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ABSTRACT: Background: Free flap reconstructions are an important reconstructive option for soft tissue defects in mangled lower extremities. Microsurgery facilitates soft tissue coverage of defects that otherwise would result in amputation. However, the success rates of traumatic lower extremity free flap reconstructions remain lower than those in other locations. Nevertheless, post-free flap failure salvage strategies have rarely been addressed. Therefore, the current review aims to provide an overview of post-free flap failure strategies in lower extremity trauma and their subsequent outcomes. Methods: A search of Pubmed, Cochrane, and Embase databases was performed on June 9, June 2021 using the following medical subject headings (MeSH) search terms: ‘lower extremity’, ‘leg injuries’, ‘reconstructive surgical procedures’, ‘reoperation’, ‘microsurgery’ and ‘treatment failure’. This review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Partial and total free flap failures after traumatic reconstruction were included. Results: Twenty-eight studies with a total of 102 free flap failures fulfilled the eligibility criteria. Following the total failure, a second free flap is the predominant reconstructive strategy (69%). In comparison to the failure rate of a first free flap (10%), the fate of a second free flap is less favorable with a failure rate of 17%. The amputation rate following flap failure is 12%. The risk of amputation increases between primary and secondary free flap failures. After partial flap loss, the preferred strategy is a split skin graft (50%). Conclusion: To our knowledge, this is the first systematic review on the outcome of salvage strategies after free flap failure in traumatic lower extremity reconstruction. This review provides valuable evidence to take into consideration in the decision-making regarding post-free flap failure strategies.

BackgroundTens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.MethodsIn this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).FindingsIn total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children

Post-traumatic critical-sized bone defects pose a reconstructive challenge for reconstructive surgeons. The vascularized fibula graft is a well-described treatment for osseous defects of the femur and tibia. This study aimed to assess long-term patient-reported quality of life, the success-, and complication rates in lower extremity reconstruction with vascularized fibula grafts. A retrospective cohort of 29 patients who underwent fibula graft reconstruction for critical-sized bone defects after post-traumatic tibial and femoral bone loss between 1990 and 2021 was included. To assess the health-related quality of life and return to work and satisfaction, a cross-sectional survey was performed using the short-form-36, lower extremity functional scale, and a self-made questionnaire including the DN4, satisfaction, and subjective ankle function. The median bone defect size was 8 cm (IQR 9–7 cm). The mental component scores were comparable to the Dutch population norm, whereas the impaired physical function scores were associated with pain (r 0.849, p < 0.001). Neuropathic symptoms were reported in 7 out of 19 patients, and 11 out of 19 patients returned to normal daily activity. All respondents reported positive or neutral scores on overall satisfaction with the recovery. Bone healing was uneventful in 19 out of 29 patients. Union was achieved in 25 out of 29 patients. Persistent nonunion was observed in 4 patients, leading to amputation in 2 patients. Vascularized fibula graft use led to high union rates and limb salvage in patients with post-traumatic segmental bone loss of the tibia and femur. Patient satisfaction with the overall recovery was positive; however, functional outcomes remained impaired. [ABSTRACT FROM AUTHOR]

Abstract Postmenopausal women and renal transplant recipients are at increased risk of recurrent urinary tract infections (RUTI). Urine and vaginal microbiota of premenopausal controls (N = 18) and RUTI cases (18), and of postmenopausal controls (30) and RUTI cases (20) with and without a renal transplant, were characterized using 16S rRNA sequencing. Participants did not have UTI symptoms at the time of sampling. Gram-negative uropathobionts (predominantly Escherichia/Shigella, Pseudomonas, Klebsiella, and Acinetobacter) had a much higher mean relative abundance in urine than vaginal samples, especially in premenopausal women. No statistically significant differences in mean relative abundances of bacterial groups were found within the premenopausal group or within the postmenopausal group by RUTI or renal transplant status without chronic antibiotic use. Comparing postmenopausal to premenopausal women, mean relative abundances of lactobacilli (especially L. crispatus) in urine and vaginal samples and of Gram-negative uropathobionts in urine were lower, and of BV-anaerobes and Gram-positive uropathobionts in urine and vaginal samples were higher. While RUTI in premenopausal women is predominantly caused by Escherichia, the causative organisms in postmenopausal women are likely more diverse. The relative importance of individual organisms is currently unknown. We recommend that future studies, including intervention studies, include longitudinal microbiota assessments.

The blood-brain barrier separates circulating blood from the central nervous system (CNS). The scope of this barrier is not fully understood which limits our ability to relate biological measurements from peripheral to central phenotypes. For example, it is unknown to what extent gene expression levels in peripheral blood are reflective of CNS metabolism. In this study, we examine links between central monoamine metabolite levels and whole-blood gene expression to better understand the connection between peripheral systems and the CNS. To that end, we correlated the prime monoamine metabolites in cerebrospinal fluid (CSF) with whole-genome gene expression microarray data from blood (N=240 human subjects). We additionally applied gene-enrichment analysis and weighted gene co-expression network analyses (WGCNA) to identify modules of co-expressed genes in blood that may be involved with monoamine metabolite levels in CSF. Transcript levels of two genes were significantly associated with CSF serotonin metabolite levels after Bonferroni correction for multiple testing: THAP7 (P=2.8 × 10-8, β=0.08) and DDX6 (P=2.9 × 10-7, β=0.07). Differentially expressed genes were significantly enriched for genes expressed in the brain tissue (P=6.0 × 10-52). WGCNA revealed significant correlations between serotonin metabolism and hub genes with known functions in serotonin metabolism, for example, HTR2A and COMT. We conclude that gene expression levels in whole blood are associated with monoamine metabolite levels in the human CSF. Our results, including the strong enrichment of brain-expressed genes, illustrate that gene expression profiles in peripheral blood can be relevant for quantitative metabolic phenotypes in the CNS.

