Assessing Direct and Spillover Effects of Intervention Packages in Network-randomized Studies.

BACKGROUND: Intervention packages may result in a greater public health impact than single interventions. Understanding the separate impact of each component on the overall package effectiveness can improve intervention delivery. METHODS: We adapted an approach to evaluate the effects of a time-varying intervention package in a network-randomized study. In some network-randomized studies, only a subset of participants in exposed networks receive the intervention themselves. The spillover effect contrasts average potential outcomes if a person was not exposed to themselves under intervention in the network versus no intervention in a control network. We estimated the effects of components of the intervention package in HIV Prevention Trials Network 037, a Phase III network-randomized HIV prevention trial among people who inject drugs and their risk networks using marginal structural models to adjust for time-varying confounding. The index participant in an intervention network received a peer education intervention initially at baseline, then boosters at 6 and 12 months. All participants were followed to ascertain HIV risk behaviors. RESULTS: There were 560 participants with at least one follow-up visit, 48% of whom were randomized to the intervention, and 1,598 participant visits were observed. The spillover effect of the boosters in the presence of initial peer education training was a 39% rate reduction (rate ratio = 0.61; 95% confidence interval = 0.43, 0.87). CONCLUSIONS: These methods will be useful for evaluating intervention packages in studies with network features.

Overall, Direct, Spillover, and Composite Effects of Components of a Peer-Driven Intervention Package on Injection Risk Behavior Among People Who Inject Drugs in the HPTN 037 Study.

We sought to disentangle effects of the components of a peer-education intervention on self-reported injection risk behaviors among people who inject drugs (n = 560) in Philadelphia, US. We examined 226 egocentric groups/networks randomized to receive (or not) the intervention. Peer-education training consisted of two components delivered to the intervention network index individual only: (1) an initial training and (2) "booster" training sessions during 6- and 12-month follow up visits. In this secondary data analysis, using inverse-probability-weighted log-binomial mixed effects models, we estimated the effects of the components of the network-level peer-education intervention upon subsequent risk behaviors. This included contrasting outcome rates if a participant is a network member [non-index] under the network exposure versus under the network control condition (i.e., spillover effects). We found that compared to control networks, among intervention networks, the overall rates of injection risk behaviors were lower in both those recently exposed (i.e., at the prior visit) to a booster (rate ratio [95% confidence interval]: 0.61 [0.46-0.82]) and those not recently exposed to it (0.81 [0.67-0.98]). Only the boosters had statistically significant spillover effects (e.g., 0.59 [0.41-0.86] for recent exposure). Thus, both intervention components reduced injection risk behaviors with evidence of spillover effects for the boosters. Spillover should be assessed for an intervention that has an observable behavioral measure. Efforts to fully understand the impact of peer education should include routine evaluation of spillover effects. To maximize impact, boosters can be provided along with strategies to recruit especially committed peer educators and to increase attendance at trainings. Clinical Trials Registration Clinicaltrials.gov NCT00038688 June 5, 2002.

RESUMEN: Intentamos desenmarañar los efectos de los componentes de una intervención de educación entre pares sobre los comportamientos de inyección de riesgo autorreportados entre personas que se inyectan drogas (n = 560; 226 grupos/redes egocéntricos(as)) aleatorizados(as) a recibir (o no) la intervención en Filadelfia, EUA. Dos componentes fueron administrados a índices de redes de intervención: una capacitación inicial y sesiones de "refuerzo" durante visitas de seguimiento. Usando modelos log-binomial de efectos mixtos ponderados por probabilidad inversa, estimamos los efectos de dichos componentes sobre los comportamientos de riesgo posteriores. Encontramos que en comparación con las redes control, en las redes de intervención, las tasas generales de comportamientos de inyección de riesgo fueron más bajas en ambas aquellas expuestas recientemente a un refuerzo (razón de tasas [intervalo de confianza del 95%]: 0.61 [0.46­0.82]) y aquellas no expuestas recientemente (0.81 [0.67­0.98]). Solamente los refuerzos tuvieron efectos derrame (i.e., contraste de las tasas de resultados si es miembro [no índice] de una red en una red con exposición reciente versus bajo la condición control) significativos (p. ej., 0.59 [0.41­0.86] para la exposición reciente).

