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Background: Pharmacists have experienced declines in psychological health and wellbeing post-pandemic. The phenomena of moral distress, disengagement and burnout are associated with workforce attrition, unfitness to practice and inferior quality of patient care. A working group of the Canadian Pharmacists Association (CPhA) was formed to identify resources and interventions (R&I) for occupational psychological health and wellbeing. Objective: To characterize R&I from an evidence-based national health worker ‘burnout’ Toolkit with potential to support the pharmacy workforce. Methods: All R&I included within a draft ‘burnout’ Toolkit from the Canadian Health Workforce Network (CHWN) were screened to determine relevancy and usefulness for the pharmacy workforce. R&I with higher grades were data-charted to capture information on topic and content delivery. Final R&I were determined through consensus meetings where ‘highly rated’ R&I were discussed and selected. Results: Of 140 original CHWN Toolkit R&I, 53 (37.8%) were of potential relevance or usefulness to improve well-being for most in the pharmacy workforce. Of those 53 R&I, 28 (20% of original) were final selections. The majority of R&I at each stage were focused on ‘preventing burnout’ and ‘promoting mental health’ (>60%) rather than ‘addressing burnout’, ‘supporting recovery’ or managing specific issues in the workplace (i.e. stigma, discrimination, bullying, hostility, workload). No R&I were specifically developed or studied within the pharmacy workforce. Conclusions: Health professions may benefit from the CHWN Toolkit and the knowledge translation activity described here. R&I relevant and useful to the pharmacy workforce generally require adaptation for dissemination and/or implementation. The set of final R&I form the basis for orchestrated plans to support the pharmacy workforce with respect to psychological health and wellbeing. There is a relative lack of R&I devoted to addressing and recovering from burnout and workload management issues.

Brain function is mediated by the physiological coordination of a vast, intricately connected network of molecular and cellular components. The physiological properties of neural network components can be quantified with high throughput. The ability to assess many animals per study has been critical in relating physiological properties to behavior. By contrast, the synaptic structure of neural circuits is presently quantifiable only with low throughput. This low throughput hampers efforts to understand how variations in network structure relate to variations in behavior. For neuroanatomical reconstruction, there is a methodological gulf between electron microscopic (EM) methods, which yield dense connectomes at considerable expense and low throughput, and light microscopic (LM) methods, which provide molecular and cell-type specificity at high throughput but without synaptic resolution. To bridge this gulf, we developed a high-throughput analysis pipeline and imaging protocol using tissue expansion and light sheet microscopy (ExLLSM) to rapidly reconstruct selected circuits across many animals with single-synapse resolution and molecular contrast. Using Drosophila to validate this approach, we demonstrate that it yields synaptic counts similar to those obtained by EM, enables synaptic connectivity to be compared across sex and experience, and can be used to correlate structural connectivity, functional connectivity, and behavior. This approach fills a critical methodological gap in studying variability in the structure and function of neural circuits across individuals within and between species.

The spread of COVID-19 misinformation highlights the need to correct misperceptions about health and science. Research on climate change suggests that informing people about a scientific consensus can reduce misinformation endorsement, but these studies often fail to isolate the effects of consensus messaging and may not translate to other issues. We therefore conduct a survey experiment comparing standard corrections with those citing a scientific consensus for three issues: COVID-19 threat, climate change threat, and vaccine efficacy. We find that consensus corrections are never more effective than standard corrections at countering misperceptions and generally fail to reduce them with only one exception. We also find that consensus corrections endorsed by co-partisans do not reduce misperceptions relative to standard corrections, while those endorsed by opposition partisans are viewed as less credible and can potentially even provoke a backfire effect. These results indicate that corrections citing a scientific consensus, including corrective messages from partisans, are less effective than previous research suggests when compared with appropriate baseline messages.

Animals employ diverse learning rules and synaptic plasticity dynamics to record temporal and statistical information about the world. However, the molecular mechanisms underlying this diversity are poorly understood. The anatomically defined compartments of the insect mushroom body function as parallel units of associative learning, with different learning rates, memory decay dynamics and flexibility (Aso and Rubin, 2016). Here, we show that nitric oxide (NO) acts as a neurotransmitter in a subset of dopaminergic neurons in Drosophila. NO’s effects develop more slowly than those of dopamine and depend on soluble guanylate cyclase in postsynaptic Kenyon cells. NO acts antagonistically to dopamine; it shortens memory retention and facilitates the rapid updating of memories. The interplay of NO and dopamine enables memories stored in local domains along Kenyon cell axons to be specialized for predicting the value of odors based only on recent events. Our results provide key mechanistic insights into how diverse memory dynamics are established in parallel memory systems.

Calcium imaging is commonly used to measure the neural activity of large groups of neurons in mice. Genetically encoded calcium indicators (GECIs) can be delivered for this purpose using non-invasive genetic methods. Compared to viral gene transfer, transgenic targeting of GECIs provides stable long-term expression and obviates the need for invasive viral injections. Transgenic mice expressing the green GECI GCaMP6 are already widely used. Here we present the generation and characterization of transgenic mice expressing the sensitive red GECI jRGECO1a, driven by the Thy1 promoter. Four transgenic lines with different expression patterns showed sufficiently high expression for cellular in vivo imaging. We used two-photon microscopy to characterize visual responses of individual neurons in the visual cortex in vivo. The signal-to-noise ratio in transgenic mice was comparable to, or better than, mice transduced with adeno-associated virus. In addition, we show that Thy1-jRGECO1a transgenic mice are useful for transcranial population imaging and functional mapping using widefield fluorescence microscopy. We also demonstrate imaging of visual responses in retinal ganglion cells in vitro. Thy1-jRGECO1a transgenic mice are therefore a useful addition to the toolbox for imaging activity in intact neural networks.

