External validation of genetically predicted protein biomarkers for pancreatic cancer risk using aptamer-based plasma levels: A prospective analysis in the Atherosclerosis Risk in Communities Study.

Genetically predicted proteins have been associated with pancreatic cancer risk previously. We aimed to externally validate the associations of 53 candidate proteins with pancreatic cancer risk using directly measured, prediagnostic levels. We conducted a prospective cohort study of 10 355 US Black and White men and women in the Atherosclerosis Risk in Communities (ARIC) study. Aptamer-based plasma proteomic profiling was previously performed using blood collected in 1993 to 1995, from which the proteins were selected. By 2015 (median: 20 years), 93 incident pancreatic cancer cases were ascertained. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for protein tertiles, and adjust for age, race, and known risk factors. Of the 53 proteins, three were statistically significantly, positively associated with risk-GLCE (tertile 3 vs 1: HR = 1.88, 95% CI: 1.12-3.13; P-trend = 0.01), GOLM1 (aptamer 1: HR = 1.98, 95% CI: 1.16-3.37; P-trend = 0.01; aptamer 2: HR = 1.86, 95% CI: 1.07-3.24; P-trend = 0.05), and QSOX2 (HR = 1.96, 95% CI: 1.09-3.58; P-trend = 0.05); two were inversely associated-F177A (HR = 0.59, 95% CI: 0.35-1.00; P-trend = 0.05) and LIFsR (HR = 0.55, 95% CI: 0.32-0.93; P-trend = 0.03); and one showed a statistically significant lower risk in the middle tertile-endoglin (HR = 0.50, 95% CI: 0.29-0.86); by chance, we expected significant associations for 2.65 proteins. FAM3D, IP10, sTie-1 (positive); SEM6A and JAG1 (inverse) were suggestively associated with risk. Of these 11, 10 proteins-endoglin, FAM3D, F177A, GLCE, GOLM1, JAG1, LIFsR, QSOX2, SEM6A and sTie-1-were consistent in direction of association with the discovery studies. This prospective study validated or supports 10 proteins as associated with pancreatic cancer risk.

Solid fuel use for heating and risks of breast and cervical cancer mortality in China.

BACKGROUND: Carcinogens released from indoor burning of solid fuels are believed to enter the bloodstream and to be metabolized in breast and cervical tissues. Little evidence exists about the relationship of solid fuel use from heating with breast and cervical cancer. OBJECTIVES: To examine the association of solid heating fuel use with breast and cervical cancer mortality. METHODS: This study included female participants aged 30-79 years who were enrolled in the China Kadoorie Biobank during 2004-2008 from 10 diverse regions across China. During a 10.2-year median follow-up, 177 breast cancer deaths and 113 cervical cancer deaths were documented. Multivariable Cox regression models yielded adjusted hazard ratios (HRs) for the associations of self-reported long-term heating fuel exposure with two cancer deaths. Stratified analyses were used to assess effect modification. RESULTS: We included 236,116 participants for breast cancer analyses and 228,795 for cervical cancer analyses. Compared with non-solid fuel use, the fully adjusted HRs of cervical cancer deaths were 1.75 (0.91-3.38) for wood use, 2.23 (1.09-4.59) for mixed fuel (coal and wood) use. No evident relationship was observed for breast cancer deaths. Cervical cancer risk increased with the duration of solid fuel use (P for trend = 0.041). Elevated cervical cancer risk was observed in post-menopausal women (HR 2.01, 1.01-4.03), not in pre-menopausal women (HR 0.77, 0.56-2.31) (P for heterogeneity = 0.004); and in those aged ≥50 years (HR 2.56, 1.17-5.86), not in those aged < 50 years (HR 0.69, 0.26-1.84) (P < 0.001). CONCLUSION: Indoor solid fuel combustion for heating may be associated with a higher risk for cervical cancer death, but not for breast cancer. The strength of the association increased with the duration of exposure and was modified by age and menopause status.

Environmental complex exposure and the risk of influenza-like illness among housewives: A case study in Shanxi Province, China.

