Atypical structural connectivity of language networks in autism spectrum disorder: A meta-analysis of diffusion tensor imaging studies.

Patients with autism spectrum disorder (ASD) often show pervasive and complex language impairments that are closely associated with aberrant structural connectivity of language networks. However, the characteristics of white matter connectivity in ASD have remained inconclusive in previous diffusion tensor imaging (DTI) studies. The current meta-analysis aimed to comprehensively elucidate the abnormality in language-related white matter connectivity in individuals with ASD. We searched PubMed, Web of Science, Scopus, and Medline databases to identify relevant studies. The standardized mean difference was calculated to measure the pooled difference in DTI metrics in each tract between the ASD and typically developing (TD) groups. The moderating effects of age, sex, language ability, and symptom severity were investigated using subgroup and meta-regression analysis. Thirty-three DTI studies involving 831 individuals with ASD and 836 TD controls were included in the meta-analysis. ASD subjects showed significantly lower fractional anisotropy or higher mean diffusivity across language-associated tracts than TD controls. These abnormalities tended to be more prominent in the left language networks than in the right. In addition, children with ASD exhibit more pronounced and pervasive disturbances in white matter connectivity than adults. These results support the under-connectivity hypothesis and demonstrate the widespread abnormal microstructure of language-related tracts in patients with ASD. Otherwise, white matter abnormalities in the autistic brain could vary depending on the developmental stage and hemisphere. LAY SUMMARY: This meta-analysis explored abnormalities in white matter connectivity in language networks of individuals with ASD. Significantly reduced white matter integrity was found in all language-associated tracts in subjects with ASD compared with TD controls. In addition, structural disturbances of language networks in the autistic brain exhibit a leftward tendency, and more prominent abnormalities are observed in younger people with ASD than in adults.

Association between body mass index and oesophageal cancer mortality: a pooled analysis of prospective cohort studies with >800 000 individuals in the Asia Cohort Consortium.

BACKGROUND: The association between body mass index (BMI) and oesophageal cancer (OC) has been consistently negative among Asians, whereas different associations based on histological OC subtypes have been observed in Europeans and North Americans. We examined the association between BMI and OC mortality in the Asia Cohort Consortium. METHODS: We performed a pooled analysis to evaluate the association between BMI and OC mortality among 842 630 Asians from 18 cohort studies. Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. RESULTS: A wide J-shaped association between BMI and overall OC mortality was observed. The OC mortality risk was increased for underweight (BMI <18.5 kg/m2: HR = 2.20, 95% CI 1.80-2.70) and extreme obesity (BMI ≥35 kg/m2: HR = 4.38, 95% CI 2.25-8.52) relative to the reference BMI (23-25 kg/m2). This association pattern was confirmed by several alternative analyses based on OC incidence and meta-analysis. A similar wide J-shaped association was observed in oesophageal squamous cell carcinoma (OSCC). Smoking and alcohol synergistically increased the OC mortality risk in underweight participants (HR = 6.96, 95% CI 4.54-10.67) relative to that in reference BMI participants not exposed to smoking and alcohol. CONCLUSION: Extreme obesity and being underweight were associated with an OC mortality risk among Asians. OC mortality and BMI formed a wide J-shaped association mirrored by OSCC mortality. Although the effect of BMI on OSCC and oesophageal adenocarcinoma mortality can be different in Asians, further research based on a large case-control study is recommended.

Trend and projection of skilled birth attendants and institutional delivery coverage for adolescents in 54 low- and middle-income countries, 2000-2030.

