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Abstract Salmonella utilizes a type 3 secretion system to translocate virulence proteins (effectors) into host cells during infection1. The effectors modulate host cell machinery to drive uptake of the bacteria into vacuoles, where they can establish an intracellular replicative niche. A remarkable feature of Salmonella invasion is the formation of actin-rich protuberances (ruffles) on the host cell surface that contribute to bacterial uptake. However, the membrane source for ruffle formation and how these bacteria regulate membrane mobilization within host cells remains unclear. Here, we show that Salmonella exploits membrane reservoirs for the generation of invasion ruffles. The reservoirs are pre-existing tubular compartments associated with the plasma membrane (PM) and are formed through the activity of RAB10 GTPase. Under normal growth conditions, membrane reservoirs contribute to PM homeostasis and are preloaded with the exocyst subunit EXOC2. During Salmonella invasion, the bacterial effectors SipC, SopE2, and SopB recruit exocyst subunits from membrane reservoirs and other cellular compartments, thereby allowing exocyst complex assembly and membrane delivery required for bacterial uptake. Our findings reveal an important role for RAB10 in the establishment of membrane reservoirs and the mechanisms by which Salmonella can exploit these compartments during host cell invasion.

O principal objetivo desse artigo é avaliar os indicadores de qualidade de vida no trabalho (QVT) para os professores universitários, e comparar os indicadores de QVT em universidades públicas no Brasil e no Canadá. A amostra deste estudo é constituída por 205 professores de Minas Gerais e 269 do Quebec. Os dados foram coletados através de um questionário online aplicado em fevereiro e março de 2013. Três diferenças significativas foram encontradas entre as duas amostras: sentido no trabalho, comprometimento afetivo e comprometimento de continuidade. Os professores brasileiros parecem encontrar mais sentido no trabalho do que os canadenses e têm mais comprometimento afetivo com suas instituições.

Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while late-stage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies.

Abstract Background Universal Health Coverage ensures access to quality health services for all, with no financial hardship when accessing the needed services. Nevertheless, access to quality health services is marred by substantial resource shortages creating service delivery gaps in low-and middle-income countries, including Kenya. The Innovative Partnership for Universal Sustainable Healthcare (i-PUSH) program, developed by AMREF Health Africa and PharmAccess Foundation (PAF), aims to empower low-income women of reproductive age and their families through innovative digital tools. This study aims to evaluate the impact of i-PUSH on maternal and child health care utilization, women’s health including their knowledge, behavior, and uptake of respective services, as well as women’s empowerment and financial protection. It also aims to evaluate the impact of the LEAP training tool on empowering and enhancing community health volunteers’ health literacy and to evaluate the impact of the M-TIBA health wallet on savings for health and health insurance uptake. Methods This is a study protocol for a cluster randomized controlled trial (RCT) study that uses a four-pronged approach—including year-long weekly financial and health diaries interviews, baseline and endline surveys, a qualitative study, and behavioral lab-in-the-field experiments—in Kakemega County, Kenya. In total, 240 households from 24 villages in Kakamega will be followed to capture their health, health knowledge, health-seeking behavior, health expenditures, and enrolment in health insurance over time. Half of the households live in villages randomly assigned to the treatment group where i-PUSH will be implemented after the baseline, while the other half of the households live in control village where i-PUSH will not be implemented until after the endline. The study protocol was reviewed and approved by the AMREF Ethical and Scientific Review Board. Research permits were obtained from the National Commission for Science, Technology and Innovation agency of Kenya. Discussion People in low-and middle-income countries often suffer from high out-of-pocket healthcare expenditures, which, in turn, impede access to quality health services. Saving for healthcare as well as enrolment in health insurance can improve access to healthcare by building capacities at all levels—individuals, families, and communities. Notably, i-PUSH fosters savings for health care through the mobile-phone based “health wallet,” it enhances enrolment in subsidized health insurance through the mobile platform—M-TIBA—developed by PAF, and it seeks to improve health knowledge and behavior through community health volunteers (CHVs) who are trained using the LEAP tool—AMREF’s mHealth platform. The findings will inform stakeholders to formulate better strategies to ensure access to Universal Health Coverage in general, and for a highly vulnerable segment of the population in particular, including low-income mothers and their children. Trial registration Registered with Protocol Registration and Results System (protocol ID: AfricanPHRC; trial ID: NCT04068571 : AEARCTR-0006089 ; date: 29 August 2019) and The American Economic Association’s registry for randomized controlled trials (trial ID: AEARCTR-0006089; date: 26 June 2020).

Salmonella secretes the effector protein SopD into the host cell cytoplasm, leading to scission of the plasma membrane through unclear mechanisms. Here, Boddy et al. show that SopD binds to and inhibits the small GTPase Rab10, thus promoting removal of Rab10 and recruitment of dynamin-2 to drive plasma membrane scission.

