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Background: Health care workers have a critical role in the pandemic response to COVID-19 and may be at increased risk of infection. The objective of this study was to assess the seroprevalence of SARS-CoV-2 immunoglobulin G (IgG) antibodies among health care workers during and after the first wave of the pandemic. Methods: We conducted a prospective multicentre cohort study involving health care workers in Ontario, Canada, to detect IgG antibodies against SARS-CoV-2. Blood samples and self-reported questionnaires were obtained at enrolment, at 6 weeks and at 12 weeks. A community hospital, tertiary care pediatric hospital and a combined adult–pediatric academic health centre enrolled participants from Apr. 1 to Nov. 13, 2020. Predictors of seropositivity were evaluated using a multivariable logistic regression, adjusted for clustering by hospital site. Results: Among the 1062 health care workers participating, the median age was 40 years, and 834 (78.5%) were female. Overall, 57 (5.4%) were seropositive at any time point (2.5% when participants with prior infection confirmed by polymerase chain reaction testing were excluded). Seroprevalence was higher among those who had a known unprotected exposure to a patient with COVID-19 (p < 0.001) and those who had been contacted by public health because of a nonhospital exposure (p = 0.003). Providing direct care to patients with COVID-19 or working on a unit with a COVID-19 outbreak was not associated with higher seroprevalence. In multivariable logistic regression, presence of symptomatic contacts in the household was the strongest predictor of seropositivity (adjusted odds ratio 7.15, 95% confidence interval 5.42–9.41). Interpretation: Health care workers exposed to household risk factors were more likely to be seropositive than those not exposed, highlighting the need to emphasize the importance of public health measures both inside and outside of the hospital.

The demographic age structure of sub-Saharan Africa contributes significantly to the low morbidity and mortality of COVID-19 compared to other regions in the world., Key Messages Evidence suggests the demographic age structure of sub-Saharan Africa is the leading factor of the low morbidity and mortality of COVID-19 compared to other regions of the world.Widespread social mitigation strategies, such as lockdowns, have resulted in severe economic and societal consequences in terms of food security, adolescent pregnancy, gender-based violence, and disruptions in treating other diseases.It is imperative to weigh the risks and benefits of social mitigation strategies for future waves.

The role of remdesivir in the treatment of hospitalized patients with COVID-19 remains ill-defined. We conducted a cost-effectiveness analysis alongside the Canadian Treatments for COVID-19 (CATCO) open-label, randomized clinical trial evaluating remdesivir.Patients with COVID-19 in Canadian hospitals from Aug. 14, 2020, to Apr. 1, 2021, were randomly assigned to receive remdesivir plus usual care versus usual care alone. Taking a public health care payer's perspective, we collected in-hospital outcomes and health care resource utilization alongside estimated unit costs in 2020 Canadian dollars over a time horizon from randomization to hospital discharge or death. Data from 1281 adults admitted to 52 hospitals in 6 Canadian provinces were analyzed.The total mean cost per patient was $37 918 (standard deviation [SD] $42 413; 95% confidence interval [CI] $34 617 to $41 220) for patients randomly assigned to the remdesivir group and $38 026 (SD $46 021; 95% CI $34 480 to $41 573) for patients receiving usual care (incremental cost -$108 [95% CI -$4953 to $4737],From a health care payer perspective, treating patients hospitalized with COVID-19 with remdesivir and usual care appears to be preferrable to treating with usual care alone, albeit with marginal incremental cost and small clinical effects. The added cost of remdesivir was offset by shorter lengths of stay in the intensive care unit and less need for ventilation.ClinicalTrials. gov, no. NCT04330690.

Primary lateral sclerosis (PLS) is a neurodegenerative disease characterized by progressive upper motor neuron dysfunction. Because PLS patients represent only 1 to 4% of patients with adult motor neuron diseases, there is limited information about the disease's natural history. The objective of this study was to establish a large multicenter retrospective longitudinal registry of PLS patients seen at Northeast ALS Consortium (NEALS) sites to better characterize the natural progression of PLS.

To explore the mental health consequences of COVID-19-related social restrictions on pregnant women living in low socioeconomic status. Prenatal women appearing at the Mount Sinai Hospital Ambulatory Practice were screened for mood symptomatology from February 2, 2020, through June 12, 2020. An improvement in prenatal mood was observed following social restrictions compared to before the pandemic. The impact of COVID-19 remains largely unknown and may be useful towards understanding the needs of pregnant women living in poverty.

Background The rising incidence of infective endocarditis (IE) among people who inject drugs (PWID) has been a major concern across North America. The coincident rise in IE and change of drug preference to hydromorphone controlled-release (CR) among our PWID population in London, Ontario intrigued us to study the details of injection practices leading to IE, which have not been well characterized in literature. Methods A case–control study, using one-on-one interviews to understand risk factors and injection practices associated with IE among PWID was conducted. Eligible participants included those who had injected drugs within the last 3 months, were > 18 years old and either never had or were currently admitted for an IE episode. Cases were recruited from the tertiary care centers and controls without IE were recruited from outpatient clinics and addiction clinics in London, Ontario. Results Thirty three cases (PWID IE+) and 102 controls (PWID but IE-) were interviewed. Multivariable logistic regressions showed that the odds of having IE were 4.65 times higher among females (95% CI 1.85, 12.28; p = 0.001) and 5.76 times higher among PWID who did not use clean injection equipment from the provincial distribution networks (95% CI 2.37, 14.91; p p = 0.197). Discussion Our study highlights the importance of distributing clean injection materials for IE prevention. Furthermore, our study showcases that females are at higher risk of IE, which is contrary to the reported literature. Gender differences in injection techniques, which may place women at higher risk of IE, require further study. We suspect that the very high prevalence of hydromorphone-CR use made our sample size too small to identify a significant association between its use and IE, which has been established in the literature.

The incidence of infective endocarditis related to injection drug use is increasing. On the basis of clinical practice and epidemiological and in-vitro data, we postulated that exposure to controlled-release hydromorphone is associated with an increased risk of infective endocarditis among people who inject drugs.We used linked health administrative databases in Ontario, Canada, to assemble a retrospective cohort of adults (aged 18-55 years) who inject drugs for the period of April 1, 2006, to Sept 30, 2015. Cases of infective endocarditis among this cohort were identified using International Classification of Diseases 10 codes. We estimated exposure to hydromorphone and risk of infective endocarditis among this cohort in two ways. First, in a population-level analysis, we identified patients living in regions with high (≥25%) and low (≤15%) hydromorphone prescription rates and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis. Second, in a patient-level analysis including only those with prescription drug data, we identified those who had filled prescriptions (ie, received the drug from the pharmacy) for controlled-release or immediate-release hydromorphone and, after matching 1:1 on various baseline characteristics, compared their frequency of infective endocarditis with that of patients who had filled prescriptions for other opioids.Between April 1, 2006, and Sept 30, 2015, 60 529 patients had evidence of injection drug use, 733 (1·2%, 95% CI 1·1-1·3) of whom had infective endocarditis. In the population-level analysis of 32 576 matched patients, we identified 254 (1·6%) admissions with infective endocarditis in regions with high hydromorphone use and 113 (0·7%) admissions in regions with low use (adjusted odds ratio [OR] 2·2, 95% CI 1·8-2·8, p0·0001). In the patient-level analysis of 3884 matched patients, the frequency of infective endocarditis was higher among patients who filled prescriptions for hydromorphone than among those who filled prescriptions for non-hydromorphone opioids (2·8% [109 patients] vs 1·1% [41 patients]; adjusted OR 2·5, 95% CI 1·8-3·7, p0·0001). This significant association was seen for controlled-release hydromorphone (3·9% [73 of 1895 patients] vs 1·1% [20 of 1895]; adjusted OR 3·3, 95% CI 2·1-5·6, p0·0001), but not for immediate-release hydromorphone (1·8% [36 of 1989] vs 1·1% [21 of 1989]; 1·7, 0·9-3·6, p=0·072.Among people who inject drugs, the risk of infective endocarditis is significantly higher for those exposed to controlled-release hydromorphone than to other opioids. This association might be mediated by the controlled-release mechanism and should be the subject of further investigation.Ontario Ministry of Health and Long-Term Care, Academic Medical Organization of Southwestern Ontario, Schulich School of Medicine and Dentistry (Western University), and Lawson Health Research Institute.

