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BackgroundNoninvasive respiratory support modalities are common alternatives to mechanical ventilation in acute hypoxemic respiratory failure. However, studies historically compare noninvasive respiratory support to conventional oxygen rather than mechanical ventilation. In this study, we compared outcomes in patients with acute hypoxemic respiratory failure treated initially with noninvasive respiratory support to patients treated initially with invasive mechanical ventilation.MethodsThis is a retrospective observational cohort study between January 1, 2018 and December 31, 2019 at a large healthcare network in the United States. We used a validated phenotyping algorithm to classify adult patients (≥18 years) with eligible International Classification of Diseases codes into two cohorts: those treated initially with noninvasive respiratory support or those treated invasive mechanical ventilation only. The primary outcome was time-to-in-hospital death analyzed using an inverse probability of treatment weighted Cox model adjusted for potential confounders. Secondary outcomes included time-to-hospital discharge alive. A secondary analysis was conducted to examine potential differences between noninvasive positive pressure ventilation and nasal high flow.ResultsDuring the study period, 3177 patients met inclusion criteria (40% invasive mechanical ventilation, 60% noninvasive respiratory support). Initial noninvasive respiratory support was not associated with a decreased hazard of in-hospital death (HR: 0.65, 95% CI: 0.35-1.2), but was associated with an increased hazard of discharge alive (HR: 2.26, 95% CI: 1.92-2.67). In-hospital death varied between the nasal high flow (HR 3.27, 95% CI: 1.43-7.45) and noninvasive positive pressure ventilation (HR 0.52, 95% CI 0.25-1.07), but both were associated with increased likelihood of discharge alive (nasal high flow HR 2.12, 95 CI: 1.25-3.57; noninvasive positive pressure ventilation HR 2.29, 95% CI: 1.92-2.74).ConclusionsThese data show that noninvasive respiratory support is not associated with reduced hazards of in-hospital death but is associated with hospital discharge alive.

Households are a significant source of SARS-CoV-2 transmission, even during periods of low community-level spread. Comparing household transmission rates by SARS-CoV-2 variant may provide relevant information about current risks and prevention strategies. This investigation aimed to estimate differences in household transmission risk comparing the SARS-CoV-2 Delta and Omicron variants using data from contact tracing and interviews conducted from November 2021 through February 2022 in five U.S. public health jurisdictions (City of Chicago, Illinois; State of Connecticut; City of Milwaukee, Wisconsin; State of Maryland; and State of Utah). Generalized estimating equations were used to estimate attack rates and relative risks for index case and household contact characteristics. Data from 848 households, including 2,622 individuals (median household size = 3), were analyzed. Overall transmission risk was similar in households with Omicron (attack rate = 47.0%) compared to Delta variant (attack rate = 48.0%) circulation. In the multivariable model, a pattern of increased transmission risk was observed with increased time since a household contact's last COVID-19 vaccine dose in Delta households, although confidence intervals overlapped (0-3 months relative risk = 0.8, confidence interval: 0.5-1.2; 4-7 months relative risk = 1.3, 0.9-1.8; ≥8 months relative risk = 1.2, 0.7-1.8); no pattern was observed in Omicron households. Risk for household contacts of symptomatic index cases was twice that of household contacts of asymptomatic index cases (relative risk = 2.0, 95% confidence interval: 1.4-2.9), emphasizing the importance of symptom status, regardless of variant. Uniquely, this study adjusted risk estimates for several index case and household contact characteristics and demonstrates that few characteristics strongly dictate risk, likely reflecting the complexity of the biological and social factors which combine to impact SARS-CoV-2 transmission.

PurposeGlobal prevalence of tinnitus (15%) is rising, indicating an increase in patients seeking help for this common symptom and potentially affecting the accessibility of care. The aim of this retrospective study is twofold; describing the morbidity trends and healthcare utilization among patients with recorded tinnitus at Dutch general practices (GP), and comparing overall healthcare utilization before and after tinnitus to similar patients without recorded tinnitus.Patients and methodsRoutine electronic health records data from general practices participating in Nivel Primary Care Database were used to describe trends in age- and sex-specific incidence, contact prevalence and healthcare utilization (contacts, prescriptions, and referrals to secondary care) for tinnitus from 2012 to 2021. Patients with tinnitus were matched (on sex, age, general practice) to patients without tinnitus (1:2). Healthcare use one year before and after a first GP contact for tinnitus (period) was analyzed with negative binominal (number of contacts) and logistic regression (prescriptions or referrals).ResultsBetween 2012 and 2021, tinnitus incidence increased by 33% (3.3 to 4.4 per 1000 person-years). The largest increase was observed among 20-44-years (2.6 to 3.8 per 1000 person-years). One year after the first GP contact for tinnitus, patients with tinnitus utilized healthcare more frequently than patients without tinnitus. The referral rate increased the most (OR 1.99, 95%CI 1.83-2.16). The year before tinnitus at the GP, patients with tinnitus had more often GP consultations (IRR 1.16, 95%CI 1.12-1.19) and referrals (OR 1.09, 95%CI 1.01-1.18) than patients without tinnitus.ConclusionAlthough GPs saw an increased number of patients with tinnitus, absolute numbers of patients remained low. Patients' healthcare use increased after the first tinnitus complaint at the GP, mainly for secondary care. Yet, they already used healthcare services more frequently than similar patients without tinnitus. Insight into possible explanations for these health disparities could contribute to targeted prevention.

While molecular testing is recommended for symptomatic patients suspected of having coronavirus disease 2019 (COVID-19), limited data are available examining real-world use of tests for severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the impact of SARS-CoV-2 testing on patient outcomes. In this retrospective cohort study using de-identified administrative claims data in the Optum Labs Data Warehouse, we identified 2 groups of patients with ≥1 outpatient claims with a procedure code for SARS-CoV-2 testing between January 2021 and September 2022. Group 1 had ≥1 claims with CPT code 0240U or 0241U ("Xpert Xpress") (N = 51,602); Group 2 had ≥1 claims for laboratory-based molecular testing (N = 317,192). Outcomes assessed on the identification date and through the 90-day follow-up included claims evidence of use of SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) tests, diagnosis of active COVID-19, influenza, or RSV, and use of treatments (antivirals for COVID-19, influenza, and RSV and other treatments for COVID-19 and RSV). Patients in Group 1 had fewer tests for SARS-CoV-2, influenza, or RSV (mean ± standard deviation 1.6±1.4 versus 2.6±2.6, standardized difference -0.45), faster time to diagnosis of COVID-19 (median 0 versus 4 days, standardized difference -0.27) or influenza (median 0 versus 5 days, standardized difference -0.74), and faster time to treatment of COVID-19, influenza, or RSV (median 1 versus 5 days, standardized difference 0.16) than patients in Group 2. In this nationwide real-world study of outpatient testing, use of point-of-care molecular multiplex SARS-CoV-2 testing resulted in fewer claims for SARS-CoV-2, influenza, and RSV tests, faster time to diagnosis, and faster time to treatment than laboratory-based molecular testing.

In the emerging field of whole-brain imaging at single-cell resolution, which represents one of the new frontiers to investigate the link between brain activity and behavior, the nematode Caenorhabditis elegans offers one of the most characterized models for systems neuroscience. Whole-brain recordings consist of 3D time series of volumes that need to be processed to obtain neuronal traces. Current solutions for this task are either computationally demanding or limited to specific acquisition setups. Here, we propose See Elegans, a direct programming algorithm that combines different techniques for automatic neuron segmentation and tracking without the need for the RFP channel, and we compare it with other available algorithms. While outperforming them in most cases, our solution offers a novel method to guide the identification of a subset of head neurons based on position and activity. The built-in interface allows the user to follow and manually curate each of the processing steps. See Elegans is thus a simple-to-use interface aimed at speeding up the post-processing of volumetric calcium imaging recordings while maintaining a high level of accuracy and low computational demands. (Contact: enrico.lanza@iit.it).

