Variation in the utilization of medical devices across Germany, Italy, and the Netherlands: a multilevel approach

: Variation in healthcare utilization has been discussed extensively, with many studies showing that variation exists, but fewer studies investigating the underlying factors. In our study, we used a logistic multilevel-model at the patient, hospital, and regional levels to investigate (i) the levels to which variation could be attributed and (ii) the hospital and regional factors associated with treatment decisions. To do so, we used hospital discharge records for the years 2012-2016 in Germany and Italy and for 2014-2016 in the Netherlands combined with hospital and regional characteristics in nine case studies. We used a theoretical framework to categorize these case studies into effective, preference-sensitive, and supply-sensitive care. Our results suggest that most variation in the treatment decision can be attributed to the hospital level (e.g., case volume), whereas only a minor part is explained by regional characteristics. Italy had the highest share attributable to the regional level, whereas the Netherlands had the lowest. We observed less variation for procedures in the effective-care category compared to the preference- and supply-sensitive categories. Although our results were heterogeneous, we identified patterns in line with the theoretical framework for treatment categories, underlining the need to address variation differently depending on the category in question

Sofosbuvir and Ribavirin Therapy for Children Aged 3 to <12 Years With Hepatitis C Virus Genotype 2 or 3 Infection.

Currently, the only approved hepatitis C virus (HCV) treatment for children aged <12 years is pegylated interferon plus ribavirin. In an open-label study, we evaluated the safety and efficacy of sofosbuvir plus ribavirin for 12 weeks in children aged 3 to <12 years chronically infected with genotype 2 or for 24 weeks in patients with genotype 3. Patients aged 3 to <6 years weighing <17 kg received sofosbuvir 150 mg, and patients aged 3 to <6 years weighing ≥17 kg and all patients aged 6 to <12 years received sofosbuvir 200 mg once daily. Intensive pharmacokinetic sampling conducted in each age group confirmed the appropriateness of sofosbuvir doses. For all patients, ribavirin dosing was determined by baseline weight (up to 1,400 mg/day, two divided doses). The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Fifty-four patients were enrolled (41 aged 6 to <12 years and 13 aged 3 to <6 years). Most were treatment naïve (98%) and infected perinatally (94%). All but one patient achieved SVR12 (53/54, 98%; 95% confidence interval, 90%-100%). The patient who did not achieve SVR12 was a 4-year-old who discontinued treatment after 3 days because of "abnormal drug taste." The most commonly reported adverse events in patients aged 6 to <12 years were vomiting (32%) and headache (29%), and those in patients aged 3 to <6 years were vomiting (46%) and diarrhea (39%). One 3-year-old patient had a serious adverse event of accidental ribavirin overdose requiring hospitalization for monitoring; this patient completed treatment and achieved SVR12. Conclusion: Sofosbuvir plus ribavirin was well tolerated and highly effective in children aged 3 to <12 years with chronic HCV genotype 2 or 3 infection

Comparison of Cardiovascular Risk Factors in European Population Cohorts for Predicting Atrial Fibrillation and Heart Failure, Their Subsequent Onset, and Death

Background: Differences in risk factors for atrial fibrillation (AF) and heart failure (HF) are incompletely understood. Aim of this study was to understand whether risk factors and biomarkers show different associations with incident AF and HF and to investigate predictors of subsequent onset and mortality. Methods and Results: In N=58 693 individuals free of AF/HF from 5 population-based European cohorts, Cox regressions were used to find predictors for AF, HF, subsequent onset, and mortality. Differences between associations were estimated using bootstrapping. Median follow-up time was 13.8 years, with a mortality of 15.7%. AF and HF occurred in 5.0% and 5.4% of the participants, respectively, with 1.8% showing subsequent onset. Age, male sex, myocardial infarction, body mass index, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) showed similar associations with both diseases. Antihypertensive medication and smoking were stronger predictors of HF than AF. Cholesterol, diabetes mellitus, and hsCRP (high-sensitivity C-reactive protein) were associated with HF, but not with AF. No variable was exclusively associated with AF. Population-attributable risks were higher for HF (75.6%) than for AF (30.9%). Age, male sex, body mass index, diabetes mellitus, and NT-proBNP were associated with subsequent onset, which was associated with the highest all-cause mortality risk. Conclusions: Common risk factors and biomarkers showed different associations with AF and HF, and explained a higher proportion of HF than AF risk. As the subsequent onset of both diseases was strongly associated with mortality, prevention needs to be rigorously addressed and remains challenging, as conventional risk factors explained o:nly 31% of AF risk

Risk Factors, Subsequent Disease Onset, and Prognostic Impact of Myocardial Infarction and Atrial Fibrillation