The role of remdesivir in the treatment of patients in hospital with COVID-19 remains ill defined in a global context. The World Health Organization Solidarity randomized controlled trial (RCT) evaluated remdesivir in patients across many countries, with Canada enrolling patients using an expanded data collection format in the Canadian Treatments for COVID-19 (CATCO) trial. We report on the Canadian findings, with additional demographics, characteristics and clinical outcomes, to explore the potential for differential effects across different health care systems.We performed an open-label, pragmatic RCT in Canadian hospitals, in conjunction with the Solidarity trial. We randomized patients to 10 days of remdesivir (200 mg intravenously [IV] on day 0, followed by 100 mg IV daily), plus standard care, or standard care alone. The primary outcome was in-hospital mortality. Secondary outcomes included changes in clinical severity, oxygen- and ventilator-free days (at 28 d), incidence of new oxygen or mechanical ventilation use, duration of hospital stay, and adverse event rates. We performed a priori subgroup analyses according to duration of symptoms before enrolment, age, sex and severity of symptoms on presentation.Across 52 Canadian hospitals, we randomized 1282 patients between Aug. 14, 2020, and Apr. 1, 2021, to remdesivir (Remdesivir, when compared with standard of care, has a modest but significant effect on outcomes important to patients and health systems, such as the need for mechanical ventilation.

People who inject drugs and have infective endocarditis have a high risk of recurrent infective endocarditis and death. We aimed to characterize clinical factors associated with mortality and assess the probability of infective endocarditis recurrence in the presence of death as a competing risk.A retrospective cohort study was conducted of people who inject drugs, identified between April 5, 2007 and March 15, 2018 with the Modified Duke Criteria for definite infective endocarditis. Fine-Gray sub-distribution and Cox proportional hazards modeling were conducted to determine variables associated with the rate of infective endocarditis recurrence and mortality, respectively.Of the 310 patients with infective endocarditis who inject drugs, 236 experienced a single episode and 74 experienced recurrent episodes. Peripherally inserted central catheter misuse was associated with an increased rate of infective endocarditis recurrence (sub-distribution hazard ratio 2.41; 95% confidence interval [CI], 1.17-4.98; P = .02) and mortality (hazard ratio [HR] 2.44; 95% CI, 1.15-5.17; P = .02). Non-right-sided infection, peripheral intravenous therapy, and intensive care unit admission were also associated with increased mortality. Oral therapy (HR 0.38; 95% CI, 0.16-0.91; P = .03), outpatient treatment (HR 0.39; 95% CI, 0.19-0.82; P = .01), and inpatient referral to addiction services (HR 0.39; 95% CI, 0.22-0.70; P = .002) were associated with a decrease in mortality.Patients who misuse their peripherally inserted central catheter are at higher risk of recurrent infective endocarditis and death. Avoidance of peripherally inserted central catheter lines and use of intravenous peripheral therapy did not reduce mortality, but oral therapy was associated with reduced risk. Inpatient addiction services referral is important.

Because antiretroviral therapy (ART) is allowing people living with human immunodeficiency virus (PLWH) to survive longer, they are developing more age-related comorbidities. We evaluated the effects of age and gender on the burden of age-related comorbidities among PLWH. In this retrospective real-world study, de-identified data were extracted from the medical charts of 2000 HIV-positive adults on ART across 10 sites in Canada. The prevalence of age-related comorbidities was determined in 6 age subgroups (30, 30-39, 40-49, 50-59, 60-69, and ≥70 years). The effects of gender on these comorbidities were also examined. Risks of cardiovascular disease and chronic kidney disease (CKD) were calculated using the Framingham and D:A:D equations. Most persons were White (68%), male (87%), and virologically suppressed (94%). The mean age was 50.3 years (57% aged ≥50 years), and mean CD4+ T-cell count was 616 cells/mm3. The most common comorbidities were neuropsychiatric symptoms (61%), overweight/obesity (43%), liver disease (37%), and dyslipidemia (37%). The mean number of comorbidities increased across age subgroups (P.001). Across all age subgroups, the prevalence of hypertension (P = .04), dyslipidemia (P = .04), CKD (P = .03), bone fragility (P = .03), and depression (P = .02) differed between males and females. Both age (P.001) and gender (P.001) impacted cardiovascular disease and CKD risk. Age and gender influenced the burden, types, and risks of age-related comorbidities in PLWH in this Canadian cohort. These comorbidities should be diagnosed and treated in routine clinical practice.

ObjectivesMany studies suggest that infective endocarditis (IE) in people who inject drugs is predominantly right sided, while other studies suggest left sided disease; few have differentiated by class of drug used. We hypothesised that based on differing physiological mechanisms, opioids but not stimulants would be associated with right sided IE.MethodsA retrospective case series of 290 adult (age ≥18) patients with self-reported recent injection drug use, admitted for a first episode of IE to one of three hospitals in London Ontario between April 2007 and March 2018, stratified patients by drug class used (opioid, stimulant or both), and by site of endocarditis. Other outcomes captured included demographics, causative organisms, cardiac and non-cardiac complications, referral to addiction services, medical versus surgical management, and survival.ResultsOf those who injected only opioids, 47/71 (69%) developed right-sided IE, 17/71 (25%) developed left-sided IE and 4/71 (6%) had bilateral IE. Of those who injected only stimulants, 11/24 (46%) developed right-sided IE, 11/24 (46%) developed left-sided IE and 2/24 (8%) had bilateral IE. Relative to opioid-only users, stimulant-only users were 1.75 (95% CI 1.05 to 2.93; p=0.031) times more likely to have a left or bilateral IE versus right IE.ConclusionsWhile injection use of opioids is associated with a strong predisposition to right-sided IE, stimulants differ in producing a balanced ratio of right and left-sided disease. As the epidemic of crystal methamphetamine injection continues unabated, the rate of left-sided disease, with its attendant higher morbidity and mortality, may also grow.

