Collaborative Cross mice have diverse phenotypic responses to infection with Methicillin-resistant Staphylococcus aureus USA300.

Staphylococcus aureus (S. aureus) is an opportunistic pathogen causing diseases ranging from mild skin infections to life threatening conditions, including endocarditis, pneumonia, and sepsis. To identify host genes modulating this host-pathogen interaction, we infected 25 Collaborative Cross (CC) mouse strains with methicillin-resistant S. aureus (MRSA) and monitored disease progression for seven days using a surgically implanted telemetry system. CC strains varied widely in their response to intravenous MRSA infection. We identified eight 'susceptible' CC strains with high bacterial load, tissue damage, and reduced survival. Among the surviving strains, six with minimal colonization were classified as 'resistant', while the remaining six tolerated higher organ colonization ('tolerant'). The kidney was the most heavily colonized organ, but liver, spleen and lung colonization were better correlated with reduced survival. Resistant strains had higher pre-infection circulating neutrophils and lower post-infection tissue damage compared to susceptible and tolerant strains. We identified four CC strains with sexual dimorphism: all females survived the study period while all males met our euthanasia criteria earlier. In these CC strains, males had more baseline circulating monocytes and red blood cells. We identified several CC strains that may be useful as new models for endocarditis, myocarditis, pneumonia, and resistance to MRSA infection. Quantitative Trait Locus (QTL) analysis identified two significant loci, on Chromosomes 18 and 3, involved in early susceptibility and late survival after infection. We prioritized Npc1 and Ifi44l genes as the strongest candidates influencing survival using variant analysis and mRNA expression data from kidneys within these intervals.

Overdose responses among rural people who use drugs: A multi-regional qualitative study.

BACKGROUND: Efforts to distribute naloxone have equipped more people with the ability to reverse opioid overdoses but people who use drugs are often reluctant to call 911 due to concerns for legal repercussions. Rural communities face unique challenges in reducing overdose deaths compared to urban communities, including limited access to harm reduction services as well as greater concerns about stigma and privacy. METHODS: The Rural Opioid Initiative was funded in 2017 to better understand the health-related harms associated with the opioid crisis in rural US communities and consists of eight studies spanning ten states and 65 counties. Each study conducted semi-structured qualitative interviews with people who use drugs to understand contextual factors influencing drug use and health behaviors. We analyzed qualitative data from seven studies with data available at the time of analysis to understand peer response to overdose. RESULTS: Of the 304 participants interviewed, 55% were men, 70% were white, 80% reported current injection drug use, and 60% reported methamphetamine use. Similar to what has been found in studies focused on urban settings, people who use drugs in rural communities use a range of strategies to reverse overdoses, including non-evidence-based approaches. Several reported that multiple doses of naloxone are needed to reverse overdose. Three themes emerged around the willingness to call 911, including (1) hesitancy to call 911 for fear of legal consequences, (2) negative perceptions or experiences with law enforcement officers, and (3) efforts to obtain medical intervention while avoiding identification/law enforcement involvement. CONCLUSION: People who use drugs employ multiple strategies to attempt overdose reversal, including non-evidence-based approaches. Greater education about the most effective and least harmful strategies is needed. Reluctance to call 911 is rooted in concerns about potential legal consequences as well as perceptions about law enforcement officers, which may be heightened in rural communities where people who use drugs are more easily identified by law enforcement. People who use drugs will go to great strides to connect their peers to needed medical services, suggesting that comprehensive interventions to reduce interactions with law enforcement officers and eliminate legal consequences for reporting overdoses are critical.

The relationship between felt stigma and non-fatal overdose among rural people who use drugs.

BACKGROUND: Drug overdose deaths in the United States exceeded 100,000 in 2021 and 2022. Substance use stigma is a major barrier to treatment and harm reduction utilization and is a priority target in ending the overdose epidemic. However, little is known about the relationship between stigma and overdose, especially in rural areas. We aimed to characterize the association between felt stigma and non-fatal overdose in a multi-state sample of rural-dwelling people who use drugs. METHODS: Between January 2018 and March 2020, 2,608 people reporting past 30-day opioid use were recruited via modified chain-referral sampling in rural areas across 10 states. Participants completed a computer-assisted survey of substance use and substance-related attitudes, behaviors, and experiences. We used multivariable logistic regression with generalized estimating equations to test the association between felt stigma and recent non-fatal overdose. RESULTS: 6.6% of participants (n = 173) reported an overdose in the past 30 days. Recent non-fatal overdose was significantly associated with felt stigma after adjusting for demographic and substance use-related covariates (aOR: 1.47, 95% CI: 1.20-1.81). The association remained significant in sensitivity analyses on component fear of enacted stigma items (aOR: 1.48, 95% CI: 1.20-1.83) and an internalized stigma item (aOR: 1.51, 95% CI: 1.07-2.14). CONCLUSIONS: Felt stigma related to substance use is associated with higher risk of non-fatal overdose in rural-dwelling people who use drugs. Stigma reduction interventions and tailored services for those experiencing high stigma are underutilized approaches that may mitigate overdose risk.