BackgroundNoninvasive respiratory support modalities are common alternatives to mechanical ventilation in acute hypoxemic respiratory failure. However, studies historically compare noninvasive respiratory support to conventional oxygen rather than mechanical ventilation. In this study, we compared outcomes in patients with acute hypoxemic respiratory failure treated initially with noninvasive respiratory support to patients treated initially with invasive mechanical ventilation.MethodsThis is a retrospective observational cohort study between January 1, 2018 and December 31, 2019 at a large healthcare network in the United States. We used a validated phenotyping algorithm to classify adult patients (≥18 years) with eligible International Classification of Diseases codes into two cohorts: those treated initially with noninvasive respiratory support or those treated invasive mechanical ventilation only. The primary outcome was time-to-in-hospital death analyzed using an inverse probability of treatment weighted Cox model adjusted for potential confounders. Secondary outcomes included time-to-hospital discharge alive. A secondary analysis was conducted to examine potential differences between noninvasive positive pressure ventilation and nasal high flow.ResultsDuring the study period, 3177 patients met inclusion criteria (40% invasive mechanical ventilation, 60% noninvasive respiratory support). Initial noninvasive respiratory support was not associated with a decreased hazard of in-hospital death (HR: 0.65, 95% CI: 0.35-1.2), but was associated with an increased hazard of discharge alive (HR: 2.26, 95% CI: 1.92-2.67). In-hospital death varied between the nasal high flow (HR 3.27, 95% CI: 1.43-7.45) and noninvasive positive pressure ventilation (HR 0.52, 95% CI 0.25-1.07), but both were associated with increased likelihood of discharge alive (nasal high flow HR 2.12, 95 CI: 1.25-3.57; noninvasive positive pressure ventilation HR 2.29, 95% CI: 1.92-2.74).ConclusionsThese data show that noninvasive respiratory support is not associated with reduced hazards of in-hospital death but is associated with hospital discharge alive.

The New York Bight is an ecologically and economically important marine region along the U.S. Atlantic Coast. Extensive assessments have characterized the habitats and biota in this ecosystem; however, most have focused on fishes, benthic habitats, and human impacts. To investigate the spatial and temporal occurrence of whales in this region, we conducted a three-year passive acoustic monitoring survey that documented the acoustic presence of five baleen whale species that occur within the New York Bight and are of conservation concern: North Atlantic right whales (Eubalaena glacialis), humpback whales (Megaptera novaeangliae), fin whales (Balaenoptera physalus), sei whales (Balaenoptera borealis), and blue whales (Balaenoptera musculus). Data were recorded with 14 bottom-mounted acoustic sensors across the continental shelf between 2017 and 2020. Right whales were detected across all seasons, with most detections in autumn closer to New York Harbor and spring detections at sites closer to the continental shelf edge. Humpbacks were detected during all months of the year with varying distribution of detections across the shelf. The year-round presence of right and humpback whales challenges previous hypotheses that this region is primarily a stopover location along their migration paths. Fin whales were detected at all sites on most days. Sei whales were detected primarily during the spring at offshore sites. Blue whales were detected in the winter at sites closer to the continental shelf edge, but were rare. These data improve our understanding of baleen whale seasonal occurrences in the New York Bight and can inform monitoring and mitigation efforts associated with the management and conservation of these species. [ABSTRACT FROM AUTHOR]

Households are a significant source of SARS-CoV-2 transmission, even during periods of low community-level spread. Comparing household transmission rates by SARS-CoV-2 variant may provide relevant information about current risks and prevention strategies. This investigation aimed to estimate differences in household transmission risk comparing the SARS-CoV-2 Delta and Omicron variants using data from contact tracing and interviews conducted from November 2021 through February 2022 in five U.S. public health jurisdictions (City of Chicago, Illinois; State of Connecticut; City of Milwaukee, Wisconsin; State of Maryland; and State of Utah). Generalized estimating equations were used to estimate attack rates and relative risks for index case and household contact characteristics. Data from 848 households, including 2,622 individuals (median household size = 3), were analyzed. Overall transmission risk was similar in households with Omicron (attack rate = 47.0%) compared to Delta variant (attack rate = 48.0%) circulation. In the multivariable model, a pattern of increased transmission risk was observed with increased time since a household contact's last COVID-19 vaccine dose in Delta households, although confidence intervals overlapped (0–3 months relative risk = 0.8, confidence interval: 0.5–1.2; 4–7 months relative risk = 1.3, 0.9–1.8; ≥8 months relative risk = 1.2, 0.7–1.8); no pattern was observed in Omicron households. Risk for household contacts of symptomatic index cases was twice that of household contacts of asymptomatic index cases (relative risk = 2.0, 95% confidence interval: 1.4–2.9), emphasizing the importance of symptom status, regardless of variant. Uniquely, this study adjusted risk estimates for several index case and household contact characteristics and demonstrates that few characteristics strongly dictate risk, likely reflecting the complexity of the biological and social factors which combine to impact SARS-CoV-2 transmission. [ABSTRACT FROM AUTHOR]

Background Death certificates are crucial for understanding population health trends including the burden of disease mortality. Accurate reporting of causes of death on these records is necessary in order to implement adequate public health policies and fund disease research. While there is evidence that Alzheimer disease and unspecified dementia are prevalent among people with Down syndrome, a 2014 Centers for Disease Control and Prevention (CDC) rule change instructing that Down syndrome should be reported as the underlying cause of death in instances when death occurred from Alzheimer disease or unspecified dementia threatens the accuracy and the utility of death certificates for this population. Methods This study used 15 years (2005–2019) of US death certificate data for adults with and without Down syndrome. We compare the mortality burden due to Alzheimer disease and unspecified dementia prior to and after amending death certificates that report Down syndrome as the underlying cause of death. Results When analyzing death certificates without addressing the reporting of Down syndrome as the underlying cause of death, rates of death due to Alzheimer disease and dementia ranked as the third leading cause of death for both adults with and without Down syndrome. After amending death certificates that reported Down syndrome as the underlying cause of death, Alzheimer disease and dementia were the leading cause of death among those with Down syndrome, occurring 2.7 times more in adults with compared to without Down syndrome. Conclusion The findings of this study highlight the importance of accurate mortality data for studying and addressing population health trends. The current practice of reporting Down syndrome as the underlying cause of death rather than the disease responsible for death needs to be reconsidered and modified. If not, people with Down syndrome may be further marginalized within dementia related support and research.

Understanding metabolism in the pathogen Candida glabrata is key to identifying new targets for antifungals. The thiamine biosynthetic (THI) pathway is partially defective in C. glabrata, but the transcription factor CgPdc2 upregulates some thiamine biosynthetic and transport genes. One of these genes encodes a recently evolved thiamine pyrophosphatase (CgPMU3) that is critical for accessing external thiamine. Here, we demonstrate that CgPdc2 primarily regulates THI genes. In Saccharomyces cerevisiae, Pdc2 regulates both THI and pyruvate decarboxylase (PDC) genes, with PDC proteins being a major thiamine sink. Deletion of PDC2 is lethal in S. cerevisiae in standard growth conditions, but not in C. glabrata. We uncover cryptic cis elements in C. glabrata PDC promoters that still allow for regulation by ScPdc2, even when that regulation is not apparent in C. glabrata. C. glabrata lacks Thi2, and it is likely that inclusion of Thi2 into transcriptional regulation in S. cerevisiae allows for a more complex regulation pattern and regulation of THI and PDC genes. We present evidence that Pdc2 functions independent of Thi2 and Thi3 in both species. The C-terminal activation domain of Pdc2 is intrinsically disordered and critical for species differences. Truncation of the disordered domains leads to a gradual loss of activity. Through a series of cross species complementation assays of transcription, we suggest that there are multiple Pdc2-containing complexes, and C. glabrata appears to have the simplest requirement set for THI genes, except for CgPMU3. CgPMU3 has different cis requirements, but still requires Pdc2 and Thi3 to be upregulated by thiamine starvation. We identify the minimal region sufficient for thiamine regulation in CgTHI20, CgPMU3, and ScPDC5 promoters. Defining the cis and trans requirements for THI promoters should lead to an understanding of how to interrupt their upregulation and provide targets in metabolism for antifungals.