Genetically encoded calcium indicators (GECIs) allow measurement of activity in large populations of neurons and in small neuronal compartments, over times of milliseconds to months. Although GFP-based GECIs are widely used for in vivo neurophysiology, GECIs with red-shifted excitation and emission spectra have advantages for in vivo imaging because of reduced scattering and absorption in tissue, and a consequent reduction in phototoxicity. However, current red GECIs are inferior to the state-of-the-art GFP-based GCaMP6 indicators for detecting and quantifying neural activity. Here we present improved red GECIs based on mRuby (jRCaMP1a, b) and mApple (jRGECO1a), with sensitivity comparable to GCaMP6. We characterized the performance of the new red GECIs in cultured neurons and in mouse, Drosophila, zebrafish and C. elegans in vivo. Red GECIs facilitate deep-tissue imaging, dual-color imaging together with GFP-based reporters, and the use of optogenetics in combination with calcium imaging.

Genetically-encoded calcium indicators (GECIs) facilitate imaging activity of genetically defined neuronal populations in vivo. The high intracellular GECI concentrations required for in vivo imaging are usually achieved by viral gene transfer using adeno-associated viruses. Transgenic expression of GECIs promises important advantages, including homogeneous, repeatable, and stable expression without the need for invasive virus injections. Here we present the generation and characterization of transgenic mice expressing the GECIs GCaMP6s or GCaMP6f under the Thy1 promoter. We quantified GCaMP6 expression across brain regions and neurons and compared to other transgenic mice and AAV-mediated expression. We tested three mouse lines for imaging in the visual cortex in vivo and compared their performance to mice injected with AAV expressing GCaMP6. Furthermore, we show that GCaMP6 Thy1 transgenic mice are useful for long-term, high-sensitivity imaging in behaving mice.

Abstract Background Evidence suggests that coordination of care for people affected by rare diseases is poor. In order to improve the way that care is coordinated it is necessary to understand the preferences of people affected by these conditions, and providers. The aim of this study was to examine patient, parent and carer, and health care professional preferences for different attributes of care coordination for people affected by rare diseases. We conducted a discrete choice experiment using online surveys. There were no restrictions on participants in terms of rare conditions, demographic factors other than age, or geographical location within the UK. Choice scenarios were based on the following attributes: annual cost of attending appointments; access to health records; access to clinical expertise; support of a care coordinator; access to a specialist centre; and, the existence of a documented plan for emergency care. Data were analysed using alternative-specific conditional logit regression models. Results Valid responses were obtained from 996 individuals (528 patients, 280 carers, 188 health care professionals) between August and December 2019. All attributes significantly influenced the type of service respondents preferred. Patients, carers and health professionals’ preferences for care coordination were influenced by: the cost of attending appointments; access to health records; clinical expertise; role of care coordinators; access to specialist centres; and the existence of plan for emergency care. There were no statistically significant differences in the preferences between patients and carers. Preferences of health professionals differed to those of patients and carers. Both patients and carers selected responses which granted them a greater degree of autonomy in relation to the role of care coordinators, whereas health professionals preferred services where care coordinators had more autonomy. Health care professionals also expressed a stronger preference for a documented formal emergency plan to be in place. Conclusions The findings highlight that people value better coordinated care, in line with policy documents emphasising commitments to coordinated care for people affected by rare diseases. This study highlights the factors that could be included in service provision as ways of improving the coordination of care for people affected by rare diseases.

Abstract Previous research has demonstrated a critical link between maternal mental health and infant development. However, there is limited understanding of the role of autonomic regulation in postpartum maternal mental health and infant outcomes. In the current study, we tested 76 mother-infant dyads from diverse socioeconomic backgrounds when infants were 3-months of age. We recorded simultaneous ECG from dyads while baseline EEG was collected from the infant; ECG heart rate variability (HRV) and EEG theta-beta ratio and alpha asymmetry were calculated. Dyadic physiological synchrony was also analyzed to better understand the role of autonomic co-regulation. Results demonstrated that lower maternal HRV was associated with higher self-reported maternal depression and anxiety. Additionally, mothers with lower HRV had infants with lower HRV. Maternal HRV was also associated with higher infant theta-beta ratios, but not alpha asymmetry. Exploratory analyses suggested that for mother-infant dyads with greater physiological synchrony, higher maternal HRV predicted increased infant theta-beta ratio via infant HRV. These findings support a model in which maternal mental health may influence infant neurophysiology via alterations in autonomic stress regulation and dyadic physiological co-regulation.

Background: Colon cancers are categorized into mismatch repair deficient/microsatellite unstable (MSI-H) and mismatch repair proficient/microsatellite stable (MSS) cancers. This study aims to compare the disease characteristics and trends in the utilization of cancer therapies across different age groups and stages in these two groups. Methods: MSI-H and MSS colon adenocarcinomas from 2010 to 2016 were identified using the National Cancer Database. We compared patient and disease characteristics between the two groups and evaluated the use of adjuvant chemotherapy across age groups and cancer stages. Within MSI-H and MSS groups, we conducted a landmark analysis after propensity score matching for adjuvant chemotherapy versus no chemotherapy to determine its effect on survival. Results: Of the 542,368 patients that met inclusion criteria, 120,751 (22%) had mismatch repair results available—out of these 96,928 (80%) had MSS colon cancers while 23,823 (19.7%) had MSI-H cancers. MSI-H disease had a bimodal age distribution (

