Point-of-Care Capillary Blood Ketone Measurements and the Prediction of Future Ketoacidosis Risk in Type 1 Diabetes.

OBJECTIVE: Rather than during illness while diabetic ketoacidosis (DKA) is developing, we aimed to determine if levels of routine point-of-care capillary blood ketones could predict future DKA. RESEARCH DESIGN AND METHODS: We examined previously collected data from placebo-assigned participants in an adjunct-to-insulin medication trial program that included measurement of fasted capillary blood ketone levels twice per week in a 2-month baseline period. The outcome was 6- to 12-month trial-adjudicated DKA. RESULTS: DKA events occurred in 12 of 484 participants at a median of 105 (interquartile range 43, 199) days. Maximum ketone levels were higher in patient cases compared with in control patients (0.8 [0.6, 1.2] vs. 0.3 [0.2, 0.7] mmol/L; P = 0.002), with a nonparametric area under the receiver operating characteristic curve of 0.77 (95% CI 0.66-0.88). Ketone levels ≥0.8 mmol/L had a sensitivity of 64%, a specificity of 78%, and positive and negative likelihood ratios of 2.9 and 0.5, respectively. CONCLUSIONS: This proof of concept that routine capillary ketone surveillance can identify individuals at high risk of future DKA implies a role for future technologies including continuous ketone monitoring.

Thromboprophylaxis Reduced Venous Thromboembolism in Sickle Cell Patients with Central Venous Access Devices: A Retrospective Cohort Study.

Sickle cell disease (SCD) induces a chronic prothrombotic state. Central venous access devices (CVADs) are commonly used for chronic transfusions and iron chelation in this population. CVADs are an additional venous thromboembolism (VTE) risk factor. The role of thromboprophylaxis in this setting is uncertain. The objectives are: (1) to determine whether thromboprophylaxis reduces VTE risk in SCD patients with CVAD and (2) to explore characteristics associated with VTE risk. We identified adults with SCD and CVAD intended for chronic use (≥3 months) at two comprehensive SCD centers. Thromboprophylaxis presence; type; intensity; and patient-, catheter-, and treatment-related VTE risk factors were recorded. Among 949 patients, 49 had a CVAD (25 without and 24 with VTE prophylaxis). Thromboprophylaxis type and intensity varied widely. Patients without thromboprophylaxis had higher VTE rates (rate ratio (RR) = 4.0 (95% confidence interval: 1.2−12.6), p = 0.02). Hydroxyurea was associated with lower VTE rates (RR = 20.5 (6.4−65.3), p < 0.001). PICC lines and Vortex and Xcela Power implantable devices were associated with higher rates compared with Port-a-Cath (RR = 5.8 (1.3−25.9), p = 0.02, and RR = 58.2 (15.0−225.0), p < 0.001, respectively). Thromboprophylaxis, hydroxyurea, and CVAD subtype were independently associated with VTE. The potentially protective role of thromboprophylaxis and hydroxyurea for VTE prevention in patients with SCD and CVAD merits further exploration.

Genetic syndromes with diabetes: A systematic review.

Previous reviews and clinical guidelines have identified 10-20 genetic syndromes associated with diabetes, but no systematic review has been conducted to date. We provide the first comprehensive catalog for syndromes with diabetes mellitus. We conducted a systematic review of MEDLINE, Embase, CENTRAL, PubMed, OMIM, and Orphanet databases for case reports, case series, and observational studies published between 1946 and January 15, 2020, that described diabetes mellitus in adults and children with monogenic or chromosomal syndromes. Our literature search identified 7,122 studies, of which 160 fulfilled inclusion criteria. Our analysis of these studies found 69 distinct diabetes syndromes. Thirty (43.5%) syndromes included diabetes mellitus as a cardinal clinical feature, and 56 (81.2%) were fully genetically elucidated. Sixty-three syndromes (91.3%) were described more than once in independent case reports, of which 59 (93.7%) demonstrated clinical heterogeneity. Syndromes associated with diabetes mellitus are more numerous and diverse than previously anticipated. While knowledge of the syndromes is limited by their low prevalence, future reviews will be needed as more cases are identified. The genetic etiologies of these syndromes are well elucidated and provide potential avenues for future gene identification efforts, aid in diagnosis and management, gene therapy research, and developing personalized medicine treatments.