Purpose: Global prevalence of tinnitus (15%) is rising, indicating an increase in patients seeking help for this common symptom and potentially affecting the accessibility of care. The aim of this retrospective study is twofold; describing the morbidity trends and healthcare utilization among patients with recorded tinnitus at Dutch general practices (GP), and comparing overall healthcare utilization before and after tinnitus to similar patients without recorded tinnitus. Patients and methods: Routine electronic health records data from general practices participating in Nivel Primary Care Database were used to describe trends in age- and sex-specific incidence, contact prevalence and healthcare utilization (contacts, prescriptions, and referrals to secondary care) for tinnitus from 2012 to 2021. Patients with tinnitus were matched (on sex, age, general practice) to patients without tinnitus (1:2). Healthcare use one year before and after a first GP contact for tinnitus (period) was analyzed with negative binominal (number of contacts) and logistic regression (prescriptions or referrals). Results: Between 2012 and 2021, tinnitus incidence increased by 33% (3.3 to 4.4 per 1000 person-years). The largest increase was observed among 20-44-years (2.6 to 3.8 per 1000 person-years). One year after the first GP contact for tinnitus, patients with tinnitus utilized healthcare more frequently than patients without tinnitus. The referral rate increased the most (OR 1.99, 95%CI 1.83–2.16). The year before tinnitus at the GP, patients with tinnitus had more often GP consultations (IRR 1.16, 95%CI 1.12–1.19) and referrals (OR 1.09, 95%CI 1.01–1.18) than patients without tinnitus. Conclusion: Although GPs saw an increased number of patients with tinnitus, absolute numbers of patients remained low. Patients' healthcare use increased after the first tinnitus complaint at the GP, mainly for secondary care. Yet, they already used healthcare services more frequently than similar patients without tinnitus. Insight into possible explanations for these health disparities could contribute to targeted prevention. [ABSTRACT FROM AUTHOR]

While molecular testing is recommended for symptomatic patients suspected of having coronavirus disease 2019 (COVID-19), limited data are available examining real-world use of tests for severe acute respiratory syndrome coronavirus (SARS-CoV-2) and the impact of SARS-CoV-2 testing on patient outcomes. In this retrospective cohort study using de-identified administrative claims data in the Optum Labs Data Warehouse, we identified 2 groups of patients with ≥1 outpatient claims with a procedure code for SARS-CoV-2 testing between January 2021 and September 2022. Group 1 had ≥1 claims with CPT code 0240U or 0241U ("Xpert Xpress") (N = 51,602); Group 2 had ≥1 claims for laboratory-based molecular testing (N = 317,192). Outcomes assessed on the identification date and through the 90-day follow-up included claims evidence of use of SARS-CoV-2, influenza, and respiratory syncytial virus (RSV) tests, diagnosis of active COVID-19, influenza, or RSV, and use of treatments (antivirals for COVID-19, influenza, and RSV and other treatments for COVID-19 and RSV). Patients in Group 1 had fewer tests for SARS-CoV-2, influenza, or RSV (mean ± standard deviation 1.6±1.4 versus 2.6±2.6, standardized difference -0.45), faster time to diagnosis of COVID-19 (median 0 versus 4 days, standardized difference -0.27) or influenza (median 0 versus 5 days, standardized difference -0.74), and faster time to treatment of COVID-19, influenza, or RSV (median 1 versus 5 days, standardized difference 0.16) than patients in Group 2. In this nationwide real-world study of outpatient testing, use of point-of-care molecular multiplex SARS-CoV-2 testing resulted in fewer claims for SARS-CoV-2, influenza, and RSV tests, faster time to diagnosis, and faster time to treatment than laboratory-based molecular testing. [ABSTRACT FROM AUTHOR]

The pressure on land resources continuously increases not only with the rising demand for agricultural commodities, but also with the growing need for action on global challenges, such as biodiversity loss or climate change, where land plays a crucial role. Land saving as a strategy, where agricultural productivity is increased to allow a reduction of required cropland while sustaining production volumes and meeting demand, could address this trade-off. With our interdisciplinary model-based study, we globally assess regional potentials of land saving and analyze resulting effects on agricultural production, prices and trade. Thereby, different land saving strategies are investigated that (1) minimize required cropland (2) minimize spatial marginalization induced by land saving and (3) maximize the attainable profit. We find that current cropland requirements could be reduced between 37% and 48%, depending on the applied land saving strategy. The generally more efficient use of land would cause crop prices to fall in all regions, but also trigger an increase in global agricultural production of 2.8%. While largest land saving potentials occur in regions with high yield gaps, the impacts on prices and production are strongest in highly populated regions with already high pressure on land. Global crop prices and trade affect regional impacts of land saving on agricultural markets and can displace effects to spatially distant regions. Our results point out the importance of investigating the potentials and effects of land saving in the context of global markets within an integrative, global framework. The resulting land saving potentials can moreover reframe debates on global potentials for afforestation and carbon sequestration, as well as on how to reconcile agricultural production and biodiversity conservation and thus contribute to approaching central goals of the 21st century, addressed for example in the Sustainable Development Goals, the Paris Agreement or the post-2020 global biodiversity framework.

Aboriginal and Torres Strait Islander women have lower participation in Australia's National Cervical Screening Program than other Australian women. Under-screened (including never screened) women's voices are rarely heard in research evidence, despite being a priority group for interventions to increase cervical screening participation. This study aimed to describe under-screened Aboriginal and Torres Strait Islander women's perspectives on cervical screening. Participants were 29 under-screened (women who had either never screened, had not screened in the previous five years or had recently screened in the past three months after more than five years) Aboriginal and Torres Strait Islander women from five communities across three states/territories. Female Aboriginal and Torres Strait Islander researchers Yarned with women about why they did not participate in screening and how to improve screening. Yarning is an Indigenous qualitative research method in which relationships and trust facilitate culturally safe conversation. Transcripts were analysed thematically. The proportion of eligible women who screened within 30 days after the Yarn was calculated. We identified four themes describing how the harms outweighed the benefits of cervical screening for under-screened women. These were: 1) distress, discomfort, and trauma; 2) lack of privacy and control; 3) complicated relationships with health care providers (HCPs); and 4) pressured, insensitive, and/or culturally unsafe communication from HCPs. Under-screened women who had recently screened had maintained privacy and control through self-collection and had experienced trauma-informed and empathetic care from their HCPs. While we cannot unequivocally attribute women's subsequent participation in screening to their involvement in this study, it is notable that one third of eligible under-screened women were screened within 30 days after the Yarn. Enhancing privacy, implementing trauma-informed approaches to care and sensitivity to the clinician-client relationship dynamics could enhance women's sense of comfort in, and control over, the screening procedure. The opportunity to Yarn about cervical screening and self-collection may address these issues and support progress toward cervical cancer elimination in Australia.

Background Racial/ethnic disparities during the first six months of the COVID-19 pandemic led to differences in COVID-19 testing and adverse outcomes. We examine differences in testing and adverse outcomes by race/ethnicity and sex across a geographically diverse and system-based COVID-19 cohort collaboration. Methods Observational study among adults (≥18 years) within six US cohorts from March 1, 2020 to August 31, 2020 using data from electronic health record and patient reporting. Race/ethnicity and sex as risk factors were primary exposures, with health system type (integrated health system, academic health system, or interval cohort) as secondary. Proportions measured SARS-CoV-2 testing and positivity; attributed hospitalization and death related to COVID-19. Relative risk ratios (RR) with 95% confidence intervals quantified associations between exposures and main outcomes. Results 5,958,908 patients were included. Hispanic patients had the highest proportions of SARS-CoV-2 testing (16%) and positivity (18%), while Asian/Pacific Islander patients had the lowest portions tested (11%) and White patients had the lowest positivity rates (5%). Men had a lower likelihood of testing (RR = 0.90 [0.89–0.90]) and a higher positivity risk (RR = 1.16 [1.14–1.18]) compared to women. Black patients were more likely to have COVID-19-related hospitalizations (RR = 1.36 [1.28–1.44]) and death (RR = 1.17 [1.03–1.32]) compared with White patients. Men were more likely to be hospitalized (RR = 1.30 [1.16–1.22]) or die (RR = 1.70 [1.53–1.89]) compared to women. These racial/ethnic and sex differences were reflected in both health system types. Conclusions This study supports evidence of disparities by race/ethnicity and sex during the COVID-19 pandemic that persisted even in healthcare settings with reduced barriers to accessing care. Further research is needed to understand and prevent the drivers that resulted in higher burdens of morbidity among certain Black patients and men.

