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A lack of prospective studies has been a major barrier for assessing the role of the microbiome in human health and disease on a population-wide scale. To address this significant knowledge gap, we have launched a large-scale collection targeting fecal and oral microbiome specimens from 20,000 women within the Nurses’ Health Study II cohort (the Microbiome Among Nurses study, or Micro-N). Leveraging the rich epidemiologic data that have been repeatedly collected from this cohort since 1989; the established biorepository of archived blood, urine, buccal cell, and tumor tissue specimens; the available genetic and biomarker data; the cohort’s ongoing follow-up; and the BIOM-Mass microbiome research platform, Micro-N furnishes unparalleled resources for future prospective studies to interrogate the interplay between host, environmental factors, and the microbiome in human health. These prospectively collected materials will provide much-needed evidence to infer causality in microbiome-associated outcomes, paving the way toward development of microbiota-targeted modulators, preventives, diagnostics and therapeutics. Here, we describe a generalizable, scalable and cost-effective platform used for stool and oral microbiome specimen and metadata collection in the Micro-N study as an example of how prospective studies of the microbiome may be carried out. This Perspective from the Harvard Chan Microbiome in Public Health Center describes a generalizable and scalable approach to stool and oral microbiome and metadata collection in the Micro-N (Microbiome Among Nurses) study, to show how to carry out prospective studies of the microbiome.

Objective Skin conditions have been associated with increased risk of Parkinson's disease (PD). Little is known about clinical and biomarker differences according to presence of skin conditions among PD patients. Studying these differences might provide insight into PD pathogenesis. Methods We examined the association between common skin conditions and risk of PD in a case-control study of 423 early drug-naive PD cases and 196 healthy controls (HC) in the Parkinson's Progression Markers Initiative (PPMI). Among PD participants, we examined if skin conditions were associated with clinical and PD-relevant biomarkers. Results Skin conditions occurred more frequently among PD participants (41%) relative to HC (32%). In multivariate analyses, we observed an association between any skin condition and PD (OR = 1.49, 95% CI = 1.03–2.16) and basal cell carcinoma and PD (OR = 2.05, 95% CI = 1.02–4.08). PD participants who reported skin conditions were older (OR = 1.68, 95% CI = 1.21–2.35) more educated (OR = 1.70, 95% CI = 0.99–2.91), had higher Semantic Fluency Test (SFT) scores (OR = 1.45, 95% CI = 1.07–1.96) and Hopkins Verbal Learning Test (HVLT) retention scores (OR = 1.55, 95% CI = 1.09–2.22) compared to PD patients without skin conditions. None of the associations remained significant after Bonferroni correction for multiple comparisons. Conclusions We observed a positive association between any skin condition as well as basal cell carcinoma and PD. PD participants with skin conditions were older, more educated, had higher SFT and HVLT retention scores compared to those without skin conditions. However, all associations were no longer significant after Bonferroni multiple comparisons correction. Observed associations should be confirmed in larger, longitudinal studies.

BACKGROUND: There is evidence that low plasma vitamin B-12 and folate individually, as well as an imbalance of high folic acid and low vitamin B-12 status, may be associated with lower cognitive function. OBJECTIVES: We examined dietary and plasma folate and vitamin B-12 status, and their interaction, in relation to cognitive function in a cohort of older Puerto Rican adults. METHODS: The design is cross-sectional, with 1408 participants from the Boston Puerto Rican Health Study (mean ± SD age: 57.1 ± 7.9 y). Cognitive function was assessed with a comprehensive test battery and a global composite score was derived. Plasma folate, vitamin B-12, and methylmalonic acid (MMA) were assessed in fasting blood samples. RESULTS: After adjusting for covariates, high plasma folate and high plasma vitamin B-12 were each positively associated with global cognitive score (β: 0.063; 95% CI: −0.0008, 0.127; P = 0.053 and β: 0.062; 95% CI: 0.009, 0.12; P = 0.023, respectively, for logged values, and β: 0.002; 95% CI: 0.00005, 0.004; P-trend = 0.044 and β: 0.00018; 95% CI: 0.00001, 0.0003; P-trend = 0.036, respectively, across tertiles). Nine percent of participants had vitamin B-12 deficiency (plasma vitamin B-12 271 nmol/L), but none were folate deficient (plasma folate

Background Food insecurity is prevalent among Puerto Rican adults in the USA and is associated with adverse psychosocial outcomes. However, the direction of this association has not been established in this understudied population. Objectives In this study, we aimed to examine the longitudinal association between a group of psychosocial risk factors and subsequent food insecurity in a cohort of Puerto Rican adults. Methods Secondary analysis was conducted using data from the prospective Boston Puerto Rican Health Study. A total of 517 Puerto Rican participants aged 45-75 y in the Boston area who were food secure at baseline, and who completed food security surveys at baseline and 5 y were included. Psychosocial factors, including depressive symptoms, stress, tangible social support, and acculturation were assessed with validated instruments. Multivariable logistic regression models were used to examine the risk of food insecurity at 5 y, as a function of psychosocial factors at baseline and their changes over 5 y, adjusting for age, sex, education, baseline and change in total annual household income, and in family size. Results The cumulative incidence of food insecurity at 5 y was 12.6%. The odds of incident food insecurity was significantly associated with baseline depressive symptom score [OR = 1.78 (1.16, 2.76) per each 10 score units], with change in depressive symptom score [OR = 1.50 (1.07, 2.09) per each 10-unit increase], and with change in perceived stress [OR = 1.59 (1.01, 2.51) per each 10-unit increase], after adjusting for potential confounders. Conclusion In this cohort of Puerto Rican adults, depressive symptoms at baseline, and increases in depressive symptoms and perceived stress over 5 y were associated with a higher risk of food insecurity. Psychosocial health and environment appear to play important roles in predicting risk of food insecurity in the Puerto Rican community.

Background Despite its important role in cognitive development and regulation of nervous system function, vitamin B-6 has been under-studied in relation to cognitive aging. Objective We investigated whether plasma pyridoxal-5'-phosphate (PLP, vitamin B-6) concentrations were associated with cognitive function and subsequent cognitive decline. Methods In a longitudinal study of 949 participants (aged 45-75 y at baseline; 70% women) from the Boston Puerto Rican Health Study cohort, we examined the association between baseline plasma PLP and baseline cognitive function and 2-y cognitive decline. Cognitive function was assessed with an in-person 7-test cognitive battery, at baseline and 2-y follow-up. We also used logistic regression to estimate the odds of major 2-y decline in global cognitive function (defined as decline ≥1 SD below the mean), as well as decline in executive function and memory. We also used multivariable linear regression to calculate adjusted mean differences in cognitive scores, and 95% CIs, across tertiles of plasma PLP at baseline, as well as cross-sectional and longitudinal associations with individual test scores. Results In analyses adjusted for potential confounders, the OR of having a major 2-y decline in global cognitive function was 2.46 (95% CI: 1.49, 4.05; P-trend: 0.001) among participants in the lowest tertile of PLP compared with those in the top tertile of PLP. The association of PLP with cognition was stronger in participants older than 55 y at baseline (OR for bottom to top tertile: 4.58; 95% CI: 2.02, 10.35; P-interaction: 0.01) compared with those 55 y old or younger, as well as in ever smokers (OR for bottom to top tertile: 2.99; 95% CI: 1.45, 6.19; P-interaction: 0.02) compared with never smokers. Conclusions Lower baseline plasma PLP was associated with increased odds of 2-y cognitive decline in a cohort of Boston area Puerto Ricans. The association was stronger among older participants and among ever smokers.