Timing of Antiretroviral Therapy Initiation and Risk of Cancer Among Persons Living With Human Immunodeficiency Virus.

BACKGROUND: Persons living with human immunodeficiency virus (HIV; PLWH) experience a high burden of cancer. It remains unknown which cancer types are reduced in PLWH with earlier initiation of antiretroviral therapy (ART). METHODS: We evaluated AIDS-free, ART-naive PLWH during 1996-2014 from 22 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. PLWH were followed from first observed CD4 of 350-500 cells/µL (baseline) until incident cancer, death, lost-to-follow-up, or December 2014. Outcomes included 6 cancer groups and 5 individual cancers that were confirmed by chart review or cancer registry linkage. We evaluated the effect of earlier (in the first 6 months after baseline) versus deferred ART initiation on cancer risk. Marginal structural models were used with inverse probability weighting to account for time-dependent confounding and informative right-censoring, with weights informed by subject's age, sex, cohort, baseline year, race/ethnicity, HIV transmission risk, smoking, viral hepatitis, CD4, and AIDS diagnoses. RESULTS: Protective results for earlier ART were found for any cancer (adjusted hazard ratio [HR] 0.57; 95% confidence interval [CI], .37-.86), AIDS-defining cancers (HR 0.23; 95% CI, .11-.49), any virus-related cancer (HR 0.30; 95% CI, .16-.54), Kaposi sarcoma (HR 0.25; 95% CI, .10-.61), and non-Hodgkin lymphoma (HR 0.22; 95% CI, .06-.73). By 15 years, there was also an observed reduced risk with earlier ART for virus-related NADCs (0.6% vs 2.3%; adjusted risk difference -1.6; 95% CI, -2.8, -.5). CONCLUSIONS: Earlier ART initiation has potential to reduce the burden of virus-related cancers in PLWH but not non-AIDS-defining cancers (NADCs) without known or suspected viral etiology.

Association of Immunosuppression and Human Immunodeficiency Virus (HIV) Viremia With Anal Cancer Risk in Persons Living With HIV in the United States and Canada.

BACKGROUND: People living with human immunodeficiency virus (HIV; PLWH) have a markedly elevated anal cancer risk, largely due to loss of immunoregulatory control of oncogenic human papillomavirus infection. To better understand anal cancer development and prevention, we determined whether recent, past, cumulative, or nadir/peak CD4+ T-cell count (CD4) and/or HIV-1 RNA level (HIV RNA) best predict anal cancer risk. METHODS: We studied 102 777 PLWH during 1996-2014 from 21 cohorts participating in the North American AIDS Cohort Collaboration on Research and Design. Using demographics-adjusted, cohort-stratified Cox models, we assessed associations between anal cancer risk and various time-updated CD4 and HIV RNA measures, including cumulative and nadir/peak measures during prespecified moving time windows. We compared models using the Akaike information criterion. RESULTS: Cumulative and nadir/peak CD4 or HIV RNA measures from approximately 8.5 to 4.5 years in the past were generally better predictors for anal cancer risk than their corresponding more recent measures. However, the best model included CD4 nadir (ie, the lowest CD4) from approximately 8.5 years to 6 months in the past (hazard ratio [HR] for <50 vs ≥500 cells/µL, 13.4; 95% confidence interval [CI], 3.5-51.0) and proportion of time CD4 <200 cells/µL from approximately 8.5 to 4.5 years in the past (a cumulative measure; HR for 100% vs 0%, 3.1; 95% CI, 1.5-6.6). CONCLUSIONS: Our results are consistent with anal cancer promotion by severe, prolonged HIV-induced immunosuppression. Nadir and cumulative CD4 may represent useful markers for identifying PLWH at higher anal cancer risk.

Citrus fruit intake and gastric cancer: The stomach cancer pooling (StoP) project consortium.

