Environmental factors shaping the gut microbiome in a Dutch population.

The gut microbiome is associated with diverse diseases1-3, but a universal signature of a healthy or unhealthy microbiome has not been identified, and there is a need to understand how genetics, exposome, lifestyle and diet shape the microbiome in health and disease. Here we profiled bacterial composition, function, antibiotic resistance and virulence factors in the gut microbiomes of 8,208 Dutch individuals from a three-generational cohort comprising 2,756 families. We correlated these to 241 host and environmental factors, including physical and mental health, use of medication, diet, socioeconomic factors and childhood and current exposome. We identify that the microbiome is shaped primarily by the environment and cohabitation. Only around 6.6% of taxa are heritable, whereas the variance of around 48.6% of taxa is significantly explained by cohabitation. By identifying 2,856 associations between the microbiome and health, we find that seemingly unrelated diseases share a common microbiome signature that is independent of comorbidities. Furthermore, we identify 7,519 associations between microbiome features and diet, socioeconomics and early life and current exposome, with numerous early-life and current factors being significantly associated with microbiome function and composition. Overall, this study provides a comprehensive overview of gut microbiome and the underlying impact of heritability and exposures that will facilitate future development of microbiome-targeted therapies.

Molnupiravir; molecular and functional descriptors of mitochondrial safety.

Molnupiravir is an orally active nucleoside analog antiviral drug that recently was approved by the U.S. FDA for emergency treatment of adult patients infected with the SARS-CoV-2 (COVID-19) virus and at risk for severe progression. The active form of the drug, N-hydroxycytidine (NHC) triphosphate competes for incorporation by RNA-dependent RNA-polymerase (RdRp) into the replicating viral genome resulting in mutations and arrest of the replicating virus. Historically, some nucleoside analog antiviral drugs have been found to lack specificity for the virus and also inhibit replication and/or expression of the mitochondrial genome. The objective of the present study was to test whether molnupiravir and/or NHC also target mitochondrial DNA polymerase gamma (PolG) or RNA polymerase (POLRMT) activity to inhibit the replication and/or expression of the mitochondrial genome leading to impaired mitochondrial function. Human-derived HepG2 cells were exposed for 48 h in culture to increasing concentrations of either molnupiravir or NHC after which cytotoxicity, mtDNA copy number and mitochondrial gene expression were determined. The phenotypic endpoint, mitochondrial respiration, was measured with the Seahorse® XF96 Extracellular Flux Analyzer. Both molnupiravir and NHC were cytotoxic at concentrations of ≥10 µM. However, at non-cytotoxic concentrations, neither significantly altered mitochondrial gene dose or transcription, or mitochondrial respiration. From this we conclude that mitochondrial toxicity is not a primary off target in the mechanism of cytotoxicity for either molnupiravir or its active metabolite NHC in the HepG2 cell line.

Remdesivir; molecular and functional measures of mitochondrial safety.

Remdesivir is one of a few antiviral drugs approved for treating severe cases of coronavirus 2 (SARS-CoV-2) infection in hospitalized patients. The prodrug is a nucleoside analog that interferes with viral replication by inhibiting viral RNA-dependent RNA polymerase. The drug has also been shown to be a weak inhibitor of human mitochondrial RNA polymerase, leaving open the possibility of mitochondrial off-targets and toxicity. The investigation was designed to explore whether remdesivir causes mitochondrial toxicity, using both genomic and functional parameters in the assessment. Human-derived HepG2 liver cells were exposed for up to 48 h in culture to increasing concentrations of remdesivir. At sub-cytotoxic concentrations (<1 µM), the drug failed to alter either the number of copies or the expression of the mitochondrial genome. mtDNA copy number was unaffected as was the relative rates of expression of mtDNA-encoded and nuclear encoded subunits of complexes I and IV of the mitochondrial respiratory chain. Consistent with this is the observation that remdesivir was without effect on mitochondrial respiration, including basal respiration, proton leak, maximum uncoupled respiration, spare respiratory capacity or coupling efficiency. We conclude that although remdesivir has weak inhibitory activity towards mitochondrial RNA polymerase, mitochondria are not primary off-targets for the mechanism of cytotoxicity of the drug.

Baseline brain function in the preadolescents of the ABCD Study.