Characteristics of SARS-CoV-2 testing for rapid diagnosis of COVID-19 during the initial stages of a global pandemic.

Accurate SARS-CoV-2 diagnosis is essential to guide prevention and control of COVID-19. Here we examine SARS-CoV-2 molecular-based test performance characteristics and summarize case-level data related to COVID-19 diagnosis. From January 11 through April 22, 2020, Public Health Ontario conducted SARS-CoV-2 testing of 86,942 specimens collected from 80,354 individuals, primarily using real-time reverse-transcription polymerase chain reaction (rRT-PCR) methods. We analyzed test results across specimen types and for individuals with multiple same-day and multi-day collected specimens. Nasopharyngeal compared to throat swabs had a higher positivity (8.8% vs. 4.8%) and an adjusted estimate 2.9 Ct lower (SE = 0.5, p<0.001). Same-day specimens showed high concordance (98.8%), and the median Ct of multi-day specimens increased over time. Symptomatic cases had rRT-PCR results with an adjusted estimate 3.0 Ct (SE = 0.5, p<0.001) lower than asymptomatic/pre-symptomatic cases. Overall test sensitivity was 84.6%, with a negative predictive value of 95.5%. Molecular testing is the mainstay of SARS-CoV-2 diagnosis and testing protocols will continue to be dynamic and iteratively modified as more is learned about this emerging pathogen.

Essential diabetes medicines and health outcomes in 127 countries.

AIM: Diabetes is the ninth leading cause of death. Improving access to diabetes medicines may decrease mortality. Diabetes medicines on national essential medicines lists (NEMLs) vary considerably. We examine the association between diabetes population health outcomes relating to mortality and the listing of diabetes medicines on national essential medicine lists for 127 countries. MATERIALS AND METHODS: We conducted a cross-sectional study. We determined the number of diabetes medicines on NEMLs and used multiple linear regression to analyse the association between diabetes health outcomes and the number of medicines on NEMLs. We used linear regression to assess the association between diabetes health outcomes and the listing of or not listing of medicines that were listed by 25-75% of countries. Diabetes prevalence, gross domestic product (GDP) per capita and mean expenditure per person with diabetes were controlled for in all analyses. RESULTS: The total number of diabetes medicines listed on NEMLs ranged from 0 to 16 (median: 4; interquartile range: 3-6). Diabetes health outcome scores were associated with the number of diabetes medicines on NEMLs [1.3-point increase (95% confidence interval, 95% CI 0.5-2.1) for every additional medicine on NEMLs; P = .002] and GDP per capita [19.5-point increase (95% CI 5.4-33.6) for every 10-fold increase in GDP; P = .003]. Diabetes expenditure was not associated with health outcome scores (P = .23). Increases in diabetes health outcomes score were associated with the listing of glimepiride (7.9-point increase, 95% CI 2.3-13.5, P = .006) and glipizide (5.8-point increase, 95% CI 0.03-11.6, P = .049) on NEMLs. CONCLUSIONS: Listing of diabetes medicines on NEMLs has the potential to improve population health outcomes related to mortality in countries with diverse incomes and diabetes prevalence without necessarily increasing diabetes health expenditure.

Essential tobacco dependence medicines in 137 countries.

AIMS: To use a database of national essential medicine lists to determine how many include the three tobacco dependence medicines: nicotine replacement therapy, varenicline and bupropion. METHODS: Retrospective observational study using national essential medicine lists for 137 countries. RESULTS: Of the 137 countries, 34 listed at least one of the three tobacco dependence medicines included in this analysis. Bupropion was listed by 23 countries, nicotine replacement therapy by 17 countries and varenicline by eight countries. CONCLUSIONS: Tobacco dependence medicines do not appear on the essential medicines lists of most countries.

