A transformer architecture for retention time prediction in liquid chromatography mass spectrometry-based proteomics.

Accurate retention time (RT) prediction is important for spectral library-based analysis in data-independent acquisition mass spectrometry-based proteomics. The deep learning approach has demonstrated superior performance over traditional machine learning methods for this purpose. The transformer architecture is a recent development in deep learning that delivers state-of-the-art performance in many fields such as natural language processing, computer vision, and biology. We assess the performance of the transformer architecture for RT prediction using datasets from five deep learning models Prosit, DeepDIA, AutoRT, DeepPhospho, and AlphaPeptDeep. The experimental results on holdout datasets and independent datasets exhibit state-of-the-art performance of the transformer architecture. The software and evaluation datasets are publicly available for future development in the field.

Essential childhood immunization in 43 low- and middle-income countries: Analysis of spatial trends and socioeconomic inequalities in vaccine coverage.

BACKGROUND: Globally, access to life-saving vaccines has improved considerably in the past 5 decades. However, progress has started to slow down and even reverse in recent years. Understanding subnational heterogeneities in essential child immunization will be critical for closing the global vaccination gap. METHODS AND FINDINGS: We use vaccination information for over 220,000 children across 1,366 administrative regions in 43 low- and middle-income countries (LMICs) from the most recent Demographic and Health Surveys. We estimate essential immunization coverage at the national and subnational levels and quantify socioeconomic inequalities in such coverage using adjusted concentration indices. Within- and between-country variations are summarized via the Theil index. We use local indicator of spatial association (LISA) statistics to identify clusters of administrative regions with high or low values. Finally, we estimate the number of missed vaccinations among children aged 15 to 35 months across all 43 countries and the types of vaccines most often missed. We show that national-level vaccination rates can conceal wide subnational heterogeneities. Large gaps in child immunization are found across West and Central Africa and in South Asia, particularly in regions of Angola, Chad, Nigeria, Guinea, and Afghanistan, where less than 10% of children are fully immunized. Furthermore, children living in these countries consistently lack all 4 basic vaccines included in the WHO's recommended schedule for young children. Across most countries, children from poorer households are less likely to be fully immunized. The main limitations include subnational estimates based on large administrative divisions for some countries and different periods of survey data collection. CONCLUSIONS: The identified heterogeneities in essential childhood immunization, especially given that some regions consistently are underserved for all basic vaccines, can be used to inform the design and implementation of localized intervention programs aimed at eliminating child suffering and deaths from existing and novel vaccine-preventable diseases.

Societal Adaptation to Aging and Prevalence of Depression Among Older Adults: Evidence From 20 Countries.

Policy Points Countries have adopted different strategies to support aging populations, which are broadly reflected in social, economic, and contextual environments. Referred to as "societal adaptation to aging," these factors affect countries' capacity to support older adults. Results from our study show that countries with more robust societal adaptation to aging had lower depression prevalence. Reductions in depression prevalence occurred among every investigated sociodemographic group and were most pronounced among the old-old. Findings suggest that societal factors have an underacknowledged role in shaping depression risk. Policies that improve societal approaches to aging may reduce depression prevalence among older adults. CONTEXT: Countries have adopted various formal and informal approaches to support older adults, which are broadly reflected in different policies, programs, and social environments. These contextual environments, broadly referred to as "societal adaptation to aging," may affect population health. METHODS: We used a new theory-based measure that captured societal adaptation to aging, the Aging Society Index (ASI), which we linked with harmonized individual-level data from 89,111 older adults from 20 countries. Using multi-levels models that accounted for differences in the population composition across countries, we estimated the association between country-level ASI scores and depression prevalence. We also tested if associations were stronger among the old-old and among sociodemographic groups that experience more disadvantage (i.e., women, those with lower educational attainment, unmarried adults). FINDINGS: We found that countries with higher ASI scores, indicating more comprehensive approaches to supporting older adults, had lower depression prevalence. We found especially strong reductions in depression prevalence among the oldest adults in our sample. However, we did not find stronger reductions among sociodemographic groups who may experience more disadvantage. CONCLUSIONS: Country-level strategies to support older adults may affect depression prevalence. Such strategies may become increasingly important as adults grow older. These results offer promising evidence that improvements in societal adaptation to aging-such as through adoption of more comprehensive policies and programs targeting older adults-may be one avenue to improve population mental health. Future research could investigate observed associations using longitudinal and quasi-experimental study designs, offering additional information regarding a potential causal relationship.

