Incidence and outcomes of infective endocarditis after transcatheter aortic valve implantation versus surgical aortic valve replacement

ObjectivesTranscatheter aortic valve implantation (TAVI) is an alternative to surgical aortic valve replacement (AVR) in aortic stenosis (AS). Infective endocarditis (IE) in patients with prosthetic heart valves is associated with significant morbidity and mortality. Data on the incidence, risk factors, and outcomes of IE after TAVI are conflicting. We evaluated these issues in patients with percutaneous TAVI vs. isolated surgical AVR (SAVR) at a nationwide level.MethodsBased on the administrative hospital discharge database, the study collected information for all patients with aortic stenosis treated with AVR in France between 2010 and 2018.ResultsA total of 47 553 patients undergoing TAVI and 60 253 patients undergoing isolated SAVR were identified. During a mean follow-up of 2.0 years (median (25th to 75th percentile) 1.2 (0.1–3.4) years), the incidence rates of IE were 1.89 (95% confidence interval (CI) 1.78–2.00) and 1.40 (95% CI 1.34–1.46) events per 100 person-years in unmatched TAVI and SAVR patients, respectively. In 32 582 propensity-matched patients (16 291 with TAVI and 16 291 with SAVR), risk of IE was not different in patients treated with TAVI vs. SAVR (incidence rates of IE 1.86 (95% CI 1.70–2.04) %/year vs 1.71 (95% CI 1.58–1.85) %/year respectively, relative risk (RR) 1.09, 95% CI 0.96–1.23). In these matched patients, total mortality was higher in TAVI patients with IE (43.0% 95% CI 37.3–49.3) than in SAVR patients with IE (32.8% 95% CI 28.6–37.3; RR 1.32, 95% CI 1.08–1.60).DiscussionIn a nationwide cohort of patients with AS, treatment with TAVI was associated with a risk of IE similar to that following SAVR. Mortality was higher for patients with IE following TAVI than for those with IE following SAVR.     

Current state and completeness of reporting clinical prediction models using machine learning in systemic lupus erythematosus: A systematic review

ObjectiveWe carried out a systematic review (SR) of adherence in diagnostic and prognostic applications of ML in SLE using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) Statement.MethodsA SR employing five databases was conducted from its inception until December 2021. We identified articles that evaluated the utilization of ML for prognostic and/or diagnostic purposes. This SR was reported based on the PRISMA guidelines. The TRIPOD statement assessed adherence to reporting standards. Assessment for risk of bias was done using PROBAST tool.ResultsWe included 45 studies: 29 (64.4%) diagnostic and 16 (35.5%) prognostic prediction- model studies. Overall, articles adhered by between 17% and 67% (median 43%, IQR 37–49%) to TRIPOD items. Only few articles reported the model's predictive performance (2.3%, 95% CI 0.06–12.0), testing of interaction terms (2.3%, 95% CI 0.06–12.0), flow of participants (50%, 95% CI; 34.6–65.4), blinding of predictors (2.3%, 95% CI 0.06–12.0), handling of missing data (36.4%, 95% CI 22.4–52.2), and appropriate title (20.5%, 95% CI 9.8–35.3). Some items were almost completely reported: the source of data (88.6%, 95% CI 75.4–96.2), eligibility criteria (86.4%, 95% CI 76.2–96.5), and interpretation of findings (88.6%, 95% CI 75.4–96.2). In addition, most of model studies had high risk of bias.ConclusionsThe reporting adherence of ML-based model developed for SLE, is currently inadequate. Several items deemed crucial for transparent reporting were not fully reported in studies on ML-based prediction models.Review registration. PROSPERO ID# CRD42021284881. (Amended to limit the scope).     

Influence of perioperative opioid-related patient education: A systematic review and meta-analysis