The Adolescent Brain Cognitive Development (ABCD) Study® is a 10-year longitudinal study of children recruited at ages 9 and 10. A battery of neuroimaging tasks are administered biennially to track neurodevelopment and identify individual differences in brain function. This study reports activation patterns from functional MRI (fMRI) tasks completed at baseline, which were designed to measure cognitive impulse control with a stop signal task (SST; N = 5,547), reward anticipation and receipt with a monetary incentive delay (MID) task (N = 6,657) and working memory and emotion reactivity with an emotional N-back (EN-back) task (N = 6,009). Further, we report the spatial reproducibility of activation patterns by assessing between-group vertex/voxelwise correlations of blood oxygen level-dependent (BOLD) activation. Analyses reveal robust brain activations that are consistent with the published literature, vary across fMRI tasks/contrasts and slightly correlate with individual behavioral performance on the tasks. These results establish the preadolescent brain function baseline, guide interpretation of cross-sectional analyses and will enable the investigation of longitudinal changes during adolescent development.

Hand strength and dexterity in individuals with hand eczema.

BACKGROUND: Patients with hand eczema often describe symptoms such as pain, clumsiness and difficulty flexing their fingers, thus impairing the function of the hand. OBJECTIVE: The aim of this study was to investigate whether hand eczema is associated with a measurable impairment of hand strength and dexterity. We also studied the relationship between hand function and the ability to perform activities of daily living (ADL), pain level and quality of life measured with the Dermatology Life Quality Index (DLQI). METHODS: Twenty-one participants with ongoing hand eczema were examined with well-established methods for measuring hand grip strength, pinch strength and dexterity. A questionnaire was designed to investigate perceived ability to perform ADL. The participants were also asked to grade their current pain level, and the DLQI was used to assess the participants' quality of life. A group of 12 participants was reinvestigated when healed. RESULTS: The participants demonstrated a significant improvement in all functional tests when healed. There was a strong correlation between ADL and both dexterity and hand grip strength. There was also a strong correlation between ADL and pain. All participants reported some difficulty performing ADL. CONCLUSIONS: Our results suggest that ongoing hand eczema may lead to a measurable decrease of strength and dexterity of the hand, leading to an impairment of the ability to perform ADL and consequently to a poorer quality of life.

Nationwide study of appendicitis in children.

BACKGROUND: Paediatric surgical care is increasingly being centralized away from low-volume centres, and prehospital delay is considered a risk factor for more complicated appendicitis. The aim of this study was to determine the incidence of paediatric appendicitis in Sweden, and to assess whether distance to the hospital was a risk factor for complicated disease. METHODS: A nationwide cohort study of all paediatric appendicitis cases in Sweden, 2001-2014, was undertaken, including incidence of disease in different population strata, with trends over time. The risk of complicated disease was determined by regression methods, with travel time as the primary exposure and individual-level socioeconomic determinants as independent variables. RESULTS: Some 38 939 children with appendicitis were identified. Of these, 16·8 per cent had complicated disease, and the estimated risk of paediatric appendicitis by age 18 years was 2·5 per cent. Travel time to the treating hospital was not associated with complicated disease (adjusted odds ratio (OR) 1·00 (95 per cent c.i. 0·96 to 1·05) per 30-min increase; P = 0·934). Level of education (P = 0·177) and family income (P = 0·120) were not independently associated with increased risk of complicated disease. Parental unemployment (adjusted OR 1·17, 95 per cent c.i. 1·05 to 1·32; P = 0·006) and having parents born outside Sweden (1 parent born in Sweden: adjusted OR 1·12, 1·01 to 1·25; both parents born outside Sweden: adjusted OR 1·32, 1·18 to 1·47; P < 0·001) were associated with an increased risk of complicated appendicitis. CONCLUSION: Every sixth child diagnosed with appendicitis in Sweden has a more complicated course of disease. Geographical distance to the surgical facility was not a risk factor for complicated appendicitis.