Diets rich in vegetables and fruit have been associated with reduced risk of gastric cancer, and there is suggestive evidence that citrus fruits have a protective role. Our study aimed at evaluating and quantifying the association between citrus fruit intake and gastric cancer risk. We conducted a one-stage pooled analysis including 6,340 cases and 14,490 controls from 15 case-control studies from the stomach cancer pooling (StoP) project consortium. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer across study-specific tertiles of citrus fruit intake (grams/week) were estimated by generalized linear mixed effect models, with logistic link function and random intercept for each study. The models were adjusted for sex, age, and the main recognized risk factors for gastric cancer. Compared to the first third of the distribution, the adjusted pooled OR (95% CI) for the highest third was 0.80 (0.73-0.87). The favourable effect of citrus fruits increased progressively until three servings/week and leveled off thereafter. The magnitude of the association was similar between cancer sub-sites and histotypes. The analysis by geographic area showed no association in studies from the Americas. Our data confirm an inverse association between citrus fruits and gastric cancer and provide precise estimates of the magnitude of the association. However, the null association found in studies from America and in some previous cohort studies prevent to draw definite conclusions on a protective effect of citrus fruit consumption.

Genetic polymorphisms of PPAR gamma, arsenic methylation capacity and breast cancer risk in Mexican women.

OBJECTIVE: To evaluate whether the presence of polymorphisms of peroxisome proliferator-activated receptor gamma PPARγ (Pro 1 2Ala) and PPARGC1B (Ala203Pro) modifies the association between the inorganic arsenic (iAs) methylation capacity and breast cancer (BC). MATERIALS AND METHODS: Mexican women were interviewed, and blood and urine samples were collected from them (cases/controls= 197/220). The concentration of urinary arsenic species and the polymorphisms of interest were determined by high-performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and polymerase chain reaction (PCR), respectively. RESULTS: In women with a high %MMA (urinary monomethyl arsenic) and high primary methylation ratio (PM = MMA/iAs), the risk of BC was increased (odds ratio [OR]%MMA T3 vs.T1= 3.60: 95% confidence interval [CI] 2.02-6.41, ORPMI T3 vs.T1= 3.47: 95%CI 1.95-6.17), which was maintained after adjusting for polymorphisms. No significant interactions were observed between the polymorphisms and the arsenic variables on the risk of BC. CONCLUSION: Pro 12Ala and Ala203Pro polymorphisms did not modify the association between the iAs methylation capacity and BC.

Dietary patterns and gastric cancer risk in Mexico.

Multiple epidemiological studies have evaluated the relationship between diet and gastric cancer (GC), focusing on individual foods and nutrients. However, some studies have estimated the association between dietary patterns and GC risk. To identify the dietary patterns of residents of Mexico City and to assess the association of these patterns with GC, a population-based case-control study with 248 histologically confirmed GC cases and 478 controls paired by age and sex was carried out. The dietary patterns were characterized from 22 food groups through factorial analysis. Three major dietary patterns were identified. Pattern 1 was characterized by the consumption of vegetables, fruits, and white meat; subjects in the highest quintile of this pattern had a lower GC risk than those in the lowest quintile [odds ratio (OR(Q5 vs. Q1)) = 0.43; 95% confidence interval (95%CI): 0.24-0.77; P trend = 0.010]. A comparison between the extreme quintiles of the third pattern (which included major consumption of refined grains and desserts), resulted in the following: OR(Q5 vs. Q1) = 4.80; 95%CI: 2.56-8.98; P-trend < 0.001). Additionally, we found no significant association between the second pattern (characterized by high consumption of Mexican food) and GC risk. This is the first study of associations between dietary patterns and GC in Mexico to confirm that GC risk is lower in individuals with healthy dietary patterns.

[Diet and gastric cancer in Mexico and in the world]. / Dieta y cáncer gástrico en México y en el mundo.

Gastric cancer (GC) is the fourth leading cause of cancer death at global level. Diet, alcohol and tobacco, in addition to Helicobacter pylori infection, account for a large number of cases. Some substances contained in foods may influence GC carcinogenesis process; however, the underlying mechanisms have not been fully elucidated. In Mexico and worldwide, a low intake of fruits, non-starchy and allium vegetables, pulses, and foods containing selenium, as well as high intake of salt, salty, salted and smoked foods, chili pepper, processed and grilled/barbecued meats, have been respectively associated with an increased risk of GC. Based on the available evidence, programs for GC prevention and control could be developed and evaluated.

