Showing papers by "Public Health Research Institute published in 2018"

Analysis of shared heritability in common disorders of the brain

Abstract: Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

COSMIN guideline for systematic reviews of patient-reported outcome measures

Abstract: Systematic reviews of patient-reported outcome measures (PROMs) differ from reviews of interventions and diagnostic test accuracy studies and are complex. In fact, conducting a review of one or more PROMs comprises of multiple reviews (i.e., one review for each measurement property of each PROM). In the absence of guidance specifically designed for reviews on measurement properties, our aim was to develop a guideline for conducting systematic reviews of PROMs. Based on literature reviews and expert opinions, and in concordance with existing guidelines, the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) steering committee developed a guideline for systematic reviews of PROMs. A consecutive ten-step procedure for conducting a systematic review of PROMs is proposed. Steps 1–4 concern preparing and performing the literature search, and selecting relevant studies. Steps 5–8 concern the evaluation of the quality of the eligible studies, the measurement properties, and the interpretability and feasibility aspects. Steps 9 and 10 concern formulating recommendations and reporting the systematic review. The COSMIN guideline for systematic reviews of PROMs includes methodology to combine the methodological quality of studies on measurement properties with the quality of the PROM itself (i.e., its measurement properties). This enables reviewers to draw transparent conclusions and making evidence-based recommendations on the quality of PROMs, and supports the evidence-based selection of PROMs for use in research and in clinical practice.

COSMIN Risk of Bias checklist for systematic reviews of Patient-Reported Outcome Measures

Abstract: The original COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist was developed to assess the methodological quality of single studies on measurement properties of Patient-Reported Outcome Measures (PROMs). Now it is our aim to adapt the COSMIN checklist and its four-point rating system into a version exclusively for use in systematic reviews of PROMs, aiming to assess risk of bias of studies on measurement properties. For each standard (i.e., a design requirement or preferred statistical method), it was discussed within the COSMIN steering committee if and how it should be adapted. The adapted checklist was pilot-tested to strengthen content validity in a systematic review on the quality of PROMs for patients with hand osteoarthritis. Most important changes were the reordering of the measurement properties to be assessed in a systematic review of PROMs; the deletion of standards that concerned reporting issues and standards that not necessarily lead to biased results; the integration of standards on general requirements for studies on item response theory with standards for specific measurement properties; the recommendation to the review team to specify hypotheses for construct validity and responsiveness in advance, and subsequently the removal of the standards about formulating hypotheses; and the change in the labels of the four-point rating system. The COSMIN Risk of Bias checklist was developed exclusively for use in systematic reviews of PROMs to distinguish this application from other purposes of assessing the methodological quality of studies on measurement properties, such as guidance for designing or reporting a study on the measurement properties.

WHO World Mental Health Surveys International College Student Project: Prevalence and distribution of mental disorders.

Abstract: Increasingly, colleges across the world are contending with rising rates of mental disorders, and in many cases, the demand for services on campus far exceeds the available resources. The present study reports initial results from the first stage of the WHO World Mental Health International College Student project, in which a series of surveys in 19 colleges across 8 countries (Australia, Belgium, Germany, Mexico, Northern Ireland, South Africa, Spain, United States) were carried out with the aim of estimating prevalence and basic sociodemographic correlates of common mental disorders among first-year college students. Web-based self-report questionnaires administered to incoming first-year students (45.5% pooled response rate) screened for six common lifetime and 12-month DSM-IV mental disorders: major depression, mania/hypomania, generalized anxiety disorder, panic disorder, alcohol use disorder, and substance use disorder. We focus on the 13,984 respondents who were full-time students: 35% of whom screened positive for at least one of the common lifetime disorders assessed and 31% screened positive for at least one 12-month disorder. Syndromes typically had onsets in early to middle adolescence and persisted into the year of the survey. Although relatively modest, the strongest correlates of screening positive were older age, female sex, unmarried-deceased parents, no religious affiliation, nonheterosexual identification and behavior, low secondary school ranking, and extrinsic motivation for college enrollment. The weakness of these associations means that the syndromes considered are widely distributed with respect to these variables in the student population. Although the extent to which cost-effective treatment would reduce these risks is unclear, the high level of need for mental health services implied by these results represents a major challenge to institutions of higher education and governments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

