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Background: Voluntary assisted partner notification (VAPN) services that use contract, provider, or dual referral modalities may be efficient to identify individuals with undiagnosed HIV infection. We aimed to assess the relative effectiveness of VAPN modalities in identifying undiagnosed HIV infections. Setting: VAPN was piloted in 23 health facilities in Kigali, Rwanda. Methods: We identified individuals with a new HIV diagnosis before antiretroviral therapy initiation or individuals on antiretroviral therapy (index cases), who reported having had sexual partners with unknown HIV status, to assess the association between referral modalities and the odds of identifying HIV-positive partners using a Bayesian hierarchical logistic regression model. We adjusted our model for important factors identified through a Bayesian variable selection. Results: Between October 2018 and December 2019, 6336 index cases were recruited, leading to the testing of 7690 partners. HIV positivity rate was 7.1% (546/7690). We found no association between the different referral modalities and the odds of identifying HIV-positive partners. Notified partners of male individuals (adjusted odds ratio 1.84; 95% credible interval: 1.50 to 2.28) and index cases with a new HIV diagnosis (adjusted odds ratio 1.82; 95% credible interval: 1.45 to 2.30) were more likely to be infected with HIV. Conclusion: All 3 VAPN modalities were comparable in identifying partners with HIV. Male individuals and newly diagnosed index cases were more likely to have partners with HIV. HIV-positive yield from index testing was higher than the national average and should be scaled up to reach the first UNAIDS-95 target by 2030. The authors thank all study participants and health care providers in the city of Kigali. Furthermore, the authors acknowledge the support and contributions of the Rwandan Ministry of Health, Rwanda Biomedical Centre, Stiftung Institut für klinische Epidemiologie, and Basel Institute for Clinical Epidemiology and Biostatistics Department of Clinical Research, University Hospital Basel, Switzerland, MTEK Sciences.

Background In 2013 Swiss health authorities implemented annual hospital caseload requirements (CR) for five areas of visceral surgery. We assess the impact of the implementation of CR on indication for surgery in esophageal, pancreatic and rectal cancer. Materials and methods Retrospective analysis of national registry data of all inpatient admissions between January 1st, 2005 and December 31st, 2015. Primary end-point was the age-adjusted resection rate for esophageal, pancreatic and rectal cancer among patients with at least one cancer-specific hospitalization per year. We calculated age-adjusted rate ratios for period effects before and after implementation of CR and odds ratios (OR) based on a generalized estimation equation. A relative increase of 5% in age-adjusted relative risk was set a priori as relevant from a health policy perspective. Results Age-adjusted resection rates before and after the implementation of CR were 0.12 and 0.13 (Relative Risk [RR] 1.08; 95%-Confidence Interval [CI] 0.85–1.36) in esophageal cancer, 0.22 and 0.26 (RR 1.17; 95%-CI 0.85–1.58) in pancreatic cancer and 0.38 and 0.43 (RR 1.14; 95%-CI 0.99–1.30) in rectal cancer. In adjusted models OR for resection after the implementation of CR were 1.40 (95%-CI 1.24–1.58) in esophageal cancer, 1.05 (95%-CI 0.96–1.15) in pancreatic cancer and 0.92 (95%-CI 0.87–0.97) in rectal cancer. Conclusion Implementation of CR was associated with an increase of resection rates above the a priori set margins in all resections groups. In adjusted models, odds for resection were significantly higher for esophageal cancer, while they remained unchanged for pancreatic and decreased for rectal cancer.

Objective: Antibiotics are largely overprescribed for acute rhinosinusitis in primary care, mainly due to the lack of diagnostic tests to confirm or rule out bacterial infection. The study objective was to assess the on-site applicability and safety of the newly developed JGG endoscope® for the diagnosis of acute bacterial rhinosinusitis in primary care. Design: Five Swiss primary care centres and one university-affiliated ENT unit participated in this single-arm pilot study. Participants: Adults with acute suspected bacterial rhinosinusitis. The newly developed JGG endoscope®, which is attached to a pocket otoscope, was used to inspect after local anaesthesia the nasal cavity and middle meatus and to gain material for bacterial culture from paranasal sinuses draining ostium. Main outcome measures: Applicability and safety. Results: The visualisation of the middle meatus was successful in 16 of 21 patients (13 in both sides and three in one side), and unclear or unsuccessful in five patients. Sample collection from the middle meatus was successful in 10 patients (six on both and four on one side) and unclear or unsuccessful in the remaining patients. Only one culture-confirmed bacterial rhinosinusitis and 11 PCR-confirmed viral infections were identified from collected samples. After a 2-week follow-up, no serious adverse events were observed. Conclusions: The on-site use of the JGG endoscope® in daily primary care routine is feasible and safe and was well accepted by the trial physicians and patients (assessed with structured questionnaires). The JGG endoscope® may support general practitioners to differentiate between bacterial and viral rhinosinusitis.

Undoubtedly, comorbidities complicate long‐term HIV management and have significant cost implications for healthcare systems. A better understanding of these comorbidities and underlying causes would allow for a more considered and proactive approach to the long‐term management of HIV. This review examines cross‐sectional analyses of six European cohort studies (Athens Multicenter AIDS Cohort Study, Aquitaine Cohort, EuroSIDA Cohort study, French claims EGB, German InGef Cohort and the Italian Cohort of Individuals, Naïve for Antiretrovirals), which included individuals with HIV followed over a certain period of time. Based on these cohorts, we examined how comorbidities have changed over time; how they compromise HIV management; and how much of a financial burden they impart. These data also provided a framework to explore the major issues of ageing and HIV and the practical implications of managing such issues in real‐life practice.