The association between environmental pollution and risk of influenza-like illness (ILI) among general population has been reported. However, the relationships between the individual pollutants and ILI risk are still under discussion. Our study aimed to explore the associations of the typical environmental polycyclic aromatic hydrocarbons (PAHs) and metal(loid)s with ILI risk among women population. We carried out a cross-sectional study and included a total of 396 housewives in Shanxi Province, China. The information on their general characteristics and ILI frequency was collected by questionnaire. We collected their hair samples and analyzed the concentrations of PAHs and various metal(loid)s. The results indicated that only acenaphthylene concentration of the nine detected PAH congeners in the hair was significantly associated with ILI risk with adjusted odds ratio (AOR) and 95% confidence interval (95% CI) of 0.58 (0.38 - 0.91). Among the concerned 4 toxic metal(loid)s and 15 rare earth elements, only the hair concentration of arsenic had a positive dose-response relationship with ILI risk. In addition, we found that there were negative dose-response associations of the three essential trace elements (i.e. chromium, cobalt, and nickel), and four essential alkaline earth elements (i.e. magnesium, calcium, strontium, barium) with ILI risk. It was concluded that the environmental exposure to certain compounds of housewives may contribute to their ILI development.

Serial nerve ultrasound and motor nerve conduction studies in chronic inflammatory demyelinating polyradiculoneuropathy.

INTRODUCTION: The objective of this study was to evaluate the correlation between cross-sectional area (CSA) and nerve conduction studies (NCS) in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and to determine how CSA changes over time after standard treatment. METHODS: Fifty-four patients with CIDP were recruited prospectively, and 21 patients were followed for more than 6 months. Ultrasonography and motor NCS were performed in the median and ulnar nerves. RESULTS: No or weak correlation was observed between the maximum CSA and motor conduction velocity. There were segmental nerve enlargements at 61% of sites with conduction block or temporal dispersion. Among 19 patients with clinical improvement after immunotherapy, CSA decreased to normal in 5, increased in 10, and were unchanged in 4. DISCUSSION: Different patterns of CSA and motor NCS changes after immune treatment may indicate different CIDP pathologic mechanisms. Exploration of these pathologic mechanisms could guide treatment choices in the future. Muscle Nerve, 2019.

Early-life tobacco exposure is causally implicated in aberrant RAG-mediated recombination in childhood acute lymphoblastic leukemia.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, yet few environmental risk factors have been identified. We previously found an association between early-life tobacco smoke exposure and frequency of somatic deletions of 8 leukemia driver genes among childhood ALL patients in the California Childhood Leukemia Study. To expand analysis genome-wide and examine potential mechanisms, we conducted tumor whole-genome sequencing in 35 ALL patients, including 18 with high prenatal tobacco exposure and 17 with low exposure as determined by established epigenetic biomarkers. High tobacco exposure patients had significantly more structural variants (P < .001) and deletions (P = .001) genome-wide than low exposure patients. Investigation of off-target RAG recombination revealed that 41% of deletions in the high tobacco exposure patients were putatively RAG-mediated (full RAG motif identified at one or both breakpoints) compared with only 21% in the low exposure group (P = .001). In a multilevel model, deletions in high tobacco exposure patients were 2.44-fold (95% CI:1.13-5.38) more likely to be putatively RAG-mediated than deletions in low exposure patients. No point mutational signatures were associated with prenatal tobacco exposure. Our findings suggest that early-life tobacco smoke exposure may promote leukemogenesis by driving development of somatic deletions in pre-leukemic lymphocytes via off-target RAG recombination.