COSMIN methodology for evaluating the content validity of patient-reported outcome measures: a Delphi study

Abstract: Content validity is the most important measurement property of a patient-reported outcome measure (PROM) and the most challenging to assess. Our aims were to: (1) develop standards for evaluating the quality of PROM development; (2) update the original COSMIN standards for assessing the quality of content validity studies of PROMs; (3) develop criteria for what constitutes good content validity of PROMs, and (4) develop a rating system for summarizing the evidence on a PROM’s content validity and grading the quality of the evidence in systematic reviews of PROMs. An online 4-round Delphi study was performed among 159 experts from 21 countries. Panelists rated the degree to which they (dis)agreed to proposed standards, criteria, and rating issues on 5-point rating scales (‘strongly disagree’ to ‘strongly agree’), and provided arguments for their ratings. Discussion focused on sample size requirements, recording and field notes, transcribing cognitive interviews, and data coding. After four rounds, the required 67% consensus was reached on all standards, criteria, and rating issues. After pilot-testing, the steering committee made some final changes. Ten criteria for good content validity were defined regarding item relevance, appropriateness of response options and recall period, comprehensiveness, and comprehensibility of the PROM. The consensus-based COSMIN methodology for content validity is more detailed, standardized, and transparent than earlier published guidelines, including the previous COSMIN standards. This methodology can contribute to the selection and use of high-quality PROMs in research and clinical practice.

Many Labs 2: Investigating Variation in Replicability Across Samples and Settings

Abstract: We conducted preregistered replications of 28 classic and contemporary published findings, with protocols that were peer reviewed in advance, to examine variation in effect magnitudes across samples and settings. Each protocol was administered to approximately half of 125 samples that comprised 15,305 participants from 36 countries and territories. Using the conventional criterion of statistical significance (p < .05), we found that 15 (54%) of the replications provided evidence of a statistically significant effect in the same direction as the original finding. With a strict significance criterion (p < .0001), 14 (50%) of the replications still provided such evidence, a reflection of the extremely high-powered design. Seven (25%) of the replications yielded effect sizes larger than the original ones, and 21 (75%) yielded effect sizes smaller than the original ones. The median comparable Cohen’s ds were 0.60 for the original findings and 0.15 for the replications. The effect sizes were small (< 0.20) in 16 of the replications (57%), and 9 effects (32%) were in the direction opposite the direction of the original effect. Across settings, the Q statistic indicated significant heterogeneity in 11 (39%) of the replication effects, and most of those were among the findings with the largest overall effect sizes; only 1 effect that was near zero in the aggregate showed significant heterogeneity according to this measure. Only 1 effect had a tau value greater than .20, an indication of moderate heterogeneity. Eight others had tau values near or slightly above .10, an indication of slight heterogeneity. Moderation tests indicated that very little heterogeneity was attributable to the order in which the tasks were performed or whether the tasks were administered in lab versus online. Exploratory comparisons revealed little heterogeneity between Western, educated, industrialized, rich, and democratic (WEIRD) cultures and less WEIRD cultures (i.e., cultures with relatively high and low WEIRDness scores, respectively). Cumulatively, variability in the observed effect sizes was attributable more to the effect being studied than to the sample or setting in which it was studied.

Transancestral GWAS of alcohol dependence reveals common genetic underpinnings with psychiatric disorders

Abstract: Liability to alcohol dependence (AD) is heritable, but little is known about its complex polygenic architecture or its genetic relationship with other disorders. To discover loci associated with AD and characterize the relationship between AD and other psychiatric and behavioral outcomes, we carried out the largest genome-wide association study to date of DSM-IV-diagnosed AD. Genome-wide data on 14,904 individuals with AD and 37,944 controls from 28 case-control and family-based studies were meta-analyzed, stratified by genetic ancestry (European, n = 46,568; African, n = 6,280). Independent, genome-wide significant effects of different ADH1B variants were identified in European (rs1229984; P = 9.8 × 10-13) and African ancestries (rs2066702; P = 2.2 × 10-9). Significant genetic correlations were observed with 17 phenotypes, including schizophrenia, attention deficit-hyperactivity disorder, depression, and use of cigarettes and cannabis. The genetic underpinnings of AD only partially overlap with those for alcohol consumption, underscoring the genetic distinction between pathological and nonpathological drinking behaviors.

