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Practitioners place importance on high-speed running (HSR) to monitor training practice and match-play demands, whilst attempting to maximise fitness and minimize the risk of injury occurrence. Practitioners apply various methods to quantify HSR, such as absolute thresholds, percentage of maximum sprint speed and maximal aerobic speed (MAS). A recent survey demonstrates the 5-minute run and 1200m shuttle test (ST) to be implemented among rugby league practitioners to quantify HSR by incorporating MAS. However, it is unclear as to how valid these methods are to accurately quantify MAS. Therefore, the aim of this study was to assess the validity of the 5-minute run and 1200m ST when compared to a gold standard measure for MAS. Twenty 1st team professional rugby league players competing in the European Super League participated in this study. Players were required to complete an incremental treadmill test, 5-minute run and 1200m ST over a two-week period in pre-season. MAS, peak heart rate (HRmax), peak lactate (Lapeak) and rating of perceived exertion (RPE) where collected upon completion of each test. Results demonstrated the 1200m ST to have a higher correlation for MAS than the 5-minute run (1200m ST: r = 0.73, 5-minute run: r = 0.64). However, when assessing validity using the level of agreement between data, the 5-minute run underreported MAS by 0.45 m·s-1 whereas the 1200m ST underreported MAS by 0.77 m·s-1. Ultimately, both field-based tests used in this study underreport MAS when compared to an incremental treadmill test, although the 5-minute run provides a closer agreement and therefore a more valid measurement for MAS than the 1200m ST.

BackgroundSuicide is the second leading cause of death among young people worldwide. Research indicates that negative social contexts involving familial and peer relationships have far-reaching influences on levels of suicidality in later life. While previous systematic reviews have focused on evaluating associations between negative life events such as abuse and bullying in childhood and subsequent suicidality, this systematic review examines the prevalence of, and association between the processes of humiliation and shame in later self-harm, suicidal ideation, and suicide among adolescents and young adults.MethodsA systematic literature search of databases including MEDLINE, Web of Science Core Collection, CINAHL, PsycINFO, and Embase was conducted to identify potential studies. ProQuest was searched to identify relevant grey literature research. A combination of MESH terms and keywords was used. All original quantitative studies published in English that examined the prevalence, or association between humiliation or shame and suicidal behaviours and/or death by suicide were included. Studies were assessed for methodological quality using Joanna Briggs Institute critical appraisal tools. The protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) [CRD42022289843].ResultsNarrative synthesis was performed. A total of 33 studies reporting the prevalence of, or association between humiliation (n = 10) or shame (n = 23) and suicidal thoughts/behaviours were included. The prevalence of humiliation among those with any suicidality ranged from 18% to 28.1%, excluding an outlier (67.1%), with two studies presenting a significant association between humiliation and self-harm in their fully adjusted analyses. The studies that outlined humiliation and suicidal thinking (intent/suicide plan) had no association after adjustment for confounders. For shame, half of the studies found an association in adjusted models (n = 10), and this was evident for both suicidal ideation and self-harm.ConclusionTo our knowledge, this is the first study to attempt a systematic review on this topic. The dearth of research in this field of enquiry is reflective of unique challenges associated with assessments of humiliation and shame in various clinical settings amongst adolescent and young adult populations. Nonetheless, given the importance and relevance of the psychological imprint of humiliation in youth morbidity and mortality in the field of mental health, it is timely to attempt such a systematic review. In light of the associated role of humiliation and shame in self-harm and suicidality among young people, we recommend that these processes need to be explored further via prospective studies and assessed as part of a comprehensive bio-psycho-social assessment when focusing on life stressors for adolescent and young adults presenting with suicidality to emergency departments and mental health services.

Although malaria is endemic in coastal Côte d'Ivoire, updated data on the resistance profile of the main vector, Anopheles gambiae sensu lato (s.l.), are still lacking, thus compromising decision-making for an effective vector control intervention. This study investigated the complex members and the insecticide resistance in the Anopheles gambiae s.l. populations in coastal Côte d'Ivoire. Between 2018 and 2020, cross sectional survey bioassays were conducted on female An. gambiae s.l. mosquitoes in three coastal health districts (Aboisso, Jacqueville and San Pedro) of Côte d'Ivoire. Pyrethroids deltamethrin, permethrin and alphacypermethrin (1X, 5X and 10X), clothianidin and synergist piperonyl butoxide (PBO) combined with pyrethroid 1X were tested using WHO tube bioassays. Chlorfenapyr was evaluated using CDC bottle bioassays. An. gambiae complex members and kdr 995F, kdr 995S and Ace-1 280S mutations were identified using polymerase chain reaction (PCR) technique. Overall, An. gambiae s.l. populations were primarily composed of Anopheles coluzzii (88.24%, n = 312), followed by Anopheles gambiae sensu stricto (7.56%) and hybrids (4.17%). These populations displayed strong resistance to pyrethroids at standard diagnostic doses, with mortality remaining below 98% even at 10X doses, except for alphacypermethrin in Aboisso. Pre-exposure to PBO significantly increased mortality but did not induce susceptibility, except for alphacypermethrin in Jacqueville. Clothianidin induced full susceptibility in Jacqueville and San Pedro, while chlorfenapyr induced susceptibility in Aboisso at 100 μg ai/bottle and all three districts at 200 μg ai/bottle. kdr 995F mutation dominated, with frequencies varying from 71.2% to 79.3%. kdr 995S had low, rates with frequencies ranging from 2.3% to 5.7%. Ace-1 280S prevalence varied between 4.2% and 42.9%. Coastal Côte d'Ivoire's An. gambiae s.l. populations were mainly composed of An. coluzzii and showed high resistance to pyrethroids. Clothianidin, chlorfenapyr, and PBO with pyrethroids increased mortality, indicating their potential use as an alternative for malaria vector control. [ABSTRACT FROM AUTHOR]

ObjectiveThe overall goal of this work is to produce a set of recommendations (SoNHR-Social Networks in Health Research) that will improve the reporting and dissemination of social network concepts, methods, data, and analytic results within health sciences research.MethodsThis study used a modified-Delphi approach for recommendation development consistent with best practices suggested by the EQUATOR health sciences reporting guidelines network. An initial set of 28 reporting recommendations was developed by the author team. A group of 67 (of 147 surveyed) experienced network and health scientists participated in an online feedback survey. They rated the clarity and importance of the individual recommendations, and provided qualitative feedback on the coverage, usability, and dissemination opportunities of the full set of recommendations. After examining the feedback, a final set of 18 recommendations was produced.ResultsThe final SoNHR reporting guidelines are comprised of 18 recommendations organized within five domains: conceptualization (how study research questions are linked to network conceptions or theories), operationalization (how network science portions of the study are defined and operationalized), data collection & management (how network data are collected and managed), analyses & results (how network results are analyzed, visualized, and reported), and ethics & equity (how network-specific human subjects, equity, and social justice concerns are reported). We also present a set of exemplar published network studies which can be helpful for seeing how to apply the SoNHR recommendations in research papers. Finally, we discuss how different audiences can use these reporting guidelines.ConclusionsThese are the first set of formal reporting recommendations of network methods in the health sciences. Consistent with EQUATOR goals, these network reporting recommendations may in time improve the quality, consistency, and replicability of network science across a wide variety of important health research areas.

Hidradenitis Suppurativa is a chronic inflammatory disease of which the pathogenesis is incompletely understood. Dermal fibroblasts have been previously identified as a major source of inflammatory cytokines, however information pertaining to the characteristics of subpopulations of fibroblasts in HS remains unexplored. Using in silico-deconvolution of whole-tissue RNAseq, Nanostring gene expression panels and confirmatory immunohistochemistry we identified fibroblast subpopulations in HS tissue and their relationship to disease severity and lesion morphology. Gene signatures of SFRP2+ fibroblast subsets were increased in lesional tissue, with gene signatures of SFRP1+ fibroblast subsets decreased. SFRP2+ and CXCL12+ fibroblast numbers, measured by IHC, were increased in HS tissue, with greater numbers associated with epithelialized tunnels and Hurley Stage 3 disease. Pro-inflammatory CXCL12+ fibroblasts were also increased, with reductions in SFRP1+ fibroblasts compared to healthy controls. Evidence of Epithelial Mesenchymal Transition was seen via altered gene expression of SNAI2 and altered protein expression of ZEB1, TWIST1, Snail/Slug, E-Cadherin and N-Cadherin in HS lesional tissue. The greatest dysregulation of EMT associated proteins was seen in biopsies containing epithelialized tunnels. The use of the oral Spleen tyrosine Kinase inhibitor Fostamatinib significantly reduced expression of genes associated with chronic inflammation, fibroblast proliferation and migration suggesting a potential role for targeting fibroblast activity in HS.