Background: Vitamin D has been suggested as a protective factor for cognitive health, however results of prior studies have been mixed. To examine whether serum 25(OH)D concentration is related to cognition and cognitive decline in a study of Boston Area Puerto Ricans. Methods: We examined the association between serum 25(OH)D, cognitive function and cognitive decline in a longitudinal study of 967 Boston Area Puerto Rican adults. Results: In analyses adjusted for potential confounders, participants in the bottom quintile of 25(OH)D had similar cognitive function at baseline, as measured by a global cognitive score (mean difference: 0.09 (95% CI: -0.02, 0.19); p-trend: 0.18), and similar 2-year rates of cognitive decline (mean difference: -0.01 (95% CI: -0.09, 0.07), p-trend: 0.61) as those in the top 25(OH)D quintile. No significant associations were observed between baseline serum 25(OH)D concentration and 2-year change in individual cognitive test scores or change in executive function or memory domains. Conclusions: We observed no significant association between serum 25(OH)D and cognition in this cohort of Boston Area Puerto Ricans.

This study aimed to estimate the maximal lactate steady-state velocity (vMLSS) from non-invasive bloodless variables and/or blood lactate-related thresholds (BLRTs) measured during an Incremental s...

Resistance training (RT) and n-3 polyunsaturated fatty acids (n-3 PUFA) supplementation have emerged as strategies to improve muscle function in older adults. Overweight/obese postmenopausal women (55–70 years) were randomly allocated to one of four experimental groups, receiving placebo (olive oil) or docosahexaenoic acid (DHA)-rich n-3 PUFA supplementation alone or in combination with a supervised RT-program for 16 weeks. At baseline and at end of the trial, body composition, anthropometrical measures, blood pressure and serum glucose and lipid biomarkers were analyzed. Oral glucose tolerance tests (OGTT) and strength tests were also performed. All groups exhibit a similar moderate reduction in body weight and fat mass, but the RT-groups maintained bone mineral content, increased upper limbs lean mass, decreased lower limbs fat mass, and increased muscle strength and quality compared to untrained-groups. The RT-program also improved glucose tolerance (lowering the OGTT incremental area under the curve). The DHA-rich supplementation lowered diastolic blood pressure and circulating triglycerides and increased muscle quality in lower limbs. In conclusion, 16-week RT-program improved segmented body composition, bone mineral content, and glucose tolerance, while the DHA-rich supplement had beneficial effects on cardiovascular health markers in overweight/obese postmenopausal women. No synergistic effects were observed for DHA supplementation and RT-program combination.

Background: The impact of Levodopa on the gut microbiota of Parkinson's disease (PD) patients has not been sufficiently addressed.Methods: We conducted a longitudinal study to examine the impact of Levodopa initiation on the gut microbiota composition of 19 PD patients who had not previously been exposed to Levodopa. Patients provided two stool samples prior to and two samples 90 days after starting Levodopa. Motor impairment (MDS-UPDRS Part III), diet, and other patient characteristics were assessed. 16S rRNA gene amplicon sequencing was used to characterize the microbiota. We examined, cross-sectionally and longitudinally, the associations between Levodopa use and alpha and beta diversity and performed feature-wise, multivariate modeling to identify taxa associated longitudinally with Levodopa use and with improvement in motor function after Levodopa administration.Results: We did not observe significant differences in alpha or beta diversity before vs. after initiation of Levodopa. In longitudinal feature-wise analyses, at the genus level, no taxa were significantly associated with Levodopa use after false discovery rate (FDR) correction (q < 0.05). We observed a marginally lower relative abundance of bacteria belonging to Clostridium group IV in PD patients who experienced a medium or large improvement in motor impairment in response to Levodopa compared to those with a small response [β = −0.64 (SE: 0.18), p-trend: 0.00015 p-FDR: 0.019].Conclusions: In this study, Levodopa was not associated with changes in microbiota composition in this longitudinal analysis. The association between abundance of Clostridium group IV and short-term motor symptom response to Levodopa is preliminary and should be investigated in larger, longer-term studies, that include a control group.

Background Healthy diets have been associated with better cognitive function. Socioeconomic factors including education, poverty, and job complexity may modify the relationship between diet and cognition. Methods We used adjusted linear mixed models to examine the association between long-term adherence to the Mediterranean-Dietary Approaches to Stop Hypertension - Intervention for Neurodegenerative Delay (MIND) diet and cognitive function over 8 years of follow-up in Puerto Rican adults residing in the Boston, MA area (aged 45–75 years at baseline). We also examined whether the MIND diet—cognition association was confounded or modified by socioeconomic measures. Results In both cross-sectional and longitudinal analyses the highest, versus lowest, MIND quintile was associated with better cognition function (β = 0.093; 95% CI: 0.035, 0.152; p trend = .0019), but not with cognitive trajectory over 8 years. Education Conclusion Adherence to the MIND diet was associated with better cognitive function at baseline and over 8 years of follow-up; however, MIND diet was not associated with 8-year cognitive trajectory. More studies are needed to better understand whether the MIND diet is protective against long-term cognitive decline.