Sex and gender disparities in the epidemiology and outcomes of chronic kidney disease.

Abstract: Improved understanding of sex and gender-specific differences in the aetiology, mechanisms and epidemiology of chronic kidney disease (CKD) could help nephrologists better address the needs of their patients. Population-based studies indicate that CKD epidemiology differs by sex, affecting more women than men, especially with regard to stage G3 CKD. The effects of longer life expectancy on the natural decline of glomerular filtration rate (GFR) with age, as well as potential overdiagnosis of CKD through the inappropriate use of GFR equations, might be in part responsible for the greater prevalence of CKD in women. Somewhat paradoxically, there seems to be a preponderance of men among patients starting renal replacement therapy (RRT); the protective effects of oestrogens in women and/or the damaging effects of testosterone, together with unhealthier lifestyles, might cause kidney function to decline faster in men than in women. Additionally, elderly women seem to be more inclined to choose conservative care instead of RRT. Dissimilarities between the sexes are also apparent in the outcomes of CKD. In patients with predialysis CKD, mortality is higher in men than women; however, this difference disappears for patients on RRT. Although access to living donor kidneys among men and women seems equal, women have reduced access to deceased donor transplantation. Lastly, health-related quality of life while on RRT is poorer in women than men, and women report a higher burden of symptoms. These findings provide insights into differences in the underlying pathophysiology of disease as well as societal factors that can be addressed to reduce disparities in access to care and outcomes for patients with CKD.

The physical activity paradox: six reasons why occupational physical activity (OPA) does not confer the cardiovascular health benefits that leisure time physical activity does

Abstract: Physical activity (PA) is well documented to improve health. However, this documentation is restricted to leisure time physical activity (LTPA; eg, sports, recreation and transportation). Increasing evidence shows that occupational physical activity (OPA) does not improve health.1 Actually, OPA can be detrimental. These contrasting health effects of LTPA and OPA constitute the so-called PA health paradox.2 For a considerable fraction of the adult population, work constitutes the main setting for PA. Workers in many occupations, such as construction, cleaning, refuse collection, elderly care, farming and manufacturing, are physically active for large parts of their working days, for most of the year. Despite this PA at work, these and other manual workers have relatively poor health. Many epidemiological studies document that high OPA increases the risk for cardiovascular disease (CVD) and mortality outcomes, even after extensive adjustments for other risk factors including socioeconomic status, LTPA and other health behaviours.1 This increased risk from high OPA has been shown to be particularly pronounced among workers with low job resources, low cardiorespiratory fitness3 or pre-existing …

Culture-independent discovery of the malacidins as calcium-dependent antibiotics with activity against multidrug-resistant Gram-positive pathogens.

Abstract: Despite the wide availability of antibiotics, infectious diseases remain a leading cause of death worldwide 1 . In the absence of new therapies, mortality rates due to untreatable infections are predicted to rise more than tenfold by 2050. Natural products (NPs) made by cultured bacteria have been a major source of clinically useful antibiotics. In spite of decades of productivity, the use of bacteria in the search for new antibiotics was largely abandoned due to high rediscovery rates2,3. As only a fraction of bacterial diversity is regularly cultivated in the laboratory and just a fraction of the chemistries encoded by cultured bacteria are detected in fermentation experiments, most bacterial NPs remain hidden in the global microbiome. In an effort to access these hidden NPs, we have developed a culture-independent NP discovery platform that involves sequencing, bioinformatic analysis and heterologous expression of biosynthetic gene clusters captured on DNA extracted from environmental samples. Here, we describe the application of this platform to the discovery of the malacidins, a distinctive class of antibiotics that are commonly encoded in soil microbiomes but have never been reported in culture-based NP discovery efforts. The malacidins are active against multidrug-resistant pathogens, sterilize methicillin-resistant Staphylococcus aureus skin infections in an animal wound model and did not select for resistance under our laboratory conditions. Analysis of secondary metabolite biosynthesis clusters from diverse soil samples identifies a distinct class of calcium-dependent antibiotics—the malacidins—that bind lipid II and are active against multidrug-resistant Gram-positive pathogens.