BackgroundIn November 2020, during the SARS-CoV-2 pandemic, Missouri allowed local public health jurisdictions the option to implement a modified quarantine policy allowing kindergarten through 12 (K-12) students with low-risk exposures to continue in-person learning. We assessed adherence to quarantine among participants in modified quarantine and standard home quarantine and the psychosocial impacts of quarantine on students and families.MethodsIn January-March 2021, as part of an investigation of in-school transmission of SARS-CoV-2, parents of 586 participating K-12 students identified as a close contact with a person with SARS-CoV-2 were sent a survey to assess their activities and psychosocial impacts to the child and family.ResultsAmong the 227 (39%) survey respondents, 26 (11%) participated in modified quarantine and 201 (89%) participated in standard home quarantine. Forty-six percent of students in modified quarantine and 72% of students in standard home quarantine reported abstaining from non-school activities during quarantine. Parents of 17 (65%) students in modified quarantine and 80 (40%) in standard home quarantine reported low or neutral levels of stress in their children. Parents of students in standard home quarantine described greater stress, negative impacts to family functioning, and interruptions to educational opportunities for students.ConclusionsStudents in modified quarantine reported lower adherence to quarantine recommendations but lower daily impact and stressors than those in standard home quarantine. Because in-school transmission of SARS-CoV-2 has been shown to be low when layered prevention strategies are in place regardless of the use of modified or standard home quarantine, this modified quarantine approach provides a reasonable option for balancing the needs of students and families with SARS-CoV-2 prevention measures.

Spectrotemporal receptive field (STRF) characterization is a central goal of auditory physiology. STRFs are often approximated by the spike-triggered average (STA), which reflects the average stimulus preceding a spike. In many cases, the raw STA is subjected to a threshold defined by gain values expected by chance. However, such correction methods have not been universally adopted, and the consequences of specific gain-thresholding approaches have not been investigated systematically. Here, we evaluate two classes of statistical correction techniques, using the resulting STRF estimates to predict responses to a novel validation stimulus. The first, more traditional technique eliminated STRF pixels (time-frequency bins) with gain values expected by chance. This correction method yielded significant increases in prediction accuracy, including when the threshold setting was optimized for each unit. The second technique was a two-step thresholding procedure wherein clusters of contiguous pixels surviving an initial gain threshold were then subjected to a cluster mass threshold based on summed pixel values. This approach significantly improved upon even the best gain-thresholding techniques. Additional analyses suggested that allowing threshold settings to vary independently for excitatory and inhibitory subfields of the STRF resulted in only marginal additional gains, at best. In summary, augmenting reverse correlation techniques with principled statistical correction choices increased prediction accuracy by over 80% for multi-unit STRFs and by over 40% for single-unit STRFs, furthering the interpretational relevance of the recovered spectrotemporal filters for auditory systems analysis.

BackgroundSuicide is the second leading cause of death among young people worldwide and remains a major public health concern. Research indicates that negative social contexts involving familial and peer relationships, have far-reaching influences on levels of suicidal behaviours in later life. Previous systematic reviews have focused on evaluating associations between negative life events such as abuse and bullying in childhood and subsequent self-harm or suicidality. However, the association between adolescent experiences of humiliation and shame, and subsequent self-harm or suicidal behaviour among children and young adults has not been well examined. As such, this systematic review is conducted to examine the prevalence and association between humiliation and shame and self-harm, suicidal ideation, and death by suicide among adolescents and young adults.MethodsA systematic literature search in extant electronic databases including; MEDLINE, Web of Science Core Collection, CINAHL, PsycINFO, and Embase will be conducted to identify potential studies. Google Scholar, and the reference list of the retrieved articles and/or previous systematic reviews in this area, will also be scanned to identify further potential studies. ProQuest will be searched to identify relevant studies available within grey literature. There are no restrictions on the date of publications. Based on our initial review, the following terms were identified: Population: Adolescent (MESH), young adult (MESH), teen, teenage. Exposure: Humiliation, degradation, shame (MESH) or embarrassment (MESH), harassment victimisation, abasement. Outcome: Self-injurious behaviour (MESH), suicide (MESH), suicide attempted (MESH), suicide completed (MESH), self-harm, intentional self-injury, deliberate self-harm, overdose, deliberate self-poisoning, non-suicidal self-injury, self-mutilation, suicidal thought, suicidal ideation, suicidal intent, suicide. At least one term from each category will be used for conducting the literature search. All original quantitative studies published in the English language which examined the prevalence or association between humiliation or shame and self-harm and/or suicidal ideation and/or completed suicide will be included. The studies will be assessed for methodological quality using the Joanna Briggs Institute critical appraisal tools. Narrative synthesis will be performed for all of the studies. If the studies are sufficiently homogenous, the results will be pooled for a meta-analysis. This systematic review protocol followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocol (PRISMA-P) guidelines. The protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) [CRD42022289843].DiscussionThis is the first review to synthesise evidence on the prevalence of, and associations between the experiences of humiliation and shame and subsequent self-harm and/or suicidal behaviours among adolescents and young adults. As there is growing evidence on increased self-harm among this age group, it is important to identify population-specific risk factors for self-harm and suicidality which will have significance in formulating tailored and effective treatment and therapeutic services for adolescents and young adults.

Objective To determine whether modified K–12 student quarantine policies that allow some students to continue in-person education during their quarantine period increase schoolwide SARS-CoV-2 transmission risk following the increase in cases in winter 2020–2021. Methods We conducted a prospective cohort study of COVID-19 cases and close contacts among students and staff (n = 65,621) in 103 Missouri public schools. Participants were offered free, saliva-based RT-PCR testing. The projected number of school-based transmission events among untested close contacts was extrapolated from the percentage of events detected among tested asymptomatic close contacts and summed with the number of detected events for a projected total. An adjusted Cox regression model compared hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy. Results From January–March 2021, a projected 23 (1%) school-based transmission events occurred among 1,636 school close contacts. There was no difference in the adjusted hazard rates of school-based SARS-CoV-2 infections between schools with a modified versus standard quarantine policy (hazard ratio = 1.00; 95% confidence interval: 0.97–1.03). Discussion School-based SARS-CoV-2 transmission was rare in 103 K–12 schools implementing multiple COVID-19 prevention strategies. Modified student quarantine policies were not associated with increased school incidence of COVID-19. Modifications to student quarantine policies may be a useful strategy for K–12 schools to safely reduce disruptions to in-person education during times of increased COVID-19 community incidence.

Since first identified in 1879, plasma, the fourth state of matter, has been developed and utilised in many fields. Nonthermal atmospheric plasma, also known as cold plasma, can be applied to liquids, where plasma reactive species such as reactive Oxygen and Nitrogen species and their effects can be retained and mediated through plasma-activated liquids (PAL). In the medical field, PAL is considered promising for wound treatment, sterilisation and cancer therapy due to its rich and relatively long-lived reactive species components. This study sought to identify any potential antagonistic effect between antioxidative intracellularly accumulated platinum nanoparticles (PtNPs) and PAL. We found that PAL can significantly reduce the viability of glioblastoma U-251MG cells. This did not involve measurable ROS influx but instead lead to lipid damage on the plasma membrane of cells exposed to PAL. Although the intracellular antioxidative PtNPs showed no protective effect against PAL, this study contributes to further understanding of principle cell killing routes of PAL and discovery of potential PAL-related therapy and methods to inhibit side effects.

