Protocol: Prospective evaluation of feasibility, added value and satisfaction of remote digital self-assessment for mild cognitive impairment in routine care with the neotivCare app.

INTRODUCTION: Timely diagnosis of mild cognitive impairment (MCI) in Alzheimer's disease is crucial for early interventions, but its implementation is often challenging due to the complexity and time burden of required cognitive assessments. To address these challenges, the usability of new unsupervised digital remote assessment tools needs to be validated in a care context. METHODS AND ANALYSIS: This multicentric healthcare research evaluation survey, re.cogni.ze, aims to evaluate physician satisfaction with a remote digital assessment solution (neotivCare) in primary and specialised routine care in Germany. Over a period of 22 months, physicians in different regions of Germany will recommend the application (app) to approximately 1000 patients for a 12-week self-assessment of cognition. The primary endpoint is the evaluation of physicians' and patients' overall satisfaction with neotivCare and with neuropsychological questionnaires/standard procedures using a Likert scale, while secondary endpoints include user-friendliness, qualitative assessment of acceptance and potential improvements on medical routine services. The study also aims to evaluate the proportion of physicians or patients attributing added value to neotivCare compared with standard paper-pencil tests. The study results will provide insights into the feasibility, efficiency and acceptance of new digital tools for MCI diagnosis in routine care. The re.cogni.ze survey will thus provide proof-of-concept information for the implementation of remote digital cognitive assessment apps for MCI into medical routine care. ETHICS AND DISSEMINATION: This study was approved by the ethics committee of the State Medical Association (Landesärztekammer) Baden-Württemberg, (F-2021-161) as the leading committee and nine ethics committees local to the participating healthcare professionals (Lower Saxony, North Rhine, Westphalia-Lippe, Hesse, Bremen, Berlin, University of Göttingen, Charite, University of Rostock). The results can be shared (upon reasonable quest) to improve routine clinical processes and holistic approaches.

Association between intake of non-sugar sweeteners and health outcomes: systematic review and meta-analyses of randomised and non-randomised controlled trials and observational studies.

OBJECTIVE: To assess the association between intake of non-sugar sweeteners (NSS) and important health outcomes in generally healthy or overweight/obese adults and children. DESIGN: Systematic review following standard Cochrane review methodology. DATA SOURCES: Medline (Ovid), Embase, Cochrane CENTRAL, WHO International Clinical Trials Registry Platform, Clinicaltrials.gov, and reference lists of relevant publications. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies including generally healthy adults or children with or without overweight or obesity were eligible. Included study designs allowed for a direct comparison of no intake or lower intake of NSS with higher NSS intake. NSSs had to be clearly named, the dose had to be within the acceptable daily intake, and the intervention duration had to be at least seven days. MAIN OUTCOME MEASURES: Body weight or body mass index, glycaemic control, oral health, eating behaviour, preference for sweet taste, cancer, cardiovascular disease, kidney disease, mood, behaviour, neurocognition, and adverse effects. RESULTS: The search resulted in 13 941 unique records. Of 56 individual studies that provided data for this review, 35 were observational studies. In adults, evidence of very low and low certainty from a limited number of small studies indicated a small beneficial effect of NSSs on body mass index (mean difference -0.6, 95% confidence interval -1.19 to -0.01; two studies, n=174) and fasting blood glucose (-0.16 mmol/L, -0.26 to -0.06; two, n=52). Lower doses of NSSs were associated with lower weight gain (-0.09 kg, -0.13 to -0.05; one, n=17 934) compared with higher doses of NSSs (very low certainty of evidence). For all other outcomes, no differences were detected between the use and non-use of NSSs, or between different doses of NSSs. No evidence of any effect of NSSs was seen on overweight or obese adults or children actively trying to lose weight (very low to moderate certainty). In children, a smaller increase in body mass index z score was observed with NSS intake compared with sugar intake (-0.15, -0.17 to -0.12; two, n=528, moderate certainty of evidence), but no significant differences were observed in body weight (-0.60 kg, -1.33 to 0.14; two, n=467, low certainty of evidence), or between different doses of NSSs (very low to moderate certainty). CONCLUSIONS: Most health outcomes did not seem to have differences between the NSS exposed and unexposed groups. Of the few studies identified for each outcome, most had few participants, were of short duration, and their methodological and reporting quality was limited; therefore, confidence in the reported results is limited. Future studies should assess the effects of NSSs with an appropriate intervention duration. Detailed descriptions of interventions, comparators, and outcomes should be included in all reports. SYSTEMATIC REVIEW REGISTRATION: Prospero CRD42017047668.