Abstract Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

BackgroundFamily dynamics play an important role in determining the glycemic outcomes of type 1 diabetes (T1D) in children. The time interval immediately following T1D diagnosis is particularly stressful for families, and interventions to support families in adjusting their family practices to support adjustment to and management of T1D in the months following diagnosis may improve glycemic outcomes. Self-guided digital interventions offer a sustainable model for interventions to support caregivers in learning evidence-based family management skills for adjustment to and management of T1D. ObjectiveWe hypothesized that a self-guided, web-based, family skills management program (addressing caregiver social support as well as family problem-solving, communication, and supportive behavior change strategies) initiated at the time of T1D diagnosis would improve glycemic outcomes in children with T1D. In this study, we report on the feasibility and acceptability of this program. MethodsWe prospectively evaluated a sample of 37 children newly diagnosed with T1D recruited from a pediatric endocrinology clinic. Parent participants were asked to complete web-based modules addressing social support, family problem-solving, communication, and supportive behavior change strategies. Module completion was analyzed for percentage completion, patterns of completion, and differences in completion rates by coparenting status. Qualitative open-ended feedback was collected at the completion of each module. ResultsA total of 31 (84%) of the 37 participants initiated the web-based program. Of those 31 participants, 25 (81%) completed some content and 15 (48%) completed all 5 modules. Completion rates were higher when coparenting partners engaged in the intervention together (P=.04). Of the 18 participants given a choice about the spacing of content delivery, 15 (83%) chose to have all sessions delivered at once and 3 (17%) chose to space sessions out at 2-week intervals. Qualitative feedback supported the acceptability of the program for delivery soon after T1D diagnosis. Families reported on positive benefits, including requesting future access to the program and describing helpful changes in personal or family processes for managing T1D. ConclusionsIn this study, we found that a self-guided digital family support intervention initiated at the time of a child’s T1D diagnosis was largely feasible and acceptable. Overall, rates of participation and module completion were similar to or higher than other self-guided digital prevention interventions for mental and physical health outcomes. Self-guided digital programs addressing family management skills may help prevent challenges common with T1D management and can decrease cost, increase access, and add flexibility compared to traditional interventions. Trial RegistrationClinicalTrials.gov NCT03720912; https://clinicaltrials.gov/study/NCT03720912

IntroductionRacial/ethnic disparities in maternal mortality rates represent one of the most significant areas of disparities amongst all conventional population perinatal health measures in the U.S. The alarming trends and persistent disparities of outcomes by race/ethnicity and geographic location reinforce the need to focus on ensuring quality and safety of maternity care for all women. Despite complex multilevel factors impacting maternal mortality and morbidity, there are evidence-based interventions that, when facilitated consistently and properly, are known to improve the health of mothers before, during and after pregnancy. The objective of this project is to test implementation of pre-conception counseling with father involvement in community-based settings to improve cardiovascular health outcomes before and during pregnancy in southeastern United States.Methods and analysisThis study has two components: a comprehensive needs and assets assessment and a small-scale pilot study. We will conduct a community informed needs and assets assessment with our diverse stakeholders to identify opportunities and barriers to preconception counseling as well as develop a stakeholder-informed implementation plan. Next, we will use the implementation plan to pilot preconception counseling with father involvement in community-based settings. Finally, we will critically assess the context, identify potential barriers and facilitators, and iteratively adapt the way preconception counseling can be implemented in diverse settings. Results of this research will support future research focused on identifying barriers and opportunities for scalable and sustainable public health approaches to implementing evidence-based strategies that reduce maternal morbidity and mortality in the southeastern United States’ vulnerable communities.DiscussionFindings will demonstrate that preconception counseling can be implemented in community health settings in the southeastern United States. Furthermore, this study will build the capacity of community-based organizations in addressing the preconception health of their clients. We plan for this pilot to inform a larger scaled-up clinical trial across community health settings in multiple southeastern states.

Objectives and Approach Neighborhood influences pregnancy outcomes through effects on maternal health. We evaluated prevalence of >140 congenital anomalies monitored by the population-based Texas Birth Defects Registry among residents of Hispanic/Latino enclaves (census tracts with high proportions of Hispanic/Latino residents, immigrants, and Spanish-speaking households) and tracts with low socioeconomic status (low nSES). We included all cases regardless of pregnancy outcome (1999-2018) and a reference population of all livebirths, identified by linkage to Texas vital records. We calculated Yost socioeconomic index and Hispanic/Latino enclave index scores using linked U.S. Census Bureau data. We used Poisson regression to estimate the prevalence ratio (PR) and 95% confidence interval of anomalies among residents of: low nSES/enclave (34.5%); low nSES/non-enclave (25.6%); high nSES/enclave (4.6%); and high nSES/non-enclave (referent; 35.3%) tracts. We adjusted for maternal age, education, race/ethnicity, parity, and pre-pregnancy body mass index. Results Low nSES was associated with microcephaly, pulmonary artery anomalies, atrial septal defect, and Down syndrome (PRs 1.1-1.6), and inversely associated with hypospadias and other male genital anomalies (PRs 0.8-0.9). Offspring of women in low nSES enclaves were at increased risk of several congenital heart defects relative to those in other neighborhoods. Conversely, prevalence of hypospadias was lowest among offspring of women in low nSES enclaves. Conclusions Linkage between a population-based registry, vital records, and Census Bureau data revealed novel associations between neighborhood characteristics and congenital anomalies. Implications Further research is warranted to understand mechanisms linking neighborhood factors to congenital anomalies.