ObjectiveTo determine the role of perioperative protocolized opioid-specific patient education on opioid consumption for individuals undergoing surgical procedures.MethodsWe searched Medline, Embase, and the Cochrane Central Register of Controlled Trials for randomized controlled trials (RCTs) that compared protocolized perioperative opioid-specific patient education to the usual care for adult individuals undergoing surgical interventions. The standardized mean difference (SMD) was used to represent continuous outcomes while the risk ratio (RR) was used to represent dichotomous outcomes.ResultsIn total, 15 RCTs that enrolled 2546 participants were deemed eligible. Protocolized opioid-specific patient education showed a significant reduction in postoperative opioid consumption and postoperative pain score compared to usual care (SMD= –0.15, 95% confidence interval [CI]: –0.28 to –0.03 and SMD= –0.17, 95% CI: –0.28 to –0.06, respectively). No significant difference was found between the protocolized opioid-specific patient education and the usual care in terms of the number of refill requests (RR=0.82, 95% CI: 0.50–1.34), patients with opioid leftovers (RR=0.92, 95% CI: 0.78–1.08), and patients taking opioids after hospital discharge.ConclusionsThis meta-analysis demonstrated that protocolized opioid-specific patient education significantly reduces postoperative opioid consumption and pain score but has no influence on the number of opioid refill requests, opioid leftovers, and opioid use after hospital discharge.Practice implicationsHealthcare professionals may offer opioid-related educational sessions for the surgical patients during the perioperative period through a video-based material that emphasizes the role of alternative analgesics to opioids, patients’ expectations about the post-operative pain, and the potential side effects of opioid consumptions.     

Time to blood culture positivity in Staphylococcus aureus bacteraemia to determine risk of infective endocarditis

ObjectivesPatients with Staphylococcus aureus bacteraemia (SAB) at risk for infective endocarditis (IE) need to be identified because they should undergo echocardiography. We validated previous scoring systems for IE risk determination and evaluated whether time to blood culture positivity (TTP) could improve scoring systems.MethodsThis retrospective population-based study included adults with SAB in 2016 in a derivation cohort and those from 2017 in a validation cohort. TTP was compared between patients with and without IE. A new score including TTP was constructed using a least absolute shrinkage selection operator. The new POSITIVE score was compared to the previously described PREDICT and VIRSTA scores.ResultsA total of 465 episodes with SAB were included in the derivation cohort, of which 38 (8.2%) represented IE. Median (interquartile range) TTP was significantly shorter in episodes with IE, at 8.7 (7.7–10.6) hours compared to those without, at 13.3 (10.5–16.5) hours. When using a cutoff at 13 hours, TTP had a sensitivity of 100% (95% confidence interval (CI), 91–100) and specificity of 52% (95% CI, 47–57) for IE. The POSITIVE score included TTP, intravenous drug use, embolizations and presence of preexisting heart conditions. It had a sensitivity of 93% (95% CI, 76–99) and a specificity of 70% (95% CI, 66–74) in the validation cohort. The performance of POSITIVE was superior to PREDICT, and the specificity was higher than that of VIRSTA.ConclusionsTTP, either by itself or as part of the POSITIVE score, can be used to identify patients with SAB at low risk for IE. Further validation is needed because TTP is sensitive to several external factors.     

Tuberculosis incidence and mortality in people living with human immunodeficiency virus: a Danish nationwide cohort study

ObjectivesTo explore changes over time in the epidemiology of tuberculosis (TB) in Denmark in people living with human immunodeficiency virus (HIV) (PLWH).MethodsIn this nationwide, population-based cohort study we included all adult PLWH from the Danish HIV Cohort Study (1995–2017) without previous TB. We estimated TB incidence rate (IR), all-cause mortality rate (MR), associated risk and prognostic factors using Poisson regression.ResultsAmong 6982 PLWH (73 596 person-years (PY)), we observed 217 TB events (IR 2.9/1000 PY, 95% CI 2.6–3.4: IR 6.7, 95% CI 5.7–7.9 among migrants and IR 1.4, 95% CI 1.1–1.7 among Danish-born individuals; p < 0.001). The IR of concomitant HIV/TB remained high and unchanged over time. The IR of TB diagnosed >3 months after HIV diagnosis declined with calendar time, longer time from HIV diagnosis, and CD4 cell recovery. Independent TB risk factors were African/Asian/Greenland origin (adjusted incidence rate ratio (aIRR) 5.2, 95% CI 3.5–7.6, aIRR 6.5, 95% CI 4.2–10.0, aIRR 7.0, 95% CI 3.4–14.6, respectively), illicit drug use (aIRR 6.9, 95% CI 4.2–11.2), CD4 <200 cells/μL (aIRR 2.7, 95% CI 2.0–3.6) and not receiving antiretroviral therapy (aIRR 3.7, 95% CI 2.5–5.3). Fifty-five patients died (MR 27.9/1000 PY, 95% CI 21.4–36.3), with no improvement in mortality over time. Mortality prognostic factors were Danish-origin (adjusted mortality rate ratio (aMRR) 2.3, 95% CI 1.3–4.3), social burden (aMRR 3.9, 95% CI 2.2–7.0), CD4 <100 cells/μL at TB diagnosis (aMRR 2.6, 95% CI 1.3–4.9), TB diagnosed >3 months after HIV versus concomitant diagnosis (aMRR 4.3, 95% CI 2.2–8.7) and disseminated TB (aMRR 3.3, 95% CI 1.1–9.9).ConclusionLate HIV presentation with concomitant TB remains a challenge. Declining TB rates in PLWH were observed over time and with CD4 recovery, highlighting the importance of early and successful antiretroviral therapy. However, MR remained high. Our findings highlight the importance of HIV and TB screening strategies and treatment of latent TB in high-risk groups.     