Background Centralization of care is an established concept in complex visceral surgery. Switzerland introduced case load requirements (CR) in 2013 in five areas of cancer surgery. The current study investigates the effects of CR on indication and mortality in liver surgery. Methods This is a retrospective analysis of a complete national in-hospital data set including all admissions between January 1, 2005, and December 31, 2015. Primary outcome variables were the incidence proportion and the 60-day in-hospital mortality of liver resections. Incidence proportion was calculated as the overall yearly number of liver resections performed in relation to the population living in Switzerland before and after the introduction of CR. Results Our analysis shows an increase number of liver resections compared to the period before introduction of CR from 2005–2012 (4.67 resections/100,000) to 2013–2015 (5.32 resections/100,000) after CR introduction. Age-adjusted incidence proportion increased by 14% (OR 1.14 95 CI [1.07–1.22]). National in-hospital mortality remained stable before and after CR (4.1 vs 3.7%), but increased in high-volume institutions (3.6 vs 5.6%). The number of hospitals performing liver resections decreased after the introduction of CR from 86 to 43. Half of the resections were performed in institutions reaching the stipulated numbers (53% before vs 49% after introduction of CR). After implementation of CR, patients undergoing liver surgery had more comorbidities (88 vs 92%). Conclusion The introduction of CR for liver surgery in Switzerland in 2013 was accompanied by an increase in operative volume with limited effects on centralization of care.

We identified determinants of SARS-CoV-2 mRNA vaccine antibody response in people with HIV (PWH). Antibody response was higher among PWH less than 60 years, with CD4+ cell count superior to 350 cells/μl and vaccinated with mRNA-1273 by Moderna compared with BNT162b2 by Pfizer-BioNTech. Preinfection with SARS-CoV-2 boosted the antibody response and smokers had an overall lower antibody response. Elderly PWH and those with low CD4+ cell count should be prioritized for booster vaccinations.

BACKGROUND Very small anterior communicating artery aneurysms (vsACoA) of

Background BNT162b2 by Pfizer-BioNTech and mRNA-1273 by Moderna are the most commonly used vaccines to prevent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Head-to-head comparison of the efficacy of these vaccines in immunocompromised patients is lacking. Methods Parallel, 2-arm (allocation 1:1), open-label, noninferiority randomized clinical trial nested into the Swiss HIV Cohort Study and the Swiss Transplant Cohort Study. People living with human immunodeficiency virus (PLWH) or solid organ transplant recipients (SOTR; ie, lung and kidney) from these cohorts were randomized to mRNA-1273 or BNT162b2. The primary endpoint was antibody response to SARS-CoV-2 spike (S1) protein receptor binding domain (Elecsys Anti-SARS-CoV-2 immunoassay, Roche; cutoff ≥0.8 units/mL) 12 weeks after first vaccination (ie, 8 weeks after second vaccination). In addition, antibody response was measured with the Antibody Coronavirus Assay 2 (ABCORA 2). Results A total of 430 patients were randomized and 412 were included in the intention-to-treat analysis (341 PLWH and 71 SOTR). The percentage of patients showing an immune response was 92.1% (95% confidence interval [CI]: 88.4–95.8; 186/202) for mRNA-1273 and 94.3% (95% CI: 91.2–97.4; 198/210) for BNT162b2 (difference: -2.2%; 95% CI: -7.1 to 2.7), fulfilling noninferiority of mRNA-1273. With the ABCORA 2 test, 89.1% had an immune response to mRNA-1273 (95% CI: 84.8–93.4; 180/202) and 89.5% to BNT162b2 (95% CI: 85.4–93.7; 188/210). Based on the Elecsys test, all PLWH had an antibody response (100.0%; 341/341), whereas for SOTR, only 60.6% (95% CI: 49.2–71.9; 43/71) had titers above the cutoff level. Conclusions In immunocompromised patients, the antibody response of mRNA-1273 was noninferior to BNT162b2. PLWH had in general an antibody response, whereas a high proportion of SOTR had no antibody response.

Lay Summary Influenza is usually diagnosed clinically. However, the accuracy of a diagnosis of influenza based on clinical features is limited because symptoms overlap considerably with those caused by other microorganisms. This study examined whether identification of the severity rather than the presence of key signs and symptoms could aid in the diagnosis of influenza, thereby helping clinicians to determine when antiviral agent use is appropriate. The authors used the database of a previous randomized clinical trial on the effectiveness of an antiviral carried out in primary care centers in 15 countries in Europe during three epidemic periods from 2015/2016 to 2017/2018. Participants with influenza symptoms were included and they were asked about the presence and severity of different symptoms during the baseline visit with their doctors and a nasopharyngeal swab was taken for microbiological analysis. Overall, only 51% of the patients aged 18 or older had a confirmed influenza infection. Clinical findings are not particularly useful for confirming or excluding the diagnosis of influenza. However, the results of our study recommend considering how intense the different symptoms are, since key symptoms rated as moderate or severe are slightly better for predicting flu rather than the presence or absence of these symptoms. Background Clinical findings do not accurately predict laboratory diagnosis of influenza. Early identification of influenza is considered useful for proper management decisions in primary care. Objective We evaluated the diagnostic value of the presence and the severity of symptoms for the diagnosis of laboratory-confirmed influenza infection among adults presenting with influenza-like illness (ILI) in primary care. Methods Secondary analysis of patients with ILI who participated in a clinical trial from 2015 to 2018 in 15 European countries. Patients rated signs and symptoms as absent, minor, moderate, or major problem. A nasopharyngeal swab was taken for microbiological identification of influenza and other microorganisms. Models were generated considering (i) the presence of individual symptoms and (ii) the severity rating of symptoms. Results A total of 2,639 patients aged 18 or older were included in the analysis. The mean age was 41.8 +/- 14.7 years, and 1,099 were men (42.1%). Influenza was microbiologically confirmed in 1,337 patients (51.1%). The area under the curve (AUC) of the model for the presence of any of seven symptoms for detecting influenza was 0.66 (95% confidence interval [CI]: 0.65-0.68), whereas the AUC of the symptom severity model, which included eight variables-cough, fever, muscle aches, sweating and/or chills, moderate to severe overall disease, age, abdominal pain, and sore throat-was 0.70 (95% CI: 0.69-0.72). Conclusion Clinical prediction of microbiologically confirmed influenza in adults with ILI is slightly more accurate when based on patient reported symptom severity than when based on the presence or absence of symptoms.