Exploring the dynamics of flagellar dynein within the axoneme with Fluctuating Finite Element Analysis.

Flagellar dyneins are the molecular motors responsible for producing the propagating bending motions of cilia and flagella. They are located within a densely packed and highly organised super-macromolecular cytoskeletal structure known as the axoneme. Using the mesoscale simulation technique Fluctuating Finite Element Analysis (FFEA), which represents proteins as viscoelastic continuum objects subject to explicit thermal noise, we have quantified the constraints on the range of molecular conformations that can be explored by dynein-c within the crowded architecture of the axoneme. We subsequently assess the influence of crowding on the 3D exploration of microtubule-binding sites, and specifically on the axial step length. Our calculations combine experimental information on the shape, flexibility and environment of dynein-c from three distinct sources; negative stain electron microscopy, cryo-electron microscopy (cryo-EM) and cryo-electron tomography (cryo-ET). Our FFEA simulations show that the super-macromolecular organisation of multiple protein complexes into higher-order structures can have a significant influence on the effective flexibility of the individual molecular components, and may, therefore, play an important role in the physical mechanisms underlying their biological function.

Extremes in water availability and suicide: Evidence from a nationally representative sample of rural Indian adults.

BACKGROUND: Extremes in water availability, either exceptionally wet or dry conditions, can damage crops and may detrimentally affect the livelihood and well-being of people engaged in agriculture. We estimated the effect of water availability on suicide in rural India, a context where the majority of households are dependent upon agriculture. METHODS: We used data from a nationally representative sample of 8.5 million people who were monitored for causes of death from 2001 to 2013. Water availability was measured with high-resolution precipitation and temperature data (i.e., the Standardized Precipitation Evapotranspiration Index). We used a fixed effects approach that modeled changes in water availability within districts (n = 569) over time (n = 13 years) to estimate the impact on suicide deaths. We restricted our analysis to rural areas and to deaths occurring during the growing season (June-March) among adults aged 15 or older, and controlled for sex, age, region, and year. We used Poisson regression with standard errors clustered at the district level and total deaths as the offset. RESULTS: There were 9456 suicides and 249,786 total deaths in our study population between 2001 and 2013. Compared to normal growing seasons, the percent of deaths due to suicide increased by 18.7% during extremely wet growing seasons (95% CI: 6.2, 31.2) and by 3.6% during extremely dry growing seasons (95% CI: -17.9, 25.0). We found that effects varied by age. CONCLUSIONS: We found extremes is water availability associated with an increase in suicide. Abnormally wet growing conditions may play an important, yet overlooked, role in suicide among rural Indian adults.

The effect of intimate partner violence on women's mental distress: a prospective cohort study of 3010 rural Indian women.

PURPOSE: Intimate partner violence (IPV) encompasses physical, sexual, and psychological abuse, as well as controlling behavior. Most research focuses on physical and sexual abuse, and other aspects of IPV are rarely investigated. We estimated the effect of these neglected aspects of IPV on women's mental distress. METHODS: We used data from 3010 women living in rural tribal communities in Rajasthan, India. Women completed baseline interviews and were re-interviewed approximately 1.5 years later. We measured IPV with questions adopted from the Demographic and Health Survey's Domestic Violence Module, which asked seven questions about physical abuse, three questions about psychological abuse, and five questions about partner controlling behavior. Mental distress was measured with the 12-item General Health Questionnaire (score range 0-12). We used Poisson regression models to estimate the relation between changes in IPV and mental distress, accounting for time-fixed characteristics of individuals using individual fixed effects. RESULTS: Women reported an average of 2.1 distress symptoms during baseline interviews. In models that controlled for time-varying confounding (e.g., wealth, other types of abuse), experiencing psychological abuse was associated with an increase of 0.65 distress symptoms (95% CI 0.32, 0.98), and experiencing controlling behavior was associated with an increase of 0.31 distress symptoms (95% CI 0.18, 0.44). However, experiencing physical abuse was not associated with an increase in distress symptoms (mean difference = - 0.15, 95% CI - 0.45, 0.15). CONCLUSIONS: Psychological abuse and controlling behavior may be important drivers of the relation between IPV and women's mental health.