Mutations in RAS-MAPK pathway genes are implicated in Noonan-spectrum, yet up to 20% of cases have unknown cause. Here, the authors identify RREB1 underlying a 6p microdeletion RASopathy-like syndrome and show that RREB1, SIN3A and KDM1A form a transcriptional repressive complex to control methylation of MAPK pathway genes.

Determining the structural organisation of viral replication complexes and unravelling the impact of infection on cellular homeostasis represent important challenges in virology. This may prove particularly useful when confronted with viruses that pose a significant threat to human health, that appear unique within their family, or for which knowledge is scarce. Among Mononegavirales, bornaviruses (family Bornaviridae) stand out due to their compact genomes and their nuclear localisation for replication. The recent recognition of the zoonotic potential of several orthobornaviruses has sparked a surge of interest in improving our knowledge on this viral family. In this work, we provide a complete analysis of the structural organisation of Borna disease virus 1 (BoDV-1) phosphoprotein (P), an important cofactor for polymerase activity. Using X-ray diffusion and diffraction experiments, we revealed that BoDV-1 P adopts a long coiled-coil α-helical structure split into two parts by an original β-strand twist motif, which is highly conserved across the members of whole Orthobornavirus genus and may regulate viral replication. In parallel, we used BioID to determine the proximal interactome of P in living cells. We confirmed previously known interactors and identified novel proteins linked to several biological processes such as DNA repair or mRNA metabolism. Altogether, our study provides important structure/function cues, which may improve our understanding of BoDV-1 pathogenesis.

There are many outstanding questions about how to control the global COVID-19 pandemic. The information void has been especially stark in the World Health Organization Africa Region, which has low per capita reported cases, low testing rates, low access to therapeutic drugs, and has the longest wait for vaccines. As with all disease, the central challenge in responding to COVID-19 is that it requires integrating complex health systems that incorporate prevention, testing, front line health care, and reliable data to inform policies and their implementation within a relevant timeframe. It requires that the population can rely on the health system, and decision-makers can rely on the data. To understand the process and challenges of such an integrated response in an under-resourced rural African setting, we present the COVID-19 strategy in Ifanadiana District, where a partnership between Malagasy Ministry of Public Health (MoPH) and non-governmental organizations integrates prevention, diagnosis, surveillance, and treatment, in the context of a model health system. These efforts touch every level of the health system in the district—community, primary care centers, hospital—including the establishment of the only RT-PCR lab for SARS-CoV-2 testing outside of the capital. Starting in March of 2021, a second wave of COVID-19 occurred in Madagascar, but there remain fewer cases in Ifanadiana than for many other diseases (e.g., malaria). At the Ifanadiana District Hospital, there have been two deaths that are officially attributed to COVID-19. Here, we describe the main components and challenges of this integrated response, the broad epidemiological contours of the epidemic, and how complex data sources can be developed to address many questions of COVID-19 science. Because of data limitations, it still remains unclear how this epidemic will affect rural areas of Madagascar and other developing countries where health system utilization is relatively low and there is limited capacity to diagnose and treat COVID-19 patients. Widespread population based seroprevalence studies are being implemented in Ifanadiana to inform the COVID-19 response strategy as health systems must simultaneously manage perennial and endemic disease threats.

Schistosomiasis remains the fourth most prevalent parasitic disease affecting over 200 million people worldwide. Control efforts have focussed on the disruption of the life cycle targeting the parasite, vector and human host. Parasite burdens are highly skewed, and the majority of eggs are shed into the environment by a minority of the infected population. Most morbidity results from hepatic fibrosis leading to portal hypertension and is not well-correlated with worm burden. Genetics as well as environmental factors may play a role in these skewed distributions and understanding the genetic risk factors for intensity of infection and morbidity may help improve control measures. In this review, we focus on how genetic factors may influence parasite load, hepatic fibrosis and portal hypertension. We found 28 studies on the genetics of human infection and 20 studies on the genetics of pathology in humans. S. mansoni and S. haematobium infection intensity have been showed to be controlled by a major quantitative trait locus SM1, on chromosome 5q31-q33 containing several genes involved in the Th2 immune response, and three other loci of smaller effect on chromosomes 1, 6, and 7. The most common pathology associated with schistosomiasis is hepatic and portal vein fibroses and the SM2 quantitative trait locus on chromosome six has been linked to intensity of fibrosis. Although there has been an emphasis on Th2 cytokines in candidate gene studies, we found that four of the five QTL regions contain Th17 pathway genes that have been included in schistosomiasis studies: IL17B and IL12B in SM1, IL17A and IL17F in 6p21-q2, IL6R in 1p21-q23 and IL22RA2 in SM2. The Th17 pathway is known to be involved in response to schistosome infection and hepatic fibrosis but variants in this pathway have not been tested for any effect on the regulation of these phenotypes. These should be priorities for future studies.

