Edaravone for Acute Ischemic Stroke: A Systematic Review and Meta-analysis

PurposeThe management of acute stroke is challenging. The aim of this meta-analysis was to determine the efficacy and tolerability of edaravone, with or without thrombolytic therapy, in the treatment of patients with acute ischemic stroke.MethodsThe PubMed, EMBASE, and Cochrane databases were searched for randomized controlled trials (RCTs) and cohort studies. Mean differences (MD), risk ratios (RR), 95% confidence interval (CI), and heterogeneity were calculated.FindingsTotals of nine RCTs and four cohort studies were included, for a total of 2102 patients. In patients with acute ischemic stroke, edaravone monotherapy was associated with significantly improved Barthel Index of functioning in activities for daily living (MD, 23.95; 95% CI, 18.48 to 29.41; P < 0.001) and neurologic deficit, (as measured using the National Institutes of Health Stroke Scale score) (MD = –3.49; 95% CI, –5.76 to 1.22; P = 0.003), on short-term follow-up. However, edaravone was not associated with an improved rate of death or disability (RR = 0.75; 95% CI, 0.45 to 1.23; P = 0.25) on long-term follow-up.When plus to thrombolytic therapy, edaravone was associated with significant improvements in recanalization rate (RR = 1.71; 95% CI, 1.05 to 2.77; P = 0.03) and neurologic deficit (MD = 3.97; 95% CI, 5.14 to 2.79; P < 0.001), without an increase in the prevalence of bleeding events (RR = 1.11; 95% CI, 0.76 to 1.62; P = 0.59). However, edaravone did not have a significant effect on death or disability (RR = 0.85; 95% CI, 0.69 to 1.04; P = 0.12).ImplicationsBased on the findings from the present meta-analysis, edaravone was an effective and well-tolerated neuroprotective agent in these patients with ischemic stroke. With the use of edaravone, activities of daily living and neurologic deficits, along with recanalization rates, were improved on short-term follow-up, but the long-term effects still need confirmation in larger-scale clinical trials.     

Effect of Omega-3 Dosage on Cardiovascular Outcomes: An Updated Meta-Analysis and Meta-Regression of Interventional Trials

ObjectivesTo quantify the effect of eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids on cardiovascular disease (CVD) prevention and the effect of dosage.MethodsThis study is designed as a random effects meta-analysis and meta-regression of randomized control trials with EPA/DHA supplementation. This is an update and expanded analysis of a previously published meta-analysis which covers all randomized control trials with EPA/DHA interventions and cardiovascular outcomes published before August 2019. The outcomes included are myocardial infarction (MI), coronary heart disease (CHD) events, CVD events (a composite of MI, angina, stroke, heart failure, peripheral arterial disease, sudden death, and non-scheduled cardiovascular surgical interventions), CHD mortality and fatal MI. The strength of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework.ResultsA total of 40 studies with a combined 135,267 participants were included. Supplementation was associated with reduced risk of MI (relative risk [RR], 0.87; 95% CI, 0.80 to 0.96), high certainty number needed to treat (NNT) of 272; CHD events (RR, 0.90; 95% CI, 0.84 to 0.97), high certainty NNT of 192; fatal MI (RR, 0.65; 95% CI, 0.46 to 0.91]), moderate certainty NNT = 128; and CHD mortality (RR, 0.91; 95% CI, 0.85 to 0.98), low certainty NNT = 431, but not CVD events (RR, 0.95; 95% CI, 0.90 to 1.00). The effect is dose dependent for CVD events and MI.ConclusionCardiovascular disease remains the leading cause of death worldwide. Supplementation with EPA and DHA is an effective lifestyle strategy for CVD prevention, and the protective effect probably increases with dosage.     

A meta-analysis of the target trough concentration of gentamicin and amikacin for reducing the risk of nephrotoxicity

IntroductionAntimicrobial resistance is one of the biggest threats to public health systems worldwide, and aminoglycosides are key drugs for treating drug-resistant infections. Because of the nephrotoxicity of aminoglycosides, therapeutic drug monitoring is recommended, but few studies of the target trough concentration (Cmin) have been reported. To address the problem, we performed a meta-analysis to confirm the target Cmin of aminoglycosides for minimizing the risk of nephrotoxicity.MethodsWe conducted a literature search using MEDLINE, the Cochrane Library, and Ichushi-Web. In the meta-analysis, nephrotoxicity was compared between the Cmin ≥2 mg/L and Cmin <2 mg/L groups for gentamicin and between the Cmin ≥10 mg/L and Cmin <10 mg/L groups for amikacin.ResultsNo randomized controlled trials were reported for any of the drugs. Five observational studies involving 615 patients were reported for gentamicin, and two observational studies involving 159 patients were identified for amikacin. For gentamicin, Cmin <2 mg/L was linked to a significantly lower rate of nephrotoxicity than Cmin ≥2 mg/L (odds ratio [OR] = 0.22, 95% confidence interval [CI] = 0.12–0.40). For amikacin, Cmin <10 mg/L was associated with a significantly lower rate of nephrotoxicity than Cmin ≥10 mg/L (OR = 0.05, 95% CI = 0.01–0.21).ConclusionsAlthough further well-controlled studies with a low risk of bias are needed, the current meta-analysis demonstrated that Cmin <2 mg/L and Cmin <10 mg/L may reduce the risk of nephrotoxicity linked to gentamicin and amikacin, respectively.     