Proteome-wide association study and functional validation identify novel protein markers for pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy, largely due to the paucity of reliable biomarkers for early detection and therapeutic targeting. Existing blood protein biomarkers for PDAC often suffer from replicability issues, arising from inherent limitations such as unmeasured confounding factors in conventional epidemiologic study designs. To circumvent these limitations, we use genetic instruments to identify proteins with genetically predicted levels to be associated with PDAC risk. Leveraging genome and plasma proteome data from the INTERVAL study, we established and validated models to predict protein levels using genetic variants. By examining 8,275 PDAC cases and 6,723 controls, we identified 40 associated proteins, of which 16 are novel. Functionally validating these candidates by focusing on 2 selected novel protein-encoding genes, GOLM1 and B4GALT1, we demonstrated their pivotal roles in driving PDAC cell proliferation, migration, and invasion. Furthermore, we also identified potential drug repurposing opportunities for treating PDAC. SIGNIFICANCE: PDAC is a notoriously difficult-to-treat malignancy, and our limited understanding of causal protein markers hampers progress in developing effective early detection strategies and treatments. Our study identifies novel causal proteins using genetic instruments and subsequently functionally validates selected novel proteins. This dual approach enhances our understanding of PDAC etiology and potentially opens new avenues for therapeutic interventions.

Self-Reported Primary Cooking Fuels Use and Risk of Chronic Digestive Diseases: A Prospective Cohort Study of 0.5 Million Chinese Adults.

BACKGROUND: Household air pollution (HAP) from inefficient combustion of solid fuels is a major health concern worldwide. However, prospective evidence on the health impacts of solid cooking fuels and risks of chronic digestive diseases remains scarce. OBJECTIVES: We explored the effects of self-reported primary cooking fuels on the incidence of chronic digestive diseases. METHODS: The China Kadoorie Biobank recruited 512,726 participants 30-79 years of age from 10 regions across China. Information on primary cooking fuels at the current and previous two residences was collected via self-reporting at baseline. Incidence of chronic digestive diseases was identified through electronic linkage and active follow-up. Cox proportional hazards regression models were used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of self-reported long-term cooking fuel patterns and weighted duration of self-reported solid cooking fuel use with chronic digestive diseases incidence. Linear trend was tested by assigning the medians of weighted duration in each group and then taking those as continuous variables in the models. Subgroup analyses were undertaken across the baseline characteristics of participants. RESULTS: During 9.1±1.6 y of follow-up, 16,810 new cases of chronic digestive diseases were documented, among which 6,460 were diagnosed as cancers. Compared with long-term cleaner fuel use, self-reported long-term use of solid cooking fuels (i.e., coal, wood) was associated with elevated risks of chronic digestive diseases (HR=1.08; 95% CI: 1.02, 1.13), including nonalcoholic fatty liver disease (NAFLD) (HR=1.43; 95% CI: 1.10, 1.87), hepatic fibrosis/cirrhosis (HR=1.35; 95% CI: 1.05, 1.73), cholecystitis (HR=1.19; 95% CI: 1.07, 1.32), and peptic ulcers (HR=1.15; 95% CI: 1.00, 1.33). The longer the weighted duration of self-reported solid cooking fuel use, the higher the risks of chronic digestive diseases, hepatic fibrosis/cirrhosis, peptic ulcers, and esophageal cancer (pTrend<0.05). The aforementioned associations were modified by sex and body mass index (BMI). Positive associations of always solid cooking fuel use with chronic digestive disease, hepatic fibrosis/cirrhosis, NAFLD, and cholecystitis were observed among women but not men. The longer the weighted duration of self-reported solid cooking fuel use, the higher the risk of NAFLD among those with a BMI ≥28 kg/m2. DISCUSSION: Long-term self-reported solid cooking fuels use was associated with higher risks of chronic digestive diseases. The positive association of HAP from solid cooking fuels with chronic digestive diseases indicates for an imminent promotion of cleaner fuels as public health interventions. https://doi.org/10.1289/EHP10486.

Levels of Parental Human Papillomavirus Vaccine Hesitancy and Their Reasons for Not Intending to Vaccinate: Insights From the 2019 National Immunization Survey-Teen.