Abstract Background Adolescents are a prime target group for tuberculosis (TB) vaccine trials that include prevention of infection (POI). The BCG vaccine is given at birth and does not prevent TB infection. TB infection, a critical endpoint for POI vaccine trials would need to be documented to estimate sample sizes in target populations. Methods Adolescents aged 12–18 years of age were enrolled in an area under continuous demographic surveillance. A tuberculin skin test (TST) survey was conducted as part of a study on TB prevalence and incidence. All adolescents got TSTs at enrolment and returned after 72 h for reading. A TST of ≥10 mm if HIV negative or ≥ 5 mm if HIV positive, was considered positive. Results Of 4808 adolescents returning for TST readings (96% of those enrolled), mean age was 14.4 (SD 1.9), 4518(94%) were enrolled in school and 21(0.4%) gave a previous history of tuberculosis. Among adolescents with TST reactivity, the mean TST induration was 13.2 mm (SD 5.4). The overall prevalence of latent TB infection was 1544/4808 (32.1, 95% CI 29.2–35.1) with a corresponding annual risk of TB infection (ARTI) of 2.6% (95% CI 2.2–3.1). Risk factors for a positive TST included being male (OR 1.3, 95% CI 1.2,1.5), history of having a household TB contact (OR 1.5, 95% CI 1.2,1.8), having a BCG scar (OR 1.5,95% CI 1.2,1.8), living in a rural area (OR 1.4, 95% CI 1.1,1.9), and being out of school (OR 1.8, 95% CI 1.4,2.3). Conclusion We conclude that the high TB transmission rates we found in this study, suggest that adolescents in this region may be an appropriate target group for TB vaccine trials including TB vaccine trials aiming to prevent infection.

Studying monoaminergic seasonality is likely to improve our understanding of neurobiological mechanisms underlying season-associated physiological and pathophysiological behavior. Studies of monoaminergic seasonality and the influence of the serotonin-transporter-linked polymorphic region (5-HTTLPR) on serotonin seasonality have yielded conflicting results, possibly due to lack of power and absence of multi-year analyses. We aimed to assess the extent of seasonal monoamine turnover and examined the possible involvement of the 5-HTTLPR. To determine the influence of seasonality on monoamine turnover, 5-hydroxyindoleacetic acid (5-HIAA) and homovanillic acid (HVA) were measured in the cerebrospinal fluid of 479 human subjects collected during a 3-year period. Cosine and non-parametric seasonal modeling were applied to both metabolites. We computed serotonin (5-HT) seasonality values and performed an association analysis with the s/l alleles of the 5-HTTLPR. Depressive symptomatology was assessed using the Beck Depression Inventory-II. Circannual variation in 5-HIAA fitted a spring-peak cosine model that was significantly associated with sampling month (P=0.0074). Season of sampling explained 5.4% (P=1.57 × 10(-7)) of the variance in 5-HIAA concentrations. The 5-HTTLPR s-allele was associated with increased 5-HIAA seasonality (standardized regression coefficient=0.12, P=0.020, N=393). 5-HIAA seasonality correlated with depressive symptoms (Spearman's rho=0.13, P=0.018, N=345). In conclusion, we highlight a dose-dependent association of the 5-HTTLPR with 5-HIAA seasonality and a positive correlation between 5-HIAA seasonality and depressive symptomatology. The presented data set the stage for follow-up in clinical populations with a role for seasonality, such as affective disorders.

BackgroundAnimal studies have revealed seasonal patterns in cerebrospinal fluid (CSF) monoamine (MA) turnover. In humans, no study had systematically assessed seasonal patterns in CSF MA turnover in a large set of healthy adults.Methodology/principal findingsStandardized amounts of CSF were prospectively collected from 223 healthy individuals undergoing spinal anesthesia for minor surgical procedures. The metabolites of serotonin (5-hydroxyindoleacetic acid, 5-HIAA), dopamine (homovanillic acid, HVA) and norepinephrine (3-methoxy-4-hydroxyphenylglycol, MPHG) were measured using high performance liquid chromatography (HPLC). Concentration measurements by sampling and birth dates were modeled using a non-linear quantile cosine function and locally weighted scatterplot smoothing (LOESS, span = 0.75). The cosine model showed a unimodal season of sampling 5-HIAA zenith in April and a nadir in October (p-value of the amplitude of the cosine = 0.00050), with predicted maximum (PC(max)) and minimum (PC(min)) concentrations of 173 and 108 nmol/L, respectively, implying a 60% increase from trough to peak. Season of birth showed a unimodal 5-HIAA zenith in May and a nadir in November (p = 0.00339; PC(max) = 172 and PC(min) = 126). The non-parametric LOESS showed a similar pattern to the cosine in both season of sampling and season of birth models, validating the cosine model. A final model including both sampling and birth months demonstrated that both sampling and birth seasons were independent predictors of 5-HIAA concentrations.ConclusionIn subjects without mental illness, 5-HT turnover shows circannual variation by season of sampling as well as season of birth, with peaks in spring and troughs in fall.

