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Abstract Background Socioeconomically disadvantaged children are disproportionately affected by oral disease. Mobile dental services help underserved communities overcome barriers to accessing health care, including time, geography, and trust. The NSW Health Primary School Mobile Dental Program (PSMDP) is designed to provide diagnostic and preventive dental services to children at their schools. The PSMDP is mainly targeted toward high-risk children and priority populations. This study aims to evaluate the program’s performance across five local health districts (LHDs) where the program is being implemented. Methods The evaluation will use routinely collected administrative data, along with other program-specific data sources, from the district public oral health services to conduct a statistical analysis that determines the reach and uptake of the program, its effectiveness, and the associated costs and cost-consequences. The PSMDP evaluation program utilises data from Electronic Dental Records (EDRs) and other data sources, including patient demographics, service mix, general health, oral health clinical data and risk factor information. The overall design includes cross-sectional and longitudinal components. The design combines comprehensive output monitoring across the five participating LHDs and investigates the associations between socio-demographic factors, service patterns and health outcomes. Time series analysis using difference-in-difference estimation will be conducted across the four years of the program, involving services, risk factors, and health outcomes. Comparison groups will be identified via propensity matching across the five participating LHDs. An economic analysis will estimate the costs and cost-consequences for children who participate in the program versus the comparison group. Discussion The use of EDRs for oral health services evaluation research is a relatively new approach, and the evaluation works within the limitations and strengths of utilising administrative datasets. The study will also provide avenues to improve the quality of data collected and system-level improvements to better enable future services to be aligned with disease prevalence and population needs.

Nina L Wittwer,1,2 Christoph R Meier,1– 3 Carola A Huber,4 Henriette E Meyer zu Schwabedissen,1 Samuel Allemann,1,* Cornelia Schneider1,2,* 1Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; 2Hospital Pharmacy, University Hospital Basel, Basel, Switzerland; 3Boston Collaborative Drug Surveillance Program, Lexington, MA, USA; 4Department of Health Sciences, Helsana Insurance Group, Zürich, Switzerland*These authors contributed equally to this workCorrespondence: Samuel Allemann, Pharmaceutical Care Research Group University of Basel, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, Basel, 4056, Switzerland, Tel +41 61 207 61 76, Email s.allemann@unibas.chPurpose: In Switzerland 167 drugs on the market contain information about pharmacogenetics in their drug label (PGx drug). Preemptive pharmacogenetic testing is reimbursed by health care insurance for only seven drugs (abacavir, carbamazepine, 6-mercaptopurine, azathioprine, 5-fluorouracil, capecitabine, and irinotecan) although, it is proposed to be a cost-effective approach to personalized medicine. The aim of this study was to describe the use of PGx drugs and their corresponding genes in Switzerland.Methods: We identified 90 drugs with dosing recommendations from the Pharmacogenetic Knowledgebase involving 24 genes. We assessed the utilization of those drugs between 2016 and 2020, using claims data from a large Swiss insurance company (Helsana).Results: Of 841 491 persons with drug claims during the whole study period, 78.7% were exposed to PGx drugs. Ibuprofen, pantoprazole, and tramadol had the highest number of users. Seven genes (CYP2C19, CYP2C9, CYP2D6, SLCO1B1, HLA-B, MT-RNR1, and VKORC1) were responsible for over 95% of all potential drug-gene interactions.Conclusion: The prevalence of PGx drug prescriptions is high in the Swiss population. Therefore, intensified preemptive testing may be a useful option as a substantial amount of the Swiss population might benefit.Keywords: PGx, drug use, claims data, pharmacoepidemiology

For Clostridioides difficile infections (CDIs) in Germany no longitudinal multi-centre studies with standardized protocols for diagnosing CDI are available. Recent evaluations of general surveillance databases in Germany indicate a downward trend in CDI rates. We aimed to describe the actual burden and trends of CDI in German university hospitals from 2016 to 2020. Our study was a prospective multi-centre study covering six German university hospitals. We report the data in total, stratified by year, by medical specialty as well as by CDI severity. Multi-variable regression analyses were performed to assess risk factors for severe CDI. We registered 3780 CDI cases among 1,436,352 patients. The median length of stay (LOS) of CDI cases was 20 days (interquartile range 11–37) compared with a general LOS of 4.2 days. In-hospital all-cause mortality in CDI patients was 11.7% (N = 444/3780), while mortality attributed to CDI was 0.4% (N = 16/3761). CDI recurrence rate was comparatively low at 7.2%. The incidence density of severe healthcare-associated healthcare onset (HAHO)-CDI showed a significant decrease from 2.25/10,000 patient days (pd) in 2016 to 1.49/10,000 pd in 2020 (trend calculation P =0.032). Compared with a European point-prevalence study in 2013/2014, where overall CDI incidence density was 11.2 cases/10,000 pd in Germany (EUCLID), we see in our study halved overall CDI rates of 5.6 cases/10,000 pd in 2020. Our study shows current data on the distribution of CDI cases in German university hospitals and thus provides international comparative data on the key indicators of CDI. [ABSTRACT FROM AUTHOR]