Oseltamivir is usually not often prescribed (or reimbursed) for non-high-risk patients consulting for influenza-like-illness (ILI) in primary care in Europe. We aimed to evaluate the cost-effectiveness of adding oseltamivir to usual primary care in adults/adolescents (13 years +) and children with ILI during seasonal influenza epidemics, using data collected in an open-label, multi-season, randomised controlled trial of oseltamivir in 15 European countries.Direct and indirect cost estimates were based on patient reported resource use and official country-specific unit costs. Health-Related Quality of Life was assessed by EQ-5D questionnaires. Costs and quality adjusted life-years (QALY) were bootstrapped (N = 10,000) to estimate incremental cost-effectiveness ratios (ICER), from both the healthcare payers' and the societal perspectives, with uncertainty expressed through probabilistic sensitivity analysis and expected value for perfect information (EVPI) analysis. Additionally, scenario (self-reported spending), comorbidities subgroup and country-specific analyses were performed.The healthcare payers' expected ICERs of oseltamivir were €22,459 per QALY gained in adults/adolescents and €13,001 in children. From the societal perspective, oseltamivir was cost-saving in adults/adolescents, but the ICER is €8,344 in children. Large uncertainties were observed in subgroups with comorbidities, especially for children. The expected ICERs and extent of decision uncertainty varied between countries (EVPI ranged €1-€35 per patient).Adding oseltamivir to primary usual care in Europe is likely to be cost-effective for treating adults/adolescents and children with ILI from the healthcare payers' perspective (if willingness-to-pay per QALY gained €22,459) and cost-saving in adults/adolescents from a societal perspective.

Aims We prospectively assessed and compared the accuracy of cardiovascular risk scores in people living with HIV (PLWH) and individuals from the general population. Methods and results The Systematic Coronary Risk Evaluation Score 2 (SCORE2), the Pooled Cohort Equations (PCE), and the HIV-specific Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) score were calculated in participants free from atherosclerotic cardiovascular disease (ASCVD) between 2003 and 2009. In total, 6373 [mean age, 40.6 years (SD, 9.9)] PLWH from the Swiss HIV Cohort Study (SHCS) and 5403 [52.8 years (SD, 10.7)] individuals from the CoLaus|PsyCoLaus study were eligible for analysis. We tested discrimination and calibration, and the value of adding HIV-specific factors to scores using the net reclassification improvement (NRI). During mean follow-ups of 13.5 (SD, 4.1) in SHCS and 9.9 (SD, 2.3) years in CoLaus|PsyCoLaus study, 533 (8.4%) and 374 (6.9%) people developed an incident ASCVD, respectively. This translated into age-adjusted incidence rates of 12.9 and 7.5 per 1000 person-year, respectively. In SHCS, SCORE2, PCE, and D:A:D presented comparable discriminative capacities [area under the receiver operating characteristic curve of 0.745 (95% confidence interval, CI, 0.723–0.767), 0.757 (95% CI, 0.736–0.777), and 0.763 (95% CI, 0.743–0.783)]. Adding HIV-specific variables (CD4 nadir and abacavir exposure) to SCORE2 and PCE resulted in an NRI of −0.1% (95% CI, −1.24 to 1, P = 0.83) and of 2.7% (95% CI, 0.3–5.1, P = 0.03), respectively. Conclusions PLWH present a two-fold higher rate of incident ASCVD compared to individuals from the general population. SCORE2 and PCE, which are clinically easier to use (reduced set of variables without adding HIV-specific factors), are valid to predict ASCVD in PLWH.

BACKGROUND: For people living with HIV, major guidelines in high-income countries recommend testing for transmitted drug resistance (TDR) to guide the choice of first-line antiretroviral therapy (ART). However, individuals who fail a first-line regimen can now be switched to one of several effective regimens. Therefore, the virological and clinical benefit of TDR testing needs to be evaluated. METHODS: We included individuals from the HIV-CAUSAL Collaboration who enrolled

Background and objective Novel cancer therapies are often approved with evidence from a single pivotal trial alone. There are concerns about the credibility of this evidence. Higher validity may be indicated by five methodological and statistical characteristics of pivotal trial evidence that were described by the U.S. Food and Drug Administration (FDA), which may corroborate the reliance on a single trial alone for approval decisions. Study design We did a metaepidemiologic evaluation of all single pivotal trials supporting FDA approval of novel drugs and therapeutic biologicals for cancers between 2000 and 2016. For each trial, we determined the presence of these five characteristics, which we operationalized as (1) large and multicenter trial (≥200 patients; more than one center); consistent treatment benefits across (2) multiple patient subgroups (in view of FDA reviewers), (3) multiple endpoints (including overall survival, progression-free survival, response rate, health related quality of life), and (4) multiple treatment comparisons (e.g., multi-arm studies); and (5) “statistically very persuasive” results (P-values Results Thirty-five of 100 approvals were based on evidence from a single pivotal trial without any further supporting evidence on beneficial effects (20 randomized controlled trials and 15 single-arm trials). The number increased substantially from one approval before 2006 to 23 after 2011. Sixty-six percent (23/35) of the trials were large multicenter trials (median 301 patients and 63 centers). Consistent effects were demonstrated across subgroups in 66% (23/35), across endpoints in 43% (15/35), and across multiple comparisons in 3% (1/35). Very lowP-values for the primary endpoint were seen in 34% (12/35). At least one of the corroborating characteristics was present in 94% (33/35) of all approvals, two or more were present in 54% (19/35), and none had all characteristics. Conclusions Single pivotal trials typically have some of the corroborating characteristics, but often only one or two. These characteristics need to be better operationalized, defined, and reported and whether single trials with such characteristics provide similar evidence about benefits and harms of novel treatments as multiple trials would do needs to be shown.