Sequencing studies have shown that optimal vaginal microbiota (VMB) are lactobacilli-dominated and that anaerobes associated with bacterial vaginosis (BV-anaerobes) are commonly present. However, they overlooked a less prevalent but more pathogenic group of vaginal bacteria: the pathobionts that cause maternal and neonatal infections and pelvic inflammatory disease. We conducted an individual participant data meta-analysis of three VMB sequencing studies that included diverse groups of women in Rwanda, South Africa, and the Netherlands (2,044 samples from 1,163 women in total). We identified 40 pathobiont taxa but only six were non-minority taxa (at least 1% relative abundance in at least one sample) in all studies: Streptococcus (54% of pathobionts reads), Staphylococcus, Enterococcus, Escherichia/Shigella, Haemophilus, and Campylobacter. When all pathobionts were combined into one bacterial group, the VMB of 17% of women contained a relative abundance of at least 1%. We found a significant negative correlation between relative abundances (ρ = −0.9234), but not estimated concentrations (r = 0.0031), of lactobacilli and BV-anaerobes; and a significant positive correlation between estimated concentrations of pathobionts and BV-anaerobes (r = 0.1938) but not between pathobionts and lactobacilli (r = 0.0436; although lactobacilli declined non-significantly with increasing pathobionts proportions). VMB sequencing data were also classified into mutually exclusive VMB types. The overall mean bacterial load of the ≥20% pathobionts VMB type (5.85 log10 cells/μl) was similar to those of the three lactobacilli-dominated VMB types (means 5.13–5.83 log10 cells/μl) but lower than those of the four anaerobic dysbiosis VMB types (means 6.11–6.87 log10 cells/μl). These results suggest that pathobionts co-occur with both lactobacilli and BV-anaerobes and do not expand as much as BV-anaerobes do in a dysbiotic situation. Pathobionts detection/levels were increased in samples with a Nugent score of 4–6 in both studies that conducted Nugent-scoring. Having pathobionts was positively associated with young age, non-Dutch origin, hormonal contraceptive use, smoking, antibiotic use in the 14 days prior to sampling, HIV status, and the presence of sexually transmitted pathogens, in at least one but not all studies; inconsistently associated with sexual risk-taking and unusual vaginal discharge reporting; and not associated with vaginal yeasts detection by microscopy. We recommend that future VMB studies quantify common vaginal pathobiont genera.

Abstract Background HIV is a major driver of the tuberculosis epidemic in sub-Saharan Africa. The population-level impact of antiretroviral therapy (ART) scale-up on tuberculosis rates in this region has not been well studied. We conducted a descriptive analysis to examine evidence of population-level effect of ART on tuberculosis by comparing trends in estimated tuberculosis notification rates, by HIV status, for countries in sub-Saharan Africa. Methods We estimated annual tuberculosis notification rates, stratified by HIV status during 2010–2015 using data from WHO, the Joint United Nations Programme on HIV/AIDS, and the United Nations Population Division. Countries were included in this analysis if they had ≥4 years of HIV prevalence estimates and ≥ 75% of tuberculosis patients with known HIV status. We compared tuberculosis notification rates among people living with HIV (PLHIV) and people without HIV via Wilcoxon rank sum test. Results Among 23 included countries, the median annual average change in tuberculosis notification rates among PLHIV during 2010–2015 was -5.7% (IQR -6.9 to -1.7%), compared to a median change of -2.3% (IQR -4.2 to -0.1%) among people without HIV (p-value = 0.0099). Among 11 countries with higher ART coverage, the median annual average change in TB notification rates among PLHIV was -6.8% (IQR -7.6 to -5.7%) compared to a median change of -2.1% (IQR -6.0 to 0.7%) for PLHIV in 12 countries with lower ART coverage (p = 0.0106). Conclusion Tuberculosis notification rates declined more among PLHIV than people without HIV, and have declined more in countries with higher ART coverage. These results are consistent with a population-level effect of ART on decreasing TB incidence among PLHIV. To further reduce TB incidence among PLHIV, additional scale-up of ART as well as greater use of isoniazid preventive therapy and active case-finding will be necessary.