[Correct utilization of breast cancer detection techniques in Mexican women]. / Utilización correcta de las técnicas de detección de cáncer de mama en mujeres mexicanas.

OBJECTIVE: Identify the characteristics associated with correct utilization of self examination (SE), clinical exam (CE) and mammography (MA) for breast cancer (BC) early detection. MATERIALS AND METHODS: Interviews were undertaken with 1 030 Mexican women (n=1 030), 20 to 88 years of age, regarding their reproductive and sociodemographic characteristics. An index of correct utilization was constructed based on the form and frequency practice of those techniques. RESULTS: The prevalence of correct utilization of SE was 11% and 5.4% for CE. Further, 7.6% of women 40-49 years of age with 2 or more BC risk factors had MA during the two years prior to the interview, and for 31.6% among women ≥50 years of age the MA was annually. The main determinant of MA utilization was having financial protection from either IMSS, ISSSTE or Seguro Popular. CONCLUSIONS: It is necessary to improve the correct utilization of BC detection techniques in Mexico.

Efficacy and Impact of Peer-Led Education for Persons with Tuberculosis in Kampala, Uganda: A Pre-Post Implementation Study.

Introduction: Universal TB education and counseling (TEC) is routinely recommended for promoting knowledge and medication adherence, but the quality of delivery often varies because of inadequate clinic space, time, and health worker training. Peer-led counseling is a promising but understudied solution to these challenges. We sought to evaluate the efficacy of a peer-led TEC strategy among newly diagnosed adults initiating TB treatment in Kampala, Uganda. Methods: We conducted a longitudinal, pre-post implementation study comparing the routine, healthcare-worker-led and peer-led strategies for delivery of TEC to consecutive adult persons with TB at a large, public primary-care clinic. Trained staff administered a standardized TB knowledge survey to all persons with TB immediately following TEC. We compared TB knowledge by type of TEC received using t-tests. Results: We enrolled 161 persons with TB, 80 who received conventional TEC from health workers between June and July 2018, and 81 who received peer-led TEC between August and November 2019. The proportions of women (28% vs. 31%, p = 0.64) and persons living with HIV (36% vs 30%, p = 0.37) were similar in the pre- and post-implementation periods. Peer-led TEC was associated with a more significant increase in disease-specific (difference +21%, 95% CI +18% to + 24%, p < 0.0001) and treatment-specific TB knowledge scores (difference +14%, 95% CI + 10% to + 18%, p< 0.0001) than routine healthcare worker-delivered TEC. All TB knowledge constructs were significantly higher for those in the post-implementation period than those in the pre-implementation period. Nine participants met our threshold for adequate knowledge (score ≥ 90%) for disease-specific TB knowledge in the pre-implementation period compared to 63 (78%) in the post-implementation period (+67%, 95% CI + 55% - +78%, p < 0.001). Twenty-eight (35%) met the adequate knowledge threshold for TB treatment-specific knowledge in the pre-implementation period compared to 60 (74%) in the post-implementation period (+ 39%, 95% CI + 25 to + 53%, p < 0.0001). Finally, the proportion achieving TB treatment success (cure or completed) increased substantially from the pre-implementation period (n = 49, 68%) to the post-implementation period (n = 63, 88%), a difference of + 19% (95% CI + 6% to + 33%, p = 0.005). Conclusion: Our findings suggest that peer-led TEC is more efficacious than routine TEC at improving TB knowledge and treatment outcomes. Future studies should evaluate the implementation and effectiveness of the peer-led TEC strategy when scaled to a larger number of clinics.

Navigating grey areas in HIV and mental health implementation science.