Introduction: An infection with SARS-CoV-2 is relevant especially in high-performance sport due to possible organ damage and reduced performance which occurs in individual cases. Various recommendations are found in the literature concerning when safe return to sports is possible and what examinations are suitable to support this decision. The dominance of other virus variants than those at the start of the pandemic makes revision of earlier recommendations necessary. Methods and Analysis: The recommended actions are based on the currently-available scientific knowledge of the pathogenicity of the virus and on clinical experiences in general and elite athletes. Twenty-one recommended actions were proposed by the Scientific Council of the DGSP, discussed and agreed on in consensus with experts from German-language sports-medical facilities and evaluated by an independent co-author. The resultant position paper was subsequently released by mutual agreement. Results: The recommendations are oriented to the severity of the course and the symptoms. The required medical diagnostic is deduced therefrom. During persistent symptoms, sports should be paused and training only begun again at low intensity after a three-day symptom-free period. If COVID-19-associated complaints recur, physical exertion should be stopped and a doctor consulted. After moderate and serious course, medical diagnostics are required prior to the start of training. Summary: To prevent a health risk due to sports and thereby resultant organ damage after a SARS-CoV-2 infection, a procedure adapted to the symptoms and course before return to training and finally to competitive sports is recommended.

Nora Freyer,1 Fanny Knöspel,1 Georg Damm,2 Selina Greuel,1 Christin Schneider,1 Daniel Seehofer,2 Thomas Stöhr,3 Karl-Uwe Petersen,3 Katrin Zeilinger1 1Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité – Universitätsmedizin Berlin, Berlin 13353, Germany; 2Department of Hepatobiliary Surgery and Visceral Transplantation, University of Leipzig, Leipzig 04103, Germany; 3PAION Deutschland GmbH (Non-clinical development), Aachen 52062, Germany Background: Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. It is hydrolyzed by CES1 to an inactive metabolite (CNS7054). Purpose: In this study, the effect of continuous remimazolam exposure on its metabolism and on CES1 expression was investigated in a dynamic 3-D bioreactor culture model inoculated with primary human hepatocytes. Methods: Remimazolam was continuously infused into bioreactors for 5 days at a final concentration of 3,000 ng/ml (6.8 µM). In parallel, 2-D cultures were run with cells from the same donors, but with discontinuous exposure to remimazolam. Results: Daily measurement of clinical chemistry parameters (glucose, lactate, urea, ammonia, and liver enzymes) in culture supernatants indicated no noxious effect of remimazolam on hepatocyte integrity as compared to untreated controls. Concentrations of remimazolam reached steady-state values of around 250 ng/ml within 8 hours in 3-D bioreactors whereas in 2-D cultures remimazolam concentrations declined to almost zero within the same time frame. Levels of CNS7054 showed an inverse time-course reaching average values of 1,350 ng/ml in perfused 3-D bioreactors resp. 2,800 ng/ml in static 2-D cultures. Analysis of mRNA expression levels of CES1 indicated no changes in gene expression over the culture period. Conclusion: The results indicated a stable metabolism of remimazolam during 5 days of continuous exposure to clinically relevant concentrations of the drug. Moreover, there was no evidence for a harmful effect of remimazolam exposure on the integrity and metabolic activity of in vitro cultivated primary human hepatocytes. Keywords: benzodiazepine, metabolite, CNS7054, carboxylesterase 1, steady state

