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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.

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.

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.

BACKGROUND: Infective endocarditis is an increasingly common complication among people who inject drugs. We conducted this study to determine whether the removal of traditional controlled-release oxycodone from the Canadian market would be associated with an increase in the use of hydromorphone and an increased risk of infective endocarditis. METHODS: We conducted a retrospective, population-based time series analysis using the linked health administrative databases of Ontario, Canada. We measured the quarterly risk of admissions for infective endocarditis related to injection drug use and changes in opioid prescription rates from 2006 to 2015. We set the intervention point at the fourth quarter of 2011, when traditional controlled-release oxycodone was removed from the Canadian market. RESULTS: We observed an increase in the risk of admissions for infective endocarditis related to injection drug use during the study period. Before the intervention point, we observed a mean of 13.4 admissions per quarter, and after the intervention, we observed a mean of 35.1 admissions per quarter. However, no significant change in this risk occurred at the intervention point. Rather, the risk of infectious endocarditis appeared to have increased earlier and in parallel with the rise in hydromorphone prescriptions. Hydromorphone represented 16% of all opioid prescriptions at the start of the observation period and 53% by the end. INTERPRETATION: The risk of infective endocarditis related to injection drug use is increasing and is temporally associated with increasing prescriptions for hydromorphone. This relation warrants further exploration.

Objective: Postpartum depression (PPD) is a prevalent disorder that can result in negative child developmental outcomes. While a maternal history of unipolar depression is understood to be the larg...

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.

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.

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 Checkpoint inhibitors have changed the outcomes for patients with advanced melanoma. However, many patients still show primary resistance to single-agent therapy. Recently, the role of the gut microbiome in influencing antitumor immunity has been established. Currently, various methods of modifying the gut microbiome of cancer patients are being explored. We report the initial safety results of the first two patients treated on a phase I study combining Fecal Microbiota Transplantation (FMT) with single-agent anti-PD1 in treatment-naive patients with advanced melanoma. Methods Two healthy donors were selected through our screening process and approximately 100 grams of fresh stool was processed and prepared for FMT as per our standardized protocol. FMT recipients were melanoma patients with unresectable or metastatic disease who were treatment naive for their advanced disease. Bowel preparation was completed the day prior and FMT was performed using oral administration of approximately 40 capsules. Anti-PD1 was started at least 1 week after FMT to allow for microbiome engraftment. Blood and stool were analyzed at baseline (pre-FMT), before immunotherapy, and three weeks after it. Results Patient 1 was diagnosed with recurrent melanoma of the lower limb with multiple in-transit lesions refractory to control with surgery and a single intralesional injection of IL-2. Patient received stool from Donor 1 and did not experience any adverse effects from FMT. At the time of treatment #4, a solitary large cutaneous lesion stabilized but the patient experienced grade 1 diarrhoea, grade 2 nausea, and grade 2 fatigue, and grade 2 depression (NCI-CTCAE v5.0). Patient 2 was diagnosed with recurrent melanoma of the parotid gland with metastatic lesions in the lungs. Patient 2 received stool from Donor 2 and experienced only grade 1 flatus from FMT. At the time of treatment #3, the patient experienced grade 1 constipation. Both patients had a vigorous immune response to FMT measured by changes in the immune subpopulations in peripheral blood one week after FMT, including an increase in CD28+ CD8+ T cells and a decrease in PDL1+ CD3- cells. Following anti-PD1 therapy, both patients had an increase in CD39+ CD8+ T cell population. The PD1+ CD38+ CD8+ dysfunctional T cell levels decreased in both patients post-FMT and anti-PD1 therapy. Conclusions FMT combined with anti-PD1 therapy in patients with advanced melanoma appears to be safe. A measurable immune response was observed one week after FMT in both patients. One patient experienced several grade 2 toxicities with stabilization of a large cutaneous lesion. Acknowledgements This study is funded by a grant from The Lotte & John Hecht Memorial Foundation and a grant from The Medical Oncology Research Funds (MORF) from Western University. Trial Registration NCT03772899 Ethics Approval The study was approved by Western University Institutution‘s Ethics Board, approval number 113131, date of approval March 15, 2019.