Development of transcatheter mitral valve interventions has ushered a significant need for large animal models of secondary mitral regurgitation. Though currently used heart failure models that chronically develop secondary mitral regurgitation are viable, the severity is lower than patients, the incubation time is long, and mortality is high. We sought to develop a swine model of acute secondary mitral regurgitation that uses image-guided placement of snares around the mitral chordae. Twenty-seven adult swine (n = 27) were assigned to secondary mitral regurgitation induced by valve tethering with image-guided chordal encircling snares (group 1, n = 7, tether MR (tMR)); secondary mitral regurgitation by percutaneous posterolateral myocardial infarction causing ventricular dysfunction and regurgitation (group 2, n = 6, functional MR (fMR)); and control animals (group 3, n = 14). Regurgitant fraction in tMR was 42.1 ± 14.2%, in fMR was 22 ± 9.6%, and in controls was 5.3 ± 3.8%. Mitral tenting height was 9.6 ± 1.3 mm in tMR, 10.1 ± 1.5 mm in fMR, and 5.8 ± 1.2 mm in controls. Chordal encircling tethers reproducibly induce clinically relevant levels of secondary mitral regurgitation, providing a new animal model for use in translational research.

Importance People who inject drugs (PWID) who are being treated for infective endocarditis remain at risk of new bloodstream infections (BSIs) due to ongoing intravenous drug use (IVDU). Objectives To characterize new BSIs in PWID receiving treatment for infective endocarditis, to determine the clinical factors associated with their development, and to determine whether new BSIs and treatment setting are associated with mortality. Design, Setting, and Participants This retrospective cohort study was performed at 3 tertiary care hospitals in London, Ontario, Canada, from April 1, 2007, to March 31, 2018. Participants included a consecutive sample of all PWID 18 years or older admitted with infective endocarditis. Data were analyzed from April 1, 2007, to June 29, 2018. Main Outcomes and Measures New BSIs and factors associated with their development, treatment setting of infective endocarditis episodes (ie, inpatient vs outpatient), and 90-day mortality. Results The analysis identified 420 unique episodes of infective endocarditis in 309 PWID (mean [SD] patient age, 35.7 [9.7] years; 213 episodes [50.7%] involving male patients), with 82 (19.5%) complicated by new BSIs. There were 138 independent new BSIs, of which 68 (49.3%) were polymicrobial and 266 were unique isolates. Aerobic gram-negative bacilli (143 of 266 [53.8%]) andCandidaspecies (75 of 266 [28.2%]) were the most common microorganisms. Ongoing inpatient IVDU was documented by a physician in 194 infective endocarditis episodes (46.2%), and 127 of these (65.5%) were confirmed by urine toxicology results. Multivariable time-dependent Cox regression demonstrated that previous infective endocarditis (hazard ratio [HR], 1.89; 95% CI, 1.20-2.98), inpatient treatment (HR, 4.49; 95% CI, 2.30-8.76), and physician-documented inpatient IVDU (HR, 5.07; 95% CI, 2.68-9.60) were associated with a significantly higher rate of new BSIs, whereas inpatient addiction treatment was associated with a significantly lower rate (HR, 0.53; 95% CI, 0.32-0.88). New BSIs were not significantly associated with 90-day mortality (HR, 1.76; 95% CI, 0.78-4.02); significant factors associated with mortality included inpatient infective endocarditis treatment (HR, 3.39; 95% CI, 1.53-7.53), intensive care unit admission (HR, 9.51; 95% CI, 4.91-18.42), and methicillin-resistantStaphylococcus aureusinfective endocarditis (HR, 1.77; 95% CI, 1.03-3.03), whereas right-sided infective endocarditis was associated with a significantly lower mortality rate (HR, 0.41; 95% CI, 0.25-0.67). Conclusions and Relevance In this study, new BSIs were common in PWID receiving parenteral treatment for infective endocarditis. Discharging patients to outpatient treatment was not associated with an increase in new BSI incidence or mortality; carefully selected PWID may therefore be considered for such treatment.

COVID-19 mitigation strategies have led to widespread school closures around the world. Initially, these were undertaken based on data from influenza outbreaks in which children were highly susceptible and important in community-wide transmission. An argument was made that school closures were necessary to prevent harm to vulnerable adults, especially the elderly. Although data are still accumulating, the recently described complication, pediatric multisystem inflammatory syndrome, is extremely rare and children remain remarkably unaffected by COVID-19. We also do not have evidence that children are epidemiologically important in community-wide viral spread. Previous studies have shown long-term educational, social, and medical harms from school exclusion, with very young children and those from marginalized groups such as immigrants and racialized minorities most affected. The policy and ethical implications of ongoing mandatory school closures, in order to protect others, need urgent reassessment in light of the very limited data of public health benefit.

Introduction Nonalcoholic fatty liver disease (NAFLD) is an obesity-related disorder that is rapidly increasing in incidence and is considered the hepatic manifestation of the metabolic syndrome. The gut microbiome plays a role in metabolism and maintaining gut barrier integrity. Studies have found differences in the microbiota between NAFLD and healthy patients and increased intestinal permeability in patients with NAFLD. Fecal microbiota transplantation (FMT) can be used to alter the gut microbiome. It was hypothesized that an FMT from a thin and healthy donor given to patients with NAFLD would improve insulin resistance (IR), hepatic proton density fat fraction (PDFF), and intestinal permeability. Methods Twenty-one patients with NAFLD were recruited and randomized in a ratio of 3:1 to either an allogenic (n = 15) or an autologous (n = 6) FMT delivered by using an endoscope to the distal duodenum. IR was calculated by HOMA-IR, hepatic PDFF was measured by MRI, and intestinal permeability was tested using the lactulose:mannitol urine test. Additional markers of metabolic syndrome and the gut microbiota were examined. Patient visits occurred at baseline, 2, 6 weeks, and 6 months post-FMT. Results There were no significant changes in HOMA-IR or hepatic PDFF in patients who received the allogenic or autologous FMT. Allogenic FMT patients with elevated small intestinal permeability (>0.025 lactulose:mannitol, n = 7) at baseline had a significant reduction 6 weeks after allogenic FMT. Discussion FMT did not improve IR as measured by HOMA-IR or hepatic PDFF but did have the potential to reduce small intestinal permeability in patients with NAFLD.