Abstract Background Tuberculosis (TB) case finding is an important component of TB control because it can reduce transmission of Mycobacterium tuberculosis (MTB) through prompt detection and treatment of infectious patients. Methods Using population-based infectious disease surveillance (PBIDS) platforms with links to health facilities in Kenya we implemented intensified TB case finding in the community and at the health facilities, as an adjunct to routine passive case finding conducted by the national TB program. From 2011 to 2014, PBIDS participants ≥15 years were screened either at home or health facilities for possible TB symptoms which included cough, fever, night sweats or weight loss in the preceding 2 weeks. At home, participants with possible TB symptoms had expectorated sputum collected. At the clinic, HIV-infected participants with possible TB symptoms were invited to produce sputum. Those without HIV but with symptoms lasting 7 days including the visit day had chest radiographs performed, and had sputum collected if the radiographs were abnormal. Sputum samples were tested for the presence of MTB using the Xpert MTB/RIF assay. TB detection rates were calculated per 100,000 persons screened. Results Of 11,191 participants aged ≥15 years screened at home at both sites, 2695 (23.9%) reported possible TB symptoms, of whom 2258 (83.8%) produced sputum specimens. MTB was detected in 32 (1.4%) of the specimens resulting in a detection rate of 286/100,000 persons screened. At the health facilities, a total of 11,762 person were screened, 7500 (63.8%) had possible TB symptoms of whom 1282 (17.1%) produced sputum samples. MTB was detected in 69 (5.4%) of the samples, resulting in an overall detection rate of 587/100,000 persons screened. The TB detection rate was higher in persons with HIV compared to those without at both home (HIV-infected - 769/100,000, HIV-uninfected 141/100,000, rate ratio (RR) – 5.45, 95% CI 3.25–22.37), and health facilities (HIV-infected 3399/100,000, HIV-uninfected 294/100,000, RR 11.56, 95% CI 6.18–18.44). Conclusion Facility-based intensified TB case finding detected more TB cases per the number of specimens tested and the number of persons screened, including those with HIV, than home-based TB screening and should be further evaluated to determine its potential programmatic impact.

BackgroundDevelopment of new, effective, and affordable tuberculosis (TB) therapies has been identified as a critical priority for global TB control. As new candidates emerge from the global TB drug pipeline, the potential impacts of novel, shorter regimens on TB incidence and mortality have not yet been examined.Methods and findingsWe used a mathematical model of TB to evaluate the expected benefits of shortening the duration of effective chemotherapy for active pulmonary TB. First, we considered general relationships between treatment duration and TB dynamics. Next, as a specific example, we calibrated the model to reflect the current situation in the South-East Asia region. We found that even with continued and rapid progress in scaling up the World Health Organization's DOTS strategy of directly observed, short-course chemotherapy, the benefits of reducing treatment duration would be substantial. Compared to a baseline of continuing DOTS coverage at current levels, and with currently available tools, a 2-mo regimen introduced by 2012 could prevent around 20% (range 13%-28%) of new cases and 25% (range 19%-29%) of TB deaths in South-East Asia between 2012 and 2030. If effective treatment with existing drugs expands rapidly, overall incremental benefits of shorter regimens would be lower, but would remain considerable (13% [range 8%-19%] and 19% [range 15%-23%] reductions in incidence and mortality, respectively, between 2012 and 2030). A ten-year delay in the introduction of new drugs would erase nearly three-fourths of the total expected benefits in this region through 2030.ConclusionsThe introduction of new, shorter treatment regimens could dramatically accelerate the reductions in TB incidence and mortality that are expected under current regimens-with up to 2- or 3-fold increases in rates of decline if shorter regimens are accompanied by enhanced case detection. Continued progress in reducing the global TB burden will require a balanced approach to pursuing new technologies while promoting wider implementation of proven strategies.

Desde a década de 1990, o debate internacional sobre a pesquisa artística tem se ampliado. Países como Finlândia (pioneira), Reino Unido, Holanda, Suécia, Canadá, Austrália e África do Sul tem tido sucesso no reconhecimento da “pesquisa nas artes”, a abordagem mais diferenciada dentro da pesquisa artística, chegando em alguns casos a inseri-la em documentos governamentais que regem as políticas públicas de Educação e pesquisa acadêmica. Desde 2010, a literatura sobre pesquisa artística tem sido sensivelmente ampliada, destacando-se The Conflict of the Faculties: Perspectives on Artistic Research and Academia do musicólogo holandês Henk Borgdorff. Esse livro traz textos que tiveram significativo impacto no debate sobre a pesquisa artística, a exemplo do segundo capítulo – The Debate on Research in the Arts. Aqui, apresenta-se a tradução para o português de seu primeiro capítulo, cujo título dá origem àquele escolhido para o livro e oferece um panorama inicial sobre o tema.

INTRODUCTION: To determine the predictors of mortality in infants in Siaya, western Kenya, ahead of novel tuberculosis (TB) vaccine trials in the same population. METHODS: in a study to determine tuberculosis incidence, 2900 infants aged 0-45 days, weighing e" 1700g were enrolled. Four monthly follow up visits were conducted for at least 12 months. HIV testing was done at six weeks of age. Free ancillary care was provided. Deaths were reported by parents, study staff and community workers. Cox proportional Hazard analysis was used to identify risk factors. The period of analysis commenced at six weeks old and was censored at 12 months of age. RESULTS: included in the analysis were 2528 infants with 2020 person years of follow up (pyo). There were 117 deaths (4.6 %). The post-neonatal mortality rate was 58 (95% CI: 48, 69) per 1000 pyo. In multivariate analysis, health facility births were protective against mortality (Hazard Ratio (HR) 0.54; 95% CI: 0.34, 0.84) and infant HIV infection at baseline was associated with increased mortality (HR 10.3; 95% CI: 6.40, 16.7). HIV uninfected infants born to HIV infected mothers had increased hazards of mortality (HR 1.73; 95% CI: 1.03, 2.90). Gender, weight at six weeks, maternal education and occupation were not significant predictors of mortality. CONCLUSION: infant mortality was high and was associated with being born outside a health facility, maternal HIV infection and HIV infection of the infant. Measures to decrease mother to child transmission and other HIV control measures need to be strengthened further to see incremental reductions in infant mortality.