Jeffrey Man Hay Wong,1 Neha Kanga,1 Nupur Dogra,1 Mary Shilalukey Ngoma,2 Lena Serghides,3 Michael Silverman4 1Faculty of Medicine, University of Toronto, Toronto, ON, Canada; 2Department of Pediatrics, University of Zambia, Lusaka, Zambia; 3Toronto General Research Institute, University Health Network, Toronto, ON, Canada; 4Department of Infectious Diseases, Western University, London, ON, Canada Introduction: Intramuscular and vaginal progesterone are recommended for prevention of preterm labor (PTL) in women with risk factors. Studies are emerging to indicate that HIV-infected women on combination antiretroviral therapy (cART) are at risk of PTL and low birth weight (LBW), and may benefit from supplemental progesterone. This study aims to determine the perceived acceptability of various modes of progesterone supplementation to prevent PTL and LBW in HIV-infected and HIV-uninfected women.Methods: HIV-infected and HIV-uninfected women were recruited in Lusaka, Zambia. The participants completed a questionnaire to assess their willingness to take oral, vaginal, or intramuscular progesterone supplementation for preventing PTL and LBW, preferred modes of supplementation, and concern for PTL and LBW.Results: The study questionnaire was completed by 147 participants. Of the participants, 98.6% would consider using a medication to help prevent PTL and LBW, of whom 97.9% would consider using an oral form of progesterone.In addition, 83.3% and 84.0% of women would consider intramuscular and vaginal (gel or tablet) administration of progesterone respectively. Between intramuscular and vaginal modes of progesterone, 60.5% of participants (n=147) preferred intramuscular progesterone, while 39.5% preferred vaginal progesterone. There was no difference in preference between HIV-infected (n=70) and HIV-uninfected (n=77) women.Conclusions/implications: Pregnant Zambian women demonstrated a high degree of acceptance for all modes of progesterone supplementation for the prevention of PTL and LBW. Women preferred intramuscular over vaginal supplementation. Progesterone supplementation can be considered a feasible intervention for preventing PTL and LBW in both HIV-infected and HIV-uninfected pregnant Zambian women. Keywords: HIV/AIDS, progesterone, preterm labor, low birth weight, global health

KEY POINTS A 52-year-old man in a long-term, same-gender sexual relationship presented with agitation, confusion and problems speaking for about two weeks. On assessment, his vital signs were normal, but he was agitated and had global aphasia. No other focal deficits were identified on a screening

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.

Background Postpartum depression (PPD) can result in negative personal and child developmental outcomes. Only a few large population-based studies of PPD have used clinical diagnoses of depression and no study has examined how a maternal depression history interacts with known risk factors. The objective of this study was to examine the impact of a depression history on PPD and pre- and perinatal risk factors. Methods A nationwide prospective cohort study of all women with live singleton births in Sweden from 1997 through 2008 was conducted. Relative risk (RR) of clinical depression within the first year postpartum and two-sided 95% confidence intervals were estimated. Results The RR of PPD in women with a history of depression was estimated at 21.03 (confidence interval: 19.72–22.42), compared to those without. Among all women, PPD risk increased with advanced age (1.25 (1.13–1.37)) and gestational diabetes (1.70 (1.36–2.13)). Among women with a history of depression, pregestational diabetes (1.49 (1.01–2.21)) and mild preterm delivery also increased risk (1.20 (1.06–1.36)). Among women with no depression history, young age (2.14 (1.79–2.57)), undergoing instrument-assisted (1.23 (1.09–1.38)) or cesarean (1.64(1.07–2.50)) delivery, and moderate preterm delivery increased risk (1.36 (1.05–1.75)). Rates of PPD decreased considerably after the first postpartum month (RR = 0.27). Conclusion In the largest population-based study to date, the risk of PPD was more than 20 times higher for women with a depression history, compared to women without. Gestational diabetes was independently associated with a modestly increased PPD risk. Maternal depression history also had a modifying effect on pre- and perinatal PPD risk factors.

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 Infective endocarditis (IE) is increasing among persons who inject drugs (PWID) and has high morbidity and mortality. Recurrent IE in PWID is not well described. Methods This was a retrospective cohort study conducted between February 2007 and March 2016. It included adult inpatients (≥18) at any of 3 tertiary care centers in London, Ontario, with definite IE based on the Modified Duke's Criteria. The objectives were to characterize recurrent IE in PWID, identify risk factors for recurrent IE, identify the frequency of fungal endocarditis, and establish whether fungal infection was associated with higher mortality. Results Three hundred ninety patients had endocarditis, with 212/390 in PWID. Sixty-eight of 212 (32%) PWID had a second episode, with 28/212 (12%) having additional recurrences. Second-episode IE was more common in PWID (11/178 [6.2%] vs 68/212 [32.1%]; P < .001). Peripherally inserted central catheter (PICC) line abuse was associated with increased risk of recurrent endocarditis (odds ratio [OR], 1.97; 95% confidence interval [CI], 1.01–3.87; P = .04). In PWID, fungal IE was more common in second episodes than first episodes (1/212 [0.5%] vs 5/68 [7.4%]; P = .004). Additionally, fungal infections were associated with mortality in second-episode IE in PWID with an adjusted OR of 16.49 (95% CI, 1.12–243.17; P = .041). Despite recurrent infection, likely due to continued drug use, there was a low rate of referral to addiction treatment (14/68 [20.6%]). Conclusions PWID have a high risk of recurrent endocarditis, particularly in patients who abuse PICC lines. Fungal endocarditis is more common in second-episode endocarditis and is associated with increased mortality. Consideration of empiric antifungal therapy in PWID with IE history and suspected IE should be considered.