ENGRAILED 2 (En2), a homeobox transcription factor, functions as a patterning gene in the early development and connectivity of rodent hindbrain and cerebellum, and regulates neurogenesis and development of monoaminergic pathways. To further understand the neurobiological functions of En2, we conducted neuroanatomical expression profiling of En2 wildtype mice. RTQPCR assays demonstrated that En2 is expressed in adult brain structures including the somatosensory cortex, hippocampus, striatum, thalamus, hypothalamus and brainstem. Human genetic studies indicate that EN2 is associated with autism. To determine the consequences of En2 mutations on mouse behaviors, including outcomes potentially relevant to autism, we conducted comprehensive phenotyping of social, communication, repetitive, and cognitive behaviors. En2 null mutants exhibited robust deficits in reciprocal social interactions as juveniles and adults, and absence of sociability in adults, replicated in two independent cohorts. Fear conditioning and water maze learning were impaired in En2 null mutants. High immobility in the forced swim test, reduced prepulse inhibition, mild motor coordination impairments and reduced grip strength were detected in En2 null mutants. No genotype differences were found on measures of ultrasonic vocalizations in social contexts, and no stereotyped or repetitive behaviors were observed. Developmental milestones, general health, olfactory abilities, exploratory locomotor activity, anxiety-like behaviors and pain responses did not differ across genotypes, indicating that the behavioral abnormalities detected in En2 null mutants were not attributable to physical or procedural confounds. Our findings provide new insight into the role of En2 in complex behaviors and suggest that disturbances in En2 signaling may contribute to neuropsychiatric disorders marked by social and cognitive deficits, including autism spectrum disorders.

Can outside interventions foster socio-culturally diverse friendships? We executed a large field experiment that randomized the seating charts of 182 3rd through 8th grade classrooms (N = 2,966 students) for the duration of one semester. We found that being seated next to each other increased the probability of a mutual friendship from 15% to 22% on average. Furthermore, induced proximity increased the latent propensity toward friendship equally for all students, regardless of students’ dyadic similarity with respect to educational achievement, gender, and ethnicity. However, the probability of a manifest friendship increased more among similar than among dissimilar students—a pattern mainly driven by gender. Our findings demonstrate that a scalable light-touch intervention can affect face-to-face networks and foster diverse friendships in groups that already know each other, but they also highlight that transgressing boundaries, especially those defined by gender, remains an uphill battle.

DNA polymerases play essential functions in replication fork progression and genome maintenance. DNA lesions and drug-induced replication stress result in up-regulation and re-localization of specialized DNA polymerases η and κ. Although oncogene activation significantly alters DNA replication dynamics, causing replication stress and genome instability, little is known about DNA polymerase expression and regulation in response to oncogene activation. Here, we investigated the consequences of mutant H-RAS G12V overexpression on the regulation of DNA polymerases in h-TERT immortalized and SV40-transformed human cells. Focusing on DNA polymerases associated with the replication fork, we demonstrate that DNA polymerases are depleted in a temporal manner in response to H-RAS G12V overexpression. The polymerases targeted for depletion, as cells display markers of senescence, include the Pol α catalytic subunit (POLA1), Pol δ catalytic and p68 subunits (POLD1 and POLD3), Pol η, and Pol κ. Both transcriptional and post-transcriptional mechanisms mediate this response. Pol η (POLH) depletion is sufficient to induce a senescence-like growth arrest in human foreskin fibroblast BJ5a cells, and is associated with decreased Pol α expression. Using an SV-40 transformed cell model, we observed cell cycle checkpoint signaling differences in cells with H-RasG12V-induced polymerase depletion, as compared to Pol η-deficient cells. Our findings contribute to our understanding of cellular events following oncogene activation and cellular transformation.

BackgroundClimate change is expected to decrease food security globally. Many Indigenous communities have heightened sensitivity to climate change and food insecurity for multifactorial reasons including close relationships with the local environment and socioeconomic inequities which increase exposures and challenge adaptation to climate change. Pregnant women have additional sensitivity to food insecurity, as antenatal undernutrition is linked with poor maternal-infant health. This study examined pathways through which climate change influenced food security during pregnancy among Indigenous and non-Indigenous women in rural Uganda. Specific objectives were to characterize: 1) sensitivities to climate-associated declines in food security for pregnant Indigenous women; 2) women's perceptions of climate impacts on food security during pregnancy; and 3) changes in food security and maternal-infant health over time, as observed by women.MethodsUsing a community-based research approach, we conducted eight focus group discussions-four in Indigenous Batwa communities and four in non-Indigenous communities-in Kanungu District, Uganda, on the subject of climate and food security during pregnancy. Thirty-six women with ≥1 pregnancy participated. Data were analysed using a constant comparative method and thematic analysis.ResultsWomen indicated that food insecurity was common during pregnancy and had a bidirectional relationship with antenatal health issues. Food security was thought to be decreasing due to weather changes including extended droughts and unpredictable seasons harming agriculture. Women linked food insecurity with declines in maternal-infant health over time, despite improved antenatal healthcare. While all communities described food security struggles, the challenges Indigenous women identified and described were more severe.ConclusionsPrograms promoting women's adaptive capacity to climate change are required to improve food security for pregnant women and maternal-infant health. These interventions are particularly needed in Indigenous communities, which often face underlying health inequities. However, resiliency among mothers was strong and, with supports, they can reduce food security challenges in a changing climate.

BackgroundRheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients.Methods78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4+ helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT.ResultsFlow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3+ Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3+ Th17 cells were associated with bone density or bone microarchitecture measurements.ConclusionsOur findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3+ Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.

Pediatric firearm-related injuries pose a significant public health problem in the United States, yet the associated financial burden has not been well described. This is the first study examining national data on the cost of initial hospitalization for pediatric firearm-related injuries. In this retrospective review, the Healthcare Cost and Utilization Project Kids' Inpatient Database from the years 2003, 2006, 2009, and 2012 was used to identify all patients 18 years of age and under who were admitted with firearm-related injuries. We compared demographic and discharge-level data including injury severity score, hospital length of stay, income quartile, injury intent, and inflation-adjusted hospital costs across age groups (0-5, 6-9, 10-15, 16-18 years). There were approximately 4,753 pediatric firearm-related admissions each year, with a median hospitalization cost of $12,984 per patient. Annual initial hospitalization costs for pediatric firearm injuries were approximately $109 million during the study period. Pediatric firearm-related injuries predominately occured among older teenagers (74%, 16-18 years), males (89%), black individuals (55%), and those from the lowest income quartile (53%). We found significant cost variation based on patient race, income quartile, injury severity score, intent, hospital length of stay, disposition, and hospital region. Inflation-adjusted hospitalization costs have increased significantly over the study period (p < 0.001). Pediatric firearm-related injuries are a large financial burden to the United States healthcare system. There are significant variations in cost based on predictable factors like hospital length of stay and injury severity score; however, there are also substantial discrepancies based on hospital region, patient race, and income quartile that require further investigation.