Fluctuating Finite Element Analysis (FFEA): A continuum mechanics software tool for mesoscale simulation of biomolecules.

Fluctuating Finite Element Analysis (FFEA) is a software package designed to perform continuum mechanics simulations of proteins and other globular macromolecules. It combines conventional finite element methods with stochastic thermal noise, and is appropriate for simulations of large proteins and protein complexes at the mesoscale (length-scales in the range of 5 nm to 1 µm), where there is currently a paucity of modelling tools. It requires 3D volumetric information as input, which can be low resolution structural information such as cryo-electron tomography (cryo-ET) maps or much higher resolution atomistic co-ordinates from which volumetric information can be extracted. In this article we introduce our open source software package for performing FFEA simulations which we have released under a GPLv3 license. The software package includes a C ++ implementation of FFEA, together with tools to assist the user to set up the system from Electron Microscopy Data Bank (EMDB) or Protein Data Bank (PDB) data files. We also provide a PyMOL plugin to perform basic visualisation and additional Python tools for the analysis of FFEA simulation trajectories. This manuscript provides a basic background to the FFEA method, describing the implementation of the core mechanical model and how intermolecular interactions and the solvent environment are included within this framework. We provide prospective FFEA users with a practical overview of how to set up an FFEA simulation with reference to our publicly available online tutorials and manuals that accompany this first release of the package.

WITHDRAWN: Ozone therapy for the treatment of dental caries.

BACKGROUND: Dental caries is a bacterially mediated disease characterised by demineralisation of the tooth surface, which may lead to cavitation, discomfort, pain and eventual tooth loss. Ozone is toxic to certain bacteria in vitro and it has been suggested that delivering ozone into a carious lesion might reduce the number of cariogenic bacteria. This possibly could arrest the progress of the lesion and may, in the presence of fluoride, perhaps allow remineralisation to occur. This may in turn delay or prevent the need for traditional dental conservation by 'drilling and filling'. OBJECTIVES: To assess whether ozone is effective in arresting or reversing the progression of dental caries. SEARCH METHODS: We searched the Cochrane Oral Health Group's Trials Register (to 7 November 2003); Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2003, Issue 3); MEDLINE and PREMEDLINE (OVID) (1966 to November 2003); EMBASE (OVID) (1980 to November 2003); CINAHL (OVID) (1982 to November 2003); AMED (OVID) (1985 to November 2003). Quintessence was handsearched through 2002 and KaVo were contacted as manufacturers of the HealOzone apparatus for any additional published or unpublished trials. SELECTION CRITERIA: Inclusion was assessed independently by at least two reviewers. Trials were only included if they met the following criteria: randomisation in a controlled trial; single surface in vivo carious lesion accessible to ozone application; clear allocation concealment; ozone application to the lesions in the intervention group; no such application of ozone in the control group; outcomes measured after at least 6 months. DATA COLLECTION AND ANALYSIS: Reviewers independently extracted information in duplicate. A paucity of comparable data did not allow meta-analytic pooling of the included studies. MAIN RESULTS: Three trials were included, with a combined total of 432 randomised lesions (137 participants). Forty-two conference papers, abstracts and posters were excluded (from an unknown number of studies). The risk of bias in all studies appeared high. The analyses of all three studies were conducted at the level of the lesion, which is not independent of the person, for this reason pooling of data was not appropriate or attempted. Individual studies showed inconsistent effects of ozone on caries, across different measures of caries progression or regression. Few secondary outcomes were reported, but one trial reported an absence of adverse events. AUTHORS' CONCLUSIONS: Given the high risk of bias in the available studies and lack of consistency between different outcome measures, there is no reliable evidence that application of ozone gas to the surface of decayed teeth stops or reverses the decay process. There is a fundamental need for more evidence of appropriate rigour and quality before the use of ozone can be accepted into mainstream primary dental care or can be considered a viable alternative to current methods for the management and treatment of dental caries.

Are work demands associated with mental distress? Evidence from women in rural India.

