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BackgroundBrucellosis, as a serious zoonotic infectious disease, has been recognized as a re-emerging disease in the developing countries worldwide. In china, the incidence of brucellosis is increasing each year, seriously threatening the health of humans as well as animal populations. Despite a quite number of diagnostic methods currently being used for brucellosis, innovative technologies are still needed for its rapid and accurate diagnosis, especially in area where traditional diagnostic is unavailable.Methodology/principal findingsIn this study, a total of 22 B cell linear epitopes were predicted from five Brucella outer membrane proteins (OMPs) using an immunoinformatic approach. These epitopes were then chemically synthesized, and with the method of indirect ELISA (iELISA), each of them displayed a certain degree of capability in identifying human brucellosis positive sera. Subsequently, a fusion protein consisting of the 22 predicted epitopes was prokaryotically expressed and used as diagnostic antigen in a newly established brucellosis testing method, nano-ZnO modified paper-based ELISA (nano-p-ELISA). According to the verifying test using a collection of sera collected from brucellosis and non-brucellosis patients, the sensitivity and specificity of multiepitope based nano-p-ELISA were 92.38% and 98.35% respectively. The positive predictive value was 98.26% and the negative predictive value was 91.67%. The multiepitope based fusion protein also displayed significantly higher specificity than Brucella lipopolysaccharide (LPS) antigen.ConclusionsB cell epitopes are important candidates for serologically testing brucellosis. Multiepitope fusion protein based nano-p-ELISA displayed significantly sensitivity and specificity compared to Brucella LPS antigen. The strategy applied in this study will be helpful to develop rapid and accurate diagnostic method for brucellosis in human as well as animal populations.

The use of misidentified and contaminated cell lines continues to be a problem in biomedical research. Research Resource Identifiers (RRIDs) should reduce the prevalence of misidentified and contaminated cell lines in the literature by alerting researchers to cell lines that are on the list of problematic cell lines, which is maintained by the International Cell Line Authentication Committee (ICLAC) and the Cellosaurus database. To test this assertion, we text-mined the methods sections of about two million papers in PubMed Central, identifying 305,161 unique cell-line names in 150,459 articles. We estimate that 8.6% of these cell lines were on the list of problematic cell lines, whereas only 3.3% of the cell lines in the 634 papers that included RRIDs were on the problematic list. This suggests that the use of RRIDs is associated with a lower reported use of problematic cell lines.

Building on long-term benefits of early intervention (Paper 2 of this Series) and increasing commitment to early childhood development (Paper 1 of this Series), scaled up support for the youngest children is essential to improving health, human capital, and wellbeing across the life course. In this third paper, new analyses show that the burden of poor development is higher than estimated, taking into account additional risk factors. National programmes are needed. Greater political prioritisation is core to scale-up, as are policies that afford families time and financial resources to provide nurturing care for young children. Effective and feasible programmes to support early child development are now available. All sectors, particularly education, and social and child protection, must play a role to meet the holistic needs of young children. However, health provides a critical starting point for scaling up, given its reach to pregnant women, families, and young children. Starting at conception, interventions to promote nurturing care can feasibly build on existing health and nutrition services at limited additional cost. Failure to scale up has severe personal and social consequences. Children at elevated risk for compromised development due to stunting and poverty are likely to forgo about a quarter of average adult income per year, and the cost of inaction to gross domestic product can be double what some countries currently spend on health. Services and interventions to support early childhood development are essential to realising the vision of the Sustainable Development Goals.

ObjectiveElectronic health records (EHRs) are widely adopted, but the time demands of EHR use on ophthalmology trainees are not well understood. This study evaluated ophthalmology trainee time spent on clinical activities in an outpatient clinic undergoing EHR implementation.DesignProspective, manual time-motion observations of ophthalmology trainees in 2018.ParticipantsEleven ophthalmology residents and fellows observed during 156 patient encounters.MethodsProspective time-motion study of ophthalmology trainees 2 weeks before and 6 weeks after EHR implementation in an academic ophthalmology department. Manual time-motion observations were conducted for 11 ophthalmology trainees in 6 subspecialty clinics during 156 patient encounters. Time spent documenting, examining, and talking with patients were recorded. Factors influencing time requirements were evaluated using linear mixed effects models.Main outcome measuresTotal time spent by ophthalmology residents and fellows per patient, time spent on documentation, examination, and talking with patients.ResultsSeven ophthalmology residents and four ophthalmology fellows with mean (standard deviation) postgraduate year of 3.7 (1.2) were observed during 156 patient encounters. Using paper charts, mean total time spent on each patient was 11.6 (6.5) minutes, with 5.4 (3.5) minutes spent documenting (48%). After EHR implementation, mean total time spent on each patient was 11.8 (6.9) minutes, with 6.8 (4.7) minutes spent documenting (57%). Total time expenditure per patient did not significantly change after EHR implementation (+0.17 minutes, 95% confidence interval [CI] for difference in means: -2.78, 2.45; p = 0.90). Documentation time did not change significantly after EHR implementation in absolute terms (+1.42 minutes, 95% CI: -3.13, 0.29; p = 0.10), but was significantly greater as a proportion of total time (48% on paper to 57% on EHR; +9%, 95% CI: 2.17, 15.83; p = 0.011).ConclusionTotal time spent per patient and absolute time spent on documentation was not significantly different whether ophthalmology trainees used paper charts or the recently implemented EHR. Percentage of total time spent on documentation increased significantly with early EHR use. Evaluating EHR impact on ophthalmology trainees may improve understanding of how trainees learn to use the EHR and may shed light on strategies to address trainee burnout.

UnlabelledThis position paper reviews how the National Bone Health Alliance (NBHA) will execute a project to help assure health professionals of the clinical utility of bone turnover markers; the current clinical approaches concerning osteoporosis and the status and use of bone turnover markers in the USA; the rationale for focusing this effort around two specific bone turnover markers; the need to standardize bone marker sample collection procedures, reference ranges, and bone turnover marker assays in clinical laboratories; and the importance of harmonization for future research of bone turnover markers.IntroductionOsteoporosis is a major global health problem, with the prevalence and incidence of osteoporosis for at-risk populations estimated to be 44 million Americans. The potential of bone markers as an additional tool for health care professionals to improve patient outcomes and impact morbidity and mortality is crucial in providing better health care and addressing rising health care costs. This need to advance the field of bone turnover markers has been recognized by a number of organizations, including the International Osteoporosis Foundation (IOF), National Osteoporosis Foundation, International Federation of Clinical Chemistry, and Laboratory Medicine (IFCC), and the NBHA.MethodsThis position paper elucidates how this project will standardize bone turnover marker sample collection procedures in the USA, establish a USA reference range for one bone formation (serum procollagen type I N propeptide, s-PINP) and one bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) marker, and standardize bone turnover marker assays used in clinical laboratories. This effort will allow clinicians from the USA to have confidence in their use of bone turnover markers to help monitor osteoporosis treatment and assess future fracture risk. This project builds on the recommendations of the IOF/IFCC Bone Marker Standards Working Group by developing USA reference standards for s-PINP and s-CTX, the markers identified as most promising for use as reference markers.ResultsThe goals of this project will be realized through the NBHA and will include its governmental, academic, for-profit, and non-profit sector stakeholders as well as major academic and commercial laboratories. Upon completion, a parallel effort will be pursued to make bone turnover marker measurements reliable and accepted by all health care professionals for facilitating treatment decisions and ultimately be reimbursed by all health insurance payers.ConclusionsSuccessful completion of this project will help assure health professionals from the USA of the clinical utility of bone turnover markers and ties in with the parallel effort of the IOF/IFCC to develop worldwide bone turnover reference ranges.