Background A number of studies have reported the association between the use of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin-II receptor blocker (ARB) medications and the occurrence or severity of coronavirus disease 2019 (COVID-19). Published results are inconclusive, possibly due to differences in participant comorbidities and sociodemographic backgrounds. Since ACEI and ARB are frequently used anti-hypertension medications, we aim to determine whether the use of ACEI and ARB is associated with the occurrence and severity of COVID-19 in a large study of US Veterans with hypertension. Methods Data were collected from the Department of Veterans Affairs (VA) National Corporate Data Warehouse (VA-COVID-19 Shared Data Resource) between February 28, 2020 and August 18, 2020. Using data from 228,722 Veterans with a history of hypertension who received COVID-19 testing at the VA, we investigated whether the use of ACEI or ARB over the two years prior to the index date was associated with increased odds of (1) a positive COVID-19 test, and (2) a severe outcome (hospitalization, mortality, and use of intensive care unit (ICU) and/or mechanical ventilation) among COVID-19-positive patients. We used logistic regression with and without propensity score weighting (PSW) to estimate the odds ratio (OR) and 95% confidence interval (95% CI) for the association between ACEI/ARB use and a positive COVID-19 test result. The association between medication use and COVID-19 outcome severity was examined using multinomial logistic regression comparing participants who were not hospitalized to participants who were hospitalized, were admitted to the ICU, used a mechanical ventilator, or died. All models were adjusted for relevant covariates, including demographics (age, sex, race, ethnicity), selected comorbidities, and the Charlson Comorbidity Index (CCI). Results The use of ACEI significantly decreased the odds of a positive COVID-19 test among Veterans with hypertension (OR = 0.917, (0.887, 0.948) and OR = 0.926, (0.894, 0.958) with PSW). The use of ACEI, but not of ARB, was also associated with significantly increased odds of using mechanical ventilators (OR = 1.265, (1.010, 1.584) and OR = 1.210, (1.053, 1.39) with PSW) among all COVID-19 inpatients compared to outpatients. Conclusions In this study of Veterans with hypertension, ACEI was significantly associated with decreased odds of testing positive for COVID-19. With the exception of the association of ACEI with a small non-clinically-important increase in the odds of using mechanical ventilators, neither ACEI nor ARB was found to be associated with clinical severity or mortality among COVID-19-positive Veterans. The results of this study need further corroboration and validation in other cohort samples outside the VA.

Introduction: The prosthetic connection of implants has been related to the loss of marginal bone. The aim of this study was to evaluate bone loss around external connection (EC) and internal conical connection (ICC) implants prior to prosthetic loading. Material and methods: A randomized clinical trial (RCT) was carried out, with a sample size of 93 implants (31 EC and 62 ICC) placed in 27 patients. Radiological controls were performed and stability was measured by resonance frequency analysis (RFA) on the day of placement, at 1 month and at 4 months after the placement. Results: Bone loss in EC implants was not statistically different than in ICC implants between the time of placement (T0) and the subsequent month (T1): (EC = 0.18 mm and ICC = 0.17 mm). Between one month (T1) and four months (T2): (EC = 0.39 mm and ICC = 0.19 mm) this difference was highly significant (p = 0.00). Bone loss between T0 and T2 was significantly lower in the ICC (EC = 0.57 mm and ICC = 0.36 mm), (p = 0.01). The overall success rate of the implants was 97.8%. The stability of the implants increased from 70.69 (T0) to 73.91 (T1) and 75.32 (T2). Conclusions: ICC showed less bone loss up to the time of prosthesis placement. Such bone loss did not have a significant impact on bone stability. Long term RCTs are needed to demonstrate whether this bone loss, which is more pronounced at the beginning in EC, tends to stabilize and equate to ICC.

How exercise intensity targets, calibrated according to oxygen consumption, relate to vertical impacts during weight-bearing exercise is currently unknown. The authors investigated the relationship between vertical peaks (VPs) and metabolic equivalents (METs) of oxygen consumption in 82 women during walking and running. The magnitude of VPs, measured using a hip-worn triaxial accelerometer, was derived from recommended aerobic exercise intensity targets. VPs were 0.63 ± 0.18g at the lower recommended absolute exercise intensity target (3 METs) but >1.5g at the upper end of moderate-intensity activities (1.90 ± 1.13g at 6 METs). Multilevel linear regression analyses identified speed and type of locomotion as the strongest independent predictors of VPs, explaining 54% and 11% of variance, respectively. The authors conclude that, in contrast to lower intensities, exercising close to or above the 6-MET threshold generates VPs of osteogenic potential, suggesting this could provide simultaneous benefits to decrease all-cause mortality and osteoporosis risk.

To investigate how objectively measured physical activity (PA) levels differ according to absolute moderate intensity recommendation (3-6 METs) and relative to individual lactate thresholds (LT1 and LT2), and to verify if high-fit women record higher PA levels compared to women with lower aerobic fitness.Seventy-five postmenopausal women performed an incremental exercise test and several constant-velocity tests wearing an accelerometer to identify the activity counts (ct minAccording to absolute intensity categorisation, high-fit postmenopausal women recorded twice as much time at moderate-to-vigorous PA (MVPA) (P 0.01) than low-fit women. However, when PA intensity was calculated relative to individual lactate thresholds, MVPA was significantly reduced by half (P 0.01) and the data revealed no differences (P = 0.62) between groups (∼20 min dayAccelerometer cut-points derived from absolute moderate-intensity recommendations overestimated MVPA. Similar time at MVPA was recorded by high- and low-fit postmenopausal women when the cut-points were tailored to individual lactate thresholds. A more accurate estimation of PA behaviour could be provided with the use of individually tailored accelerometer cut-points.

La desnutrición es un problema que afecta el crecimiento, desarrollo y salud en general, especialmente de los niños menores de cinco años y mujeres embarazadas. En México, los indicadores de bajo peso y talla señalan una reducción de 8 y 13.3 %, respectivamente, entre 1988 y 2012. A pesar de las intervenciones de salud pública la prevalencia de baja talla continúa siendo un importante problema de salud pública (13.6 % en promedio), especialmente en zonas rurales y urbanas marginales. La biofortificación de cultivos como maíz (Zea mays L.) con zinc es una forma de contribuir a combatir la deficiencia de este micronutriente, sobre todo en estados donde se observa una importante producción y un alto consumo per capita del grano (cerca de 200 kg/año). El objetivo del presente trabajo fue identificar áreas con mayor potencial para la introducción de maíces biofortificados con zinc; para ésto, se determinó un Índice de Priorización para Biofortificación (IPB) y las Condiciones de Intervención para Biofortificación (CIB). Los dos parámetros fueron determinados mediante la estimación de tres índices: producción, consumo y deficiencia de zinc. El IPB constituye una media geométrica de los tres índices, mientras que CIB establece los parámetros de atención para la biofortificación. Los resultados tanto del IPB como CIB indican que las áreas con prioridad elevada para biofortificación son Chiapas, Oaxaca, Guerrero, Hidalgo y Puebla. Las áreas establecidas con prioridad media son Nayarit y Durango, mientras que Quintana Roo fue determinada como de prioridad baja.