Objective: The aim of this study was to determine the prevalence of tuberculosis (TB) in adolescents in western Kenya. Methods: A cohort study of 5004 adolescents aged 12–18 years was conducted. Adolescents were screened for prevalent TB using clinical criteria, history of TB contact, and a Mantoux test. Cases of suspected TB were investigated through two sputum examinations (microscopy and liquid culture) and chest radiography. Results: Out of 5004 adolescents enrolled, 1960 (39.2%) were identified with suspected TB, including 1544 with a positive Mantoux (prevalence 1544/4808, 32.1%), 515 with symptoms suggestive of TB (10.3%), and 144 (2.9%) with household TB contact. Sixteen culture-confirmed (definite) and 18 probable pulmonary TB (PTB) cases were identified, reflecting a prevalence estimate of 3.2/1000 (definite) and 6.8/1000 all PTB, respectively. Only one smear-positive case was detected. The case notification rate among 12–18-year-old adolescents for all TB was 101/100 000, yielding a patient diagnostic rate of 0.13 (95% confidence interval 0.03–3.7) cases detected per person-year for all TB. Conclusion: The prevalence of PTB among adolescents is high, with the majority of cases not detected routinely. Innovative active case finding including the wider use of Xpert MTB/RIF is needed to detect smear-negative TB among adolescents.

Background: Current diagnostic tests cannot identify which infected individuals are at risk for progression to tuberculosis (TB). Our aim was to identify biomarkers which can predict the development of TB prior to clinical diagnosis. Method: In a retrospective case–control study, RNA of 14 HIV-infected drug users obtained before TB diagnosis (cases) and of 15 who did not develop TB (controls) was analyzed for the expression of 141 genes by dcRT-MLPA followed by Lasso regression analysis. Findings: A combined analysis of IL13 and AIRE had the highest discriminatory power to identify cases up to 8 months prior to clinical diagnosis. Cases expressing IL13 had a gene expression pattern strongly enriched for type I IFN related signaling genes, suggesting that these genes represent processes that contribute to TB pathogenesis. Interpretation: We here demonstrated that biomarkers, such as IL13-AIRE, can identify individuals that progress to TB within a high risk population, months prior to clinical diagnosis.

Mortality from TB continues to be a global public health challenge. TB ranks alongside Human Immunodeficiency Virus (HIV) as the leading infectious causes of death globally. HIV is a major driver of TB related morbidity and mortality while TB is the leading cause of mortality among people living with HIV/AIDS. We sought to determine excess mortality associated with HIV and the effect of antiretroviral therapy on reducing mortality among tuberculosis patients in Kenya.We conducted a retrospective analysis of Kenya national tuberculosis program data of patients enrolled from 2013 through 2014. We used direct standardization to obtain standardized mortality ratios for tuberculosis patients compared with the general population. We calculated the population attributable fraction of tuberculosis deaths due to HIV based on the standardized mortality ratio for deaths among TB patients with HIV compared to TB patients without HIV. We used Cox proportional hazards regression for assessing risk factors for mortality.Of 162,014 patients included in the analysis, 6% died. Mortality was 10.6 (95% CI: 10.4-10.8) times higher among TB patients than the general population; 42% of deaths were attributable to HIV infection. Patients with HIV who were not receiving ART had an over four-fold risk of death compared to patients without HIV (aHR = 4.2, 95% CI 3.9-4.6). In contrast, patients with HIV who were receiving ART had only 2.6 times the risk of death (aHR = 2.6, 95% CI 2.5-2.7).HIV was a significant contributor to TB-associated deaths in Kenya. Mortality among HIV-infected individuals was higher among those not on ART than those on ART. Early initiation of ART among HIV infected people (a "test and treat" approach) should further reduce TB-associated deaths.

To evaluate whether ethnicity is independently associated with vaginal microbiota (VMB) composition in women living in Amsterdam, the Netherlands, as has been shown for American women.Women (18-34 years, non-pregnant, N = 610) representing the six largest ethnic groups (Dutch, African Surinamese, South-Asian Surinamese, Turkish, Moroccan, and Ghanaian) were sampled from the population-based HELIUS study. Sampling was performed irrespective of health status or healthcare seeking behavior. DNA was extracted from self-sampled vaginal swabs and sequenced by Illumina MiSeq (16S rRNA gene V3-V4 region).The overall prevalence of VMBs not dominated by lactobacilli was 38.5%: 32.2% had a VMB resembling bacterial vaginosis and another 6.2% had a VMB dominated by Bifidobacteriaceae (not including Gardnerella vaginalis), Corynebacterium, or pathobionts (streptococci, staphylococci, Proteus or Enterobacteriaceae). The most prevalent VMB in ethnically Dutch women was a Lactobacillus crispatus-dominated VMB, in African Surinamese and Ghanaian women a polybacterial G. vaginalis-containing VMB, and in the other ethnic groups a L. iners-dominated VMB. After adjustment for sociodemographic, behavioral and clinical factors, African Surinamese ethnicity (adjusted odds ratio (aOR) 5.1, 95% confidence interval (CI) 2.1-12.0) and Ghanaian ethnicity (aOR 4.8, 95% CI 1.8-12.6) were associated with having a polybacterial G. vaginalis-containing VMB, and African Surinamese ethnicity with a L. iners-dominated VMB (aOR 2.8, 95% CI 1.2-6.2). Shorter steady relationship duration, inconsistent condom use with casual partners, and not using hormonal contraception were also associated with having a polybacterial G. vaginalis-containing VMB, but human papillomavirus infection was not. Other sexually transmitted infections were uncommon.The overall prevalence of having a VMB not dominated by lactobacilli in this population-based cohort of women aged 18-34 years in Amsterdam was high (38.5%), and women of sub-Saharan African descent were significantly more likely to have a polybacterial G. vaginalis-containing VMB than Dutch women independent of modifiable behaviors.