Associations of sarcopenia definitions, and their components, with the incidence of recurrent falling and fractures : The longitudinal aging study Amsterdam

Abstract: Background: The aim was to investigate the associations of sarcopenia as defined by European Working Group on Sarcopenia in Older People (EWGSOP) and Foundation for the National Institutes of Health (FNIH) Sarcopenia Project, and their underlying components, with the incidence of recurrent falling and fractures. Methods: In 498 older men and women (mean age = 75.2 [SD = 6.4]) from the Longitudinal Aging Study Amsterdam (LASA), the sarcopenia components lean mass (DXA), handgrip strength (handheld dynamometer), and gait speed were measured. Data on falls (3-year follow-up) and fractures (10-year follow-up) were collected. Cox regression analyses were performed, adjusting for age, sex, and total body fat. Results: Recurrent falling occurred in 130 persons and 60 persons experienced a fracture during follow-up. Participants who were identified as sarcopenic based on the FNIH definitions had a more than 2-fold increased risk to become a recurrent faller. There was no association between sarcopenia based on the EWGSOP definition and incidence of recurrent falling. When the sarcopenia components were examined individually, only a low grip strength was associated with incidence of recurrent falling, independent of a low lean mass or a slow gait speed. Sarcopenia according to both definitions was not associated with incident fractures, which may be caused by low statistical power. Conclusion: Sarcopenia according to the FNIH definitions, but not according to the EWGSOP definition was associated with recurrent falling. When examining the individual components, only a low grip strength was independently associated with recurrent falling. No associations between sarcopenia with incidence of fractures were found.

Lack of placental transfer of certolizumab pegol during pregnancy: results from CRIB, a prospective, postmarketing, pharmacokinetic study.

Abstract: Objectives There is a need for effective and safe treatment during pregnancy in women with chronic inflammatory diseases. This study evaluated placental transfer of certolizumab pegol (CZP), an Fc-free anti-tumour necrosis factor drug, from CZP-treated pregnant women to their infants. Methods CRIB was a pharmacokinetic (PK) study of women ≥30 weeks pregnant receiving commercial CZP for a locally approved indication (last dose ≤35 days prior to delivery). Blood samples were collected from mothers, umbilical cords and infants at delivery, and infants again at weeks 4 and 8 post-delivery. CZP plasma concentrations were measured with a highly sensitive and CZP-specific electrochemiluminescence immunoassay (lower limit of quantification 0.032 μg/ mL). Results Sixteen women entered and completed the study. Maternal CZP plasma levels at delivery were within the expected therapeutic range (median [range] 24.4 [5.0–49.4] μg/mL). Of the 16 infants, 2 were excluded from the per-protocol set: 1 due to missing data at birth and 1 due to implausible PK data. Of the remaining 14 infants, 13 had no quantifiable CZP levels at birth ( Conclusions There was no to minimal placental transfer of CZP from mothers to infants, suggesting lack of in utero foetal exposure during the third trimester. These results support continuation of CZP treatment during pregnancy, when considered necessary. Trial registration number NCT02019602; Results.

Genome Analyses of >200,000 Individuals Identify 58 Loci for Chronic Inflammation and Highlight Pathways that Link Inflammation and Complex Disorders.

Abstract: C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 × 10−8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

The European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry Annual Report 2016: a summary.