ANTECEDENTES: La atención quirúrgica pediátrica está cada vez más centralizada lejos de los centros de bajo volumen, y el retraso pre-hospitalario se considera un factor de riesgo para las apendicitis más complicadas. El objetivo de este estudio fue determinar la incidencia de apendicitis pediátrica en Suecia y evaluar si la distancia al hospital era un factor de riesgo para una enfermedad complicada. MÉTODOS: Se analizó un estudio de cohortes a nivel nacional que incluyó todos los casos de apendicitis pediátrica en Suecia durante el periodo 2001-2014, incluida la incidencia de la enfermedad en diferentes estratos de la población y las tendencias a lo largo del tiempo. El riesgo de enfermedad complicada se determinó mediante métodos de regresión, con el tiempo de viaje como exposición primaria y los determinantes socioeconómicos a nivel individual como variables independientes. RESULTADOS: Se identificaron 38.939 casos de apendicitis pediátrica. De estos, el 17% eran complicados y el riesgo estimado de apendicitis pediátrica a los 18 años era del 2,5%. El tiempo de viaje al hospital de tratamiento no se asoció con una enfermedad complicada (razón de oportunidades, odds ratio OR ajustada 1,00 (i.c. del 95%: 0,96 a 1,05) por aumentos de 30 minutos, P = 0,93). El nivel de educación (P = 0,18) y los ingresos familiares (P = 0,120) no se asociaron de forma independiente con un aumento del riesgo de enfermedad complicada. El desempleo de los padres (OR ajustada 1,17 (1,05 a 1,32), P = 0,006) y tener padres nacidos fuera de Suecia se asociaron con un mayor riesgo de apendicitis complicada (P < 0,001; un progenitor nacido en Suecia: OR ajustada 1,12 (1,01 a 1,25), ambos progenitores nacidos fuera de Suecia: OR ajustada 1,32 (1,18 a 1,47)). CONCLUSIÓN: Uno de cada seis niños diagnosticados de apendicitis en Suecia sufre un curso de enfermedad más complicado. La distancia geográfica al hospital donde se llevó a cabo la cirugía no fue un factor de riesgo para la apendicitis complicada.

Adolescent neurocognitive development and impacts of substance use: Overview of the adolescent brain cognitive development (ABCD) baseline neurocognition battery.

Adolescence is characterized by numerous social, hormonal and physical changes, as well as a marked increase in risk-taking behaviors. Dual systems models attribute adolescent risk-taking to tensions between developing capacities for cognitive control and motivational strivings, which may peak at this time. A comprehensive understanding of neurocognitive development during the adolescent period is necessary to permit the distinction between premorbid vulnerabilities and consequences of behaviors such as substance use. Thus, the prospective assessment of cognitive development is fundamental to the aims of the newly launched Adolescent Brain and Cognitive Development (ABCD) Consortium. This paper details the rationale for ABC'lected measures of neurocognition, presents preliminary descriptive data on an initial sample of 2299 participants, and provides a context for how this large-scale project can inform our understanding of adolescent neurodevelopment.

Population-based incidence rate of inpatient and outpatient surgical procedures in a high-income country.

BACKGROUND: The WHO and the World Bank ask countries to report the national volume of surgery. This report describes these data for Sweden, a high-income country. METHODS: In an 8-year population-based observational cohort study, all inpatient and outpatient care in the public and private sectors was detected in the Swedish National Patient Register and screened for the occurrence of surgery. The entire Swedish population was eligible for inclusion. All patients attending healthcare for any disease were included. Incidence rates of surgery and likelihood of surgery were calculated, with trends over time, and correlation with sex, age and disease category. RESULTS: Almost one in three hospitalizations involved a surgical procedure (30·6 per cent). The incidence rate of surgery exceeded 17 480 operations per 100 000 person-years, and at least 58·5 per cent of all surgery was performed in an outpatient setting (range 58·5 to 71·6 per cent). Incidence rates of surgery increased every year by 5·2 (95 per cent c.i. 4·2 to 6·1) per cent (P < 0·001), predominantly owing to more outpatient surgery. Women had a 9·8 (95 per cent c.i. 5·6 to 14·0) per cent higher adjusted incidence rate of surgery than men (P < 0·001), mainly explained by more surgery during their fertile years. Incidence rates peaked in the elderly for both women and men, and varied between disease categories. CONCLUSION: Population requirements for surgery are greater than previously reported, and more than half of all surgery is performed in outpatient settings. Distributions of age, sex and disease influence estimates of population surgical demand, and should be accounted for in future global and national projections of surgical public health needs.

Wet work exposure and hand eczema among healthcare workers: a cross-sectional study.