Background Prior work on appendectomy and PD has produced mixed results. In this study we examined whether history of self-reported appendectomy was related to risk of incident Parkinson's disease in the Nurses' Health Study and the Health Professionals Follow-up Study. Methods We used the Cox proportional hazards model to estimate the hazard ratio of Parkinson's disease associated with self-report of appendectomy in men and women. Among women, we estimated the hazard ratio of Parkinson's disease associated with appendectomy for appendicitis and incidental appendectomy. Results In pooled analyses, self-report of any appendectomy was not related to Parkinson's disease risk: the hazard ratio of Parkinson's disease comparing participants who reported any appendectomy with those who did not was 1.08 (95% confidence interval, 0.94-1.23). In women, appendectomy for appendicitis, but not incidental appendectomy, was associated with a modestly elevated risk of Parkinson's disease (hazard ratio, 1.23 [95% confidence interval, 1.00-1.50]). Conclusions Overall, this study suggests limited to no association between appendectomy and Parkinson's disease risk. © 2018 International Parkinson and Movement Disorder Society.

Purpose The objective of this systematic review was to compare the loss of marginal bone between implants with internal and external connections by analyzing results reported in studies published after 2010. Materials and methods A literature search in MEDLINE with the keywords "dental implant connections, external internal implant connection, bone loss implant designs, internal and external connection implant studies in humans" was conducted. Clinical trials on human beings, comparing both connections and published in English, from 2010 to 2016 were selected. Their methodologic quality was assessed using the Jadad scale. Results From the initial search, 415 articles were obtained; 32 were chosen as potentially relevant based on their titles and abstracts. Among them, only 10 finally met the inclusion criteria. A total of 1,523 patients with 3,965 implants were analyzed. Six out of 10 studies observed that internal connections showed significantly less bone loss compared with external connections. The remaining four articles did not find statistically significant differences between the two connections. Conclusion According to this systematic review and considering its limitation due to the degree of heterogeneity between the included studies, both internal and external connections present high survival rates. To assess whether marginal bone loss differs significantly between the two connections, more homogenous clinical studies are needed with identical implant characteristics, larger samples, and longer follow-up periods. Studies included in this review and characterized by long-term follow-ups showed that the external connection is a reliable connection on a long-term basis.

Background: Air pollution is thought to raise the risk of neurological disease by promoting neuroinflammation, oxidative stress, glial activation and cerebrovascular damage. Multiple Sclerosis is a common auto-immune disorder, primarily affecting young women. We conducted, to a large prospective study of particulate matter (PM) exposure and multiple sclerosis (MS) risk in two prospective cohorts of women: the Nurses Health Study (NHS) and the Nurses Health Study II (NHS II). Methods: Cumulative average exposure to different size fractions of PM up to the onset of MS was estimated using spatio-temporal models. We used multivariable Cox proportional hazards models to estimate the hazard ratios (HR) and 95% confidence intervals (CI) of MS associated with each size fraction of PM independently. Participants were followed from 1998 through 2004 in NHS and from 1988 through 2007 for NHS II. We conducted additional sensitivity analyses stratified by smoking, region of the US, and age, as well as analyses restricted to women who did not move during the study. Analyses were adjusted for age, ancestry, smoking, body mass index at age 18, region, tract level population density, latitude at age 15, and UV index. Results: We did not observe significant associations between air pollution and MS risk in our cohorts. Among women in the NHS II, the HRs comparing the top vs. bottom quintiles of PM was 1.11 (95% Confidence Intervals (CI): 0.74, 1.66), 1.04 (95% CI: 0.73, 1.50) and 1.09 (95% CI: 0.73, 1.62) for PM10 (≤10μm in diameter), PM2.5 (≤2.5μm in diameter), and PM2.5–10 (2.5 to 10μm in diameter) respectively, and tests for linear trends were not statistically significant. No association between exposure to PM and risk of MS was observed in the NHS. Conclusions: In this study, exposure to PM air pollution was not related to MS risk. Keywords: Epidemiology, Cohort studies, Incidence studies, Parkinson disease

Biofortification of crops to enhance provitamin A carotenoids is a strategy to increase the intake where vitamin A deficiency presents a widespread problem. Heat, light, and oxygen cause isomerization and oxidation of carotenoids, reducing provitamin A activity. Understanding provitamin A retention is important for assessing efficacy of biofortified foods. Retention of carotenoids in high-xanthophyll and high-β-carotene maize was assessed after a long-term storage at three temperatures. Carotenoid retention in high-β-cryptoxanthin maize was determined in muffins, non-nixtamalized tortillas, porridge, and fried puffs made from whole-grain and sifted flour. Retention in eggs from hens fed high-β-cryptoxanthin maize was assessed after frying, scrambling, boiling, and microwaving. Loss during storage in maize was accelerated with increasing temperature and affected by genotype. Boiling whole-grain maize into porridge resulted in the highest retention of all cooking and sifting methods (112%). Deep-fried maize and scrambled eggs had the lowest carotenoid retention rates of 67-78 and 84-86%, respectively.

Background: The incidence of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), the rates of both under-diagnosis and over-diagnosis, and the nature of the onset of the condition have not...

BACKGROUND: Minorities, including mainland Puerto Ricans, are impacted disproportionally by Alzheimer’s disease (AD), dementia, and cognitive decline. Studying blood metabolomics in this population has the potential to probe the biological underpinnings of this health disparity. OBJECTIVE: We performed a comprehensive analysis of circulating plasma metabolites in relation to cognitive function in 736 participants from the Boston Puerto Rican Health Study (BPRHS) who underwent untargeted mass-spectrometry based metabolomics analysis and had undergone a battery of in-person cognitive testing at baseline. METHODS: After relevant exclusions, 621 metabolites were examined. We used multivariable regression, adjusted for age, sex, education, apolipoprotein E genotype, smoking, and Mediterranean dietary pattern, to identify metabolites related to global cognitive function in our cohort. LASSO machine learning was used in a complementary analysis to identify metabolites that could discriminate good from poor extremes of cognition. We also conducted sensitivity analyses: restricted to participants without diabetes, and to participants with good adherence to Mediterranean diet. RESULTS: Of 621 metabolites, FDR corrected (p

Objective. Antibiotic use is one of the strongest environmental predictors of an altered and less diverse gut microbiome, which has been linked to Parkinson’s disease. To our knowledge, no prior study has examined the association between long-term antibiotic use and Parkinson’s disease. Design. We conducted a prospective study of 59,637 women in the Nurses’ Health Study who reported total duration of antibiotic use at ages 20–39, 40–59, 60 +, or during the past 4 years. We used Cox Proportional Hazard regression to estimate hazard ratios and 95% confidence intervals for the association between categories of antibiotic use and risk of PD. Results. One hundred and eighty cases of PD were confirmed during the follow-up. Self-reported antibiotic use at ages 20–39, 40–59, and 60 +, as assessed in 2004, was not significantly associated with PD risk in our cohort. The hazard ratio comparing participants who used antibiotics for 2 or more months vs. 1–14 days at age 20–39 was 0.98 (95% CI: 0.54, 1.78), at age 40–59 was 1.44 (95% CI: 0.88, 2.33), and at age 60 +was 0.88 (95% CI: 0.53, 1.47). Antibiotic use during the past four years, as assessed in 2008, was also not associated with future risk of PD (HR: 1.14, 95% CI: 0.62, 2.10). Conclusion. In this cohort study, we did not observe a significant association between antibiotic use and incidence PD. A major limitation of our study is assessment of exposure, which required many participants to recall their antibiotic use decades in the past. Thus, although the results of this study do not support an effect of antibiotic use on PD risk, larger investigations relying on records of antibiotic prescriptions would provide more definitive evidence.