PURPOSE: High work demands might be a determinant of poor mental health among women in low- and middle-income countries, especially in rural settings where women experience greater amounts of labor-intensive unpaid work. Research originating from such settings is lacking. METHODS: We estimated the cross-sectional association between work demands and mental distress among 3177 women living in 160 predominantly tribal communities in southern Rajasthan, India. A structured questionnaire captured the number of minutes women spent on various activities in the last 24 h, and we used this information to measure women's work demands, including the total work amount, nature of work (e.g., housework), and type of work (e.g., cooking). Mental distress was measured with the Hindi version of the 12-item General Health Questionnaire. We used negative binomial regression models to estimate the association between work demands (amount, nature, and type) and mental distress. RESULTS: On average, women spent more than 9.5 h a day on work activities. The most time, intensive work activity was caring for children, the elderly, or disabled (149 min). In adjusted models, we found a U-shaped association between work amount and mental distress. High amounts of housework were associated with higher distress, whereas paid work and farmwork amount were not. Certain types of housework, including collecting water and cleaning, were associated with increased distress scores. CONCLUSIONS: We found an association between aspects of work demands and mental distress. Research in other contexts where women perform high amounts of unpaid work, particularly within the home or farm, is warranted.

In pursuit of an accurate spatial and temporal model of biomolecules at the atomistic level: a perspective on computer simulation.

Despite huge advances in the computational techniques available for simulating biomolecules at the quantum-mechanical, atomistic and coarse-grained levels, there is still a widespread perception amongst the experimental community that these calculations are highly specialist and are not generally applicable by researchers outside the theoretical community. In this article, the successes and limitations of biomolecular simulation and the further developments that are likely in the near future are discussed. A brief overview is also provided of the experimental biophysical methods that are commonly used to probe biomolecular structure and dynamics, and the accuracy of the information that can be obtained from each is compared with that from modelling. It is concluded that progress towards an accurate spatial and temporal model of biomacromolecules requires a combination of all of these biophysical techniques, both experimental and computational.

Modelling biomacromolecular assemblies with continuum mechanics.

We have developed a continuum mechanical description of proteins using a finite element algorithm which has been generalized to include thermal fluctuations and which is therefore known as fluctuating finite element analysis (FFEA). Whereas conventional molecular dynamics (MD) simulations provide a trajectory in which each individual atomic position fluctuates, a FFEA trajectory shows how the overall shape of the protein changes due to thermal agitation. We describe the theoretical background to FFEA, its relationship to more established biomolecular modelling methods and provide examples of its application to the mesoscale biomolecular dynamics of the molecular motor dynein.

Trends in Educational Inequalities in Drug Poisoning Mortality: United States, 1994-2010.

OBJECTIVES: We estimated trends in drug poisoning death rates by educational attainment and investigated educational inequalities in drug poisoning mortality by race, gender, and region. METHODS: We linked drug poisoning death counts from the National Vital Statistics System to population denominators from the Current Population Survey to estimate drug poisoning rates by gender, race, region, and educational attainment (less than high school degree, high school degree, some college, college degree) from 1994 to 2010. RESULTS: There were 372,485 drug poisoning deaths. Education-related inequalities increased during the study among all demographic groups and varied by region. Absolute increases in educational inequalities were higher among Whites than Blacks and men than women. The age-adjusted rate difference between White men with less than a high school degree increased from 8.7 per 100,000 in 1994 to 27.4 in 2010 (change = 18.7). Among Black men, the corresponding increases were 11.7 and 18.3, respectively (change = 6.6). CONCLUSIONS: We found strong educational patterning in drug poisoning rates, chiefly by region and race. Rates are highest and increasing the fastest among groups with less education.

Neighborhood socioeconomic conditions and depression: a systematic review and meta-analysis.