BACKGROUND: Limitations to accessing delivery care services increase the risks of adverse outcomes during pregnancy and delivery for all pregnant women, particularly among adolescents in LMICs. In order to inform adolescent-specific delivery care initiatives and coverage, we conducted a comprehensive analysis of trends, projections and inequalities in coverage of delivery care services among adolescents at national, urban-rural and socio-economic levels in LMICs. METHODS: Using 224 nationally representative cross-sectional survey data between 2000 and 2019, we estimated the coverage of institutional delivery (INSD) and skilled birth attendants (SBA). Bayesian hierarchical regression models were used to estimate trends, projections and determinants of INSD and SBA. RESULTS: Coverage of delivery care services among adolescents increased substantially at the national level, as well as in both urban and rural areas in most countries between 2000 and 2018. Of the 54 LMICs, 24 countries reached 80% coverage of both INSD and SBA in 2018, and predictions for 40 countries are set to exceed 80% by 2030. The trends in coverage of INSD and SBA of adult mothers mostly align with those for adolescent mothers. Our findings show that urban-rural and wealth-based inequalities to delivery care remain persistent by 2030. In 2018, urban settings across 54 countries had higher rates of coverage exceeding 80% compared to rural for both INSD (45 urban, 16 rural) and SBA (50 urban, 19 rural). Several factors such as household head age ≥ 46 years, household head being female, access to mass media, lower parity, higher education, higher ANC visits and higher socio-economic status could increase the coverage of INSD and SBA among adolescents and adult women. CONCLUSIONS: More than three-quarters of the LMICs are predicted to achieve 80% coverage of INSD and SBA among adolescent mothers in 2030, although with sustained inequalities.

Reduction in total and major cause-specific mortality from tobacco smoking cessation: a pooled analysis of 16 population-based cohort studies in Asia.

BACKGROUND: Little is known about the time course of mortality reduction following smoking cessation in Asians who have smoking behaviours distinct from their Western counterparts. We evaluated the level of reduction in all-cause, cardiovascular disease (CVD) and lung cancer mortality by years since quitting smoking, in Asia. METHODS: Using Cox regression, we analysed individual participant data (n = 709 151) from 16 prospective cohorts conducted in China, Japan, Korea/Singapore, and India/Bangladesh, separately by cohorts. Cohort-specific hazard ratios (HRs) were combined using a random-effects meta-analysis. RESULTS: During a mean follow-up of 12.0 years, 108 287 deaths were ascertained-35 658 from CVD and 7546 from lung cancer. Among Asian men, a dose-response relationship of risk reduction in deaths from all causes, CVD and lung cancer was observed with an increase in years after smoking cessation. Compared with never smokers, however, all-cause and CVD mortality among former smokers remained elevated 10-14 years after quitting [multivariable-adjusted HR (95% confidence interval (CI) = 1.25 (1.13-1.37) and 1.20 (1.02-1.41), respectively]. Lung cancer mortality stayed almost 2-fold higher than among never smokers 15-19 years after smoking cessation [1.97 (1.41-2.73)], particularly among former heavy smokers [2.62 (1.71-4.00)]. Women who quitted for ≥5 years retained a significantly elevated mortality from all causes, CVD and lung cancer. Overall patterns of the cessation-mortality associations were similar across countries. CONCLUSIONS: Our findings suggest that adverse effects of tobacco smoking persist for an extended time period, even for more than two decades, which is beyond the time windows defined in current clinical guidelines for risk assessment of lung cancer and CVD.

Association of Sleep Duration With All- and Major-Cause Mortality Among Adults in Japan, China, Singapore, and Korea.