Background: Electronic health records (EHRs) may support randomized controlled trials (RCTs). We aimed to describe the current use and costs of EHRs in RCTs, with a focus on recruitment and outcome assessment. Methods: This descriptive study was based on a PubMed search of RCTs published since 2000 that evaluated any medical intervention with the use of EHRs. Cost information was obtained from RCT investigators who used EHR infrastructures for recruitment or outcome measurement but did not explore EHR technology itself. Results: We identified 189 RCTs, most of which (153 [81.0%]) were carried out in North America and were published recently (median year 2012 [interquartile range 2009–2014]). Seventeen RCTs (9.0%) involving a median of 732 (interquartile range 73–2513) patients explored interventions not related to EHRs, including quality improvement, screening programs, and collaborative care and disease management interventions. In these trials, EHRs were used for recruitment (14 [82%]) and outcome measurement (15 [88%]). Overall, in most of the trials (158 [83.6%]), the outcome (including many of the most patient-relevant clinical outcomes, from unscheduled hospital admission to death) was measured with the use of EHRs. The per-patient cost in the 17 EHR-supported trials varied from US$44 to US$2000, and total RCT costs from US$67 750 to US$5 026 000. In the remaining 172 RCTs (91.0%), EHRs were used as a modality of intervention. Interpretation: Randomized controlled trials are frequently and increasingly conducted with the use of EHRs, but mainly as part of the intervention. In some trials, EHRs were used successfully to support recruitment and outcome assessment. Costs may be reduced once the data infrastructure is established.

Background Mother-to-child HIV transmission (MTCT) has substantially declined since the scale-up of prevention programs around the world, including Rwanda. To achieve full elimination of MTCT, it is important to understand the risk factors associated with residual HIV transmission, defined as MTCT at the population-level that still occurs despite universal access to PMTCT. Methods We performed a case control study of children born from mothers with HIV with known vital status at 18 months from birth, who were followed in three national cohorts between October and December 2013, 2014, and 2015 in Rwanda. Children with HIV were matched in a ratio of 1:2 with HIV-uninfected children and a conditional logistic regression model was used to investigate risk factors for MTCT. Results In total, 84 children with HIV were identified and matched with 164 non-infected children. The median age of mothers from both groups was 29 years (interquartile range (IQR): 24–33). Of these mothers, 126 (51.4 %) initiated antiretroviral therapy (ART) before their pregnancy on record. In a multivariable regression analysis, initiation of ART in the third trimester (Adjusted Odds Ratio [aOR]: 9.25; 95 % Confidence Interval [95 % CI]: 2.12–40.38) and during labour or post-partum (aOR: 8.87; 95 % CI: 1.92–40.88), compared to initiation of ART before pregnancy, increased the risk of MTCT. Similarly, offspring of single mothers (aOR: 7.15; 95 % CI: 1.15–44.21), and absence of postpartum neonatal ART prophylaxis (aOR: 7.26; 95 % CI: 1.66–31.59) were factors significantly associated with MTCT. Conclusions Late ART initiation for PMTCT and lack of postpartum infant prophylaxis are still the most important risk factors to explain MTCT in the era of universal access. Improved early attendance at antenatal care, early ART initiation, and enhancing the continuum of care especially for single mothers is crucial for MTCT elimination in Rwanda.

Objective To assess the overall effect of delayed antibiotic prescribing on average symptom severity for patients with respiratory tract infections in the community, and to identify any factors modifying this effect. Design Systematic review and individual patient data meta-analysis. Data sources Cochrane Central Register of Controlled Trials, Ovid Medline, Ovid Embase, EBSCO CINAHL Plus, and Web of Science. Eligibility criteria for study selection Randomised controlled trials and observational cohort studies in a community setting that allowed comparison between delayed versus no antibiotic prescribing, and delayed versus immediate antibiotic prescribing. Main outcome measures The primary outcome was the average symptom severity two to four days after the initial consultation measured on a seven item scale (ranging from normal to as bad as could be). Secondary outcomes were duration of illness after the initial consultation, complications resulting in admission to hospital or death, reconsultation with the same or worsening illness, and patient satisfaction rated on a Likert scale. Results Data were obtained from nine randomised controlled trials and four observational studies, totalling 55 682 patients. No difference was found in follow-up symptom severity (seven point scale) for delayed versus immediate antibiotics (adjusted mean difference −0.003, 95% confidence interval −0.12 to 0.11) or delayed versus no antibiotics (0.02, −0.11 to 0.15). Symptom duration was slightly longer in those given delayed versus immediate antibiotics (11.4 v 10.9 days), but was similar for delayed versus no antibiotics. Complications resulting in hospital admission or death were lower with delayed versus no antibiotics (odds ratio 0.62, 95% confidence interval 0.30 to 1.27) and delayed versus immediate antibiotics (0.78, 0.53 to 1.13). A significant reduction in reconsultation rates (odds ratio 0.72, 95% confidence interval 0.60 to 0.87) and an increase in patient satisfaction (adjusted mean difference 0.09, 0.06 to 0.11) were observed in delayed versus no antibiotics. The effect of delayed versus immediate antibiotics and delayed versus no antibiotics was not modified by previous duration of illness, fever, comorbidity, or severity of symptoms. Children younger than 5 years had a slightly higher follow-up symptom severity with delayed antibiotics than with immediate antibiotics (adjusted mean difference 0.10, 95% confidence interval 0.03 to 0.18), but no increased severity was found in the older age group. Conclusions Delayed antibiotic prescribing is a safe and effective strategy for most patients, including those in higher risk subgroups. Delayed prescribing was associated with similar symptom duration as no antibiotic prescribing and is unlikely to lead to poorer symptom control than immediate antibiotic prescribing. Delayed prescribing could reduce reconsultation rates and is unlikely to be associated with an increase in symptoms or illness duration, except in young children. Study registration PROSPERO CRD42018079400.

