Psychosocial aspects of diabetes technology.

AIM: To identify key psychosocial research in the domain of diabetes technology. RESULTS: Four trajectories of psychosocial diabetes technology research are identified that characterize research over the past 25 years. Key evidence is reviewed on psychosocial outcomes of technology use as well as psychosocial barriers and facilitating conditions of diabetes technology uptake. Psychosocial interventions that address modifiable barriers and psychosocial factors have proven to be effective in improving glycaemic and self-reported outcomes in diabetes technology users. CONCLUSIONS: Psychosocial diabetes technology research is essential for designing interventions and education programmes targeting the person with diabetes to facilitate optimized outcomes associated with technology uptake. Psychosocial aspects of diabetes technology use and related research will be even more important in the future given the advent of systems for automated insulin delivery and the increasingly widespread digitalization of diabetes care.

A functional assay to classify ZBTB24 missense variants of unknown significance.

Increasing use of next-generation sequencing technologies in clinical diagnostics allows large-scale discovery of genetic variants, but also results in frequent identification of variants of unknown significance (VUSs). Their classification into disease-causing and neutral variants is often hampered by the absence of robust functional tests. Here, we demonstrate that a luciferase reporter assay, in combination with ChIP-qPCR, reliably separates pathogenic ZBTB24 missense variants in the context of immunodeficiency, centromeric instability, facial anomalies (ICF) syndrome from natural variants in healthy individuals and patients of other diseases. Application of our assay to two published ZBTB24 missense VUSs indicates that they are likely not to cause ICF2 syndrome. Furthermore, we show that rare gnomAD ZBTB24 missense variants in key residues of the C2H2-ZF domain lead to a loss of function phenotype that resembles ICF2, suggesting that these individuals are carriers of ICF syndrome. In summary, we have developed a robust functional test to validate missense variants in ZBTB24.

Converging disease genes in ICF syndrome: ZBTB24 controls expression of CDCA7 in mammals.

For genetically heterogeneous diseases a better understanding of how the underlying gene defects are functionally interconnected will be important for dissecting disease etiology. The Immunodeficiency, Centromeric instability, Facial anomalies (ICF) syndrome is a chromatin disorder characterized by mutations in DNMT3B, ZBTB24, CDCA7 or HELLS Here, we generated a Zbtb24 BTB domain deletion mouse and found that loss of functional Zbtb24 leads to early embryonic lethality. Transcriptome analysis identified Cdca7 as the top down-regulated gene in Zbtb24 homozygous mutant mESCs, which can be restored by ectopic ZBTB24 expression. We further demonstrate enrichment of ZBTB24 at the CDCA7 promoter suggesting that ZBTB24 can function as a transcription factor directly controlling Cdca7 expression. Finally, we show that this regulation is conserved between species and that CDCA7 levels are reduced in patients carrying ZBTB24 nonsense mutations. Together, our findings demonstrate convergence of the two ICF genes ZBTB24 and CDCA7 at the level of transcription.

CDCA7-associated global aberrant DNA hypomethylation translates to localized, tissue-specific transcriptional responses.

Disruption of cell division cycle associated 7 (CDCA7) has been linked to aberrant DNA hypomethylation, but the impact of DNA methylation loss on transcription has not been investigated. Here, we show that CDCA7 is critical for maintaining global DNA methylation levels across multiple tissues in vivo. A pathogenic Cdca7 missense variant leads to the formation of large, aberrantly hypomethylated domains overlapping with the B genomic compartment but without affecting the deposition of H3K9 trimethylation (H3K9me3). CDCA7-associated aberrant DNA hypomethylation translated to localized, tissue-specific transcriptional dysregulation that affected large gene clusters. In the brain, we identify CDCA7 as a transcriptional repressor and epigenetic regulator of clustered protocadherin isoform choice. Increased protocadherin isoform expression frequency is accompanied by DNA methylation loss, gain of H3K4 trimethylation (H3K4me3), and increased binding of the transcriptional regulator CCCTC-binding factor (CTCF). Overall, our in vivo work identifies a key role for CDCA7 in safeguarding tissue-specific expression of gene clusters via the DNA methylation pathway.

The role of MORC3 in silencing transposable elements in mouse embryonic stem cells.