BACKGROUND: Hand eczema is more common in healthcare workers than in the general population. Hands are subject to changing occupational exposures as a result of mandatory hygiene regulations for healthcare workers. OBJECTIVES: To describe exposure to hygiene procedures and investigate the associations between occupational hand washing, use of nonsterile gloves and hand disinfectant, and self-reported hand eczema. METHODS: This was a cross-sectional study; an electronic questionnaire was distributed to 28 762 hospital employees in southern Sweden. Nurses, assistant nurses or physicians constituted the group of healthcare workers analysed. Adjustments were made for sex, age, wet work at home, lifestyle factors and atopic dermatitis. RESULTS: In total, 12 288 (43%) responded, including 9051 healthcare workers. In this group the 1-year prevalence of self-reported hand eczema was 21%. On a daily basis, 30% reported hand washing with soap > 20 times at work, 45% used hand disinfectants > 50 times and 54% wore nonsterile gloves for > 2 h. After adjustment for confounding factors, a dose-dependent association with self-reported hand eczema was found for the daily number of hand washes with soap at work and time working with disposable gloves but not for alcoholic disinfectant use. Hand washing outside work was not associated with self-reported hand eczema in the adjusted multivariate analysis. CONCLUSIONS: In this study, we found a higher 1-year prevalence of self-reported hand eczema among Swedish healthcare workers than reported in the general population. Hand washing with soap and use of disposable gloves were associated with the occurrence of self-reported hand eczema in a dose-dependent way. Use of hand disinfectant was not associated with self-reported hand eczema.

Validation of Random Sampling as an Estimation Procedure for Lyme Disease Surveillance in Massachusetts and Minnesota.

Many disease surveillance programs, including the Massachusetts Department of Public Health and the Minnesota Department of Health, are challenged by marked increases in Lyme disease (LD) reports. The purpose of this study was to retrospectively analyse LD reports from 2005 through 2012 to determine whether key epidemiologic characteristics were statistically indistinguishable when an estimation procedure based on sampling was utilized. Estimates of the number of LD cases were produced by taking random 20% and 50% samples of laboratory-only reports, multiplying by 5 or 2, respectively, and adding the number of provider-reported confirmed cases. Estimated LD case counts were compared to observed, confirmed cases each year. In addition, the proportions of cases that were male, were ≤12 years of age, had erythema migrans (EM), had any late manifestation of LD, had a specific late manifestation of LD (arthritis, cranial neuritis or carditis) or lived in a specific region were compared to the proportions of cases identified using standard surveillance to determine whether estimated proportions were representative of observed proportions. Results indicate that the estimated counts of confirmed LD cases were consistently similar to observed, confirmed LD cases and accurately conveyed temporal trends. Most of the key demographic and disease manifestation characteristics were not significantly different (P < 0.05), although estimates for the 20% random sample demonstrated greater deviation than the 50% random sample. Applying this estimation procedure in endemic states could conserve limited resources by reducing follow-up effort while maintaining the ability to track disease trends.

Recent hip fracture trends in Sweden and Denmark with age-period-cohort effects.

This study used nationwide hip fracture data from Denmark and Sweden during 1987-2010 to examine effects of (birth) cohort and period. We found that time trends, cohort, and period effects were different in the two countries. Results also indicated that hip fracture rates may increase in the not so far future. INTRODUCTION: The reasons for the downturn in hip fracture rates remain largely unclear but circumstances earlier in life seem important. METHODS: We ascertained hip fractures in the populations ≥50 years in Denmark and Sweden in national discharge registers. Country- and sex-specific age-period-cohort (APC) effects during 1987-2010 were evaluated by log-likelihood estimates in Poisson regression models presented as incidence rate ratios (IRR). RESULTS: There were 399,596 hip fractures in SE and 248,773 in DK. Age-standardized hip fracture rate was stable in SE men but decreased in SE women and in DK. Combined period + cohort effects were generally stronger in SE than DK and in women than men. IRR per period ranged from 1.05 to 1.30 in SE and 0.95 to 1.21 in DK. IRR per birth cohort ranged from 1.07 to 3.13 in SE and 0.77 to 1.67 in DK. Relative period effects decreased with successive period in SE and described a convex curve in DK. Relative cohort effects increased with successive birth cohort in both countries but with lower risks for DK women and men and SE women born around the 1930s (age 75-86 years today and responsible for most hip fractures) partly explaining the recent downturn. Men and women born thereafter however seem to have a higher hip fracture risk, and we expect a reversal of the present decline in rates, with increasing hip fracture rates in both Denmark and Sweden during the upcoming decade. CONCLUSIONS: Time trends, cohort, and period effects were different in SE and DK. This may reflect differences in general health as evident in known differences in life expectancy, healthcare organization, and prevention such as use of anti-osteoporosis drugs. Analyses indicate that hip fracture rates may increase in the not so far future.