Predictors for treatment outcomes among patients with drug-susceptible tuberculosis in the Netherlands: a retrospective cohort study

ObjectivesWe evaluated treatment outcomes and predictors for poor treatment outcomes for tuberculosis (TB) among native- and foreign-born patients with drug-susceptible TB (DSTB) in the Netherlands.MethodsThis retrospective cohort study included adult patients with DSTB treated from 2005 to 2015 from a nationwide exhaustive registry. Predictors for unsuccessful treatment outcomes (default and failure) and TB-associated mortality were analysed using multivariate logistic regression.ResultsAmong 5674 identified cases, the cumulative incidence of unsuccessful treatment and mortality were 2.6% (n/N = 146/5674) and 2.0% (112/5674), respectively. Although most patients were foreign-born (71%; 4042/5674), no significant differences in these outcomes were observed between native- and foreign-born patients (p > 0.05). Significant predictors for unsuccessful treatment were aged 18–24 years (odds ratio (OR), 2.04; 95% CI 1.34–3.10), homelessness (OR, 2.56; 95% CI 1.16–5.63), prisoner status (OR, 5.39; 95% CI 2.90–10.05) and diabetes (OR, 2.02; 95% CI 1.03–3.97). Furthermore, predictors for mortality were aged 74–84 years (OR, 5.58; 95% CI 3.10–10.03) or ≥85 years (OR, 9.35, 95% CI 4.31–20.30), combined pulmonary and extra-pulmonary TB (OR, 4.97; 95% CI 1.42–17.41), central nervous system (OR, 120, 95% CI 34.43–418.54) or miliary TB (OR, 10.73, 95% CI 2.50–46.02), drug addiction (OR, 3.56; 95% CI 1.34–9.47) and renal insufficiency/dialysis (OR, 3.23; 95% CI 1.17–8.96).ConclusionsNative- and foreign-born patients exhibited similar TB treatment outcomes. To further reduce disease transmission and inhibit drug resistance, special attention should be given to high-risk patients.     

Repeat endocarditis: analysis of risk factors based on the International Collaboration on Endocarditis – Prospective Cohort Study

Repeat episodes of infective endocarditis (IE) can occur in patients who survive an initial episode. We analysed risk factors and 1-year mortality of patients with repeat IE. We considered 1874 patients enrolled in the International Collaboration on Endocarditis – Prospective Cohort Study between January 2000 and December 2006 (ICE-PCS) who had definite native or prosthetic valve IE and 1-year follow-up. Multivariable analysis was used to determine risk factors for repeat IE and 1-year mortality. Of 1874 patients, 1783 (95.2%) had single-episode IE and 91 (4.8%) had repeat IE: 74/91 (81%) with new infection and 17/91 (19%) with presumed relapse. On bivariate analysis, repeat IE was associated with haemodialysis (p 0.002), HIV (p 0.009), injection drug use (IDU) (p < 0.001), Staphylococcus aureus IE (p 0.003), healthcare acquisition (p 0.006) and previous IE before ICE enrolment (p 0.001). On adjusted analysis, independent risk factors were haemodialysis (OR, 2.5; 95% CI, 1.2–5.3), IDU (OR, 2.9; 95% CI, 1.6–5.4), previous IE (OR, 2.8; 95% CI, 1.5–5.1) and living in the North American region (OR, 1.9; 95% CI, 1.1–3.4). Patients with repeat IE had higher 1-year mortality than those with single-episode IE (p 0.003). Repeat IE is associated with IDU, previous IE and haemodialysis. Clinicians should be aware of these risk factors in order to recognize patients who are at risk of repeat IE.     