Abstract Background During the pandemic, a notable increase in diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS), conditions that warrant emergent management, was reported. We aimed to investigate the trend of DKA‐ and HHS‐related mortality and excess deaths during the pandemic. Methods Annual age‐standardized mortality rates related to DKA and HHS between 2006 and 2021 were estimated using a nationwide database. Forecast analyses based on prepandemic data were conducted to predict the mortality rates during the pandemic. Excess mortality rates were calculated by comparing the observed versus predicted mortality rates. Subgroup analyses of demographic factors were performed. Results There were 71 575 DKA‐related deaths and 8618 HHS‐related deaths documented during 2006–2021. DKA, which showed a steady increase before the pandemic, demonstrated a pronounced excess mortality during the pandemic (36.91% in 2020 and 46.58% in 2021) with an annual percentage change (APC) of 29.4% (95% CI: 16.0%–44.0%). Although HHS incurred a downward trend during 2006–2019, the excess deaths in 2020 (40.60%) and 2021 (56.64%) were profound. Pediatric decedents exhibited the highest excess mortality. More than half of the excess deaths due to DKA were coronavirus disease 2019 (COVID‐19) related (51.3% in 2020 and 63.4% in 2021), whereas only less than a quarter of excess deaths due to HHS were COVID‐19 related. A widened racial/ethnic disparity was observed, and females exhibited higher excess mortality than males. Conclusions The DKA‐ and HHS‐related excess mortality during the pandemic and relevant disparities emphasize the urgent need for targeted strategies to mitigate the escalated risk in these populations during public health crises.

Public health responses to the COVID-19 pandemic varied across the world. Some countries (e.g. mainland China, New Zealand and Taiwan) implemented elimination strategies involving strict travel measures and periods of rigorous non-pharmaceutical interventions (NPIs) in the community, aiming to achieve periods with no disease spread; while others (e.g. many European countries and the USA) implemented mitigation strategies involving less strict NPIs for prolonged periods, aiming to limit community spread. Travel measures and community NPIs have high economic and social costs, and there is a need for guidelines that evaluate the appropriateness of an elimination or mitigation strategy in regional contexts. To guide decisions, we identify key criteria and provide indicators and visualizations to help answer each question. Considerations include determining whether disease elimination is: (1) necessary to ensure healthcare provision; (2) feasible from an epidemiological point of view and (3) cost-effective when considering, in particular, the economic costs of travel measures and treating infections. We discuss our recommendations by considering the regional and economic variability of Canadian provinces and territories, and the epidemiological characteristics of different SARS-CoV-2 variants. While elimination may be a preferable strategy for regions with limited healthcare capacity, low travel volumes, and few ports of entry, mitigation may be more feasible in large urban areas with dense infrastructure, strong economies, and with high connectivity to other regions.

Abstract Background Although individually rare, collectively, rare conditions are common and affect a large number of people and are often chronic, life threatening and affect multiple body systems; the majority of them have no effective treatment. The literature has identified many specific challenges for those living with rare conditions, however, we do not know which of these in combination are most likely to impact how someone rates their overall experience of care. The aim of this study is to do further exploratory analysis of the Genetic Alliance UK 2020 Rare Experience survey data to identify which variables are most strongly associated with respondents’ overall care experience. Results There were strong associations between most of the selected survey variables and the overall rated experience of care variable. In the multiple linear regression only nine variables remained in the best fit model: ‘Trust and confidence in hospital staff involved in ongoing care’; ‘Satisfaction with information provided by healthcare professionals—following diagnosis’; ‘The professionals providing care work as a team’; ‘Feel care is coordinated effectively’; ‘The timing and frequency of appointments are convenient for the patient/carer/family’; ‘Whether or not there is a specific healthcare professional to ask questions of about the rare/undiagnosed condition’; ‘Experience of searching for a diagnosis’; ‘Knowledge of whether there is a specialist centre for the condition’; and ‘Number of different clinics attend for the condition’. Conclusions Our findings indicate the challenges that play the largest part in explaining the varied experiences with rare disease healthcare in the UK for our survey respondents. These challenges should be further investigated with a broader sample of people affected by rare conditions, ideally through the implementation of a comprehensive national rare condition patient registry. Our findings highlight an important potential gap in the Framework, ‘trust and confidence in healthcare professionals’; further research is required to fully understand the foundations of trust and confidence.

Abstract Burkitt lymphoma (BL) is responsible for many childhood cancers in sub-Saharan Africa, where it is linked to recurrent or chronic infection by Epstein-Barr virus or Plasmodium falciparum. However, whether human leukocyte antigen (HLA) polymorphisms, which regulate immune response, are associated with BL has not been well investigated, which limits our understanding of BL etiology. Here we investigate this association among 4,645 children aged 0-15 years, 800 with BL, enrolled in Uganda, Tanzania, Kenya, and Malawi. HLA alleles are imputed with accuracy >90% for HLA class I and 85-89% for class II alleles. BL risk is elevated with HLA-DQA1*04:01 (adjusted odds ratio [OR] = 1.61, 95% confidence interval [CI] = 1.32-1.97, P = 3.71 × 10−6), with rs2040406(G) in HLA-DQA1 region (OR = 1.43, 95% CI = 1.26-1.63, P = 4.62 × 10−8), and with amino acid Gln at position 53 versus other variants in HLA-DQA1 (OR = 1.36, P = 2.06 × 10−6). The associations with HLA-DQA1*04:01 (OR = 1.29, P = 0.03) and rs2040406(G) (OR = 1.68, P = 0.019) persist in mutually adjusted models. The higher risk rs2040406(G) variant for BL is associated with decreased HLA-DQB1 expression in eQTLs in EBV transformed lymphocytes. Our results support the role of HLA variation in the etiology of BL and suggest that a promising area of research might be understanding the link between HLA variation and EBV control.