Long-term outcome of infliximab treatment in chronic active ulcerative colitis: a Swedish multicentre study of 250 patients.

BACKGROUND: Real-life long-term data on infliximab treatment in ulcerative colitis are limited. AIM: To study the long-term efficacy and safety of infliximab in chronic active ulcerative colitis and possible predictors of colectomy and response were also examined. METHODS: A retrospective multi-centre study of infliximab treatment in 250 patients with chronic active ulcerative colitis with inclusion criteria: age ≥18 years, ambulatory treated, steroid-dependent or intolerant and/or immunomodulator refractory or intolerant. RESULTS: Steroid-free clinical remission was achieved by 123/250 patients (49.2%) at 12 months and in 126/250 patients at a median follow-up of 2.9 years (50.4%). Primary response at 3 months was achieved by 190/250 (76.0%) patients and associated with a high probability of response 168/190 (88.4%) at 12 months and 143/190 (75.3%) at follow-up. Long-term rate of colectomy in primary responders was 6/190 (3.2%) at 12 months and 27/190 (14.2%) at last follow-up. Failure to achieve response at 3 months was associated with a high risk of subsequent colectomy, 29/60 (48.3%) at 12 months and 41/60 (68.3%) at follow-up. Response at 12 months was associated with a low risk of subsequent colectomy, 14/181 (7.7%) compared with non-response 19/34 (55.9%) (P < 0.0001). Non-response at 3 months was an independent predictor of subsequent colectomy (HR = 9.40, 95% CI = 5.10-17.35, P < 0.001). Concomitant azathioprine therapy did not influence outcome in terms of colectomy. CONCLUSIONS: Long-term efficacy of infliximab treatment in chronic active ulcerative colitis is excellent especially in patients who respond to induction treatment. Conversely, non-response at 3 months predicts a poor outcome, with a high risk of subsequent colectomy.

Habitat Suitability Model for the Distribution of Ixodes scapularis (Acari: Ixodidae) in Minnesota.

Ixodes scapularis Say, the black-legged tick, is the primary vector in the eastern United States of several pathogens causing human diseases including Lyme disease, anaplasmosis, and babesiosis. Over the past two decades, I. scapularis-borne diseases have increased in incidence as well as geographic distribution. Lyme disease exists in two major foci in the United States, one encompassing northeastern states and the other in the Upper Midwest. Minnesota represents a state with an appreciable increase in counties reporting I. scapularis-borne illnesses, suggesting geographic expansion of vector populations in recent years. Recent tick distribution records support this assumption. Here, we used those records to create a fine resolution, subcounty-level distribution model for I. scapularis using variable response curves in addition to tests of variable importance. The model identified 19% of Minnesota as potentially suitable for establishment of the tick and indicated with high accuracy (AUC = 0.863) that the distribution is driven by land cover type, summer precipitation, maximum summer temperatures, and annual temperature variation. We provide updated records of established populations near the northwestern species range limit and present a model that increases our understanding of the potential distribution of I. scapularis in Minnesota.

Reaction mechanisms for on-surface synthesis of covalent nanostructures.

In recent years, on-surface synthesis has become an increasingly popular strategy to form covalent nanostructures. The approach has great prospects for facilitating the manufacture of a range of fascinating materials with atomic precision. However, the on-surface reactions are enigmatic to control, currently restricting its bright perspectives and there is a great need to explore how the reactions are governed. The objective of this topical review is to summarize theoretical work that has focused on comprehending on-surface synthesis protocols through studies of reaction mechanisms.

The importance of work organization on workload and musculoskeletal health--Grocery store work as a model.

We have evaluated the consequences of work organization on musculoskeletal health. Using a postal questionnaire, answered by 1600 female grocery store workers, their main work tasks were identified and four work groups were defined (cashier, picking, and delicatessen work, and a mixed group, who performed a mix of these tasks). The crude odds ratios (ORs) for neck/shoulder complaints were 1.5 (95% CI 1.0-2.2), 1.1 (0.7-1.5) and 1.6 (1.1-2.3), respectively, compared to mixed work. Adjusting for individual and psychosocial factors had no effect on these ORs. For elbows/hands, no significant differences were found. Technical measurements of the workload showed large differences between the work groups. Picking work was the most strenuous, while cashier work showed low loads. Quantitative measures of variation revealed for mixed work high between minutes variation and the highest between/within minutes variation. Combining work tasks with different physical exposure levels increases the variation and may reduce the risk of musculoskeletal complaints.