Importance: The association between long sleep duration and mortality appears stronger in East Asian populations than in North American or European populations. Objectives: To assess the sex-specific association between sleep duration and all-cause and major-cause mortality in a pooled longitudinal cohort and to stratify the association by age and body mass index. Design, Setting, and Participants: This cohort study of individual-level data from 9 cohorts in the Asia Cohort Consortium was performed from January 1, 1984, to December 31, 2002. The final population included participants from Japan, China, Singapore, and Korea. Mean (SD) follow-up time was 14.0 (5.0) years for men and 13.4 (5.3) years for women. Data analysis was performed from August 1, 2018, to May 31, 2021. Exposures: Self-reported sleep duration, with 7 hours as the reference category. Main Outcomes and Measures: Mortality, including deaths from all causes, cardiovascular disease, cancer, and other causes. Sex-specific hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards regression with shared frailty models adjusted for age and the key self-reported covariates of marital status, body mass index, smoking status, alcohol consumption, physical activity, history of diabetes and hypertension, and menopausal status (for women). Results: For 322 721 participants (mean [SD] age, 54.5 [9.2] years; 178 542 [55.3%] female), 19 419 deaths occurred among men (mean [SD] age of men, 53.6 [9.0] years) and 13 768 deaths among women (mean [SD] age of women, 55.3 [9.2] years). A sleep duration of 7 hours was the nadir for associations with all-cause, cardiovascular disease, and other-cause mortality in both men and women, whereas 8 hours was the mode sleep duration among men and the second most common sleep duration among women. The association between sleep duration and all-cause mortality was J-shaped for both men and women. The greatest association for all-cause mortality was with sleep durations of 10 hours or longer for both men (hazard ratio [HR], 1.34; 95% CI, 1.26-1.44) and women (HR, 1.48; 95% CI, 1.36-1.61). Sex was a significant modifier of the association between sleep duration and mortality from cardiovascular disease (χ25 = 13.47, P = .02), cancer (χ25 = 16.04, P = .007), and other causes (χ25 = 12.79, P = .03). Age was a significant modifier of the associations among men only (all-cause mortality: χ25 = 41.49, P < .001; cancer: χ25 = 27.94, P < .001; other-cause mortality: χ25 = 24.51, P < .001). Conclusions and Relevance: The findings of this cohort study suggest that sleep duration is a behavioral risk factor for mortality in both men and women. Age was a modifier of the association between sleep duration in men but not in women. Sleep duration recommendations in these populations may need to be considered in the context of sex and age.

Quantifying the association of low-intensity and late initiation of tobacco smoking with total and cause-specific mortality in Asia.

BACKGROUND: Little is known about the health harms associated with low-intensity smoking in Asians who, on average, smoke fewer cigarettes and start smoking at a later age than their Western counterparts. METHODS: In this pooled analysis of 738 013 Asians from 16 prospective cohorts, we quantified the associations of low-intensity (<5 cigarettes/day) and late initiation (≥35 years) of smoking with mortality outcomes. HRs and 95% CIs were estimated for each cohort by Cox regression. Cohort-specific HRs were pooled using random-effects meta-analysis. FINDINGS: During a mean follow-up of 11.3 years, 92 068 deaths were ascertained. Compared with never smokers, current smokers who consumed <5 cigarettes/day or started smoking after age 35 years had a 16%-41% increased risk of all-cause, cardiovascular disease (CVD), respiratory disease mortality and a >twofold risk of lung cancer mortality. Furthermore, current smokers who started smoking after age 35 and smoked <5 cigarettes/day had significantly elevated risks of all-cause (HRs (95% CIs)=1.14 (1.05 to 1.23)), CVD (1.27 (1.08 to 1.49)) and respiratory disease (1.54 (1.17 to 2.01)) mortality. Even smokers who smoked <5 cigarettes/day but quit smoking before the age of 45 years had a 16% elevated risk of all-cause mortality; however, the risk declined further with increasing duration of abstinence. CONCLUSIONS: Our study showed that smokers who smoked a small number of cigarettes or started smoking later in life also experienced significantly elevated all-cause and major cause-specific mortality but benefited from cessation. There is no safe way to smoke-not smoking is always the best choice.

Association of Diabetes With All-Cause and Cause-Specific Mortality in Asia: A Pooled Analysis of More Than 1 Million Participants.