Optimizing the Design and Analysis of Clinical Trials for Antibacterials Against Multidrug-resistant Organisms: A White Paper From COMBACTE's STAT-Net.

Innovations are urgently required for clinical development of antibacterials against multidrug-resistant organisms. Therefore, a European, public-private working group (STAT-Net; part of Combatting Bacterial Resistance in Europe [COMBACTE]), has reviewed and tested several innovative trials designs and analytical methods for randomized clinical trials, which has resulted in 8 recommendations. The first 3 focus on pharmacokinetic and pharmacodynamic modeling, emphasizing the pertinence of population-based pharmacokinetic models, regulatory procedures for the reassessment of old antibiotics, and rigorous quality improvement. Recommendations 4 and 5 address the need for more sensitive primary end points through the use of rank-based or time-dependent composite end points. Recommendation 6 relates to the applicability of hierarchical nested-trial designs, and the last 2 recommendations propose the incorporation of historical or concomitant trial data through Bayesian methods and/or platform trials. Although not all of these recommendations are directly applicable, they provide a solid, evidence-based approach to develop new, and established, antibacterials and address this public health challenge.

The Impact of Early Adequate Treatment on Extubation and Discharge Alive of Patients With Pseudomonas aeruginosa-Related Ventilator-Associated Pneumonia.

OBJECTIVES: We aim to examine the effect of early adequate treatment in comparison with inadequate or delayed treatment on being extubated or discharged alive over time, in patients with Pseudomonas aeruginosa-related ventilator-associated pneumonia. DESIGN: Retrospective analyses of a prospective observational multicenter cohort study. SETTING: ICU. PATIENTS: Patients of the French prospective database (OUTCOMEREA) were included if they acquired a ventilator-associated pneumonia due to P. aeruginosa between 1997 and 2014 and were mechanically ventilated for more than 48 hours. INTERVENTIONS: Early adequate treatment in comparison with inadequate or delayed adequate treatment. MEASUREMENTS AND MAIN RESULTS: Multistate models were applied to estimate the time-dependent probability of being extubated or discharged alive, and separate Cox regression analyses were used to assess the treatment effect on all important events that influence the outcome of interest. A propensity score-adjusted innovative regression technique was used for a combined and comprehensive patient-relevant summary effect measure. No evidence was found for a difference between adequate and inadequate or delayed treatment on being extubated or discharged alive. However, for all patients, the probability of being extubated or discharged alive remains low and does not exceed 50% even 40 days after a P. aeruginosa-related ventilator-associated pneumonia. CONCLUSIONS: Early adequate treatment does not seem to be associated with an improved prognosis. Its potential benefit requires further investigation in larger observational studies.

Assessing Noninferiority in Treatment Trials for Severe Infectious Diseases: an Extension to the Entire Follow-Up Period Using a Cure-Death Multistate Model.