Abstract In high-income countries, mosaic chromosomal alterations in peripheral blood leukocytes are associated with an elevated risk of adverse health outcomes, including hematologic malignancies. We investigate mosaic chromosomal alterations in sub-Saharan Africa among 931 children with Burkitt lymphoma, an aggressive lymphoma commonly characterized by immunoglobulin-MYC chromosomal rearrangements, 3822 Burkitt lymphoma-free children, and 674 cancer-free men from Ghana. We find autosomal and X chromosome mosaic chromosomal alterations in 3.4% and 1.7% of Burkitt lymphoma-free children, and 8.4% and 3.7% of children with Burkitt lymphoma (P-values = 5.7×10−11 and 3.74×10−2, respectively). Autosomal mosaic chromosomal alterations are detected in 14.0% of Ghanaian men and increase with age. Mosaic chromosomal alterations in Burkitt lymphoma cases include gains on chromosomes 1q and 8, the latter spanning MYC, while mosaic chromosomal alterations in Burkitt lymphoma-free children include copy-neutral loss of heterozygosity on chromosomes 10, 14, and 16. Our results highlight mosaic chromosomal alterations in sub-Saharan African populations as a promising area of research.

We collected stool from school-age children from 352 households living in the Black Belt region of Alabama, USA, where sanitation infrastructure is lacking. We used quantitative reverse transcription PCR to measure key pathogens in stool that may be associated with water and sanitation, as an indicator of exposure. We detected genes associated with >1 targets in 26% of specimens, most frequently Clostridioides difficile (6.6%), atypical enteropathogenic Escherichia coli (6.1%), and enteroaggregative E. coli (3.9%). We used generalized estimating equations to assess reported risk factors for detecting >1 pathogen in stool. We found no association between lack of sanitation and pathogen detection (adjusted risk ratio 0.95 [95% CI 0.55–1.7]) compared with specimens from children served by sewerage. However, we did observe an increased risk for pathogen detection among children living in homes with well water (adjusted risk ratio 1.7 [95% CI 1.1–2.5]) over those reporting water utility service.

We conducted a cross-sectional study to determine the prevalence of soil-transmitted helminthiases (STH) in areas of rural Alabama, USA, that have sanitation deficits. We enrolled 777 children; 704 submitted stool specimens and 227 a dried blood spot sample. We microscopically examined stool specimens from all 704 children by using Mini-FLOTAC for helminth eggs. We tested a subset by using molecular techniques: real-time PCR analysis for 5 STH species, TaqMan Array Cards for enteric helminths, and digital PCR for Necator americanus hookworm. We analyzed dried blood spots for Strongyloides stercoralis and Toxocara spp. roundworms by using serologic testing. Despite 12% of our cohort reporting living in homes that directly discharge untreated domestic wastewater, stool testing for STH was negative; however, 5% of dried blood spots were positive for Toxocara spp. roundworms. Survey data suggests substantial numbers of children in this region may be exposed to raw sewage, which is itself a major public health concern.

Abstract Introduction Differentiated service delivery (DSD) models aim to increase the responsiveness of HIV treatment programmes to the individual needs of antiretroviral therapy (ART) clients to improve treatment outcomes and quality of life. Little is known about how DSD client experiences differ from conventional care. Methods From May to November 2021, we interviewed adult (≥18) ART clients at 21 primary clinics in four districts of South Africa. Participants were enrolled consecutively at routine visits and stratified into four groups: conventional care‐not eligible for DSD (conventional‐not‐eligible); conventional care eligible for but not enrolled in DSD (conventional‐not‐enrolled); facility pickup point DSD model; and external pickup point DSD model. Satisfaction was assessed using questions with 5‐point Likert‐scale responses. Mean scores were categorized as not satisfied (score ≤3) or satisfied (>3). We used logistic regression to assess differences and report crude and adjusted odds ratios (aORs). Qualitative themes were identified through content analysis. Results Eight hundred and sixty‐seven participants (70% female, median age 39) were surveyed: 24% facility pick‐up points; 27% external pick‐up points; 25% conventional‐not‐eligible; and 24% conventional‐not‐enrolled. Seventy‐four percent of all study participants expressed satisfaction with their HIV care. Those enrolled in DSD models were more likely to be satisfied, with an aOR of 6.24 (95% CI [3.18–12.24]) for external pick‐up point versus conventional‐not‐eligible and an aOR of 3.30 (1.95–5.58) for facility pick‐up point versus conventional‐not‐eligible. Conventional‐not‐enrolled clients were slightly but not significantly more satisfied than conventional‐not‐eligible clients (1.29, 0.85–1.96). Those seeking outside healthcare (crude OR 0.57, 0.41–0.81) or reporting more annual clinic visits (0.52, 0.29–0.93) were less likely to be satisfied. Conventional care participants reporting satisfaction with their current model of care perceived providers as helpful, respectful, and friendly and were satisfied with care despite long queues. DSD model participants emphasized ease and convenience, particularly not having to queue. Conclusions Most adult ART clients in South Africa were satisfied with their care, but those enrolled in DSD models expressed slightly greater satisfaction than those remaining in conventional care. Efforts should focus on enrolling more eligible patients into DSD models, expanding eligibility criteria to cover a wider client base, and further improving the models’ desirable characteristics.

Abstract Background Poorly coordinated care can have major impacts on patients and families affected by rare conditions, with negative physical health, psychosocial and financial consequences. This study aimed to understand how care is coordinated for rare diseases in the United Kingdom. Methods We undertook a national survey in the UK involving 760 adults affected by rare diseases, 446 parents/carers of people affected by rare diseases, and 251 healthcare professionals who care for people affected by rare diseases. Results Findings suggested that a wide range of patients, parents and carers do not have coordinated care. For example, few participants reported having a care coordinator (12% patients, 14% parents/carers), attending a specialist centre (32% patients, 33% parents/carers) or having a care plan (10% patients, 44% parents/carers). A very small number of patients (2%) and parents/carers (5%) had access to all three—a care coordinator, specialist centre and care plan. Fifty four percent of patients and 33% of parents/carers reported access to none of these. On the other hand, a higher proportion of healthcare professionals reported that families with rare conditions had access to care coordinators (35%), specialist centres (60%) and care plans (40%). Conclusions Care for families with rare conditions is generally not well coordinated in the UK, with findings indicating limited access to care coordinators, specialist centres and care plans. Better understanding of these issues can inform how care coordination might be improved and embrace the needs and preferences of patients and families affected by rare conditions.