Media advocacy plays a critical role in tobacco control, shaping the content of news in ways that generate public support for tobacco control. We examined US media coverage of nonsmoker-only hiring policies, which have little US public support, exploring the extent to which tobacco control advocates and experts have engaged the media on this controversial issue.We searched online media databases (Lexis Nexis, Access World News, and Proquest) for articles published from 1995-2013, coding retrieved items through a collaborative, iterative process. We analyzed the volume, type, provenance, prominence, content and slant of coverage.We found 1,159 media items on nonsmoker-only hiring policies, most published in local newspapers in regions where such policies were enacted. The most common reason given for implementing such policies was to reduce healthcare costs. Most news items offered reasons both to support and oppose such policies; thus, the slant of the majority of news items was neutral or mixed. Tobacco control advocates or experts were infrequently cited or quoted in news items, and rarely authored opinion pieces. Those who expressed opinions were more likely to support than oppose nonsmoker-only hiring policies, for economic and health reasons. Ethical concerns about the policies were seldom raised.As presented in the media, nonsmoker-only hiring policies were primarily framed in terms of business cost savings and had little connection to health initiatives. Tobacco control advocates were rarely quoted and their positions were not consistent. Given their intrusiveness and the lack of strong evidence that such business policies actually do improve worker health, tobacco control advocates may feel that the status quo is preferable to engaging on a policy that the majority of Americans dislike.

Globally, small-scale fisheries are influenced by dynamic climate, governance, and market drivers, which present social and ecological challenges and opportunities. It is difficult to manage fisheries adaptively for fluctuating drivers, except to allow participants to shift effort among multiple fisheries. Adapting to changing conditions allows small-scale fishery participants to survive economic and environmental disturbances and benefit from optimal conditions. This study explores the relative influence of large-scale drivers on shifts in effort and outcomes among three closely linked fisheries in Monterey Bay since the Magnuson-Stevens Fisheries Conservation and Management Act of 1976. In this region, Pacific sardine (Sardinops sagax), northern anchovy (Engraulis mordax), and market squid (Loligo opalescens) fisheries comprise a tightly linked system where shifting focus among fisheries is a key element to adaptive capacity and reduced social and ecological vulnerability. Using a cluster analysis of landings, we identify four modes from 1974 to 2012 that are dominated (i.e., a given species accounting for the plurality of landings) by squid, sardine, anchovy, or lack any dominance, and seven points of transition among these periods. This approach enables us to determine which drivers are associated with each mode and each transition. Overall, we show that market and climate drivers are predominantly attributed to dominance transitions. Model selection of external drivers indicates that governance phases, reflected as perceived abundance, dictate long-term outcomes. Our findings suggest that globally, small-scale fishery managers should consider enabling shifts in effort among fisheries and retaining existing flexibility, as adaptive capacity is a critical determinant for social and ecological resilience.

BackgroundBackground Population-based data on SARS-CoV-2 infection in pregnancy and assessment of passive immunity to the neonate, is lacking. We profiled the maternal and fetal response using a combination of viral RNA from naso-pharyngeal swabs and serological assessment of antibodies against SARS-CoV-2.MethodsThis multicentre prospective observational study was conducted between March 24th and August 31st 2020. Two independent cohorts were established, a symptomatic SARS-CoV-2 cohort and a cohort of asymptomatic pregnant women attending two of the largest maternity hospitals in Europe. Symptomatic women were invited to provide a serum sample to assess antibody responses. Asymptomatic pregnant women provided a nasopharyngeal swab and serum sample. RT-PCR for viral RNA was performed using the Cobas SARS-CoV-2 6800 platform (Roche). Umbilical cord bloods were obtained at delivery. Maternal and fetal serological response was measured using both the Elecsys® Anti-SARS-CoV-2 immunoassay (Roche), Abbott SARS-CoV-2 IgG Assay and the IgM Architect assay. Informed written consent was obtained from all participants.ResultsTen of twenty three symptomatic women had SARS-CoV-2 RNA detected on nasopharyngeal swabs. Five (5/23, 21.7%) demonstrated serological evidence of anti-SARS-CoV-2 IgG antibodies and seven (30.4%, 7/23) were positive for IgM antibodies. In the asymptomatic cohort, the prevalence of SARS-CoV-2 infection in RNA was 0.16% (1/608). IgG SARS-CoV-2 antibodies were detected in 1·67% (10/598, 95% CI 0·8%-3·1%) and IgM in 3·51% (21/598, 95% CI 2·3-5·5%). Nine women had repeat testing post the baseline test. Four (4/9, 44%) remained IgM positive and one remained IgG positive. 3 IgG anti-SARS-CoV-2 antibodies were detectable in cord bloods from babies born to five seropositive women who delivered during the study. The mean gestation at serological test was 34 weeks. The mean time between maternal serologic positivity and detection in umbilical cord samples was 28 days.ConclusionUsing two independent serological assays, we present a comprehensive illustration of the antibody response to SARS-CoV-2 in pregnancy, and show a low prevalence of asymptomatic SARS-CoV2. Transplacental migration of anti-SARS-CoV-2 antibodies was identified in cord blood of women who demonstrated antenatal anti-SARS-CoV-2 antibodies, raising the possibility of passive immunity.

Twin and family studies have established the contribution of genetic factors to variation in metabolic, hematologic and immunological parameters. The majority of these studies analyzed single or combined traits into pre-defined syndromes. In the present study, we explore an alternative multivariate approach in which a broad range of metabolic, hematologic, and immunological traits are analyzed simultaneously to determine the resemblance of monozygotic (MZ) twin pairs, twin-spouse pairs and unrelated, non-cohabiting individuals. A total of 517 participants from the Netherlands Twin Register, including 210 MZ twin pairs and 64 twin-spouse pairs, took part in the study. Data were collected on body composition, blood pressure, heart rate, and multiple biomarkers assessed in fasting blood samples, including lipid levels, glucose, insulin, liver enzymes, hematological measurements and cytokine levels. For all 51 measured traits, pair-wise Pearson correlations, correcting for family relatedness, were calculated across all the individuals in the cohort. Hierarchical clustering techniques were applied to group the measured traits into sub-clusters based on similarity. Sub-clusters were observed among metabolic traits and among inflammatory markers. We defined a phenotypic profile as the collection of all the traits measured for a given individual. Average within-pair similarity of phenotypic profiles was determined for the groups of MZ twin pairs, spouse pairs and pairs of unrelated individuals. The average similarity across the full phenotypic profile was higher for MZ twin pairs than for spouse pairs, and lowest for pairs of unrelated individuals. Cohabiting MZ twins were more similar in their phenotypic profile compared to MZ twins who no longer lived together. The correspondence in the phenotypic profile is therefore determined to a large degree by familial, mostly genetic, factors, while household factors contribute to a lesser degree to profile similarity.

PurposeThe ability to detect small malignant lesions with magnetic resonance imaging (MRI) is limited by inadequate accumulations of Gd with standard chelate agents. To date, no T1-targeted agents have proven superiority to Gd chelates in their ability to detect small tumors at clinically relevant field strengths. Activatable cell-penetrating peptides and their Gd-loaded dendrimeric form (ACPPD-Gd) have been shown to selectively accumulate in tumors. In this study we compared the performance of ACPPD-Gd vs. untargeted Gd chelates to detect small tumors in rodent models using a clinical 3T-MR system.Materials and methodsThis study was approved by the Institutional-Animal Care-and-Use Committee. 2 of 4 inguinal breast fat pads of 16 albino-C57BL/6 mice were inoculated with tumor Py8119 cells and the other 2 with saline at random. MRI at 3T was performed at 4, 9, and 14 days after inoculation on 8 mice 24-hours after injection of 0.036mmol Gd/kg (ACPPD-Gd), and before and 2-3 minutes after 0.1 mmol/kg gadobutrol on the other 8 mice. T1-weighted (T1w) tumor signal normalized to muscle, was compared among the non-contrast, gadobutrol, and ACPPD-Gd groups using ANOVA. Experienced and trainee readers blinded to experimental conditions assessed for the presence of tumor in each of the 4 breast regions. Receiver operator characteristic (ROC) curves and area-under-curve (AUC) values were constructed and analyzed.ResultsTumors ≥1mm3 were iso-intense to muscle without contrast on T1w sequences. They enhanced diffusely and homogeneously by 57±20% (p5mm3) were removed from the ROC analysis for both the experienced observer (0.96 vs. 0.86) and more so for the trainee (0.86 vs. 0.69, p = 0.04).ConclusionACPPD-Gd enhances MMP-expressing tumors of any size at 3T 24 hours after administration, improving their detection by blinded observers when compared to non-contrast and contrast groups given commercial Gd-chelates and imaged during the equilibrium phase.