In current and former clinical trials for the development of antibacterial drugs, various primary endpoints have been used, and treatment effects are evaluated mostly in noninferiority analyses at the end of follow-up, which varies between studies. A more convincing and highly patient-relevant statement would be a noninferiority assessment over the entire follow-up period with cure and death as coprimary endpoints, while preserving the desired alpha level for statistical testing. To account for the time-dynamic pattern of cure and death, we apply a cure-death multistate model. The endpoint of interest is "get cured and stay alive over time." Noninferiority between treatments over the entire follow-up period is studied by means of one-sided confidence bands provided by a flexible resampling technique. We illustrate the technique by applying it to a recently published study and establish noninferiority in being cured and alive over a time frame of interest for the entire population, patients with hospital-acquired pneumonia, but not for the subset of patients with ventilator-associated pneumonia. Our analysis improves the original results in the sense that our endpoint is more patient benefiting, a stronger noninferiority statement is demonstrated, and the time dependency of cure and death, competing events, and different follow-up times is captured. Multistate methodology combined with confidence bands adds a valuable statistical tool for clinical trials in the context of infection control. The framework is not restricted to the cure-death model but can be adapted to more complex multistate endpoints and equivalence or superiority analyses.

The time-dependent "cure-death" model investigating two equally important endpoints simultaneously in trials treating high-risk patients with resistant pathogens.

A variety of primary endpoints are used in clinical trials treating patients with severe infectious diseases, and existing guidelines do not provide a consistent recommendation. We propose to study simultaneously two primary endpoints, cure and death, in a comprehensive multistate cure-death model as starting point for a treatment comparison. This technique enables us to study the temporal dynamic of the patient-relevant probability to be cured and alive. We describe and compare traditional and innovative methods suitable for a treatment comparison based on this model. Traditional analyses using risk differences focus on one prespecified timepoint only. A restricted logrank-based test of treatment effect is sensitive to ordered categories of responses and integrates information on duration of response. The pseudo-value regression provides a direct regression model for examination of treatment effect via difference in transition probabilities. Applied to a topical real data example and simulation scenarios, we demonstrate advantages and limitations and provide an insight into how these methods can handle different kinds of treatment imbalances. The cure-death model provides a suitable framework to gain a better understanding of how a new treatment influences the time-dynamic cure and death process. This might help the future planning of randomised clinical trials, sample size calculations, and data analyses.

Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE's STAT-Net.

PURPOSE: In this era of rising antimicrobial resistance, slowly refilling antibiotic development pipelines, and an aging population, we need to ensure that randomized clinical trials (RCTs) determine the added benefit of new antibiotic agents effectively and in a valid way, especially for severely ill patients. Unfortunately, universally accepted endpoints for the evaluation of new drugs in severe infections are lacking. METHODS: We review and discuss the current practices and challenges regarding endpoints in RCTs in this field and propose novel approaches. RESULTS: Usual endpoints actually recommended for drug development suffer from important flaws. Mortality requires large sample size and only partly related to the infectious process. Clinical cure rate is highly subjective in critically ill patients where symptoms may be related to other intercurrent events. Currently, composite endpoints, hierarchical nested designs, and competing risks analysis seem to be the most promising new tools for designing and analyzing clinical trials in this area, although they require further validation. CONCLUSION: Regulatory authorities, pharmaceutical companies, and clinicians need to agree on the most appropriate clinical endpoints for severe infections to ensure efficient approval of new, effective antibiotic agents.

Accuracy of FENO for diagnosing asthma: a systematic review.

BACKGROUND: Measurement of FENO might substitute bronchial provocation for diagnosing asthma. We aimed to investigate the diagnostic accuracy of FENO measurement compared with established reference standard. METHODS: Systematic review and diagnostic meta-analysis. Data sources were Medline, Embase and Scopus up to 29 November 2015. Sensitivity and specificity were estimated using a bivariate model. Additionally, summary receiver-operating characteristic curves were estimated. RESULTS: 26 studies with 4518 participants (median 113) were included. Risk of bias was considered low for six of seven items in five studies and for five items in seven studies. The overall sensitivity in the meta-analysis was 0.65 (95% CI 0.58 to 0.72), the overall specificity 0.82 (0.76 to 0.86), the diagnostic OR 9.23 (6.55 to 13.01) and the area under the curve 0.80 (0.77 to 0.85). In meta-regression analyses, higher cut-off values were associated with increasing specificity (OR 1.46 per 10 ppb increase in cut-off) while there was no association with sensitivity. Sensitivities varied significantly within the different FENO devices, but not specificities. Neither prevalence, age, use of bronchoprovocation in >90% of participants or as exclusive reference standard test, nor risk of bias were significantly associated with diagnostic accuracy. CONCLUSIONS: There appears to be a fair accuracy of FENO for making the diagnosis of asthma. The overall specificity was higher than sensitivity, which indicates a higher diagnostic potential for ruling in than for ruling out the diagnosis of asthma.