BACKGROUND AND AIMS Residual inflammatory risk (RIR) after acute coronary syndromes (ACS) may identify patients likely to benefit from anti-inflammatory therapies. METHODS Patients from the Special Program University Medicine ACS cohort were divided into four groups according to level of hsCRP at baseline and after 12 months: persistently high RIR, increased RIR (first low, then high hsCRP), attenuated RIR (first high, then low hsCRP), or persistently low RIR. High RIR was defined as hsCRP ≥ 2 mg/L. An independently adjudicated incident of combined adverse events was defined as the composite of myocardial infarction, clinically indicated coronary revascularization or cerebrovascular events. RESULTS Among 1209 patients with available hsCRP, clinical and demographic data, 295 (24.4%) patients had persistently high RIR (delta hsCRP median (IQR): 2.3 (-9.9; 0.3) (mg/L) and 72 (5.96%) patients had increased RIR (delta hsCRP median (IQR): +2.45 (1.2; 8.35) (mg/L). A total of 390 (32.26%) patients had attenuated RIR (delta hsCRP median (IQR): 3.55 (-10; -2) (mg/L) and 452 (37.38%) patients had persistently low RIR (delta hsCRP median (IQR): 0.2 (-0.6; 0.1) (mg/L). Of 90 combined adverse events, 31 (10.5%) occurred in the persistently high (multivariable adjusted OR: 1.71, (95% CI 1.08-2.7), p = 0.022) compared with the three other groups combined (increased RIR: 3 (4.2%), attenuated RIR 30 (7.7%), persistently low RIR 26 (5.8%). CONCLUSIONS Persistently elevated hsCRP after ACS is found in a quarter of patients with the highest risk of combined adverse events. This underlines the need to perform anti-inflammatory intervention trials in RIR patients.

Introduction Antibiotic consumption is highest in primary care, and antibiotic overuse furthers antimicrobial resistance. In our recently published pilot-RCT, we used monthly aggregated claims data to provide personalized antibiotic prescription feedback to general practitioners (GPs). The pilot-RCT has shown that personalized prescription feedback is a feasible and promising low-cost intervention to reduce antibiotic prescribing. Here, we describe the rationale and design of the follow-up RCT with 3426 GPs in Switzerland. We now have access to pseudonymized patient-level data from routinely collected health insurance data of the three largest health insurers in Switzerland. Methods and analysis 1713 GPs randomized to the intervention group received once evidence-based treatment guidelines at the beginning, including region-specific antibiotic resistance information from the community and personalized feedback of their antibiotic prescribing, followed by quarterly personalized prescription feedback for two years. The first and the last mailings were sent out in December 2017 and September 2019, respectively. The 1713 GPs randomized to the control group were not notified about the study and they received no guidelines and no prescription feedback. The personalized prescription feedbacks and the analyses of the primary and secondary outcomes are entirely based on pseudonymized patient-level data from routinely collected health insurance data. The primary outcome is prescribed antibiotics per 100 patient consultations during the second year of intervention. The secondary outcomes include antibiotic use during the entire two-year trial period, use of broad-spectrum antibiotics, hospitalization rates (all-cause and infection-related), and antibiotic use in different age groups. If the feedback intervention proves to be efficacious, the intervention could be continued systemwide. Ethics and dissemination The trial is publicly funded by the Swiss National Science Foundation (SNSF, grant number 407240_167066). The trial was approved by the ethics committee "Ethikkommission Nordwest-und Zentralschweiz" (EKNZ Project-ID 2017-00888). Results will be disseminated in peer-reviewed journals and international conferences., Highlights • The randomized trial design and blinding assure internal validity. • The use of routinely collected claims data maximizes the external validity. • The control group reflects the actual practice of antibiotic prescribing in primary care. • The primary analysis focuses on the longer-term effect of the feedback intervention. • The feedback intervention is inexpensive and could be continued systemwide.

Background Limited data exist that compare clinical outcomes of 2-drug regimens (2DRs) and 3-drug regimens (3DRs) in people living with human immunodeficiency virus. Methods Antiretroviral treatment–experienced individuals in the International Cohort Consortium of Infectious Diseases (RESPOND) who switched to a new 2DR or 3DR from 1 January 2012–1 October 2018 were included. The incidence of clinical events (AIDS, non-AIDS cancer, cardiovascular disease, end-stage liver and renal disease, death) was compared between regimens using Poisson regression. Results Of 9791 individuals included, 1088 (11.1%) started 2DRs and 8703 (88.9%) started 3DRs. The most common 2DRs were dolutegravir plus lamivudine (22.8%) and raltegravir plus boosted darunavir (19.8%); the most common 3DR was dolutegravir plus 2 nucleoside reverse transcriptase inhibitors (46.9%). Individuals on 2DRs were older (median, 52.6 years [interquartile range, 46.7–59.0] vs 47.7 [39.7–54.3]), and a higher proportion had ≥1 comorbidity (81.6% vs 73.9%). There were 619 events during 27 159 person-years of follow-up (PYFU): 540 (incidence rate [IR] 22.5/1000 PYFU; 95% confidence interval [CI]: 20.7–24.5) on 3DRs and 79 (30.9/1000 PYFU; 95% CI: 24.8–38.5) on 2DRs. The most common events were death (7.5/1000 PYFU; 95% CI: 6.5–8.6) and non-AIDS cancer (5.8/1000 PYFU; 95% CI: 4.9–6.8). After adjustment for baseline demographic and clinical characteristics, there was a similar incidence of events on both regimen types (2DRs vs 3DRs IR ratio, 0.92; 95% CI: .72–1.19; P = .53). Conclusions This is the first large, international cohort to assess clinical outcomes on 2DRs. After accounting for baseline characteristics, there was a similar incidence of events on 2DRs and 3DRs. 2DRs appear to be a viable treatment option with regard to clinical outcomes. Further research on resistance barriers and long-term durability of 2DRs is needed.