In the US, denormalizing tobacco use is key to tobacco control; less attention has been paid to denormalizing tobacco sales. However, some localities have placed limits on the number and type of retailers who may sell tobacco, and some retailers have abandoned tobacco sales voluntarily. Understanding community norms surrounding tobacco sales may help accelerate tobacco denormalization.We conducted 15 focus groups with customers of California, New York, and Ohio retailers who had voluntarily discontinued tobacco sales to examine normative assumptions about where cigarettes should or should not be sold, voluntary decisions to discontinue tobacco sales, and government limits on such sales.Groups in all three states generally agreed that grocery stores that sold healthy products should not sell tobacco; California groups saw pharmacies similarly, while this was a minority opinion in the other two states. Convenience stores were regarded as a natural place to sell tobacco. In each state, it was regarded as normal and commendable for some stores to want to stop selling tobacco, although few participants could imagine convenience stores doing so. Views on government's role in setting limits on tobacco sales varied, with California and New York participants generally expressing support for restrictions, and Ohio participants expressing opposition. However, even those who expressed opposition did not approve of tobacco sales in all possible venues. Banning tobacco sales entirely was not yet normative.Limiting the ubiquitous availability of tobacco sales is key to ending the tobacco epidemic. Some limits on tobacco sales appear to be normative from the perspective of community members; it may be possible to shift norms further by problematizing the ubiquitous presence of cigarettes and drawing connections to other products already subject to restrictions.

Practitioners place importance on high-speed running (HSR) to monitor training practice and match-play demands, whilst attempting to maximise fitness and minimize the risk of injury occurrence. Practitioners apply various methods to quantify HSR, such as absolute thresholds, percentage of maximum sprint speed and maximal aerobic speed (MAS). A recent survey demonstrates the 5-minute run and 1200m shuttle test (ST) to be implemented among rugby league practitioners to quantify HSR by incorporating MAS. However, it is unclear as to how valid these methods are to accurately quantify MAS. Therefore, the aim of this study was to assess the validity of the 5-minute run and 1200m ST when compared to a gold standard measure for MAS. Twenty 1st team professional rugby league players competing in the European Super League participated in this study. Players were required to complete an incremental treadmill test, 5-minute run and 1200m ST over a two-week period in pre-season. MAS, peak heart rate (HRmax), peak lactate (Lapeak) and rating of perceived exertion (RPE) where collected upon completion of each test. Results demonstrated the 1200m ST to have a higher correlation for MAS than the 5-minute run (1200m ST: r = 0.73, 5-minute run: r = 0.64). However, when assessing validity using the level of agreement between data, the 5-minute run underreported MAS by 0.45 m·s-1 whereas the 1200m ST underreported MAS by 0.77 m·s-1. Ultimately, both field-based tests used in this study underreport MAS when compared to an incremental treadmill test, although the 5-minute run provides a closer agreement and therefore a more valid measurement for MAS than the 1200m ST. [ABSTRACT FROM AUTHOR]

Tobacco retailers are key players in the ongoing tobacco epidemic. Tobacco outlet density is linked to a greater likelihood of youth and adult smoking and greater difficulty quitting. While public policy efforts to address the tobacco problem at the retail level have been limited, some retailers have voluntarily ended tobacco sales. A previous pilot study examined this phenomenon in California, a state with a strong tobacco program focused on denormalizing smoking and the tobacco industry. We sought to learn what motivated retailers in other states to end tobacco sales and how the public and media responded.We conducted interviews with owners, managers, or representatives of six grocery stores in New York and Ohio that had voluntarily ended tobacco sales since 2007. We also conducted unobtrusive observations at stores and analyzed media coverage of each retailer's decision.Grocery store owners ended tobacco sales for two reasons, alone or in combination: health or ethics-related, including a desire to send a consistent health message to employees and customers, and business-related, including declining tobacco sales or poor fit with the store's image. The decision to end sales often appeared to resolve troubling contradictions between retailers' values and selling deadly products. New York retailers attributed declining sales to high state tobacco taxes. All reported largely positive customer reactions and most received media coverage. Forty-one percent of news items were letters to the editor or editorials; most (69%) supported the decision.Voluntary decisions by retailers to abandon tobacco sales may lay the groundwork for mandatory policies and further denormalize tobacco. Our study also suggests that high tobacco taxes may have both direct and indirect effects on tobacco use. Highlighting the contradictions between being a responsible business and selling deadly products may support voluntary decisions by retailers to end tobacco sales.

Ecological network models and analyses are recognized as valuable tools for understanding the dynamics and resiliency of ecosystems, and for informing ecosystem-based approaches to management. However, few databases exist that can provide the life history, demographic and species interaction information necessary to parameterize ecological network models. Faced with the difficulty of synthesizing the information required to construct models for kelp forest ecosystems along the West Coast of North America, we developed an online database (http://kelpforest.ucsc.edu/) to facilitate the collation and dissemination of such information. Many of the database's attributes are novel yet the structure is applicable and adaptable to other ecosystem modeling efforts. Information for each taxonomic unit includes stage-specific life history, demography, and body-size allometries. Species interactions include trophic, competitive, facilitative, and parasitic forms. Each data entry is temporally and spatially explicit. The online data entry interface allows researchers anywhere to contribute and access information. Quality control is facilitated by attributing each entry to unique contributor identities and source citations. The database has proven useful as an archive of species and ecosystem-specific information in the development of several ecological network models, for informing management actions, and for education purposes (e.g., undergraduate and graduate training). To facilitate adaptation of the database by other researches for other ecosystems, the code and technical details on how to customize this database and apply it to other ecosystems are freely available and located at the following link (https://github.com/kelpforest-cameo/databaseui).

Anthropogenic impacts are increasingly affecting the world's oceans. Networks of marine protected areas (MPAs) provide an option for increasing the ecological and economic benefits often provided by single MPAs. It is vital to empirically assess the effects of MPA networks and to prioritize the monitoring data necessary to explain those effects. We summarize the types of MPA networks based on their intended management outcomes and illustrate a framework for evaluating whether a connectivity network is providing an outcome greater than the sum of individual MPA effects. We use an analysis of an MPA network in Hawai'i to compare networked MPAs to non-networked MPAs to demonstrate results consistent with a network effect. We assert that planning processes for MPA networks should identify their intended outcomes while also employing coupled field monitoring-simulation modeling approaches, a powerful way to prioritize the most relevant monitoring data for empirically assessing MPA network performance.

The world is currently in a pandemic of COVID-19 (Coronavirus disease-2019) caused by a novel positive-sense, single-stranded RNA β-coronavirus referred to as SARS-CoV-2. Here we investigated rates of SARS-CoV-2 infection in the greater Cincinnati, Ohio, USA metropolitan area from August 13 to December 8, 2020, just prior to initiation of the national vaccination program. Examination of 9,550 adult blood donor volunteers for serum IgG antibody positivity against the SARS-CoV-2 Spike protein showed an overall prevalence of 8.40%, measured as 7.56% in the first 58 days and 9.24% in the last 58 days, and 12.86% in December 2020, which we extrapolated to ~20% as of March, 2021. Males and females showed similar rates of past infection, and rates among Hispanic or Latinos, African Americans and Whites were also investigated. Donors under 30 years of age had the highest rates of past infection, while those over 60 had the lowest. Geographic analysis showed higher rates of infectivity on the West side of Cincinnati compared with the East side (split by I-75) and the lowest rates in the adjoining region of Kentucky (across the Ohio river). These results in regional seroprevalence will help inform efforts to best achieve herd immunity in conjunction with the national vaccination campaign.