Maize is a major source of food security and economic development in sub-Saharan Africa (SSA), Latin America, and the Caribbean, and is among the top three cereal crops in Asia. Yet, maize is deficient in certain essential amino acids, vitamins, and minerals. Biofortified maize cultivars enriched with essential minerals and vitamins could be particularly impactful in rural areas with limited access to diversified diet, dietary supplements, and fortified foods. Significant progress has been made in developing, testing, and deploying maize cultivars biofortified with quality protein maize (QPM), provitamin A, and kernel zinc. In this review, we outline the status and prospects of developing nutritionally enriched maize by successfully harnessing conventional and molecular marker-assisted breeding, highlighting the need for intensification of efforts to create greater impacts on malnutrition in maize-consuming populations, especially in the low- and middle-income countries. Molecular marker-assisted selection methods are particularly useful for improving nutritional traits since conventional breeding methods are relatively constrained by the cost and throughput of nutritional trait phenotyping.

OBJECTIVES: We sought to determine the metabolic signature associated with poor vs good cognition in a cohort of Boston-area Puerto Ricans. METHODS: We studied 638 participants the Boston Puerto Rican Health Study (BRPHS), a prospective Boston-area cohort study of Puerto Ricans, with comprehensive metabolite profiling (>700 metabolites) at baseline and a concurrent assessment of global cognitive function. Cognition was assessed at baseline using a comprehensive cognitive battery from which a global cognitive score was derived. Our analysis focused on 638 annotated metabolites that had reported values in ≥80% of the participants. We performed univariate linear regression analyses to identify metabolites significantly associated with global cognitive score.To examine whether these metabolites could then discriminate between the low from (=1SD above the mean, N = 99) cognition groups, and to identify metabolites that could best discriminate between low and high cognition groups, we conducted partial least square discrimination analysis (PLS-DA). We used separation distance as the test statistic and plotted the scores of the first two partial least square components to inspect the separation of cases from controls. We also identified metabolites contributing most strongly to the separation (VIP > 1). RESULTS: 113 metabolites were significantly associated with cognitive function in univariate analyses. In PLS-DA analyses using these 113 metabolites. when plotting the first two PLS components, there was a clear separation between the low and high cognition groups and controls (Figure 1) (permutation test based on separation distance p-value 0.012) (Figure 1). 23 metabolites had a Variable Importance in Projection (VIP) scores > 1. The metabolites with the highest VIP scores and elevated in the low relative to the high cognition group included cystathionine (amino acid and downstream metabolite of homocysteine), quinate (xenobiotic/food component, component medication used to treat malaria) and p-cresol-glucuronide (amino acid). (Table 1). CONCLUSIONS: In this cross sectional study of Boston Area Puerto Ricans, we observed a separation between high and low cognitive function groups in the Boston Puerto Rican study based on metabolomic profiles. FUNDING SOURCES: This work was supported by the National Institutes of Health. SUPPORTING TABLES, IMAGES AND/OR GRAPHS

In vast swathes of Sub-Saharan Africa, maize is the staple food with consumption of up to 450 g/person/day. Additionally, maize is used as a weaning food for infants as well as for special ceremonies, caring for the sick, aged and pregnant women. Malnutrition persists in regions with heavy maize consumption, partly due to compositional maize characteristics, nutrient loss during processing and consumer preferences. This paper reviews the traditional uses and processing of maize, opportunities and necessary improvements to ensure (micro)nutrient security. Better use of maize can enhance its contribution to meeting the dietary needs and livelihood of Africa’s growing populace.

A nivel mundial una de cada tres personas padece al menos una forma de malnutrición como desnutrición, sobrepeso u obesidad. En México, a pesar de las intervenciones de salud pública para incrementar la ingesta de micronutrientes como el zinc, la desnutrición crónica aún representa 13.6 %, mientras 23.3 % sufre anemia, causada principalmente por deficiencia de hierro. El frijol (Phaseolus vulgaris) es el segundo cultivo que más se produce y consume, después del maíz (Zea mays L.), con una ingesta promedio anual per capita de 10 kg. La biofortificación podría contribuir a reducir la desnutrición en zonas rurales y marginales al incrementar la ingesta de micronutrientes sin modificar los patrones de consumo. El objetivo de este estudio fue priorizar los estados del país para la intervención con frijol biofortifcado con hierro y zinc, según su mayor impacto potencial, mediante el Índice de Priorización para Biofortificación y las condiciones de biofortificación, basados en producción, consumo y deficiencia de micronutrientes. Chiapas, Oaxaca, Guerrero, Veracruz, Campeche y Tabasco deberían ser priorizados para la intervención con frijol negro biofortificado, mientras que Baja California Sur y Sonora para frijol pinto bioforificado; Guanajuato y Tlaxcala son prioritarios para frijol claro biofortificado.

Biofortification is a strategy to reduce micronutrient malnutrition. The aim of this study was to investigate whether consumption of biofortified fresh maize can supply nutritionally meaningful amounts of provitamin A carotenoids (PVA), zinc, lysine, and tryptophan. The accumulation patterns for PVA and tocochromanol compounds in developing grain of 23 PVA hybrids was studied, and nutritionally meaningful amounts of those compounds were found in grain by milk stage, when fresh maize is eaten. The highest PVA and tocochromanol accumulation occurred by physiological maturity. The percent apparent retention in boiled fresh maize was 92%, 117%, 99%, and 66% for PVA, zinc, lysine, and tryptophan, respectively. Consumption of 0.5 to 2 ears of fresh maize daily could supply 33–62.2%, 11–24% and more than 85% of the estimated average requirement of PVA, tryptophan, and zinc, respectively. The results indicate that eating biofortified fresh maize can contribute to improved micronutrient nutrition.