PURPOSE: A nuanced understanding of human papillomavirus (HPV) vaccine hesitancy is key to tailoring public health interventions to reach HPV vaccination goals in the United States. We aimed to understand the spectrum of parental vaccine hesitancy and identify reasons for lack of vaccination. METHODS: Using cross-sectional data from the 2019 National Immunization Survey-Teen, we examined parents of adolescents aged 13-17 years who had not initiated HPV vaccination. Parents who did not intend to vaccinate their child in the next year were classified into three categories: "unsure," "somewhat hesitant," or "very hesitant." Survey-weighted multinomial logistic regression was used to identify factors associated with level of vaccine hesitancy. RESULTS: Of the 13,090 parents of unvaccinated adolescents, 8,253 (63%) were hesitant. Among those, 63% were very hesitant, 29% were somewhat hesitant, and 8% were unsure. Parents who had received a provider recommendation were less likely to be unsure (adjusted relative risk ratio 0.3, 95% confidence interval 0.2-0.4) or somewhat hesitant (adjusted relative risk ratio 0.8, 95% confidence interval 0.6-0.9). Compared with non-Hispanic White parents, parents of minority race/ethnicity adolescents were more likely to be unsure versus very hesitant. Safety concerns/side effects were the most common reason for lack of intent to vaccinate among very (30%) and somewhat hesitant parents (20%), whereas lack of provider recommendation was the most common reason among unsure parents (34%). DISCUSSION: We identify three distinct levels of HPV vaccine hesitancy and demonstrate that the characteristics and reasons for lack of vaccination differ among these levels. Understanding a parent's level of hesitancy may help maximize the potential impact of public health interventions to reach HPV vaccination goals.

Household Air Pollution From Solid Cooking Fuel Combustion and Female Breast Cancer.

Background: Women bear a large share of disease burden caused by household air pollution due to their great involvement in domestic activities. Pollutant emissions are believed to vary by exposure patterns such as cooking and space heating. Little is known about the independent effect of solid cooking fuel combustion on breast cancer risk. We aimed to examine the association of indoor coal and wood combustion for cooking with breast cancer risk. Methods: During June 2004-July 2008, participants aged 30-79 from 10 diverse regions across China were enrolled in the China Kadoorie Biobank. Primary cooking fuel use information in up to three residences was self-reported at baseline. Multivariable logistic regression models yielded adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: A total of 290,396 female participants aged 30-79 were included in the main analysis. Compared with long-term clean fuel users, the fully adjusted ORs were 2.07 (95%CI: 1.37-3.13) for long-term coal users, 1.12 (95% CI: 0.72-1.76) for long-term wood users, and 0.98 (95% CI: 0.55-1.74) for those who used mixed solid fuels to cook. Those who had switched from solid to clean fuels did not have an excess risk of breast cancer (OR: 0.88, 95%CI 0.71-1.10). Conclusion: Long-term solid fuel combustion for cooking may increase the risk of breast cancer. The strength of association is stronger among coal users than wood users. Targeted interventions are needed to accelerate the access to clean and affordable energy.

Global variation in prevalence and incidence of amyotrophic lateral sclerosis: a systematic review and meta-analysis.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a global disease, which adversely affects the life quality of patients and significantly increases the burden of families and society. We aimed to assess the changing incidence, prevalence of ALS around the world. METHODS: We searched Medline, Embase, Web of Science, and Cochrane library to identify articles published until September 9, 2018. Each included study was independently reviewed for methodological quality by two reviewers. We used a random-effects model to summarize individual studies and assessed heterogeneity (I2) with the χ2 test on Cochrane's Q statistic. RESULTS: We identified 124 studies that were eligible for final inclusion, including 110 studies of incidence and 58 studies of prevalence. The overall crude worldwide ALS prevalence and incidence were 4.42 (95% CI 3.92-4.96) per 1,00,000 population and 1.59 (95% CI 1.39-1.81) per 1,00,000 person-years, respectively. ALS prevalence and incidence increased by age until the age of 70-79. Since 1957, incidence has been significantly rising year by year, and this upward trend was weakened after standardization. The longest survival time were in Asia (ranging from 3.74 years in South Asia to 9.23 years in West Asia). CONCLUSIONS: With the aggravation of population aging and the rapid growth of economy, developing regions following the development pattern of the developed regions may suffer rising ALS prevalence and incidence which may increase their disease burden as well. These data highlight the need for research into underlying mechanism and innovations in health-care systems.