Despite recent improvements, men still have worse HIV outcomes than women in South Africa. This study describes how young men form distinct behavioural and attitudinal subgroups, and is intended to inform the design of targeted interventions to encourage HIV testing and initiation on antiretroviral therapy. Data were collected using a cross-sectional survey with questions on men's attitudes, beliefs and behaviours around HIV/AIDS. A total of 2,019 men were randomly sampled from eight district municipalities in KwaZulu-Natal and Mpumalanga provinces between October 2018 and January 2019. Men were eligible to participate if they were aged 20-34, Black African, had an education level below university graduation, were aware of HIV and were willing to disclose whether they had tested for HIV. Each participant responded to a questionnaire asking about their demographic characteristics, reported sexual behaviour, engagement with HIV testing and treatment services, alcohol consumption, HIV knowledge, attitudes to gender equity and reported level of depressive symptoms. Data were analysed using canonical correlation, hierarchical clustering and factor analysis techniques to produce five groups of men. The results were synthesised using Human Centred Design principles to suggests areas for potential intervention for each segment. The results showed that men vary based on their attitudes to gender and masculinity, use of alcohol, testing and treatment behaviour, HIV-related fears and preferences for testing modalities. Segment 1 (21%) avoids the topic of HIV, perhaps fearful of the impact on his life. Segment 2 (23%) is well connected to his community and has social concerns about HIV. Segment 3 (15%) struggles with more distal determinants of HIV acquisition such as unemployment and poor mental health. Segment 4 (25%) has concerns about the lifestyle changes that would be required if he were HIV positive. Segment 5 (16%) has a strong traditional mindset and is fearful of the ramifications of HIV in his community. The results will be used to design targeted interventions to increase HIV testing and treatment rates among young men in South Africa. Further research is required to understand the impact of interventions designed in this way.

PurposeThe Expanded Prostate Cancer Index Composite (EPIC) is the most commonly used patient reported outcome (PRO) tool in prostate cancer (PC) clinical trials, but health utilities associated with the different health states assessed with this tool are unknown, limiting our ability to perform cost-utility analyses. This study aimed to map EPIC tool to EuroQoL-5D-3L (EQ5D) to generate EQ5D health utilities.Methods and materialsThis is a secondary analysis of a prospective, randomized non-inferiority clinical trial, conducted between 04/2006 and 12/2009 at cancer centers across the United States, Canada, and Switzerland. Eligible patients included men >18 years with a known diagnosis of low-risk PC. Patient HRQoL data were collected using EPIC and health utilities were obtained using EQ5D. Data were divided into an estimation sample (n = 765, 70%) and a validation sample (n = 327, 30%). The mapping algorithms that capture the relationship between the instruments were estimated using ordinary least squares (OLS), Tobit, and two-part models. Five-fold cross-validation (in-sample) was used to compare the predictive performance of the estimated models. Final models were selected based on root mean square error (RMSE).ResultsA total of 565 patients in the estimation sample had complete information on both EPIC and EQ5D questionnaires at baseline. Mean observed EQ5D utility was 0.90±0.13 (range: 0.28-1) with 55% of patients in full health. OLS models outperformed their counterpart Tobit and two-part models for all pre-determined model specifications. The best model fit was: "EQ5D utility = 0.248541 + 0.000748*(Urinary Function) + 0.001134*(Urinary Bother) + 0.000968*(Hormonal Function) + 0.004404*(Hormonal Bother)- 0.376487*(Zubrod) + 0.003562*(Urinary Function*Zubrod)"; RMSE was 0.10462.ConclusionsThis is the first study to identify a comprehensive set of mapping algorithms to generate EQ5D utilities from EPIC domain/ sub-domain scores. The study results will help estimate quality-adjusted life-years in PC economic evaluations.

BackgroundThe search for immune correlates of protection against Mycobacterium tuberculosis (MTB) infection in humans is limited by the focus on peripheral blood measures. Bronchoalveolar lavage (BAL) can safely be done and provides insight into cellular function in the lung where infection is first established. In this study, blood and lung samples were assayed to determine if heavily MTB exposed persons who resist development of latent MTB infection (RSTR) vs those who develop latent MTB infection (LTBI), differ in the make-up of resident BAL innate and adaptive immune cells.MethodsBronchoscopy was performed on 21 healthy long-term Ugandan RSTR and 25 LTBI participants. Immune cell distributions in BAL and peripheral blood were compared by differential cell counting and flow cytometry.ResultsThe bronchoscopy procedure was well tolerated with few adverse reactions. Differential macrophage and lymphocyte frequencies in BAL differed between RSTR and LTBI. When corrected for age, this difference lost statistical significance. BAL CD4+ and CD8+ T cells were almost entirely composed of effector memory T cells in contrast to PBMC, and did not differ between RSTR and LTBI. BAL NKT, γδ T cells and NK cells also did not differ between RTSR and LTBI participants. There was a marginally significant increase (p = 0.034) in CD8 T effector memory cells re-expressing CD45RA (TEMRA) in PBMC of LTBI vs RSTR participants.ConclusionThis observational case-control study comparing unstimulated BAL from RSTR vs LTBI, did not find evidence of large differences in the distribution of baseline BAL immune cells. PBMC TEMRA cell percentage was higher in LTBI relative to RSTR suggesting a role in the maintenance of latent MTB infection. Functional immune studies are required to determine if and how RSTR and LTBI BAL immune cells differ in response to MTB.

Novel chemistry for vector control is urgently needed to counter insecticide resistance in mosquitoes. Here a new meta-diamide insecticide, broflanilide (TENEBENALTM), was evaluated in East African experimental huts in Moshi, northern Tanzania. Two consecutive experimental hut trials with broflanilide 50WP were conducted; the first evaluating the efficacy of three concentrations, 50 mg/m2, 100 mg/m2, and 200 mg/m2 using a prototype formulation, and the second trial evaluating an improved formulation. The IRS treatments were applied on both mud and concrete surfaces and efficacy was monitored over time. The mortality, blood-feeding inhibition and exiting behaviour of free-flying wild mosquitoes was compared between treatment arms. Additionally, cone assays with pyrethroid-susceptible and resistant mosquito strains were conducted in the huts to determine residual efficacy. The first trial showed a dosage-mortality response of the prototype formulation and 3-8 months of residual activity, with longer activity on concrete than mud. The second trial with an improved formulation showed prolonged residual efficacy of the 100 mg/m2 concentration to 5-6 months on mud, and mosquito mortality on the concrete surface ranged between 94-100% for the full duration of the trial. In both trials, results with free-flying, wild Anopheles arabiensis echoed the mortality trend shown in cone assays, with the highest dose inducing the highest mortality and the improved formulation showing increased mortality rates. No blood-feeding inhibition or insecticide-induced exiting effects were observed with broflanilide. Broflanilide 50WP was effective against both susceptible and pyrethroid-resistant mosquito strains, demonstrating an absence of cross resistance between broflanilide and pyrethroids. The improved formulation, which has now been branded VECTRONTM T500, resulted in a prolonged residual efficacy. These results indicate the potential of this insecticide as an addition to the arsenal of IRS products needed to maintain both control of malaria and resistance management of malaria-transmitting mosquitoes.

Epilepsy is a complex neurological condition characterized by repeated spontaneous seizures and can be induced by initiating seizures known as status epilepticus (SE). Elaborating the critical molecular mechanisms following SE are central to understanding the establishment of chronic seizures. Here, we identify a transient program of molecular and metabolic signaling in the early epileptogenic period, centered on day five following SE in the pre-clinical kainate or pilocarpine models of temporal lobe epilepsy. Our work now elaborates a new molecular mechanism centered around Wnt signaling and a growing network comprised of metabolic reprogramming and mTOR activation. Biochemical, metabolomic, confocal microscopy and mouse genetics experiments all demonstrate coordinated activation of Wnt signaling, predominantly in neurons, and the ensuing induction of an overall aerobic glycolysis (Warburg-like phenomenon) and an altered TCA cycle in early epileptogenesis. A centerpiece of the mechanism is the regulation of pyruvate dehydrogenase (PDH) through its kinase and Wnt target genes PDK4. Intriguingly, PDH is a central gene in certain genetic epilepsies, underscoring the relevance of our elaborated mechanisms. While sharing some features with cancers, the Warburg-like metabolism in early epileptogenesis is uniquely split between neurons and astrocytes to achieve an overall novel metabolic reprogramming. This split Warburg metabolic reprogramming triggers an inhibition of AMPK and subsequent activation of mTOR, which is a signature event of epileptogenesis. Interrogation of the mechanism with the metabolic inhibitor 2-deoxyglucose surprisingly demonstrated that Wnt signaling and the resulting metabolic reprogramming lies upstream of mTOR activation in epileptogenesis. To augment the pre-clinical pilocarpine and kainate models, aspects of the proposed mechanisms were also investigated and correlated in a genetic model of constitutive Wnt signaling (deletion of the transcriptional repressor and Wnt pathway inhibitor HBP1). The results from the HBP1-/- mice provide a genetic evidence that Wnt signaling may set the threshold of acquired seizure susceptibility with a similar molecular framework. Using biochemistry and genetics, this paper outlines a new molecular framework of early epileptogenesis and advances a potential molecular platform for refining therapeutic strategies in attenuating recurrent seizures.