BACKGROUND: Microrchidia proteins (MORCs) are involved in epigenetic gene silencing in a variety of eukaryotic organisms. Deletion of MORCs result in several developmental abnormalities and their dysregulation has been implicated in developmental disease and multiple cancers. Specifically, mammalian MORC3 mutations are associated with immune system defects and human cancers such as bladder, uterine, stomach, lung, and diffuse large B cell lymphomas. While previous studies have shown that MORC3 binds to H3K4me3 in vitro and overlaps with H3K4me3 ChIP-seq peaks in mouse embryonic stem cells, the mechanism by which MORC3 regulates gene expression is unknown. RESULTS: In this study, we identified that mutation in Morc3 results in a suppressor of variegation phenotype in a Modifiers of murine metastable epialleles Dominant (MommeD) screen. We also find that MORC3 functions as an epigenetic silencer of transposable elements (TEs) in mouse embryonic stem cells (mESCs). Loss of Morc3 results in upregulation of TEs, specifically those belonging to the LTR class of retrotransposons also referred to as endogenous retroviruses (ERVs). Using ChIP-seq we found that MORC3, in addition to its known localization at H3K4me3 sites, also binds to ERVs, suggesting a direct role in regulating their expression. Previous studies have shown that these ERVs are marked by the repressive histone mark H3K9me3 which plays a key role in their silencing. However, we found that levels of H3K9me3 showed only minor losses in Morc3 mutant mES cells. Instead, we found that loss of Morc3 resulted in increased chromatin accessibility at ERVs as measured by ATAC-seq. CONCLUSIONS: Our results reveal MORC3 as a novel regulator of ERV silencing in mouse embryonic stem cells. The relatively minor changes of H3K9me3 in the Morc3 mutant suggests that MORC3 acts mainly downstream of, or in a parallel pathway with, the TRIM28/SETDB1 complex that deposits H3K9me3 at these loci. The increased chromatin accessibility of ERVs in the Morc3 mutant suggests that MORC3 may act at the level of chromatin compaction to effect TE silencing.

The prebiotic inulin modulates gut microbiota but does not ameliorate atherosclerosis in hypercholesterolemic APOE*3-Leiden.CETP mice.

Gut microbiota have been implicated in the development of atherosclerosis and cardiovascular disease. Since the prebiotic inulin is thought to beneficially affect gut microbiota, we aimed to determine the effect of inulin supplementation on atherosclerosis development in APOE*3-Leiden.CETP (E3L.CETP) mice. Female E3L.CETP mice were fed a western-type diet containing 0.1% or 0.5% cholesterol with or without 10% inulin. The effects of inulin were determined on: microbiota composition, cecal short-chain fatty acid (SCFA) levels, plasma lipid levels, atherosclerosis development, hepatic morphology and hepatic inflammation. Inulin with 0.5% dietary cholesterol increased specific bacterial genera and elevated levels of cecal SCFAs, but did not affect plasma cholesterol levels or atherosclerosis development. Surprisingly, inulin resulted in mild hepatic inflammation as shown by increased expression of inflammation markers. However, these effects were not accompanied by increased hepatic macrophage number. Analogously, inulin induced mild steatosis and increased hepatocyte size, but did not affect hepatic triglyceride content. Inulin with 0.1% dietary cholesterol did not affect hepatic morphology, nor hepatic expression of inflammation markers. Overall, inulin did not reduce hypercholesterolemia or atherosclerosis development in E3L.CETP mice despite showing clear prebiotic activity, but resulted in manifestations of hepatic inflammation when combined with a high percentage of dietary cholesterol.

Hypomethylation of ERVs in the sperm of mice haploinsufficient for the histone methyltransferase Setdb1 correlates with a paternal effect on phenotype.

The number of reports of paternal epigenetic influences on the phenotype of offspring in rodents is increasing but the molecular events involved remain unclear. Here, we show that haploinsufficiency for the histone 3 lysine 9 methyltransferase Setdb1 in the sire can influence the coat colour phenotype of wild type offspring. This effect occurs when the allele that directly drives coat colour is inherited from the dam, inferring that the effect involves an "in trans" step. The implication of this finding is that epigenetic state of the sperm can alter the expression of genes inherited on the maternally derived chromosomes. Whole genome bisulphite sequencing revealed that Setdb1 mutant mice show DNA hypomethylation at specific classes of transposable elements in the sperm. Our results identify Setdb1 as a paternal effect gene in the mouse and suggest that epigenetic inheritance may be more likely in individuals with altered levels of epigenetic modifiers.

