Forecasting the Incidence and Prevalence of Inflammatory Bowel Disease: A Canadian Nationwide Analysis.

INTRODUCTION: Canada has a high burden of inflammatory bowel disease (IBD). Historical trends of IBD incidence and prevalence were analyzed to forecast the Canadian burden over the next decade. METHODS: Population-based surveillance cohorts in 8 provinces derived from health administrative data assessed the national incidence (2007-2014) and prevalence (2002-2014) of IBD. Autoregressive integrated moving average models were used to forecast incidence and prevalence, stratified by age, with 95% prediction intervals (PI), to 2035. The average annual percentage change (AAPC) with 95% confidence interval (CI) was calculated for the forecasted incidence and prevalence. RESULTS: The national incidence of IBD is estimated to be 29.9 per 100,000 (95% PI 28.3-31.5) in 2023. With a stable AAPC of 0.36% (95% CI -0.05 to 0.72), the incidence of IBD is forecasted to be 31.2 per 100,000 (95% PI 28.1-34.3) in 2035. The incidence in pediatric patients (younger than 18 years) is increasing (AAPC 1.27%; 95% CI 0.82-1.67), but it is stable in adults (AAPC 0.26%; 95% CI -0.42 to 0.82). The prevalence of IBD in Canada was 843 per 100,000 (95% PI 716-735) in 2023 and is expected to steadily climb (AAPC 2.43%; 95% CI 2.32-2.54) to 1,098 per 100,000 (95% PI 1,068-1,127) by 2035. The highest prevalence is in seniors with IBD (1,174 per 100,000 in 2023; AAPC 2.78%; 95% CI 2.75-2.81). DISCUSSION: Over the next decade, the Canadian health care systems will contend with the juxtaposition of rising incidence of pediatric IBD and a rising prevalence of overall IBD driven by the aging population.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 2: Inactivated Vaccines.

BACKGROUND AND AIMS: The effectiveness and safety of vaccinations can be altered by immunosuppressive therapies, and perhaps by inflammatory bowel disease (IBD) itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on inactivated vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative online platform, and voted on by a multidisciplinary group. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Consensus was reached on 15 of 20 questions. Recommendations address the following vaccines: Haemophilus influenzae type b, recombinant zoster, hepatitis B, influenza, pneumococcus, meningococcus, tetanus-diphtheria-pertussis, and human papillomavirus. Most of the recommendations for patients with IBD are congruent with the current Centers for Disease Control and Prevention and Canada's National Advisory Committee on Immunization recommendations for the general population, with the following exceptions. In patients with IBD, the panel suggested Haemophilus influenzae type b vaccine for patients older than 5 years of age, recombinant zoster vaccine for adults younger than 50 year of age, and hepatitis B vaccine for adults without a risk factor. Consensus was not reached, and recommendations were not made for 5 statements, due largely to lack of evidence, including double-dose hepatitis B vaccine, timing of influenza immunization in patients on biologics, pneumococcal and meningococcal vaccines in adult patients without risk factors, and human papillomavirus vaccine in patients aged 27-45 years. CONCLUSIONS: Patients with IBD may be at increased risk of some vaccine-preventable diseases. Therefore, maintaining appropriate vaccination status in these patients is critical to optimize patient outcomes. In general, IBD is not a contraindication to the use of inactivated vaccines, but immunosuppressive therapy may reduce vaccine responses.

Canadian Association of Gastroenterology Clinical Practice Guideline for Immunizations in Patients With Inflammatory Bowel Disease (IBD)-Part 1: Live Vaccines.