Family, twin, and adoption studies have documented a strong genetic basis for ADHD/HKD, but these studies do not identify specific genes linked to the disorder. Molecular genetic studies can identify allelic variations of specific genes that are functionally associated with ADHD/HKD, and dopamine genes have been the initial candidates based on the site of action of the stimulants drugs, which for a half century have provided the primary pharmacological treatment for ADHD/HKD. Two candidate dopamine genes have been investigated and reported to be associated with ADHD/HKD: the dopamine transporter (DAT1) gene [Cook et al., American Journal of Human Genetics 1995;56:993-998, Gill et al., Molecular Psychiatry 1997;2:311-313] and the dopamine receptor D4 (DRD4) gene [LaHoste et al., Molecular Psychiatry 1996;1:121-124: Smalley et al., 1998;3:427-430; Swanson et al., Molecular Psychiatry 1998;3:38-41]. Speculative hypotheses [Swanson and Castellanos, NIH Consensus Development Conference: Diagnosis and Treatment of Attention Deficit Hyperactivity Disorder, November 1998. p. 37-42] have suggested that specific alleles of these dopamine genes may alter dopamine transmission in the neural networks implicated in ADHD/HKD (e.g. that the 10-repeat allele of the DAT1 gene may be associated with hyperactive re-uptake of dopamine or that the 7-repeat allele of the DRD4 gene may be associated with a subsensitive postsynaptic receptor). These and other variants of the dopamine hypothesis of ADHD will be discussed.

Engagement is an important component in the advancement of gene-drive vector control research programs as developers look to transition the technology from the laboratory to the field. As research advances and engagement surrounding this novel technology is put into practice, knowledge can be gained from practical experiences and applications in the field. A relationship-based model (RBM) provides a framework for end-user development of engagement programs and strategies. The model places end users at the center of the engagement decision-making processes rather than as recipients of predetermined strategies, methods, and definitions. Successful RBM application for healthcare delivery has previously been demonstrated, and the University of California Malaria Initiative (UCMI) has applied this model to its gene-drive program in the Democratic Republic of São Tomé and Príncipe. The model emphasizes the importance of local leadership in the planning, development, and implementation of all phases of project engagement. The primary aim of this paper is to translate the model from paper to practice and provide a transparent description, using practical examples, of the UCMI program implementation of RBM at its field site. End-user development of the UCMI engagement program provides a unique approach to the development of ethical, transparent, and effective engagement strategies for malaria control programs. This paper may also serve as a reference and example for projects looking to establish an engagement program model that integrates end-user groups in the decision-making processes surrounding engagement.

In 2019, the National Health Interview survey found that nearly 59% of adults reported pain some, most, or every day in the past 3 months, with 39% reporting back pain, making back pain the most prevalent source of pain, and a significant issue among adults. Often, identifying a direct, treatable cause for back pain is challenging, especially as it is often attributed to complex, multifaceted issues involving biological, psychological, and social components. Due to the difficulty in treating the true cause of chronic low back pain (cLBP), an over-reliance on opioid pain medications among cLBP patients has developed, which is associated with increased prevalence of opioid use disorder and increased risk of death. To combat the rise of opioid-related deaths, the National Institutes of Health (NIH) initiated the Helping to End Addiction Long-TermSM (HEAL) initiative, whose goal is to address the causes and treatment of opioid use disorder while also seeking to better understand, diagnose, and treat chronic pain. The NIH Back Pain Consortium (BACPAC) Research Program, a network of 14 funded entities, was launched as a part of the HEAL initiative to help address limitations surrounding the diagnosis and treatment of cLBP. This paper provides an overview of the BACPAC research program's goals and overall structure, and describes the harmonization efforts across the consortium, define its research agenda, and develop a collaborative project which utilizes the strengths of the network. The purpose of this paper is to serve as a blueprint for other consortia tasked with the advancement of pain related science.

Patient-reported outcomes (PROs) are used in clinical trials to provide valuable evidence on the impact of disease and treatment on patients' symptoms, function and quality of life. High-quality PRO data from trials can inform shared decision-making, regulatory and economic analyses and health policy. Recent evidence suggests the PRO content of past trial protocols was often incomplete or unclear, leading to research waste. To address this issue, international, consensus-based, PRO-specific guidelines were developed: the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT)-PRO Extension. The SPIRIT-PRO Extension is a 16-item checklist which aims to improve the content and quality of aspects of clinical trial protocols relating to PRO data collection to minimise research waste, and ultimately better inform patient-centred care. This SPIRIT-PRO explanation and elaboration (E&E) paper provides information to promote understanding and facilitate uptake of the recommended checklist items, including a comprehensive protocol template. For each SPIRIT-PRO item, we provide a detailed description, one or more examples from existing trial protocols and supporting empirical evidence of the item's importance. We recommend this paper and protocol template be used alongside the SPIRIT 2013 and SPIRIT-PRO Extension paper to optimise the transparent development and review of trial protocols with PROs.

BackgroundWe were tasked by the World Health Organization (WHO) to address the following question: What techniques should be used to diagnose Schistosoma infections in snails and in the water in potential transmission sites? Our goal was to review and evaluate the available literature and provide recommendations and insights for the development of WHO's Guidelines Development Group for schistosomiasis control and elimination.MethodologyWe searched several databases using strings of search terms, searched bibliographies of pertinent papers, and contacted investigators who have made contributions to this field. Our search covered from 1970 to Sept 2020. All papers were considered in a PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) framework, and retained papers were grouped by technique and subjected to our GRADE (Grading of Recommendations, Assessment, Development and Evaluations) evidence assessment profile determined in consultation with WHO. We also considered issues of sensitivity, specificity, coverage, cost, robustness, support needs, schistosome species discrimination, and relevant detection limits.Principal findingsOur PRISMA process began with the perusal of 949 articles, of which 158 were retained for data extraction and evaluation. We identified 25 different techniques and for each applied a GRADE assessment considering limitations, inconsistency, imprecision, indirectness, and publication bias. We also provide advantages and disadvantages for each category of techniques.ConclusionsOur GRADE analysis returned an assessment of moderate quality of evidence for environmental DNA (eDNA), qPCR and LAMP (Loop-mediated isothermal amplification). No single ideal diagnostic approach has yet been developed, but considerable recent progress has been made. We note a growing trend to use eDNA techniques to permit more efficient and replicable sampling. qPCR-based protocols for follow-up detection offer a versatile, mature, sensitive, and specific platform for diagnosis though centralized facilities will be required to favor standardization. Droplet digital PCR (ddPCR) can play a complementary role if inhibitors are a concern, or more sensitivity or quantification is needed. Snail collection, followed by shedding, is encouraged to provide specimens for sequence verifications of snails or schistosomes. LAMP or other isothermal detection techniques offer the prospect of less expensive and more distributed network of analysis but may face standardization and verification challenges related to actual sequences amplified. Ability to detect schistosome infections in snails or in the water is needed if control and elimination programs hope to succeed. Any diagnostic techniques used need to be regularly verified by the acquisition of DNA sequences to confirm that the detected targets are of the expected species. Further improvements may be necessary to identify the ideal schistosome or snail sequences to target for amplification. More field testing and standardization will be essential for long-term success.

The last decade has seen nearly 20 papers reviewing the totality of the data on saturated fats and cardiovascular outcomes, which, altogether, have demonstrated a lack of rigorous evidence to support continued recommendations either to limit the consumption of saturated fatty acids or to replace them with polyunsaturated fatty acids. These papers were unfortunately not considered by the process leading to the most recent U.S. Dietary Guidelines for Americans, the country's national nutrition policy, which recently reconfirmed its recommendation to limit saturated fats to 10% or less of total energy intake, based on insufficient and inconsistent evidence. Continuation of a cap on saturated fat intake also fails to consider the important effects of the food matrix and the overall dietary pattern in which saturated fatty acids are consumed.