Efficacy and safety of pharmacological treatments for Lyme neuroborreliosis in children: a systematic review.

BACKGROUND: Many aspects of pharmacological treatment of Lyme neuroborreliosis in children, such as choice of drug, dosage, and duration are subject to intense debates, leading to uncertainties in patients' parents and healthcare providers alike. To assess the available evidence for pharmacological treatment for children with Lyme neuroborreliosis we conducted a systematic review. METHODS: The comprehensive systematic literature search included randomized-controlled trials (RCTs) and non-randomized studies (NRS) on treatment of Lyme neuroborreliosis in children (age <18 years). Our primary outcome was neurological symptoms after treatment. Risk of bias was assessed with the Cochrane risk of bias tools for RCTs and NRS. Quality of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: Two RCTs and four NRS were eligible for inclusion. Risk of bias in RCTs and NRS was generally high. Reporting of studies was generally poor. Regarding the primary outcome neurological symptoms at 1-3 months, no statistically significant difference could be found in cohort studies between doxycycline and beta-lactam antibiotics. In two RCTs comparing penicillin G and ceftriaxone, no patient experienced residual neurological symptoms at the last reported time points. Quality of evidence according to GRADE was judged very low. CONCLUSIONS: Data is scarce and with limited quality. Several issues could not be addressed due to scarcity of information. No eligible study compared different treatment durations. According to the available evidence, there seems to be no difference between different antibiotic agents for the treatment of Lyme neuroborreliosis in children regarding neurological symptoms. We found no evidence that supports extended antibiotic regimes. REVIEW REGISTRATION: Systematic review registration: CRD42014008839 .

Efficacy and safety of pharmacological agents in the treatment of erythema migrans in early Lyme borreliosis-systematic review protocol.

BACKGROUND: Erythema migrans represents an early cutaneous and most common manifestation of Lyme borreliosis. Recommendations regarding pharmacological agents, dose and duration of treatment are subject of intense debate. This review aims to explore differences in efficacy and safety between pharmacological treatments and control treatment. METHODS: To identify relevant studies, we will conduct a systematic literature search. We will include randomised controlled trials (RCTs) and non-RCTs. Eligible comparative studies need to (1) consider patients with a diagnosis of erythema migrans resulting from Lyme borreliosis and (2) compare different pharmacological agents against each other, against any other non-pharmacological treatment, placebo or no treatment. Two review authors will independently assess included studies for risk of bias according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and related to specific study designs. We will address patient-relevant outcomes including clinical remission of cutaneous symptoms, any treatment-related adverse events, quality of life and progressive symptoms such as neuroborreliosis or Lyme carditis and flu-like symptoms. Provided that the identified trials are comparable in terms of clinical issues, combined estimates will be provided. Estimations of treatment effects will be calculated based on a random effects model. Heterogeneity will be evaluated based on I (2) and chi-square test. In case of significant heterogeneity, a pooled estimate will not be provided, but heterogeneity will be investigated on the basis of methodological and clinical study aspects. We plan subgroup analysis to reveal potential differences in the effect estimates between patient populations and treatment specifications. We will consider risk of bias using sensitivity analyses to decide whether to rely on the pooled estimates. The quality of a body of evidence for individual outcomes will be assessed using the GRADE approach. DISCUSSION: Benefits and harms of pharmacological treatment in erythema migrans have not yet been adequately assessed. This systematic review will evaluate and summarise available evidence addressing benefits and harms of different pharmacological treatments. In addition, this summary of clinical evidence will inform decision-making between clinicians and patients and will play an important part in patient care. PROSPERO: CRD42016037932.