Background: People living with HIV treated with antiretroviral therapy (ART) are now living longer and thus many are requiring surgical procedures. For healthcare resource planning, it would be helpful to better understand the prevalence of HIV in surgical patients, the types of surgery HIV-positive patients are undergoing and whether HIV status impacts mortality. Objective: The goal of this study was to determine the prevalence of HIV in surgical inpatients and the extent of ART coverage, as well as to assess any differences between HIV-positive and HIV-negative patients in type of surgery undergone and in-hospital mortality at Karanda Mission Hospital, Mount Darwin, Zimbabwe. Method: A 1-year retrospective chart review was undertaken to collect clinical and demographic data for adult (excluding maternity cases) and paediatric surgical inpatients including age, sex, type of surgery, HIV status, CD4+ counts and, if patient was HIV-positive, whether he or she was taking ART. Results and conclusion : Charts for 1510 surgical inpatient stays were reviewed. HIV prevalence among the adults was higher than that in the general population in Zimbabwe in 2016 (23.2% vs. 14.7%). There was no significant difference in inpatient mortality between the HIV-negative group and the HIV-positive group. Within the group of patients with malignancies, people living with HIV were significantly younger than uninfected patients (mean age 50.5 vs. 64.4 years; p < 0.01). There were correlations between HIV and certain malignancies. Thus, in addition to AIDS-defining illnesses, clinicians must be alert to squamous cell carcinoma and oesophageal, anal and penile cancers in HIV-positive patients.

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 =

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.

Experimental studies performing fecal microbiota transplants (FMTs) from human to animals and between animals is providing enlightening information with regards to phenotypical characteristics that can potentially be influenced by the microbiome. A recent study by De Palma (1) has shown that fecal material from humans with irritable bowel syndrome (IBS) with diarrhea (IBS-D) invoked physical changes in the intestinal environment and in behavior. This is an interesting outcome, given the questions that have been raised about the relevance of certain models’ in light of the differences between the rodent gut physiology, the microbiome and the human condition (2,3).

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.

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.

The composition and activity of microorganisms in the gut, the microbiome, is emerging as an important factor to consider with regard to the treatment of many diseases. Dysbiosis of the normal community has been implicated in inflammatory bowel disease, Crohn’s disease, diabetes and, most notoriously, Clostridium difficile infection. In Canada, the leading treatment strategy for recalcitrant C. difficile infection is to receive faecal material which by nature is filled with microorganisms and their metabolites, from a healthy individual, known as a faecal microbiota transplantation. This influx of bacteria into the gut helps to restore the microbiota to a healthy state, preventing C. difficile from causing further disease. Much of what is known with respect to the microbiota and faecal microbiota transplantation comes from animal studies simulating the human disease. Although these models allow researchers to perform studies that would be difficult in humans, they do not always recapitulate the human microbiome. This makes the translation of these results to humans somewhat questionable. The purpose of this review is to analyse these animal models and discuss the advantages and the disadvantages of them in relation to human translation. By understanding some of the limitation of animal models, we will be better able to design and perform experiments of most relevance to human applications.

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.

Schemes for classifying skin and soft tissue infections (SSTIs) pose limitations for clinicians and regulatory agencies. Diabetic foot infections (DFIs) are a subset of SSTIs. We developed and are proposing a classification to harmonize current schemes for SSTIs and DFIs. Existing schemes for classifying SSTIs are limited in both their usefulness to clinicians and to regulatory agencies. The guidelines on SSTI from the Infectious Diseases Society of America (IDSA) and the guidance from the US Food and Drug Administration do not adequately address many types of wound infections. However, guidelines developed by the IDSA for DFIs provide a classification scheme that has been validated and widely used. Diabetic foot infections are similar to SSTIs in pathophysiology, microbiology, and treatment and can be seen as a subset of SSTI. Thus, based on the documents noted above, and our review of the literature, we have developed a proposed classification scheme for SSTI that harmonizes well with the DFI classification. We believe this new scheme will assist clinicians in classifying most wound infections and potentially aid regulatory agencies in testing and approving new antimicrobials for these infections.