Sledding injuries in patients presenting to the emergency department in a northern city.

OBJECTIVES: Sledding is a common recreational activity in northern communities. The objective of this study was to examine the frequency and nature of sledding injuries (SIs) in patients presenting to emergency departments (EDs). METHODS: The data were derived from a cohort of patients treated at all five EDs in an urban Canadian health region over a two-year period. Following chart review, consenting patients were interviewed by telephone about their sledding activities and the circumstances surrounding the injury. RESULTS: Three hundred twenty-eight patients were correctly coded as having SIs, with 212 patients (65%) reached during the follow-up survey. The median age of those with SIs was 12 years (IQR = 8, 21), and 206 (59%) were male. Injury rates peaked in the 10--14-year age group (87/100,000) for boys and in the 5--9-year age group (75/100,000) for girls. Most patients stated they were drivers (75%), fewer than half were thrown from the sled (42%), and fewer than half (44%) were sledding on community-designated sledding hills at the time of injury. Injuries to the lower extremity (32%), upper extremity (31%), and head (13%) were most common. Thirty-seven (11%) patients with SIs were admitted to hospital vs 4% of patients with other sports/recreation injuries (p < 0.05). CONCLUSIONS: Sledding injuries are common and potentially serious wintertime injuries in northern communities, involving primarily younger patients, with a large pre-adolescent group. However, older sledders (>20 years) have poorer outcomes (hospitalization, lost time from work/school) than their younger counterparts. The SIs treated in the ED appear to lead to hospitalization more frequently than other types of sport/recreation injury, and injury prevention strategies appear warranted.

Faculty evaluation by residents in an emergency medicine program: a new evaluation instrument.

OBJECTIVE: Evaluation of preceptors in training programs is essential; however, little research has been performed in the setting of the emergency department (ED). The goal of this pilot study was to determine the validity and reliability of a faculty evaluation instrument-the Emergency Rotation (ER) scale-developed specifically for use in emergency medicine (EM). METHODS: A prospective study comparing the ER scale with two alternative faculty evaluation instruments was completed in three of the five EDs affiliated with an EM teaching program, where emergency physicians are members of the clinical teaching faculty. The participants were 18 residents (postgraduate years 1, 2, and 3) who were completing four-week clinical rotations in EM. Residents at the end of the rotation recorded their evaluations of each emergency physician with whom they had clinical encounters on the following evaluation tools: the ER scale, a longer validated scale (Irby), and a global assessment scale (GAS). Domain scores were correlated with the previously validated scale and the GAS to determine validity using a multitrait-multimethod matrix. The reliability of the ER scale was measured using a Chronbach's alpha coefficient. RESULTS: Forty-eight preceptor evaluations were completed on 29 individual preceptors. The rating of preceptors was high using the ER scale (median: 16 of 20; IQR: 13, 18), Irby (median: 300 of 378; IQR: 267, 321), or GAS (mean: 7.8 of 10; SD: 1.3). Domain scores for each tool were used in the multitrait-multimethod matrix and the correlations between a previously validated tool and the ER scale were found to be high (>0.70) in the various domains. The internal consistency of the ER scale was also high (r = 0.85). CONCLUSIONS: The ER scale appears to be valid and reliable. It performs well when compared with previously psychometrically tested tools. It is a sensible, well-adapted tool for the teaching environment offered by EM.

Women's fear of crime and abuse in college and university dating relationships.

Several government-sponsored victimization surveys have found women's fear of crime to be much higher than that of men even though their probability of being victimized is much lower than men's. On the basis of these results, several criminologists contend that women's fear is subjectively based. However, government surveys have not adequately examined the consequences of the physical, sexual, and psychological abuse of women by male intimates. Feminist researchers contend that these assaults greatly contribute to a generalized fear of crime that is objectively based. Using data from a national survey on female abuse in Canadian college/university dating relationships, this study tested and failed to support the feminist hypothesis that violence by male intimates results in higher levels of fear. However, an examination of an ex post facto hypothesis assessing the relationship between fear in private places (the home) and abuse by male dating partners found positive correlations. Women who had been psychologically or sexually victimized by male dating partners felt more insecure in their own homes than other women. These increased feelings of fear were linked to experiences of sexual coercion, unwanted sexual touching, psychological abuse, and sexual abuse. The results suggest that women reassess their feelings of fear when victimized by male intimates. In particular, places generally viewed as safe by women, their own homes, are seen as more threatening than they had been in the past.