BACKGROUND & AIMS: Patients with inflammatory bowel disease (IBD) may be at increased risk of some vaccine-preventable diseases. The effectiveness and safety of vaccinations may be altered by immunosuppressive therapies or IBD itself. These recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on immunizations in adult and pediatric patients with IBD. This publication focused on live vaccines. METHODS: Systematic reviews evaluating the efficacy, effectiveness, and safety of vaccines in patients with IBD, other immune-mediated inflammatory diseases, and the general population were performed. Critical outcomes included mortality, vaccine-preventable diseases, and serious adverse events. Immunogenicity was considered a surrogate outcome for vaccine efficacy. Certainty of evidence and strength of recommendations were rated according to the GRADE (Grading of Recommendation Assessment, Development, and Evaluation) approach. Key questions were developed through an iterative process and voted on by a multidisciplinary panel. Recommendations were formulated using the Evidence-to-Decision framework. Strong recommendation means that most patients should receive the recommended course of action, whereas a conditional recommendation means that different choices will be appropriate for different patients. RESULTS: Three good practice statements included reviewing a patient's vaccination status at diagnosis and at regular intervals, giving appropriate vaccinations as soon as possible, and not delaying urgently needed immunosuppressive therapy to provide vaccinations. There are 4 recommendations on the use of live vaccines. Measles, mumps, rubella vaccine is recommended for both adult and pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). Varicella vaccine is recommended for pediatric patients with IBD not on immunosuppressive therapy, but not for those using immunosuppressive medications (conditional). For adults, recommendations are conditionally in favor of varicella vaccine for those not on immunosuppressive therapy, and against for those on therapy. No recommendation was made regarding the use of live vaccines in infants born to mothers using biologics because the desirable and undesirable effects were closely balanced and the evidence was insufficient. CONCLUSIONS: Maintaining appropriate vaccination status in patients with IBD is critical to optimize patient outcomes. In general, live vaccines are recommended in patients not on immunosuppressive therapy, but not for those using immunosuppressive medications. Additional studies are needed to evaluate the safety and efficacy of live vaccines in patients on immunosuppressive therapy.

Hospitalization With Clostridioides difficile in Pediatric Inflammatory Bowel Disease: a Population-Based Study.

OBJECTIVES: Several studies have demonstrated higher rates of Clostridioides difficile infection (CDI) in adults with inflammatory bowel disease (IBD). We conducted a population-based study comparing the risk of hospitalization with CDI in children with and without IBD. METHODS: Using health administrative data and validated algorithms, we identified all children (<16 years) diagnosed with IBD in 5 Canadian provinces, then age and sex matched to 5 children without IBD. Province-specific 5-year incidence rates of hospitalization with CDI were pooled and generalized linear mixed-effects models were used to estimate the crude incidence rate ratio (IRR) comparing (1) children with and without IBD and (2) children with Crohn disease and ulcerative colitis. Hazard ratios (HR) from Cox proportional hazards models adjusting for age, sex, rural/urban household, and income were pooled using fixed-effects models. RESULTS: The incidence rate of CDI identified during hospitalization was 49.06 [95% confidence interval (CI), 39.40-61.08] per 10,000 person-years (PY) in 3593 children with IBD compared to 0.39 (95% CI, 0.13-1.21) per 10,000 PY in 16,284 children without IBD (crude IRR, 133.4, 95% CI, 42.1-422.7; adjusted HR, 68.2, 95% CI, 24.4-190.4). CDI was identified less often in children with Crohn disease than ulcerative colitis (crude IRR, 0.51, 95% CI, 0.32-0.82; adjusted HR, 0.69, 95% CI, 0.46-1.05). CONCLUSIONS: Children with IBD have a markedly higher incidence of CDI identified during a hospitalization relative to children without IBD. Consequently, symptomatic children with IBD who are hospitalized should be screened for CDI.

Drowning prevention counselling by paediatricians to educate caregivers on water safety.

AIM: Drowning is the leading cause of unintentional injury death for children 1-4 years of age in the USA. Texas, a southeastern state, is disproportionately burdened by paediatric drowning. The aim of this project was to increase drowning prevention counselling provided during well-child visits to families with children aged 0-10 years. METHODS: We developed and implemented a water safety counselling programme for paediatricians to impart to families during well child, urgent care and ED visits for 0-10 year age group. Physicians completed and self-reported demographic, pre- and post-intervention, counselling rate and project evaluation surveys, while caregivers completed post-intervention surveys only. Both physicians and caregivers were surveyed on evidence-based drowning prevention strategies (four-sided fencing of pools, touch supervision, life jackets and swim/cardio-pulmonary resuscitation classes). RESULTS: Thirty-three physicians and 1934 caregivers participated in the project. Physicians demonstrated statistically significant improvement in discussing drowning prevention with patients (3.5 vs. 4 on Likert scale; P = 0.002) in 2018 versus 2019. The counselling frequency in primary care settings increased from 54% to 70% from year 1 to 2. 100% of physicians correctly identified the best drowning prevention strategy and 80.6% of caregivers reported learning new water safety information in 2019 versus 68.8% in 2018 (P value < 0.001). CONCLUSIONS: This water safety education programme demonstrated increased drowning prevention counselling during well-child visits. The counselling was effective as demonstrated by increased caregiver acquisition of new water safety information. Paediatricians had adequate drowning prevention knowledge; an efficient counselling strategy helped them impart this knowledge to their patients.