Circulating antibodies against M-type phospholipase A2 receptor and thrombospondin type-1 domain-containing 7A in Chinese patients with membranous nephropathy.

BACKGROUND: M-type phospholipase A2 receptor (PLA2R) and thrombospondin type-1 domain-containing 7A (THSD7A) have recently been identified as target antigens for patients with idiopathic membranous nephropathy (IMN). The prevalence of PLA2R and THSD7A in the serum of MN patients deserves further investigation. METHODS: Here, we studied the presence of anti-PLA2R and anti-THSD7A antibodies in patients with biopsy-proven IMN (n = 212), secondary membranous nephropathy (SMN, n = 118), and other kidney diseases (n = 84). The progress of 49 IMN patients [anti-PLA2R(+), n = 27; anti-THSD7A(+), n = 6; anti-PLA2R(-) and anti-THSD7A(-) dual negative, n = 16] who received immunosuppressive therapy was observed for 12 months. Serum concentrations of antibodies against PLA2R and THSD7A were detected using an indirect immunofluorescent assay. RESULTS: One hundred fifty-two (71.7%) IMN patients and 11 (9.3%) SMN patients were identified as anti-PLA2R(+) anti-THSD7A(-). Five (2.4%) IMN patients and two (1.7%) SMN patients were identified as anti-THSD7A(+) anti-PLA2R(-). One of the IMN patients was identified as anti-PLA2R(+) and anti-THSD7A(+). The rate of partial remission was lower in anti-PLA2R(+) patients than in anti-PLA2R(-) patients 3 months (P = 0.045) and 6 months (P = 0.006) after immunosuppressive therapy. The rate of complete remission was lower in anti-PLA2R(+) patients than in anti-PLA2R(-) patients 12 months (P = 0.037) after immunosuppressive therapy. CONCLUSIONS: The serum concentration of anti-PLA2R antibodies may be used as a sensitive and specific marker for diagnosing IMN. Immunosuppressive therapy is more effective for IMN patients who are anti-PLA2R(-) than for those who are anti-PLA2R(+).

Early onset but long survival and other prognostic factors in Chinese sporadic amyotrophic lateral sclerosis.

OBJECTIVES: To explore the cause of long survival but early onset and other prognostic factors among Chinese sporadic amyotrophic lateral sclerosis (ALS) patients. METHODS: Patients with ALS were recruited and followed up from Jan 2013 to Jan 2017. Phenotype and survival were compared among different age-at-onset groups. Candidate prognostic factors were analyzed by Kaplan-Meier method, Cox regression and Royston Parmar (RP) model dealing with breaches of proportional hazard assumption. RESULTS: In the cohort of 531 patients, mean age-at-onset was 53.68 years (SD:10.85) and overall estimated median survival time was 59 months (95% CI: 48.29-69.71). Pairwise comparison showed that patients above 65 years at onset were more frequently bulbar onset (adjusted residual: 3.0), less frequently lumbosacral onset (adjusted residual: -3.0), and had shorter survival compared with other age groups (p = 0.002). Cox and RP model demonstrated independent prognostic variables including age at onset, bulbar onset, diagnostic delay, MRC-score at first diagnosis and region of residence. CONCLUSIONS: This clinic-based study suggested that Chinese sporadic ALS patients had relatively long survival probably due to young age and less bulbar onset cases. Short diagnostic delay, low MRC-score and northern residence were also predicative of short survival. Reallocation of resources is needed to optimize quality care and prolong survival time.

Conduction Block and Nerve Cross-Sectional Area in Multifocal Motor Neuropathy.