INTRODUCTION: Implementation science (IS) offers methods to systematically achieve the Ending the HIV Epidemic goals in the United States, as well as the global UNAIDS targets. Federal funders such as the National Institutes of Mental Health (NIMH) have invested in implementation research to achieve these goals, including supporting the AIDS Research Centres (ARCs), which focus on high-impact science in HIV and mental health (MH). To facilitate capacity building for the HIV/MH research workforce in IS, "grey areas," or areas of IS that are confusing, particularly for new investigators, should be addressed in the context of HIV/MH research. DISCUSSION: A group of IS experts affiliated with NIMH-funded ARCs convened to identify common and challenging grey areas. The group generated a preliminary list of 19 grey areas in HIV/MH-related IS. From the list, the authors developed a survey which was distributed to all ARCs to prioritize grey areas to address in this paper. ARC members across the United States (N = 60) identified priority grey areas requiring clarification. This commentary discusses topics with 40% or more endorsement. The top grey areas that ARC members identified were: (1) Differentiating implementation strategies from interventions; (2) Determining when an intervention has sufficient evidence for adaptation; (3) Integrating recipient perspectives into HIV/MH implementation research; (4) Evaluating whether an implementation strategy is evidence-based; (5) Identifying rigorous approaches for evaluating the impact of implementation strategies in the absence of a control group or randomization; and (6) Addressing innovation in HIV/MH IS grants. The commentary addresses each grey area by drawing from the existing literature (when available), providing expert guidance on addressing each in the context of HIV/MH research, and providing domestic and global HIV and HIV/MH case examples that address these grey areas. CONCLUSIONS: HIV/MH IS is key to achieving domestic and international goals for ending HIV transmission and mitigating its impact. Guidance offered in this paper can help to overcome challenges to rigorous and high-impact HIV/MH implementation research.

PPARγ and PPARGC1B polymorphisms modify the association between phthalate metabolites and breast cancer risk.

CONTEXT: Breast cancer (BC) risk has been differentially associated with urinary levels of some phthalate metabolites. OBJECTIVE: To investigate whether PPARγ and PPARGC1B polymorphisms modulate these associations. MATERIALS AND METHODS: 208 BC cases were age-matched with 220 population controls. Phthalate metabolites were determined by HPLC-MS. PPARγ Pro12Ala (rs1801281) and PPARGC1B Ala203Pro (rs7732671) and Val279Ile (rs17572019) were genotyped. RESULTS: The association between mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and BC risk was positively modified in PPARγ Pro12Ala C carriers. The association with mono-iso-butyl phthalate (MiBP) in PPARGC1B Ala203Pro G carriers was negatively modified. CONCLUSION: PPARγ and PPARGC1B polymorphisms modulate the association between phthalate exposure and BC risk.

Factors associated with receiving results and attending colposcopy in patients with positive HPV screens in Mexico City.

We identified patient and healthcare system factors related to receipt of screening results and attendance to colposcopy among patients with positive screening results in a cervical cancer screening program in Mexico City, Mexico. We analyzed data from 1,351 patients with high-risk human papillomavirus (HPV)-positive results from two screening demonstration studies conducted between 2017 and 2018. Factors associated with receipt of screening results and with adherence to a colposcopy appointment were identified using multivariable logistic regression. Participants had a median age of 40 years (IQR = 32-48), 60% had less than high school education, and 74% had a previous Pap screening in the last 5 years. Fifty-five percent of participants retrieved their screening results at the healthcare facility (HCF) without any reminder. Providing an email address for contact information, attending a HCF with family medicine, and receiving care from experienced nurses were associated with greater adherence to obtaining screening test results. Fifty-seven percent of participants attended their first scheduled colposcopy appointment. Providing a phone number improved adherence to colposcopy, whereas longer travel times between the HCF and the colposcopy clinic was associated with a decrease in colposcopy adherence. Having a Pap test in the last 5 years was positively associated with better compliance with both outcomes. Securing contact information may help to overcome barriers to future follow-up. Additional research is necessary on strategies for obtaining screening test results and scheduling appointments, which may help address barriers to access, such as limited staff availability, distance from the clinic, and travel costs.

Is aggregated surveillance data a reliable method for constructing tuberculosis care cascades? A secondary data analysis from Uganda.