Artificial neural networks have been widely adopted as ansatzes to study classical and quantum systems. However, for some notably hard systems, such as those exhibiting glassiness and frustration, they have mainly achieved unsatisfactory results, despite their representational power and entanglement content, thus suggesting a potential conservation of computational complexity in the learning process. We explore this possibility by implementing the neural annealing method with autoregressive neural networks on a model that exhibits glassy and fractal dynamics: the two-dimensional Newman–Moore model on a triangular lattice. We find that the annealing dynamics is globally unstable because of highly chaotic loss landscapes. Furthermore, even when the correct ground-state energy is found, the neural network generally cannot find degenerate ground-state configurations due to mode collapse. These findings indicate that the glassy dynamics exhibited by the Newman–Moore model caused by the presence of fracton excitations in the configurational space likely manifests itself through trainability issues and mode collapse in the optimization landscape.

Resumo Servidores públicos comprometidos e orientados por valores do éthos público é um dos principais desafios da gestão de pessoas. Conhecer o que lhes dá sentido ao trabalho pode ser um caminho para ações pertinentes, fora de estigmas e más interpretações sobre a relação entre o indivíduo e seu trabalho no setor público. O propósito deste artigo é avaliar os fatores antecedentes da experiência de sentido do trabalho, bem como sua relação com bem-estar psicológico, sofrimento psicológico e comprometimento afetivo em peritos criminais da Polícia Federal. Trata-se de pesquisa de natureza quantitativa, com uso de análise fatorial confirmatória e modelagem de equações estruturais. Os resultados indicam que os peritos veem sentido em seu trabalho, o qual advém de sua utilidade social e das oportunidades de aprendizagem e desenvolvimento. O sentido está positivamente relacionado com bem-estar psicológico e comprometimento afetivo e negativamente com sofrimento psicológico. São discutidos os resultados da aplicação do modelo à luz de um marco de responsabilidade gerencial para desenvolvimento da função pública e conclui-se que ele oferece boa contribuição para gestão de pessoas no setor público possibilitando discutir fatores que favorecem a experiência de comprometimento e qualidade de vida psíquica no ambiente de trabalho.

Abstract Sub-Saharan Africa (SSA) experiences an acute dearth of well-trained and skilled researchers. This dearth constrains the region’s capacity to identify and address the root causes of its poor social, health, development, and other outcomes. Building sustainable research capacity in SSA requires, among other things, locally led and run initiatives that draw on existing regional capacities as well as mutually beneficial global collaborations. This paper describes a regional research capacity strengthening initiative—the African Doctoral Dissertation Research Fellowship (ADDRF) program. This Africa-based and African-led initiative has emerged as a practical and tested platform for producing and nurturing research leaders, strengthening university-wide systems for quality research training and productivity, and building a critical mass of highly-trained African scholars and researchers. The program deploys different interventions to ensure the success of fellows. These interventions include research methods and scientific writing workshops, research and reentry support grants, post-doctoral research support and placements, as well as grants for networking and scholarly conferences attendance. Across the region, ADDRF graduates are emerging as research leaders, showing signs of becoming the next generation of world-class researchers, and supporting the transformations of their home-institutions. While the contributions of the ADDRF program to research capacity strengthening in the region are significant, the sustainability of the initiative and other research and training fellowship programs on the continent requires significant investments from local sources and, especially, governments and the private sector in Africa. The ADDRF experience demonstrates that research capacity building in Africa is possible through innovative, multifaceted interventions that support graduate students to develop different critical capacities and transferable skills and build, expand, and maintain networks that can sustain them as scholars and researchers.

O principal objetivo deste artigo é testar a aplicabilidade de um modelo de Qualidade de Vida no Trabalho (QVT). Especificamente, buscou-se descrever o modelo de QVT adotado, analisar os indicadores e fatores de QVT na perspectiva dos professores universitários de instituições públicas, e verificar a adequabilidade do referido modelo para avaliar QVT em instituições do setor público. Aplicou-se um questionário online em dois momentos distintos, sendo que a amostra foi constituída inicialmente por 354 professores de Minas Gerais e 317 professores do Quebec. No segundo momento, respectivamente, 274 e 252 professores participaram da pesquisa. Os dados foram coletados entre janeiro e maio de 2013. A análise de correlação mostrou que, tanto os indicadores quanto os fatores que foram analisados apresentaram resultados consistentes com os do modelo de referência. Os resultados mostram que os construtos complementares relacionados ao sentido do trabalho, também foram consistentes com as pesquisas anteriores que subsidiaram a construção do modelo sistêmico de análise da QVT.

Whatman FTA® Cards are a fast and efficient method for capturing and storing nucleic acids but can be cost-prohibitive for large numbers of samples. We developed a method that substitutes a readily-available cellulose matrix and homemade washing buffer for commercial FTA® Cards and FTA® Purification Reagent. This method is suitable for long-term storage of DNA from many plant species prior to PCR.