Case example of a female solo sailor competing in the Vendée Globe reveals extraordinary biological demands.

The Vendée Globe is a non-stop, unassisted, single-handed round the world sailing race. It is regarded as the toughest sailing race, requiring high cognitive functioning and constant alertness. Little is known about the amount of sleep restriction and nutritional deficit experienced at sea and effects that fatigue have on sailors' performance. This report aimed to investigate these aspects by monitoring one of the female participants of the latest Vendée Globe. Sleep, food intake and stress were self-reported daily using specific app. Cognitive assessments were digitally completed. Heart rate and activity intensity were measured using a wrist-worn wearable device. Mean self-report sleep duration per 24 h was 3 hours 40 minutes. By the end of the 95 race days, the sailor reached a caloric deficit of 27,900 kcal. On average, the sailor spent 50 minutes per day in moderate-to-vigorous activity. Cognitive assessments did not show any effect of fatigue or stress on completion time or performance. Recent technological and communication advancement for offshore sailors, enabled continuous data to be monitored in near real time, even from the Southern Ocean. Moving forward this will enable greater understanding of when sailors will be at risk of poor decision making, illness or injury.

Interventions to reduce self-stigma in people who use drugs: A systematic review.

BACKGROUND: Substance use stigma is a key barrier to treatment and harm reduction engagement among people who use drugs (PWUD). Previous systematic reviews have focused on interventions to reduce stigma in healthcare providers and the public; less is known about interventions to address self-stigma among PWUD. The purpose of this review is to evaluate the evidence for substance use self-stigma reduction interventions. METHODS: We reviewed English-language studies published between 2011 and 2023 using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (PROSPERO #CRD42022321305). We searched seven bibliographic databases (PubMed; SCOPUS; APA PsycInfo; CINAHL; Social Work Abstracts; Sociological Abstracts; ProQuest Dissertations & Theses). This review included studies if 1) they evaluated the effectiveness of a psychosocial intervention, 2) participants were PWUD, 3) authors reported self-stigma as a primary outcome, 4) the study design was experimental or quasi-experimental. We reviewed, interpreted and reported intervention characteristics and effectiveness using narrative synthesis. We assessed study quality with the Downs & Black checklist. RESULTS: Among 1195 screened studies, 15 met the inclusion criteria (N = 2280 PWUD). We categorized the interventions according to three approaches: psychotherapeutic (n = 8), psychoeducational (n = 5), and multimodal (n = 2). Most interventions were delivered in clinical settings (n = 11) and in a group format (n = 13). Study quality was fair-to-good and included nine randomized controlled trials (RCTs) and six quasi-experiments. Measurement heterogeneity was high, with 11 different stigma-related scales used across the 15 studies. Eleven studies showed significant favorable effects in at least one stigma measure. Six of these demonstrated positive effects in all stigma measures. Evidence was mixed for all three intervention categories; however, Acceptance and Commitment Therapy, a form of group psychotherapy, demonstrated effectiveness in four of five RCTs incorporating this approach. CONCLUSIONS: Overall, there is promising evidence for the effectiveness of substance use self-stigma interventions, although more studies are needed to determine which approaches are most effective. Consistent conceptualization and measurement of self-stigma across studies will improve comparability in future intervention trials. Current offerings are largely limited to clinical settings and group-based formats; self-help interventions, available for other stigmatized conditions, could be developed to serve the majority of PWUD not engaged in treatment.

An Automated Text Messaging Intervention to Reduce Substance Use Self-Stigma (Project RESTART): Protocol for a Feasibility and Acceptability Pilot Study.