In the last four decades, enormous progress has been made in the treatment of congenital heart diseases (CHD); most patients now survive into adulthood, albeit with residual lesions. As a consequence, the focus has shifted from initial treatment to long-term morbidity and mortality. An important predictor for long-term outcome is right ventricular (RV) dysfunction, but knowledge on the mechanisms of RV adaptation and dysfunction is still scarce. This review will summarize the main features of RV adaptation to CHD, focusing on recent knowledge obtained in experimental models of the most prevalent abnormal loading conditions, i.e., pressure load and volume load. Models of increased pressure load for the RV have shown a similar pattern of responses, i.e., increased contractility, RV dilatation and hypertrophy. Evidence is accumulating that RV failure in response to increased pressure load is marked by progressive diastolic dysfunction. The mechanisms of this progressive dysfunction are insufficiently known. The RV response to pressure load shares similarities with that of the LV, but also has specific features, e.g., capillary rarefaction, oxidative stress and inflammation. The contribution of these pathways to the development of failure needs further exploration. The RV adaptation to increased volume load is an understudied area, but becomes increasingly important in the growing groups of survivors of CHD, especially with tetralogy of Fallot. Recently developed animal models may add to the investigation of the mechanisms of RV adaptation and failure, leading to the development of new RV-specific therapies.

BACKGROUND:A Lactobacillus-dominated cervicovaginal microbiota (VMB) protects women from adverse reproductive health outcomes, but the role of L. iners in the VMB is poorly understood. Our aim was to explore the association between the cervicovaginal L. iners and L. crispatus proteomes and VMB composition. METHODS:The vaginal proteomes of 50 Rwandan women at high HIV risk, grouped into four VMB groups (based on 16S rDNA microarray results), were investigated by mass spectrometry using cervicovaginal lavage (CVL) samples. Only samples with positive 16S results for L. iners and/or L. crispatus within each group were included in subsequent comparative protein analyses: Lactobacillus crispatus-dominated VMB cluster (with 16S-proven L. iners (ni) = 0, and with 16S-proven L. crispatus (nc) = 5), L. iners-dominated VMB cluster (ni = 11, nc = 4), moderate dysbiosis (ni = 12, nc = 2); and severe dysbiosis (ni = 8, nc = 2). The relative abundances of proteins that were considered specific for L. iners and L. crispatus were compared among VMB groups. RESULTS:Forty Lactobacillus proteins were identified of which 7 were specific for L. iners and 11 for L. crispatus. The relative abundances of L. iners DNA starvation/stationary phase protection protein (DPS), and the glycolysis enzymes glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and glucose-6-phosphate isomerase (GPI), were significantly decreased in women with L. iners-containing dysbiosis compared to women with a L. iners-dominated VMB, independent of vaginal pH and L. iners abundance. Furthermore, L. iners DPS, GAPDH, GPI, and fructose-bisphosphate aldolase (ALDO) were significantly negatively associated with vaginal pH. Glycolysis enzymes of L. crispatus showed a similar negative, but nonsignificant, trend related to dysbiosis. CONCLUSIONS:Most identified Lactobacillus proteins had conserved intracellular functions, but their high abundance in CVL supernatant might imply an additional extracellular (moonlighting) role. Our findings suggest that these proteins can be important in maintaining a Lactobacillus-dominated VMB. Functional studies are needed to investigate their roles in vaginal bacterial communities and whether they can be used to prevent vaginal dysbiosis.

We conducted a case–control study to investigate risk factors for multidrug-resistant tuberculosis (MDR TB) in the People’s Republic of China. Genotyping analysis was used to estimate the percentage of cases from recent transmission among 100 MDR TB case-patients hospitalized during April 2007–July 2009. Molecular subtyping of isolates showed that 41% of MDR TB strains clustered. Beijing genotype was found in 94% of the MDR TB isolates and 79% of the pan-susceptible isolates. In multivariate analysis, MDR TB was independently associated with Beijing genotype, retreatment for TB, symptoms lasting >3 months before first evaluation at the hospital, lack of health insurance, and being a farmer (vs. being a student). MDR TB was associated with Beijing genotype and lower socioeconomic status. A large percentage of MDR TB cases seemed to result from recent transmission. Early detection, effective treatment, and infection control measures for MDR TB are needed to reduce transmission.