Purpose: To explore the meaning of work, analyzing and comparing how it is experienced by workers who are subject to different employment relationships. Originality/value: The research is important because it advances in the discussion about the flexibilization of labor relations and its impact on how professionals experience and attribute meaning to their work. In addition, we found a gap in empirical research relating to the meaning of work and different types of employment relationships. Design/methodology/approach: We conducted qualitative and exploratory research with professors from the same higher education institution that work under different employment relationships. Forty-five professors participated in the study, whose reports were submitted to discourse analysis. Findings: Initially, the results reinforced the six categories proposed by Morin (2001): work that 1. generates results; 2. is intrinsically satisfactory; 3. morally acceptable; 4. source of satisfactory relationships; 5. guarantees security and autonomy, and 6. keeps the person occupied. In addition, three new categories associated with the professors' work have been identified: "work as a calling", "work as identity construction", and "work as a masochistic practice". Our results point to the complexity of maintaining professionals working side by side but under different employment relationships. Resentment, anguish, and frustration were some of the feelings that we consider to be associated with this reality, and represent a challenge to be faced by organizations. Objetivo: Explorar o sentido do trabalho, analisando e comparando como ele é vivenciado por trabalhadores submetidos a diferentes vínculos empregatícios. Originalidade/valor: A pesquisa é relevante porque avança na discussão sobre a flexibilização das relações de trabalho e aponta o impacto da flexibilização na forma como profissionais vivenciam o trabalho e atribuem sentido a ele. Ademais, detectamos na literatura uma lacuna em pesquisas empíricas que relacionem sentido do trabalho a diferentes tipos de vínculos empregatícios. Design/metodologia/abordagem: Conduzimos uma pesquisa qualitativa e exploratória com professores de uma mesma instituição de ensino superior (IES), mas que atuam sob diferentes vínculos de trabalho. Participaram da pesquisa 45 docentes, cujos relatos foram submetidos à análise do discurso.

BackgroundInjectable cabotegravir was superior to daily oral tenofovir disoproxil fumarate plus emtricitabine for HIV prevention in two clinical trials. Both trials had the primary aim of establishing the HIV prevention efficacy of long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) compared with tenofovir disoproxil fumarate plus emtricitabine daily oral PrEP. Long-acting PrEP was associated with diagnostic delays and integrase strand-transfer inhibitor (INSTI) resistance. This report presents findings from the first unblinded year of the HIV Prevention Trials Network (HPTN) 083 study.MethodsThe HPTN 083 randomised controlled trial enrolled HIV-uninfected cisgender men and transgender women at elevated HIV risk who have sex with men, from 43 clinical research sites in Africa, Asia, Latin America, and the USA. Inclusion criteria included: a negative HIV serological test at the screening and study entry, undetectable HIV RNA levels within 14 days of study entry, age 18 years or older, overall good health as determined by clinical and laboratory evaluations, and a creatinine clearance of 60 mL/min or higher. Participants were randomly allocated to receive long-acting injectable cabotegravir or daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP. After study unblinding, participants remained on their original regimen awaiting an extension study. HIV infections were characterised retrospectively at a central laboratory. Here we report the secondary analysis of efficacy and safety for the first unblinded year. The primary outcome was incident HIV infection. Efficacy analyses were done on the modified intention-to-treat population using a Cox regression model. Adverse events were compared across treatment groups and time periods (blinded vs unblinded). This trial is registered with ClinicalTrials.gov, NCT02720094.FindingsOf the 4488 participants who contributed person-time to the blinded analysis, 3290 contributed person-time to the first unblinded year analysis between May 15, 2020, and May 14, 2021. Updated HIV incidence in the blinded phase was 0·41 per 100 person-years for long-acting injectable cabotegravir PrEP and 1·29 per 100 person-years for daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP (hazard ratio [HR] 0·31 [95% CI 0·17-0·58], p=0·0003). HIV incidence in the first unblinded year was 0·82 per 100 person-years for long-acting PrEP and 2·27 per 100 person-years for daily oral PrEP (HR 0·35 [0·18-0·69], p=0·002). Adherence to both study products decreased after study unblinding. Additional infections in the long-acting PrEP group included two with on-time injections; three with one or more delayed injections; two detected with long-acting PrEP reinitiation; and 11 more than 6 months after their last injection. Infection within 6 months of cabotegravir exposure was associated with diagnostic delays and INSTI resistance. Adverse events were generally consistent with previous reports; incident hypertension in the long-acting PrEP group requires further investigation.InterpretationLong-acting injectable cabotegravir PrEP retained high efficacy for HIV prevention in men and transgender women who have sex with men during the first year of open-label follow-up, with a near-identical HR for HIV risk reduction between long-acting injectable cabotegravir and daily oral tenofovir disoproxil fumarate plus emtricitabine PrEP during the first year after unblinding compared with the blinded period. Extended follow-up further defined the risk period for diagnostic delays and emergence of INSTI resistance.FundingDivision of AIDS at the National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and Gilead Sciences.