BACKGROUND: Stigma is a barrier to treatment and harm reduction seeking in people who use drugs. Most stigma reduction interventions offer psychotherapy or psychoeducation in group-based clinical settings, failing to reach people who are not in treatment. SMS text messaging is an effective and acceptable modality for delivering health information to people who use drugs and may be a suitable conduit for providing information and advice to understand and cope with stigma. OBJECTIVE: This paper presents the protocol for a study that aims to determine the feasibility, acceptability, and preliminary effectiveness of a 4-week automated SMS text message intervention to increase stigma resistance and reduce self-stigma in people who use drugs. METHODS: We designed a novel automated SMS text message intervention to address the four personal-level constructs of stigma resistance: (1) not believing stigma and catching and challenging stigmatizing thoughts, (2) empowering oneself through learning about substance use and one's recovery, (3) maintaining one's recovery and proving stigma wrong, and (4) developing a meaningful identity and purpose apart from one's substance use. Theory-based messages were developed and pilot-tested in qualitative elicitation interviews with 22 people who use drugs, resulting in a library of 56 messages. In a single-group, within-subjects, community-based pilot trial, we will enroll 30 participants in the Resisting Stigma and Revaluating Your Thoughts (RESTART) intervention. Participants will receive 2 daily SMS text messages for 4 weeks. Implementation feasibility will be assessed through recruitment, enrollment, retention, and message delivery statistics. User feasibility and acceptability will be assessed at follow-up using 23 survey items informed by the Theoretical Framework of Acceptability. Primary effectiveness outcomes are changes in self-stigma (Substance Abuse Self-Stigma Scale) and stigma resistance (Stigma Resistance Scale) from baseline to follow-up measured via a self-administered survey. Secondary outcomes are changes in hope (Adult Dispositional Hope Scale) and self-esteem (Rosenberg Self-Esteem Scale). Feasibility and acceptability will be assessed with descriptive statistics; effectiveness outcomes will be assessed with paired 2-tailed t tests, and group differences will be explored using ANOVA. Overall, 12 participants will also be selected to complete acceptability interviews. RESULTS: This pilot study was funded by the National Institute on Drug Abuse in April 2023 and received regulatory approval in January 2024 by the University of North Carolina-Chapel Hill Institutional Review Board. Recruitment and enrollment began in March 2024. Follow-up visits are expected to conclude by May 2024. Results will be disseminated in relevant peer-reviewed journals. CONCLUSIONS: To the best of our knowledge, this is the first study to address substance use stigma via a self-help SMS text messaging program. Results will add to the nascent literature on stigma reduction in people who use drugs. This protocol may interest researchers who are considering text messaging to address psychosocial needs in hard-to-reach populations. TRIAL REGISTRATION: ClinicalTrials.gov NCT06281548; https://clinicaltrials.gov/ct2/show/NCT06281548. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/59224.

Late-life dietary folate restriction reduces biosynthesis without compromising healthspan in mice.

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low-folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

Late-life dietary folate restriction reduces biosynthetic processes without compromising healthspan in mice.

Folate is a vitamin required for cell growth and is present in fortified foods in the form of folic acid to prevent congenital abnormalities. The impact of low folate status on life-long health is poorly understood. We found that limiting folate levels with the folate antagonist methotrexate increased the lifespan of yeast and worms. We then restricted folate intake in aged mice and measured various health metrics, metabolites, and gene expression signatures. Limiting folate intake decreased anabolic biosynthetic processes in mice and enhanced metabolic plasticity. Despite reduced serum folate levels in mice with limited folic acid intake, these animals maintained their weight and adiposity late in life, and we did not observe adverse health outcomes. These results argue that the effectiveness of folate dietary interventions may vary depending on an individual's age and sex. A higher folate intake is advantageous during the early stages of life to support cell divisions needed for proper development. However, a lower folate intake later in life may result in healthier aging.

Pathogenesis of Salmonella-induced enteritis

Infections with Salmonella serotypes are a major cause of food-borne diseases worldwide. Animal models other than the mouse have been employed for the study of nontyphoidal Salmonella infections because the murine model is not suitable for the study of Salmonella-induced diarrhea. The microbe has developed mechanisms to exploit the host cell machinery to its own purpose. Bacterial proteins delivered directly into the host cell cytosol cause cytoskeletal changes and interfere with host cell signaling pathways, which ultimately enhance disease manifestation. Recently, marked advances have been made in our understanding of the molecular interactions between Salmonella serotypes and their hosts. Here, we discuss the molecular basis of the pathogenesis of Salmonella-induced enteritis

Estudos epidemiológicos entre populações ameríndias da amazônia. iii. parasitoses intestinais em povoações recentemente contactadas e em aculturação