Jean-Baptiste Beuscart,1 Olivia Dalleur,1 Benoit Boland,2 Stefanie Thevelin,1 Wilma Knol,3 Shane Cullinan,4 Claudio Schneider,5 Denis O’Mahony,6 Nicolas Rodondi,4,7 Anne Spinewine1,8 1Université catholique de Louvain, Louvain Drug Research Institute, Clinical Pharmacy Research Group, Brussels, Belgium; 2Geriatric Medicine, Cliniques universitaires Saint-Luc, Brussels, Université catholique de Louvain, Belgium; 3Department of Geriatric Medicine and Expertise Centre Pharmacotherapy in Old Persons (EPHOR), University Medical Centre Utrecht, Netherlands; 4School of Pharmacy, Royal College of Surgeons in Ireland, Dublin, Ireland; 5Department of General Internal Medicine, Bern University Hospital, Bern, Switzerland; 6Department of Medicine (Geriatrics), University College Cork, Cork, Ireland; 7Institute of Primary Health Care (BIHAM), University of Bern, Bern, Switzerland; 8Université catholique de Louvain, CHU UCL Namur, Pharmacy Department, Yvoir, Belgium Background: Medication review has been advocated to address the challenge of polypharmacy in older patients, yet there is no consensus on how best to evaluate its efficacy. Heterogeneity of outcomes reported in clinical trials can hinder the comparison of clinical trial findings in systematic reviews. Moreover, the outcomes that matter most to older patients might be under-reported or disregarded altogether. A core outcome set can address this issue as it defines a minimum set of outcomes that should be reported in all clinical trials in any particular field of research. As part of the European Commission-funded project, called OPtimising thERapy to prevent Avoidable hospital admissions in the Multimorbid elderly, this paper describes the methods used to develop a core outcome set for clinical trials of medication review in older patients with multimorbidity. Methods/design: The study was designed in several steps. First, a systematic review established which outcomes were measured in published and ongoing clinical trials of medication review in older patients. Second, we undertook semistructured interviews with older patients and carers aimed at identifying additional relevant outcomes. Then, a multilanguage European Delphi survey adapted to older patients was designed. The international Delphi survey was conducted with older patients, health care professionals, researchers, and clinical experts in geriatric pharmacotherapy to validate outcomes to be included in the core outcome set. Consensus meetings were conducted to validate the results. Discussion: We present the method for developing a core outcome set for medication review in older patients with multimorbidity. This study protocol could be used as a basis to develop core outcome sets in other fields of geriatric research. Keywords: core outcome set, study protocol, polypharmacy, multimorbidity

Cornelia Schneider,1,2 Blai Coll,3 Susan S Jick,4 Christoph R Meier1,2,4 1Basel Pharmacoepidemiology Unit, Division of Clinical Pharmacy and Epidemiology, Department of Pharmaceutical Sciences, University of Basel, Basel, Switzerland; 2Hospital Pharmacy, University Hospital Basel, Basel, Switzerland; 3Renal Development, AbbVie, North Chicago, IL, USA; 4Boston Collaborative Drug Surveillance Program, Boston University School of Public Health, MA, USA Background: Doubling of serum creatinine is often used as a marker for worsening kidney function in nephrology trials. Most people with chronic kidney disease die of other causes before reaching end-stage renal disease. We were interested in the association between doubling of serum creatinine and the risk of a first-time diagnosis of angina pectoris, congestive heart failure (CHF), myocardial infarction (MI), stroke, or transient ischemic attack in patients with chronic kidney disease and with diagnosed type 2 diabetes mellitus. Methods: We identified all adult patients registered in the “Clinical Practice Research Datalink” between 2002 and 2011 with incident chronic kidney disease and type 2 diabetes mellitus and did a cohort study with a Cox proportional hazard analysis. Results: We identified in total 27,811 patients, 693 developed angina pectoris, 1,069 CHF, 508 MI, 970 stroke, and 578 transient ischemic attacks. Patients whose serum creatinine doubled during follow-up had increased risks of CHF (hazard ratio [HR] 2.98, 95% confidence interval [CI] 2.27–3.89), MI (HR 2.53, 95% CI 1.62–3.96), and stroke (HR 1.93, 95% CI 1.38–2.69), as compared with patients whose serum creatinine did not double. The relative risks of angina pectoris (HR 1.18, 95% CI 0.66–2.10) or a transient ischemic attack (HR 1.32, 95% CI 0.78–2.22) were similar in both groups. Conclusion: Diabetic patients with a doubling of serum creatinine were at an increased risk of CHF, MI, or stroke, compared with diabetic patients whose serum creatinine did not double during follow-up. Keywords: glomerular filtration rate, angina pectoris, transient ischemic attack, gender, ­myocardial infarction, congestive heart failure, stroke

Idiopathic as well as nonspecific low back pain is relevant in health care systems as well asinleisure and high-performance sports. Neuromuscular and/or structural deficits, mostly accompanied by biopsychological factors,are known risk factors for both the onset and chronification of symptoms. Meta-analytic evidence describes positive effects of physical activity. However, type, dose-response relation, minimum of training required and setting-specific implementation has not been fullyclarified. Since 2011, the national research network Medicine in Spine Exercise [MiSpEx] has beenfollowing a project layout called Ran Rcken focussing on the development and validation of intervention programs including neuromuscular and pain adaptation moderated by individual training status, pain behaviour, allostatic load and social settings. Overall about 8000 patients and athletes have been and are being followed experimentally and clinically in 34 studies. It could be shownthat a training program focussing on compensation of external loads elicited by perturbations is effective in prevention and rehabilitation in both athletes and general population. Besides validation of further consecutively developed programs emphasis is put on the evaluation of transfer strategies to medical systems, sports as well as general population. Finally, the evaluation of an efficient dose-response relation is addressed.KEY WORDS: Low Back Pain, MiSpEx, Sports, Perturbations, Therapy, Prevention, Training