Objectives Chronic hepatitis C virus (HCV) infection affects the immune system. Whether elimination of HCV with direct-acting antivirals (DAA) restores immunity is unclear. We used mass cytometry to get a broad and in-depth assessment of blood cell populations of patients with chronic HCV before and after DAA therapy. Methods Before and 12 weeks after sustained virological response (SVR12) to DAA therapy, 22 cell populations were analysed by mass cytometry in blood collected from ten healthy control individuals and 20 HCV-infected patients with (ten patients) or without (ten patients) human immunodeficiency virus (HIV) infection. Results HCV infection altered the frequency of 14/22 (64%) blood cell populations. At baseline, the frequencies (median, interquartile range (IQR); control, HCV, HCV/HIV) of intermediate monocytes (1.2, IQR 0.47–1.46; 1.76, IQR 0.83–2.66; 0.78, IQR 0.28–1.77), non-classical monocytes (1.11, IQR 0.49–1.26; 0.9, IQR 0.18–0.99; 0.54, IQR 0.28–1.77), conventional dendritic cells type 2 (0.55, IQR 0.35–0.59; 0.31, IQR 0.16–0.38; 0.19, IQR 0.11–0.36) and CD56dim natural killer cells (8.08, IQR 5.34–9.79; 4.72, IQR 2.59–6.05) 3.61, IQR 2.98–5.07) were reduced by 35% to 65%, particularly in HCV/HIV co-infected patients. In contrast, activated double-negative T cells (0.07, IQR 0.06–0.10; 0.10, IQR 0.09–0.19; 0.19, IQR 0.12–0.25), activated CD4 T cells (0.28, IQR 0.21–0.36; 0.56, IQR 0.33–0.77; 0.40, IQR 0.22–0.53) and activated CD8 T cells (0.23, IQR 0.14–0.42; 0.74, IQR 0.30–1.65; 0.80, IQR 0.58–1.16) were increased 1.4 to 3.5 times. Upon stimulation with Toll-like receptor ligands, the expression of cytokines was up-regulated in 7/9 (78%) and 17/19 (89%) of the conditions in HCV- and HCV/HIV-infected patients, respectively. Most alterations persisted at SVR12. Conclusions Chronic HCV and HCV/HIV infections induce profound and durable perturbations of innate and adaptive immune homeostasis.

Background Negative pressure wound therapy (NPWT) is a widely used method of wound treatment. We performed a systematic review of randomised controlled trials (RCTs) comparing the patient-relevant benefits and harms of NPWT with standard wound therapy (SWT) in patients with wounds healing by secondary intention. Methods We searched for RCTs in MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, and study registries (last search: July 2018) and screened reference lists of relevant systematic reviews and health technology assessments. Manufacturers and investigators were asked to provide unpublished data. Eligible studies investigated at least one patient-relevant outcome (e.g. wound closure). We assessed publication bias and, if feasible, performed meta-analyses, grading the results into different categories (hint, indication or proof of a greater benefit or harm). Results We identified 48 eligible studies of generally low quality with evaluable data for 4315 patients and 30 eligible studies with missing data for at least 1386 patients. Due to potential publication bias (proportion of inaccessible data, 24%), we downgraded our conclusions. A meta-analysis of all wound healing data showed a significant effect in favour of NPWT (OR 1.56, 95% CI 1.15 to 2.13, p = 0.008). As further analyses of different definitions of wound closure did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. A meta-analysis of hospital stay (in days) showed a significant difference in favour of NPWT (MD − 4.78, 95% CI − 7.79 to − 1.76, p = 0.005). As further analyses of different definitions of hospital stay/readmission did not contradict that analysis, we inferred an indication of a greater benefit of NPWT. There was neither proof (nor indication nor hint) of greater benefit or harm of NPWT for other patient-relevant outcomes such as mortality and adverse events. Conclusions In summary, low-quality data indicate a greater benefit of NPWT versus SWT for wound closure in patients with wounds healing by secondary intention. The length of hospital stay is also shortened. The data show no advantages or disadvantages of NPWT for other patient-relevant outcomes. Publication bias is an important problem in studies on NPWT, underlining that all clinical studies need to be fully reported.

Background Prevalence of potential drug–drug interactions (PDDIs) between antiretroviral drugs (ARVs) and co-medications was high in 2008 in a Swiss HIV Cohort Study (SHCS) survey. We reassessed the prevalence of PDDIs in the era of human immunodeficiency virus (HIV) integrase inhibitors (INIs), characterized by more favorable interaction profiles. Methods The prevalence of PDDIs in treated HIV-positive individuals was assessed for the period 01–12/2018 by linkage of the Liverpool HIV drug interactions and SHCS databases. PDDIs were categorized as harmful (red flagged), of potential clinical relevance (amber flagged), or of weak clinical significance (yellow flagged). Results In 9298 included individuals, median age was 51 years (IQR, 43–58), and 72% were males. Individuals received unboosted INIs (40%), boosted ARVs (30%), and nonnucleoside reverse transcriptase inhibitor (NNRTIs) (32%)–based regimens. In the entire cohort, 68% received ≥1 co-medication, 14% had polypharmacy (≥5 co-medications) and 29% had ≥1 PDDI. Among individuals with co-medication, the prevalence of combined amber and yellow PDDIs was 43% (33% amber—mostly with cardiovascular drugs—and 20% yellow-flagged PDDIs) compared to 59% in 2008. Two percent had red-flagged PDDIs (mostly with corticosteroids), the same as in the 2008 survey. Compared with 2008, fewer individuals received boosted ARVs (−24%) and NNRTIs (−13%) but the use of co-medications was higher. Conclusions Prevalence of PDDIs was lower with more widespread use of INIs in 2018 than in 2008. Continued use of boosted regimens and increasing needs for co-medications in this aging population impeded lower rates of PDDIs.