BACKGROUND: Although myocardial infarction (MI) and atrial fibrillation (AF) are frequent comorbidities and share common cardiovascular risk factors, the direction and strength of the association of the risk factors with disease onset, subsequent disease incidence, and mortality are not completely understood. METHODS AND RESULTS: In pooled multivariable Cox regression analyses, we examined temporal relations of disease onset and identified predictors of MI, AF, and all-cause mortality in 108 363 individuals (median age, 46.0 years; 48.2% men) free of MI and AF at baseline from 6 European population-based cohorts. During a maximum follow-up of 10.0 years, 3558 (3.3%) individuals were diagnosed exclusively with MI, 1922 (1.8%) with AF but no MI, and 491 (0.5%) individuals developed both MI and AF. Association of sex, systolic blood pressure, antihypertensive treatment, and diabetes appeared to be stronger with incident MI than with AF, whereas increasing age and body mass index showed a higher risk for incident AF. Total cholesterol and daily smoking were significantly related to incident MI but not AF. Combined population attributable fraction of cardiovascular risk factors was >70% for incident MI, whereas it was only 27% for AF. Subsequent MI after AF (hazard ratio [HR], 1.68; 95% CI, 1.03–2.74) and subsequent AF after MI (HR, 1.75; 95% CI, 1.31–2.34) both significantly increased overall mortality risk. CONCLUSIONS: We observed different associations of cardiovascular risk factors with both diseases indicating distinct pathophysiological pathways. Subsequent diagnoses of MI and AF significantly increased mortality risk

Fat Mass and Obesity-Associated Gene (FTO) in Eating Disorders: Evidence for Association of the rs9939609 Obesity Risk Allele with Bulimia nervosa and Anorexia nervosa

Objective: The common single nucleotide polymorphism (SNP) rs9939609 in the fat mass and obesity-associated gene (FTO) is associated with obesity. As genetic variants associated with weight regulation might also be implicated in the etiology of eating disorders, we evaluated whether SNP rs9939609 is associated with bulimia nervosa (BN) and anorexia nervosa (AN). Methods: Association of rs9939609 with BN and AN was assessed in 689 patients with AN, 477 patients with BN, 984 healthy non-population-based controls, and 3,951 population-based controls (KORA-S4). Based on the familial and premorbid occurrence of obesity in patients with BN, we hypothesized an association of the obesity risk A-allele with BN. Results: In accordance with our hypothesis, we observed evidence for association of the rs9939609 A-allele with BN when compared to the non-population-based controls (unadjusted odds ratio (OR) = 1.142, one-sided 95% confidence interval (CI) 1.001-infinity; one-sided p = 0.049) and a trend in the population-based controls (OR = 1.124, one-sided 95% CI 0.932-infinity; one-sided p = 0.056). Interestingly, compared to both control groups, we further detected a nominal association of the rs9939609 A-allele to AN (OR = 1.181, 95% CI 1.027-1.359, two-sided p = 0.020 or OR = 1.673, 95% CI 1.101-2.541, two-sided p = 0.015,). Conclusion: Our data suggest that the obesity-predisposing FTO allele might be relevant in both AN and BN. Copyright (C) 2012 S. Karger GmbH, Freibur

D-cycloserine augmentation of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders: a systematic review and meta-analysis of individual participant data

Importance: Whether and under which conditions D-cycloserine (DCS) augments the effects of exposure-based cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders is unclear. Objective: To clarify whether DCS is superior to placebo in augmenting the effects of cognitive behavior therapy for anxiety, obsessive-compulsive, and posttraumatic stress disorders and to evaluate whether antidepressants interact with DCS and the effect of potential moderating variables. Data Sources: PubMed, EMBASE, and PsycINFO were searched from inception to February 10, 2016. Reference lists of previous reviews and meta-analyses and reports of randomized clinical trials were also checked. Study Selection: Studies were eligible for inclusion if they were (1) double-blind randomized clinical trials of DCS as an augmentation strategy for exposure-based cognitive behavior therapy and (2) conducted in humans diagnosed as having specific phobia, social anxiety disorder, panic disorder with or without agoraphobia, obsessive-compulsive disorder, or posttraumatic stress disorder. Data Extraction and Synthesis: Raw data were obtained from the authors and quality controlled. Data were ranked to ensure a consistent metric across studies (score range, 0-100). We used a 3-level multilevel model nesting repeated measures of outcomes within participants, who were nested within studies. Results: Individual participant data were obtained for 21 of 22 eligible trials, representing 1047 of 1073 eligible participants. When controlling for antidepressant use, participants receiving DCS showed greater improvement from pretreatment to posttreatment (mean difference, -3.62; 95% CI, -0.81 to -6.43; P = .01; d = -0.25) but not from pretreatment to midtreatment (mean difference, -1.66; 95% CI, -4.92 to 1.60; P = .32; d = -0.14) or from pretreatment to follow-up (mean difference, -2.98, 95% CI, -5.99 to 0.03; P = .05; d = -0.19). Additional analyses showed that participants assigned to DCS were associated with lower symptom severity than those assigned to placebo at posttreatment and at follow-up. Antidepressants did not moderate the effects of DCS. None of the prespecified patient-level or study-level moderators was associated with outcomes. Conclusions and Relevance: D-cycloserine is associated with a small augmentation effect on exposure-based therapy. This effect is not moderated by the concurrent use of antidepressants. Further research is needed to identify patient and/or therapy characteristics associated with DCS response.2018-05-0