BackgroundChildren on the autism spectrum are consistently reported to underachieve compared to ability. In typically developing children, anxiety is a strong predictor of poor school performance. Despite the high prevalence of anxiety disorders among children on the spectrum, the impact of their anxiety on academic achievement is under-researched. The main aim of this project is to determine the moderating role anxiety may have in the development of academic learning behaviours (academic enablers) in children on the spectrum. This project addresses a gap in knowledge about the possible associations between anxiety and academic achievement in children on the spectrum. Understanding these associations opens up the possibility of new intervention pathways to enhance academic outcomes through anxiety reduction/prevention.MethodsThis longitudinal study will aim to recruit 64 children on the spectrum aged 4-5 years and their parents. Information will be gathered from children, parents and teachers. Children will be randomly assigned to one of two conditions in order to experimentally manipulate anxiety levels in the sample: experimental (to receive an anxiety reduction/prevention program, N = 32) or control (no intervention/treatment as usual, N = 32). The primary outcome measures are child academic skills and enabling behaviours assessed using the Academic Competence Evaluation Scales and the WIAT-II. Anxiety will be assessed through parent and teacher report. Assessments will be conducted at baseline, post-experimental manipulation of anxiety, and within the first year of formal schooling. It is hypothesised that anxiety will moderate the relationship between autism characteristics and academic enablers.DisseminationResults will be disseminated through peer-reviewed manuscripts and conference presentations. Lay summaries will be provided to all participants and available on the research centre website.

The purpose of this study was to identify individual and residency program factors associated with increased suicide risk, as measured by suicidal ideation. We utilized a prospective, longitudinal cohort study design to assess the prevalence and predictors of suicidal ideation in 6,691 (2012-2014 cohorts, training data set) and 4,904 (2015 cohort, test data set) first-year training physicians (interns) at hospital systems across the United States. We assessed suicidal ideation two months before internship and then quarterly through intern year. The prevalence of reported suicidal ideation in the study population increased from 3.0% at baseline to a mean of 6.9% during internship. 16.4% of interns reported suicidal ideation at least once during their internship. In the training dataset, a series of baseline demographic (male gender) and psychological factors (high neuroticism, depressive symptoms and suicidal ideation) were associated with increased risk of suicidal ideation during internship. Further, prior quarter psychiatric symptoms (depressive symptoms and suicidal ideation) and concurrent work-related factors (increase in self-reported work hours and medical errors) were associated with increased risk of suicidal ideation. A model derived from the training dataset had a predicted area under the Receiver Operating Characteristic curve (AUC) of 0.83 in the test dataset. The suicidal ideation risk predictors analyzed in this study can help programs and interns identify those at risk for suicidal ideation before the onset of training. Further, increases in self-reported work hours and environments associated with increased medical errors are potentially modifiable factors for residency programs to target to reduce suicide risk.

BACKGROUND:In June 2019, Beverly Hills, California, became the first American city in the 21st century to pass an ordinance ending the sale of most tobacco products, including cigarettes, and it is unlikely to be the last. Knowledge of previous efforts to ban tobacco sales in the US, both successful and unsuccessful, may help inform tobacco control advocates' approach to future efforts. METHODS:We retrieved and analyzed archival tobacco industry documents. We confirmed and supplemented information from the documents with news media coverage and publicly available state and local government materials, such as meeting minutes and staff reports, related to proposed bans. RESULTS:We found 22 proposals to end the sale of cigarettes or tobacco products from 1969-2020 in the US. Proposals came from five states, twelve cities or towns, and one county. Most came from elected officials or boards of health, and were justified on public health grounds. In opposing tobacco sales bans, the tobacco industry employed no tactics or arguments that it did not also employ in campaigns against other tobacco control measures. Public health groups typically opposed sales ban proposals on the grounds that they were not evidence-based. This changed with Beverly Hills' 2019 proposal, with public health organizations supporting this and other California city proposals because of their likely positive health impacts. This support did not always translate into passage of local ordinances, as some city council members expressed reservations about the impact on small businesses. CONCLUSION:Tobacco control advocates are likely to encounter familiar tobacco industry tactics and arguments against tobacco sales ban proposals, and can rely on past experience and the results of a growing body of retail-related research to counter them. Considering how to overcome concerns about harming retailers will likely be vital if other jurisdictions are to succeed in ending tobacco sales.

ObjectiveTo develop and validate a machine-learning algorithm to improve prediction of incident OUD diagnosis among Medicare beneficiaries with ≥1 opioid prescriptions.MethodsThis prognostic study included 361,527 fee-for-service Medicare beneficiaries, without cancer, filling ≥1 opioid prescriptions from 2011-2016. We randomly divided beneficiaries into training, testing, and validation samples. We measured 269 potential predictors including socio-demographics, health status, patterns of opioid use, and provider-level and regional-level factors in 3-month periods, starting from three months before initiating opioids until development of OUD, loss of follow-up or end of 2016. The primary outcome was a recorded OUD diagnosis or initiating methadone or buprenorphine for OUD as proxy of incident OUD. We applied elastic net, random forests, gradient boosting machine, and deep neural network to predict OUD in the subsequent three months. We assessed prediction performance using C-statistics and other metrics (e.g., number needed to evaluate to identify an individual with OUD [NNE]). Beneficiaries were stratified into subgroups by risk-score decile.ResultsThe training (n = 120,474), testing (n = 120,556), and validation (n = 120,497) samples had similar characteristics (age ≥65 years = 81.1%; female = 61.3%; white = 83.5%; with disability eligibility = 25.5%; 1.5% had incident OUD). In the validation sample, the four approaches had similar prediction performances (C-statistic ranged from 0.874 to 0.882); elastic net required the fewest predictors (n = 48). Using the elastic net algorithm, individuals in the top decile of risk (15.8% [n = 19,047] of validation cohort) had a positive predictive value of 0.96%, negative predictive value of 99.7%, and NNE of 104. Nearly 70% of individuals with incident OUD were in the top two deciles (n = 37,078), having highest incident OUD (36 to 301 per 10,000 beneficiaries). Individuals in the bottom eight deciles (n = 83,419) had minimal incident OUD (3 to 28 per 10,000).ConclusionsMachine-learning algorithms improve risk prediction and risk stratification of incident OUD in Medicare beneficiaries.