PURPOSE: The evidence linking neighborhood socioeconomic conditions (NSEC) with depression is mixed. We performed a systematic review of this literature, including a rigorous quality assessment that was used to explore if methodological or contextual factors explained heterogeneity across studies. METHODS: A systematic literature search in three databases identified longitudinal studies among adolescents and adults living in high-income countries. Two independent reviewers screened studies for inclusion and performed data abstraction. We conducted a formal quality assessment and investigated sources of study heterogeneity. RESULTS: Our database search identified 3711 articles, 84 of which were determined to be potentially relevant, and 14 articles were included in this review. About half of the studies found a significant association between NSEC and depression, and pooled estimates suggest poorer socioeconomic conditions were associated with higher odds of depression (OR = 1.14, 95% CI 1.01, 1.28). Study results varied by follow-up time. Among studies with less than 5 years of follow-up, there was a significant association between NSEC and depression (OR = 1.28, 95% CI 1.13, 1.44), although pooling of study results may not be warranted due to heterogeneity across studies. Among studies with at least 5 years of follow-up, which were homogeneous, there was no association (OR = 1.00, 95% CI 0.95, 1.06) between NSEC and depression. CONCLUSIONS: We found inconsistent evidence in support of a longitudinal association between NSEC and depression, and heterogeneity according to the length of follow-up time might partly explain the mixed evidence observed in the literature on NSEC and depression.

Understanding the apparent stator-rotor connections in the rotary ATPase family using coarse-grained computer modeling.

Advances in structural biology, such as cryo-electron microscopy (cryo-EM) have allowed for a number of sophisticated protein complexes to be characterized. However, often only a static snapshot of a protein complex is visualized despite the fact that conformational change is frequently inherent to biological function, as is the case for molecular motors. Computer simulations provide valuable insights into the different conformations available to a particular system that are not accessible using conventional structural techniques. For larger proteins and protein complexes, where a fully atomistic description would be computationally prohibitive, coarse-grained simulation techniques such as Elastic Network Modeling (ENM) are often employed, whereby each atom or group of atoms is linked by a set of springs whose properties can be customized according to the system of interest. Here we compare ENM with a recently proposed continuum model known as Fluctuating Finite Element Analysis (FFEA), which represents the biomolecule as a viscoelastic solid subject to thermal fluctuations. These two complementary computational techniques are used to answer a critical question in the rotary ATPase family; implicit within these motors is the need for a rotor axle and proton pump to rotate freely of the motor domain and stator structures. However, current single particle cryo-EM reconstructions have shown an apparent connection between the stators and rotor axle or pump region, hindering rotation. Both modeling approaches show a possible role for this connection and how it would significantly constrain the mobility of the rotary ATPase family.

Determinants of increased opioid-related mortality in the United States and Canada, 1990-2013: a systematic review.

We review evidence of determinants contributing to increased opioid-related mortality in the United States and Canada between 1990 and 2013. We identified 17 determinants of opioid-related mortality and mortality increases that we classified into 3 categories: prescriber behavior, user behavior and characteristics, and environmental and systemic determinants. These determinants operate independently but interact in complex ways that vary according to geography and population, making generalization from single studies inadvisable. Researchers in this area face significant methodological difficulties; most of the studies in our review were ecological or observational and lacked control groups or adjustment for confounding factors; thus, causal inferences are difficult. Preventing additional opioid-related mortality will likely require interventions that address multiple determinants and are tailored to specific locations and populations.

Does domestic violence legislation reduce permissive attitudes about intimate partner violence? Longitudinal evidence from men and women from 61 countries.

Background: Intimate partner violence (IPV) is highly prevalent and has substantial implications for women's health. Changing IPV attitudes is one pathway to reduce IPV. While evidence suggests that interventions targeting individuals may change IPV attitudes, the effect of wider-scale interventions, such as legislation, remain unknown. Methods: We used individual-level IPV attitudes information collected between 1997 and 2020 by the Demographic and Health Surveys (DHS) and the Multiple Indicator Cluster Surveys (MICS), which we linked with national-level domestic violence (DV) legislation information. We evaluated the effect of adoption of DV legislation on changes in IPV attitudes using a difference-in-differences study design that controlled for time-varying country-level confounding and accounted for staggered timing of legislation adoption. Findings: Our sample included 2,184,047 women from 60 countries and 390,877 men from 40 countries. After controlling for country-level confounders, adoption of DV legislation reduced IPV acceptability among women (average treatment effect among treated (ATT) = -0.07, 95% CI: -0.16, 0.06) and men (ATT = -0.11, 95% CI: -0.22, 0.03) although estimates were imprecise and included the null. Interpretation: DV legislation may reduce permissive IPV attitudes, especially among men, although conclusions should be interpreted cautiously due to imprecise estimates. Funding: Eunice Kennedy Shriver National Institute of Child Health and Human Development (5R00HD104896).