Gender differences in antibiotic prescribing in the community: a systematic review and meta-analysis.

OBJECTIVES: Determinants of inappropriate antibiotic prescription in the community are not clearly defined. The objective of this study was to perform a systematic review and meta-analysis evaluating gender differences in antibiotic prescribing in primary care. METHODS: All studies analysing antibiotic prescription in primary care were eligible. PubMed and MEDLINE entries with publication dates from 1976 until December 2013 were searched. The primary outcomes were the incidence rate ratio (IRR) (measured as DDD/1000 inhabitants/day) and the prevalence rate ratio (PRR) (measured as prevalence rate/1000 inhabitants) of antimicrobial prescription, stratified by gender, age and antibiotic class. Random-effects estimates of the IRR and PRR and standard deviations were calculated. RESULTS: Overall, 576 articles were reviewed. Eleven studies, comprising a total of 44 333 839 individuals, were included. The studies used data from prospective national (five studies) or regional (six studies) surveillance of community pharmacy, insurance or national healthcare systems. Women were 27% (PRR 1.27 ±â€Š0.12) more likely than men to receive an antibiotic prescription in their lifetimes. The amount of antibiotics prescribed to women was 36% (IRR 1.36 ±â€Š0.11) higher than that prescribed for men in the 16 to 34 years age group and 40% (IRR 1.40 ±â€Š0.03) greater in the 35 to 54 years age group. In particular, the amounts of cephalosporins and macrolides prescribed to women were 44% (IRR 1.44 ±â€Š0.30) and 32% (IRR 1.32 ±â€Š0.15) higher, respectively, than those prescribed for men. CONCLUSIONS: This meta-analysis shows that women in the 16 to 54 years age group receive a significantly higher number of prescriptions of cephalosporins and macrolides in primary care than men do. Prospective studies are needed to address reasons for gender inequality in prescription and to determine whether a difference in adverse events, including resistance development, also occurs.

Treatment as Required versus Regular Monthly Treatment in the Management of Neovascular Age-Related Macular Degeneration: A Systematic Review and Meta-Analysis.

BACKGROUND: To investigate whether treatment as required 'pro re nata' (PRN) versus regular monthly treatment regimens lead to differences in outcomes in neovascular age-related macular degeneration (nAMD). Regular monthly administration of vascular endothelial growth factor (VEGF) inhibitors is an established gold standard treatment, but this approach is costly. Replacement of monthly by PRN treatment can only be justified if there is no difference in patient relevant outcomes. METHODS: Systematic review and meta-analysis. The intervention was PRN treatment and the comparator was monthly treatment with VEGF-inhibitors. Four bibliographic databases were searched for randomised controlled trials comparing both treatment regimens directly (head-to-head studies). The last literature search was conducted in December 2014. Risk of bias assessment was performed after the Cochrane Handbook for Systematic Reviews of Interventions. FINDINGS: We included 3 head-to-head studies (6 reports) involving more than 2000 patients. After 2 years, the weighted mean difference in best corrected visual acuity (BCVA) was 1.9 (95% CI 0.5 to 3.3) ETDRS letters in favour of monthly treatment. Systemic adverse events were higher in PRN treated patients, but these differences were not statistically significant. After 2 years, the total number of intravitreal injections required by the patients in the PRN arms were 8.4 (95% CI 7.9 to 8.9) fewer than those having monthly treatment. The studies were considered to have a moderate risk of bias. CONCLUSIONS: PRN treatment resulted in minor but statistically significant decrease in mean BCVA which may not be clinically meaningful. There is a small increase in risk of systemic adverse events for PRN treated patients. Overall, the results indicate that an individualized treatment approach with anti-VEGF using visual acuity and OCT-guided re-treatment criteria may be appropriate for most patients with nAMD.