OBJECTIVE: To estimate the prevalence of tuberculosis in Viet Nam with data from a population-based survey, compare it with the prevalence estimated by the World Health Organization, and identify major demographic determinants of tuberculosis prevalence. METHODS: A cross-sectional survey with multistage cluster sampling, stratified by urban, rural and remote areas, was done in 2006-2007 in 70 communes. All inhabitants aged > 15 years were invited for cough and chest X-ray examination. Participants with findings suggestive of tuberculosis provided sputum specimens for smear examination and culture. Point prevalence estimates, 95% confidence intervals and design effects were calculated. Confidence intervals and P-values were adjusted for the cluster design. FINDINGS: Of 114 389 adult inhabitants, 94 179 (82.3%) were screened. Of 87 314 (92.7%) screened by both questionnaire and chest X-ray, 3522 (4.0%) had productive cough, 518 (0.6%) had a recent history of tuberculosis and 2972 (3.4%) had chest X-ray abnormalities suggestive of tuberculosis. Sputum tests were done for 7648 participants. Sputum test, bacterial culture or both confirmed 269 tuberculosis cases, 174 of which were smear-positive. The prevalence rate of smear-positive tuberculosis was 145 per 100 000 (95% confidence interval: 110-180) assuming no tuberculosis in persons aged < 15 years. Prevalence was 5.1 times as high in men as in women, increased with age, was higher in rural than in urban or remote areas and showed a north-to-south gradient. CONCLUSION: In Viet Nam, the tuberculosis prevalence rate based on positive sputum smear tests was 1.6 times as high as previously estimated. Age and sex patterns were consistent with notification data. Tuberculosis control should remain a high priority in Viet Nam.

Tuberculosis case notification rates (CNRs) for young adults in Vietnam are increasing. To determine whether this finding could reflect emergence of Mycobacterium tuberculosis Beijing genotype, we studied all new sputum smear–positive pulmonary tuberculosis patients registered for treatment in 3 rural districts in Vietnam during 2003–2006. Beijing strain infections were more frequent in younger patients (15–24 years of age, 53%) than in older patients (31%; p65 years of age, respectively (p

The frequency of typical and atypical Beijing strains of Mycobacterium tuberculosis was determined in the Netherlands; Vietnam; and Hong Kong Special Administrative Region, People’s Republic of China. The strains’ associations with drug resistance, M. bovis BCG vaccination, and patient characteristics were assessed. BCG vaccination may have positively selected the prevalent typical Beijing strains.

OBJECTIVE: To evaluate the validity of the fixed mathematical relationship between the annual risk of tuberculous infection (ARTI), the prevalence of smear-positive tuberculosis (TB) and the incidence of smear-positive TB specified as the Styblo rule, which TB control programmes use to estimate the incidence of TB disease at a population level and the case detection rate. METHODS: Population-based tuberculin surveys and surveys on prevalence of smear-positive TB since 1975 were identified through a literature search. For these surveys, the ratio between the number of tuberculous infections (based on ARTI estimates) and the number of smear-positive TB cases was calculated and compared to the ratio of 8 to 12 tuberculous infections per prevalent smear- positive TB case as part of the Styblo rule. FINDINGS: Three countries had national population-based data on both ARTI and prevalence of smear-positive TB for more than one point in time. In China the ratio ranged from 3.4 to 5.8, in the Philippines from 2.6 to 4.4, and in the Republic of Korea, from 3.2 to 4.7. All ratios were markedly lower than the ratio that is part of the Styblo rule. CONCLUSION: According to recent country data, there are typically fewer than 8 to 12 tuberculous infections per prevalent smear-positive TB case, and it remains unclear whether this ratio varies significantly among countries. The decrease in the ratio compared to the Styblo rule probably relates to improvements in the prompt treatment of TB disease (by national TB programmes). A change in the number of tuberculous infections per prevalent smear-positive TB case in population-based surveys makes the assumed fixed mathematical relationship between ARTI and incidence of smear-positive TB no longer valid.

In Ho Chi Minh City, Vietnam, reporting rates for tuberculosis (TB) are rising in an emerging HIV epidemic. To describe the HIV epidemic among TB patients and quantify its impact on rates of reported TB, we performed a repeated cross-sectional survey from 1997 through 2002 in a randomly selected sample of inner city TB patients. We assessed effect by adjusting TB case reporting rates by the fraction of TB cases attributable to HIV infection. HIV prevalence in TB patients rose exponentially from 1.5% to 9.0% during the study period. Young (

OBJECTIVE: To obtain an estimate of the prevalence of new cases of smear-positive tuberculosis in Eritrea using a new low-cost approach. METHODS: The study was designed to include a sample of 35 000 people divided between 40 clusters. The clusters were selected by sampling proportional to population size. In each cluster, census data were obtained from eligible individuals. Individuals aged 15 years or more were questioned about cough and its duration and smoking and were asked to provide two samples of sputum (spot and morning) for examination by fluorescence microscopy. FINDINGS: A total of 38 032 individuals were included in the study. Of the 19 197 individuals aged 15 years or more, 18 152 (94.6%) provided at least one sample of sputum. Fifteen individuals fulfilled the case definition, providing a prevalence of new cases of smear-positive tuberculosis of 90 per 100 000 (95% confidence interval, CI, 35-145 per 100 000) individuals aged 15 years or more and 50 per 100 000 (95% CI, 19-80 per 100 000) in the total population. CONCLUSION: The estimated prevalence of new cases of smear-positive tuberculosis obtained from our study is considerably lower than the estimate published by the World Health Organization. The new methodology for surveys to determine the prevalence of tuberculosis that we used is feasible in the field. This methodology should be validated in other countries and compared with other methods for measuring prevalence.