O principal objetivo desse artigo é avaliar os indicadores de qualidade de vida no trabalho (QVT) para os professores universitários, e comparar os indicadores de QVT em universidades públicas no Brasil e no Canadá. A amostra deste estudo é constituída por 205 professores de Minas Gerais e 269 do Quebec. Os dados foram coletados através de um questionário online aplicado em fevereiro e março de 2013. Três diferenças significativas foram encontradas entre as duas amostras: sentido no trabalho, comprometimento afetivo e comprometimento de continuidade. Os professores brasileiros parecem encontrar mais sentido no trabalho do que os canadenses e têm mais comprometimento afetivo com suas instituições.

Objective: Verbal autopsies (VAs) are interviews with a relative or friend of the deceased; VAs are a technique used in surveillance sites in many countries with incomplete death certification. The goal of this study was to assess the accuracy and validity of data on HIV status and antiretroviral therapy (ART) usage reported in VAs and their influence on physician attribution of cause of death. Design: This was a prospective cohort study. Methods: The Karonga Health and Demographic Surveillance Site monitors demographic events in a population in a rural area of northern Malawi; a VA is attempted on all deaths reported. VAs are reviewed by clinicians, who, with additional HIV test information collected pre-mortem, assign a cause of death. We linked HIV/ART information reported by respondents during adult VAs to database information on HIV testing and ART use and analysed agreement using chi-square and kappa statistics. We used multivariable logistic regression to analyse factors associated with agreement. Results: From 2003 to 2014, out of a total of 1,952 VAs, 80% of respondents reported the HIV status of the deceased. In 2013–2014, this figure was 99%. Of those with an HIV status known to the study, there was 89% agreement on HIV status between the VA and pre-mortem data, higher for HIV-negative people (92%) than HIV-positive people (83%). There was 84% agreement on whether the deceased had started ART, and 72% of ART initiation dates matched within 1 year. Conclusions: In this population, HIV/ART information was often disclosed during a VA and matched well with other data sources. Reported HIV/ART status appears to be a reliable source of information to help classification of cause of death.

The original purpose of this study was to conduct an exploratory analysis of the meaning of work to nursing professionals, comparing meanings by hierarchical level (non-degree and college-degreed levels) and by characteristics of the work environment. We applied a structured questionnaire containing scales for the meaning of work, affective commitment, and work stress. Results were treated with descriptive statistics, exploratory factor analysis, correlation analysis, and mean comparison, and confirmed that hierarchical level and work environment define differences in the perception of work meaning and related constructs. Since our field work demanded long hours of permanence in hospitals, the study was enriched with observations and conversations. This combination of methods allowed expanding the knowledge about the factors that elicit experiencing the meaning of work in nursing. Meaning can emerge from factors such as increase in employability, social distinction, work-family harmonization, and the nature of the relationship with managers and leaders. Loss of meaning can cause a drop in productivity and be associated with resistance behaviors or even retaliatory behaviors in the form of absenteeism and changing jobs.

http://dx.doi.org/10.5007/1983-4535.2015v8n4p117 Este estudo avalia a relação entre sentido do trabalho e a orientação para o trabalho de professores universitários de Minas Gerais e do Quebec e correlaciona estes resultados com questões de Qualidade de Vida no Trabalho. A amostra foi constituída por 274 professores de Minas Gerais e 252 professores do Quebec. Os dados foram coletados através de um questionário online enviado, para 3 universidades públicas de Minas Gerais e 3 universidades do Quebec, no primeiro semestre de 2013. Foram encontradas diferenças significativas entre as médias de percepção dos dois grupos de professores para meu trabalho é um emprego e meu trabalho é um carreira. Com relação ao sentido do trabalho e sentido no trabalho observou-se que estes dois indicadores de qualidade de vida no trabalho estão diretamente relacionados com a orientação para a vocação profissional dos professores que participaram da pesquisa. Estes resultados podem orientar os gestores universitários a conduzirem ações que melhorem as condições do ambiente físico de trabalho e as relações de trabalho, pois são estes aspectos que ajudam a melhorar a qualidade de vida no trabalho e a dar mais sentido ao trabalho como um todo.