Importance: Asia is home to the largest diabetic populations in the world. However, limited studies have quantified the association of diabetes with all-cause and cause-specific mortality in Asian populations. Objectives: To evaluate the association of diabetes with all-cause and cause-specific mortality in Asia and to investigate potential effect modifications of the diabetes-mortality associations by participants' age, sex, education level, body mass index, and smoking status. Design, Setting, and Participants: This pooled analysis incorporated individual participant data from 22 prospective cohort studies of the Asia Cohort Consortium conducted between 1963 and 2006. A total of 1 002 551 Asian individuals (from mainland China, Japan, South Korea, Singapore, Taiwan, India, and Bangladesh) were followed up for more than 3 years. Cohort-specific hazard ratios and 95% confidence intervals for all-cause and cause-specific mortality were estimated using Cox regression models and then pooled using random-effects meta-analysis. Analysis was conducted between January 10, 2018, and August 31, 2018. Exposures: Doctor-diagnosed diabetes, age, sex, education level, body mass index, and smoking status. Main Outcomes and Measures: All-cause and cause-specific mortality. Results: Of 1 002 551 participants (518 537 [51.7%] female; median [range] age, 54.0 [30.0-98.0] years), 148 868 deaths were ascertained during a median (range) follow-up of 12.6 (3.0-38.9) years. The overall prevalence of diabetes reported at baseline was 4.8% for men and 3.6% for women. Patients with diabetes had a 1.89-fold risk of all-cause death compared with patients without diabetes (hazard ratio [HR], 1.89; 95% CI, 1.74-2.04), with the highest relative risk of death due to diabetes itself (HR, 22.8; 95% CI, 18.5-28.1), followed by renal disease (HR, 3.08; 95% CI, 2.50-3.78), coronary heart disease (HR, 2.57; 95% CI, 2.19-3.02), and ischemic stroke (HR, 2.15; 95% CI, 1.85-2.51). The adverse diabetes-mortality associations were more evident among women (HR, 2.09; 95% CI, 1.89-2.32) than among men (HR, 1.74; 95% CI, 1.62-1.88) (P for interaction < .001) and more evident among adults aged 30 to 49 years (HR, 2.43; 95% CI, 2.08-2.84) than among adults aged 70 years and older (HR, 1.51; 95% CI, 1.40-1.62) (P for interaction < .001). A similar pattern of association was found between diabetes and cause-specific mortality, with significant variations noted by sex and age. Conclusions and Relevance: This study found that diabetes was associated with increased risk of death from several diseases among Asian populations. Development and implementation of diabetes management programs are urgently needed to reduce the burden of diabetes in Asia.

Tobacco Smoking and Mortality in Asia: A Pooled Meta-analysis.

Importance: Understanding birth cohort-specific tobacco smoking patterns and their association with total and cause-specific mortality is important for projecting future deaths due to tobacco smoking across Asian populations. Objectives: To assess secular trends of tobacco smoking by countries or regions and birth cohorts and evaluate the consequent mortality in Asian populations. Design, Setting, and Participants: This pooled meta-analysis was based on individual participant data from 20 prospective cohort studies participating in the Asia Cohort Consortium. Between September 1, 2017, and March 31, 2018, a total of 1 002 258 Asian individuals 35 years or older were analyzed using Cox proportional hazards regression analysis and random-effects meta-analysis. The pooled results were presented for mainland China; Japan; Korea, Singapore, and Taiwan; and India. Exposures: Tobacco use status, age at starting smoking, number of cigarettes smoked per day, and age at quitting smoking. Main Outcomes and Measures: Country or region and birth cohort-specific mortality and the population attributable risk for deaths from all causes and from lung cancer. Results: Of 1 002 258 participants (51.1% women and 48.9% men; mean [SD] age at baseline, 54.6 [10.4] years), 144 366 deaths (9158 deaths from lung cancer) were ascertained during a mean (SD) follow-up of 11.7 (5.3) years. Smoking prevalence for men steadily increased in China and India, whereas it plateaued in Japan and Korea, Singapore, and Taiwan. Among Asian male smokers, the mean age at starting smoking decreased in successive birth cohorts, while the mean number of cigarettes smoked per day increased. These changes were associated with an increasing relative risk of death in association with current smoking in successive birth cohorts of pre-1920, 1920s, and 1930 or later, with hazard ratios for all-cause mortality of 1.26 (95% CI, 1.17-1.37) for the pre-1920 birth cohort, 1.47 (95% CI, 1.35-1.61) for the 1920s birth cohort, and 1.70 (95% CI, 1.57-1.84) for the cohort born in 1930 or later. The hazard ratios for lung cancer mortality were 3.38 (95% CI, 2.25-5.07) for the pre-1920 birth cohort, 4.74 (95% CI, 3.56-6.32) for the 1920s birth cohort, and 4.80 (95% CI, 3.71-6.19) for the cohort born in 1930 or later. Tobacco smoking accounted for 12.5% (95% CI, 8.4%-16.3%) of all-cause mortality in the pre-1920 birth cohort, 21.1% (95% CI, 17.3%-24.9%) of all-cause mortality in the 1920s birth cohort, and 29.3% (95% CI, 26.0%-32.3%) of all-cause mortality for the cohort born in 1930 or later. Tobacco smoking among men accounted for 56.6% (95% CI, 44.7%-66.3%) of lung cancer mortality in the pre-1920 birth cohort, 66.6% (95% CI, 58.3%-73.5%) of lung cancer mortality in the 1920s birth cohort, and 68.4% (95% CI, 61.3%-74.4%) of lung cancer mortality for the cohort born in 1930 or later. For women, tobacco smoking patterns and lung cancer mortality varied substantially by countries and regions. Conclusions and Relevance: In this study, mortality associated with tobacco smoking continued to increase among Asian men in recent birth cohorts, indicating that tobacco smoking will remain a major public health problem in most Asian countries in the coming decades. Implementing comprehensive tobacco-control programs is warranted to end the tobacco epidemic.