The Drug Abuse Research Training (DART) Program for Psychiatry Residents and Summer Fellows: 15-Year Outcomes.

OBJECTIVE: To increase the number of physician-scientists in research, the Drug Abuse Research Training (DART) program at the Medical University of South Carolina offers a 2-year research track for psychiatry residents and a 10-week summer fellowship for students. The goal of this study was to examine program outcomes and alumni diversity levels over DART's 15-year history. METHODS: To date, 215 trainees (44 residents, 171 summer fellows) have completed the program. An anonymous online survey was sent to the 143 program alumni with valid contact information. Survey data included demographic characteristics, post-program research involvement, and self-reported barriers to continued research engagement. RESULTS: Overall survey completion response was 83.5% (N = 122). The alumni included 59.0% women, and 36.1% of respondents identified as a member of a minority racial/ethnic group. Following program completion, 77.0% of the alumni reported continued research involvement. More than half of the alumni reported scientific publications (57.4%) and conference presentations (63.1%) since completing DART. Among respondents who did not subsequently engage in research, the most common modifiable barriers included difficulty finding a mentor, self-perceived deficits in statistical skills and research methodology, and overall lack of confidence in research ability. CONCLUSIONS: Over the past 15 years, the DART program has established a diverse research training program that now spans the educational spectrum from undergraduate to residency training. Future program goals include additional training to address self-reported modifiable research barriers. This program provides a model for other training programs designed to cultivate research interests and promote the diversity of clinical researchers.

Access to inflammatory bowel disease speciality care: the primary healthcare physician perspective.

BACKGROUND: There is little literature related to access to inflammatory bowel disease (IBD) care that incorporates the perspective of key system stakeholders, such as primary healthcare providers (PHCP), despite their clear and integral role in facilitating access. OBJECTIVE: This study aimed to identify barriers to referring patients to speciality IBD care as perceived by referring PHCP. In particular, we sought to understand PHCP satisfaction with the current IBD specialist referral system, as well as indicators of geographic variance to access. METHODS: A population-based survey was mailed out to currently practising PHCPs who have referred or who are currently referring patients to IBD speciality care in Nova Scotia (Canada). Descriptive statistics and multivariate analyses were performed. Qualitative comments were themed using framework analysis to identify key barriers. RESULTS: The majority of PHCP (57%) were dissatisfied with the current referral process due to long patient wait times and perceived system inefficiency. Key areas of geographic variance in access included access to speciality care in the community and patient wait times. PHCPs suggested ideas to improve access including increased gastroenterologist supply, particularly in rural areas, and the creation of a provincial centralized referral and triage process. CONCLUSIONS: PHCPs play an important role in identifying and managing patients with IBD in partnership with gastroenterologists. This study identifies key PHCP perceived barriers that may prevent patients from accessing speciality IBD care. Understanding and addressing barriers to access from multiple stakeholder perspectives, including PHCPs, has the potential to support informed system redesign and overcome access inequities.

Primary healthcare providers (e.g. family doctors and nurse practitioners) play an important role in connecting patients with speciality health care. Patients with digestive diseases, such as inflammatory bowel diseases (e.g. Crohn's and colitis), may rely on primary healthcare providers to connect them with inflammatory bowel disease specialists (e.g. gastroenterologists). Past research on access to inflammatory bowel disease care has focused on the patient perspective; however, almost no research has focused on how primary healthcare providers perceive access to inflammatory bowel disease speciality care, despite their important role in facilitating access. This paper focuses on what 155 primary healthcare providers in Nova Scotia (Canada) perceive as key barriers for their patients when accessing speciality Inflammatory bowel disease care. This paper also presents potential improvements to the referral process and healthcare system, as suggested by primary healthcare providers, which may improve global access to inflammatory bowel disease care.