Socioeconomic disparities and COVID-19 vaccination acceptance: a nationwide ecologic study

ObjectiveTo analyse the correlation between COVID-19 vaccination percentage and socioeconomic status (SES).MethodsA nationwide ecologic study based on open-sourced, anonymized, aggregated data provided by the Israel Ministry of Health. The correlations between municipal SES, vaccination percentage and active COVID-19 cases during the vaccination campaign were analysed by using weighted Pearson correlations. To assess the adequacy of first dose vaccination rollout relative to the municipality COVID-19 disease burden, a metric termed the vaccination need ratio was devised by dividing the total number of active cases (per 10 000 people) by the vaccination percentage of the population over 60 in each municipality, and its correlation with the SES was examined.Results23 days after initiation of the vaccination campaign, 760 916 (56.8%) individuals over the age of 60 were vaccinated in Israel with the first dose of the BNT162b2 COVID-19 vaccine. A negative correlation was found between the COVID-19 active case burden and the vaccination percentage of the study population in each municipality (r = –0.47, 95% CI –0.59 to –0.30). The vaccination percentage significantly correlated with the municipal SES (r = 0.83, 95% CI 0.79 to 0.87). This finding persisted but was attenuated over a 5-week period. A negative correlation between the vaccination need ratio and municipal SES (r = –0.80, 95% CI –0.88 to –0.66) was found.DiscussionLower COVID-19 vaccination percentage was associated with lower SES and high active disease burden. Vaccination efforts should focus on areas with lower SES and high disease burden to assure equality of vaccine allocation and potentially provide a more diligent disease mitigation.     

Impact of Staphylococcus aureus phenotype and genotype on the clinical characteristics and outcome of infective endocarditis. A multicentre,longitudinal, prospective,observational study

ObjectiveWe aimed to evaluate the impact of Staphylococcus aureus phenotype (vancomycin MIC) and genotype (agr group, clonal complex CC) on the prognosis and clinical characteristics of infective endocarditis (IE).MethodsWe performed a multicentre, longitudinal, prospective, observational study (June 2013 to March 2016) in 15 Spanish hospitals. Two hundred and thirteen consecutive adults (≥18 years) with a definite diagnosis of S. aureus IE were included. Primary outcome was death during hospital stay. Main secondary end points were persistent bacteraemia, sepsis/septic shock, peripheral embolism and osteoarticular involvement.ResultsOverall in-hospital mortality was 37% (n = 72). Independent risk factors for death were age-adjusted Charlson co-morbidity index (OR 1.20; 95% CI 1.08–1.34), congestive heart failure (OR 3.60; 95% CI 1.72–7.50), symptomatic central nervous system complication (OR 3.17; 95% CI 1.41–7.11) and severe sepsis/septic shock (OR 4.41; 95% CI 2.18–8.96). In the subgroup of methicillin-susceptible S. aureus IE (n = 173), independent risk factors for death were the age-adjusted Charlson co-morbidity index (OR 1.17; 95% CI 1.03–1.31), congestive heart failure (OR 3.39; 95% CI 1.51–7.64), new conduction abnormality (OR 4.42; 95% CI 1.27–15.34), severe sepsis/septic shock (OR 5.76; 95% CI 2.57–12.89) and agr group III (OR 0.27; 0.10–0.75). Vancomycin MIC ≥1.5 mg/L was not independently associated with death during hospital nor was it related to secondary end points. No other genotype variables were independently associated with in-hospital death.ConclusionsThis is the first prospective study to assess the impact of S. aureus phenotype and genotype. Phenotype and genotype provided no additional predictive value beyond conventional clinical characteristics. No evidence was found to justify therapeutic decisions based on vancomycin MIC for either methicillin-resistant or methicillin-susceptible S. aureus.     

FAM19A4/miR124-2 methylation analysis as a triage test for HPV-positive women: cross-sectional and longitudinal data from a Dutch screening cohort