To accelerate tuberculosis (TB) control and elimination, reliable data is needed to improve the quality of TB care. We assessed agreement between a surveillance dataset routinely collected for Uganda's national TB program and a high-fidelity dataset collected from the same source documents for a research study from 32 health facilities in 2017 and 2019 for six measurements: 1) Smear-positive and 2) GeneXpert-positive diagnoses, 3) bacteriologically confirmed and 4) clinically diagnosed treatment initiations, and the number of people initiating TB treatment who were also 5) living with HIV or 6) taking antiretroviral therapy. We measured agreement as the average difference between the two methods, expressed as the average ratio of the surveillance counts to the research data counts, its 95% limits of agreement (LOA), and the concordance correlation coefficient. We used linear mixed models to investigate whether agreement changed over time or was associated with facility characteristics. We found good overall agreement with some variation in the expected facility-level agreement for the number of smear positive diagnoses (average ratio [95% LOA]: 1.04 [0.38-2.82]; CCC: 0.78), bacteriologically confirmed treatment initiations (1.07 [0.67-1.70]; 0.82), and people living with HIV (1.11 [0.51-2.41]; 0.82). Agreement was poor for Xpert positives, with surveillance data undercounting relative to research data (0.45 [0.099-2.07]; 0.36). Although surveillance data overcounted relative to research data for clinically diagnosed treatment initiations (1.52 [0.71-3.26]) and number of people taking antiretroviral therapy (1.71 [0.71-4.12]), their agreement as assessed by CCC was not poor (0.82 and 0.62, respectively). Average agreement was similar across study years for all six measurements, but facility-level agreement varied from year to year and was not explained by facility characteristics. In conclusion, the agreement of TB surveillance data with high-fidelity research data was highly variable across measurements and facilities. To advance the use of routine TB data as a quality improvement tool, future research should elucidate and address reasons for variability in its quality.

Effect modification by sex for associations of fine particulate matter (PM2.5) with cardiovascular mortality, hospitalization, and emergency room visits: systematic review and meta-analysis.

Particulate matter with aerodynamic diameter no larger than 2.5 µm (PM2.5) has been linked to cardiovascular diseases (CVDs) but evidence for vulnerability by sex remains unclear. We performed systematic review and meta-analysis to synthesize the state of scientific evidence on whether cardiovascular risks from PM2.5 differ for men compared to women. The databases Pubmed, Scopus, Embase, and GreenFILE were searched for studies published Jan. 1995 to Feb. 2020. Observational studies conducting subgroup analysis by sex for impacts of short-term or long-term exposure to PM2.5 on target CVDs were included. Data were independently extracted in duplicate and pooled with random-effects meta-regression. Risk ratios (RRs) for long-term exposure and percent changes in outcomes for short-term exposure were calculated per 10 µg/m3 PM2.5 increase. Quality of evidence of risk differences by sex was rated following Grading of Recommendations Assessment, Development and Evaluation (GRADE). A total of 12,502 articles were screened, with 61 meeting inclusion criteria. An additional 32 studies were added from citation chaining. RRs of all CVD mortality for long-term PM2.5 for men and women were the same (1.14; 95% CI: 1.09, 1.22) indicating no statistically different risks. Men and women did not have statistically different risks of daily CVD mortality, hospitalizations from all CVD, ischemic heart disease, cardiac arrest, acute myocardial infarction, and heart failure from short-term PM2.5 exposure (difference in % change in risk per 10 µg/m3 PM2.5: 0.04 (95% CI, -0.42 to 0.51); -0.05 (-0.47 to 0.38); 0.17 (-0.90, 1.24); 1.42 (-1.06, 3.97); 1.33 (-0.05, 2.73); and -0.48 (-1.94, 1.01), respectively). Analysis using GRADE found low or very low quality of evidence for sex differences for PM2.5-CVD risks. In conclusion, this meta-analysis and quality of evidence assessment of current observational studies found very limited evidence of the effect modification by sex for effects of PM2.5 on CVD outcomes in adults, which can inform clinical approaches and policies.

Phthalate exposure associated with self-reported diabetes among Mexican women.