The aims of the Oncoplastic Breast Consortium initiative were to identify important knowledge gaps in the field of oncoplastic breast-conserving surgery and nipple-sparing or skin-sparing mastectomy with immediate breast reconstruction, and to recommend appropriate research strategies to address these gaps. A total of 212 surgeons and 26 patient advocates from 55 countries prioritised the 15 most important knowledge gaps from a list of 38 in two electronic Delphi rounds. An interdisciplinary panel of the Oncoplastic Breast Consortium consisting of 63 stakeholders from 20 countries obtained consensus during an in-person meeting to select seven of these 15 knowledge gaps as research priorities. Three key recommendations emerged from the meeting. First, the effect of oncoplastic breast-conserving surgery on quality of life and the optimal type and timing of reconstruction after nipple-sparing or skin-sparing mastectomy with planned radiotherapy should be addressed by prospective cohort studies at an international level. Second, the role of adjunctive mesh and the positioning of implants during implant-based breast reconstruction should ideally be investigated by randomised controlled trials of pragmatic design. Finally, the BREAST-Q questionnaire is a suitable tool to assess primary outcomes in these studies, but other metrics to measure patient-reported outcomes should be systematically evaluated and quality indicators of surgical morbidity should be further assessed.

BackgroundRwanda has identified several targeted HIV prevention strategies, such as promotion of condom use and provision of antiretroviral therapy (ART) and pre-exposure prophylaxis (PrEP) for female sex workers (FSWs). Given this country’s limited resources, understanding how the HIV epidemic will be affected by these strategies is crucial.MethodsWe developed a Markov model to estimate the effects of targeted strategies to FSWs on the HIV prevalence/incidence in Rwanda from 2017 to 2027. Our model consists of the six states: HIV-; HIV+ undiagnosed/diagnosed pre-ART; HIV+ diagnosed with/without ART; and death. We considered three populations: FSWs, sex clients and the general population. For the period 2017–2027, the HIV epidemic among each of these population was estimated using Rwanda’s demographic, sexual risk behaviour and HIV-associated morbidity and mortality data.ResultsBetween 2017 and 2027, with no changes in the current condom and ART use, the overall number of people living with HIV is expected to increase from 344,971 to 402,451. HIV incidence will also decrease from 1.36 to 1.20 100 person-years. By 2027, a 30% improvement in consistent condom use among FSWs will result in absolute reduction of HIV prevalence among FSWs, sex clients and the general population by 7.86%, 5.97% and 0.17%, respectively. While recurring HIV testing and improving the ART coverage mildly reduced the prevalence/incidence among FSWs and sex clients, worsening the two (shown by our worst-case scenario) will result in an increase in the HIV prevalence/incidence among FSWs and sex clients. Introduction of PrEP to FSWs in 2019 will reduce the HIV incidence among FSWs by 1.28%.ConclusionsContinued efforts toward improving condom and ART use will be critical for Rwanda to continue their HIV epidemic control. Implementing a targeted intervention strategy in PrEP for FSWs will reduce the HIV epidemic in this high-risk population.

Background Antivirals are infrequently prescribed in European primary care for influenza-like illness, mostly because of perceived ineffectiveness in real world primary care and because individuals who will especially benefit have not been identified in independent trials. We aimed to determine whether adding antiviral treatment to usual primary care for patients with influenza-like illness reduces time to recovery overall and in key subgroups. Methods We did an open-label, pragmatic, adaptive, randomised controlled trial of adding oseltamivir to usual care in patients aged 1 year and older presenting with influenza-like illness in primary care. The primary endpoint was time to recovery, defined as return to usual activities, with fever, headache, and muscle ache minor or absent. The trial was designed and powered to assess oseltamivir benefit overall and in 36 prespecified subgroups defined by age, comorbidity, previous symptom duration, and symptom severity, using a Bayesian piece-wise exponential primary analysis model. The trial is registered with the ISRCTN Registry, number ISRCTN 27908921. Findings Between Jan 15, 2016, and April 12, 2018, we recruited 3266 participants in 15 European countries during three seasonal influenza seasons, allocated 1629 to usual care plus oseltamivir and 1637 to usual care, and ascertained the primary outcome in 1533 (94%) and 1526 (93%). 1590 (52%) of 3059 participants had PCR-confirmed influenza infection. Time to recovery was shorter in participants randomly assigned to oseltamivir (hazard ratio 1·29, 95% Bayesian credible interval [BCrI] 1·20–1·39) overall and in 30 of the 36 prespecified subgroups, with estimated hazard ratios ranging from 1·13 to 1·72. The estimated absolute mean benefit from oseltamivir was 1·02 days (95% [BCrI] 0·74–1·31) overall, and in the prespecified subgroups, ranged from 0·70 (95% BCrI 0·30–1·20) in patients younger than 12 years, with less severe symptoms, no comorbidities, and shorter previous illness duration to 3·20 (95% BCrI 1·00–5·50) in patients aged 65 years or older who had more severe illness, comorbidities, and longer previous illness duration. Regarding harms, an increased burden of vomiting or nausea was observed in the oseltamivir group. Interpretation Primary care patients with influenza-like illness treated with oseltamivir recovered one day sooner on average than those managed by usual care alone. Older, sicker patients with comorbidities and longer previous symptom duration recovered 2–3 days sooner. Funding European Commission's Seventh Framework Programme.