Intrafamilial variability in SLC6A1-related neurodevelopmental disorders

IntroductionPhenotypic spectrum of SLC6A1-related neurodevelopmental disorders (SLC6A1-NDD) includes intellectual disability (ID), autistic spectrum disorders (ASD), epilepsy, developmental delay, beginning from early infancy or after seizure onset, and other neurological features such as hypotonia and movement disorders. Data on familial phenotypic heterogeneity have been rarely reported, thus in our study we aimed to investigate intrafamilial phenotypic variability in families with SLC6A1 variants.MethodsWe collected clinical, laboratory and genetic data on 39 individuals, including 17 probands, belonging to 13 families harboring inherited variants of SLC6A1. Data were collected through an international network of Epilepsy and Genetic Centers.ResultsMain clinical findings in the whole cohort of 39 subjects were: (a) epilepsy, mainly presenting with generalized seizures, reported in 71% of probands and 36% of siblings or first/second-degree relatives. Within a family, the same epilepsy type (generalized or focal) was observed; (b) ID reported in 100% and in 13% of probands and siblings or first/second-degree relatives, respectively; (c) learning disabilities detected in 28% of the SLC6A1 carriers, all of them were relatives of a proband; (d) around 51% of the whole cohort presented with psychiatric symptoms or behavioral disorders, including 82% of the probands. Out of the 19 patients with psychiatric symptoms, ASD were diagnosed in 40% of them; (e) neurological findings (primarily tremor and speech difficulties) were observed 38.5% of the whole cohort, including 10 probands. Our families harbored 12 different SLC6A1 variants, one was a frameshift, two stop-gain, while the remaining were missense. No genotype–phenotype associations were identified.DiscussionOur study showed that first-or second-degree relatives presented with a less severe phenotype, featuring mainly mild intellectual and/or learning disabilities, at variance with the probands who suffered from moderate to severe ID, generalized, sometimes intractable, epileptic seizures, behavioral and psychiatric disorders. These findings may suggest that a proportion of individuals with mild SLC6A1-NDD might be missed, in particular those with an older age where genetic testing is not performed. Further studies on intrafamilial phenotypic variability are needed to confirm our results and possibly to expand the phenotypic spectrum of these disorders and benefit genetic counseling

Unveiling hidden physics at the LHC

The field of particle physics is at the crossroads. The discovery of a Higgs-like boson completed the Standard Model (SM), but the lacking observation of convincing resonances Beyond the SM (BSM) offers no guidance for the future of particle physics. On the other hand, the motivation for New Physics has not diminished and is, in fact, reinforced by several striking anomalous results in many experiments. Here we summarise the status of the most significant anomalies, including the most recent results for the flavour anomalies, the multi-lepton anomalies at the LHC, the Higgs-like excess at around 96 GeV, and anomalies in neutrino physics, astrophysics, cosmology, and cosmic rays. While the LHC promises up to 4 ab of integrated luminosity and far-reaching physics programmes to unveil BSM physics, we consider the possibility that the latter could be tested with present data, but that systemic shortcomings of the experiments and their search strategies may preclude their discovery for several reasons, including: final states consisting in soft particles only, associated production processes, QCD-like final states, close-by SM resonances, and SUSY scenarios where no missing energy is produced. New search strategies could help to unveil the hidden BSM signatures, devised by making use of the CERN open data as a new testing ground. We discuss the CERN open data with its policies, challenges, and potential usefulness for the community. We showcase the example of the CMS collaboration, which is the only collaboration regularly releasing some of its data. We find it important to stress that individuals using public data for their own research does not imply competition with experimental efforts, but rather provides unique opportunities to give guidance for further BSM searches by the collaborations. Wide access to open data is paramount to fully exploit the LHCs potential.Acknowledgements We thank S. Kraml for useful comments. SK is supported by the Austrian Science Fund Elise-Richter grant project number V592-N27. ND acknowledges the support of Department of Science and Technology of the Government of India via the Ramanujan Fellowship SB/S2/RJN-070/2018. BB is supported by the ERC research grant NEO-NAT no. 669668. ZB is supported in part by the MIUR grant PRIN 2017X7X85K and in part by the SRNSF grant DI- 18-335. TH is supported in part by the U.S. Department of Energy under grant No. DE-FG02-95ER40896. KC is supported in part by Taiwan Ministry of Sciences and Technology with grant number MoST- 110-2112-M-007-017-MY3. JT is supported by the National Science Foundation under Cooperative Agreement PHY-2019786 (The NSF AI Institute for Artificial Intelligence and Fundamental Interactions, http://iaifi.org/), and by the U.S. DOE Office of High Energy Physics under grant number DE-SC0012567. A.C. and C.A.M. acknowledge financial support by the Swiss National Science Foundation, Project No. PP00P2_176884. M.H. is supported by the Swiss National Science Foundation, Project No. PCEFP2_181117. MB is supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under grant 396021762 – TRR 257. B.C. is supported by the Italian Ministry of Research (MIUR) under the Grant No. PRIN 20172LNEEZ. A.P. is supported by the SpanishGovernment and ERDF funds from the EU Commission [grant FPA2017-84445-P] and by the Generalitat Valenciana [grant Prometeo/2017/053]. BM and XR are grateful for support from the South African Department of Science and Innovation through the SA-CERN programme and the National Research Foundation for various forms of support. MK was supported by MIUR (Italy) under a contract PRIN 2015P5SBHT and by INFN Sezione di Roma La Sapienza and partially supported by the ERC- 2010 DaMESyFla Grant Agreement Number: 267985. Contribution by MB is based upon work supported by the National Science Foundation under Grant No. PHY-1913923. DM acknowledges support by MIUR grant PRIN 2017L5W2PT and the INFN grant SESAMO. The work of BD is supported in part by the U.S. Department of Energy under Grant No. DE-SC0017987. GB acknowledges the support of the National Research Foundation of South Africa via Thuthuka grant no. 117969