The establishment of the Household Air Pollution Consortium (HAPCO).

Household air pollution (HAP) is of public health concern with ~3 billion people worldwide (including >15 million in the US) exposed. HAP from coal use is a human lung carcinogen, yet the epidemiological evidence on carcinogenicity of HAP from biomass use, primarily wood, is not conclusive. To robustly assess biomass's carcinogenic potential, prospective studies of individuals experiencing a variety of HAP exposures are needed. We have built a global consortium of 13 prospective cohorts (HAPCO: Household Air Pollution Consortium) that have site- and disease-specific mortality and solid fuel use data, for a combined sample size of 587,257 participants and 57,483 deaths. HAPCO provides a novel opportunity to assess the association of HAP with lung cancer death while controlling for important confounders such as tobacco and outdoor air pollution exposures. HAPCO is also uniquely positioned to determine the risks associated with cancers other than lung as well as non-malignant respiratory and cardiometabolic outcomes, for which prospective epidemiologic research is limited. HAPCO will facilitate research to address public health concerns associated with HAP-attributed exposures by enabling investigators to evaluate sex-specific and smoking status-specific effects under various exposure scenarios.

Drug diffusion, integration, and stability of nanoengineered drug-releasing implants in bone ex-vivo.

To treat skeletal conditions such as bone infections, osteoporotic fractures, and osteosarcoma, it would be ideal to introduce drugs directly to the affected site. Localized drug delivery from the bone implants is a promising alternative to systemic drug administration. In this study we investigated electrochemically nanoengineered Ti wire implants with titania nanotubes (TNTs), as minimally invasive drug-releasing implants for the delivery of drugs directly into the bone tissue. Since trabecular bone in vivo contains a highly interconnected bone marrow, we sought to determine the influence of marrow on drug release and diffusion. Electrochemical anodization of Ti wires (length 10 mm) was performed to create an oxide layer with TNTs on the surface, followed by loading with a fluorescent model drug, Rhodamine B (RhB). Cores of bovine trabecular bone were generated from the sternum of a young steer, and were processed to have an intact bone marrow, or the marrow was removed. RhB-loaded TNTs/Ti wires were inserted into the bone cores, which were then cultured ex vivo using the ZetOS™ bioreactor system to maintain bone viability. Release and diffusion of RhB inside the bone was monitored using fluorescence imaging and different patterns of drug transport in the presence or absence of marrow were observed. Scanning electron microscopy of the implants after retrieval from bone cores confirmed survival of the TNTs structures. Histological investigation showed the presence of bone cells adherent on the implants. This study shows a potential of Ti drug-releasing implants based on TNTs technology towards localized bone therapy. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 714-725, 2016.

Nanoengineered drug releasing aluminium wire implants: a model study for localized bone therapy.