For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i., For patients hospitalized with severe influenza A virus infection, morbidity and mortality remain high. MHAA4549A, a human monoclonal antibody targeting the influenza A virus hemagglutinin stalk, has demonstrated pharmacological activity in animal studies and in a human influenza A challenge study. We evaluated the safety and efficacy of MHAA4549A plus oseltamivir against influenza A virus infection in hospitalized patients. The CRANE trial was a phase 2b randomized, double-blind, placebo-controlled study of single intravenous (i.v.) doses of placebo, 3,600 mg MHAA4549A, or 8,400 mg MHAA4549A each combined with oral oseltamivir (+OTV) in patients hospitalized with severe influenza A virus infection. Patients, enrolled across 68 clinical sites in 18 countries, were randomized 1:1:1. The primary outcome was the median time to normalization of respiratory function, defined as the time to removal of supplemental oxygen support to maintain a stable oxygen saturation (SpO2) of ≥95%. Safety, pharmacokinetics, and effects on influenza viral load were also assessed. One hundred sixty-six patients were randomized and analyzed during a preplanned interim analysis. Compared to placebo+OTV, MHAA4549A+OTV did not significantly reduce the time to normalization of respiratory function (placebo+OTV, 4.28 days; 3,600 mg MHAA4549A+OTV, 2.78 days; 8,400 mg MHAA4549A+OTV, 2.65 days), nor did it improve other secondary clinical outcomes. Adverse event frequency was balanced across cohorts. MHAA4549A+OTV did not further reduce viral load versus placebo+OTV. In hospitalized patients with influenza A virus infection, MHAA4549A did not improve clinical outcomes over OTV alone. Variability in patient removal from oxygen supplementation limited the utility of the primary endpoint. Validated endpoints are needed to assess novel treatments for severe influenza A virus infection. (This study has been registered at ClinicalTrials.gov under registration no. NCT02293863.)

BackgroundCombination antiretroviral therapy (cART) during pregnancy prevents vertical transmission, but many antiretrovirals cross the placenta and several can affect mitochondria. Exposure to maternal human immunodeficiency virus (HIV) and/or cART could have long-term effects on children who are HIV exposed and uninfected (CHEU). Our objective was to compare blood mitochondrial DNA (mtDNA) content in CHEU and children who are HIV unexposed and uninfected (CHUU), at birth and in early life.MethodsWhole-blood mtDNA content at birth and in early life (age 0–3 years) was compared cross-sectionally between CHEU and CHUU. Longitudinal changes in mtDNA content among CHEU was also evaluated.ResultsAt birth, CHEU status and younger gestational age were associated with higher mtDNA content. These remained independently associated with mtDNA content in multivariable analyses, whether considering all infants, or only those born at term. Longitudinally, CHEU mtDNA levels remained unchanged during the first 6 months of life, and gradually declined thereafter. A separate age- and sex-matched cross-sectional analysis (in 214 CHEU and 214 CHUU) illustrates that the difference in mtDNA between the groups remains detectable throughout the first 3 years of life.ConclusionThe persistently elevated blood mtDNA content observed among CHEU represents a long-term effect, possibly resulting from in utero stresses related to maternal HIV and/or cART. The clinical impact of altered mtDNA levels is unclear.

Background Approximately 25% of outpatient antibiotic prescriptions are unnecessary among family physicians in Canada. Minimizing unnecessary antibiotics is key for community antibiotic stewardship. However, unnecessary antibiotic prescribing is much harder to measure than total antibiotic prescribing. We investigated the association between total and unnecessary antibiotic use by family physicians and evaluated inter-physician variability in unnecessary antibiotic prescribing. Methods This was a cohort study based on electronic medical records of family physicians in Ontario, Canada, between April 2011 and March 2016. We used predefined expected antibiotic prescribing rates for 23 common primary care conditions to calculate unnecessary antibiotic prescribing rates. We used multilevel Poisson regression models to evaluate the association between total antibiotic volume (number of antibiotic prescriptions per patient visit), adjusted for multiple practice- and physician-level covariates, and unnecessary antibiotic prescribing. Results There were 499 570 physician–patient encounters resulting in 152 853 antibiotic prescriptions from 341 physicians. Substantial inter-physician variability was observed. In the fully adjusted model, we observed a significant association between total antibiotic volume and unnecessary prescribing rate (adjusted rate ratio 2.11 per 10% increase in total use; 95% CI 2.05–2.17), and none of the practice- and physician-level variables were associated with unnecessary prescribing rate. Conclusions We demonstrated substantial inter-physician variability in unnecessary antibiotic prescribing in this cohort of family physicians. Total antibiotic use was strongly correlated with unnecessary antibiotic prescribing. Total antibiotic volume is a reasonable surrogate for unnecessary antibiotic use. These results can inform community antimicrobial stewardship efforts.

The COVID-19 pandemic has led to an exponential increase in SARS-CoV-2 infections and associated deaths, and represents a significant challenge to healthcare professionals and facilities. Individual countries have taken several prevention and containment actions to control the spread of infection, including measures to guarantee safety of both healthcare professionals and patients who are at increased risk of infection from COVID-19. Faecal microbiota transplantation (FMT) has a well-established role in the treatment of Clostridioides difficile infection. In the time of the pandemic, FMT centres and stool banks are required to adopt a workflow that continues to ensure reliable patient access to FMT while maintaining safety and quality of procedures. In this position paper, based on the best available evidence, worldwide FMT experts provide guidance on issues relating to the impact of COVID-19 on FMT, including patient selection, donor recruitment and selection, stool manufacturing, FMT procedures, patient follow-up and research activities.

Three hospital emergency rooms (ERs) routinely referred all cases of cellulitis requiring outpatient intravenous antibiotics, to a central ER-staffed cellulitis clinic. We performed a retrospective cohort study of all patients seen by the ER clinic in the last 4months preceding a policy change (ER management cohort [ERMC]) (n=149) and all those seen in the first 3months of a new policy of automatic referral to an infectious disease (ID) specialist-supervised cellulitis clinic (ID management cohort [IDMC]) (n=136). Fifty-four (40%) of 136 patients in the IDMC were given an alternative diagnosis (noncellulitis), compared to 16 (11%) of 149 in the ERMC (P0.0001). Logistic regression-demonstrated rates of disease recurrence were lower in the IDMC than the ERMC (hazard ratio [HR], 0.06; P=0.003), as were rates of hospitalization (HR, 0.11; P=0.01). There was no significant difference in mortality. Automatic ID consultation for cellulitis was beneficial in differentiating mimickers from true cellulitis, reducing recurrence, and preventing hospital admissions.

Data are lacking on factors that may impact conception-related decision-making among individuals living with HIV. This study’s aim was to shed light on these considerations. Participants were invited to complete a survey on preconception considerations. A rank-ordered logit model was fit to estimate the relative importance of listed consideration factors; the interaction of HIV status and the factors was assessed. Fifty-nine participants living with HIV and 18 partners (11 HIV-negative participants and 7 living with HIV) were included. Risk of vertical and horizontal HIV transmission and the effect of antiretroviral therapy on the fetus were the top considerations. However, individuals living with HIV prioritized vertical transmission, whereas HIV-negative participants prioritized horizontal transmission. Other factors of importance were probability of conception, stress of trying to conceive, cost associated with fertility clinics, and stigma associated with certain conception methods. This study builds our understanding of the preconception considerations for people living with HIV.

Background: The gut microbiome, which consists of a highly diverse ecologic community of micro-organisms, has increasingly been studied regarding its role in multiple sclerosis (MS) immunopathogenesis. This review critically examines the literature investigating the gut microbiome in MS. Methods: A comprehensive search was performed of PubMed databases and ECTRIMS meeting abstracts for literature relating to the gut microbiome in MS. Controlled studies examining the gut microbiome in patients with MS were included for review. Results: Identified studies were predominantly case-control in their design and consistently found differences in the gut microbiome of MS patients compared to controls. We examine plausible mechanistic links between these differences and MS immunopathogenesis, and discuss the therapeutic implications of these findings. Conclusions: Review of the available literature reveals potential immunopathogenic links between the gut microbiome and MS, identifies avenues for therapeutic advancement, and emphasizes the need for further systematic study in this emerging field.