Problem: Physical activity has an enormous relevance for the treatment of back pain (BP) in the clinical field. This paper givesa brief overview of the evidence of physical activity for the treatment of chronic back pain and summarizes the current approach of the German national project Medicine in Spine Exercise (MiSpEx: sensorimotor training (SMT) with perturbation).Methods: 35 literature reviews were screened for inclusion criteria concerning physical activity for the treatment of cBP. Of these, 16 systematic reviews and 2 guidelines were included following the criteria: systematic review in English, evaluating pain and disability in the context of physical activity for the treatment of back pain, published 2000-2017 and considering less than a third of RCTs without a subclassification of patients. We did not conduct a quantitative meta-analysis but a qualitative synthesis. Results: Exercise Therapy reduces pain and disability in cBP patients but there is still no evidence thatanyone specific approach isthe mostfavorable. Motor control exercises (MCE) seem to improve outcomes best, but SMT was mostly unconsidered.Conclusion: SMT further improves motor control by training the adjustment to unexpected stimuli incomplex tasks considering both: afferent and efferent workloads. Furthermore, additional perturbation may improve sensorimotor adaptations through higher demands on core stability and increase the precise stabilizing feedback in cBP patients.KEY WORDS: Exercise Therapy, Chronic Back Pain, Sensorimotor Training, Proprioception

Chantal E Holy,1 John M Ellison,1 Charles Schneider,1 Howard L Levine2,3 1Health Economics and Reimbursement, 2Medical Affairs, Acclarent Inc., a Johnson & Johnson Company, Menlo Park, CA, USA; 3Cleveland Nasal-Sinus and Sleep Center, Cleveland, OH, USA Purpose: Endoscopic sinus surgery for patients with chronic rhinosinusitis (CRS) unresponsive to medical therapy has traditionally been performed under general anesthesia and in the operating room. Balloons for catheter dilation of paranasal sinuses were introduced in 2005, allowing sinus surgery to be safely performed either in the operating room or the office care setting, under local anesthesia. This change in care setting has raised concerns of overuse or expanded indications for sinus surgery. This study was thus designed to evaluate changes in surgical volumes in the United States, for the period 2006–2011, and to evaluate the impact of the sinus balloons on surgical practice. Methods: The MarketScan® Commercial Claims and Encounter Database was queried for the period 2006 to 2011 using CRS International Classification of Diseases, Ninth Revision codes (473.X) and sinus surgery US-based Common Procedural Terminology (CPT) codes (endoscopic sinus surgery: CPT codes 31254–31294 and 31299; balloon catheter dilation: CPT codes 31295–31297). MarketScan's projection methodology was applied to estimate the nationwide prevalence of CRS and the incidence of sinus surgery. Procedural case mix and total average payment per surgery were analyzed. Results: From 2006 to 2011, the yearly prevalence of CRS and sinus surgery volume remained flat with ~430 patients with CRS per 100,000 in the employer-sponsored insured population, of which ~117/100,000 underwent surgery. In 2006, 2.69 paranasal sinuses (95% confidence interval [95% CI]: 2.65–2.71) were treated during each individual sinus surgery, with an additional 1.11 nasal procedures (95% CI: 1.08–1.13) performed concurrently. By 2011, the procedural case mix had expanded to 2.90 sinus (95% CI: 2.87–2.93) and 1.16 nasal procedures (95% CI: 1.14–1.85) per surgery. Payments increased from $7,011.06 (α=$6,378.30; β=3.1490) in 2006 to $9,090.11 (α=$8,350.20; β=2.9535) in 2011, in line with US medical inflation. Conclusion: In the study population, approximately 1 in 3.7 patients diagnosed with CRS underwent sinus surgery. This ratio remained constant from 2006 to 2011. There was no evidence that the number of distinct sinus surgeries per 100,000 people increased despite the introduction and utilization of balloon catheter dilation tools that enabled migration of sinus surgery to the office. Keywords: needs and demand, surgical incidence, sinus surgery, lower-cost setting, balloon sinuplasty, ESS, office-based surgery