Unveiling hidden physics at the LHC

The field of particle physics is at the crossroads. The discovery of a Higgs-like boson completed the Standard Model (SM), but the lacking observation of convincing resonances Beyond the SM (BSM) offers no guidance for the future of particle physics. On the other hand, the motivation for New Physics has not diminished and is, in fact, reinforced by several striking anomalous results in many experiments. Here we summarise the status of the most significant anomalies, including the most recent results for the flavour anomalies, the multi-lepton anomalies at the LHC, the Higgs-like excess at around 96 GeV, and anomalies in neutrino physics, astrophysics, cosmology, and cosmic rays. While the LHC promises up to 4 ab−1 of integrated luminosity and far-reaching physics programmes to unveil BSM physics, we consider the possibility that the latter could be tested with present data, but that systemic shortcomings of the experiments and their search strategies may preclude their discovery for several reasons, including: final states consisting in soft particles only, associated production processes, QCD-like final states, close-by SM resonances, and SUSY scenarios where no missing energy is produced. New search strategies could help to unveil the hidden BSM signatures, devised by making use of the CERN open data as a new testing ground. We discuss the CERN open data with its policies, challenges, and potential usefulness for the community. We showcase the example of the CMS collaboration, which is the only collaboration regularly releasing some of its data. We find it important to stress that individuals using public data for their own research does not imply competition with experimental efforts, but rather provides unique opportunities to give guidance for further BSM searches by the collaborations. Wide access to open data is paramount to fully exploit the LHCs potential

Unveiling hidden physics at the LHC

The field of particle physics is at the crossroads. The discovery of a Higgs-like boson completed the Standard Model (SM), but the lacking observation of convincing resonances Beyond the SM (BSM) offers no guidance for the future of particle physics. On the other hand, the motivation for New Physics has not diminished and is, in fact, reinforced by several striking anomalous results in many experiments. Here we summarise the status of the most significant anomalies, including the most recent results for the flavour anomalies, the multi-lepton anomalies at the LHC, the Higgs-like excess at around 96 GeV, and anomalies in neutrino physics, astrophysics, cosmology, and cosmic rays. While the LHC promises up to 4 ab(-1) of integrated luminosity and far-reaching physics programmes to unveil BSM physics, we consider the possibility that the latter could be tested with present data, but that systemic shortcomings of the experiments and their search strategies may preclude their discovery for several reasons, including: final states consisting in soft particles only, associated production processes, QCD-like final states, close-by SM resonances, and SUSY scenarios where no missing energy is produced. New search strategies could help to unveil the hidden BSM signatures, devised by making use of the CERN open data as a new testing ground. We discuss the CERN open data with its policies, challenges, and potential usefulness for the community. We showcase the example of the CMS collaboration, which is the only collaboration regularly releasing some of its data. We find it important to stress that individuals using public data for their own research does not imply competition with experimental efforts, but rather provides unique opportunities to give guidance for further BSM searches by the collaborations. Wide access to open data is paramount to fully exploit the LHCs potential.Peer reviewe