BACKGROUND Colon ischaemia is a common disease which has been associated with various medications and comorbidities. AIM To test the hypothesis that there are differences in the frequencies of these associations in older compared with younger patients. METHODS A retrospective cohort study was performed of patients hospitalized with colon ischaemia at two major medical centres from 2005-2017. Clinical, colonoscopic and pathologic criteria were used to identify patients admitted with colon ischaemia; patients with other types of colitis were excluded. Demographic and medical data were extracted. Two cohorts were created: patients aged 18-64 years and patients > 65 years. These were compared using SAS 14.3. RESULTS A total of 788 patients were included, of which 271 (34.4%) were of ages 18-64 years, and 517 (66.6%) were 65 years old or older. In the older cohort, constipation-inducing medications (83.8% vs 64.1%; P =

AIMS: Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray‐dried formulation of tiotropium that enables more efficient lung delivery than Spiriva(®) HandiHaler(®) (HH). The ratio of tiotropium lung‐to‐oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics, and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block. METHODS: A seven‐period, single‐dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation. RESULTS: PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung‐to‐oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 μg tiotropium) lung deposition was similar to Spiriva HH (18 μg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The C (max) and AUC(0–0.5h) of Spiriva HH with and without charcoal block were bioequivalent; however, Spiriva HH AUC(0–8h) was lower when gastrointestinal absorption was inhibited with oral charcoal administration. CONCLUSIONS: Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC(0–t) than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract.

Background Postpartum depression (PPD) reportedly affects between 6.5–19% of all new mothers. Identifying those at greatest risk for PPD has implications for prevention, early detection and intervention. While the relationship between extremes of body mass index (BMI) and depression has been frequently studied, the association between BMI and PPD is less understood. Methods Prospective cohort of all women with live singleton births in Sweden 1997–2008. We calculated the relative risk (RR) for PPD in relation to each woman's BMI and depression history. PPD diagnosis was based on a clinical diagnosis of depression within the first postpartum year. Results First trimester BMI measurements were available for 611,506 women. Low BMI ( 35) RRadj = 1.23, [95% CI: 1.04–1.45] were associated with increased PPD risk. Women with a depression history had an increased risk with low BMI (RRadj = 1.51, [95% CI: 1.17–1.95]). Limitations Only first births were analyzed, potentially underestimating PPD incidence. Clinical data from health registries offers limited resolution regarding the specificity of diagnoses and incomplete sensitivity if women do not seek care. Conclusions First trimester of pregnancy BMI is associated with PPD risk. This risk is further modified by depression history. While low BMI places all women at risk for PPD, being overweight increases risk of PPD only in women without a history of depression. Future research should explore potentially modifiable mechanisms involved in the relationship between PPD and BMI and should also examine interventional strategies for pregnant women at the extremes of BMI and/or with a depression history.

PURPOSE: Postpartum depression (PPD) is characterized as a depressive episode conditional on childbirth. We examined whether the risk of depression is higher following childbirth than a randomly generated time unrelated to childbirth. METHODS: In a prospective cohort of all women with live singleton births in Sweden, 1997–2008, we first calculated the relative risk (RR) of PPD for mothers with a history of depression compared to mothers without such a history. Next we repeated the calculations, but now for depression following a computer generated arbitrary “phantom delivery” date, unrelated to the true date of delivery. For this phantom delivery date, we used the average expected date of delivery for all women of the same age. For the analyses of each group, women were followed for a full calendar year. We fitted Poisson regression and calculated RR and two-sided 95% confidence intervals (CI). RESULTS: Among a total of 707,701 deliveries, there were 4,397 PPD cases and 4,687 control depression cases. The RR of PPD was 21.0 (CI: 19.7–22.4). The RR of depression in the control group was 26.2 (CI: 24.7–27.9). CONCLUSION: We provide evidence that the risk for PPD is no greater following childbirth than following a random date unrelated to childbirth. This finding suggests that the postpartum period may not necessarily represent a time of heightened vulnerability for clinically significant depression and that the well established observation of depression covarying with childbirth does not necessarily equate to causation, but rather may be a secondary effect of postpartum women representing a medically captured population.

Introduction Infective endocarditis is associated with high morbidity and mortality. Currently, there is concern that the incidence of infective endocarditis associated with people who inject drugs (PWID) is increasing. However, it is difficult to monitor population-wide trends in PWID-associated infective endocarditis, as there is no International Statistical Classification of Diseases, 10th Revision (ICD-10) code for injection drug use. To address this barrier, we sought to develop a validated algorithm using ICD-10 discharge diagnosis codes. Materials and methods We constructed a cohort of patients whose hospital discharge diagnosis included infective endocarditis. We reviewed 100 patients with incident infective endocarditis from 2014 to 2016 for their infective endocarditis and injection drug use status. We calculated the operating characteristics for algorithms constructed using permutations of ICD-10 codes associated with injection drug use. We repeated this analysis in a cohort of 100 patients with incident infective endocarditis from 2009 to 2011 to examine the temporal stability of the operating characteristics of each algorithm. Results We found that a combination of hepatitis C virus, drug use, and mental/behavioral disorder codes yielded the highest sensitivity (93%) and positive predictive value (83%) of the algorithms analyzed. Discussion We have described the first algorithm, validated against chart review data, for identifying PWID-associated infective endocarditis cases using ICD-10 codes. The high sensitivity and positive predictive value indicate that this algorithm can be used for surveillance and research with confidence. Conclusions This algorithm will enable researchers to examine epidemiological trends in PWID-associated infective endocarditis.

Background Combination antiretroviral therapy (cART) use in pregnancy has been associated with hormonal dysregulation. We performed a secondary retrospective analysis of longitudinal progesterone and estradiol levels in pregnancy using specimens from the Protease Inhibitors to Reduce Malaria Morbidity in HIV-infected Pregnant Women study, which randomized Ugandan human immunodeficiency virus (HIV)-infected ART-naive women to initiate either lopinavir/ritonavir (LPV/r)-based or efavirenz (EFV)-based cART. Methods Three hundred twenty-six women (160 randomized to the EFV arm and 166 women to the LPV/r arm) with at least 1 plasma sample collected during pregnancy were included. Enrollment samples collected prior to cART initiation were used as a cART-naive comparator group. Hormone levels were quantified by enzyme-linked immunosorbent assay. Results Estradiol levels were differentially affected by the 2 cART regimens. Exposure to LPV/r was associated with an increase in estradiol (P < .0001), whereas exposure to EFV was associated with a decrease in estradiol (P < .0001), relative to the cART-naive gestationally matched comparator group. Lower estradiol levels correlated with small for gestational age (SGA) (P = .0019) and low birth weight (P = .019) in the EFV arm, while higher estradiol levels correlated with SGA in the LPV/r arm (P = .027). Although progesterone levels were similar between treatment arms, we observed an association between SGA and lower progesterone in the LPV/r arm (P = .04). No association was observed between hormone levels and preterm birth in either arm. Levels of progesterone and estradiol were lower in cases of stillbirth, and levels of both hormones declined immediately prior to stillbirth in 5 of 8 cases. Conclusions Combination ART regimens differentially affect estradiol levels in pregnancy, a hormone critical to the maintenance of a healthy pregnancy. Identifying cART regimens that minimize perinatal HIV transmission without contributing to hormonal dysregulation represents an urgent public health priority. Clinical Trials Registration NCT00993031.