BackgroundAging increases the risk of tuberculosis (TB) and its adverse outcomes, but most studies are based on secondary analyses, and few are in Hispanics. Diabetes is a risk factor for TB in adults, but its contribution in the elderly is unknown. We aimed to identify the role of diabetes and other risk factors for TB in elderly Hispanics.MethodsCross-sectional study among newly-diagnosed TB patients, recent contacts (ReC), or community controls (CoC) totaling 646 participants, including 183 elderly (>60 years; 43 TB, 80 ReC, 60 CoC) and 463 adults (18 to 50 years; 80 TB, 301 ReC and 82 CoC). Host characteristics associated with TB and latent Mycobacterium tuberculosis infection (LTBI) were identified in the elderly by univariable and confirmed by multivariable logistic regression.ResultsLTBI was more prevalent among the elderly CoC (55% vs. 23.2% in adults; pConclusionsWe report novel distinctions in TB risk factors in the elderly vs. adults, notably in diabetes and BCG vaccination at birth. Further studies are warranted to address disparities in this vulnerable, understudied population.

BackgroundSystematic reviews (SRs) are cornerstones of evidence-based medicine and have contributed significantly to breakthroughs since the 1980's. However, preclinical SRs remain relatively rare despite their many advantages. Since 2011 the Dutch health funding organisation (ZonMw) has run a grant scheme dedicated to promoting the training, coaching and conduct of preclinical SRs. Our study focuses on this funding scheme to investigate the relevance, effects and benefits of conducting preclinical SRs on researchers and their research.MethodsWe recruited researchers who attended funded preclinical SR workshops and who conducted, are still conducting, or prematurely stopped a SR with funded coaching. We gathered data using online questionnaires followed by semi-structured interviews. Both aimed to explore the impact of conducting a SR on researchers' subsequent work, attitudes, and views about their research field. Data-analysis was performed using Excel and ATLAS.ti.ResultsConducting preclinical SRs had two distinct types of impact. First, the researchers acquired new skills and insights, leading to a change in mindset regarding the quality of animal research. This was mainly seen in the way participants planned, conducted and reported their subsequent animal studies, which were more transparent and of a higher quality than their previous work. Second, participants were eager to share their newly acquired knowledge within their laboratories and to advocate for change within their research teams and fields of interest. In particular, they emphasised the need for preclinical SRs and improved experimental design within preclinical research, promoting these through education and published opinion papers.ConclusionBeing trained and coached in the conduct of preclinical SRs appears to be a contributing factor to many beneficial changes which will impact the quality of preclinical research in the long-term. Our findings suggest that this ZonMw funding scheme is helpful in improving the quality and transparency of preclinical research. Similar funding schemes should be encouraged, preferably by a broader group of funders or financers, in the future.

A non-invasive functional-brain-imaging system based on optically-pumped-magnetometers (OPM) is presented. The OPM-based magnetoencephalography (MEG) system features 20 OPM channels conforming to the subject's scalp. We have conducted two MEG experiments on three subjects: assessment of somatosensory evoked magnetic field (SEF) and auditory evoked magnetic field (AEF) using our OPM-based MEG system and a commercial MEG system based on superconducting quantum interference devices (SQUIDs). We cross validated the robustness of our system by calculating the distance between the location of the equivalent current dipole (ECD) yielded by our OPM-based MEG system and the ECD location calculated by the commercial SQUID-based MEG system. We achieved sub-centimeter accuracy for both SEF and AEF responses in all three subjects. Due to the proximity (12 mm) of the OPM channels to the scalp, it is anticipated that future OPM-based MEG systems will offer enhanced spatial resolution as they will capture finer spatial features compared to traditional MEG systems employing SQUIDs.

BackgroundEarly detection of breast cancer can improve survival rates and decrease mortality rates. This study investigates whether there are significant differences in participation in breast screening among women born in Muslim countries compared to women born in Non-Muslim countries and Australia.MethodsScreening data from January 1st, 2000 to December 31st, 2013 from the Breast Screen Victoria Registry (BSV) was linked with hospital records from the Victorian Admitted Episodes Dataset (VAED). Countries having more than 50% of their population as Muslim were categorised as Muslim countries. Age adjusted rates were calculated for women born in Muslim and Non-Muslim countries and compared with the Australian age adjusted rates. Logistic regression assessed the association between screening status and other factors which include country of birth, marital status, age and socio-economic status.ResultsWomen born in Muslim countries (Odds Ratio (OR) = 0.70, 95%CI = 0.68-0.72) and in other Non-Muslim countries (OR = 0.87, 95%CI = 0.86-0.88) had lower odds of participation in breast screening than Australian born women. Women aged 60-64 years (OR = 1.42, 95%CI = 1.40-1.44) had higher odds of participation in the BreastScreen program than 50-54 age group.ConclusionThis study provides valuable insights to understanding breast screening participation among women born in Muslim countries residing in Victoria. This population level study contributes to the broader knowledge of screening participation of women born in Muslim countries, an understudied population group in Australia and across the world. This study has implications for breast screening programs as it highlights the need for culturally sensitive approaches to support breast screening participation among women born in Muslim countries.

Failing to mitigate propagation of disease spread can result in dire economic consequences for agricultural networks. Pathogens like Porcine Epidemic Diarrhea virus, can quickly spread among producers. Biosecurity is designed to prevent infection transmission. When considering biosecurity investments, management must balance the cost of protection versus the consequences of contracting an infection. Thus, an examination of the decision making processes associated with investment in biosecurity is important for enhancing system wide biosecurity. Data gathered from experimental gaming simulations can provide insights into behavioral strategies and inform the development of decision support systems. We created an online digital experiment to simulate outbreak scenarios among swine production supply chains, where participants were tasked with making biosecurity investment decisions. In Experiment One, we quantified the risk associated with each participant's decisions and delineated three dominant categories of risk attitudes: risk averse, risk tolerant, and opportunistic. Each risk class exhibited unique approaches in reaction to risk and disease information. We also tested how information uncertainty affects risk aversion, by varying the amount of visibility of the infection as well as the amount of biosecurity implemented across the system. We found evidence that more visibility in the number of infected sites increases risk averse behaviors, while more visibility in the amount of neighboring biosecurity increased risk taking behaviors. In Experiment Two, we were surprised to find no evidence for differences in behavior of livestock specialists compared to Amazon Mechanical Turk participants. Our findings provide support for using experimental gaming simulations to study how risk communication affects behavior, which can provide insights towards more effective messaging strategies.

The National Cervical Screening Program (NCSP) in Australia underwent major changes on December 1st, 2017. The program changed from 2-yearly Pap testing for women aged 18-69 years to 5-yearly HPV testing for women aged 25-74 years including differential management pathways for oncogenic HPV 16/18 positive versus HPV non16/18 positive test results and the option of self-collection for under-screened women. We conducted a survey among cervical screening providers in primary care to assess their level of preparedness in undertaking cervical screening before (pre-renewal) and after (post-renewal) the new program was implemented. Surveys were conducted between 14th August and 30th November 2017 (pre-renewal) and 9th February and 26th October 2018 (post-renewal) among cervical screening providers who attended education sessions related to the new guidelines. Preparedness was assessed in three areas: 1) level of comfort implementing the new guidelines (7 questions), 2) level of confidence in their ability to convey information about the new guidelines (9 questions) and 3) level of agreement regarding access to resources to support implementation (11 questions). Proportions were calculated for each question response and pre- and post-renewal periods compared using generalised linear models. Open-ended questions related to anticipated barriers and ways to overcome barriers were also included in the questionnaires. Compared to the pre-renewal period, a higher proportion of practitioners in the post-renewal period were more comfortable offering routine screening to women ≥25 years (p = 0.005) and more confident explaining the rationale for not screening before 25 years (p = 0.015); confident explaining a positive HPV 16/18 (p = 0.04) and HPV non 16/18(p = 0.013) test result and were comfortable with not referring women with a positive HPV non 16/18 test result and low grade/negative cytology for colposcopy (p = 0.01). A higher proportion of Victorian practitioners in the post-renewal period sample were also comfortable (p = 0.04) and confident (p = 0.015) recommending self-collection to under-screened women and agreed that self-collection is a reliable test (p = 0.003). The most commonly reported suggestion was to provide information, education and communication materials to both patients and practitioners. Compared to the pre-renewal period, practitioners in the post-renewal period were better prepared to implement the renewed screening program. Healthcare providers require further support to implement the self-collection pathway.