Factors associated with destination of pediatric EMS transports.

OBJECTIVE: Pediatric patients comprise 13% of emergency medical services (EMS) transports, and most are transported to general emergency departments (ED). EMS transport destination policies may guide when to transport patients to a children's hospital, especially for medical complaints. Factors that influence EMS providers 'decisions about where to transport children are unknown. Our objective was to evaluate the factors associated with pediatric EMS transports to children's hospitals for medical complaints. METHODS: We performed a cross-sectional study of a large, urban EMS system over a 12-month period for all transports of patients 0-17 years old. We electronically queried the EMS database for demographic data, medical presentation and management, comorbidities, and documented reasons for choosing destination. Distances to the destination hospital and nearest children's and community hospital (if not the transport destination) were calculated. Univariate and multiple logistic regression analyses were conducted to determine the association between independent variables and the transport destination. RESULTS: We identified 10,065 patients, of which 6982 (69%) were for medical complaints. Of these medical complaints, 3518 (50.4%) were transported to a children's hospital ED. Factors associated with transport to a children's hospital include ALS transport, greater transport distance, protocol determination, developmental delay, or altered consciousness. Factors associated with transport to general EDs were older age, unknown insurance status, lower income, greater distance to children's or community hospital, destination determined by closest facility or diversion, abnormal respiratory rate or blood glucose, psychiatric primary impression, or communication barriers present. CONCLUSIONS: We found that younger patient age, EMS protocol requirements, and paramedic scene response may influence pediatric patient transport to both children's and community hospitals. Socioeconomic factors, ED proximity, diversion status, respiratory rate, chief complaints, and communication barriers may also be contributing factors. Further studies are needed to determine the generalizability of these findings to other EMS systems.

Past and Future Burden of Inflammatory Bowel Diseases Based on Modeling of Population-Based Data.

BACKGROUND & AIMS: Inflammatory bowel diseases (IBDs) exist worldwide, with high prevalence in North America. IBD is complex and costly, and its increasing prevalence places a greater stress on health care systems. We aimed to determine the past current, and future prevalences of IBD in Canada. METHODS: We performed a retrospective cohort study using population-based health administrative data from Alberta (2002-2015), British Columbia (1997-2014), Manitoba (1990-2013), Nova Scotia (1996-2009), Ontario (1999-2014), Quebec (2001-2008), and Saskatchewan (1998-2016). Autoregressive integrated moving average regression was applied, and prevalence, with 95% prediction intervals (PIs), was forecasted to 2030. Average annual percentage change, with 95% confidence intervals, was assessed with log binomial regression. RESULTS: In 2018, the prevalence of IBD in Canada was estimated at 725 per 100,000 (95% PI 716-735) and annual average percent change was estimated at 2.86% (95% confidence interval 2.80%-2.92%). The prevalence in 2030 was forecasted to be 981 per 100,000 (95% PI 963-999): 159 per 100,000 (95% PI 133-185) in children, 1118 per 100,000 (95% PI 1069-1168) in adults, and 1370 per 100,000 (95% PI 1312-1429) in the elderly. In 2018, 267,983 Canadians (95% PI 264,579-271,387) were estimated to be living with IBD, which was forecasted to increase to 402,853 (95% PI 395,466-410,240) by 2030. CONCLUSION: Forecasting prevalence will allow health policy makers to develop policy that is necessary to address the challenges faced by health systems in providing high-quality and cost-effective care.

Dexmedetomidine Provides Fewer Respiratory Events Compared With Propofol and Fentanyl During Third Molar Surgery: A Randomized Clinical Trial.