BACKGROUND: Biofortification of staple crops with β-carotene is a strategy to reduce vitamin A deficiency, and several varieties are available in some African countries. β-Cryptoxanthin (BCX)-enhanced maize is currently in field trials. To our knowledge, maize BCX bioavailability has not been assessed in humans. Serum retinol (13)C content and xanthophyll concentrations are proposed effectiveness biomarkers for biofortified maize adoption. OBJECTIVE: We determined the relative difference in BCX and zeaxanthin bioavailability from whole-grain and refined BCX-biofortified maize during chronic feeding compared with white maize and evaluated short-term changes in (13)C-abundance in serum retinol. DESIGN: After a 7-d washout, 9 adults (mean ± SD age: 23.4 ± 2.3 y; 5 men) were provided with muffins made from BCX-enhanced whole-grain orange maize (WGOM), refined orange maize (ROM), or refined white maize (RWM) for 12 d in a randomized, blinded, crossover study followed by a 7-d washout. Blood was drawn on days 0, 3, 6, 9, 12, 15, and 19. Carotenoid areas under the curve (AUCs) were compared by using a fixed-effects model. (13)C-Abundance in serum retinol was determined by using gas chromatography/combustion/isotope-ratio mass spectrometry on days 0, 12, and 19. Vitamin A status was determined by (13)C-retinol isotope dilution postintervention. RESULTS: The serum BCX AUC was significantly higher for WGOM (1.70 ± 0.63 μmol ⋅ L(−1) ⋅ d) and ROM (1.66 ± 1.08 μmol ⋅ L(−1) ⋅ d) than for RWM (−0.06 ± 0.13 μmol ⋅ L(−1) ⋅ d; P

Preeclampsia represents a major public health burden worldwide, but predictive and diagnostic biomarkers are lacking. Metabolomics is emerging as a valuable approach to generating novel biomarkers whilst increasing the mechanistic understanding of this complex condition. To summarize the published literature on the use of metabolomics as a tool to study preeclampsia. PubMed and Web of Science were searched for articles that performed metabolomic profiling of human biosamples using either Mass-spectrometry or Nuclear Magnetic Resonance based approaches and which included preeclampsia as a primary endpoint. Twenty-eight studies investigating the metabolome of preeclampsia in a variety of biospecimens were identified. Individual metabolite and metabolite profiles were reported to have discriminatory ability to distinguish preeclamptic from normal pregnancies, both prior to and post diagnosis. Lipids and carnitines were among the most commonly reported metabolites. Further work and validation studies are required to demonstrate the utility of such metabolites as preeclampsia biomarkers. Metabolomic-based biomarkers of preeclampsia have yet to be integrated into routine clinical practice. However, metabolomic profiling is becoming increasingly popular in the study of preeclampsia and is likely to be a valuable tool to better understand the pathophysiology of this disorder and to better classify its subtypes, particularly when integrated with other omic data.

Parkinson's disease (PD) is a neurodegenerative disease of unknown etiology that is thought to be caused by a complex combination of environmental and/or genetic factors. Air pollution exposure is linked to numerous adverse effects on human health, including brain inflammation and oxidative stress, processes that are believed to contribute to the development and progression of PD. This review provides an overview of recent advances in the epidemiology of air pollution and PD, including evidence of the effects of various pollutants (ozone, PM10, PM2.5, PM2.5-10, NOx, NO2, CO, traffic air pollution, second-hand smoking) on PD risk. Based on this evidence, promising opportunities for future research are outlined, including: (1) studies of smaller particle sizes that cross the blood-brain barrier, (2) studies of the effects of air pollution on PD mortality and/or progression; (3) studies of interactions of air pollution with gene environment and other environmental factors.

Maize (Zea mays L.) cultivars with increased con centrations of provitamin A (proVA) carotenoids can improve the health of millions of consumers who are vitamin A deficient and rely on maize as a staple food. Three open-pollinated maize culti vars ( opC) were subjected to three cycles of S1 recurrent selection for increased proVA concen tration. Agronomic performance of Cycles 0, 1, 2, and 3 for each op C was evaluated using three replications at 10 locations, and changes in proVA concentration were assessed for hand-pollinated grain produced at two sites. Selection resulted in significant ( P < 0.01 for 11, and P < 0.05 for 1 occurrence) linear increases of 25 to 67% per cycle for total proVA, 28 to 60% for b -carotene, 18 to 70% for b-cryptoxanthin, and 11 to 46% for zeaxanthin. These findings are especially signifi cant because, in contrast to recent trends, they demonstrate the feasibility of developing proVAenhanced maize while meeting nutritionists’ rec ommendations not to sacrifice b -cryptoxanthin and zeaxanthin to increase b-carotene concentration in grain. Grain yield increased in one but decreased ( P < 0.01) in two of the op Cs, and we hypothesize that linkage drag associated with proVA-enhancing genes from exotic donor lines may be responsible for the negative trends. We conclude that breeding proVA-enriched maize without sacrificing b-cryptoxanthin and zea xanthin concentrations is feasible, but that (i) it remains unknown whether such approaches can achieve the high concentrations of proVA reported elsewhere by using marker-assisted selection for genes that favor b

Several maize landraces were evaluated using microstructural and rheological starch properties and related them to pozole quality. Annealed starch produced during traditional nixtamalization and additional boiling step enhances the viscosity, swelling and starch stability to collapse by forming amylose–lipid complexes. Regarding pozole broth, Cacahuacintle maize (pozole end-use) presented significantly higher (P

Background: Exposure to air pollution has been implicated in a number of adverse health outcomes, and the effect of particulate matter (PM) on the brain is beginning to be recognized. Objectives: We aimed to examine whether exposure to PM air pollution is related to risk of Parkinson's disease (PD) in the Health Professionals Follow-up Study (HPFS), a large prospective cohort of U.S. men. Methods: We prospectively followed 50,352 men in the HPFS, a large prospective cohort of U.S. men, and identified 550 incident PD cases. Cumulative average exposure to various size fractions of PM [PM10 (≤10μm microns in diameter), PM2.5 (≤2.5μm in diameter), and PM2.5–10 (between 2.5 and 10μm in diameter)] up to 2 years before the onset of PD was estimated using a spatiotemporal model by linking each participant’s place of residence throughout the study with location-specific PM levels. We used multivariable Cox proportional hazards models to independently estimate the risk of PD associated with each size fraction of PM. Results: In models adjusted for age, smoking, region, and population density, we did not observe statistically significant associations between exposure to PM and PD risk. In analyses considering cumulative average PM exposure, the comparing the top to the bottom quintile of PM exposure was 0.85 [95% confidence interval (CI): (0.63, 1.15)] for PM10, 0.97 [95% CI: (0.72, 1.32)] for PM2.5, and 0.88 [95% CI: (0.64, 1.22)] for hazard ratio (HR) PM2.5–10. The results did not change markedly when restricted to men who did not move during the study or when stratified by smoking status or population density. Conclusions: In this study, we found no evidence that exposure to air pollution is a risk factor for PD in men. https://doi.org/10.1289/EHP259

Addictive behaviors, such as cigarette smoking and coffee drinking, have been associated with a reduced risk of Parkinson's disease (PD). Whether alcohol consumption is also associated with PD risk is less certain. We prospectively followed 132,403 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2005. Alcohol intake was assessed at baseline. Incident cases of PD (n = 605; 389 male and 216 female) were confirmed by treating physicians and medical record review. Relative risks (RRs) were estimated using proportional hazards models, adjusting for age, smoking, and other risk factors. Alcohol consumption was not significantly associated with PD risk. After adjustment for age, smoking, and other risk factors, the RR comparing men consuming 30 or more grams of alcohol per day (highest category) to nondrinker men was 1.29 (95% confidence interval [CI]: 0.90, 1.86; P trend: 0.40), and the RR comparing women consuming 15 or more grams of alcohol (highest category) per day to nondrinker women was 0.77 (95% CI: 0.41, 1.45; P trend: 0.87). Consumption of beer, wine, or liquor was also not associated with PD risk. The results of this large, prospective study do not support an association between alcohol intake and risk of PD.