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.

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.

Background Persons who inject drugs (PWID) represent a distinct demographic of patients with infective endocarditis (IE). Many centers do not perform valvular surgery on these patients due to concerns about poor outcomes. Methods Retrospective cohort study comparing PWID patients to non-PWID patients presenting between February 2007 and March 2016 in London, Ontario, among adult (>18) inpatients with first episode IE. Results In 370 first episode IE cases, 53.9% occurred in PWIDs. PWID patients were younger (35.4 SD 10.0 vs. 59.4 SD 14.9) (P < 0.001), more likely to have right-sided infection [125/202 (62%), vs. 16/168 (9.5%) (P < 0.001)], and more often due to S. aureus (156/202 (77.3%) vs. 54/168 (32.1%), P < 0.001). Myocardial and aortic root abscesses were less common in PWIDs [17/202 (8.4%) vs. 50/168 (30%) (P < 0.01)]. There was no difference in the frequency of noncardiac complications. In total, 36.5% of patients were treated surgically with PWID patients less likely to undergo surgery [39/202 (19.3%) vs. 98/168 (58%) P < 0.001]. Cox regression analysis identified the protective effect of cardiac surgery with regards to survival in all patients, with a hazard ratio of 0.49 (95% CI 0.31–0.76, P < 0.001), as well as among PWIDs (HR 0.39, 95% CI 0.17–0.87, P = 0.02). Among all patients, lower survival was associated with older age (HR 1.03, 95% CI 1.00–1.05, P < 0.001), injection drug use (HR 2.72, 95% CI 1.52–4.88, P < 0.001), left-sided infection (HR 3.48, 95% CI 2.01–6.03, P < 0.001), and bilateral infection (HR 3.19, 95% CI 1.45–7.01, P = 0.004). The lower survival of left-sided infection (HR 4.01, 95% CI 1.97–8.18, P < 0.001) or bilateral infection (HR 6.94, 95% CI 2.39–20.2,P < 0.001) was re-demonstrated in PWIDs. Conclusion This study identifies important clinical differences between PWIDs and nondrug users with respect to valve involvement, causative organism, complications, and management strategies. Our results highlight the important role of surgical treatment in a carefully selected PWID patient population. Disclosures All authors: No reported disclosures.

Background S. aureus is the most common pathogen associated with injection drug use-associated endocarditis (IDUaIE). Our center has a high incidence of IDUaIE and the opiate of choice in our population is hydromorphone-controlled release (HCR), a prescribed oral opiate widely used in Canada and Europe. The complex technique for preparation for injection provides multiple opportunities for contamination of the solution and the controlled-release preparation contains several excipients (carbohydrates, protein, and iron), which could enhance Staphylococcal survival. A large amount of drug remains in the injection drug preparation equipment (IDPE) after each use and therefore, used IDPE is saved by people who inject drugs (PWID) for subsequent reuse by adding more water and then injecting the solution intravenously. Methods Used IDPE was collected from active PWID, rinsed with sterile water, aspirated into a syringe in a technique which mimicked reuse of equipment by PWID, and then plated on Mannitol salt agar (MSA). Bacterial isolates from local bacteremic PWID were used to test the survival of S. aureus (MRSA and MSSA) and S. pyogenes on unused IDPE with HCR or hydromorphone immediate release (HIR). The solutions were aspirated using techniques similar to that of local PWID and then plated on MSA and Blood agar. Results A total of 109 used IDPE samples were collected between March 2017 and March 2018. S. aureus was detected in 15/94 (16%) IDPE samples that had been used for injection of HMC (seven MRSA, seven MSSA, and two borderline resistant [one sample contained both MRSA and MSSA]), but 0/15 (0%) samples used for hydromorphone immediate release (HIR). HCR, but not HM, was associated with greater survival of MSSA and MRSA (but not S. pyogenes) in solutions of the drug when compared with sterile water vehicle control (Figure 1). There was a 2-log reduction in the number of viable S. aureus when IDPE containing HCR solutions spiked with MRSA or MSSA were heated with a cigarette lighter until bubbling ( Conclusion IDPE that has been used in the preparation of HCR is frequently contaminated with S. aureus; and in vitro HCR, but not HM, prolongs the survival of MRSA and MSSA. Heating IDPE may be an effective harm-reduction strategy to reduce bacterial complications of injection of HCR. Disclosures All authors: No reported disclosures.