INTRODUCTION:A global strategy of mass drug administration (MDA) has greatly reduced the burden of lymphatic filariasis (LF) in endemic countries. In Madagascar, the National Programme to eliminate LF has scaled-up annual MDA of albendazole and diethylcarbamazine across the country in the last decade, but its impact on LF transmission has never been reported. The objective of this study was to evaluate progress towards LF elimination in southeastern Madagascar. METHODS:Three different surveys were carried out in parallel in four health districts of the Vatovavy Fitovinany region in 2016: i) a school-based transmission assessment survey (TAS) in the districts of Manakara Atsimo, Mananjary, and Vohipeno (following a successful pre-TAS in 2013); ii) a district-representative community prevalence survey in Ifanadiana district; and iii) a community prevalence survey in sentinel and spot-check sites of these four districts. LF infection was assessed using the Alere Filariasis Test Strips, which detect circulating filarial antigens (CFA) of adult worms. A brief knowledge, attitudes and practices questionnaire was included in the community surveys. PRINCIPAL FINDINGS:None of the 1,825 children sampled in the TAS, and only one in 1,306 children from sentinel and spot-check sites, tested positive to CFA. However, CFA prevalence rate in individuals older than 15 years was still high in two of these three districts, at 3.5 and 9.7% in Mananjary and Vohipeno, respectively. Overall CFA prevalence in sentinel and spot-check sites of these three districts was 2.80% (N = 2,707), but only two individuals had detectable levels of microfilaraemia (0.06%). Prevalence rate estimates for Ifanadiana were substantially higher in the district-representative survey (15.8%; N = 545) than in sentinel and spot-check sites (0.8%; N = 618). Only 51.2% of individuals surveyed in these four districts reported taking MDA in the last year, and 42.2% reported knowing about LF. CONCLUSIONS:Although TAS results suggest that MDA can be stopped in three districts of southeastern Madagascar, the adult population still presents high CFA prevalence levels. This discordance raises important questions about the TAS procedures and the interpretation of their results.

Background: Expanding access to antiretroviral therapy (ART) means that HIV is no longer a death sentence. This change has implications for reproductive decisions and behaviors of HIV-infected individuals. Design: Using multiple rounds of biomarker data from Demographic and Health Surveys (2004–2012) in nine sub-Saharan African countries, we compare patterns of associations between HIV status and fertility intention and between current use of modern contraception and HIV status in the context of expanding ART coverage. Results: Generally, results show that knowledge of HIV status and proportion of women ever tested for HIV increased substantially between the two surveys for almost all countries. Whereas modern contraceptive use slightly increased, fertility intentions remained relatively stable, except for Rwanda, where they decreased. Results from the two surveys for the nine countries do however indicate that there is no clear consistent pattern of fertility intention and modern contraceptive use behavior by HIV status, with variations observed across countries. However, multivariate analyses show that for Rwanda and Zimbabwe women who were HIV positive, with knowledge of their status, had lower odds of wanting more children. Similarly only in Rwanda (both surveys) were HIV-positive women who knew their status more likely to be current users of contraception compared with women who were HIV negative. The reverse was observed for Zimbabwe. Conclusions: Generally, the results point to the fact that the assumption that reproductive intention and behavior of HIV-positive women will differ compared with that of HIV-negative women may only hold true to the extent that women know their HIV status. Continuous expansion of voluntary counseling and testing services and integration of HIV treatment and care services with reproductive health services are thus warranted.

In most organisms, including humans, meiotic recombination occurs preferentially at a limited number of sites in the genome known as hotspots. There has been substantial progress recently in elucidating the factors determining the location of meiotic recombination hotspots, and it is becoming clear that simple sequence motifs play a significant role. In S. pombe, there are at least five unique sequence motifs that have been shown to produce hotspots of recombination, and it is likely that there are more. In S. cerevisiae, simple sequence motifs have also been shown to produce hotspots or show significant correlations with hotspots. Some of the hotspot motifs in both yeasts are known or suspected to bind transcription factors (TFs), which are required for the activity of those hotspots. Here we show that four of the five hotspot motifs identified in S. pombe also create hotspots in the distantly related budding yeast S. cerevisiae. For one of these hotspots, M26 (also called CRE), we identify TFs, Cst6 and Sko1, that activate and inhibit the hotspot, respectively. In addition, two of the hotspot motifs show significant correlations with naturally occurring hotspots. The conservation of these hotspots between the distantly related fission and budding yeasts suggests that these sequence motifs, and others yet to be discovered, may function widely as hotspots in many diverse organisms.

IntroductionInsulin pumps and continuous glucose monitors (CGM) have many benefits in the management of type 1 diabetes. Unfortunately disparities in technology access occur in groups with increased risk for adverse effects (eg, low socioeconomic status [SES], public insurance).Research design & methodsUsing 2015 to 2016 data from 4,895 participants from the T1D Exchange Registry, a structural equation model (SEM) was fit to explore the hypothesized direct and indirect relationships between SES, insurance features, access to diabetes technology, and adverse clinical outcomes (diabetic ketoacidosis, hypoglycemia). SEM was estimated using the maximum likelihood method and standardized path coefficients are presented.ResultsHigher SES and more generous insurance coverage were directly associated with CGM use (β = 1.52, SE = 0.12, P < .0001 and β = 1.21, SE = 0.14, P < .0001, respectively). Though SES displayed a small inverse association with pump use (β = -0.11, SE = 0.04, P = .0097), more generous insurance coverage displayed a stronger direct association with pump use (β = 0.88, SE = 0.10, P < .0001). CGM use and pump use were both directly associated with fewer adverse outcomes (β = -0.23, SE = 0.06, P = .0002 and β = -0.15, SE = 0.04, P = .0002, respectively). Both SES and insurance coverage demonstrated significant indirect effects on adverse outcomes that operated through access to diabetes technology (β = -0.33, SE = 0.09, P = .0002 and β = -0.40, SE = 0.09, P < .0001, respectively).ConclusionsThe association between SES and insurance coverage and adverse outcomes was primarily mediated through diabetes technology use, suggesting that disparities in diabetes outcomes have the potential to be mitigated by addressing the upstream disparities in technology use.