Aboriginal and Torres Strait Islander (collectively, Indigenous Australian) women experience a higher burden of cervical cancer than other women. The National Cervical Screening Program (NCSP) is failing to meet the needs of Indigenous Australian women, resulting in many women not regularly participating in cervical screening. However, one third of Indigenous Australian women do participate in cervical screening. The reasons that some women in this population commence and continue to screen remain unheard but could provide insights to support women who currently do not participate. We aimed to describe Indigenous Australian women's experiences and views of participation in cervical screening by yarning (a culturally-appropriate interview technique) with 50 Indigenous Australian women aged 25-70 years who had completed cervical screening in the past five years, recruited via Primary Health Care Centres (PHCCs) from three jurisdictions. Aboriginal or Torres Strait Islander women researchers conducted the interviews. Thematic analysis identified six themes: screening as a means of staying strong and in control; overcoming fears, shame, and negative experiences of screening; needing to talk openly about screening; the value of trusting relationships with screening providers; logistical barriers; and overcoming privacy concerns for women employed at PHCCs. Despite describing screening as shameful, invasive, and uncomfortable, women perceived it as a way of staying healthy and exerting control over their health. This ultimately supported their participation and a sense of empowerment. Women valued open discussion about screening and strong relationships with health providers. We identified logistical barriers and specific barriers faced by women employed at PHCCs. This study is strengthened by a research approach that centred Indigenous Australian women's voices. Understanding the experiences of Indigenous Australian women who participate in screening will help screening providers support women to start and continue to screen regularly. Recommendations for practice are provided.

BackgroundAutoimmune conditions (AICs) and/or their treatment may alter risk of human papilloma virus (HPV) infection and females with AICs are therefore at an increased risk of cervical dysplasia. However, inclusion of these at-risk populations in cervical cancer screening and HPV-vaccination guidelines, are mostly lacking. This study aimed to determine the prevalence of cervical dysplasia in a wide range of AICs and compare that to HIV and immunocompetent controls to support the optimisation of cervical cancer preventive health measures.MethodsData linkage was used to match cervical screening episodes to emergency department records of females with AICs or HIV to immunocompetent controls over a 14-year period. The primary outcome was histologically confirmed high-grade cervical disease. Results, measured as rates by cytology and histology classification per 1,000 females screened, were analysed per disease group, and intergroup comparisons were performed.ResultsFemales with inflammatory bowel disease (2,683), psoriatic and enteropathic arthropathies (1,848), multiple sclerosis (MS) (1,426), rheumatoid arthritis (1,246), systemic lupus erythematosus and/or mixed connective tissue disease (SLE/MCTD) (702), HIV (44), and 985,383 immunocompetent controls were included. SLE/MCTD and HIV groups had greater rates of high-grade histological and cytological abnormalities compared to controls. Increased rates of low-grade cytological abnormalities were detected in all females with AICs, with the exception of the MS group.ConclusionsFemales with SLE/MCTD or HIV have increased rates of high-grade cervical abnormalities. The increased low-grade dysplasia rate seen in most females with AICs is consistent with increased HPV infection. These findings support expansion of cervical cancer preventative programs to include these at-risk females.

Insulin and insulin-like growth factors are longevity determinants that negatively regulate Forkhead box class O (FoxO) transcription factors. In C. elegans mutations that constitutively activate DAF-16, the ortholog of mammalian FoxO3a, extend lifespan by two-fold. While environmental insults induce DAF-16 activity in younger animals, it also becomes activated in an age-dependent manner in the absence of stress, modulating gene expression well into late adulthood. The mechanism by which DAF-16 activity is regulated during aging has not been defined. Since phosphorylation of DAF-16 generally leads to its inhibition, we asked whether phosphatases might be necessary for its increased transcriptional activity in adult C. elegans. We focused on the PP2A/4/6 subfamily of phosphoprotein phosphatases, members of which had been implicated to regulate DAF-16 under low insulin signaling conditions but had not been investigated during aging in wildtype animals. Using reverse genetics, we functionally characterized all C. elegans orthologs of human catalytic, regulatory, and scaffolding subunits of PP2A/4/6 holoenzymes in postreproductive adults. We found that PP2A complex constituents PAA-1 and PPTR-1 regulate DAF-16 transcriptional activity during aging and that they cooperate with the catalytic subunit LET-92 to protect adult animals from ultraviolet radiation. PP4 complex members PPH-4.1/4.2, and SMK-1 also appear to regulate DAF-16 in an age-dependent manner, and together with PPFR-2 they contribute to innate immunity. Interestingly, SUR-6 but no other subunit of the PP2A complex was necessary for the survival of pathogen-infected animals. Finally, we found that PP6 complex constituents PPH-6 and SAPS-1 contribute to host defense during aging, apparently without affecting DAF-16 transcriptional activity. Our studies indicate that a set of PP2A/4/6 complexes protect adult C. elegans from environmental stress, thus preserving healthspan. Therefore, along with their functions in cell division and development, the PP2A/4/6 phosphatases also appear to play critical roles later in life.

In the emerging field of whole-brain imaging at single-cell resolution, which represents one of the new frontiers to investigate the link between brain activity and behavior, the nematode Caenorhabditis elegans offers one of the most characterized models for systems neuroscience. Whole-brain recordings consist of 3D time series of volumes that need to be processed to obtain neuronal traces. Current solutions for this task are either computationally demanding or limited to specific acquisition setups. Here, we propose See Elegans, a direct programming algorithm that combines different techniques for automatic neuron segmentation and tracking without the need for the RFP channel, and we compare it with other available algorithms. While outperforming them in most cases, our solution offers a novel method to guide the identification of a subset of head neurons based on position and activity. The built-in interface allows the user to follow and manually curate each of the processing steps. See Elegans is thus a simple-to-use interface aimed at speeding up the post-processing of volumetric calcium imaging recordings while maintaining a high level of accuracy and low computational demands. (Contact: enrico.lanza@iit.it). [ABSTRACT FROM AUTHOR]

Connections between interindividual differences and people's behavior has been widely researched in various contexts, often by using top-down group comparisons to explain interindividual differences. In contrast, in this study, we apply a bottom-up approach in which we identify meaningful clusters in people's concerns about various areas of life (e.g., their own health, their financial situation, the environment). We apply a novel method, Dirichlet clustering, to large-scale longitudinal data from the German Socioeconomic Panel Study (SOEP) to investigate whether concerns of people living in Germany evaluated in 2010 (t0) cluster participants into robust and separable groups, and whether these groups vary regarding their party identification in 2017 (t0 + 7). Clustering results suggest a range of different groups with specific concern patterns. Some of these notably specific patterns of concerns indicate links to party identification. In particular, some patterns show an increased identification with smaller parties as the 'Bündnis 90/Die Grünen' ('Greens'), the left wing party 'Die Linke' ('The Left') or the right-wing party 'Alternative für Deutschland' ('Alternative for Germany', AfD). Considering that we identify as many as 37 clusters in total, among them at least six with clearly different party identification, it can also be concluded that the complexity of political concerns may be larger than has been assumed before.