ObjectiveBlockchain has emerged as a potential data-sharing structure in healthcare because of its decentralization, immutability, and traceability. However, its use in the biomedical domain is yet to be investigated comprehensively, especially from the aspects of implementation and evaluation, by existing blockchain literature reviews. To address this, our review assesses blockchain applications implemented in practice and evaluated with quantitative metrics.Materials and methodsThis systematic review adapts the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) framework to review biomedical blockchain papers published by August 2023 from 3 databases. Blockchain application, implementation, and evaluation metrics were collected and summarized.ResultsFollowing screening, 11 articles were included in this review. Articles spanned a range of biomedical applications including COVID-19 medical data sharing, decentralized internet of things (IoT) data storage, clinical trial management, biomedical certificate storage, electronic health record (EHR) data sharing, and distributed predictive model generation. Only one article demonstrated blockchain deployment at a medical facility.DiscussionEthereum was the most common blockchain platform. All but one implementation was developed with private network permissions. Also, 8 articles contained storage speed metrics and 6 contained query speed metrics. However, inconsistencies in presented metrics and the small number of articles included limit technological comparisons with each other.ConclusionWhile blockchain demonstrates feasibility for adoption in healthcare, it is not as popular as currently existing technologies for biomedical data management. Addressing implementation and evaluation factors will better showcase blockchain's practical benefits, enabling blockchain to have a significant impact on the health sector.

IntroductionBehavioral health emergencies (BHEs) are a common patient encounter for emergency medical services (EMS) clinicians and other first responders, in particular law enforcement (LE) officers. It is critical for EMS clinicians to have management strategies for BHEs, yet relatively little information exists on best practices. In 2016, the Los Angeles County EMS Agency's Commission initiated a comprehensive evaluation of the 9-1-1 response for BHEs and developed a plan for improving the quality of care and safety for patients and first responders.MethodsA Behavioral Health Initiative Committee was assembled with broad representation from EMS, LE, health agencies, and the public. Committee objectives included: 1) produce a process map of the BHE response from the time of a 9-1-1 call to patient arrival at transport destination, 2) identify and describe the different agencies that respond, 3) describe the critical decision points in the EMS and LE field responses, 4) acquire data that quantitatively and/or qualitatively describe the services available, and 5) recommend interventions for system performance improvement.ResultsThe committee generated comprehensive process maps for the prehospital response to BHEs, articulated principles for evaluation, and described key observations of the current system including: 9-1-1 dispatch criteria are variable and often defaults to a LE response, the LE response inadvertently criminalizes BHEs, EMS field treatment protocols for BHEs (and especially agitated patients) are limited, substance use disorder treatment lacks integration, destination options differ by transporting agency, and receiving facilities' capabilities to address BHEs are variable. Recommendations for performance improvement interventions and initial implementation steps included: standardize dispatch protocols, shift away from a LE primary response, augment EMS treatment protocols for BHEs and the management of agitation, develop alternate destination for EMS transport.ConclusionThis paper describes a comprehensive performance improvement initiative in LAC-EMSA's 9-1-1 response to BHEs. The initiative included a thorough current state analysis, followed by future state mapping and the implementation of interventions to reduce LE as the primary responder when an EMS response is often warranted, and to improve EMS protocols and access to resources for BHEs.

The ABA pain guidelines were developed 14 years ago and have not been revised despite evolution in the practice of burn care. A sub-committee of the American Burn Association's Committee on the Organization and Delivery of Burn Care was created to revise the adult pain guidelines. A MEDLINE search of English-language publications from 1968 to 2018 was conducted using the keywords "burn pain," "treatment," and "assessment." Selected references were also used from the greater pain literature. Studies were graded by two members of the committee using Oxford Centre for Evidence-based Medicine-Levels of Evidence. We then met as a group to determine expert consensus on a variety of topics related to treating pain in burn patients. Finally, we assessed gaps in the current knowledge and determined research questions that would aid in providing better recommendations for optimal pain management of the burn patient. The literature search produced 189 papers, 95 were found to be relevant to the assessment and treatment of burn pain. From the greater pain literature 151 references were included, totaling 246 papers being analyzed. Following this literature review, a meeting to establish expert consensus was held and 20 guidelines established in the areas of pain assessment, opioid medications, nonopioid medications, regional anesthesia, and nonpharmacologic treatments. There is increasing research on pain management modalities, but available studies are inadequate to create a true standard of care. We call for more burn specific research into modalities for burn pain control as well as research on multimodal pain control.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

ObjectivesExpound upon priorities for basic/translational science identified in a recent paper by a group of experts assigned by the Society of Critical Care Medicine and the European Society of Intensive Care Medicine.Data sourcesOriginal paper, search of the literature.Study selectionBy several members of the original task force with specific expertise in basic/translational science.Data extractionNone.Data synthesisNone.ConclusionsIn the first of a series of follow-up reports to the original paper, several members of the original task force with specific expertise provided a more in-depth analysis of the five identified priorities directly related to basic/translational science. This analysis expounds on what is known about the question and what was identified as priorities for ongoing research. It is hoped that this analysis will aid the development of future research initiatives.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Burn care remains among the most complex of the time-sensitive treatment interventions in medicine today. An enormous quantity of specialized resources are required to support the critical and complex modalities needed to meet the conventional standard of care for each patient with a critical burn injury. Because of these dependencies, a sudden surge of patients with critical burn injuries requiring immediate and prolonged care following a burn mass casualty incident (BMCI) will place immense stress on healthcare system assets, including supplies, space, and an experienced workforce (staff). Therefore, careful planning to maximize the efficient mobilization and rational use of burn care resources is essential to limit morbidity and mortality following a BMCI. The U.S. burn care profession is represented by the American Burn Association (ABA). This paper has been written by clinical experts and led by the ABA to provide further clarity regarding the capacity of the American healthcare system to absorb a surge of burn-injured patients. Furthermore, this paper intends to offer responders and clinicians evidence-based tools to guide their response and care efforts to maximize burn care capabilities based on realistic assumptions when confronted with a BMCI. This effort also aims to align recommendations in part with those of the Committee on Crisis Standards of Care for the Institute of Medicine, National Academies of Sciences. Their publication guided the work in this report, identified here as "conventional, contingency, and crisis standards of care." This paper also includes an update to the burn Triage Tables- Seriously Resource-Strained Situations (v.2).

Telemedicine-based diabetic retinopathy screening (DRS) in primary care settings has increased the screening rates of patients with diabetes. However, blindness from vision-threatening diabetic retinopathy (VTDR) is a persistent problem. This study examined the extent of patients' adherence to postscreening recommendations. A retrospective record review was conducted in primary care clinics of a large county hospital in the USA. All patients with diabetes detected with VTDR in two time periods, differing in record type used, were included in the study: 2012-2014, paper charts only; 2015-2017, combined paper charts/electronic medical records (EMRs), or EMRs only. Adherence rates for keeping initial ophthalmology appointments, starting recommended treatments, and keeping follow-up appointments were determined. Adequate records were available for 6046 patients; 408 (7%) were detected with VTDR and recommended for referral to ophthalmology. Only 5% completed a first ophthalmology appointment within recommended referral interval, 15% within twice the recommended interval, and 51% within 1 year of DRS. Patients screened in 2015-2017 were more likely to complete a first ophthalmology appointment than those in 2012-2014. Ophthalmic treatment was recommended in half of the patients, of whom 94% initiated treatment. A smaller percentage (41%) adhered completely to post-treatment follow-up. Overall, 28% of referred patients: (1) kept a first ophthalmology appointment; (2) were recommended for treatment; and (3) initiated the treatment. Most patients failing to keep first ophthalmology appointments continued non-ophthalmic medical care at the institution. EMRs provided more complete information than paper charts. Reducing vision impairment from VTDR requires greater emphasis on timely adherence to ophthalmology referral and follow-up. Prevention of visual loss from VTDR starts with retinopathy screening, but must include patient engagement, adherence monitoring, and streamlining ophthalmic referral and management. Revision of these processes has already been implemented at the study site, incorporating lessons from this investigation.