Medical illness, medication use and suicide in seniors: a population-based case-control study.

BACKGROUND: Suicide among seniors is a significant health problem in north America, particularly for men in whom the rates rise steadily after 50 years of age. The goal of this study was to examine elder suicides identified from a large population-based database using case-control methods to determine disease and medication factors related to suicide. METHODS: A population-based 1 : 5 case-control study was conducted comparing seniors aged 66 years and older who had died by suicide with age and sex-matched controls. Case data were obtained through British Columbia (BC) Vital Statistics, whereas controls were randomly selected from the BC Health Insurance Registry. Cases and controls were linked to the provincial PharmaCare database to determine medication use and the provincial Physician Claims and Inpatient Hospitalization databases to determine co-morbidity. RESULTS: Between 1993 and 2002 a total of 602 seniors died by suicide in BC giving an annual rate of 13.2 per 100,000. Firearms were the most common mechanism (28%), followed by hanging/suffocation (25%), self-poisoning (21%), and jumping from height (7%). In the adjusted logistic model, variables related to suicide included: lower socioeconomic status, depression/psychosis, neurosis, stroke, cancer, liver disease, parasuicide, benzodiazepine use, narcotic pain killer use and diuretic use. There was an elevated risk for those prescribed inappropriate benzodiazepines and for those using strong narcotic pain killers. CONCLUSION: This study is consistent with previous studies that have identified a relationship between medical or psychiatric co-morbidity and suicide in seniors. In addition, new and potentially useful information confirms that certain types and dosages of benzodiazepines are harmful to seniors and their use should be avoided.

Pain, medication, and injury in older farmers.

BACKGROUND: Agricultural work continues to be a dangerous occupation. Older farmers experience high risks for work-related injury. The purpose of this research was to determine if there is a relationship between medication use and injury among older male farmers in Alberta. METHODS: Using probabilistic linkage between an Alberta Agriculture government registry of farm operators and the Alberta Health Plan registry file, older farmers (aged 66 and older) were identified. Farm related injuries were identified using an E-code search of both hospitalization and emergency department separations for a 3-year period. Cases were matched to controls on age, geographic health region, and index injury date at a ratio of 1:5. Co-morbidity and medication use for each of the cases and controls were derived from population based health system utilization files. Conditional logistic regression was used to determine which medications were related to injury. RESULTS: Overall, a total of 282 farm related injuries were suffered by the linked group. Controlling for co-morbidity, farmers who had stopped taking narcotic pain killers (OR = 9.37 [95% CI:4.95, 17.72]) and non-steroidal anti-inflammatories (OR = 2.40 [95% CI:1.43, 4.03]) 30 days prior to the date of injury were at risk of injury. Those farmers taking sedatives up until the date of injury were also at risk (OR = 3.01 [95 CI:1.39, 6.52]). In addition, those suffering from incontinence/urinary tract disorders (OR = 2.95 [95% CI:1.30, 6.71]), and prior injury (OR = 1.42 [95% CI:1.04, 1.95]) were also at greater risk of injury. CONCLUSIONS: The relationship of medication use and injury in this population is different from those observed in studies of falls in older persons. We hypothesize that distraction from either pain or co-morbidity may play an important role in the etiology of injuries suffered in this active older working population. Further investigations in this area are required to confirm these findings.

Nedocromil sodium versus sodium cromoglycate in treatment of exercise-induced bronchoconstriction: a systematic review.