The porcine valve type predicts obstructive thrombosis beyond the first three postoperative months in bioprostheses in the aortic position.

BACKGROUND: Obstructive thrombosis of bioprosthetic valves is considered rare but may have dramatic consequences for the individual patient including repeat valve replacement, thrombolysis, or long-term anticoagulation. Whether the risk of obstructive thrombosis is dependent on the type of bioprosthesis (porcine versus bovine pericardial) is uncertain. METHODS AND RESULTS: Between 2007 and 2012 a total of 1751 patients received a single stented bioprosthesis in the aortic valve position, 749 (43%) were porcine and 1002 (57%) bovine. During a mean follow-up of 3.4±1.9years, obstructive thrombosis (identified by an increase in mean pressure gradient≥20mm Hg or a decrease in velocity ratio≥0.05 and confirmed by either ECG-gated computer tomography, a return to baseline of stenosis parameters under treatment with a vitamin K antagonist, or histology in case of reoperation) was diagnosed in 17 patients with a porcine (2.3%) and none with a bovine valve (p<0.001). The cumulative probability of developing an obstructive thrombosis was significantly higher in patients with a porcine valve (p<0.001 log-rank test). Adjusting for differences in baseline variables and stratification by the estimated propensity score showed that strata with a high probability of receiving a bovine valve had the highest number of obstructive thrombosis in porcine valves. These findings were further confirmed in a Poisson model and a competing risk model including all-cause mortality. Treatment of obstructive thrombosis with a vitamin K antagonist was safe and effective in 15/17 patients. CONCLUSION: The porcine valve type is an independent predictor of obstructive thrombosis in bioprostheses in the aortic position.

Efficacy and safety of pharmacological treatments for neuroborreliosis--protocol for a systematic review.

BACKGROUND: Neuroborreliosis is a tick-borne infectious disease of the nervous system caused by Borrelia burgdorferi. Common clinical manifestations of neuroborreliosis are cranial nerve dysfunctions, polyradiculoneuritis, and meningitis. Diagnosis is usually based on clinical presentation, serologic testing, and analysis of cerebrospinal fluid. Many aspects of pharmacological treatment, such as choice of drug, dosage, and duration are subject of intense debate, leading to uncertainties in patients and healthcare providers alike. To approach the questions regarding pharmacological treatment of neuroborreliosis, we will perform a systematic review. METHODS: We will perform a comprehensive systematic literature search for potentially eligible studies that report outcomes after pharmacological interventions. To adequately consider the wealth of research that has been conducted so far, this review will evaluate randomized controlled trials (RCTs) and non-randomized studies on treatment of neuroborreliosis. We will assess potential risk of bias for each RCT meeting our selection criteria using the Cochrane risk of bias tool for RCTs. For non-randomized studies, we will use the Newcastle-Ottawa Scale and the recently piloted Cochrane risk of bias tool for non-randomized studies. Our primary outcome of interest will be neurological symptoms and the secondary outcomes will be disability, patient-reported outcomes (quality of life, and, if reported separately from other neurological symptoms, pain, fatigue, depression, cognition, and sleep), adverse events, and cerebrospinal fluid pleocytosis. Pooling of data and meta-analysis will only be deemed justified between studies with similar design (e.g., RCTs are only combined with other RCTs), characteristics (e.g., similar populations), and of acceptable heterogeneity (I2 < 80%). Pooled estimates will be calculated using RevMan software. Prespecified subgroup analyses will evaluate groups of antibiotics, length of antibiotic treatment, and different doses of doxycycline. We will assess the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. DISCUSSION: This systematic review will summarize the available evidence from RCTs and non-randomized studies regarding pharmacological treatment of neuroborreliosis. The available evidence will be summarized and discussed to provide a basis for decision-making for patients and healthcare professionals. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration number: CRD42014008839.