The rise of mental disorders, specifically depression, has shown an upward trend, especially during the COVID-19 pandemic. Previous studies have suggested that it is feasible to learn the textual and behavioral features of a user to identify depression on social media. This paper highlights three new contributions, which are, firstly, to introduce Patient Health Questionnaire-9 (PHQ-9) as the survey-based method to complement the TWINT API to collect Twitter data. Secondly, it is to propose a Bidirectional Encoder Representations from Transformers (BERT)-based model, along with emoji decoding and PHQ-9-based lexicon features for predicting the likelihood that a user will exhibit depressive symptoms. The results are promising, achieving an F1 score of 0.98 on a baseline dataset and an F1 score of 0.90 on a benchmark dataset, outperforming previous researcher’s work of achieving a F1 score of 0.85 using solely textual features. Thirdly, previous researcher’s work focuses on differentiating between depressed and non-depressed users only, while this paper further separates the users in the depressive class into before (pre-) and after (post-) self-reported diagnosis, which can potentially be used to detect early symptoms of depression. It was found that the top TF-IDF scores of the post-depressive class contain more frequently negatively implied words compared to the pre-depressive class.

Abstract Background Many countries in sub-Saharan Africa are rapidly scaling up “differentiated service delivery” (DSD) models for HIV treatment to improve the quality of care, increase access, reduce costs, and support the continued expansion and sustainability of antiretroviral therapy (ART) programs. Although there is some published evidence about the health outcomes of patients in DSD models, little is known about their impacts on healthcare providers’ job satisfaction, patients’ quality of life, costs to providers or patients, or how DSD models affect resource allocation at the facility level. Methods SENTINEL is a multi-year observational study that will collect detailed data about DSD models for ART delivery and related services from 12 healthcare facilities in Malawi, 24 in South Africa, and 12 in Zambia. The first round of SENTINEL included a patient survey, provider survey, provider time-and-motion observations, and facility resource use inventory. A survey of clients testing for HIV and a supplement to the facility resource use component to describe service delivery integration will be added for the second round. The patient survey will ask up to 10 patients enrolled in each DSD model at each study site about their experiences in HIV care and in DSD models, costs incurred seeking treatment, and preferences for HIV service delivery. The provider survey will ask up to 10 providers per site about the impact of DSD models on their positions and clinics. The time-and-motion component will directly observe the time use of a sample of providers implementing DSD models. Finally, the resource utilization component will collect facility-level data about DSD model availability and enrollment and the human and other resources needed to implement them. SENTINEL is planned to include four or more approximately annual rounds of data collection between 2021 and 2026. Discussion As national DSD programs for HIV treatment mature, it is important to understand how individual healthcare facilities are interpreting and implementing national guidelines and how healthcare workers and clients are adapting to new models of service delivery. SENTINEL will help policy makers and program managers understand the benefits and costs of differentiated service delivery and improve resource allocation going forward.

The ability to efficiently target loci in the Chlamydia trachomatis genome for deletion remains a desirable goal in the field and new strategies need to be developed and refined. Here we describe the development and application of a lambda red recombineering system for Chlamydia. Using a non-replicative plasmid encoding key lambda Red components and targeting sequences, we demonstrate the efficient deletion of numerous gene targets in the model chlamydial strains C. trachomatis L2/434 and C. muridarum. For initial development of the system, we targeted the incA gene of C. trachomatis for deletion. Deletion mutants containing a chloramphenicol resistance marker were recovered within 3 rounds of selection, or 2 rounds of passaging, in McCoy cells and the resulting clones (CTΔincA) were verified by PCR-based genotyping and whole genome sequencing. Phenotypic assessment of host cells infected with CTΔincA was performed by immunofluorescence microscopy and confirmed the lack of IncA expression and the uniform presence of nonfusogenic vacuoles (inclusions) across CTΔincA-infected monolayers. To explore the utility of this system, we deleted 5 additional candidate virulence factors in C. trachomatis and C. muridarum, including deletions of single and multiple genes. We expect lambda Red recombineering to offer a powerful new strategy for making gene deletion and/or replacement mutants in Chlamydia.

Retention on antiretroviral therapy (ART) during the early treatment period is one of the most serious challenges facing HIV programs, but the timing and patterns of early disengagement from care remain poorly understood. We describe patterns of engagement in HIV care during the first year after treatment initiation. We analysed retrospective datasets of routinely collected electronic medical register (EMR) data for ≥18-year-old clients who initiated ART at public sector clinics in South Africa after 01/01/2018 and had ≥14 months of potential follow-up. Using scheduled visit dates, we characterized engagement in care as continuous (no treatment interruption), cyclical (at least one visit >28 days late with a return visit observed) or disengaged (visit not attended and no evidence of return). We report 6- and 12-month patterns of retention in care and viral suppression. Among 35,830 participants (65% female, median age 33), in months 0-6, 59% were continuously in care, 14% had engaged cyclically, 11% had transferred to another facility, 1% had died, and 16% had disengaged from care at the initiating facility. Among disengagers in the first 6 months, 58% did not return after their initiation visit. By 12 months after initiation, the overall proportion disengaged was 23%, 45% were classified as continuously engaged in months 7-12, and only 38% of the cohort had maintained continuous engagement at both the 6- and 12-month endpoints. Participants who were cyclically engaged in months 0-6 were nearly twice as likely to disengage in months 7-12 as were continuous engagers in months 0-6 (relative risk 1.76, 95% CI:1.61-1.91) and were more likely to have an unsuppressed viral load by 12 months on ART (RR = 1.28; 95% CI1.13-1.44). The needs of continuous and cyclical engagers and those disengaging at different timepoints may vary and require different interventions or models of care.