ObjectivesThe aim was to evaluate the cross-sectional and long-term triage performance of FAM19A4/miR124-2 methylation analysis in human papillomavirus (HPV)-based cervical screening.MethodsWe conducted a post hoc analysis within a Dutch population-based HPV-positive study cohort of women aged 30–60 years (n = 979). Cross-sectional cervical intraepithelial neoplasia (CIN) 3+ sensitivity, specificity, positive predictive value and negative predictive value as well as cumulative CIN3+ or cervical cancer risks after 9 and 14 years were compared for three baseline triage strategies: (1) cytology, (2) FAM19A4/miR124-2 methylation analysis and (3) combined FAM19A4/miR124-2 methylation with cytology.ResultsCIN3+ sensitivity of FAM19A4/miR124-2 methylation analysis was similar to that of cytology (71.3% vs 76.0%, ratio 0.94, 95% CI 0.84 to 1.05), at a lower specificity (78.3% vs 87.0%, ratio 0.90, 95% CI 0.86 to 0.94). Combining FAM19A4/miR124-2 methylation analysis with cytology resulted in a CIN3+ sensitivity of 84.6% (95% CI 78.3 to 90.8) at a specificity of 69.6% (95% CI 66.5 to 72.7). Similar 9- and 14-year CIN3+ risks for baseline cytology-negative women and baseline FAM19A4/miR124-2 methylation-negative women were observed, with risk differences of –0.42% (95% CI –2.1 to 1.4) and –0.07% (95% CI –1.9 to 1.9), respectively. The 14-year cumulative cervical cancer incidence was significantly lower for methylation-negative women compared to cytology-negative women (risk difference 0.98%, 95% CI 0.26 to 2.0).DiscussionFAM19A4/miR124-2 methylation analysis has a good triage performance on baseline screening samples, with a cross-sectional CIN3+ sensitivity and long-term triage-negative CIN3+ risk equalling cytology triage. Therefore, FAM19A4/miR124-2 methylation analysis appears to be a good and objective alternative to cytology in triage scenarios in HPV-based cervical screening.     

Community-acquired pneumonia severity assessment tools in patients hospitalized with COVID-19: a validation and clinical applicability study

ObjectiveTo externally validate community-acquired pneumonia (CAP) tools on patients hospitalized with coronavirus disease 2019 (COVID-19) pneumonia from two distinct countries, and compare their performance with recently developed COVID-19 mortality risk stratification tools.MethodsWe evaluated 11 risk stratification scores in a binational retrospective cohort of patients hospitalized with COVID-19 pneumonia in São Paulo and Barcelona: Pneumonia Severity Index (PSI), CURB, CURB-65, qSOFA, Infectious Disease Society of America and American Thoracic Society Minor Criteria, REA-ICU, SCAP, SMART-COP, CALL, COVID GRAM and 4C. The primary and secondary outcomes were 30-day in-hospital mortality and 7-day intensive care unit (ICU) admission, respectively. We compared their predictive performance using the area under the receiver operating characteristics curve (AUC), sensitivity, specificity, likelihood ratios, calibration plots and decision curve analysis.ResultsOf 1363 patients, the mean (SD) age was 61 (16) years. The 30-day in-hospital mortality rate was 24.6% (228/925) in São Paulo and 21.0% (92/438) in Barcelona. For in-hospital mortality, we found higher AUCs for PSI (0.79, 95% CI 0.77–0.82), 4C (0.78, 95% CI 0.75–0.81), COVID GRAM (0.77, 95% CI 0.75–0.80) and CURB-65 (0.74, 95% CI 0.72–0.77). Results were similar for both countries. For the 1%–20% threshold range in decision curve analysis, PSI would avoid a higher number of unnecessary interventions, followed by the 4C score. All scores had poor performance (AUC <0.65) for 7-day ICU admission.ConclusionsRecent clinical COVID-19 assessment scores had comparable performance to standard pneumonia prognostic tools. Because it is expected that new scores outperform older ones during development, external validation studies are needed before recommending their use.     

Enterococcal endocarditis in the beginning of the 21st century: analysis from the International Collaboration on Endocarditis-Prospective Cohort Study

Enterococci are reportedly the third most common group of endocarditis-causing pathogens but data on enterococcal infective endocarditis (IE) are limited. The aim of this study was to analyse the characteristics and prognostic factors of enterococcal IE within the International Collaboration on Endocarditis. In this multicentre, prospective observational cohort study of 4974 adults with definite IE recorded from June 2000 to September 2006, 500 patients had enterococcal IE. Their characteristics were described and compared with those of oral and group D streptococcal IE. Prognostic factors for enterococcal IE were analysed using multivariable Cox regression models. The patients’ mean age was 65 years and 361/500 were male. Twenty-three per cent (117/500) of cases were healthcare related. Enterococcal IE were more frequent than oral and group Dstreptococcal IE in North America. The 1-year mortality rate was 28.9% (144/500). E. faecalis accounted for 90% (453/500) of enterococcal IE. Resistance to vancomycin was observed in 12 strains, eight of which were observed in North America, where they accounted for 10% (8/79) of enterococcal strains, and was more frequent in E. faecium than in E. faecalis (3/16 vs. 7/364, p 0.01). Variables significantly associated with 1-year mortality were heart failure (HR 2.4, 95% CI 1.7—3.5, p <0.0001), stroke (HR 1.9, 95% CI 1.3—2.8, p 0.001) and age (HR 1.02 per 1-year increment, 95% CI 1.01—1.04, p 0.002). Surgery was not associated with better outcome. Enterococci are an important cause of IE, with a high mortality rate. Healthcare association and vancomycin resistance are common in particular in North America.     