The aim of this work was to investigate whether obesity and diabetes are related to risk of Parkinson's disease. We prospectively followed 147,096 participants in the Cancer Prevention Study II Nutrition Cohort from 1992 to 2005. Participants provided information on anthropometric variables and medical history at baseline and on waist circumference in 1997. Incident cases of Parkinson's disease (n = 656) were confirmed by treating neurologists and medical record review. Relative risks were estimated using proportional hazards models, adjusting for age, gender, smoking, and other risk factors. Neither body mass index nor waist circumference significantly predicted Parkinson's disease risk. Relative risk comparing individuals with a baseline body mass index of ≥ 30 to those with a body mass index

Background: To assess differences in marginal bone loss in implants placed at subcrestal versus crestal level. Methods: An electronic and a manual research of articles written in English from Jaunary 2010 to January 2018 was performed by two independent reviewers. Clinical trials comparing bone loss for implants placed at crestal and subcrestal level were included. Pooled estimates from comparable studies were analyzed using a continuous random-effects model meta-analysis with the objective of assessing differences in crestal bone loss between the two vertical positions. Results: 16 studies were included; 10 studies did not encounter statistically significant differences between the two groups with respect to bone loss. Three articles found greater bone loss in subcrestal implants; while 3 found more bone loss in crestal implants. A meta-analysis for randomized control trial (RCT) studies reported an average and non-statistically different crestal bone loss of 0.028 mm. Conclusions: A high survival rate and a comparable bone loss was obtained both for crestal and subcrestal implants’ placement. Quantitative analysis considering a homogenous sample confirms that both vertical positions are equally valid in terms of perimplant bone loss. However, with respect to soft tissue; in presence of a thin tissue; a subcrestal placement of the implant should be preferred as it may reduce the probability for the implant to become exposed in the future and thus avoid the risk of suffering from peri-implant pathologies.

Caffeine intake has been associated with a decreased risk of Parkinson's disease (PD) in men but the effect in women is less clear, and appears to be modified by use of post-menopausal estrogens. In a nested case–control study within the Nurses Health Study (NHS) and the Health Professionals Follow-up Study (HPFS), we examined associations between single nucleotide polymorphisms (SNPs) of caffeine metabolizing genes (CYP1A2 and NAT2) and estrogen receptors (ESR1 and ESR2), their interaction with caffeine intake and hormone replacement therapy (PMH) use (collected prospectively) and risk of PD. We matched 159 female cases to 724 controls and 139 male cases to 561 controls on birth year, source of DNA (blood or buccal smear), age and sex. The CYP1A2 rs762551 polymorphism (lower enzyme inducibility) was marginally associated with an increased risk of PD (RR, for increasing number of minor alleles = 1.34; 95% CI 1.02, 1.78 in women, but not in men. None of the NAT2 (classified as slow vs. fast acetylator), ESR1 or ESR2 polymorphisms were significantly associated with an altered risk of PD. Marginally significant interactions were observed between caffeine intake and the ESR1 polymorphism rs3798577 ( p = 0.07) and ESR2 polymorphism rs1255998 ( p = 0.07). The observed increased risk of PD among female but not male carriers of the rs762551 polymorphism of CYP1A2 and the interactions of caffeine with ESR1 rs3798577 and ESR2 rs1255998 may provide clues to explain the relationship between gender, caffeine intake, estrogen status and risk of PD and need to be replicated.

Objective: To undertake a comprehensive investigation into the very high incidence of congenital deafness on the Macano peninsula of Margarita Island, Venezuela. Methods: Numerous visits were made to the isolated island community over a 4-year-period. During these visits, it became apparent that a significant number of individuals complained of problems with hearing and vision. Socioeconomic assessments, family pedigrees and clinical histories were recorded on standard questionnaires. All individuals underwent thorough otolaryngologic and ophthalmologic examinations. Twenty milliliters of peripheral venous blood was obtained from each participant. A Genome-wide linkage analysis study was performed. Polymorphic microsatellite markers were amplified by polymerase chain reaction and separated on polyacrylamide gels. An ABI 377XL sequencer was used to separate fragments and LOD scores were calculated by using published software. Results: Twenty-four families were identified, comprising 329 individuals, age range 1–80 years, including 184 children. All families were categorized in the lower two (least affluent) socioeconomic categories. A high incidence of consanguinity was detected. Fifteen individuals (11 adults, 4 children) had profound congenital sensorineural hearing loss, vestibular areflexia and retinitis pigmentosa. A maximum LOD score of 6.76 (Linkage >3.0), between markers D11s4186 and D11s911, confirmed linkage to chromosome 11q13.5. The gene myosin VIIA ( MYO7A ) was confirmed in the interval. Clinical and genetic findings are consistent with a diagnosis of Usher syndrome 1B for those with hearing and vision problems. Conclusions: We report 15 Usher syndrome 1B individuals from a newly detected Latin American socio-demographic origin, with a very high prevalence of 76 per 100,000 population.

We sought to assess the quality of life in PD patients before the diagnosis, in comparison to age-matched individuals free of PD, among participants in two large prospective cohorts of men and women. Components of the Short-Form Health Status Survey (SF36) were administered to all participants in 1996 and 2008 in the Health Professionals Follow-up Study (HPFS), and in 1992, 1996, 2000 and 2004 in the Nurses' Health Study (NHS). We used scores in 7 health-related quality of life-dimensions, that were rated from 1(worst) to 100(best) points. We fitted a multivariate mixed-effect model with repeated measures to estimate the expected decline with age and compared that to the decline observed among PD cases by time to diagnosis. 454 men and 414 women with PD contributed data to the analyses. A decline in physical function in PD patients relative to the whole cohort began approximately 7.5 years prior to diagnosis in women and 3 years prior to diagnosis in men, and continued to decline thereafter with a rate of 2.35 and 1.43 points per year in women and men respectively (p < 0.001 for both). For comparison, the average yearly decline in individuals without PD was 0.42 and 0.23 points per year in women and men respectively. Other measures of quality of life (only available in women) declined in a similar pattern to physical function. In summary, the quality of life in PD patients begins to decline years before the diagnosis.