Heat-shock factor 2 is a suppressor of prostate cancer invasion.

Heat-shock factors (HSFs) are key transcriptional regulators in cell survival. Although HSF1 has been identified as a driver of carcinogenesis, HSF2 has not been explored in malignancies. Here, we report that HSF2 suppresses tumor invasion of prostate cancer (PrCa). In three-dimensional organotypic cultures and the in vivo xenograft chorioallantoic membrane model HSF2 knockdown perturbs organoid differentiation and promotes invasiveness. Gene expression profiling together with functional studies demonstrated that the molecular mechanism underlying the effect on tumor progression originates from HSF2 steering the switch between acinar morphogenesis and invasion. This is achieved by the regulation of genes connected to, for example, GTPase activity, cell adhesion, extracellular matrix and actin cytoskeleton dynamics. Importantly, low HSF2 expression correlates with high Gleason score, metastasis and poor survival of PrCa patients, highlighting the clinical relevance of our findings. Finally, the study was expanded beyond PrCa, revealing that the expression of HSF2 is decreased in a wide range of cancer types. This study provides the first evidence for HSF2 acting as a suppressor of invasion in human malignancies.

Current and future impact of osteoarthritis on health care: a population-based study with projections to year 2032.

OBJECTIVE: To estimate the current and future (to year 2032) impact of osteoarthritis (OA) health care seeking. METHOD: Population-based study with prospectively ascertained data from the Skåne Healthcare Register (SHR), Sweden, encompassing more than 15 million person-years of primary and specialist outpatient care and hospitalizations. We studied all Skåne region residents aged ≥45 by the end of 2012 (n = 531, 254) and determined the prevalence of doctor-diagnosed OA defined as the proportion of the prevalent population that had received a diagnosis of OA of the knee, hip, hand, or other locations except the spine between 1999 and 2012. We projected consultation prevalence of OA until year 2032 using Statistics Sweden's (SCB) projected age and sex structure and prevalence of overweight and obesity. RESULTS: In 2012 the proportion of population aged ≥45 with any doctor-diagnosed OA was 26.6% (95% confidence interval (CI): 26.5-26.8) (men 22.4%, women 30.5%). The most common locations were knee (13.8%), hip (5.8%) and hand (3.1%). Of the prevalent cases 26.8% had OA in multiple joints. By the year 2032, the proportion of the population aged ≥45 with doctor-diagnosed OA is estimated to increase from 26.6% to 29.5% (any location), from 13.8% to 15.7% for the knee and 5.8-6.9% for the hip. CONCLUSION: In 2032, at least an additional 26,000 individuals per 1 million population aged ≥45 years are estimated to have consulted a physician for OA in a peripheral joint compared to 2012. These findings underscore the need to address modifiable risk factors and develop new effective OA treatments.

Early detection of Brucella canis via quantitative polymerase chain reaction analysis.

Canine brucellosis is a reportable zoonotic disease that can lead to canine reproductive losses and human infection through contact with infected urine or other genitourinary secretions. Although many locations require testing and euthanasia of positive dogs, current diagnosis is limited by the time required for seroconversion, for example, presence of B. canis-specific antibodies. The goal of this study was to determine the diagnostic ability of Brucella canis-specific quantitative polymerase chain reaction (qPCR) assay to detect B. canis in field samples prior to serological positivity for faster diagnosis and prevention of transmission within kennels or in households. Two kennels, one of which was located in the owner's home, were sampled following observation of suggestive clinical signs and positive serology of at least one dog. Specimens obtained were comparatively analysed via serology and qPCR analysis. 107 dogs were analysed for B. canis infection via qPCR: 105 via whole-blood samples, 65 via vaginal swab, six via urine and seven via genitourinary tract tissue taken at necropsy. Forty-five dogs were found to be infected with canine brucellosis via qPCR, of which 22 (48.89%) were seropositive. A statistically significant number (P = 0.0228) of qPCR-positive dogs, 5/25 (20.00%), seroconverted within a 30-day interval after initial serologic testing. As compared to serology, qPCR analysis of DNA from vaginal swabs had a sensitivity of 92.31% and specificity of 51.92%, and qPCR analysis of DNA from whole-blood samples had a sensitivity of 16.67% and specificity of 100%. B. canis outer membrane protein 25 DNA qPCR from non-invasive vaginal swab and urine samples provided early detection of B. canis infection in dogs prior to detection of antibodies. This assay provides a critical tool to decrease zoonotic spread of canine brucellosis, its associated clinical presentation(s), and emotional and economic repercussions.