The distinction between episodic viral wheeze (EVW) and multitrigger wheeze (MTW) is used to guide management of preschool wheeze. It has been questioned whether these phenotypes are stable over time. We examined the temporal stability of MTW and EVW in two large population-based cohorts.We classified children from the Avon Longitudinal Study of Parents and Children (n=10 970) and the Leicester Respiratory Cohorts ((LRCs), n=3263) into EVW, MTW and no wheeze at ages 2, 4 and 6 years based on parent-reported symptoms. Using multinomial regression, we estimated relative risk ratios for EVW and MTW at follow-up (no wheeze as reference category) with and without adjusting for wheeze severity.Although large proportions of children with EVW and MTW became asymptomatic, those that continued to wheeze showed a tendency to remain in the same phenotype: among children with MTW at 4 years in the LRCs, the adjusted relative risk ratio was 15.6 (95% CI 8.3–29.2) for MTW (stable phenotype) compared to 7.0 (95% CI 2.6–18.9) for EVW (phenotype switching) at 6 years. The tendency to persist was weaker for EVW and from 2–4 years. Results were similar across cohorts.This suggests that MTW, and to a lesser extent EVW, tend to persist regardless of wheeze severity.

Institution and country of all co-authors (1) Swiss Paediatric Respiratory Research Group, Department of Social and Preventive Medicine, University of Berne, Switzerland (2) The Leicester Children's Asthma Centre, Division of Child Health, Department of Infection, Immunity & Inflammation, University of Leicester, Leicester, LE2 7LX, UK (3) Specialist Community Child Health Services, Leicester City PCT, Bridge Park Plaza, Thurmaston, Leicester, LE4 8PQ, UK

BACKGROUND: Many studies showing effects of traffic-related air pollution on health rely on self-reported exposure, which may be inaccurate. We estimated the association between self-reported exposure to road traffic and respiratory symptoms in preschool children, and investigated whether the effect could have been caused by reporting bias. METHODS: In a random sample of 8700 preschool children in Leicestershire, UK, exposure to road traffic and respiratory symptoms were assessed by a postal questionnaire (response rate 80%). The association between traffic exposure and respiratory outcomes was assessed using unconditional logistic regression and conditional regression models (matching by postcode). RESULTS: Prevalence odds ratios (95% confidence intervals) for self-reported road traffic exposure, comparing the categories 'moderate' and 'dense', respectively, with 'little or no' were for current wheezing: 1.26 (1.13-1.42) and 1.30 (1.09-1.55); chronic rhinitis: 1.18 (1.05-1.31) and 1.31 (1.11-1.56); night cough: 1.17 (1.04-1.32) and 1.36 (1.14-1.62); and bronchodilator use: 1.20 (1.04-1.38) and 1.18 (0.95-1.46). Matched analysis only comparing symptomatic and asymptomatic children living at the same postcode (thus exposed to similar road traffic) showed similar ORs, suggesting that parents of children with respiratory symptoms reported more road traffic than parents of asymptomatic children. CONCLUSIONS: Our study suggests that reporting bias could explain some or even all the association between reported exposure to road traffic and disease. Over-reporting of exposure by only 10% of parents of symptomatic children would be sufficient to produce the effect sizes shown in this study. Future research should be based only on objective measurements of traffic exposure.

Background Human immunodeficiency virus (HIV)-infected pregnant women on protease inhibitor (PI)-based combination antiretroviral therapy (cART) have a greater risk for adverse birth outcomes, and an association with steroid hormone levels has been implicated. The objective of this study was to investigate the association between PI-cART and estradiol levels in pregnancy. Methods Fifty-five HIV-infected and 49 HIV-uninfected Canadian pregnant women were followed prospectively throughout gestation. All HIV-infected women were on a PI-based cART regimen. Maternal plasma samples were collected at 12-18 weeks, 24-28 weeks, 34-38 weeks, at delivery, and from the cord. Birth outcomes were recorded. Levels of estradiol, dehydroepiandrosterone sulfate (DHEAS), sex hormone-binding globulin (SHBG), cortisol, and adrenocorticotropic hormone (ACTH) were quantified by enzyme-linked immunosorbent assay. Results (median [interquartile range] for cord estradiol: 23.9 ng/mL [16.4-36.4] for HIV-infected exposed to PI-cART and 15.7 ng/mL [12.2-21.2] for HIV-negative; P = .0025). HIV-infected women had higher DHEAS levels in cord plasma that correlated with cord and maternal delivery estradiol levels. Cortisol and ACTH levels did not differ between groups. In the HIV-infected women, cord estradiol levels correlated negatively with birth weight centile (r = -0.47, P = .0016). Conclusions Our data suggest that PI-cART exposure in pregnancy is associated with elevated levels of estradiol, likely driven by higher fetal DHEAS production. Cord estradiol levels were inversely correlated with birth weight centile in infants born to PI-cART-exposed women, suggesting that fetal exposure to high estradiol levels may be contributing to cART-associated fetal growth restriction.

In rural Uganda pregnant women often lack access to health services, do not attend antenatal care, and tend to utilize traditional healers/birth attendants. We hypothesized that receiving a message advertising that “you will be able to see your baby by ultrasound” would motivate rural Ugandan women who otherwise might use a traditional birth attendant to attend antenatal care, and that those women would subsequently be more satisfied with care. A cluster randomized trial was conducted across eight rural sub-counties in southwestern Uganda. Sub-counties were randomized to a control arm, with advertisement of antenatal care with no mention of portable obstetric ultrasound (four communities, n = 59), or an intervention arm, with advertisement of portable obstetric ultrasound. Advertisement of portable obstetric ultrasound was further divided into intervention A) word of mouth advertisement of portable obstetric ultrasound and antenatal care (one communitity, n = 16), B) radio advertisement of only antenatal care and word of mouth advertisement of antenatal care and portable obstetric ultrasound (one community, n = 7), or C) word of mouth + radio advertisement of both antenatal care and portable obstetric ultrasound (two communities, n = 75). The primary outcome was attendance to antenatal care. 159 women presented to antenatal care across eight sub-counties. The rate of attendance was 65.1 (per 1000 pregnant women, 95% CI 38.3–110.4) where portable obstetric ultrasound was advertised by radio and word of mouth, as compared to a rate of 11.1 (95% CI 6.1–20.1) in control communities (rate ratio 5.9, 95% CI 2.6–13.0, p