A needle puncture approach using nanoengineered aluminium (Al) wires as drug-releasing implants is explored for localized drug delivery in bone using an ex vivo bone reactor. The wire implants were prepared by electrochemical anodization with the formation of a thin nanoporous alumina (NPA) layer on their surface and pore diameters of 30-35 nm and pore lengths of 10-60 µm. An in vitro drug release study of a model drug from the implants, prepared with different thicknesses of NPA layers (pore lengths), showed a considerable influence on drug release characteristics. The results confirmed that by controlling the pore length it is possible to tune the drug releasing performance of the implants and achieve a sustained release for an extended period. The biocompatibility study of the implants evaluated using human osteoblast cell culture showed strong growth of cells, their spreading and their adhesion to the implant surface. The drug loaded wire implants inserted inside bone by a needle puncture approach are evaluated for ex vivo drug release inside bone using a bone reactor (Zetos). The results demonstrated consistent and slow drug release from implants and distribution inside bone monitored in situ using a live imaging technique. The cross-sectional study of inserted wire implants after an extended period of release confirmed stable and unchanged NPA morphology. Histology of bone in contact with implants indicates the presence of viable osteocytes along the inserted area indicating that this method is a reliable approach and NPA wire implants are harmless devices. Overall, this study demonstrates that needle guided implantation of nanoengineered and drug loaded porous wires could be used as a new drug releasing implants for localized bone therapy and treatment of bone disease such as bacterial infection, healing, and potentially bone cancer.

Localized drug delivery of selenium (Se) using nanoporous anodic aluminium oxide for bone implants.

Electrochemically engineered nanoporous anodized aluminium oxide (AAO) prepared on aluminium (Al) foil by anodization process was employed as a platform for loading different forms of selenium (Se) in order to investigate their release behaviour and potential application for localized drug delivery targeting bone cancer. Several forms of Se including inorganic Se (H2SeO3), organic Se ((C6H5)2Se2), metallic Se, their chitosan composites, electrodeposited (ED) and chemical vapour deposited (CVD) Se were explored and combined with another model drug (indomethacin). Structural, drug-loading and in vitro drug-releasing characteristics of prepared Se-based drug delivery carriers were characterized by scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and UV-visible spectroscopy (UV-Vis), respectively. Sustained and controlled release of Se was demonstrated through chitosan-composites of inorganic, organic or metallic forms of Se loaded into nanoporous AAO carriers. Cell viability studies showed decreasing toxicity to cancer cells in the order: inorganic Se > ED Se > CVD Se > metallic Se > organic Se. The study suggests new alternatives for localized drug treatment based on low-cost nano-engineered carriers loaded with Se having anti-cancer properties.

Native and ß-cyclodextrin-enclosed curcumin: entrapment within liposomes and their in vitro cytotoxicity in lung and colon cancer.

With a view to improving the solubility and delivery characteristics of poorly water-soluble drugs, we prepared ß-cyclodextrin-curcumin (ßCD-C) inclusion complexes (hydrophilic curcumin) and entrapped both native curcumin (hydrophobic) and the complexes separately into liposomes; these were then assessed for in vitro cytotoxicity in lung and colon cancer cell lines. Optimization of curcumin entrapment within ßCD was achieved, with the resultant ßCD-C complexes prepared by methanol reflux. Inclusion complexes were confirmed using UV spectroscopy, Fourier transform infrared spectroscopy (FT-IR) and X-ray diffraction. The water solubility of ßCD-C complexes improved markedly (c.f. native curcumin) and successful entrapment of complexes into liposomes, prepared using a thin-film hydration approach, was also achieved. All the liposomal formulations were characterized for curcumin and ßCD-C complex entrapment efficiency, particle size, polydispersity and stability at 2-8°C. Curcumin, ßCD-C complex and their optimized liposomal formulations were evaluated for anticancer activity in lung (A-459) and colon (SW-620) cancer cell lines. All curcumin-containing formulations tested were effective in inhibiting cell proliferation, as determined via an MTT assay. The median effective dose (EC(50)) for all curcumin formulations was found to be in the low µM range for both lung and colon cancer cell lines tested. Our results confirm that ßCD inclusion complexes of poorly water soluble drugs, such as curcumin can be entrapped within biocompatible vesicles such as liposomes, and this does not preclude their anticancer activity.