Cardiac excitation-contraction (E-C) coupling is influenced by (at least) three dynamic systems that couple and feedback to one another (see Abstract Figure). Here we review the mechanical effects on cardiomyocytes that include mechano-electro-transduction (commonly referred to as mechano-electric coupling, MEC) and mechano-chemo-transduction (MCT) mechanisms at cell and molecular levels which couple to Ca2+ -electro and E-C coupling reviewed elsewhere. These feedback loops from muscle contraction and mechano-transduction to the Ca2+ homeodynamics and to the electrical excitation are essential for understanding the E-C coupling dynamic system and arrhythmogenesis in mechanically loaded hearts. This white paper comprises two parts, each reflecting key aspects from the 2018 UC Davis symposium: MEC (how mechanical load influences electrical dynamics) and MCT (how mechanical load alters cell signalling and Ca2+ dynamics). Of course, such separation is artificial since Ca2+ dynamics profoundly affect ion channels and electrogenic transporters and vice versa. In time, these dynamic systems and their interactions must become fully integrated, and that should be a goal for a comprehensive understanding of how mechanical load influences cell signalling, Ca2+ homeodynamics and electrical dynamics. In this white paper we emphasize current understanding, consensus, controversies and the pressing issues for future investigations. Space constraints make it impossible to cover all relevant articles in the field, so we will focus on the topics discussed at the symposium.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

BackgroundBlood chemicals are routinely measured in clinical or preclinical research studies to diagnose diseases, assess risks in epidemiological research, or use metabolomic phenotyping in response to treatments. A vast volume of blood-related literature is available via the PubMed database for data mining.ObjectivesWe aimed to generate a comprehensive blood exposome database of endogenous and exogenous chemicals associated with the mammalian circulating system through text mining and database fusion.MethodsUsing NCBI resources, we retrieved PubMed abstracts, PubChem chemical synonyms, and PMC supplementary tables. We then employed text mining and PubChem crowdsourcing to associate phrases relating to blood with PubChem chemicals. False positives were removed by a phrase pattern and a compound exclusion list.ResultsA query to identify blood-related publications in the PubMed database yielded 1.1 million papers. Matching a total of 15 million synonyms from 6.5 million relevant PubChem chemicals against all blood-related publications yielded 37,514 chemicals and 851,999 publications records. Mapping PubChem compound identifiers to the PubMed database yielded 49,940 unique chemicals linked to 676,643 papers. Analysis of open-access metabolomics papers related to blood phrases in the PMC database yielded 4,039 unique compounds and 204 papers. Consolidating these three approaches summed up to a total of 41,474 achiral structures that were linked to 65,957 PubChem CIDs and to over 878,966 PubMed articles. We mapped these compounds to 50 databases such as those covering metabolites and pathways, governmental and toxicological databases, pharmacology resources, and bioassay repositories. In comparison, HMDB, the Human Metabolome Database, links 1,075 compounds to blood-related primary publications.ConclusionThis new Blood Exposome Database can be used for prioritizing chemicals for systematic reviews, developing target assays in exposome research, identifying compounds in untargeted mass spectrometry, and biological interpretation in metabolomics data. The database is available at http://bloodexposome.org. https://doi.org/10.1289/EHP4713.

IntroductionRandomised controlled trials (RCTs) are widely viewed to generate the most reliable medical knowledge. However, RCTs are not always scientifically necessary and therefore not always ethical. Unfortunately, it is not clear when an RCT is not necessary or how this should be established. This study seeks to systematically catalogue justifications offered throughout the medical and ethics literature for performing randomisation within clinical trials.Methods and analysisWe will systematically search electronic databases of the medical literature including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, Cochrane Clinical Trials Register, Web of Science Proceedings, ClinicalTrials.gov; databases of philosophical literature including Philosopher's Index, Phil Papers, JSTOR, Periodicals Archive Online, Project MUSE, National Reference Centre for Bioethics; the library catalogue at the University of Ottawa; bibliographies of retrieved papers; and the grey literature. We will also pursue suggestions from experts in the fields of medical ethics, philosophy and clinical trial methodology. Article screening, selection and data extraction will be performed by two independent reviewers based on prespecified inclusion/exclusion criteria. A third reviewer will be consulted to resolve any discrepancies. We will then extract the reasons given to justify randomisation using methodology established to extract data in a defensible, systematic manner. We will track the reasons given, their frequency of use and changes over time. Finally, using grounded theory, we will combine the reasons into broader themes. These themes will form the foundation of our subsequent analysis from qualitative and quantitative perspectives. This review will map existing arguments that clinicians, ethicists and philosophers use to ethically justify randomisation in clinical trials.Ethics and disseminationNo research ethics board approval is necessary because we are not examining patient-level data. This protocol complies with the reported guidance for conducting systematic scoping reviews. The findings of this paper will be disseminated via presentations and academic publication. In a subsequent phase of this research, we hope to engage with stakeholders and translate any recommendations derived from our findings into operational guidelines.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

This paper examines factors associated with intimate partner violence (IPV) among newly married women in Nepal, and how IPV was affected by food insecurity and COVID-19. Given evidence that food insecurity is associated with IPV and COVID-19, we explored whether increased food insecurity during COVID-19 is associated with changes in IPV. We used data from a cohort study of 200 newly married women aged 18-25 years, interviewed five times over two years at 6-month intervals (02/2018-07/2020), including after COVID-19-associated lockdowns. Bivariate analysis and mixed-effects logistic regression models were used to examine the association between selected risk factors and recent IPV. IPV increased from 24.5% at baseline to 49.2% before COVID-19 and to 80.4% after COVID-19. After adjusting for covariates, we find that both COVID-19 (OR = 2.93, 95% CI 1.07-8.02) and food insecurity (OR = 7.12, 95% CI 4.04-12.56) are associated with increased odds of IPV, and IPV increased more for food-insecure women post COVID-19 (compared to non-food insecure), but this was not statistically significant (confidence interval 0.76-8.69, p-value = 0.131). Young, newly married women experience high rates of IPV that increase with time in marriage, and COVID-19 has exacerbated this, especially for food-insecure women in the present sample. Along with enforcement of laws against IPV, our results suggest that special attention needs to be paid to women during a crisis time like the current COVID-19 pandemic, especially those who experience other household stressors.

IntroductionNearly 30 000 Mexican women develop breast cancer annually, frequently presenting unmet supportive care needs. In high-income countries, incorporating electronic patient-reported outcomes (ePROs) into cancer care has demonstrated potential for increasing patient-centred care and reducing unmet needs. No such ePRO interventions have been implemented in Mexico. This paper presents the study protocol for designing and evaluating an ePRO digital health application combined with proactive follow-up by nurses.Methods and analysisWe designed a two-component intervention for women receiving breast cancer treatment: a responsive web application for monitoring ePROs and clinical algorithms guiding proactive follow-up by nurses. We will conduct a pilot test of the intervention with 50 patients with breast cancer for 6 weeks to assess feasibility and adjust the application. We will conduct a parallel arm randomised controlled trial assigning 205 patients each to intervention and control in one of Mexico's largest public oncology hospitals. The intervention will be provided for 6 months, with additional 3 months of post-intervention observation. The control group will receive usual healthcare and a list of breast cancer information sources. Women diagnosed with stages I, II or III breast cancer who initiate chemotherapy and/or radiotherapy will be invited to participate. The primary study outcome will be supportive care needs; secondary outcomes include global quality of life and breast symptoms. Information on the outcomes will be obtained through web-based self-administered questionnaires collected at baseline, 1, 3, 6 and 9 months.Ethics and disseminationThe National Research and Ethics Committees of the Mexican Institute of Social Security approved the study (R-2021-785-059). Participants will sign an informed consent form prior to their inclusion. Findings will be disseminated through a policy brief to the local authorities, a webinar for patients, publications in peer-reviewed journals and presentations at national and international conferences.Trial registration numberNCT05925257.