The objective of this review was to compare the effects of prophylactic doses of nedocromil sodium (NCS) and sodium cromoglycate (SCG) on postexercise lung function, in persons diagnosed with exercise-induced bronchoconstriction. Randomized controlled trials were identified from the Cochrane Airways Review Group Asthma Register, plus hand searching for trials in journals, bibliographies of relevant studies and review articles. Randomized controlled trials comparing NCS to SCG in prophylactic treatment of exercise-induced bronchoconstriction were eligible. Studies were pooled using odds ratios (OR) for dichotomous outcomes or weighted mean differences (WMD) with 95% confidence intervals (95% CI) for continuous outcomes. No significant differences were noted between NCS and SCG with respect to the maximum per cent decrease in forced expiratory volume in one second (WMD=-0.88; 95% CI -4.50-2.74), complete protection (OR=0.95; 95% CI 0.50-1.81), clinical protection (OR=0.71; 95% CI 0.36-1.39), unpleasant taste (OR=6.85; 95% CI 0.77-60.73), or sore throat (OR=3.46; 95% CI 0.32-37.48). Subgroup analyses based on age, dosages of medications and timing of exercise postinhalation were consistent with the overall pooled analyses. No significant differences were evident between the effects of nedocromil sodium and sodium cromoglycate during the immediate postexercise period in adults and children with exercise-induced bronchoconstriction, with regards to maximum per cent decrease in forced expiratory volume in one second, complete protection, or clinical protection. Side-effect profiles were similar.

Evaluating the quality of systematic reviews in the emergency medicine literature.

STUDY OBJECTIVE: The objective of this study was to examine the scientific quality of systematic reviews published in 5 leading emergency medicine journals. METHODS: MEDLINE and EMBASE databases were electronically searched to identify published systematic reviews. Searches were only conducted in emergency medicine journals during the past 10 years; 4 of the journals were also hand searched. Potential reviews were assessed independently by 2 reviewers for inclusion. Data regarding methods were extracted from each review independently by 2 reviewers. All systematic reviews were retrieved and rated for quality by using the 10 questions from the overview quality assessment questionnaire. RESULTS: Twenty-nine reviews were identified from more than 100 citations. The overall scientific quality of the systematic reviews was low (mean score, 2.7; 95% confidence interval 2.1 to 3.2; maximum possible score, 7.0). Selection and publication biases were rarely addressed in this collection of reviews. For example, the search strategies were only identified in 9 (31%) reviews, whereas independent study selection (6 [21%]) and quality assessment of included studies (9 [31%]) were infrequently performed. Overall, the majority of reviews had extensive flaws, and only 3 (10%) had minimal flaws. CONCLUSION: The results of the study indicate that many of the systematic reviews published in the emergency medicine literature contain major flaws; reviews with poor methodology may limit the validity of reported results. Further efforts should be made to improve the design, reporting, and publication of systematic reviews in emergency medicine.

ED management of cellulitis: a review of five urban centers.

Cellulitis is a common problem presenting to the emergency department (ED). This study examines the epidemiology of cellulitis in 5 Canadian urban EDs and determines the practice variation in this management among sites. From computerized provincial ED diagnosis information, 10% of cellulitis charts from April 1, 1997 to March 31, 1998 were randomly selected for review. All 5 EDs in one urban region were sampled; physicians were unaware of the study when seeing patients. A standardized audit form was used to collect information pertaining to visits for the incident infection case. Cases were excluded if simple cellulitis was not the primary diagnosis or if procedures such as incision and drainage were initially required. A total of 416 adult charts were retrospectively identified. The mean age was 46 years and 61% were men; 38% had seen another physician before the ED presentation. Cellulitis was most commonly located in the upper (41%) and lower (48%) extremities. Most cases were treated with intravenous cefazolin (58%; range among sites: 49%-66%); however, over 25 different antibiotics and doses were initially prescribed. Each case required a median of 4 (interquartile range [IQR]: 1, 9) ED visits. Some patients (14%) received an increase in dose (3%) or a change in antibiotic regimen (11%) during their treatment. Few patients (3%) required a second change in regimen. Specialist consultations were obtained in only 6% of patients and hospitalization was rare (7%). The most common discharge prescription was oral cephalexin (62%); however; many different regimens were prescribed. Cellulitis is a common ED problem which consumes considerable resources to treat. Considerable practice variation exists with respect to in-ED and post-ED management. These results suggest the need for the development of practice guidelines for the treatment of this common ED problem.

Change in pain and function while waiting for major joint arthroplasty.