Background Many preschool children have wheeze or cough, but only some have asthma later. Existing prediction tools are difficult to apply in clinical practice or exhibit methodological weaknesses. Objective We sought to develop a simple and robust tool for predicting asthma at school age in preschool children with wheeze or cough. Methods From a population-based cohort in Leicestershire, United Kingdom, we included 1- to 3-year-old subjects seeing a doctor for wheeze or cough and assessed the prevalence of asthma 5 years later. We considered only noninvasive predictors that are easy to assess in primary care: demographic and perinatal data, eczema, upper and lower respiratory tract symptoms, and family history of atopy. We developed a model using logistic regression, avoided overfitting with the least absolute shrinkage and selection operator penalty, and then simplified it to a practical tool. We performed internal validation and assessed its predictive performance using the scaled Brier score and the area under the receiver operating characteristic curve. Results Of 1226 symptomatic children with follow-up information, 345 (28%) had asthma 5 years later. The tool consists of 10 predictors yielding a total score between 0 and 15: sex, age, wheeze without colds, wheeze frequency, activity disturbance, shortness of breath, exercise-related and aeroallergen-related wheeze/cough, eczema, and parental history of asthma/bronchitis. The scaled Brier scores for the internally validated model and tool were 0.20 and 0.16, and the areas under the receiver operating characteristic curves were 0.76 and 0.74, respectively. Conclusion This tool represents a simple, low-cost, and noninvasive method to predict the risk of later asthma in symptomatic preschool children, which is ready to be tested in other populations.

Background Among children with wheeze and recurrent cough there is great variation in clinical presentation and time course of the disease. We previously distinguished 5 phenotypes of wheeze and cough in early childhood by applying latent class analysis to longitudinal data from a population-based cohort (original cohort). Objective To validate previously identified phenotypes of childhood cough and wheeze in an independent cohort. Methods We included 903 children reporting wheeze or recurrent cough from an independent population-based cohort (validation cohort). As in the original cohort, we used latent class analysis to identify phenotypes on the basis of symptoms of wheeze and cough at 2 time points (preschool and school age) and objective measurements of atopy, lung function, and airway responsiveness (school age). Prognostic outcomes (wheeze, bronchodilator use, cough apart from colds) 5 years later were compared across phenotypes. Results When using a 5-phenotype model, the analysis distinguished 3 phenotypes of wheeze and 2 of cough as in the original cohort. Two phenotypes were closely similar in both cohorts: Atopic persistent wheeze (persistent multiple trigger wheeze and chronic cough, atopy and reduced lung function, poor prognosis) and transient viral wheeze (early-onset transient wheeze with viral triggers, favorable prognosis). The other phenotypes differed more between cohorts. These differences might be explained by differences in age at measurements. Conclusions Applying the same method to 2 different cohorts, we consistently identified 2 phenotypes of wheeze (atopic persistent wheeze, transient viral wheeze), suggesting that these represent distinct disease processes. Differences found in other phenotypes suggest that the age when features are assessed is critical and should be considered carefully when defining phenotypes.

OBJECTIVES: Age- and height-adjusted spirometric lung function of South Asian children is lower than those of white children. It is unclear whether this is purely genetic, or partly explained by the environment. In this study, we assessed whether cultural factors, socioeconomic status, intrauterine growth, environmental exposures, or a family and personal history of wheeze contribute to explaining the ethnic differences in spirometric lung function. METHODS: We studied children aged 9 to 14 years from a population-based cohort, including 1088 white children and 275 UK-born South Asians. Log-transformed spirometric data were analyzed using multiple linear regressions, adjusting for anthropometric factors. Five different additional models adjusted for (1) cultural factors, (2) indicators of socioeconomic status, (3) perinatal data reflecting intrauterine growth, (4) environmental exposures, and (5) personal and family history of wheeze. RESULTS: Height- and gender-adjusted forced vital capacity (FVC) and forced expired volume in 1 second (FEV1) were lower in South Asian than white children (relative difference –11% and –9% respectively, P < .001), but PEF and FEF50 were similar (P ≥ .5). FEV1/FVC was higher in South Asians (1.8%, P < .001). These differences remained largely unchanged in all 5 alternative models. CONCLUSIONS: Our study confirmed important differences in lung volumes between South Asian and white children. These were not attenuated after adjustment for cultural and socioeconomic factors and intrauterine growth, neither were they explained by differences in environmental exposures nor a personal or family history of wheeze. This suggests that differences in lung function may be mainly genetic in origin. The implication is that ethnicity-specific predicted values remain important specifically for South Asian children.

Background Access to safe surgical care represents a critical gap in healthcare delivery and development in many low- and middle-income countries, including Ethiopia. Quality improvement (QI) initiatives at hospital level may contribute to closing this gap. Many such quality improvement initiatives are carried out through international health partnerships. Better understanding of how to optimise quality improvement in low-income settings is needed, including through partnership-based approaches. Drawing on a process evaluation of an intervention to improve surgical services in an Ethiopian hospital, this paper offers lessons to help meet this need. Methods We conducted a qualitative process evaluation of a quality improvement project which aimed to improve access to surgical services in an Ethiopian referral hospital through better management. Data was collected longitudinally and included: 66 in-depth interviews with surgical staff and project team members; observation (135 h) in the surgery department and of project meetings; project-related documentation. Thematic analysis, guided by theoretical constructs, focused on identifying obstacles to implementation. Results The project largely failed to achieve its goals. Key barriers related to project design, partnership working and the implementation context, and included: confusion over project objectives and project and partner roles and responsibilities; logistical challenges concerning overseas visits; difficulties in communication; gaps between the time and authority team members had and that needed to implement and engage other staff; limited strategies for addressing adaptive—as opposed to technical—challenges; effects of hierarchy and resource scarcity on QI efforts. While many of the obstacles identified are common to diverse settings, our findings highlight ways in which some features of low-income country contexts amplify these common challenges. Conclusion We identify lessons for optimising the design and planning of quality improvement interventions within such challenging healthcare contexts, with specific reference to international partnership-based approaches. These include: the need for a funded lead-in phase to clarify and agree goals, roles, mutual expectations and communication strategies; explicitly incorporating adaptive, as well as technical, solutions; transparent management of resources and opportunities; leadership which takes account of both formal and informal power structures; and articulating links between project goals and wider organisational interests. Electronic supplementary material The online version of this article (doi:10.1186/s12913-016-1639-4) contains supplementary material, which is available to authorized users.

To test whether dexamethasone (DEX) treatment in pregnancies at risk for congenital adrenal hyperplasia (CAH) impairs cognitive functioning in the offspring.Observational follow-up of prenatally DEX-exposed offspring and controls.Study 1 included 140 children aged 512 years: 67 DEX-exposed (long-term: eight CAH girls) and 73 unexposed (with 15 CAH girls). Study 2 included 20 participants aged 11-24 years: seven DEX-exposed (long-term: one CAH woman) and 13 unexposed (with four CAH women). Neuropsychological testing was done in hospital settings or at patients' homes. Data analysis aimed at maximizing detection of the effects of DEX exposure.The vast majority of group comparisons were not marginally or conventionally significant. The few significant findings on short-term prenatal DEX exposure suggested more positive than adverse outcomes. By contrast, few significant findings in females with CAH and long-term DEX exposure indicated slower mental processing than in controls on several neuropsychological variables, although partial correlations of DEX exposure duration with cognitive outcome did not corroborate this association.Although our studies do not replicate a previously reported adverse effect of short-term prenatal DEX exposure on working memory, our findings on cognitive function in CAH girls with long-term DEX exposure contribute to concerns about potentially adverse cognitive after effects of such exposure. Yet, our studies are not definitive, and replications in larger samples are required.