Introduction: Motor nerve conduction block (CB) is the main electrophysiological feature of multifocal motor neuropathy (MMN). Increased cross-sectional area (CSA) can be detected by nerve ultrasound in MMN. In this study, we aim to analyze the correlation between CB and CSA in MMN. Methods: Twelve patients with MMN were recruited. Ultrasonography tests and motor nerve conduction studies (NCSs) were performed on median and ulnar nerves simultaneously. CSA was measured at 10 consecutive sites on those nerves, meanwhile nerves were traced continuously and recorded thoroughly under ultrasound. Results: In motor NCSs, 12 definite CB and 12 probable CB areas were detected across standard segments of median and ulnar nerves. With ultrasound studies, increased CSA was detected at 36 sites. There were 9 standard segments with CB and increased CSA, 15 segments with CB but normal CSA, and 27 segments with increased CSA but no CB. Discussion: In MMN, motor nerve CB was not always consistent with increased CSA.

Motor conduction block and conduction velocity in Lewis-Sumner syndrome and multifocal motor neuropathy.

Motor conduction blocks (CBs) and decreased motor nerve conduction velocity (MCV) are both demyelination electrophysiological characteristics. Though CBs are both common in Lewis-Sumner syndrome (LSS) and multifocal motor neuropathy (MMN), they are two distinct disease groups, so their MCV and CBs electrophysiological characteristics may be different. In this paper, we aimed to discuss the relationship between CBs and MCV in Lewis-Sumner syndrome (LSS) and multifocal motor neuropathy (MMN). Sixteen patients with LSS and 11 with MMN were retrospectively collected. Motor nerve conduction studies were performed on bilateral median and ulnar nerves. 16/23 segments with CBs in MMN, and 50/53 segments with CBs in LSS had decreased conduction velocities respectively. There was significant difference in MCV between these two groups (MMN 53.1 ±â€¯12.5 m/s; LSS 34.3 ±â€¯17.1 m/s, mean ±â€¯SD, P < 0.05) as well as significant difference in MCV for segment with or without CBs between MMN and LSS patients (P < 0.05). Patients with LSS were prone to be found MCV decrease in segments of motor CB than patients with MMN (P = 0.017). Forty one segments in LSS patients and 6 segments in MMN had MCV ≤ 38 m/s (P < 0.05). There exist two relationships between CB and MCV no matter in LSS or MMN. The characteristics of MCV and CB can be used to distinguish these two disease groups.

Environmental risk factors and amyotrophic lateral sclerosis (ALS): A case-control study of ALS in China.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly involving central and peripheral motor neurons. The etiology of ALS is not clear. In China, there is a preliminary exploration of genetic factors, but the study on environmental factors is relatively inadequate, which needs to be further clarified. To investigate the protective or harmful effects of different environmental factors on ALS, and explore the possible etiology of ALS of the Chinese for further study. Case-control study were used in 123 patients and 239 healthy controls from 2013 to 2016. Statistical analysis and description were performed with SPSS24.0. The risk factors of ALS include head trauma (OR = 3.397, 95% [1.298, 8.893], P = 0.013), drinking (OR = 1.760, 95% CI [1.110,2.790], p = 0.016), smoking (OR = 3.196, 95% [1.375, 7.427], P = 0.351), low BMI (OR = 1.231, 95% CI [1.115, 1.319], P = 0.000), workers or famers (OR = 2.539, 95% [1.441,4.475], P = 0.001, 30-34 yrs); factors that reduce incidence of ALS including hypertension (OR = 0.526, 95% [0.313, 0.883], P = 0.015), severe physical activities (OR = 0.808, 95% [0.711, 0.918], P = 0.001), longer duration of education (OR = 0.183, 95% [0.078, 0.428], P = 0.000, >12 yrs), reading (OR = 0.225, 95% [0.126, 0.516], P = 0.000, 13-30 yrs), retirement or unemployment (OR = 0.040, 95% [0.005, 0.291], P = 0.000, 30-34 yrs); family history of neurologic disorder, general trauma, years and numbers of smoking, artistic activities, and other occupational factors did not show correlation with ALS. Head trauma, alcohol consumption, smoking, low BMI, workers or farmers are risk factors for ALS; high blood pressure, severe physical activity, longer duration of education, reading, retirement or unemployment are protective factors for ALS; whether there is a connection between ALS and family history, general trauma, years or numbers of smoking, artistic activities, and other occupational factors need to be confirmed by further study.