PURPOSE: Propofol and fentanyl can cause airway obstruction and respiratory depression when used together for intravenous sedation. This study investigated whether dexmedetomidine and midazolam would decrease respiratory events requiring intervention during deep sedation compared with propofol, fentanyl, and midazolam. PATIENTS AND METHODS: A prospective, randomized, double-blinded, controlled trial was designed to assess 2 intravenous treatment groups during third molar surgery. Patients were randomized into 2 groups. The control group (group P) received 0.8 µg/kg of fentanyl followed by propofol infusion at 125 µg/kg per minute over a 10-minute period with intraoperative boluses of 0.1 µg/kg. The study group (group D) received dexmedetomidine bolus infusion of 1 µg/kg over a 10-minute period followed by maintenance infusion at 0.5 µg/kg per hour. Both groups were given 0.03 mg/kg of midazolam before infusion. Scorers, masked to group, viewed the procedure remotely and evaluated the primary outcome variable of respiratory events requiring intervention. Secondary outcome variables evaluated by the scorers included the Behavioral Pain Scale for non-intubated patients at initial injection, cooperation score at 5 and 15 minutes, and time to ambulation and discharge. Patient satisfaction and hemodynamic stability were measured. The difference between groups regarding the occurrence of respiratory events was tested using the Fisher exact test, and mixed-effects models were used to compare repeated vital signs. RESULTS: The sample was composed of 141 patients randomly assigned to either group P (n = 67) or group D (n = 74). No statistically significant differences in the distribution of study variables were found between groups at baseline. A statistically significant difference in respiratory events requiring deliberate intervention existed between group P (25.4%) and group D (2.7%) (P < .0001). No statistically significant difference was found between groups for Behavioral Pain Scale score, cooperation score, time to ambulation or discharge, and patient satisfaction. CONCLUSIONS: Using dexmedetomidine and midazolam for outpatient surgery resulted in fewer respiratory events requiring deliberate intervention compared with propofol, fentanyl, and midazolam. Ambulation and discharge times were not prolonged using dexmedetomidine.

Chloral Hydrate Sedation in a Dexmedetomidine Era.

Brief Overview: The use of chloral hydrate as the primary sedation agent has declined across the nation after commercial production of the liquid formulation ceased. Although alternative sedatives have gained popularity, some pharmacies have continued to provide oral chloral hydrate by compounding it from raw ingredients. Thus, oral chloral hydrate use has continued in children despite the availability of alternative effective agents. Objective: The purpose of this investigation was to evaluate institutional chloral hydrate utilization as the primary agent for procedural sedation. Design/Methods: We conducted a retrospective study of patients given chloral hydrate for procedural sedation from October 2010 to December 2016. The hospital pharmacy database of chloral hydrate use at our 2 free-standing children's hospitals was reviewed and matched to procedure billing data. Results: There were 5874 chloral hydrate administrations for procedural sedation during the study period. The highest rates of use occurred in 2014, when there were 1420 chloral hydrate orders within our hospital. The large majority of sedations were for cardiac studies/procedures (n = 4250, 72.4%). Conclusions: Despite significant declines in use of chloral hydrate for procedural sedation across the country, local utilization of oral chloral hydrate remains high. Recent declines may be due to high-use clinical sites transitioning to alternative sedatives such as intranasal dexmedetomidine.

Trends in Epidemiology of Pediatric Inflammatory Bowel Disease in Canada: Distributed Network Analysis of Multiple Population-Based Provincial Health Administrative Databases.

OBJECTIVES: The incidence of pediatric-onset inflammatory bowel disease (IBD) is increasing worldwide. We used population-based health administrative data to determine national Canadian IBD incidence, prevalence, and trends over time of childhood-onset IBD. METHODS: We identified children <16 years (y) diagnosed with IBD 1999-2010 from health administrative data in five provinces (Alberta, Manitoba, Nova Scotia, Ontario, Quebec), comprising 79.2% of the Canadian population. Standardized incidence and prevalence were calculated per 100,000 children. Annual percentage change (APC) in incidence and prevalence were determined using Poisson regression analysis. Provincial estimates were meta-analyzed using random-effects models to produce national estimates. RESULTS: 5,214 incident cases were diagnosed during the study period (3,462 Crohn's disease, 1,382 ulcerative colitis, 279 type unclassifiable). The incidence in Canada was 9.68 (95% CI 9.11 to 10.25) per 100,000 children. Incidence was similar amongst most provinces, but higher in Nova Scotia. APC in incidence did not significantly change over the study period in the overall cohort (+2.06%, 95% CI -0.64% to +4.76%). However, incidence significantly increased in children aged 0-5y (+7.19%, 95% +2.82% to +11.56%). Prevalence at the end of the study period in Canada was 38.25 (95% CI 35.78 to 40.73) per 100,000 children. Prevalence increased significantly over time, APC +4.56% (95% CI +3.71% to +5.42%). CONCLUSIONS: Canada has amongst the highest incidence of childhood-onset IBD in the world. Prevalence significantly increased over time. Incidence was not statistically changed with the exception of a rapid increase in incidence in the youngest group of children.