Objective: The overall goal of this work is to produce a set of recommendations (SoNHR–Social Networks in Health Research) that will improve the reporting and dissemination of social network concepts, methods, data, and analytic results within health sciences research. Methods: This study used a modified-Delphi approach for recommendation development consistent with best practices suggested by the EQUATOR health sciences reporting guidelines network. An initial set of 28 reporting recommendations was developed by the author team. A group of 67 (of 147 surveyed) experienced network and health scientists participated in an online feedback survey. They rated the clarity and importance of the individual recommendations, and provided qualitative feedback on the coverage, usability, and dissemination opportunities of the full set of recommendations. After examining the feedback, a final set of 18 recommendations was produced. Results: The final SoNHR reporting guidelines are comprised of 18 recommendations organized within five domains: conceptualization (how study research questions are linked to network conceptions or theories), operationalization (how network science portions of the study are defined and operationalized), data collection & management (how network data are collected and managed), analyses & results (how network results are analyzed, visualized, and reported), and ethics & equity (how network-specific human subjects, equity, and social justice concerns are reported). We also present a set of exemplar published network studies which can be helpful for seeing how to apply the SoNHR recommendations in research papers. Finally, we discuss how different audiences can use these reporting guidelines. Conclusions: These are the first set of formal reporting recommendations of network methods in the health sciences. Consistent with EQUATOR goals, these network reporting recommendations may in time improve the quality, consistency, and replicability of network science across a wide variety of important health research areas. [ABSTRACT FROM AUTHOR]

The typical sprint profile in elite hurling has yet to be established. The purpose of this study was to investigate the sprinting demands of elite hurling competition and characterize the sprinting patterns of different playing positions. GPS (10-Hz, STATSports Viper) were used to collect data from 51 hurlers during 18 games. The total sprint (≥22 km·h-1) distance (TSD), the number of sprints (NOS) classified as length (90%), the between-sprint duration and the number of repeated-sprint bouts (≥2 sprints in ≤60 s) were analyzed. The NOS was 22.2 ± 6.8 accumulating 415 ± 140 m TSD. The NOS 90% was 10.6 ± 4.3, 8.2 ± 3.6, 3.4 ± 2.4 respectively. The between-sprint duration and the repeated-sprint bouts were 208 ± 86 s and 4.5 ± 2.6 respectively. TSD (ES = -0.20), NOS (ES = -0.34), NOS 90% (ES = -0.13) and repeated-sprint bouts (ES = -0.28) decreased between-halves. Full-backs performed a lower NOS

Processing of pro-interleukin (IL)-1β and IL-18 is regulated by multiprotein complexes, known as inflammasomes. Inflammasome activation results in generation of bioactive IL-1β and IL-18, which can exert potent pro-inflammatory effects. Our aim was to develop a whole blood-based assay to study the inflammasome in vitro and that also can be used as an assay in clinical studies. We show whole blood is a suitable milieu to study inflammasome activation in primary human monocytes. We demonstrated that unprocessed human blood cells can be stimulated to activate the inflammasome by the addition of adenosine 5'-triphosphate (ATP) within a narrow timeframe following lipopolysaccharide (LPS) priming. Stimulation with LPS resulted in IL-1β release; however, addition of ATP is necessary for "full-blown" inflammasome stimulation resulting in high IL-1β and IL-18 release. Intracellular cytokine staining demonstrated monocytes are the major producers of IL-1β in human whole blood cultures, and this was associated with activation of caspase-1/4/5, as detected by a fluorescently labelled caspase-1/4/5 probe. By applying caspase inhibitors, we show that both the canonical inflammasome pathway (via caspase-1) as well as the non-canonical inflammasome pathway (via caspases-4 and 5) can be studied using this whole blood-based model.

BACKGROUND:Mitochondrial disease is a family of genetic disorders characterized by defects in the generation and regulation of energy. Epilepsy is a common symptom of mitochondrial disease, and in the vast majority of cases, refractory to commonly used antiepileptic drugs. Ferroptosis is a recently-described form of iron- and lipid-dependent regulated cell death associated with glutathione depletion and production of lipid peroxides by lipoxygenase enzymes. Activation of the ferroptosis pathway has been implicated in a growing number of disorders, including epilepsy. Given that ferroptosis is regulated by balancing the activities of glutathione peroxidase-4 (GPX4) and 15-lipoxygenase (15-LO), targeting these enzymes may provide a rational therapeutic strategy to modulate seizure. The clinical-stage therapeutic vatiquinone (EPI-743, α-tocotrienol quinone) was reported to reduce seizure frequency and associated morbidity in children with the mitochondrial disorder pontocerebellar hypoplasia type 6. We sought to elucidate the molecular mechanism of EPI-743 and explore the potential of targeting 15-LO to treat additional mitochondrial disease-associated epilepsies. METHODS:Primary fibroblasts and B-lymphocytes derived from patients with mitochondrial disease-associated epilepsy were cultured under standardized conditions. Ferroptosis was induced by treatment with the irreversible GPX4 inhibitor RSL3 or a combination of pharmacological glutathione depletion and excess iron. EPI-743 was co-administered and endpoints, including cell viability and 15-LO-dependent lipid oxidation, were measured. RESULTS:EPI-743 potently prevented ferroptosis in patient cells representing five distinct pediatric disease syndromes with associated epilepsy. Cytoprotection was preceded by a dose-dependent decrease in general lipid oxidation and the specific 15-LO product 15-hydroxyeicosatetraenoic acid (15-HETE). CONCLUSIONS:These findings support the continued clinical evaluation of EPI-743 as a therapeutic agent for PCH6 and other mitochondrial diseases with associated epilepsy.

The current investigation compared the metabolic power and energetic characteristics in team sports with respect to positional lines and halves of match-play. Global positioning system (GPS) technology data were collected from 22 elite competitive hurling matches over a 3-season period. A total of 250 complete match-files were recorded with players split into positional groups of full-back; half-back; midfield; half-forward; full-forward. Raw GPS data were exported into a customized spreadsheet that provided estimations of metabolic power and speed variables across match-play events (average metabolic power [Pmet], high metabolic load distance [HMLD], total distance, relative distance, high-speed distance, maximal speed, accelerations, and deceleration). Pmet, HMLD, total, relative and high-speed distance were 8.9 ± 1.6 W·kg-1, 1457 ± 349 m, 7506 ± 1364 m, 107 ± 20 m·min-1 and 1169 ± 260 m respectively. Half-backs, midfielders and half-forwards outperformed full-backs (Effect Size [ES] = 1.03, 1.22 and 2.07 respectively), and full-forwards in Pmet (Effect Size [ES] = 1.70, 2.07 and 1.28 respectively), and HMLD (full-backs: ES = -1.23, -1.37 and -0.84 respectively, and full-forwards: ES = -1.77, -2.00 and -1.38 respectively). Half-backs (ES = -0.60), midfielders (ES = -0.81), and half-forwards (ES = -0.74) experienced a second-half temporal decrement in HMLD. The current investigation demonstrates that metabolic power may increase our understanding of the match-play demands placed on elite hurling players. Coaches may utilize these findings to construct training drills that replicate match-play demands.

One quarter of veterans returning from the 1990-1991 Persian Gulf War have developed Gulf War Illness (GWI) with chronic pain, fatigue, cognitive and gastrointestinal dysfunction. Exertion leads to characteristic, delayed onset exacerbations that are not relieved by sleep. We have modeled exertional exhaustion by comparing magnetic resonance images from before and after submaximal exercise. One third of the 27 GWI participants had brain stem atrophy and developed postural tachycardia after exercise (START: Stress Test Activated Reversible Tachycardia). The remainder activated basal ganglia and anterior insulae during a cognitive task (STOPP: Stress Test Originated Phantom Perception). Here, the role of attention in cognitive dysfunction was assessed by seed region correlations during a simple 0-back stimulus matching task ("see a letter, push a button") performed before exercise. Analysis was analogous to resting state, but different from psychophysiological interactions (PPI). The patterns of correlations between nodes in task and default networks were significantly different for START (n = 9), STOPP (n = 18) and control (n = 8) subjects. Edges shared by the 3 groups may represent co-activation caused by the 0-back task. Controls had a task network of right dorsolateral and left ventrolateral prefrontal cortex, dorsal anterior cingulate cortex, posterior insulae and frontal eye fields (dorsal attention network). START had a large task module centered on the dorsal anterior cingulate cortex with direct links to basal ganglia, anterior insulae, and right dorsolateral prefrontal cortex nodes, and through dorsal attention network (intraparietal sulci and frontal eye fields) nodes to a default module. STOPP had 2 task submodules of basal ganglia-anterior insulae, and dorsolateral prefrontal executive control regions. Dorsal attention and posterior insulae nodes were embedded in the default module and were distant from the task networks. These three unique connectivity patterns during an attention task support the concept of Gulf War Disease with recognizable, objective patterns of cognitive dysfunction.