Abstract: Background This article summarizes the European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Registry's 2015 Annual Report. It describes the epidemiology of renal replacement therapy (RRT) for end-stage renal disease (ESRD) in 2015 within 36 countries. Methods In 2016 and 2017, the ERA-EDTA Registry received data on patients who were undergoing RRT for ESRD in 2015, from 52 national or regional renal registries. Thirty-two registries provided individual patient-level data and 20 provided aggregated-level data. The incidence, prevalence and survival probabilities of these patients were determined. Results In 2015, 81 373 individuals commenced RRT for ESRD, equating to an overall unadjusted incidence rate of 119 per million population (pmp). The incidence ranged by 10-fold, from 24 pmp in Ukraine to 232 pmp in the Czech Republic. Of the patients commencing RRT, almost two-thirds were men, over half were aged ≥65 years and a quarter had diabetes mellitus as their primary renal diagnosis. Treatment modality at the start of RRT was haemodialysis for 85% of the patients, peritoneal dialysis for 11% and a kidney transplant for 4%. By Day 91 of commencing RRT, 82% of patients were receiving haemodialysis, 13% peritoneal dialysis and 5% had a kidney transplant. On 31 December 2015, 546 783 individuals were receiving RRT for ESRD, corresponding to an unadjusted prevalence of 801 pmp. This ranged throughout Europe by more than 10-fold, from 178 pmp in Ukraine to 1824 pmp in Portugal. In 2015, 21 056 kidney transplantations were performed, equating to an overall unadjusted transplant rate of 31 pmp. This varied from 2 pmp in Ukraine to 94 pmp in the Spanish region of Cantabria. For patients commencing RRT during 2006-10, the 5-year unadjusted patient survival probabilities on all RRT modalities combined was 50.0% (95% confidence interval 49.9-50.1).

Rationale and plan for vitamin D food fortification: A review and guidance paper

Abstract: Vitamin D deficiency can lead to musculoskeletal diseases such as rickets and osteomalacia, but vitamin D supplementation may also prevent extraskeletal diseases such as respiratory tract infections, asthma exacerbations, pregnancy complications and premature deaths. Vitamin D has a unique metabolism as it is mainly obtained through synthesis in the skin under the influence of sunlight (i.e., ultraviolet-B radiation) whereas intake by nutrition traditionally plays a relatively minor role. Dietary guidelines for vitamin D are based on a consensus that serum 25-hydroxyvitamin D (25[OH]D) concentrations are used to assess vitamin D status, with the recommended target concentrations ranging from ≥25 to ≥50 nmol/L (≥10-≥20 ng/mL), corresponding to a daily vitamin D intake of 10 to 20 μg (400-800 international units). Most populations fail to meet these recommended dietary vitamin D requirements. In Europe, 25(OH)D concentrations <30 nmol/L (12 ng/mL) and <50 nmol/L (20 ng/mL) are present in 13.0 and 40.4% of the general population, respectively. This substantial gap between officially recommended dietary reference intakes for vitamin D and the high prevalence of vitamin D deficiency in the general population requires action from health authorities. Promotion of a healthier lifestyle with more outdoor activities and optimal nutrition are definitely warranted but will not erase vitamin D deficiency and must, in the case of sunlight exposure, be well balanced with regard to potential adverse effects such as skin cancer. Intake of vitamin D supplements is limited by relatively poor adherence (in particular in individuals with low-socioeconomic status) and potential for overdosing. Systematic vitamin D food fortification is, however, an effective approach to improve vitamin D status in the general population, and this has already been introduced by countries such as the US, Canada, India, and Finland. Recent advances in our knowledge on the safety of vitamin D treatment, the dose-response relationship of vitamin D intake and 25(OH)D levels, as well as data on the effectiveness of vitamin D fortification in countries such as Finland provide a solid basis to introduce and modify vitamin D food fortification in order to improve public health with this likewise cost-effective approach.

Taking account of context in population health intervention research: guidance for producers, users and funders of research

Abstract: Additional co-authors: Blake Poland, Valery Ridde, Jeannie Shoveller, Sarah Viehbeck,and Daniel Wight

Causes of Emotional Eating and Matched Treatment of Obesity.