A pragmatic approach for mortality prediction after surgery in infective endocarditis: optimizing and refining EuroSCORE

ObjectiveTo simplify and optimize the ability of EuroSCORE I and II to predict early mortality after surgery for infective endocarditis (IE).MethodsMulticentre retrospective study (n = 775). Simplified scores, eliminating irrelevant variables, and new specific scores, adding specific IE variables, were created. The performance of the original, recalibrated and specific EuroSCOREs was assessed by Brier score, C-statistic and calibration plot in bootstrap samples. The Net Reclassification Index was quantified.ResultsRecalibrated scores including age, previous cardiac surgery, critical preoperative state, New York Heart Association >I, and emergent surgery (EuroSCORE I and II); renal failure and pulmonary hypertension (EuroSCORE I); and urgent surgery (EuroSCORE II) performed better than the original EuroSCOREs (Brier original and recalibrated: EuroSCORE I: 0.1770 and 0.1667; EuroSCORE II: 0.2307 and 0.1680). Performance improved with the addition of fistula, staphylococci and mitral location (EuroSCORE I and II) (Brier specific: EuroSCORE I 0.1587, EuroSCORE II 0.1592). Discrimination improved in specific models (C-statistic original, recalibrated and specific: EuroSCORE I: 0.7340, 0.7471 and 0.7728; EuroSCORE II: 0.7442, 0.7423 and 0.7700). Calibration improved in both EuroSCORE I models (intercept 0.295, slope 0.829 (original); intercept –0.094, slope 0.888 (recalibrated); intercept –0.059, slope 0.925 (specific)) but only in specific EuroSCORE II model (intercept 2.554, slope 1.114 (original); intercept –0.260, slope 0.703 (recalibrated); intercept –0.053, slope 0.930 (specific)). Net Reclassification Index was 5.1% and 20.3% for the specific EuroSCORE I and II.ConclusionsThe use of simplified EuroSCORE I and EuroSCORE II models in IE with the addition of specific variables may lead to simpler and more accurate models.     

Combined Effects of Depression and Chronic Disease on the Risk of Mortality: The Korean Longitudinal Study of Aging (2006-2016)

BackgroundThe prevalence of depression is much higher in people with chronic disease than in the general population. Depression exacerbates existing physical conditions, resulting in a higher-than-expected death rate from the physical condition itself. In our aging society, the prevalence of multimorbid patients is expected to increase; the resulting mental problems, especially depression, should be considered. Using a large-scale cohort from the Korean Longitudinal Study of Aging (KLoSA), we analyzed the combined effects of depression and chronic disease on all-cause mortality.MethodsWe analyzed 10-year (2006–2016) longitudinal data of 9,819 individuals who took part in the KLoSA, a nationwide survey of people aged 45–79 years. We examined the association between multimorbidity and depression using chi-square test and logistic regression. We used the Cox proportional hazard model to determine the combined effects of multimorbidity and depression on the all-cause mortality risk.ResultsDuring the 10-year follow up, 1,574 people (16.0%) died. The hazard ratio associated with mild depression increased from 1.35 (95% confidence interval [CI], 1.05–1.73) for no chronic disease to 1.25 (95% CI, 0.98–1.60) for 1 chronic disease, and to 2.00 (95% CI, 1.58–2.52) for multimorbidity. The hazard ratio associated with severe depression increased from 1.73 (95% CI, 1.33–2.24) for no chronic disease, to 2.03 (95% CI, 1.60–2.57) for 1 chronic disease, and to 2.94 (95% CI, 2.37–3.65) for multimorbidity.ConclusionPatients with coexisting multimorbidity and depression are at an increased risk of all-cause mortality than those with chronic disease or depression alone.     