BackgroundDiabetes distress among adolescents with type 1 diabetes has been associated with suboptimal diabetes outcomes, including lower quality of life, increased diabetes self-management challenges, and suboptimal glycemic outcomes. ObjectiveThis study examined the feasibility and acceptability of a scalable self-led mindfulness-based intervention to reduce diabetes distress in adolescents with type 1 diabetes. MethodsAdolescents (N=25) aged between 14 and 18 years diagnosed with type 1 diabetes completed a baseline assessment. Participants were randomized to receive a 10-week self-guided mindfulness-based stress reduction workbook program (e-book or paper option) immediately (n=15) or after a 10-week wait (n=10). During the intervention period, participants completed weekly assignments and feedback surveys. At 10 weeks and 20 weeks, follow-up assessments were completed. ResultsFindings indicated that participants did not find the original intervention feasible or acceptable. Adolescents reported barriers to completing the weekly material, such as that they forgot or that the material was not sufficiently related to their diabetes management. Adolescents also reported that a digital format rather than a workbook or e-book may be more acceptable. Results from weekly surveys provided the foundation for recommendations for future iterations of the mindfulness-based intervention for adolescents with type 1 diabetes. ConclusionsParticipant feedback informed recommendations for self-led mindfulness programs for youth with type 1 diabetes. Adolescents indicated that a shorter, digital mindfulness-based intervention focused on diabetes-specific behaviors may be more helpful. Trial RegistrationClinicalTrials.gov NCT05115175; https://clinicaltrials.gov/study/NCT05115175

Over 50,000 people die annually from opioid overdoses in the United States leading to what has become known as the “opioid epidemic.” This is of heightened concern in states like Alabama that experience higher rates of overall drug use and overdose deaths. Thus, it is increasingly important for college students in Alabama to learn about how the opioid epidemic is affecting their communities. Previous studies have demonstrated that engaging non-majors in innovative active-learning oriented pedagogies like service-learning can enhance their understanding and awareness about contemporary societal issues. Despite its pedagogical potential, the impact of opioid-related service-learning, particularly for non-majors, continues to remain unexplored. In this study, we describe the implementation of a service-learning module centered on opioid addiction. Students in a non-major biology course learned the science behind opioids, had Naloxone training, and engaged in active discussions with an opioid researcher, physician, and former illicit opioid user. Our assessment of the thematic analysis of pre- and post-reflection free-write data from 87 consenting students revealed 10 categories that students reported in the post- but not pre-reflections (essay gain), pre- and post-reflections (neutral), and pre- but not post-reflections (essay loss). We found essay gains in students humanizing addiction and awareness of the cultural context of opioid addiction and essay losses from students indicating that non-major students had a low level of awareness related to these issues. Eight one-on-one, semi-structured interviews revealed that students were personally impacted by the epidemic and valued its curricular inclusion. Our data supports that service-learning can increase non-major biology student’s awareness and contextual understanding about the opioid epidemic, enabling much-needed advocacy to further enhance its awareness among the public.

Abstract Lung adenocarcinoma is the most common type of lung cancer. Known risk variants explain only a small fraction of lung adenocarcinoma heritability. Here, we conducted a two-stage genome-wide association study of lung adenocarcinoma of East Asian ancestry (21,658 cases and 150,676 controls; 54.5% never-smokers) and identified 12 novel susceptibility variants, bringing the total number to 28 at 25 independent loci. Transcriptome-wide association analyses together with colocalization studies using a Taiwanese lung expression quantitative trait loci dataset (n = 115) identified novel candidate genes, including FADS1 at 11q12 and ELF5 at 11p13. In a multi-ancestry meta-analysis of East Asian and European studies, four loci were identified at 2p11, 4q32, 16q23, and 18q12. At the same time, most of our findings in East Asian populations showed no evidence of association in European populations. In our studies drawn from East Asian populations, a polygenic risk score based on the 25 loci had a stronger association in never-smokers vs. individuals with a history of smoking (Pinteraction = 0.0058). These findings provide new insights into the etiology of lung adenocarcinoma in individuals from East Asian populations, which could be important in developing translational applications.

The hawksbill sea turtle Eretmochelys imbricata is categorized as Critically Endangered on the IUCN Red List and its population has declined by over 80% in the last century. The Eastern Pacific population is one of the most threatened hawksbill populations globally. Western Mexico is the northern distribution limit for hawksbill sea turtles in the Eastern Pacific and recent research indicates that the Mexican Pacific portion of the population is a separate management unit because of the restricted movements of these turtles. Here we use the most complete database of sighting records in the north-west Pacific of Mexico to identify sites where hawksbill turtles are present. We also develop a conservation index to determine the conservation status of hawksbill turtle sites. Our results demonstrate the importance of this region for juveniles and the relevance of rocky reefs and mangrove estuaries as habitats for hawksbill turtles. We identified 52 sites with records of hawksbill turtles. Most of these sites (71%) are not protected; however, sites with high conservation value included islands and coastal sites along the Baja California peninsula that are established as marine protected areas. Reefs and mangrove estuaries relevant for hawksbill turtles are probably also significant fish nursery areas that are important for local fishing communities, creating opportunities for conservation strategies that combine science, local engagement and policy to benefit both local fishing communities and hawksbill sea turtle conservation.