BackgroundThere has been increasing interest in cortical microstructure as a complementary and earlier measure of neurodegeneration than macrostructural atrophy, but few papers have related cortical diffusion imaging to post-mortem neuropathology. This study aimed to characterise the associations between the main Alzheimer's disease (AD) neuropathological hallmarks and multiple cortical microstructural measures from in vivo diffusion MRI. Comorbidities and co-pathologies were also investigated.MethodsForty-three autopsy cases (8 cognitively normal, 9 mild cognitive impairment, 26 AD) from the National Alzheimer's Coordinating Center and Alzheimer's Disease Neuroimaging Initiative databases were included. Structural and diffusion MRI scans were analysed to calculate cortical minicolumn-related measures (AngleR, PerpPD+, and ParlPD) and mean diffusivity (MD). Neuropathological hallmarks comprised Thal phase, Braak stage, neuritic plaques, and combined AD neuropathological changes (ADNC-the "ABC score" from NIA-AA recommendations). Regarding comorbidities, relationships between cortical microstructure and severity of white matter rarefaction (WMr), cerebral amyloid angiopathy (CAA), atherosclerosis of the circle of Willis (ACW), and locus coeruleus hypopigmentation (LCh) were investigated. Finally, the effect of coexistent pathologies-Lewy body disease and TAR DNA-binding protein 43 (TDP-43)-on cortical microstructure was assessed.ResultsCortical diffusivity measures were significantly associated with Thal phase, Braak stage, ADNC, and LCh. Thal phase was associated with AngleR in temporal areas, while Braak stage was associated with PerpPD+ in a wide cortical pattern, involving mainly temporal and limbic areas. A similar association was found between ADNC (ABC score) and PerpPD+. LCh was associated with PerpPD+, ParlPD, and MD. Co-existent neuropathologies of Lewy body disease and TDP-43 exhibited significantly reduced AngleR and MD compared to ADNC cases without co-pathology.ConclusionsCortical microstructural diffusion MRI is sensitive to AD neuropathology. The associations with the LCh suggest that cortical diffusion measures may indirectly reflect the severity of locus coeruleus neuron loss, perhaps mediated by the severity of microglial activation and tau spreading across the brain. Recognizing the impact of co-pathologies is important for diagnostic and therapeutic decision-making. Microstructural markers of neurodegeneration, sensitive to the range of histopathological features of amyloid, tau, and monoamine pathology, offer a more complete picture of cortical changes across AD than conventional structural atrophy.

Racism can exert negative effects on the self-concepts, health and well-being, and life trajectories of both nondominant racial-ethnic (NDRE) youth and youth-serving providers. In the face of growing nationalism, ethnocentrism, xenophobia, and overt expressions of racism, the Society for Adolescent Health and Medicine recognizes the critically important need to address the issue of racism and its impact on both NDRE youth and youth-serving providers. Organizations involved in clinical care delivery and health professions training and education must recognize the deleterious effects of racism on health and well-being, take strong positions against discriminatory policies, practices, and events, and take action to promote safe and affirming environments. The positions presented in this paper provide a comprehensive set of recommendations to promote routine clinical assessment of youth experiences of racism and its potential impact on self-concept, health and well-being, and for effective interventions when affected youth are identified. The positions also reflect the concerns of NDRE providers, trainees, and students potentially impacted by racism, chronic minority stress, and vicarious trauma and the imperative to create safe and affirming work and learning environments across all levels of practice, training, and education in the health professions. In this position paper, Society for Adolescent Health and Medicine affirms its commitment to foundational moral and ethical principles of justice, equity, and respect for humanity; acknowledges racism in its myriad forms; defines strategies to best promote resiliency and support the health and well-being of NDRE youth, providers, trainees, and students; and provides recommendations on the ways to best effect systemic change.

Patient reported measures (PRMs), including patient-reported outcomes, play a critical role in dialysis care. The usage of PRMs is extensive in dialysis clinics. While there are excellent PRMs to choose from, and their implementation as part of quality improvement and performance monitoring is extensive, there are still methodological challenges to be addressed. In this paper, we identify key methodological concerns around use of PRMs in dialysis centers in the United States and make recommendations for improving the use of PRMs in dialysis related to Selection of PRMs, Mode of Administration, and Support for PRM Use. These recommendations include: (1) Continue the use of Kidney Disease Quality of Life 36-item survey (KDQOL™-36) for dialysis centers' internal quality improvement activities and the In-Center Hemodialysis Consumer Assessment of Health Care Providers and Systems (ICH-CAHPS survey®) for public dialysis center performance monitoring, but promote efforts to modify these instruments by incorporating PROMIS general health items (KDQOL-36) and reducing the length of the ICH-CAHPS. (2) Adopt a PRM of whether dialysis patients have been informed about all dialysis and transplant options. (3) Evaluate equivalence between electronic and paper versions of PRMs prior to widespread use of electronic administration. (4) Explore reimbursement of costs of PRM administration by the Centers for Medicare and Medicaid Services and kidney organizations. (5) Continue development of provider trainings in PRM administration and interpretation. These recommendations will help dialysis care decision-makers, clinicians, and applied researchers take the next steps toward enhancing PRM use in dialysis.

BackgroundDementia can impede the relationship and connection between the person with dementia (PWD) and their caregiver. Yet, caregiving in dementia also offers opportunities for connection, which has implications for caregiver and PWD well-being. In this qualitative study, we describe and characterize ways caregivers felt connected to the person with dementia they care for.MethodsWe conducted a telephone-based survey with caregivers of people with dementia. For this paper, we analyzed responses to an open-ended question focused on when caregivers feel most connected to the person they are caring for. Responses were analyzed and coded and themes were identified through an iterative process involving a multidisciplinary team of researchers and clinicians.Results437 caregivers participated in this study. We identified two domains of connection: activity-based and emotion-based connections. Within activity-based connections, the following themes emerged: everyday activities; reminiscing; activities of caregiving; novel experiences; and time with family and friends. Within emotional connections, the following themes emerged: expressions of love, appreciation, and gratitude; physical affection; sharing an emotion or emotional experience; and times when the PWD seems like "themself" again.ConclusionsFindings provide insights into ways caregivers experience a sense of connection with the person they care for. There is a call to shift away from focusing on reducing stress and toward optimizing positive experiences as a way to better support caregivers' health and well-being. Interventions that leverage these insights to foster caregiver - PWD connection could lead to better health and well-being for both members of the dyad. The amplification of a positive experience may be particularly important for caregivers who are struggling with limited support or respite. Clinicians may be interested in using a question about connection as a way to more fully understand a caregiver's current experience.

Visual information processing in animals with large image forming eyes is carried out in highly structured retinotopically ordered neuropils. Visual neuropils in Drosophila form the optic lobe, which consists of four serially arranged major subdivisions; the lamina, medulla, lobula and lobula plate; the latter three of these are further subdivided into multiple layers. The visual neuropils are formed by more than 100 different cell types, distributed and interconnected in an invariant highly regular pattern. This pattern relies on a protracted sequence of developmental steps, whereby different cell types are born at specific time points and nerve connections are formed in a tightly controlled sequence that has to be coordinated among the different visual neuropils. The developing fly visual system has become a highly regarded and widely studied paradigm to investigate the genetic mechanisms that control the formation of neural circuits. However, these studies are often made difficult by the complex and shifting patterns in which different types of neurons and their connections are distributed throughout development. In the present paper we have reconstructed the three-dimensional architecture of the Drosophila optic lobe from the early larva to the adult. Based on specific markers, we were able to distinguish the populations of progenitors of the four optic neuropils and map the neurons and their connections. Our paper presents sets of annotated confocal z-projections and animated 3D digital models of these structures for representative stages. The data reveal the temporally coordinated growth of the optic neuropils, and clarify how the position and orientation of the neuropils and interconnecting tracts (inner and outer optic chiasm) changes over time. Finally, we have analyzed the emergence of the discrete layers of the medulla and lobula complex using the same markers (DN-cadherin, Brp) employed to systematically explore the structure and development of the central brain neuropil. Our work will facilitate experimental studies of the molecular mechanisms regulating neuronal fate and connectivity in the fly visual system, which bears many fundamental similarities with the retina of vertebrates.