Effect of Opioids on All-cause Mortality and Opioid Addiction in Total Hip Arthroplasty: a Korea Nationwide Cohort Study

BackgroundThe purpose of this study was to investigate the use of opioids before and after total hip arthroplasty (THA), to find out the effect of opioid use on mortality in patients with THA, and to analyze whether preoperative opioid use is a risk factor for sustained opioid use after surgery using Korean nationwide cohort data.MethodsThis retrospective nationwide study identified subjects from the Korean National Health Insurance Service-Sample cohort (NHIS-Sample) compiled by the Korean NHIS. The index date (time zero) was defined as 90 days after an admission to a hospital to fulfill the eligibility criteria of the THA.ResultsIn the comparison of death risk according to current use and the defined daily dose of tramadol and strong opioids in each patient group according to past opioid use, there were no statistically significant differences in the adjusted hazard ratio for death compared to the current non-users in all groups (P > 0.05). Past tramadol and strong opioid use in current users increased the risk of the sustained use of tramadol and strong opioids 1.45-fold (adjusted rate ratio [aRR]; 95% confidence interval [CI], 1.12–1.87; P = 0.004) and 1.65-fold (aRR; 95% CI, 1.43–1.91; P < 0.001), respectively, compared to past non-users.ConclusionIn THA patients, the use of opioids within 6 months before surgery and within 3 months after surgery does not affect postoperative mortality, but a past-use history of opioid is a risk factor for sustained opioid use. Even after THA, the use of strong opioids is observed to increase compared to before surgery.     

Has the mortality from pulmonary mucormycosis changed over time? A systematic review and meta-analysis

ObjectivesPulmonary mucormycosis (PM) is increasingly being reported in immunocompromised patients and has a high mortality. Our aim was to assess the mortality of PM and its trend over time. We also evaluated the role of combined medical–surgical therapy in PM.MethodsWe performed a systematic review of Pubmed, Embase, and Cochrane central databases. Studies were eligible if they described at least five confirmed cases of PM and reported mortality. We also assessed the effect of combined medical–surgical therapy versus medical treatment alone on PM mortality. We used a random-effects model to estimate the pooled mortality of PM and compared it across three time periods. The factors influencing mortality were assessed using meta-regression. We evaluated the risk difference (RD) of death in the following: subjects undergoing combined medical–surgical therapy versus medical therapy alone, subjects with isolated PM versus disseminated disease, and PM in diabetes mellitus (DM) versus non-DM as a risk factor.ResultsWe included 79 studies (1544 subjects). The pooled mortality of PM was 57.1% (95% confidence interval [CI] 51.7–62.6%). Mortality improved significantly over time (72.1% versus 58.3% versus 49.8% for studies before 2000, 2000–2009, and 2010–2020, respectively, p 0.00001). This improved survival was confirmed in meta-regression after adjusting for the study design, the country's income level, and the sample size. Combined medical–surgical therapy was associated with a significantly lower RD (95%CI) of death: –0.32 (–0.49 to –0.16). The disseminated disease had a higher risk of death than isolated PM, but DM was not associated with a higher risk of death than other risk factors.ConclusionsWhile PM is still associated with high mortality, we noted improved survival over time. Combined medical–surgical therapy improved survival compared to medical treatment alone.     

Negative pressure wound therapy for surgical site infections: a systematic review and meta-analysis of randomized controlled trials

ObjectivesPrevious studies showed the effectiveness of negative pressure wound therapy (NPWT) in preventing surgical site infections (SSIs), but current guidelines do not recommend its routine use for surgical wounds. The aim was to compare the effectiveness and safety of NPWT with standard surgical dressing or conventional therapy for preventing SSIs.MethodsPubmed, Embase and the Cochrane Library were systematically searched on 10 April 2019. Also, we searched clinicaltrials.gov and references of relevant studies. Eligibility criteria were randomized controlled trials (RCTs) and adult surgical patients were included. The effectiveness of NPWT versus standard surgical dressing or conventional therapy was investigated. Relative risks (RRs) and mean differences (MDs) with 95% confidence intervals (CIs) were used to estimate the pooled effect of dichotomous outcomes and continuous outcomes respectively. The primary outcome was surgical site infections. The quality of included studies and the certainty of the evidence were assessed using the risk of bias tool and the GRADE approach.ResultsA total of 45 RCTs with 6624 surgical patients were included. NPWT reduced SSIs (RR 0.58; 95% CI 0.49–0.69) and wound dehiscence(17 RCTs; RR 0.80; 95% CI 0.65–1.00). NPWT did not increase the risk of hematoma (9 RCTs; RR 0.91; 95% CI 0.40–2.07) and hospital readmission(9 RCTs; RR 0.77; 95% CI 0.52–1.12) or prolong length of hospital stay(15 RCTs; MD –0.38; 95% CI, –0.78 to 0.02). NPWT significantly increased the risk of all adverse event-related outcomes (10 RCTs; RR 3.21; 95% CI, 1.17–8.78). The level of certainty was identified as low for the primary outcome and very low for all the secondary outcomes.ConclusionsCompared with standard wound care, NPWT may reduce the risk of SSIs. We are uncertain whether NPWT reduces or increases the risk of wound dehiscence, haematoma, hospital readmission and all adverse event-related outcomes or if it shortens or prolongs length of hospital stay.     