O trabalho representa um valor importante nas sociedades ocidentais contemporâneas, exercendo uma influência considerável sobre a motivação dos trabalhadores, assim como sobre sua satisfação e sua produtividade. Compreender os sentidos do trabalho hoje é um desafio importante para os administradores, tendo em vista as múltiplas transformações que têm atingido as organizações e os “mundos do trabalho”. O objetivo deste artigo é determinar, identificar e comentar as características que o trabalho deveria apresentar a fim de ter um sentido para aqueles que o realizam. Acreditamos que os momentos de transformação organizacional constituem, potencialmente, uma oportunidade para reorganizar o trabalho de tal forma que a qualidade de vida e a eficácia organizacional sejam melhoradas e que as características que se atribuem a um trabalho que tem um sentido possam orientar as decisões e as intervenções dos responsáveis pelos processos de transformação organizacional.

Objective: Intracranial complications of pediatric sinusitis are uncommon but are often associated with significant morbidity, especially when appropriate care is delayed. The present study aimed to identify commonalities for the development and progression of these complications in the pediatric population. Data Sources: CENTRAL, CINAHL, Citation searching, ClinicalTrials.gov, Embase, Google Scholar, MEDLINE, PsycINFO, PubMed, Scopus, Web of Science, and World Health Organization. Review Methods: A comprehensive literature search was performed using Preferred Reporting Items for Systematic Reviews and Meta‐analyses scoping review guidelines. Studies describing intracranial infections secondary to sinusitis in the pediatric population (age <18 years) were included. Studies in which adult and pediatric data were not separated and studies in which the pediatric cohort was fewer than 10 cases were excluded. Ultimately, 33 studies describing 1149 unique patient cases were included for data collection and analysis. Results: Our analysis revealed intracranial complications were more common in adolescent males. Most children presented with over 1 week of vague symptoms, such as headache and fever. The majority of complications were diagnosed radiographically with computed tomography. Subdural empyema and epidural abscess were the most common intracranial complications reported. On average, patients were admitted for over 2 weeks. Most children were treated with a combination of antibiotics and surgical intervention. Complications were rare, but when present, were often associated with significant morbidity. Conclusion: This scoping review of the available literature has provided insight into commonalities among pediatric patients who develop intracranial complications of sinusitis, providing a foundation for further study to inform medical and surgical decision‐making in this population. [ABSTRACT FROM AUTHOR]

IntroductionPeople who inject drugs (PWID) experience high HIV incidence and face significant barriers to engagement in HIV care and substance use treatment. Strategies for HIV treatment as prevention and substance use treatment present unique challenges in PWID that may vary regionally. Understanding differences in the risk structure for HIV transmission and disease progression among PWID is essential in developing and effectively targeting intervention strategies of HIV treatment as prevention.MethodsWe present a baseline analysis of HIV Prevention Trials Network (HPTN) 074, a two-arm, randomized controlled trial among PWID in Indonesia (n = 258), Ukraine (n = 457) and Vietnam (n = 439). HPTN 074 was designed to determine the feasibility, barriers and uptake of an integrated intervention combining health systems navigation and psychosocial counselling for the early engagement of antiretroviral therapy (ART) and substance use treatment for PWID living with HIV. Discordant PWID networks were enrolled, consisting of an HIV-positive index and their HIV-negative network injection partner(s). Among the enrolled cohort of 1154 participants (502 index participants and 652 network partners), we examine regional differences in the baseline risk structure, including sociodemographics, HIV and substance use treatment history, and injection and sexual risk behaviours.ResultsThe majority of participants were male (87%), with 82% of the enrolled females coming from Ukraine. The overall mean age was 34 (IQR: 30, 38). Most commonly injected substances included illegally manufactured methadone in Ukraine (84.2%), and heroin in Indonesia (81.8%) and Vietnam (99.5%). Injection network sizes varied by region: median number of people with whom participants self-reported injecting drugs was 3 (IQR: 2, 5) in Indonesia, 5 (IQR: 3, 10) in Ukraine and 3 (IQR: 2, 4) in Vietnam. Hazardous alcohol use, assessed using the Alcohol Use Disorders Identification Test - Alcohol Consumption Questions (AUDIT-C), was prominent in Ukraine (54.7%) and Vietnam (26.4%). Reported sexual risk behaviours in the past month, including having two or more sex partners and giving/receiving money or drugs in exchange for sex, were uncommon among all participants and regions.ConclusionsWhile regional differences in risk structure exist, PWID particularly in Ukraine need immediate attention for risk reduction strategies. Substantial regional differences in risk structure will require flexible, tailored treatment as prevention interventions for distinct PWID populations.