While contemporary diagnostic nosology characterizes postpartum depression (PPD) as a specifier of a major depressive disorder (MDD), this classification continues to be questioned. Functional magnetic resonance imaging (fMRI) holds the promise of helping to characterize the neuroanatomical dysfunction associated with dysregulated emotion after childbirth. Twenty postpartum women underwent fMRI in the presence of emotionally valenced stimuli. The observation of relative amygdala non-responsivity in subjects demonstrating greater depression symptomotology stands in contrast to imaging studies of MDD and provides insight into possible phenotypic differences of PPD.

RATIONALE: Advances in spirometry measurement techniques have made it possible to obtain measurements in children as young as 3 years of age; however, in practice, application remains limited by the lack of appropriate reference data for young children, which are often based on limited population-specific samples. OBJECTIVES: We aimed to build on previous models by collating existing reference data in young children (aged 3-7 years), to produce updated prediction equations that span the preschool years and that are also linked to established reference equations for older children and adults. METHODS: The Asthma UK Collaborative initiative was established to collate lung function data from healthy young children aged 3-7 years. Collaborators included researchers with access to pulmonary function test data in healthy preschool children. Spirometry centiles were created using the LMS (Lambda-Mu-Sigma) method and extend previously published equations down to 3 years of age. MAIN RESULTS: The Asthma UK centiles charts for spirometry are based on the largest sample of healthy young Caucasian children aged 3-7 years (n=3777) from 15 centers across 11 countries and provide a continuous reference with a smooth transition into adolescence and adulthood. These equations improve existing pediatric equations by considering the between-subject variability to define a more appropriate age-dependent lower limit of normal. The collated dataset reflects a variety of equipment, measurement protocols and population characteristics and may be generalizable across different populations. CONCLUSIONS: We present prediction equations for spirometry for preschool children and provide a foundation which will facilitate continued updating.

Epidemiological data on snoring from preschool children are scarce, although habitual snoring (snoring on almost all nights) has been associated with poor long-term outcomes. In a population survey of 6,811 children aged 1-4 yrs (from Leicestershire, UK) the present authors determined prevalence, severity and risk factors for snoring, especially habitual snoring. In 59.7% of the children, parents reported snoring in the previous 12 months, including 7.9% with habitual snoring and 0.9% with habitual snoring and sleep disturbance. Prevalence of habitual snoring increased with age from 6.6% in 1-yr-olds to 13.0% in 4-yr-olds. Habitual snoring was associated with: one and both parents smoking (adjusted odds ratio (OR) 1.46 and 2.09, respectively); road traffic (OR 1.23); single parent (OR 1.60); and in White but not South Asian children, socioeconomic deprivation (OR 1.25 and 2.03 for middle and upper thirds of Townsend score, respectively). Respiratory tract symptoms related to atopic disorders and to respiratory infections were strongly associated with snoring; however, body mass index was not. In conclusion, habitual snoring is common in preschool children with one-third of cases attributable to avoidable risk factors. The strong association with atopic disorders, viral infections and environmental exposures suggests a complex aetiology, based on a general vulnerability of the respiratory tract.

BACKGROUND: Epidemiological data for south Asian children in the United Kingdom are contradictory, showing a lower prevalence of wheeze, but a higher rate of medical consultations and admissions for asthma compared with white children. These studies have not distinguished different asthma phenotypes or controlled for varying environmental exposures. OBJECTIVE: To compare the prevalence of wheeze and related health-service use in south Asian and white pre-schoolchildren in the United Kingdom, taking into account wheeze phenotype (viral and multiple wheeze) and environmental exposures. METHODS: A postal questionnaire was completed by parents of a population-based sample of 4366 white and 1714 south Asian children aged 1-4 years in Leicestershire, UK. Children were classified as having viral wheeze or multiple trigger wheeze. RESULTS: The prevalence of current wheeze was 35.6% in white and 25.5% in south Asian 1-year-olds (P

The prostanoid DP receptor (PTGDR) is shown to be involved in the asthma patho-physiology and the results from the published genetic association studies are inconsistent. Four single nucleotide polymorphisms (SNPs) in PTGDR were genotyped in 342 and 294 families from UK and Denmark respectively. Asthma and asthma-related phenotypes were analyzed using family-based association analyses. In the UK families, a promoter polymorphism (-731A/G) showed significant associations with asthma (P=0.0022), atopic asthma (P=0.0044), bronchial hyperreactivity or BHR (P=0.00120) and strict asthma (P=0.0008). The P-values for asthma, BHR and strict asthma were significant even after the most stringent correction for the number of markers and the number of phenotypes analyzed (

Quantitative phenotypes correlated with a complex disorder offer increased power to detect linkage in comparison to affected-unaffected classifications. Asthma is a complex disorder characterized by periods of bronchial obstruction and increased bronchial hyper reactivity. In childhood and early adulthood, asthma is frequently associated also with quantitative measures of atopy. Genome wide quantitative multipoint linkage analysis was conducted for serum IgE levels and percentage of positive skin prick test (SPT(per)) using three large groups of families originally ascertained for asthma. In this report, 438 and 429 asthma families were informative for linkage using IgE and SPT(per) which represents 690 independent families. Suggestive linkage (LOD > or = 2) was found on chromosomes 1, 3, and 8q with maximum LODs of 2.34 (IgE), 2.03 (SPT(per)), and 2.25 (IgE) near markers D1S1653, D3S2322-D3S1764, and D8S2324, respectively. The results from chromosomes 1 and 3 replicate previous reports of linkage. We also replicate linkage to 5q with peak LODs of 1.96 (SPT(per)) and 1.77 (IgE) at or near marker D5S1480. Our results provide further evidence implicating chromosomes 1, 3, and 5q. The current report represents one of the biggest genome scans so far reported for asthma related phenotypes. This study also demonstrates the utility of increased sample sizes and quantitative phenotypes in linkage analysis of complex disorders.

Summary Background Studies of immigrants suggest that the environment during fetal life and duration of residence in the host country might influence the development of asthma. Little is known about the importance of the timing of the exposure in the host country and whether migrants might be especially vulnerable in certain age windows. Objective We compared the reported prevalence of asthma between young white and south Asian women in the United Kingdom, and investigated associations with country of birth and age at immigration. Methods A questionnaire on atopic disorders was posted to 2380 south Asian and 5796 white young mothers randomly sampled in Leicestershire. Data on ethnicity were also available from maternity records. Data were analysed using multivariable logistic regression and a propensity score approach. Results The reported prevalence of asthma was 10.9% in south Asian and 21.8% in white women. South Asian women who migrated to the United Kingdom aged 5 years or older reported less asthma (6.5%) than those born in the United Kingdom or who migrated before age 5 (16.0%), with an adjusted odds ratio of 0.38 [95% Confidence Interval 0.23–0.64, P