Atlantic cod (Gadus morhua) is a species of great ecological and economical importance in the Baltic Sea. Here, two genetically differentiated stocks, the western and the eastern Baltic cod, display substantial mechanical mixing, hampering our understanding of cod ecology and impeding stock assessments and management. Based on whole-genome re-sequencing data from reference samples obtained from the study area, we designed two different panels of Single Nucleotide Polymorphisms markers (SNPs), which take into account the exceptional genome architecture of cod. A minimum panel of 20 diagnostic SNPs and an extended panel (20 diagnostic and 18 biologically informative SNPs, 38 in total) were developed and validated to distinguish unambiguously between the western and the eastern Baltic cod stocks and to enable studies of local adaptation to the specific environment in the Baltic Sea, respectively. We tested both panels on cod sampled from the southern Baltic Sea (n = 603) caught in 2015 and 2016. Genotyping results showed that catches from the mixing zone in the Arkona Sea, were composed of similar proportions of individuals of the western and the eastern stock. Catches from adjacent areas to the east, the Bornholm Basin and Gdańsk Deep, were exclusively composed of eastern Baltic cod, whereas catches from adjacent western areas (Belt Sea and Öresund) were composed of western Baltic cod. Interestingly, the two Baltic cod stocks showed strong genetic differences at loci associated with life-history trait candidate genes, highlighting the species' potential for ecological adaptation even at small geographical scales. The minimum and the extended panel of SNP markers presented in this study provide powerful tools for future applications in research and fisheries management to further illuminate the mixing dynamics of cod in the Baltic Sea and to better understand Baltic cod ecology.

BackgroundWe characterize the risk factors for delayed polio dose 1, diphtheria-tetanus-pertussis (DTP) dose 1, pentavalent dose 1, and measles dose 1 in Ethiopian infants. We also examine the interaction between institutional delivery and demographic factors on the birth doses of the BCG and polio vaccines to better understand factors influencing vaccination.MethodsUsing the 2011 Ethiopia Demographic and Health Survey, we calculated the distribution of the study population across different demographic and vaccination characteristics. We computed acceleration factors using a multivariable accelerated failure time model with a Weibull distribution to account for left and right censoring. For the birth doses, we further specified an interaction term between institutional delivery and every other a priori specified independent variable to test whether institutional delivery modifies sociodemographic disparities in vaccination timeliness.ResultsLow wealth status, home delivery, and ethnicity are risk factors for delayed vaccination of polio 1, DPT 1, pentavalent 1, and measles 1. Religion is a risk factor for measles 1 vaccination delay and rural residence are risk factors for delayed DPT1 and polio 1 doses. For birth doses of polio and BCG, institutional delivery attenuated many sociodemographic disparities in vaccination delay, except for urbanicity, which showed rural dwellers with more delay than urban dwellers with an institutional vs home birth.ConclusionsLess delayed vaccination among children with institutional deliveries highlights the importance of perinatal care and the potential for promoting healthy behaviors to parents. Persistent disparities between urban and rural residents, even among those with institutional births, can be targeted for future interventions. Timely vaccination is key to prevention of unnecessary childhood mortality.

The visual color-word Stroop task is widely used in clinical and research settings as a measure of cognitive control. Numerous neuroimaging studies have used color-word Stroop tasks to investigate the neural resources supporting cognitive control, but to our knowledge all have used unimodal (typically visual) Stroop paradigms. Thus, it is possible that this classic measure of cognitive control is not capturing the resources involved in multisensory cognitive control. The audiovisual integration and crossmodal correspondence literatures identify regions sensitive to congruency of auditory and visual stimuli, but it is unclear how these regions relate to the unimodal cognitive control literature. In this study we aimed to identify brain regions engaged by crossmodal cognitive control during an audiovisual color-word Stroop task, and how they relate to previous unimodal Stroop and audiovisual integration findings. First, we replicated previous behavioral audiovisual Stroop findings in an fMRI-adapted audiovisual Stroop paradigm: incongruent visual information increased reaction time towards an auditory stimulus and congruent visual information decreased reaction time. Second, we investigated the brain regions supporting cognitive control during an audiovisual color-word Stroop task using fMRI. Similar to unimodal cognitive control tasks, a left superior parietal region exhibited an interference effect of visual information on the auditory stimulus. This superior parietal region was also identified using a standard audiovisual integration localizing procedure, indicating that audiovisual integration resources are sensitive to cognitive control demands. Facilitation of the auditory stimulus by congruent visual information was found in posterior superior temporal cortex, including in the posterior STS which has been found to support audiovisual integration. The dorsal anterior cingulate cortex, often implicated in unimodal Stroop tasks, was not modulated by the audiovisual Stroop task. Overall the findings indicate that an audiovisual color-word Stroop task engages overlapping resources with audiovisual integration and overlapping but distinct resources compared to unimodal Stroop tasks.

Timely diagnosis of tuberculosis (TB) is limited in Ethiopia. We evaluated the performance of a low technology, thin layer agar, Mycobacterium tuberculosis (M.tb) culture color plate (TB-CX) test with concurrent drug susceptibility testing (DST) to isoniazid (INH), rifampin (RIF), and pyrazinamide (PZA) directly from sputum specimens. Patients undergoing examination for TB and multidrug-resistant (MDR)-TB were enrolled in Addis Ababa, Ethiopia from March 2016 to February 2017. All subjects received a GeneXpert MTB/RIF PCR test. TB-CX test results were compared to reference Löwenstein-Jensen (LJ) culture for M.tb detection and DST for susceptibility to INH and RIF. Kappa statistic was applied to test agreement between results for TB-CX test and the reference methods, a cut-off Kappa value of 0.75 was considered as high level of agreements. A total of 137 participants were analyzed: 88 (64%) were new TB cases, 49 (36%) were re-treatment cases. The TB-CX test detected M.tb and DST in an average of 13 days compared to 50 days for the conventional DST result. The sensitivity and specificity of the TB-CX test for detecting M.tb were 94% and 98%, respectively (concordance, 96%; kappa 0.91). The sensitivity of the TB-CX test to detect drug resistance to INH, RIF, and MDR-TB was 91%, 100%, and 90% respectively. The specificity of the TB-CX test for detecting INH, RIF, and MDR-TB was 94%, 40%, and 94% respectively. Overall agreement between TB-CX test and LJ DST for detection of MDR-TB was 93%. The TB-CX test showed strong agreement with the GeneXpert test for detecting M.tb (89%, kappa 0.76) but low agreement for the detection of RIF resistance (57%, kappa 0.28). The TB-CX test was found to be a good alternative method for screening of TB and selective drug resistant-TB in a timely and cost-efficient manner.

Shape Up Under 5 (SUU5) was a two-year early childhood obesity prevention pilot study in Somerville, Massachusetts (2015-2017) designed to test a novel conceptual framework called Stakeholder-driven Community Diffusion. For whole-of-community interventions, this framework posits that diffusion of stakeholders' knowledge about and engagement with childhood obesity prevention efforts through their social networks will improve the implementation of health-promoting policy and practice changes intended to reduce obesity risk. SUU5 used systems science methods (agent-based modeling, group model building, social network analysis) to design, facilitate, and evaluate the work of 16 multisector stakeholders ('the Committee'). In this paper, we describe the design and methods of SUU5 using the conceptual framework: the approach to data collection, and methods and rationale for study inputs, activities and evaluation, which together may further our understanding of the hypothesized processes within Stakeholder-driven Community Diffusion. We also present a generalizable conceptual framework for addressing childhood obesity and similar complex public health issues through whole-of-community interventions.

Livestock industries are vulnerable to disease threats, which can cost billions of dollars and have substantial negative social ramifications. Losses are mitigated through increased use of disease-related biosecurity practices, making increased biosecurity an industry goal. Currently, there is no industry-wide standard for sharing information about disease incidence or on-site biosecurity strategies, resulting in uncertainty regarding disease prevalence and biosecurity strategies employed by industry stakeholders. Using an experimental simulation game, with primarily student participants, we examined willingness to invest in biosecurity when confronted with disease outbreak scenarios. We varied the scenarios by changing the information provided about 1) disease incidence and 2) biosecurity strategy or response by production facilities to the threat of disease. Here we show that willingness to invest in biosecurity increases with increased information about disease incidence, but decreases with increased information about biosecurity practices used by nearby facilities. Thus, the type or context of the uncertainty confronting the decision maker may be a major factor influencing behavior. Our findings suggest that policies and practices that encourage greater sharing of disease incidence information should have the greatest benefit for protecting herd health.