Altitude and gravity changes during aeromedical evacuations induce exacerbated cardiovascular responses in unstable patients. Non-invasive cardiac output monitoring is difficult to perform in this environment with limited access to the patient. We evaluated the feasibility and accuracy of stroke volume estimation by finger photoplethysmography (SVp) in hypergravity.Finger arterial blood pressure (ABP) waveforms were recorded continuously in ten healthy subjects before, during and after exposure to +Gz accelerations in a human centrifuge. The protocol consisted of a 2-min and 8-min exposure up to +4 Gz. SVp was computed from ABP using Liljestrand, systolic area, and Windkessel algorithms, and compared with reference values measured by echocardiography (SVe) before and after the centrifuge runs.The ABP signal could be used in 83.3% of cases. After calibration with echocardiography, SVp changes did not differ from SVe and values were linearly correlated (p

A Tuberculin skin test (TST) survey was conducted to assess the prevalence of latent TB Infection (LTBI) and to estimate the annual risk of M. tuberculosis infection (ARTI) in Gambian school children. The results are expected to contribute to understanding of Tuberculosis epidemiology in The Gambia.This was a nationwide, multi-cluster survey in children aged 6-11 years. Districts, 20 of 37, were selected by probability proportional to size and schools by simple random sampling. All TST were performed using the Mantoux method. Height and weight measurements were obtained for all participants. We calculated prevalence of LTBI using cut-off points of 10mm, the mirror and mixture modelling methods.TST readings were completed 13,386 children with median age of 9 years (interquartile range [IQR] 8-10 years). Mixture analysis yielded a cut-off point of 12 mm, and LTBI prevalence of 6.9% [95%CI 6.47-7.37] and the ARTI was 0.75% [95%CI 0.60-0.91]. LTBI was associated gender and urban residence (p

Right ventricular (RV) failure is a leading cause of death in patients with congenital heart disease. RV failure is kept at bay during childhood. Limited proliferation of cardiomyocytes is present in the postnatal heart. We propose that cardiomyocyte proliferation improves RV adaptation to pressure load (PL). We studied adaptation in response to increased RV PL and the role of increased cardiomyocyte cell cycle activity (CCA) in rat pups growing into adulthood. We induced RV PL at day of weaning in rats (3 weeks; 30-40 g) by pulmonary artery banding and followed rats into adulthood (300 g). We performed histological analyses and RNA sequencing analysis. To study the effects of increased cardiomyocyte cell cycle activity, we administered neuregulin-1 (NRG1), a growth factor involved in cardiac development. PL induced an increase in CCA, with subsequent decline of CCA (sham/PL at 4 weeks: 0.14%/0.83%; P =.04 and 8 weeks: 0.00%/0.00%; P =.484) and cardiac function (cardiac index: control/PL 4 weeks: 4.41/3.29; P =.468 and 8 weeks: 3.57/1.44; P =.024). RNA sequencing analysis revealed delayed maturation and increased CCA pathways. NRG1 stimulated CCA (PL vehicle/NRG1 at 2 weeks: 0.62%/2.28%; P =.003), improved cardiac function (cardiac index control vs vehicle/NRG1 at 2 weeks: 4.21 vs 3.07/4.17; P =.009/.705) and postponed fibrosis (control vs vehicle/NRG1 at 4 weeks: 1.66 vs 4.82%/2.97%; P =.009/.078) in RV PL rats during childhood. RV PL during growth induces a transient CCA increase. Further CCA stimulation improves cardiac function and delays fibrosis. This proof-of-concept study shows that stimulation of CCA can improve RV adaptation to PL in the postnatal developing heart and might provide a new approach to preserve RV function in patients with congenital heart disease. [Display omitted] [ABSTRACT FROM AUTHOR]

This study describes the epidemiology of extrapulmonary tuberculosis (TB) in the Netherlands from 1993 through 2001. We assessed whether the increasing numbers of inhabitants with a non-Western ethnic background had an effect on the number of extrapulmonary patients. We used data from the Netherlands Tuberculosis Register and included all cases of TB diagnosed in the Netherlands between January 1, 1993, and December 31, 2001. Information on age, sex, nationality, year of diagnosis, culture result, anatomic location of the site of disease, and HIV status was retrieved from the register. Of 13,258 patients with TB, 8,216 (62%) had pulmonary TB, and 5,042 (38%) had extrapulmonary TB. Non-Dutch nationals were more likely to have most types of extrapulmonary TB. The growth of the number of inhabitants with a non-Western ethnic background in the Netherlands explains the proportional growth of extrapulmonary TB. Physicians need to be aware of the changing clinical picture of TB.