This paper is the outcome of the fourth UC Davis Systems Approach to Understanding Cardiac Excitation-Contraction Coupling and Arrhythmias Symposium, a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The theme of the 2016 symposium was 'K+ Channels and Regulation'. Experts in the field contributed their experimental and mathematical modelling perspectives and discussed emerging questions, controversies and challenges on the topic of cardiac K+ channels. This paper summarizes the topics of formal presentations and informal discussions from the symposium on the structural basis of voltage-gated K+ channel function, as well as the mechanisms involved in regulation of K+ channel gating, expression and membrane localization. Given the critical role for K+ channels in determining the rate of cardiac repolarization, it is hardly surprising that essentially every aspect of K+ channel function is exquisitely regulated in cardiac myocytes. This regulation is complex and highly interrelated to other aspects of myocardial function. K+ channel regulatory mechanisms alter, and are altered by, physiological challenges, pathophysiological conditions, and pharmacological agents. An accompanying paper focuses on the integrative role of K+ channels in cardiac electrophysiology, i.e. how K+ currents shape the cardiac action potential, and how their dysfunction can lead to arrhythmias, and discusses K+ channel-based therapeutics. A fundamental understanding of K+ channel regulatory mechanisms and disease processes is fundamental to reveal new targets for human therapy.

IntroductionThe rapid scale-up of HIV care and treatment in resource-limited countries requires concurrent, rapid development of health information systems to support quality service delivery. Mozambique, a country with an 11.5% prevalence of HIV, has developed nation-wide patient monitoring systems (PMS) with standardized reporting tools, utilized by all HIV treatment providers in paper or electronic form. Evaluation of the initial implementation of PMS can inform and strengthen future development as the country moves towards a harmonized, sustainable health information system.ObjectiveThis assessment was conducted in order to 1) characterize data collection and reporting processes and PMS resources available and 2) provide evidence-based recommendations for harmonization and sustainability of PMS.MethodsThis baseline assessment of PMS was conducted with eight non-governmental organizations that supported the Ministry of Health to provide 90% of HIV care and treatment in Mozambique. The study team conducted structured and semi-structured surveys at 18 health facilities located in all 11 provinces. Seventy-nine staff were interviewed. Deductive a priori analytic categories guided analysis.ResultsHealth facilities have implemented paper and electronic monitoring systems with varying success. Where in use, robust electronic PMS facilitate facility-level reporting of required indicators; improve ability to identify patients lost to follow-up; and support facility and patient management. Challenges to implementation of monitoring systems include a lack of national guidelines and norms for patient level HIS, variable system implementation and functionality, and limited human and infrastructure resources to maximize system functionality and information use.ConclusionsThis initial assessment supports the need for national guidelines to harmonize, expand, and strengthen HIV-related health information systems. Recommendations may benefit other countries with similar epidemiologic and resource-constrained environments seeking to improve PMS implementation.

Background Currently, malaria elimination efforts are ongoing in several locations across Southeast Asia,  including in Kayin State (also known as Karen State), Myanmar . This paper describes the community engagement efforts for a pilot malaria elimination project, the challenges encountered and lessons learnt.Methods Between May 2013 and June 2015, a study on targeted malaria elimination (TME) that included mass drug administration was conducted in four villages (TPN, TOT, KNH, and HKT) of Kayin State. Community engagement efforts included workshops, meetings and house-to-house visits with community members.  Exhibitions related to malaria and fun activities were organized for children. In addition, we provided primary care, small individual incentives and village-level incentives. This paper is based on our analysis of data extracted from meeting minutes, field notes, feedback sessions among staff and with community members as well as our own reflections.Results Average participation across three rounds of MDA were 84.4%, 57.4%, 88.6% and 59.3% for TPN, TOT, KNH and HKT, respectively. Community engagement was fraught with practical challenges such as seasonal tasks of the villagers. There were challenges in explaining difficult concepts like drug resistance and submicroscopic infection. Another was understanding and navigating the politics of these villages, which are located in politically contested areas.  Managing expectations of villagers was difficult as they assumed that the community team must know everything related to health.Conclusions In the TME project, many different community engagement strategies were employed. We encountered many challenges which included logistical, scientific and political difficulties.  An approach that is tailored to the local population is key.

The predominant clonal evolution (PCE) model seeks to formulate a common population genetics framework for all micropathogens (namely, parasitic protozoa, fungi and yeasts, bacteria, and viruses). It relies on a definition of clonality that is only based on population structure features (namely, strongly restrained genetic recombination). Its clear-cut properties make it of strong interest for applied and basic research, since it permits the definition of stable, clearly delimited units of analysis below the species level: clonal genotypes and discrete genetic subdivisions ("near-clades"). These units of analysis can be used for clinical and epidemiological studies, vaccine and drug design, species description, and evolutionary studies on natural and experimental populations. In this review, the evolutionary and population genetics background of the model will be only briefly mentioned, while considerable emphasis will be given to its practical significance for the study and control of neglected tropical diseases. The goal of the paper is to make this practical usefulness accessible to a broad audience of readers, including scientists who are not evolution specialists, such as epidemiologists, field scientists, and clinicians. For extensive developments about the evolutionary background of the model, see our previous papers [1-9]. Citations of these former articles lead to the many references quoted in them, which cannot be listed again here.

In 2006, the Institute of Medicine published a report titled "Emergency Care for Children: Growing Pains," in which it described pediatric emergency care as uneven at best. Since then, telehealth has emerged as one of the great equalizers in care of children, particularly for those in rural and underresourced communities. Clinicians in these settings may lack pediatric-specific specialization or experience in caring for critically ill or injured children. Telehealth consultation can provide timely and safe management for many medical problems in children and can prevent many unnecessary and often long transport to a pediatric center while avoiding delays in care, especially for time-sensitive and acute interventions. Telehealth is an important component of pediatric readiness of hospitals and is a valuable tool in facilitating health care access in low resourced and critical access areas. This paper provides an overview of meaningful applications of telehealth programs in pediatric emergency medicine, discusses the impact of the COVID-19 pandemic on these services, and highlights challenges in setting up, adopting, and maintaining telehealth services.

The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered Report describes the proposed replication plan of key experiments from "The common feature of leukemia-associated IDH1 and IDH2 mutations is a neomorphic enzyme activity converting alpha-ketoglutarate to 2-hydroxyglutarate" by Ward and colleagues, published in Cancer Cell in 2010 (Ward et al., 2010). The experiments that will be replicated are those reported in Figures 2, 3 and 5. Ward and colleagues demonstrate the mutations in isocitrate dehydrogenase 2 (IDH2), commonly found in acute myeloid leukemia (AML), abrogate the enzyme's wild-type activity and confer to the mutant neomorphic activity that produces the oncometabolite 2-hydroxyglutarate (2-HG) (Figures 2 and 3). They then show that elevated levels of 2-HG are correlated with mutations in IDH1 and IDH2 in AML patient samples (Figure 5). The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published by eLife.

BackgroundInterest in complementary and integrative health (CIH) approaches, such as meditation, yoga, and acupuncture, continues to grow. The evidence of effectiveness for some CIH approaches has increased in the last decade, especially for pain, with many being recommended in varying degrees in national guidelines. To offer nonpharmacological health management options and meet patient demand, the nation's largest integrated healthcare system, the Veterans Health Administration (VA), greatly expanded their provision of CIH approaches recently.ObjectiveThis paper addressed the questions of how many VA patients might use CIH approaches and chiropractic care if they were available at modest to no fee, and would patients with some health conditions or characteristics be more likely than others to use these therapies.DesignUsing electronic medical records, we conducted a national, three-year, retrospective analysis of VA patients' use of eleven VA-covered therapies: chiropractic care, acupuncture, Battlefield Acupuncture, biofeedback, clinical hypnosis, guided imagery, massage therapy, meditation, Tai Chi/Qigong, and yoga.ParticipantsWe created a national cohort of veterans using VA healthcare from October 2016-September 2019.Key resultsVeterans' use of these approaches increased 70% in three years. By 2019, use was 5.7% among all VA patients, but highest among patients with chronic musculoskeletal pain (13.9%), post-traumatic stress disorder (PTSD; 10.6%), depression (10.4%), anxiety (10.2%), or obesity (7.8%). The approach used varied by age and race/ethnicity, with women being uniformly more likely than men to use each approach. Patients having chronic musculoskeletal pain, obesity, anxiety, depression, or PTSD were more likely than others to use each of the approaches.ConclusionsVeterans' use of some approaches rapidly grew recently and was robust, especially among patients most in need. This information might help shape federal/state health policy on the provision of evidence-based CIH approaches and guide other healthcare institutions considering providing them.