Corrigendum: Rural and Urban Residence During Early Life Is Associated with a Lower Risk of Inflammatory Bowel Disease: A Population-Based Inception and Birth Cohort Study.

This corrects the article DOI: 10.1038/ajg.2017.208.

Rural and Urban Residence During Early Life is Associated with Risk of Inflammatory Bowel Disease: A Population-Based Inception and Birth Cohort Study

OBJECTIVES: To determine the association between inflammatory bowel disease (IBD) and rural/urban household at the time of diagnosis, or within the first 5 years (y) of life. METHODS: Population-based cohorts of residents of four Canadian provinces were created using health administrative data. Rural/urban status was derived from postal codes based on population density and distance to metropolitan areas. Validated algorithms identified all incident IBD cases from administrative data (Alberta: 1999-2008, Manitoba and Ontario: 1999-2010, and Nova Scotia: 2000-2008). We determined sex-standardized incidence (per 100,000 patient-years) and incident rate ratios (IRR) using Poisson regression. A birth cohort was created of children in whom full administrative data were available from birth (Alberta 1996-2010, Manitoba 1988-2010, and Ontario 1991-2010). IRR was calculated for residents who lived continuously in rural/urban households during each of the first 5 years of life. RESULTS: There were 6,662 rural residents and 38,905 urban residents with IBD. Incidence of IBD per 100,000 was 33.16 (95% CI 27.24-39.08) in urban residents, and 30.72 (95% CI 23.81-37.64) in rural residents (IRR 0.90, 95% CI 0.81-0.99). The protective association was strongest in children <10 years (IRR 0.58, 95% CI 0.43-0.73) and 10-17.9 years (IRR 0.72, 95% CI 0.64-0.81). In the birth cohort, comprising 331 rural and 2,302 urban residents, rurality in the first 1-5 years of life was associated with lower risk of IBD (IRR 0.75-0.78). CONCLUSIONS: People living in rural households had lower risk of developing IBD. This association is strongest in young children and adolescents, and in children exposed to the rural environment early in life.

Transgenic expression of human amphiregulin in mouse skin: inflammatory epidermal hyperplasia and enlarged sebaceous glands.

To explore the role of amphiregulin in inflammatory epidermal hyperplasia, we overexpressed human AREG (hAREG) in FVB/N mice using a bovine K5 promoter. A construct containing AREG coding sequences flanked by 5' and 3' untranslated region sequences (AREG-UTR) led to a >10-fold increase in hAREG expression compared to an otherwise-identical construct containing only the coding region (AREG-CDR). AREG-UTR mice developed tousled, greasy fur as well as elongated nails and thickened, erythematous tail skin. No such phenotype was evident in AREG-CDR mice. Histologically, AREG-UTR mice presented with marked epidermal hyperplasia of tail skin (2.1-fold increase in epidermal thickness with a 9.5-fold increase in Ki-67(+) cells) accompanied by significantly increased CD4+ T-cell infiltration. Dorsal skin of AREG-UTR mice manifested lesser but still significant increases in epidermal thickness and keratinocyte hyperplasia. AREG-UTR mice also developed marked and significant sebaceous gland enlargement, with corresponding increases in Ki-67(+) cells. To determine the response of AREG-UTR animals to a pro-inflammatory skin challenge, topical imiquimod (IMQ) or vehicle cream was applied to dorsal and tail skin. IMQ increased dorsal skin thickness similarly in both AREG-UTR and wild type mice (1.7- and 2.2-fold vs vehicle, P < 0.001 each), but had no such effect on tail skin. These results confirm that keratinocyte expression of hAREG elicits inflammatory epidermal hyperplasia, and are consistent with prior reports of tail epidermal hyperplasia and increased sebaceous gland size in mice expressing human epigen.

Factors Associated With Poor Outcome in Childhood Swimming Pool Submersions.

