts. These data identify a molecular pathway for drug resistance connecting BRAFi, the ER stress response, and autophagy and provide a rationale for combination approaches targeting this resistance pathway.