Admixture estimation plays a crucial role in ancestry inference and genome-wide association studies (GWASs). Computer programs such as ADMIXTURE and STRUCTURE are commonly employed to estimate the admixture proportions of sample individuals. However, these programs can be overwhelmed by the computational burdens imposed by the 105 to 106 samples and millions of markers commonly found in modern biobanks. An attractive strategy is to run these programs on a set of ancestry-informative SNP markers (AIMs) that exhibit substantially different frequencies across populations. Unfortunately, existing methods for identifying AIMs require knowing ancestry labels for a subset of the sample. This supervised learning approach creates a chicken and the egg scenario. In this paper, we present an unsupervised, scalable framework that seamlessly carries out AIM selection and likelihood-based estimation of admixture proportions. Our simulated and real data examples show that this approach is scalable to modern biobank datasets. OpenADMIXTURE, our Julia implementation of the method, is open source and available for free.

Rett syndrome (RTT) is an X-linked neurogenetic disorder caused by mutations of the MECP2 (methyl-CpG-binding protein 2) gene. Over two decades of work established MeCP2 as a protein with pivotal roles in the regulation of the epigenome, neuronal physiology, synaptic maintenance, and behaviour. Given the genetic aetiology of RTT and the proof of concept of its reversal in a mouse model, considerable efforts have been made to design therapeutic approaches to re-express MeCP2. By being at the forefront of the development of innovative gene therapies, research on RTT is of paramount importance for the treatment of monogenic neurological diseases. Here we discuss the recent advances and challenges of promising genetic strategies for the treatment of RTT including gene replacement therapies, gene/RNA editing strategies, and reactivation of the silenced X chromosome. WHAT THIS PAPER ADDS: Recent advances shed light on the promises of gene replacement therapy with new vectors designed to control the levels of MeCP2 expression. New developments in DNA/RNA editing approaches or reactivation of the silenced X chromosome open the possibility to re-express the native MeCP2 locus at endogenous levels. Current strategies still face limitations in transduction efficiency and future work is needed to improve brain delivery.

PurposeRecent advancements in obtaining image-based biomarkers from CT images have enabled lung function characterization, which could aid in lung interventional planning. However, the regional heterogeneity in these biomarkers has not been well documented, yet it is critical to several procedures for lung cancer and COPD. The purpose of this paper is to analyze the interlobar and intralobar heterogeneity of tissue elasticity and study their relationship with COPD severity.MethodsWe retrospectively analyzed a set of 23 lung cancer patients for this study, 14 of whom had COPD. For each patient, we employed a 5DCT scanning protocol to obtain end-exhalation and end-inhalation images and semi-automatically segmented the lobes. We calculated tissue elasticity using a biomechanical property estimation model. To obtain a measure of lobar elasticity, we calculated the mean of the voxel-wise elasticity values within each lobe. To analyze interlobar heterogeneity, we defined an index that represented the properties of the least elastic lobe as compared to the rest of the lobes, termed the Elasticity Heterogeneity Index (EHI). An index of 0 indicated total homogeneity, and higher indices indicated higher heterogeneity. Additionally, we measured intralobar heterogeneity by calculating the coefficient of variation of elasticity within each lobe.ResultsThe mean EHI was 0.223 ± 0.183. The mean coefficient of variation of the elasticity distributions was 51.1% ± 16.6%. For mild COPD patients, the interlobar heterogeneity was low compared to the other categories. For moderate-to-severe COPD patients, the interlobar and intralobar heterogeneities were highest, showing significant differences from the other groups.ConclusionWe observed a high level of lung tissue heterogeneity to occur between and within the lobes in all COPD severity cases, especially in moderate-to-severe cases. Heterogeneity results demonstrate the value of a regional, function-guided approach like elasticity for procedures such as surgical decision making and treatment planning.

ObjectiveThe COVID-19 pandemic changed early care and education (ECE) mealtimes. Feeding practices that support children's emerging autonomy may support children's healthy eating, but it is unknown whether and how COVID-19 changed feeding practices. This paper describes caregiver feeding practices in ECE centres in Florida during COVID-19.DesignA mixed-methods design was used to understand mealtime feeding practices. Survey and interview questions were developed based on the Trust Model. More than 7000 surveys were sent to ECE centres. Analysis included descriptive statistics for survey data and thematic analysis for interview data.SettingThis statewide study included teachers in all licensed and license-exempt ECE centres.ParticipantsFour hundred and thirty-one teachers completed a survey, and twenty-nine participated in follow-up interviews.ResultsSurveys showed most teachers engaged in autonomy-supportive behaviours, such as letting children eat until they were finished (90 %). The most common controlling behaviour was praising children for cleaning their plates (70 %). The most common responses about changes to mealtimes were keeping physical distance and serving healthy food. Interview themes were Autonomy Support, Controlling Feeding Practices, Interactions are the Same, Interactions are Different, Physical Distancing and Healthy Eating.ConclusionsMealtimes are a central part of the day for young children and teachers in ECE environments. COVID-19 continues to influence ECE routines as behaviour change remains the primary method of reducing the risk of COVID-19 in the absence of a vaccine for young children. Understanding teachers' practices and perspectives is important for reducing the risk of COVID-19 and supporting children's autonomy and healthy eating.

BackgroundAdvance care planning (ACP) is influenced by several factors (e.g., patient's readiness to engage, clinician's skills, and the cultural environment). Availability of reliable and valid self-reported measures of the ACP domains is crucial, including cross-cultural equivalence.AimTo culturally adapt into Italian the 19-item Quality of Communication (QOC) and the 4-item ACP Engagement (4-item ACP-E) questionnaires.MethodsWe translated and culturally adapted the two questionnaires and produced a significant other (SO) version of the QOC (QOC-SO). Each questionnaire was field tested via cognitive interviews with users: nine patients (QOC, 4-item ACP-E) and three SOs (QOC-SO) enrolled at three palliative care services.ResultsWe made minor changes to 5/19 QOC items, to improve clarity and internal consistency; we changed the response option 'didn't do' into 'not applicable'. Finally, we slightly revised the QOC to adapt it to the paper/electronic format. QOC debriefing revealed that the section on end of life was emotionally challenging for both patients and SOs. We simplified the 4-item ACP-E layout, added a sentence in the introduction, and revised the wording of one item, to improve coherence with the Italian ACP legislation. ACP-E debriefing did not reveal any major issue.ConclusionsResults were satisfactory in terms of semantic, conceptual and normative equivalence of both questionnaires. Acceptability was satisfactory for the 4-item ACP-E, while findings of the QOC cognitive debriefing informed a major amendment of a pilot trial protocol on ACP in multiple sclerosis (ConCure-SM): use of the interviewer version only, in an adaptive form. Psychometric testing of both questionnaires on a large, independent sample will follow.

PurposeA randomized controlled trial found that patients with diabetes had lower HbA1c levels after 6 months of peer health coaching than patients who did not receive coaching. This paper explores whether the peer coaches in that trial, all low-income patients with diabetes, mastered and utilized an evidence-based health coaching training curriculum. The curriculum included 5 core features: ask-tell-ask, closing the loop, know your numbers, behavior-change action plans, and medication adherence counseling.MethodsThis paper includes the results of exams administered to trainees, exit surveys performed with peer coaches who completed the study and those who dropped out, observations of peer coaches meeting with patients, and analysis of in-depth interviews with peer coaches who completed the study.ResultsOf the 32 peer coach trainees who completed the training, 71.9% lacked a college degree; 25.0% did not graduate from high school. The 26 trainees who passed the exams attended 92.7% of training sessions compared with 80.6% for the 6 trainees who did not pass. Peer coaches who completed the study wanted to continue peer coaching work and had confidence in their abilities despite their not consistently employing the coaching techniques with their patients. Quotations describe coaches' perceptions of the training.ConclusionsOf low-income patients with diabetes who completed the evidenced-based health coaching training, 81% passed written and oral exams and became effective peer health coaches, although they did not consistently use the techniques taught.