BACKGROUND: Phthalates are ubiquitous industrial chemicals used as plasticizers in plastics made of polyvinyl chloride (PVC) to confer flexibility and durability. They are also present in products used for personal-care, industry and in medical devices. Phthalates have been associated with several adverse health effects, and recently it has been proposed that exposure to phthalates, could have an effect on metabolic homeostasis. This exploratory cross-sectional study evaluated the possible association between phthalate exposure and self-reported diabetes among adult Mexican women. METHODS: As part of an on-going case-control study for breast cancer, only controls were selected, which constituted 221 healthy women matched by age (±5 years) and place of residence with the cases. Women with diabetes were identified by self-report. Urinary concentrations of nine phthalate metabolites were measured by online solid phase extraction coupled to high performance liquid chromatography-isotope-dilution tandem mass spectrometry. RESULTS: Participants with diabetes had significantly higher concentrations of di(2-ethylhexyl) pththalate (DEHP) metabolites: mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono(2-ethyl-5-oxohexyl) phthalate (MEOHP) and mono(2-ethyl-5-carboxypentyl) phthalate (MECPP) but lower levels of monobenzyl phthalate (MBzP) a metabolite of benzylbutyl phthalate, compared to participants without diabetes. A marginally significant positive associations with diabetes status were observed over tertiles with MEHHP (OR(T3 vs. T1)=2.66; 95% CI: 0.97-7.33; p for trend=0.063) and MEOHP (OR(T3 vs. T1)=2.27; 95% CI; 0.90-5.75; P for trend=0.079) even after adjusting for important confounders. CONCLUSIONS: The results suggest that levels of some phthalates may play a role in the genesis of diabetes.

A Systematic Review and Meta-Analysis of Studies Evaluating the Effect of Medication Treatment for Opioid Use Disorder on Infectious Disease Outcomes.

The opioid epidemic has fueled infectious disease epidemics. We determined the impact of medications for opioid use disorder (MOUD) on treatment outcomes of opioid use disorder (OUD)-associated infectious diseases: antiretroviral therapy (ART) adherence, human immunodeficiency virus (HIV) viral suppression, hepatitis C virus (HCV) sustained virologic response, HCV reinfection, new hepatitis B virus infections, and infectious endocarditis-related outcomes. Manuscripts reporting on these infectious disease outcomes in adults with OUD receiving MOUD compared with those with OUD "not" receiving MOUD were included. Initial search yielded 8169 papers; 9 were included in the final review. The meta-analysis revealed that MOUD was associated with greater ART adherence (odds ratio [OR] = 1.55; 95% confidence interval [CI] = 1.12-2.15) and HIV viral suppression (OR = 2.19; 95% CI = 1.88-2.56). One study suggested a positive association between MOUD and HCV sustained virologic response. There is significant support for integrating MOUD with HIV treatment to improve viral suppression among persons with HIV (PWH) and OUD. Treatment of OUD among PWH should be a priority to combat the opioid and HIV epidemics.

Dietary intake of polyphenols, nitrate and nitrite and gastric cancer risk in Mexico City.

N-nitroso compounds (NOC) are potent animal carcinogens and potential human carcinogens. The primary source of exposure for most individuals may be endogenous formation, a process that can be inhibited by dietary polyphenols. To estimate the risk of gastric cancer (GC) in relation to the individual and combined consumption of polyphenols and NOC precursors (nitrate and nitrite), a population-based case-control study was carried out in Mexico City from 2004 to 2005 including 257 histologically confirmed GC cases and 478 controls. Intake of polyphenols, nitrate and nitrite were estimated using a food frequency questionnaire. High intakes of cinnamic acids, secoisolariciresinol and coumestrol were associated with an approximately 50% reduction in GC risk. A high intake of total nitrite as well as nitrate and nitrite from animal sources doubled the GC risk. Odds ratios around 2-fold were observed among individuals with both low intake of cinnamic acids, secoisolariciresinol or coumestrol and high intake of animal-derived nitrate or nitrite, compared to high intake of the polyphenols and low animal nitrate or nitrite intake, respectively. Results were similar for both the intestinal and diffuse types of GC. Our results show, for the first time, a protective effect for GC because of higher intake of cinnamic acids, secoisolariciresinol and coumestrol, and suggest that these polyphenols reduce GC risk through inhibition of endogenous nitrosation. The main sources of these polyphenols were pears, mangos and beans for cinnamic acids; beans, carrots and squash for secoisolariciresinol and legumes for coumestrol.