Towards precision dosing of vancomycin: a systematic evaluation of pharmacometric models for Bayesian forecasting

ObjectivesVancomycin is a vital treatment option for patients suffering from critical infections, and therapeutic drug monitoring is recommended. Bayesian forecasting is reported to improve trough concentration monitoring for dose adjustment. However, the predictive performance of pharmacokinetic models that are utilized for Bayesian forecasting has not been systematically evaluated.MethodThirty-one published population pharmacokinetic models for vancomycin were encoded in NONMEM®7.4. Data from 292 hospitalized patients were used to evaluate the predictive performance (forecasting bias and precision, visual predictive checks) of the models to forecast vancomycin concentrations and area under the curve (AUC) by (a) a priori prediction, i.e., solely by patient characteristics, and (b) also including measured vancomycin concentrations from previous dosing occasions using Bayesian forecasting.ResultsA priori prediction varied substantially—relative bias (rBias): –122.7–67.96%, relative root mean squared error (rRMSE) 44.3–136.8%, respectively—and was best for models which included body weight and creatinine clearance as covariates. The model by Goti et al. displayed the best predictive performance with an rBias of –4.41% and an rRMSE of 44.3%, as well as the most accurate visual predictive checks and AUC predictions. Models with less accurate predictive performance provided distorted AUC predictions which may lead to inappropriate dosing decisions.ConclusionThere is a diverse landscape of population pharmacokinetic models for vancomycin with varied predictive performance in Bayesian forecasting. Our study revealed the Goti model as suitable for improving precision dosing in hospitalized patients. Therefore, it should be used to drive vancomycin dosing decisions, and studies to link this finding to clinical outcomes are warranted.     

Effect of hydroxychloroquine with or without azithromycin on the mortality of coronavirus disease 2019 (COVID-19) patients: a systematic review and meta-analysis

BackgroundHydroxychloroquine or chloroquine with or without azithromycin have been widely promoted to treat coronavirus disease 2019 (COVID-19) following early in vitro antiviral effects against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).ObjectiveThe aim of this systematic review and meta-analysis was to assess whether chloroquine or hydroxychloroquine with or without azithromycin decreased COVID-19 mortality compared with the standard of care.Data sourcesPubMed, Web of Science, Embase Cochrane Library, Google Scholar and MedRxiv were searched up to 25 July 2020.Study eligibility criteriaWe included published and unpublished studies comparing the mortality rate between patients treated with chloroquine or hydroxychloroquine with or without azithromycin and patients managed with standard of care.ParticipantsPatients ≥18 years old with confirmed COVID-19.InterventionsChloroquine or hydroxychloroquine with or without azithromycin.MethodsEffect sizes were pooled using a random-effects model. Multiple subgroup analyses were conducted to assess drug safety.ResultsThe initial search yielded 839 articles, of which 29 met our inclusion criteria. All studies except one were conducted on hospitalized patients and evaluated the effects of hydroxychloroquine with or without azithromycin. Among the 29 articles, three were randomized controlled trials, one was a non-randomized trial and 25 were observational studies, including 11 with a critical risk of bias and 14 with a serious or moderate risk of bias. After excluding studies with critical risk of bias, the meta-analysis included 11 932 participants for the hydroxychloroquine group, 8081 for the hydroxychloroquine with azithromycin group and 12 930 for the control group. Hydroxychloroquine was not significantly associated with mortality: pooled relative risk (RR) 0.83 (95% CI 0.65–1.06, n = 17 studies) for all studies and RR = 1.09 (95% CI 0.97–1.24, n = 3 studies) for randomized controlled trials. Hydroxychloroquine with azithromycin was associated with an increased mortality (RR = 1.27; 95% CI 1.04–1.54, n = 7 studies). We found similar results with a Bayesian meta-analysis.ConclusionHydroxychloroquine alone was not associated with reduced mortality in hospitalized COVID-19 patients but the combination of hydroxychloroquine and azithromycin significantly increased mortality.