In February 2014, a group of scientists convened as part of the University of California Davis Cardiovascular Symposium to bring together experimental and mathematical modelling perspectives and discuss points of consensus and controversy on the topic of sodium in the heart. This paper summarizes the topics of presentation and discussion from the symposium, with a focus on the role of aberrant sodium channels and abnormal sodium homeostasis in cardiac arrhythmias and pharmacotherapy from the subcellular scale to the whole heart. Two following papers focus on Na(+) channel structure, function and regulation, and Na(+)/Ca(2+) exchange and Na(+)/K(+) ATPase. The UC Davis Cardiovascular Symposium is a biannual event that aims to bring together leading experts in subfields of cardiovascular biomedicine to focus on topics of importance to the field. The focus on Na(+) in the 2014 symposium stemmed from the multitude of recent studies that point to the importance of maintaining Na(+) homeostasis in the heart, as disruption of homeostatic processes are increasingly identified in cardiac disease states. Understanding how disruption in cardiac Na(+)-based processes leads to derangement in multiple cardiac components at the level of the cell and to then connect these perturbations to emergent behaviour in the heart to cause disease is a critical area of research. The ubiquity of disruption of Na(+) channels and Na(+) homeostasis in cardiac disorders of excitability and mechanics emphasizes the importance of a fundamental understanding of the associated mechanisms and disease processes to ultimately reveal new targets for human therapy.

The American Geriatrics Society (AGS) has consistently advocated for a healthcare system that meets the needs of older adults, including addressing impacts of ageism in healthcare. The intersection of structural racism and ageism compounds the disadvantage experienced by historically marginalized communities. Structural racism and ageism have long been ingrained in all aspects of US society, including healthcare. This intersection exacerbates disparities in social determinants of health, including poor access to healthcare and poor outcomes. These deeply rooted societal injustices have been brought to the forefront of the collective public consciousness at different points throughout history. The COVID-19 pandemic laid bare and exacerbated existing inequities inflicted on historically marginalized communities. Ageist rhetoric and policies during the COVID-19 pandemic further marginalized older adults. Although the detrimental impact of structural racism on health has been well-documented in the literature, generative research on the intersection of structural racism and ageism is limited. The AGS is working to identify and dismantle the healthcare structures that create and perpetuate these combined injustices and, in so doing, create a more just US healthcare system. This paper is intended to provide an overview of important frameworks and guide future efforts to both identify and eliminate bias within healthcare delivery systems and health professions training with a particular focus on the intersection of structural racism and ageism.

Encoding models provide a powerful framework to identify the information represented in brain recordings. In this framework, a stimulus representation is expressed within a feature space and is used in a regularized linear regression to predict brain activity. To account for a potential complementarity of different feature spaces, a joint model is fit on multiple feature spaces simultaneously. To adapt regularization strength to each feature space, ridge regression is extended to banded ridge regression, which optimizes a different regularization hyperparameter per feature space. The present paper proposes a method to decompose over feature spaces the variance explained by a banded ridge regression model. It also describes how banded ridge regression performs a feature-space selection, effectively ignoring non-predictive and redundant feature spaces. This feature-space selection leads to better prediction accuracy and to better interpretability. Banded ridge regression is then mathematically linked to a number of other regression methods with similar feature-space selection mechanisms. Finally, several methods are proposed to address the computational challenge of fitting banded ridge regressions on large numbers of voxels and feature spaces. All implementations are released in an open-source Python package called Himalaya.

This paper describes the evaluation of a longitudinal peer-support program developed to address loneliness and isolation among low-income, urban community-dwelling older adults in San Francisco. Our objective was to determine barriers, challenges, and successful strategies in implementation of the program. In-depth qualitative interviews with clients (n = 15) and peers (n = 6) were conducted and analyzed thematically by program component. We identified barriers and challenges to engagement and outlined strategies used to identify clients, match them with peers, and provide support to both peers and clients. We found that peers played a flexible, non-clinical role and were perceived as friends. Connections to community resources helped when clients needed additional support. We also documented creative strategies used to maintain inter-personal connections during the COVID-19 pandemic. This study fills a gap in understanding how a peer-support program can be designed to address loneliness and social isolation, particularly in low-income, urban settings.

Prior research has shown collective efficacy to be a key determinant of women's well-being. However, much of the work around measuring this construct has been done in high-income geographies, with very little representation from low- and middle-income countries (LMIC). To fill this gap, and guide future research in low resource settings, we aim to summarize best evidence measures of collective efficacy for women and girls from LMICs. Following PRISMA guidelines, we systematically searched five databases for English language peer-reviewed literature on measures of collective efficacy, published between 1 January 2009 and 25 August 2020. In addition, we sought expert input for relevant papers in this area. Research staff screened titles, abstracts, and full-text articles in a double-blind review. Inclusion criteria were: (i) original quantitative analysis, and (ii) sample limited to women/girls only (≥ 100), residing in LMICs. We identified 786 unique articles, 14 of which met inclusion criteria. Eligible studies captured a diversity of population groups, including pregnant women, recent mothers, adolescent girls, and female sex workers, from across national settings. Two broad constructs of collective efficacy were captured by the measures: (i) group dynamics, and (ii) collective action. All 14 studies included items on group dynamics in their measures, whereas seven studies included items on collective action. Four studies validated new measures of collective efficacy, and seven provided evidence supporting the relationship between collective efficacy and outcomes related to women's well-being. Overall, measures demonstrated good reliability and validity when tested, and those testing for associations or effects found a positive relationship of collective efficacy with women's health behaviors. The past decade has resulted in a number of new collective efficacy measures demonstrating good validity in terms of their associations with key health outcomes among women and girls from across LMIC settings, but there remains no standard measure in the field. Those that exist focus on group dynamics, but less often on collective action. A standard measure of collective efficacy inclusive of group dynamics and collective action can support better understanding of the value of women's collectives across national settings and populations.

BackgroundLatina adolescents in the USA report some of the lowest rates of physical activity of any demographic subgroup; this is paralleled by a markedly higher lifetime risk of obesity, type 2 diabetes, and other conditions related to inactivity. Despite this, to date, no fully powered clinical trials have tested physical activity interventions specifically for this population. High use of mobile technologies (including text messages, smartphone apps, and social media) suggests this could be an appropriate intervention channel, while also having potential for broad reach. This paper describes the protocol for Chicas Fuertes, a fully powered randomized trial of a mobile technology-based physical activity intervention for Latina adolescents.MethodsWe plan to recruit 200 Latina teens (age 13-18) in San Diego, CA, currently engaging in ≤ 150 min/week of moderate-to-vigorous physical activity (MVPA) to be assigned 1:1 to the intervention or control groups. Those randomly assigned to the intervention group receive a one-on-one goal setting session followed by 6 months of mobile technology-based intervention, including a personalized website, Fitbit activity tracker and app, individually tailored text messages based on Fitbit data, and daily intervention content on Instagram. Those randomized to the control group receive only a Fitbit activity tracker. The main outcome is change in weekly minutes of MVPA from baseline to 6 months, measured both objectively (ActiGraph accelerometers and Fitbit Inspire HR) and subjectively (7-Day Physical Activity Recall Interview). Additional outcomes are maintenance of activity change at 12 months and changes in psychosocial constructs, including social support and self-efficacy, engagement with mobile technology channels, and costs of intervention delivery. We are also examining the potential mediators and moderators of the intervention. The efficacy of the intervention is analyzed using a mixed effects regression model, adjusting for any potential confounders not balanced by randomization. All analyses of accelerometer measured MVPA are also adjusted for wear time.DiscussionThe Chicas Fuertes trial uses widely available mobile technologies to target critical health behavior, physical activity, in Latina teens, a population with a high lifetime risk of lifestyle-related diseases. The results will speak to the efficacy and acceptability of the intervention, which has the potential for broad dissemination.Trial registrationClinicalTrials.gov NCT04190225 . Registered on November 20, 2019.