Accuracy of Electrocardiography and Agreement with Echocardiography in the Diagnosis of Pediatric Left Atrial Enlargement.

Left atrial enlargement (LAE) is a marker for diastolic cardiac dysfunction. Echocardiograms are considered the gold-standard for diagnosis, but given their wider access and lower economic cost, electrocardiograms (ECGs) may be useful in identifying patients who would benefit from further investigation. This study investigates the utility of ECG criteria to diagnose LAE in pediatric patients. A retrospective chart review (n = 492) was conducted in patients whose echocardiograms demonstrated LAE by left atrial indexed diameter z-score ≥2.0 and/or increased left atrial to aortic root ratio at various cutoffs (≥1.4, ≥1.6, ≥1.8). ECG criteria studied included: (1) P wave ≥110 msec, (2) P mitrale ≥40 msec, in LII (3) terminal negative P wave deflection in lead V1 > 40 msec, and (4) P/PR segment >1.6 in lead II. Sensitivity, specificity, Cohen's Kappa coefficient (κ), and ROC curves were calculated. A combination of P mitrale ≥40 msec and terminal negative P wave deflection in lead V1 > 40 msec yielded the greatest agreement (κ = 0.221, 95%CI 0.060-0.382), but all ECG criteria used to diagnose LAE had poor diagnostic value (AUC < 0.60). The present ECG criteria should not be used to diagnose LAE in the absence of an echocardiogram and findings should be considered in the context of clinical symptoms.

Health outcomes attributable to carbapenemase-producing Enterobacteriaceae infections: A systematic review and meta-analysis.

BACKGROUND: Carbapenemase-producing Enterobacteriaceae (CPE) pose a significant global health threat. OBJECTIVE: To conduct a systematic review of health outcomes and long-term sequelae attributable to CPE infection. METHODS: We followed PRISMA reporting guidelines and published our review protocol on PROSPERO (CRD42018097357). We searched Medline, Embase, CINAHL and the Cochrane Library. We included primary studies with a carbapenem-susceptible control group in high-income countries, published in English. Quality appraisal was completed using Joanna Briggs Institute checklists. We qualitatively summarized frequently reported outcomes and conducted a meta-analysis. RESULTS: Our systematic review identified 8,671 studies; 17 met the eligibility criteria for inclusion. All studies reported health outcomes; none reported health-related quality-of-life. Most studies were from Europe (65%), were conducted in teaching or university-affiliated hospitals (76%), and used case-control designs (53%). Mortality was the most commonly reported consequence of CPE-infections; in-hospital mortality was most often reported (62%). Our meta-analysis (n = 5 studies) estimated an absolute risk difference (ARD) for in-hospital bloodstream infection mortality of 0.25 (95% confidence interval [CI], 0.17-0.32). Duration of antibiotic therapy (range, 4-29.7 vs 1-23.6 days) and length of hospital stay (range, 21-87 vs 15-43 days) were relatively higher for CPE-infected patients than for patients infected with carbapenem-susceptible pathogens. Most studies (82%) met >80% of their respective quality appraisal criteria. CONCLUSIONS: The risk of in-hospital mortality due to CPE bloodstream infection is considerably greater than carbapenem-susceptible bloodstream infection (ARD, 0.25; 95% CI, 0.17-0.32). Health outcome studies associated with CPE infection are focused on short-term (eg, in-hospital) outcomes; long-term sequelae and quality-of-life are not well studied. TRIAL REGISTRATION: PROSPERO (CRD42018097357).

The crossover design for studies of infertility employing in-vitro fertilization: A methodological survey.