SUMMARY The prevalences of intestinal parasites among the residents of three South American Indian villages in the process of acculturation were compared with those found in earlier unpublished surveys in two newly contacted villages. Although one individual in an acculturating village harbored 11 different intestinal parasites, in general, the average number of different parasitic species carried per person was somewhat higher in the newly contacted villages. Helminth egg counts, performed on direct smears of each specimen from one newly contacted village, were low. There were no sex-associated differences in prevalences. The overall prevalences, unadjusted for age, were among the highest recorded for Amerindians. No Taenia species were present. Balantidium coli was present in two acculturating villages, concommitant with the beginnings of agricultural practices which include raising swine. No cases of moderate or severe protein-calorie malnutrition were observed in any of the villages during the surveys. These limited data provide a baseline for future comparisons, and, perhaps, a glimpse into the past.

Resumo Os predomínios de parasitas intestinais entre os residentes de três povoações de índios sul-americanos no processo de aculturação foram comparados com os encontrados em pesquisas anteriores, não publicadas, em duas povoações recentemente contactadas. Embora um indivíduo, em uma povoação, em aculturação, hospedasse 11 diferentes parasitas intestinais, em geral, o número médio de diferentes espécies de parasitas por pessoa era um tanto maior nas povoações recentemente contactadas. A contagem de ovos de helmintos, efetuada diretamente nas sujeiras de cada espécime de uma vila recentemente contactada, foi baixa. Não houve diferenças em predomínio associadas ao sexo. Os predomínios totais, não ajustados por idade, estavam entre os mais altos registrados para ameríndios. Nenhuma espécie de Taenia ocorreu. Balantidium coli ocorreu em duas vilas em aculturação, concomitante com o início de práticas agrícolas que incluem criação de suínos. Nenhum caso de má nutrição de caloria protéica moderada ou severa foi observado em qualquer das vilas durante as pesquisas. Estes limitados dados fornecem uma linha base para futuras comparações, e, talvez, um olhar rápido no passado.

Emprego do propofol, isofluorano e morfina para a anestesia geral de longa duraçäo em bezerros / Use of propofol, isoflurane and morphine for prolonged general anesthesia in calves

Foram estudadas características da bioquímica do sangue, da pressäo arterial e da freqüência de pulso de 12 bezerros mantidos sob anestesia por 13 horas, utilizando-se propofol para a induçäo e isofluorano para manutençäo, associados à administraçäo de morfina intra-tecal. Os valores de freqüência de pulso, pressäo arterial e glicemia apresentaram pequenas variaçöes e se mantiveram próximos dos valores de referência para bezerros anestesiados. Ao longo do período de anestesia houve aumento significativo, mas discreto, do hematócrito, hemoglobina, pCO2, CO2 total, bicarbonato e potássio. O pH do sangue, pO2, Na+ e Ca++ apresentaram reduçöes significativas. Este protocolo anestésico foi seguro para a manutençäo de bezerros anestesiados por período prolongado.

Estudos epidemiologicos entre populaçoes Amerindias da Amazonia. III. Parasitoses intestinais em povoaçoes recentemente contactadas e em aculturaçao / Epidemiologic studies among Amerindian populations of Amazonia. III.Intestinal parasitosis in populations recently contacted and in process of acculturation

Os predominios de parasitas intestinais entre os residentes de tres povoaçoes de indios sul-americanos no processo de aculturaçao foram comparados com os encontrados em pesquisas anteriores, nao publicadas, em duas povoaçoes recentemente contactadas. Embora um individuo, em uma povoaçao, em aculturaçao, hospedasse 11 diferentes parasitas intestinais, em geral, o numero medio de diferentes especies de parasitas por pessoa era tanto maior nas povoaçoes recentemente contactadas. A contagem de ovos de helmintos, efetuada diretamente nas sujeiras de cada especime de uma vila recentemente contactada, foi baixa. Nao houve diferenças em predominio associadas ao sexo. Os predominios totais, nao ajustados por idade, estavam entre os mais altos reegistrados para amerindios. Nenhuma especie de Taenia ocorreu. Balastidium coli ocorreu em duas vilas em aculturaçao, concomitante com o inicio de praticas agricolas que incluem criaçao de suinos. Nenhum caso de ma nutriçao de caloria protica moderada ou severa foi observado em qualquer das vilas durante as pesquisas. Estes limitados dados fornecem uma linha base para futuras comparaçoes, e, talvez, um olhar rapido no passado