BackgroundPeople who inject drugs (PWID) have a high incidence of HIV, little access to antiretroviral therapy (ART) and medication-assisted treatment (MAT), and high mortality. We aimed to assess the feasibility of a future controlled trial based on the incidence of HIV, enrolment, retention, and uptake of the intervention, and the efficacy of an integrated and flexible intervention on ART use, viral suppression, and MAT use.MethodsThis randomised, controlled vanguard study was run in Kyiv, Ukraine (one community site), Thai Nguyen, Vietnam (two district health centre sites), and Jakarta, Indonesia (one hospital site). PWID who were HIV infected (index participants) and non-infected injection partners were recruited as PWID network units and were eligible for screening if they were aged 18-45 years (updated to 18-60 years 8 months into study), and active injection drug users. Further eligibility criteria for index participants included a viral load of 1000 copies per mL or higher, willingness and ability to recruit at least one injection partner who would be willing to participate. Index participants were randomly assigned via a computer generated sequence accessed through a secure web portal (3:1) to standard of care or intervention, stratified by site. Masking of assignment was not possible due to the nature of intervention. The intervention comprised systems navigation, psychosocial counselling, and ART at any CD4 count. Local ART and MAT services were used. Participants were followed up for 12-24 months. The primary objective was to assess the feasibility of a future randomised controlled trial. To achieve this aim we looked at the following endpoints: HIV incidence among injection partners in the standard of care group, and enrolment and retention of HIV-infected PWID and their injection partners and the uptake of the integrated intervention. The study was also designed to assess the feasibility, barriers, and uptake of the integrated intervention. Endpoints were assessed in a modified intention-to-treat popualtion after exclusion of ineligible participants. This trial is registered on ClinicalTrials.gov, NCT02935296, and is active but not recruiting new participants.FindingsBetween Feb 5, 2015, and June 3, 2016, 3343 potential index participants were screened, of whom 502 (15%) were eligible and enrolled. 1171 injection partners were referred, and 806 (69%) were eligible and enrolled. Index participants were randomly assigned to intervention (126 [25%]) and standard of care (376 [75%]) groups. At week 52, most living index participants (389 [86%] of 451) and partners (567 [80%] of 710) were retained, and self-reported ART use was higher among index participants in the intervention group than those in the standard of care group (probability ratio [PR] 1·7, 95% CI 1·4-1·9). Viral suppression was also higher in the intervention group than in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Index participants in the intervention group reported more MAT use at 52 weeks than those in the standard of care group (PR 1·7, 95% CI 1·3-2·2). Seven incident HIV infections occurred, and all in injection partners in the standard of care group (intervention incidence 0·0 per 100 person-years, 95% CI 0·0-1·7; standard of care incidence 1·0 per 100 person-years, 95% CI 0·4-2·1; incidence rate difference -1·0 per 100 person-years, 95% CI -2·1 to 1·1). No severe adverse events due to the intervention were recorded.InterpretationThis vanguard study provides evidence that a flexible, scalable intervention increases ART and MAT use and reduces mortality among PWID. The low incidence of HIV in both groups impedes a future randomised, controlled trial, but given the strength of the effect of the intervention, its implementation among HIV-infected PWID should be considered.FundingUS National Institutes of Health.

Anti-tumour T cell responses play a crucial role in controlling the progression of colorectal cancer (CRC), making this disease a promising candidate for immunotherapy. However, responses to immune-targeted therapies are currently limited to subpopulations of patients and specific types of cancer. Clinical studies have therefore focussed on identifying biomarkers that predict immunotherapy responses and elucidating the immunological landscapes of different cancers. Meanwhile, our understanding of how preclinical tumour models resemble human disease has fallen behind, despite their crucial role in immune-targeted drug development. A deeper understanding of these models is therefore needed to improve the development of immunotherapies and the translation of findings made in these systems. MC38 colon adenocarcinoma is a widely used preclinical model, yet how it recapitulates human colorectal cancer remains poorly defined. This study investigated the tumour-T cell immune landscape of MC38 tumours using histology, immunohistochemistry, and flow cytometry. We demonstrate that early-stage tumours exhibit a nascent TME, lacking important immune-resistance mechanisms of clinical interest, while latestage tumours exhibit a mature TME resembling human tumours, with desmoplasia, T cell exhaustion, and T cell exclusion. Consequently, these findings clarify appropriate timepoint selection in the MC38 model when investigating both immunotherapies and mechanisms that contribute to immunotherapy resistance. Overall, this study provides a valuable resource that will enable appropriate application of the MC38 model and expedite the development and clinical translation of new immunotherapies. [ABSTRACT FROM AUTHOR]