The objective of this study was to examine the change in pain and physical function that occurs while waiting for major arthroplasty. Data were collected prospectively from a cohort of 313 patients who were waiting > 1 month for total hip arthroplasty or total knee arthroplasty. The WOMAC and the SF-36 health status instruments were administered at the time the patient was placed on the waiting list and again just before surgery. Minimal amounts of change in pain and physical and psychosocial function occurred for hip and knee arthroplasty patients while they waited. Overall, waiting time did not appear to have a negative impact on the amount of pain and dysfunction experienced.

Sport and recreation-related head injuries treated in the emergency department.

OBJECTIVE: Head injury (HI) in sport is common and can have serious consequences. This study examines the epidemiology of sport/recreational (SR)-related HI presenting to the emergency department (ED). DESIGN: Retrospective review of medical records. SETTING: Five EDs in the Capital Health Region (Edmonton) located in the province of Alberta, Canada. PATIENTS: All persons in a 1-year period reporting to the EDs with an HI. HI was defined as IC9-CM coded skull fracture, loss of consciousness, or concussion. MAIN OUTCOME MEASURES: Hospitalization, utilization of diagnostic testing, and discharge destination. RESULTS: In total, 10,877 (3%) of 288,948 ED encounters were for sports and recreational injuries; 358 (3%) were for HI. Males (71%) were more frequently injured; patients < 20 years old were involved in 66% of all HI cases. The highest proportion of HI occurred during ice hockey (21%), cycling (13%), and playground-related activities (8%). 9% of HI were hospitalized (versus 4% admission rate for other SR injuries: p < 0.01). CONCLUSIONS: These results demonstrate the utility of an ED-based injury registry and indicate that patients with HI presenting to the ED from SR activities are common. These injuries appear to be more severe than other types of SR injuries treated in the ED.

The impact of health status on waiting time for major joint arthroplasty.

This study was conducted to determine the impact of health status on waiting time for major joint arthroplasty in a universal publicly funded health system. Data were collected prospectively from a cohort of 553 patients waiting for total hip or total knee arthroplasty. The WOMAC and SF-36 health status instruments were administered at the time the patient was placed on the waiting list. The outcome measure was length of waiting time. Multivariate analyses found increased body mass index and decreased social function as the only determinants of waiting time. This model explained only 4% of the variance in waiting time. The association between health status and waiting time for arthroplasties appears to be small. These findings suggest that major joint arthroplasty is not prioritized on the basis of burden of illness.

Immobilisation for acute ankle sprain. A systematic review.

The variation of practice with respect to the treatment of the acutely sprained ankle suggests a lack of evidence-based management strategies for this problem. The objective of this review was to assess the effectiveness of the various methods of immobilisation for acute ankle sprain. An electronic database search was conducted using MEDLINE, EMBASE, BIOSIS, CINAHL, Cochrane Controlled Trial Register and Current Contents. Randomised and quasi-randomised clinical trials describing skeletally mature individuals with an acute ankle sprain and comparing immobilisation for the treatment of injuries to the lateral ligament complex of the ankle were evaluated for inclusion. Two reviewers independently assessed the validity of included trials and extracted relevant data on the treatment outcome. Where appropriate, results of comparable studies were pooled. Individual and pooled statistics are reported as relative risks (RR) for dichotomous outcomes and weighted mean differences (WMD) for continuous outcome measures with 95% confidence intervals (95% CI). Heterogeneity between trials was tested using a standard chi-square test. A total of 22 studies met the inclusion criteria. Statistically significant differences were found for six outcome measures, all in favour of functional treatment compared with immobilisation: return to sports (RR: 1.85; 95% CI: 1.2 to 2.8), (WMD: 4.57 days; 95% CI: 1.5 to 7.6), return to work (WMD: 7.12 days; 95% CI: 5.6 to 8.7), persistent swelling (RR: 1.44; 95% CI: 1.1 to 2.0), objective instability by stress X-ray (WMD: 2.48; 95% CI: 1.3 to 3.6), range of motion (RR: 1.64; 95% CI: 1.1 to 2.6) and patient satisfaction (RR: 6.50; 95% CI: 1.8 to 24) . None of the other results were significantly in favour of immobilisation. Sensitivity analysis showed that a non-concealed treatment allocation did not influence the statistical significance of the overall results. Based on our results, functional treatment currently seems a more appropriate treatment and should be encouraged. Concerning effectiveness, immobilisation, if necessary, should be restricted to certain patients and for short time periods.