Background: Exposure to metals has been implicated in the pathogenesis of Parkinson disease (PD). Objectives: We sought to examine in a large prospective study of female nurses whether exposure to airborne metals was associated with risk of PD. Methods: We linked the U.S. Environmental Protection Agency (EPA)’s Air Toxics tract-level data with the Nurses’ Health Study, a prospective cohort of female nurses. Over the course of 18 years of follow-up from 1990 through 2008, we identified 425 incident cases of PD. We examined the association of risk of PD with the following metals that were part of the first U.S. EPA collections in 1990, 1996, and 1999: arsenic, antimony, cadmium, chromium, lead, manganese, mercury, and nickel. To estimate hazard ratios (HRs) and 95% CIs, we used the Cox proportional hazards model, adjusting for age, smoking, and population density. Results: In adjusted models, the HR for the highest compared with the lowest quartile of each metal ranged from 0.78 (95% CI: 0.59, 1.04) for chromium to 1.33 (95% CI: 0.98, 1.79) for mercury. Conclusions: Overall, we found limited evidence for the association between adulthood ambient exposure to metals and risk of PD. The results for mercury need to be confirmed in future studies. Citation: Palacios N, Fitzgerald K, Roberts AL, Hart JE, Weisskopf MG, Schwarzschild MA, Ascherio A, Laden F. 2014. A prospective analysis of airborne metal exposures and risk of Parkinson disease in the Nurses’ Health Study Cohort. Environ Health Perspect 122:933–938; http://dx.doi.org/10.1289/ehp.1307218

Biofortification, or the breeding of staple food crops to increase their micronutrient density, is widely viewed as a valuable strategy for sustainably improving the nutritional status of some malnourished populations.

Caffeine consumption has been associated with a reduced risk of Parkinson's disease (PD). The association is strong and consistent in men, but uncertain in women, possibly because of an interaction with hormone replacement therapy (HRT). We sought to confirm these findings using data on PD incidence in the Cancer Prevention Study II Nutrition Cohort (CPS II-Nutrition), a large, prospective study of men and women. We conducted a prospective study of caffeine intake and risk of PD within the CPS II Nutrition Cohort. Intakes of coffee and other sources of caffeine were assessed at baseline. Incident cases of PD (n = 317; 197 men and 120 women) were confirmed by treating physicians and medical record review. Relative risks (RRs) were estimated using proportional hazards models, adjusting for age, smoking, and alcohol consumption. After adjustment for age, smoking, and alcohol intake, high caffeine consumption was associated with a reduced risk of PD. The RR comparing the 5th to the 1st quintile of caffeine intake was 0.43 (95% confidence interval [CI]: 0.26, 0.71; P trend =

We thank Cereda et al. for including our study1 in their updated meta-analysis of diabetes and Parkinson disease (PD) published in Movement Disorders. There were only 4 prospective studies available at the time of publication of the original meta-analysis and inclusion of our investigation substantially increased the number of PD cases from 3284 in the original meta-analysis to 3940 in the updated version. Overall, this addition changed the pooled relative risk estimate for diabetes from 1.37 (95% confidence interval [CI], 1.21–1.55) to 1.25 (95% CI, 1.03–1.55), but with significant heterogeneity between studies. A key question is: what are the sources of this heterogeneity? An important difference among the studies included in this meta analysis are the methods of PD ascertainment. Those studies that relied on register data (Hu et al.)2 or unconfirmed self-report (Driver et al.),3 may have included as incident PD cases individuals with vascular Parkinsonism. The potential bias from this source was reduced in the study by Xu et al.,4 who were able to obtain confirmation from the treating neurologist of about two-thirds of the incident PD cases, and minimized in the studies by Simon et al.,5 and Palacios et al.,1 which included only neurologist-confirmed incident PD cases. Vascular parkinsonism may contribute to explain the fact that the strongest association between diabetes and PD was found in Finland (Hu et al.),2 which has relatively high rates of cardiovascular disease. Another important difference is residual confounding. For example, adjustment for changes in smoking behavior was only implemented in Simon et al.,5 and Palacios et al.;1 in the remaining studies, a spurious positive association between diabetes and PD could have resulted if individuals with diabetes were more likely to quit smoking (a negative risk factor for PD)6–8 during the follow-up than those without diabetes. Finally, losses to follow-up may contribute to bias—because only about 63% of the participants in the cohort studied by Xu et al. responded to the PD survey, a higher response rate among diabetics could induce a spurious positive association between diabetes and PD. As Cereda et al. acknowledge, it is not possible to take these differences into account in the meta-analysis. The results from the meta-analysis should therefore be considered with caution. A close analysis of the results of the studies that report a positive association between diabetes and PD raises further doubt on whether such association truly reflects an increased PD risk among diabetics The 2 U.S. studies that reported a positive association are in conflict as to the timing of diabetes prior to onset of PD. Xu et al. found an overall increased risk of PD associated with diabetes within the National Institutes of Health and AARP (formerly the American Association of Retired Persons) (NIH-AARP) cohort, but most of the risk was attributed to patients with 10 or more years of diabetes at baseline. At the same time, in the other positive study, by Driver et al., the increase in PD risk was restricted to patients with

An increased risk of MS among smokers has been consistently found in numerous longitudinal studies with excess rates ranging from 1.3 to 1.7 for heavy long-term smokers as compared to never smokers (Hernan et al., 2005, Hernan et al., 2001). Smoking has also been associated with an increased risk of MS progression from a relapsing-remitting clinical course into a secondary progressive course (Healy et al., 2009; Hernan et al., 2005). Recently, Hedstrom et al. (2011) found that exposure to passive smoking was also associated with a similar 30% increased MS risk and an even greater MS risk was associated with longer exposure to passive smoking (80% increased risk among those exposed for more than 20 years). However, it is still unclear if the relationship between smoking and MS is causal, and if so, what are the relevant components of cigarette smoking for MS risk. To provide some evidence of causation, Palacios et al. (2011) compared published data on MS incidence and smoking rates among men and women over the past several decades to determine if there were similarities consistent with a causal interpretation (Palacios et al., 2011). Correlating female to male ratios of prevalence of smoking from numerous birth cohorts within several countries with the corresponding female to male ratios of MS incidence demonstrated that a significant proportion of the increase in the female/male ratio of MS incidence could potentially be explained by the change over time in the rates of smoking in women as compared to men. The change in the smoking ratio was primarily due to a steady decrease in smoking among men over the past decades from approximately 80% to approximately 20%, while smoking among women remained relatively stable. The female to male smoking ratio was