It has been suggested that there are several distinct phenotypes of childhood asthma or childhood wheezing. Here, we review the research relating to these phenotypes, with a focus on the methods used to define and validate them. Childhood wheezing disorders manifest themselves in a range of observable (phenotypic) features such as lung function, bronchial responsiveness, atopy and a highly variable time course (prognosis). The underlying causes are not sufficiently understood to define disease entities based on aetiology. Nevertheless, there is a need for a classification that would (i) facilitate research into aetiology and pathophysiology, (ii) allow targeted treatment and preventive measures and (iii) improve the prediction of long-term outcome. Classical attempts to define phenotypes have been one-dimensional, relying on few or single features such as triggers (exclusive viral wheeze vs. multiple trigger wheeze) or time course (early transient wheeze, persistent and late onset wheeze). These definitions are simple but essentially subjective. Recently, a multi-dimensional approach has been adopted. This approach is based on a wide range of features and relies on multivariate methods such as cluster or latent class analysis. Phenotypes identified in this manner are more complex but arguably more objective. Although phenotypes have an undisputed standing in current research on childhood asthma and wheezing, there is confusion about the meaning of the term 'phenotype' causing much circular debate. If phenotypes are meant to represent 'real' underlying disease entities rather than superficial features, there is a need for validation and harmonization of definitions. The multi-dimensional approach allows validation by replication across different populations and may contribute to a more reliable classification of childhood wheezing disorders and to improved precision of research relying on phenotype recognition, particularly in genetics. Ultimately, the underlying pathophysiology and aetiology will need to be understood to properly characterize the diseases causing recurrent wheeze in children.

Properdin, a serum glycoprotein, is an important component of innate immunity, the only known positive regulator of complement, acting as an initiation point for alternative pathway activation. As an X-linked protein, we hypothesized that properdin may play a modulatory role in the pathogenesis of viral wheeze in children, which tends to be more common and more severe in boys. We aimed to determine properdin levels in a community-based paediatric sample, and to assess whether levels of properdin were associated with childhood wheeze phenotypes and atopy. We studied 137 school-children aged 8-12 yrs, a nested sample from a cohort study. Properdin was measured by a commercial enzyme-linked immunoabsorbant assay. We assessed wheeze by questionnaire, validated it by a nurse-led interview and performed skin prick tests and a methacholine challenge in all children. Forty children (29%) reported current wheeze. Serum properdin levels ranged between 18 and 40 microg/ml. Properdin was not associated with age, gender, atopy, bronchial responsiveness, current wheeze (neither the viral wheeze nor multiple-trigger wheeze phenotype) or severity of wheeze, but was slightly lower in south Asian (median 21.8 microg/ml) compared with white children (23.3 microg/ml; p = 0.006). Our data make it unlikely that properdin deficiency is common in healthy children or that levels of properdin are a major risk factor for wheeze or atopy.

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.

The interleukin 18 receptor (IL18R1) gene is a strong candidate gene for asthma. It has been implicated in the pathophysiology of asthma and maps to an asthma susceptibility locus on chromosome 2q12. The possibility of association between polymorphisms in IL18R1 and asthma was examined by genotyping seven SNPs in 294, 342 and 100 families from Denmark, United Kingdom and Norway and conducting family-based association analyses for asthma, atopic asthma and bronchial hyper-reactivity (BHR) phenotypes. Three SNPs in IL18R1 were associated with asthma (0.01131≤P≤0.01377), five with atopic asthma (0.00066≤P≤0.00405) and two with BHR (0.01450≤P≤0.03203) in the Danish population; two SNPs were associated with atopic asthma (0.00397≤P≤0.01481) and four with BHR (0.00435≤P≤0.03544) in the UK population; four SNPs showed associations with asthma (0.00015≤P≤0.03062), two with atopic asthma (0.01269≤P≤0.04042) and three with BHR (0.00259≤P≤0.01401) in the Norwegian population; five SNPs showed associations with asthma (0.00005≤P≤0.03744), five with atopic asthma (0.00001≤P≤0.04491) and three with BHR (0.03568≤P≤0.04778) in the combined population. Three intronic SNPs (rs1420099, rs1362348 and rs1974675) showed replicated association for at least one asthma-related phenotype. These results demonstrate significant association between polymorphisms in IL18R1 and asthma.

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.