Abstract: Eating in response to negative emotions (EE) may be an explanatory factor of the weight regain of many dieters. This narrative review presents evidence on possible causes of EE and the association of EE with depression and obesity and discusses implications of these findings for the treatment of obesity. Possible causes of EE are high dietary restraint, poor interoceptive awareness, alexithymia, emotion dysregulation and a reversed hypothalamic pituitary adrenal (HPA) stress axis. EE may be the outcome of inadequate parenting or depressive feelings in interaction with genetic susceptibility. There is also robust evidence that EE is a mediator between depression and obesity. The association of EE with depression and poor emotion regulation skills suggests that the treatment of obese people with high EE should not focus on calorie-restricted diets but on emotion regulation skills. The DEBQ (Dutch Eating Behavior Questionnaire) enables such a matched treatment of obesity.

Measuring Engagement in eHealth and mHealth Behavior Change Interventions: Viewpoint of Methodologies.

Abstract: Engagement in electronic health (eHealth) and mobile health (mHealth) behavior change interventions is thought to be important for intervention effectiveness, though what constitutes engagement and how it enhances efficacy has been somewhat unclear in the literature Recently published detailed definitions and conceptual models of engagement have helped to build consensus around a definition of engagement and improve our understanding of how engagement may influence effectiveness This work has helped to establish a clearer research agenda However, to test the hypotheses generated by the conceptual modules, we need to know how to measure engagement in a valid and reliable way The aim of this viewpoint is to provide an overview of engagement measurement options that can be employed in eHealth and mHealth behavior change intervention evaluations, discuss methodological considerations, and provide direction for future research To identify measures, we used snowball sampling, starting from systematic reviews of engagement research as well as those utilized in studies known to the authors A wide range of methods to measure engagement were identified, including qualitative measures, self-report questionnaires, ecological momentary assessments, system usage data, sensor data, social media data, and psychophysiological measures Each measurement method is appraised and examples are provided to illustrate possible use in eHealth and mHealth behavior change research Recommendations for future research are provided, based on the limitations of current methods and the heavy reliance on system usage data as the sole assessment of engagement The validation and adoption of a wider range of engagement measurements and their thoughtful application to the study of engagement are encouraged

Pneumonia and Renal Replacement Therapy Are Risk Factors for Ceftazidime-Avibactam Treatment Failures and Resistance among Patients with Carbapenem-Resistant Enterobacteriaceae Infections.

Abstract: Ceftazidime-avibactam was used to treat 77 patients with carbapenem-resistant Enterobacteriaceae (CRE) infections at our center. Thirty- and 90-day survival rates were 81% and 69%, respectively; these rates were higher than those predicted by SAPS II and SOFA scores at the onset of infection. Clinical success was achieved for 55% of patients but differed by the site of infection. Success rates were lowest for pneumonia (36%) and higher for bacteremia (75%) and urinary tract infections (88%). By multivariate analysis, pneumonia (P = 0.045) and receipt of renal replacement therapy (RRT) (P = 0.046) were associated with clinical failure. Microbiologic failures occurred in 32% of patients and occurred more commonly among patients infected with KPC-3-producing CRE than among those infected with KPC-2-producing CRE (P = 0.002). Pneumonia was an independent predictor of microbiologic failure (P = 0.007). Ceftazidime-avibactam resistance emerged in 10% of patients, including 14% of those infected with Klebsiella pneumoniae and 32% of those with microbiologic failure. RRT was an independent predictor of the development of resistance (P = 0.009). Resistance was identified exclusively among K. pneumoniae bacteria harboring variant KPC-3 enzymes. Upon phylogenetic analysis of whole-genome sequences, resistant isolates from 87.5% (7/8) of patients clustered within a previously defined sequence type 258 (ST258) clade II sublineage; resistant isolates from one patient clustered independently from other ST258 clade II isolates. In conclusion, our report offers new insights into the utility and limitations of ceftazidime-avibactam across CRE infection types. Immediate priorities are to identify ceftazidime-avibactam dosing and therapeutic regimens that improve on the poor outcomes among patients with pneumonia and those receiving RRT.