Activating Empathy Through Art in Cancer Communities.

Background: The Aesthetics of Health (AOH) undergraduate visual art studies course at the University of Texas at Austin aimed to enhance art students' awareness of cancer's impact not only medically but also socially, emotionally, financially, and spiritually and to examine how this experience might impact students' artwork, capacity for empathy, and connection to audience. Methods: During the spring 2021 semester, the AOH course instructors employed assorted pedagogical methods, including art, illness narrative, and community engagement, in special sessions led by professors, community practice artists, and cancer experts, respectively, as well as oral storytelling by those with lived experience of cancer (ie, cancer patients, posttreatment survivors, and loved ones). For the course's final project, the 15 student-artists created self-selected media works combining health and activism and displayed them in public spaces, including online. Student-artists took the Toronto Empathy Questionnaire during the first and last weeks of the course and provided feedback. Two group interviews were also held with cancer storytellers following their participation. Results: Student-artists' average score on the Toronto Empathy Questionnaire increased from 52.46 at pretest to 55.38 at posttest. Student-artists and storytelling participants also reported having positive experiences. Conclusions: The AOH course's social practice approach encouraged student-artists to realize new ideas and relationships and modestly increased their capacity for empathy. The AOH framework demonstrates promise for increasing empathy through the arts in other educational, clinical, and artistic institutions. Further research is needed with larger sample sizes to measure the impact of the course and to demonstrate its potential for addressing burnout and moral distress.

Social support and intimate partner violence in rural Pakistan: A longitudinal investigation of the bi-directional relationship.

A large body of cross-sectional evidence finds strong and consistent associations between social support and intimate partner violence (IPV). However, the directionality of this relationship has not been firmly established due to a dearth of longitudinal evidence. Using cohort study data collected over a 3 year period from 945 women in rural Pakistan, we investigated the longitudinal relationship between IPV and social support. Friend and family social support was measured with the Multidimensional Perceived Social Support Scale, and IPV was measured with questions adopted from the World Health Organization's Violence Against Women Instrument, which was used to construct a measure of IPV severity. We estimated longitudinal associations in linear regression models that controlled for women's educational level, age at marriage, age, household composition, household assets, depressive symptoms, and Adverse Childhood Experiences. We found evidence of a bi-directional, mutually re-enforcing relationship that showed unique associations by type of social support. Specifically, we found that high social support from family, though not friends, decreased IPV severity 1 year later, and that higher IPV severity led to reductions in both friend and family social support 1 year later. Results suggest that interventions involving family members could be especially effective at reducing IPV in this context, and - given that low social support leads to many adverse health outcomes - results suggest that IPV can result in secondary harms due to diminished social support. In summary, our study confirms a bi-directional relationship between IPV and social support and suggests that IPV interventions that integrate social support may be especially effective at reducing IPV and mitigating secondary harms.

A comparative cohort study of gastrointestinal oncology patients: Impact of a shift to telehealth on delivery of interprofessional cancer care.

Early studies of oncology visits performed via telehealth demonstrate patient and provider satisfaction; however, understanding of the impact of telehealth on clinic workflows is limited. The incorporation of telehealth visits into an interprofessional model of oncology care was evaluated to assess for changes in care delivery and patient engagement. New patients with a gastrointestinal cancer diagnosis who were actively undergoing treatment and followed for at least three months were divided into two cohorts based on telehealth utilization. Individual patient charts were reviewed by touchpoint, consisting of in-person visits, telehealth visits, phone calls, and patient portal messages. A total of 28 patient charts were analyzed, 11 pre-telehealth conventional care patients, and 17 telehealth patients. Telehealth cohort patients demonstrated an increased average number of total touchpoints when compared to the pre-telehealth cohort (p-value = 0.008) and had an increased number of patient portal and phone call touchpoints (p-value = 0.00 and 0.002). Telehealth provided more interactions between patients and providers demonstrating increased connectivity between a patient and their care team throughout their complex cancer journey. Clinic workflows may need to adjust to account for the increased demand of unscheduled patient interactions.