Sodium arsenite alters cell cycle and MTHFR, MT1/2, and c-Myc protein levels in MCF-7 cells.

There is limited available information on the effects of arsenic on enzymes participating in the folate cycle. Therefore, our aim was to evaluate the effects of sodium arsenite on the protein levels of methylenetetrahydrofolate reductase (MTHFR) and dihydrofolate reductase (DHFR) and its further relationship with the expression MT1/2 and c-myc in MCF-7 cells. Arsenite treatment (0-10 microM) for 4 h decreased MTHFR levels in a concentration-dependent fashion without significant effects on DHFR. The effects on MTHFR were observed at arsenite concentrations not significantly affecting cell viability. We also observed an increase in S-phase recruitment at all concentrations probed. Lower concentrations (<5 microM) induced cell proliferation, showing a high proportion of BrdU-stained cells, indicating a higher DNA synthesis rate. However, higher concentrations (> or =5 microM) or longer treatment periods induced apoptosis. Arsenite also induced dose-dependent increases in MT1/2 and c-Myc protein levels. The levels of MTHFR were inversely correlated to MT1/2 and c-Myc overexpression and increased S-phase recruitment. Our findings indicate that breast epithelial cells are responsive to arsenite and suggest that exposure may pose a risk for breast cancer. The reductions in MTHFR protein levels contribute to understand the mechanisms underlying the induction of genes influencing growth regulation, such as c-myc and MT1/2. However, further research is needed to ascertain if the effects here reported following short-time and high-dose exposure are relevant for human populations chronically exposed to low arsenic concentrations.

Gastric cancer in relation to the intake of nutrients involved in one-carbon metabolism among MTHFR 677 TT carriers.

BACKGROUND: DNA methylation is an important epigenetic process for transcriptional control of human genome including those genes involved in cancer initiation and progression. Clinical studies have suggested that biological explanation to the protective effect of some nutrients could be linked with the DNA methylation. Folate is a primary methyl donor nutrient; it has been shown to play a key role in DNA methylation, repair and synthesis, by acting as co-factors and/or substrates in this metabolic pathway. Likewise, activity of a key enzyme, the methylenetetrahydrofolate reductase (MTHFR) has also been shown to influence DNA methylation. Overall, these findings support the notion that dietary intake as well as genetic factors play a role in one-carbon metabolism. AIM OF THE STUDY: This study is to evaluate the dietary intake of nutrients involved in one-carbon metabolism and the genotype of MTHFR 677 C > T with respect to GC risk. METHODS: We carried out in January 2004 a population-based case-control study in the metropolitan area of Mexico City. A total of 248 histological confirmed GC patients were recruited from nine tertiary hospitals, along with 478 age and sex-matched controls. Nutrient intake was estimated from food frequency questionnaire; the MTHFR 677C > T genotype was determined by PCR-RFLP analysis. RESULTS: A significant reduction in diffuse GC risk was observed for MTHFR 677 TT genotype among individuals with high consumption of folate (OR = 0.23; 95% CI 0.06-0.84), choline (OR = 0.55; 95% CI 0.33-0.9) and Vitamin B(6) (OR = 0.59; 95% CI 0.36-0.96) compared to MTHFR 677 CC + CT carriers. Among subjects with low consumption of methionine, a reduced risk of diffuse GC was also detected (OR = 0.40; 95% CI 0.16-0.97). In contrast, carriers of the MTHFR 677 TT genotype with a low consumption of folate had a significant increased risk of intestinal GC (OR = 1.88 95% CI 1.02-3.47). A folate-MTHFR 677 C > T interaction in the borderline of significance (P = 0.055) was detected. CONCLUSIONS: It is probable that GC prevention requires dietary recommendations according to the individual genotype; nevertheless, the available information to this respect is still very limited.