Abstract Background Few studies have examined epigenetic age acceleration (AA), the difference between DNA methylation (DNAm) predicted age and chronological age, in relation to somatic genomic features in paired cancer and normal tissue, with less work done in non-European populations. In this study, we aimed to examine DNAm age and its associations with breast cancer risk factors, subtypes, somatic genomic profiles including mutation and copy number alterations and other aging markers in breast tissue of Chinese breast cancer (BC) patients from Hong Kong. Methods We performed genome-wide DNA methylation profiling of 196 tumor and 188 paired adjacent normal tissue collected from Chinese BC patients in Hong Kong (HKBC) using Illumina MethylationEPIC array. The DNAm age was calculated using Horvath’s pan-tissue clock model. Somatic genomic features were based on data from RNA sequencing (RNASeq), whole-exome sequencing (WES), and whole-genome sequencing (WGS). Pearson’s correlation (r), Kruskal–Wallis test, and regression models were used to estimate associations of DNAm AA with somatic features and breast cancer risk factors. Results DNAm age showed a stronger correlation with chronological age in normal (Pearson r = 0.78, P

Abstract Background First-line treatment of eosinophilic esophagitis (EoE) includes monotherapy with proton-pump inhibitors (PPIs), food elimination diet (FED), or topical corticosteroids. Current guidelines suggest patients with EoE should continue any responsive first-line monotherapies. However, the efficacy of FED monotherapy in patients with EoE responsive to PPI monotherapy has not been well studied. Our study aimed to investigate how attempting FED monotherapy after experiencing remission of EoE after PPI monotherapy influenced long-term EoE management. Methods We retrospectively identified patients with EoE responsive to PPI monotherapy who trialed FED monotherapy. We then employed a mixed method approach to a prospective cohort. Selected patients were observed long term for quantitative outcomes, while qualitative results were obtained from patient surveys regarding their perspectives on the trial of FED monotherapy. Results We identified 22 patients who trialed FED monotherapy after experiencing remission of EoE following PPI monotherapy. Of these 22 patients, 13 had remission of EoE with FED monotherapy, while 9 had re-activation of EoE. Out of 22 patients, 15 were enrolled in a cohort for observation. No exacerbations of EoE occurred while on maintenance treatment. Most patients stated that they would recommend this process to others with EoE (93.33%) and that trial of FED monotherapy helped them identify a treatment plan that aligned with their lifestyle (80%). Conclusion Our work shows that FED monotherapy can be an effective alternative for patients with EoE responsive to PPI monotherapy that may improve patient quality of life, suggesting alternative treatment options should be considered for monotherapy-responsive EoE.

Due to the detrimental consequences caused by cyberbullying, a great deal of research has been undertaken to propose effective techniques to resolve this reoccurring problem. The research presented in this paper is motivated by the fact that negative emotions can be caused by cyberbullying. This paper proposes cyberbullying detection models that are trained based on contextual, emotions and sentiment features. An Emotion Detection Model (EDM) was constructed using Twitter datasets that have been improved in terms of its annotations. Emotions and sentiment were extracted from cyberbullying datasets using EDM and lexicons based. Two cyberbullying datasets from Wikipedia and Twitter respectively were further improved by comprehensive annotation of emotion and sentiment features. The results show that anger, fear and guilt were the major emotions associated with cyberbullying. Subsequently, the extracted emotions were used as features in addition to contextual and sentiment features to train models for cyberbullying detection. The results demonstrate that using emotion features and sentiment has improved the performance of detecting cyberbullying by 0.5 to 0.6 recall. The proposed models also outperformed the state-of-the-art models by a 0.7 f1-score. The main contribution of this work is two-fold, which includes a comprehensive emotion-annotated dataset for cyberbullying detection, and an empirical proof of emotions as effective features for cyberbullying detection.

Abstract The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial is a prospective cohort study of nearly 155,000 U.S. volunteers aged 55–74 at enrollment in 1993–2001. We developed the PLCO Atlas Project, a large resource for multi-trait genome-wide association studies (GWAS), by genotyping participants with available DNA and genomic consent. Genotyping on high-density arrays and imputation was performed, and GWAS were conducted using a custom semi-automated pipeline. Association summary statistics were generated from a total of 110,562 participants of European, African and Asian ancestry. Application programming interfaces (APIs) and open-source software development kits (SKDs) enable exploring, visualizing and open data access through the PLCO Atlas GWAS Explorer website, promoting Findable, Accessible, Interoperable, and Re-usable (FAIR) principles. Currently the GWAS Explorer hosts association data for 90 traits and >78,000,000 genomic markers, focusing on cancer and cancer-related phenotypes. New traits will be posted as association data becomes available. The PLCO Atlas is a FAIR resource of high-quality genetic and phenotypic data with many potential reuse opportunities for cancer research and genetic epidemiology.

Myelofibrosis is a risk factor for the development of Acute Myeloid Leukaemia. Here, the authors carry out an integrated genomic investigation of 933 myelofibrosis patients, and identified interactions between germline and somatic variation in patients who required haematopoietic cell transplantation.

ABSTRACT The human fecal and oral microbiome may play a role in the etiology of breast cancer through modulation of endogenous estrogen metabolism. This study aimed to investigate associations of circulating estrogens and estrogen metabolites with the fecal and oral microbiome in postmenopausal African women. A total of 117 women with fecal (N = 110) and oral (N = 114) microbiome data measured by 16S rRNA gene sequencing, and estrogens and estrogen metabolites data measured by liquid chromatography tandem mass spectrometry were included. The outcomes were measures of the microbiome and the independent variables were the estrogens and estrogen metabolites. Estrogens and estrogen metabolites were associated with the fecal microbial Shannon index (global P