BackgroundLimited data existed exclusively describing Mycobacterium tuberculosis lineage 3 (MTB-L3), sub-lineages, and clinical manifestations in Kampala, Uganda. This study sought to elucidate the circulating MTB-L3 sub-lineages and their corresponding clinical phenotypes.MethodA total of 141 M. tuberculosis isolates were identified as M. tuberculosis lineage 3 using Single nucleotide polymorphism (SNP) marker analysis method. To ascertain the sub-lineages/sub-strains within the M. tuberculosis lineage 3, the direct repeat (DR) loci for all the isolates was examined for sub-lineage specific signatures as described in the SITVIT2 database. The infecting sub-strains were matched with patients' clinical and demographic characteristics to identify any possible association.ResultThe data showed 3 sub-lineages circulating with CAS 1 Delhi accounting for 55% (77/141), followed by CAS 1-Kili 16% (22/141) and CAS 2/CAS 8% (12/141). Remaining isolates 21% (30/141) were unclassifiable. To explore whether the sub-lineages differ in their ability to cause increased severe disease, we used extent of lung involvement as a proxy for severe disease. Multivariable analysis showed no association between M. tuberculosis lineage 3 sub-lineages with severe disease. The risk factors associated with severe disease include having a positive smear (OR = 9.384; CI 95% = 2.603-33.835), HIV (OR = 0.316; CI 95% = 0.114-0.876), lymphadenitis (OR = 0. 171; CI 95% = 0.034-0.856) and a BCG scar (OR = 0.295; CI 95% = 0.102-0.854).ConclusionIn Kampala, Uganda, there are three sub-lineages of M. tuberculosis lineage 3 that cause disease of comparable severity with CAS-Dehli as the most prevalent. Having HIV, lymphadenitis, a BCG scar and a smear negative status is associated with reduced severe disease.

Dyslipidemia is a well-established risk factor for cardiovascular diseases. Although, advances in genome-wide technologies have enabled the discovery of hundreds of genes associated with blood lipid phenotypes, most of the heritability remains unexplained. Here we performed targeted resequencing of 13 bona fide candidate genes of dyslipidemia to identify the underlying biological functions. We sequenced 940 Sikh subjects with extreme serum levels of hypertriglyceridemia (HTG) and 2,355 subjects were used for replication studies; all 3,295 participants were part of the Asian Indians Diabetic Heart Study. Gene-centric analysis revealed burden of variants for increasing HTG risk in GCKR (p = 2.1x10-5), LPL (p = 1.6x10-3) and MLXIPL (p = 1.6x10-2) genes. Of these, three missense and damaging variants within GCKR were further examined for functional consequences in vivo using a transgenic zebrafish model. All three mutations were South Asian population-specific and were largely absent in other multiethnic populations of Exome Aggregation Consortium. We built different transgenic models of human GCKR with and without mutations and analyzed the effects of dietary changes in vivo. Despite the short-term of feeding, profound phenotypic changes were apparent in hepatocyte histology and fat deposition associated with increased expression of GCKR in response to a high fat diet (HFD). Liver histology of the GCKRmut showed severe fatty metamorphosis which correlated with ~7 fold increase in the mRNA expression in the GCKRmut fish even in the absence of a high fat diet. These findings suggest that functionally disruptive GCKR variants not only increase the risk of HTG but may enhance ectopic lipid/fat storage defects in absence of obesity and HFD. To our knowledge, this is the first transgenic zebrafish model of a putative human disease gene built to accurately assess the influence of genetic changes and their phenotypic consequences in vivo.

BackgroundThe human hippocampus comprises a number of interconnected histologically and functionally distinct subfields, which may be differentially influenced by cerebral pathology. Automated techniques are now available that estimate hippocampal subfield volumes using in vivo structural MRI data. To date, research investigating the influence of cerebral β-amyloid deposition-one of the earliest hypothesised changes in the pathophysiological continuum of Alzheimer's disease-on hippocampal subfield volumes in cognitively normal older individuals, has been limited.MethodsUsing cross-sectional data from 408 cognitively normal individuals born in mainland Britain (age range at time of assessment = 69.2-71.9 years) who underwent cognitive assessment, 18F-Florbetapir PET and structural MRI on the same 3 Tesla PET/MR unit (spatial resolution 1.1 x 1.1 x 1.1. mm), we investigated the influences of β-amyloid status, age at scan, and global white matter hyperintensity volume on: CA1, CA2/3, CA4, dentate gyrus, presubiculum and subiculum volumes, adjusting for sex and total intracranial volume.ResultsCompared to β-amyloid negative participants (n = 334), β-amyloid positive participants (n = 74) had lower volume of the presubiculum (3.4% smaller, p = 0.012). Despite an age range at scanning of just 2.7 years, older age at time of scanning was associated with lower CA1 (p = 0.007), CA4 (p = 0.004), dentate gyrus (p = 0.002), and subiculum (p = 0.035) volumes. There was no evidence that white matter hyperintensity volume was associated with any subfield volumes.ConclusionThese data provide evidence of differential associations in cognitively normal older adults between hippocampal subfield volumes and β-amyloid deposition and, increasing age at time of scan. The relatively selective effect of lower presubiculum volume in the β-amyloid positive group potentially suggest that the presubiculum may be an area of early and relatively specific volume loss in the pathophysiological continuum of Alzheimer's disease. Future work using higher resolution imaging will be key to exploring these findings further.

Arsenic, a naturally occurring element, contaminates the drinking water of over 200 million people globally. Chronic arsenic exposure causes multiple cancers including those originating from skin, lung and bladder, and is associated with liver, kidney, and prostate cancers. Skin is the primary target organ for arsenic toxicity; chronic toxicity initially manifests as non-malignant hyperkeratoses (HK) and subsequently advances to malignant lesions, including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). In this study, we evaluate the miRNA expression profiles of premalignant (3 HK) and malignant (3 BCC and 3 SCC) skin lesions from individuals chronically exposed to high levels of arsenic (59-172 ppb) in their drinking water in West Bengal, India. The lesions were histologically complex requiring histopathologic identification of keratinocytes to be isolated for RNA analyses. Keratinocytes were harvested using Laser Capture Microdissection and miRNA expression profiles were determined using TaqMan® Array Human MiRNA A Card v2.0. Thirty-five miRNAs were differentially expressed among the three lesion types analyzed. Two miRNAs (miR-425-5p and miR-433) were induced in both BCC and SCC relative to HK indicating their association with malignancy. Two other miRNAs (miR-184 and miR-576-3p) were induced in SCC relative to both BCC and HK suggesting selective induction in tumors capable of metastasis. Six miRNAs (miR-29c, miR-381, miR-452, miR-487b, miR-494 and miR-590-5p) were selectively suppressed in BCC relative to both SCC and HK. In conclusion, the differential miRNA expression was both phenotype- and stage-related. These miRNAs are potential biomarkers and may serve as therapy targets for arsenic-induced internal tumors.

Like many other high elevation alpine tree species, Rocky Mountain bristlecone pine (Pinus aristata Engelm.) may be particularly vulnerable to climate change. To evaluate its potential vulnerability to shifts in climate, we defined the suitable climate space for each of four genetic lineages of bristlecone pine and for other subalpine tree species in close proximity to bristlecone pine forests. Measuring changes in the suitable climate space for lineage groups is an important step beyond models that assume species are genetically homogenous. The suitable climate space for bristlecone pine in the year 2090 is projected to decline by 74% and the proportional distribution of suitable climate space for genetic lineages shifts toward those associated with warmer and wetter conditions. The 2090 climate space for bristlecone pine exhibits a bimodal distribution along an elevation gradient, presumably due to the persistence of the climate space in the Southern Rocky Mountains and exclusion at mid-elevations by conditions that favor the climate space of other species. These shifts have implications for changes in fire regimes, vulnerability to pest and pathogens, and altered carbon dynamics across the southern Rockies, which may reduce the likelihood of bristlecone pine trees achieving exceptional longevity in the future. The persistence and expansion of climate space for southern bristlecone pine genetic lineage groups in 2090 suggests that these sources may be the least vulnerable in the future. While these lineages may be more likely to persist and therefore present opportunities for proactive management (e.g., assisted migration) to maintain subalpine forest ecosystem services in a warmer world, our findings also imply heighted conservation concern for vulnerable northern lineages facing range contractions.