[This corrects the article DOI: 10.1371/journal.pone.0212944.].

Visual object recognition is a complex skill that relies on the interaction of many spatially distinct and specialized visual areas in the human brain. One tool that can help us better understand these specializations and interactions is a set of visual stimuli that do not differ along low-level dimensions (e.g., orientation, contrast) but do differ along high-level dimensions, such as whether a real-world object can be detected. The present work creates a set of line segment-based images that are matched for luminance, contrast, and orientation distribution (both for single elements and for pair-wise combinations) but result in a range of object and non-object percepts. Image generation started with images of isolated objects taken from publicly available databases and then progressed through 3-stages: a computer algorithm generating 718 candidate images, expert observers selecting 217 for further consideration, and naïve observers performing final ratings. This process identified a set of 100 images that all have the same low-level properties but cover a range of recognizability (proportion of naïve observers (N = 120) who indicated that the stimulus "contained a known object") and semantic stability (consistency across the categories of living, non-living/manipulable, and non-living/non-manipulable when the same observers named "known" objects). Stimuli are available at https://github.com/caolman/FAOT.git.

Little is known about the impact of comorbidity on cervical cancer survival in Australian women, including whether Indigenous women's higher prevalence of comorbidity contributes to their lower survival compared to non-Indigenous women.Data for cervical cancers diagnosed in 2003-2012 were extracted from six Australian state-based cancer registries and linked to hospital inpatient records to identify comorbidity diagnoses. Five-year cause-specific and all-cause survival probabilities were estimated using the Kaplan-Meier method. Flexible parametric models were used to estimate excess cause-specific mortality by Charlson comorbidity index score (0,1,2+), for Indigenous women compared to non-Indigenous women.Of 4,467 women, Indigenous women (4.4%) compared to non-Indigenous women had more comorbidity at diagnosis (score ≥1: 24.2% vs. 10.0%) and lower five-year cause-specific survival (60.2% vs. 76.6%). Comorbidity was associated with increased cervical cancer mortality for non-Indigenous women, but there was no evidence of such a relationship for Indigenous women. There was an 18% reduction in the Indigenous: non-Indigenous hazard ratio (excess mortality) when comorbidity was included in the model, yet this reduction was not statistically significant. The excess mortality for Indigenous women was only evident among those without comorbidity (Indigenous: non-Indigenous HR 2.5, 95%CI 1.9-3.4), indicating that factors other than those measured in this study are contributing to the differential. In a subgroup of New South Wales women, comorbidity was associated with advanced-stage cancer, which in turn was associated with elevated cervical cancer mortality.Survival was lowest for women with comorbidity. However, there wasn't a clear comorbidity-survival gradient for Indigenous women. Further investigation of potential drivers of the cervical cancer survival differentials is warranted.The results highlight the need for cancer care guidelines and multidisciplinary care that can meet the needs of complex patients. Also, primary and acute care services may need to pay more attention to Indigenous Australian women who may not obviously need it (i.e. those without comorbidity).

Asymptomatic colonization with extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae has been described for humans, various mammal species, and birds. Here, antimicrobial resistant bacteria were recovered from dog feces originating in Germany, Kosovo, Afghanistan, Croatia, and Ukraine, with a subset of mostly E. coli isolates obtained from a longitudinal collection over twelve months. In vitro antimicrobial resistance testing revealed various patterns of resistance against single or all investigated beta-lactam antibiotics, with none of the 101 isolates resistant against two tested carbapenem antibiotics. Whole genome sequence analysis revealed bacteria species-specific patterns for 23 antimicrobial resistance coding DNA sequences (CDS) that were unapparent from the in vitro analysis alone. Phylogenetic analysis of single nucleotide polymorphisms (SNP) revealed clonal bacterial isolates originating from different dogs, suggesting transmission between dogs in the same community. However, individual resistant E. coli clones were not detected over a period longer than seven days. Multi locus sequence typing (MLST) of 85 E. coli isolates revealed 31 different sequence types (ST) with an accumulation of ST744 (n = 9), ST10 (n = 8), and ST648 (n = 6), although the world-wide hospital-associated CTX-M beta-lactamase producing ST131 was not detected. Neither the antimicrobial resistance CDSs patterns nor the phylogenetic analysis revealed an epidemiological correlation among the longitudinal isolates collected from a period longer than seven days. No genetic linkage could be associated with the geographic origin of isolates. In conclusion, healthy dogs frequently carry ESBL-producing bacteria, independent to prior treatment, which may be transmitted between individual dogs of the same community. Otherwise, these antimicrobial resistant bacteria share few commonalities, making their presence eerily unpredictable.

OBJECTIVES:The aim of this multicenter retrospective study was to investigate safety and efficacy of direct acting antiviral (DAA) treatment in the rare subgroup of patients with HCV/HIV-coinfection and advanced liver cirrhosis on the liver transplant waiting list or after liver transplantation, respectively. METHODS:When contacting 54 German liver centers (including all 23 German liver transplant centers), 12 HCV/HIV-coinfected patients on antiretroviral combination therapy were reported having received additional DAA therapy while being on the waiting list for liver transplantation (patient characteristics: Child-Pugh A (n = 6), B (n = 5), C (n = 1); MELD range 7-21; HCC (n = 2); HCV genotype 1a (n = 8), 1b (n = 2), 4 (n = 2)). Furthermore, 2 HCV/HIV-coinfected patients were denoted having received DAA therapy after liver transplantation (characteristics: HCV genotype 1a (n = 1), 4 (n = 1)). RESULTS:Applied DAA regimens were SOF/DAC (n = 7), SOF/LDV/RBV (n = 3), SOF/RBV (n = 3), PTV/r/OBV/DSV (n = 1), or PTV/r/OBV/DSV/RBV (n = 1), respectively. All patients achieved SVR 12, in the end. In one patient, HCV relapse occurred after 24 weeks of SOF/DAC therapy; subsequent treatment with 12 weeks PTV/r/OBV/DSV achieved SVR 12. One patient underwent liver transplantation while on DAA treatment. Analysis of liver function revealed either stable parameters or even significant improvement during DAA therapy and in follow-up. MELD scores were found to improve in 9/13 therapies in patients on the waiting list for liver transplantation; in only 2 patients a moderate increase of MELD scores persisted at the end of follow-up. CONCLUSION:DAA treatment was safe and highly effective in this nation-wide cohort of patients with HCV/HIV-coinfection awaiting liver transplantation or being transplanted.

Theoretical approaches suggest that gender inequity increases men's health risks. Previous findings from the United States support this contention, however only a small number of health outcomes have been explored. This study extends the range of health outcomes examined by using a cross-sectional, multilevel analysis to investigate whether measures of state-level gender inequity are predictors of men's self-rated health. Data were derived primarily from the Behavioral Risk Factor Surveillance System and the full-case data set included 116,594 individuals nested within 50 states. Gender inequity was measured with nine variables: higher education, women's reproductive rights, abortion provider access, elected office, management, business ownership, labour force participation, earnings and relative poverty. Covariates at the individual level were age, income, education, race/ethnicity, marital status and employment status. Covariates at the state level were income inequality and gross domestic product per capita. In fully adjusted models for all-age men the reproductive rights (OR 1.06 95% CI 1.01-1.11), abortion provider access (OR 1.11 95% CI 1.05-1.16) and earnings (OR 1.06 95% CI 1.02-1.12) measures all predicted an increased risk of men reporting poorer self-rated health for each 1 standard deviation increase in the gender inequity z-score. The most consistent effect was seen for the 65+ age group where the reproductive rights (OR 1.09 95% CI 1.03-1.16), abortion provider access (OR 1.15 95% CI 1.09-1.21), elected office (OR 1.06 95% CI 1.01-1.11) and earnings (OR 1.10 95% CI 1.04-1.16) measures all showed a significant effect. These findings provide evidence that some aspects of gender inequity increase the risk of poorer self-rated health in men. The study contributes to a growing body of literature implicating gender inequity in men's health patterns.