OBJECTIVES: The aims of the study were to determine factors associated with poor outcome in childhood swimming pool submersions and to study the association of bystander resuscitation with clinical outcome. METHODS: This was a retrospective study of swimming pool submersion victims younger than 18 years in a metropolitan area from 2003 to 2007. Submersion, prehospital, and victim data were obtained from hospital, Emergency Medical Services, and fatality records. Outcome based on survival at hospital discharge was favorable (baseline/mild impairment) or poor (death/severe impairment). Logistic regression determined factors associated with poor outcome. RESULTS: There were 260 submersions. Outcomes were available for 211 (81%). The median age was 4 years; 68% were males. Most incidents occurred at single residential pools (48%) and multiresidential pools (35%). Mortality was 23%; 75% had favorable outcomes. Favorable outcomes occurred in 8.6% (3/35) of victims with absent pulse at the scene. Descriptive analyses revealed significant differences in submersions that occurred on weekdays, during the summer, submersions lasting 5 minutes or more, with on-scene apnea or cardiac arrest needing cardiopulmonary resuscitation, rescuer type, and transfer to tertiary care. Logistic regression revealed that poor outcome was significantly associated with prolonged submersions and those that occurred on a weekday. Furthermore, hospitalization reduced the odds of a poor outcome by 81% when compared with victims who were not hospitalized. Bystander resuscitation was not significantly associated with outcome. CONCLUSIONS: Childhood swimming pool submersions, which occur on weekdays and with prolonged submersion times, are associated with poor outcome. Bystander resuscitation is not significantly associated with outcome.

An assembly of proteins and lipid domains regulates transport of phosphatidylserine to phosphatidylserine decarboxylase 2 in Saccharomyces cerevisiae.

Saccharomyces cerevisiae uses multiple biosynthetic pathways for the synthesis of phosphatidylethanolamine. One route involves the synthesis of phosphatidylserine (PtdSer) in the endoplasmic reticulum (ER), the transport of this lipid to endosomes, and decarboxylation by PtdSer decarboxylase 2 (Psd2p) to produce phosphatidylethanolamine. Several proteins and protein motifs are known to be required for PtdSer transport to occur, namely the Sec14p homolog PstB2p/Pdr17p; a PtdIns 4-kinase, Stt4p; and a C2 domain of Psd2p. The focus of this work is on defining the protein-protein and protein-lipid interactions of these components. PstB2p interacts with a protein encoded by the uncharacterized gene YPL272C, which we name Pbi1p (PstB2p-interacting 1). PstB2p, Psd2, and Pbi1p were shown to be lipid-binding proteins specific for phosphatidic acid. Pbi1p also interacts with the ER-localized Scs2p, a binding determinant for several peripheral ER proteins. A complex between Psd2p and PstB2p was also detected, and this interaction was facilitated by a cryptic C2 domain at the extreme N terminus of Psd2p (C2-1) as well the previously characterized C2 domain of Psd2p (C2-2). The predicted N-terminal helical region of PstB2p was necessary and sufficient for promoting the interaction with both Psd2p and Pbi1p. Taken together, these results support a model for PtdSer transport involving the docking of a PtdSer donor membrane with an acceptor via specific protein-protein and protein-lipid interactions. Specifically, our model predicts that this process involves an acceptor membrane complex containing the C2 domains of Psd2p, PstB2p, and Pbi1p that ligate to Scs2p and phosphatidic acid present in the donor membrane, forming a zone of apposition that facilitates PtdSer transfer.

Effects of Concomitant Immunomodulator Therapy on Efficacy and Safety of Anti-Tumor Necrosis Factor Therapy for Crohn's Disease: A Meta-analysis of Placebo-controlled Trials.