BACKGROUND: Infertility has become increasingly common worldwide. There is a need for the infertility literature to evaluate new interventions with IVF. The crossover design presents many methodological advantages for IVF trials. In addition to providing a within-person comparison of outcomes, it offers participants the opportunity to potentially benefit from more than one available treatment. However, infertility studies present a unique challenge in terms of bias: successful participants do not cross over to the second treatment group. OBJECTIVES: The main objective of our study was to survey the methodological features of crossover trials for infertility with in-vitro fertilization (IVF) based interventions. A secondary focus was reporting key results. STUDY DESIGN & SETTING: We conducted a methodological survey by systematically searching Medline and Embase databases. The capture-recapture technique was used to estimate the number of relevant studies that were not retrieved by our search strategy. We employed the Cochrane risk of bias tool to assess methodological rigour. Crossover-specific methods features were summarized. Treatment effects for pregnancy outcomes across studies are also presented. RESULTS: 15 studies met inclusion criteria. Most studies were deemed to have high or unclear risks of bias, usually because of incomplete reporting of outcome data and assessment procedures. 13 studies did not employ crossover-specific methods to analyze outcome data by period, which may bias treatment effect estimates. Four studies reported pregnancy outcome data with sample sizes from both treatment periods. Of these four studies, three reported that the control intervention was favoured. CONCLUSIONS: The main limitation of our survey was the small sample size of studies. Future reviews should be larger and seek to encompass a broader range of the infertility literature. Despite the issues identified in the included trials, consideration should still be given to using the crossover design in future infertility research. Employing crossover-specific analysis methods, such as accounting for participant non-completion, along with strict adherence to CONSORT reporting guidelines, may significantly reduce the risk of bias in individual studies.

An evidence rating service provided valid correlates of the clinical importance of medical articles and journals.

OBJECTIVES: The objective of this study was to determine reliability and validity of McMaster PLUS measures of scientific merit and clinical importance of articles in medical journals. STUDY DESIGN AND SETTING: Analytic survey of peer-reviewed medical journals was carried out. Articles were qualified for inclusion by meeting (1) scientific criteria and (2) a clinical importance rating threshold. Included articles were sent as e-mail alerts to physicians according to their clinical interests. Internal measures included the number of high-quality, clinically important studies published in source journals and response to alerts. For external validation, we correlated internal measures with the Journal Impact Factor (JIF) and citation in DynaMed Plus (DMP). RESULTS: We evaluated 34,232 articles from 57 journals. Inclusion criteria were met by 2,638 articles (7.71%). The number of qualifying articles per journal was correlated with the number of articles with high clinical importance ratings (r 0.96, P < 0.001), article alert clicks (r 0.86, P < 0.001), and DMP citations (r 0.99, P < 0.001). Correlation was lower with the JIF (r 0.68, P < 0.01). CONCLUSIONS: Measures of scientific merit and clinical importance of medical journal articles were strongly correlated with each other, less so with JIFs. Journals varied widely by these measures but, generally, few articles were both scientifically sound and clinically important.

The efficiency of database searches for creating systematic reviews was improved by search filters.

OBJECTIVES: To compare Clinical Queries (CQs) for randomized trials of therapy 'methods' and 'NOT' limits search filters with Cochrane methods filters. STUDY DESIGN AND SETTING: Analytic survey of Cochrane reviews as the reference standard for retrieving studies included in the reviews ("included studies [ISs]"). The sensitivity and precision of Cochrane content terms + Cochrane methods terms were compared in MEDLINE and Embase with Cochrane content terms + CQs maximally sensitive filter for therapy studies, without and with additional 'NOT' limits (CQ-S [CQ sensitive]; CQ-S + limits) and a balanced filter without and with additional NOT limits (CQ-B [CQ balanced]; CQ-B + limits). RESULTS: Cochrane or CQ methods terms reduced, by 64-96%, the overall retrieval of articles with minimal loss of ISs. Sensitivity was high and similar for the 4 filters. However, CQ-B + limits had the highest precision (2.64%, number needed to be read to find one eligible study [NNR] 38) followed by the CQ-B (1.05%, NNR 95), Cochrane search (0.51%, NNR 198), CQ-S + limits (0.34%, NNR 296), and CQ-S filters (0.31%, NNR 325). CONCLUSION: For systematic reviews of therapeutic interventions, the efficiency of searches in MEDLINE and Embase was better served by the CQs for therapy studies with balanced methods filter and NOT limits.