A Clinical Scoring Algorithm for Determination of the Risk of Tuberculosis in HIV-Infected Adults: A Cohort Study Performed at Ethiopian Health Centers.

BACKGROUND: The World Health Organization (WHO) tuberculosis (TB) symptom screening instrument (WHO-TB) can identify human immunodeficiency virus (HIV)-infected individuals at low risk of tuberculosis (TB); however, many patients report WHO-TB symptoms and require further TB investigations. We hypothesized that further clinical scoring could classify subjects with a positive WHO-TB screening result (WHO-TB(+)) for the likelihood of TB. METHODS: HIV-infected adults eligible to initiate antiretroviral therapy (ART) were recruited and prospectively followed at 5 Ethiopian health centers. Irrespective of symptoms, all participants underwent sputum bacteriological testing for TB. Symptoms, physical findings, hemoglobin, and CD4 cell count results were compared between subjects with and those without bacteriologically confirmed TB. Variables associated with TB in WHO-TB(+) individuals were used to construct a scoring algorithm with multiple logistic regression analysis. RESULTS: Among 812 participants, 137 (16.9%) had TB. One hundred fifty-nine persons (20%) had a negative WHO-TB screen, 10 of whom had TB (negative predictive value [NPV], 94% [95% confidence interval {CI}, 90%-97.5%]). For WHO-TB(+) subjects, the following variables were independently associated with TB, and were assigned 1 point each in the clinical scoring algorithm: cough, Karnofsky score ≤80, mid-upper arm circumference <20 cm, lymphadenopathy, and hemoglobin <10 g/dL. Among subjects with 0-1 points, 20 of 255 had TB (NPV, 92% [95% CI, 89%-95%]), vs 19 of 34 participants with ≥4 points (positive predictive value, 56% [95% CI, 39%-73%]). The use of WHO-TB alone identified 159 of 784 (20%) with a low risk of TB, vs 414 of 784 (53%) using WHO-TB followed by clinical scoring (P< .001). The difference in proportions of confirmed TB in these subsets was nonsignificant (6.3% vs 7.2%; P= .69). CONCLUSIONS: Clinical scoring can further classify HIV-infected adults with positive WHO-TB screen to assess the risk of TB, and would reduce the number of patients in need of further TB investigations before starting ART. CLINICAL TRIALS REGISTRATION: NCT01433796.

Infliximab as rescue therapy in hospitalised patients with steroid-refractory acute ulcerative colitis: a long-term follow-up of 211 Swedish patients.

BACKGROUND: Rescue therapy with infliximab (IFX) has been proven effective in a steroid-refractory attack of ulcerative colitis (UC). The long-term efficacy is not well described. AIM: To present a retrospective study of IFX as rescue therapy in UC. Primary end points were colectomy-free survival at 3 and 12 months. METHODS: In this multicentre study, 211 adult patients hospitalised between 1999 and 2010 received IFX 5 mg/kg as rescue therapy due to a steroid-refractory, moderate-to-severe attack of UC. Exclusion criteria were duration of current flare for >12 weeks, corticosteroid treatment for >8 weeks before hospitalisation, previous IFX therapy or Crohn's disease. RESULTS: Probability of colectomy-free survival at 3 months was 0.71 (95% CI, 0.64-0.77), at 12 months 0.64 (95% CI, 0.57-0.70), at 3 years 0.59 (95% CI, 0.52-0.66) and at 5 years 0.53 (95% CI, 0.44-0.61). Steroid-free, clinical remission was achieved in 105/211 (50%) and 112/209 (54%) patients at 3 and 12 months respectively. Of 75 colectomies during the first year, 48 (64%) were carried out during the first 14 days, 13 (17%) on days 15-90 and 14 (19%) between 3 and 12 months. There were three (1.4%) deaths during the first 3 months. CONCLUSIONS: Infliximab is an effective rescue treatment, both short- and long-term, in a steroid-refractory attack of UC. Most IFX failures underwent surgery during the first 14 days, which calls for studies on how to optimise induction treatment with IFX. Serious complications, including mortality, were rare.