Validation of automated screening for referable diabetic retinopathy with the IDx-DR device in the Hoorn Diabetes Care System

Abstract: Purpose To increase the efficiency of retinal image grading, algorithms for automated grading have been developed, such as the IDx-DR 2.0 device. We aimed to determine the ability of this device, incorporated in clinical work flow, to detect retinopathy in persons with type 2 diabetes. Methods Retinal images of persons treated by the Hoorn Diabetes Care System (DCS) were graded by the IDx-DR device and independently by three retinal specialists using the International Clinical Diabetic Retinopathy severity scale (ICDR) and EURODIAB criteria. Agreement between specialists was calculated. Results of the IDx-DR device and experts were compared using sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV), distinguishing between referable diabetic retinopathy (RDR) and vision-threatening retinopathy (VTDR). Area under the receiver operating characteristic curve (AUC) was calculated. Results Of the included 1415 persons, 898 (63.5%) had images of sufficient quality according to the experts and the IDx-DR device. Referable diabetic retinopathy (RDR) was diagnosed in 22 persons (2.4%) using EURODIAB and 73 persons (8.1%) using ICDR classification. Specific intergrader agreement ranged from 40% to 61%. Sensitivity, specificity, PPV and NPV of IDx-DR to detect RDR were 91% (95% CI: 0.69-0.98), 84% (95% CI: 0.81-0.86), 12% (95% CI: 0.08-0.18) and 100% (95% CI: 0.99-1.00; EURODIAB) and 68% (95% CI: 0.56-0.79), 86% (95% CI: 0.84-0.88), 30% (95% CI: 0.24-0.38) and 97% (95% CI: 0.95-0.98; ICDR). The AUC was 0.94 (95% CI: 0.88-1.00; EURODIAB) and 0.87 (95% CI: 0.83-0.92; ICDR). For detection of VTDR, sensitivity was lower and specificity was higher compared to RDR. AUC's were comparable. Conclusion Automated grading using the IDx-DR device for RDR detection is a valid method and can be used in primary care, decreasing the demand on ophthalmologists.

Factors associated with health service utilisation for common mental disorders: a systematic review.

Abstract: There is a large treatment gap for common mental disorders (CMD), with wide variation by world region. This review identifies factors associated with formal health service utilisation for CMD in the general adult population, and compares evidence from high-income countries (HIC) with that from low-and-middle-income countries (LMIC). We searched MEDLINE, PsycINFO, EMBASE and Scopus in May 2016. Eligibility criteria were: published in English, in peer-reviewed journals; using population-based samples; employing standardised CMD measures; measuring use of formal health services for mental health reasons by people with CMD; testing the association between this outcome and any other factor(s). Risk of bias was assessed using the adapted Mixed Methods Appraisal Tool. We synthesised the results using “best fit framework synthesis”, with reference to the Andersen socio-behavioural model. Fifty two studies met inclusion criteria. 46 (88%) were from HIC. Predisposing factors: There was evidence linking increased likelihood of service use with female gender; Caucasian ethnicity; higher education levels; and being unmarried; although this was not consistent across all studies. Need factors: There was consistent evidence of an association between service utilisation and self-evaluated health status; duration of symptoms; disability; comorbidity; and panic symptoms. Associations with symptom severity were frequently but less consistently reported. Enabling factors: The evidence did not support an association with income or rural residence. Inconsistent evidence was found for associations between unemployment or having health insurance and use of services. There was a lack of research from LMIC and on contextual level factors. In HIC, failure to seek treatment for CMD is associated with less disabling symptoms and lack of perceived need for healthcare, consistent with suggestions that “treatment gap” statistics over-estimate unmet need for care as perceived by the target population. Economic factors and urban/rural residence appear to have little effect on treatment-seeking rates. Strategies to address potential healthcare inequities for men, ethnic minorities, the young and the elderly in HIC require further evaluation. The generalisability of these findings beyond HIC is limited. Future research should examine factors associated with health service utilisation for CMD in LMIC, and the effect of health systems and neighbourhood factors. PROSPERO registration number: 42016046551 .