Objective To prospectively assess the construct and criterion validity of ClassIntra version 1.0, a newly developed classification for assessing intraoperative adverse events. Design International, multicentre cohort study. Setting 18 secondary and tertiary centres from 12 countries in Europe, Oceania, and North America. Participants The cohort study included a representative sample of 2520 patients in hospital having any type of surgery, followed up until discharge. A follow-up to assess mortality at 30 days was performed in 2372 patients (94%). A survey was sent to a representative sample of 163 surgeons and anaesthetists from participating centres. Main outcome measures Intraoperative complications were assessed according to ClassIntra. Postoperative complications were assessed daily until discharge from hospital with the Clavien-Dindo classification. The primary endpoint was construct validity by investigating the risk adjusted association between the most severe intraoperative and postoperative complications, measured in a multivariable hierarchical proportional odds model. For criterion validity, inter-rater reliability was evaluated in a survey of 10 fictitious case scenarios describing intraoperative complications. Results Of 2520 patients enrolled, 610 (24%) experienced at least one intraoperative adverse event and 838 (33%) at least one postoperative complication. Multivariable analysis showed a gradual increase in risk for a more severe postoperative complication with increasing grade of ClassIntra: ClassIntra grade I versus grade 0, odds ratio 0.99 (95% confidence interval 0.69 to 1.42); grade II versus grade 0, 1.39 (0.97 to 2.00); grade III versus grade 0, 2.62 (1.31 to 5.26); and grade IV versus grade 0, 3.81 (1.19 to 12.2). ClassIntra showed high criterion validity with an intraclass correlation coefficient of 0.76 (95% confidence interval 0.59 to 0.91) in the survey (response rate 83%). Conclusions ClassIntra is the first prospectively validated classification for assessing intraoperative adverse events in a standardised way, linking them to postoperative complications with the well established Clavien-Dindo classification. ClassIntra can be incorporated into routine practice in perioperative surgical safety checklists, or used as a monitoring and outcome reporting tool for different surgical disciplines. Future studies should investigate whether the tool is useful to stratify patients to the appropriate postoperative care, to enhance the quality of surgical interventions, and to improve long term outcomes of surgical patients. Trial registration ClinicalTrials.gov NCT03009929 .

BACKGROUND One-third of patients with aneurysmal subarachnoid hemorrhage (aSAH) have multiple intracranial aneurysms (MIA). OBJECTIVE To determine the predictors of outcome in aSAH patients with MIA compared to aSAH patients with a single intracranial aneurysm (SIA). METHODS The Swiss Study of Subarachnoid Hemorrhage dataset 2009-2014 was used to evaluate outcome in aSAH patients with MIA compared to patients with SIA with the aid of descriptive and multivariate regression analysis. The primary endpoints of this cohort study were presence of new stroke on computed tomography (CT) after aneurysm treatment, and presence of stroke on CT prior to discharge. The secondary endpoints were the clinical and the functional status, and the overall mortality at discharge and at 1 yr. RESULTS Among 1689 consecutive patients, 467 had MIA (prevalence: 26.4%). The incidence of stroke was higher in the MIA than in the SIA group, both after aneurysm treatment (19.3% vs 15.1%) and at discharge (24% vs 21.4%). However, the 95% confidence interval (CI) for the corresponding odds ratio (OR) in our multivariate model included 1, indicating that the detected trends did not reach statistical significance. As for the secondary endpoints, aneurysm multiplicity was found to be an independent, statistically significant predictor for occurrence of a new focal neurological deficit between admission and discharge (OR 1.40, 95% CI 1.08-1.81). Yet, the MIA and SIA groups did not differ in terms of either functional outcome or overall survival. CONCLUSION aSAH patients with MIA have a higher short-term morbidity than patients with SIA. This excess morbidity does not worsen the functional outcome or lower overall survival.

Background: Health is generally regarded as a very high good, and oral health may substantially affect the quality of life of patients. Oral health–related quality of life has usually been investigated by means of disease-specific descriptive instruments, such as the Oral Health Impact Profile and the General Oral Health Assessment Index. These instruments, however, do not enable a comparison of oral health–related quality of life with other medical diseases. Economic methods, such as the time trade-off technique, enable a comparison of the impact of oral health with other medical diseases and thus provide a means to build a bridge in quality-of-life assessments between medicine and dentistry. Methods: We included in our study a total of 58 patients who received a complete denture in our clinic in the last 10 y (between January 2001 and May 2012) and who were ≥65 y old. Patient preferences for the edentulous and poorest imaginable oral health state were assessed via the time trade-off method. Results: Edentulous patients rated their current oral health state as 0.73 (SD, 0.25) and the poorest oral health state as 0.43 (SD, 0.33) on a scale between 0 (death) and 1 (best possible health state). These results are comparable to patient preferences for other serious diseases, such as breast cancer (0.75), asymptomatic HIV infection (0.69), depression (0.44), and osteoarthritis of the hip (0.44). Conclusion: In conclusion, our results suggest that oral health may substantially affect quality of life no less than other medical diseases. Knowledge Transfer Statement: Health is generally considered the highest good of humankind. In the present article, we show that oral health substantially affects quality of life. In particular, we show that loss of teeth (i.e., being edentulous) reduces quality of life no less than other systemic diseases. Treatment modalities for the edentulous patient may therefore substantially improve the patient’s well-being and should be a research priority.

Background Observational studies have shown that dressings containing chlorhexidine gluconate (CHX) lower the incidence external ventricular drain (EVD)-associated infections (EVDAIs). This prospective, randomized controlled trial (RCT) studies the efficacy of CHX-containing dressings in reducing bacterial colonization. Methods In this RCT, patients aged ≥18 years undergoing emergency EVD placement were randomly given either a CHX-containing or an otherwise identical control dressing at the skin exit wound. The primary end-point was bacterial regrowth in cultured skin swab samples of the EVD exit wound. The secondary end-points were catheters processed by sonication, clinically diagnosed EVDAI and surgical treatment of hydrocephalus. Results From October 2013 to January 2016, a total of 57 patients were randomized to receive either a CHX or a control dressing (29 and 28 patients, respectively). Cutaneous bacterial regrowth at the EVD exit wound was significantly reduced over time (geometric mean ratio, 0.18; 95% confidence interval, .08-.42; P < .001). The incidence of colonized catheters was lower in the CHX group (5 of 28; 18%) than in the control group (10 of 27; 33%), with less microbial colonization on the subcutaneous portion. The infection rate was 4 of 28 (14%) in the CHX group, compared with 7 of 27 (26%) in the control group, with a substantially lower hydrocephalus treatment rate (7 of 28 [25%] vs 14 of 27 [52%], respectively). Conclusion Our data support the use of CHX dressings to reduce EVD exit site contamination, potentially reducing EVDAIs and permanent cerebrospinal fluid diversion procedures for hydrocephalus. Clinical Trials Registration NCT02078830.