BACKGROUND & AIMS: There is debate over whether patients with Crohn's disease who start anti-tumor necrosis factor (TNF) therapy after failed immunomodulator therapy should continue to receive concomitant immunomodulators. We conducted a meta-analysis of subgroups from randomized controlled trials (RCTs) of anti-TNF agents to compare the efficacy and safety of concomitant immunomodulator therapy vs anti-TNF monotherapy. METHODS: We performed a systematic review of literature published from 1980 through 2008 and identified 11 RCTs of anti-TNF agents in patients with luminal or fistulizing Crohn's disease. We excluded RCTs of patients who were naive to anti-TNF and immunomodulator therapy. The primary end points were clinical response at weeks 4-14 and 24-30 and remission at weeks 24-30. Secondary end points included infusion site or injection site reactions and selected adverse events. A priori subgroup analyses were performed to evaluate fistula closure and the efficacy and safety of combination therapy with different anti-TNF agents. RESULTS: Overall, combination therapy was no more effective than monotherapy in inducing 6-month remission (odds ratio [OR], 1.02; 95% confidence interval [CI], 0.80-1.31), inducing a response (OR, 1.08; 95% CI, 0.79-1.48), maintaining a response (OR, 1.53; 95% CI, 0.67-3.49), or inducing partial (OR, 1.25; 95% CI, 0.84-1.88) or complete fistula closure (OR, 1.10; 95% CI, 0.68-1.78). In subgroup analyses of individual anti-TNF agents, combination therapy was not more effective than monotherapy in inducing 6-month remission in those treated with infliximab (OR, 1.73; 95% CI, 0.97-3.07), adalimumab (OR, 0.88; 95% CI, 0.58-1.35), or certolizumab (OR, 0.93; 95% CI, 0.65-1.34). Overall, combination therapy was not associated with an increase in adverse events, but inclusion of infliximab was associated with fewer injection site reactions (OR, 0.46; 95% CI, 0.26-0.79.) CONCLUSIONS: On the basis of a meta-analysis, continued use of immunomodulator therapy after starting anti-TNF therapy is no more effective than anti-TNF monotherapy in inducing or maintaining response or remission. RCTs are needed to adequately assess the efficacy of continued immunomodulator therapy after anti-TNF therapy is initiated.

Disrupted small world topology and modular organisation of functional networks in late-life depression with and without amnestic mild cognitive impairment.

BACKGROUND: The topological architecture of the whole-brain functional networks in those with and without late-life depression (LLD) and amnestic mild cognitive impairment (aMCI) are unknown. AIMS: To investigate the differences in the small-world measures and the modular community structure of the functional networks between patients with LLD and aMCI when occurring alone or in combination and cognitively healthy non-depressed controls. METHODS: 79 elderly participants (LLD (n=23), aMCI (n=18), comorbid LLD and aMCI (n=13), and controls (n=25)) completed neuropsychiatric assessments. Graph theoretical methods were employed on resting-state functional connectivity MRI data. RESULTS: LLD and aMCI comorbidity was associated with the greatest disruptions in functional integration measures (decreased global efficiency and increased path length); both LLD groups showed abnormal functional segregation (reduced local efficiency). The modular network organisation was most variable in the comorbid group, followed by patients with LLD-only. Decreased mean global, local and nodal efficiency metrics were associated with greater depressive symptom severity but not memory performance. CONCLUSIONS: Considering the whole brain as a complex network may provide unique insights on the neurobiological underpinnings of LLD with and without cognitive impairment.

Spatial analysis of paediatric swimming pool submersions by housing type.

OBJECTIVE: Drowning is a major cause of unintentional childhood death. The relationship between childhood swimming pool submersions, neighbourhood sociodemographics, housing type and swimming pool location was examined in Harris County, Texas. STUDY DESIGN AND SETTING: Childhood pool submersion incidents were examined for spatial clustering using the Nearest Neighbor Hierarchical Cluster (Nnh) algorithm. To relate submersions to predictive factors, an Markov Chain Monte Carlo (MCMC) Poisson-Lognormal-Conditional Autoregressive (CAR) spatial regression model was tested at the census tract level. RESULTS: There were 260 submersions; 49 were fatal. Forty-two per cent occurred at single-family residences and 36% at multifamily residential buildings. The risk of a submersion was 2.7 times higher for a child at a multifamily than a single-family residence and 28 times more likely in a multifamily swimming pool than a single family pool. However, multifamily submersions were clustered because of the concentration of such buildings with pools. Spatial clustering did not occur in single-family residences. At the tract level, submersions in single-family and multifamily residences were best predicted by the number of pools by housing type and the number of children aged 0-17 by housing type. CONCLUSIONS: Paediatric swimming pool submersions in multifamily buildings are spatially clustered. The likelihood of submersions is higher for children who live in multifamily buildings with pools than those who live in single-family homes with pools.