Effects of Tai Chi on Lower Limb Proprioception in Adults Aged Over 55: A Systematic Review and Meta-Analysis

ObjectiveTo summarize and critically evaluate the effects of Tai Chi on lower limb proprioception in adults older than 55.Data SourcesSeven databases (Scopus, PubMed, Web of Science, SPORTDiscus, Cochrane Library, Wanfang, CNKI) were searched from inception until April 14, 2018.Study SelectionEleven randomized controlled trials were included for meta-analysis.Data ExtractionTwo independent reviewers screened potentially relevant studies based on the inclusion criteria, extracted data, and assessed methodological quality of the eligible studies using the Physiotherapy Evidence Database (PEDro).Data SynthesisThe pooled effect size (standardized mean difference [SMD]) was calculated while the random-effects model was selected. Physiotherapy Evidence Database scores ranged from 5 to 8 points (mean=6.7). The study results showed that Tai Chi had significantly positive effects on lower limb joint proprioception. Effect sizes were moderate to large, including ankle plantar flexion (SMD=−0.55; 95% confidence interval [95% CI], −0.9 to −0.2; P=.002; I²=0%; n=162), dorsiflexion (SMD=−0.75; 95% CI, −1.11 to −0.39; P<.001; I²=0%; n=162), nondominant or left knee flexion (SMD=−0.71; 95% CI, −1.10 to −0.41; P<.001; I²=25.1%; n=266), dominant or right knee flexion (SMD=−0.82; 95% CI, −1.06 to −0.58; P<.001; I²=33.8%; n=464).ConclusionsThere is moderate to strong evidence that suggests that Tai Chi is an effective intervention to maintain and improve lower limb proprioception in adults older than 55. More robust multicenter studies including oldest-old participants, with longer follow-ups and validated outcome measures, are needed before a definitive conclusion is drawn.     

Critically ill patients with COVID-19 in Tokyo,Japan: A single-center case series

IntroductionWe reported, in our previous study, a patient with coronavirus disease 2019 (COVID-19) who was successfully treated with extracorporeal membrane oxygenation. Data on clinical courses and outcomes of critically ill patients with COVID-19 in Japan are limited in the literature. This study aimed to describe the clinical courses and outcomes of critically ill patients with COVID-19 in Tokyo, Japan.MethodsThis is a single-center case series study. Patients with COVID-19 treated with mechanical ventilation (MV) were reviewed retrospectively. Data on baseline characteristics, in-hospital treatment, and outcomes were collected.ResultsBetween February 2, 2020, and June 30, 2020, 14 critically ill patients with COVID-19 were treated with MV. Most patients were male and had comorbidities, especially hypertension or diabetes; 35.7% were overweight and 21.4% were obese. The majority of the patients had dyspnea on admission. The median duration of MV was 10.5 days, and the 28-day mortality rate was 35.7%. In the four patients with COVID-19 who died, the cause of death was respiratory failure.ConclusionsAs in previous reports from other countries, the mortality rate of patients with COVID-19 requiring intensive care remains high in Tokyo. Further study on the appropriate timing of MV initiation and specific treatments for critically ill patients with COVID-19 is needed.     

Effect of the Renin-Angiotensin System Inhibitors on Inflammatory Markers: A Systematic Review and Meta-analysis of Randomized Controlled Trials

ObjectiveTo synthesize more conclusive evidence on the anti-inflammatory effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs).MethodsPubMed, Scopus, and Embase were searched from inception until March 1, 2021. We included randomized controlled trials (RCTs) that assessed the effect of ACEIs or ARBs, compared with placebo, on any of the following markers: C-reactive protein (CRP), interleukin 6 (IL-6), or tumor necrosis factor α (TNF-α). Mean changes in the levels of these markers were pooled as a weighted mean difference (WMD) with a 95% CI.ResultsThirty-two RCTs (n=3489 patients) were included in the final analysis. Overall pooled analysis suggested that ACEIs significantly reduced plasma levels of CRP (WMD, ?0.54 [95% CI, ?0.88 to ?0.21]; P=.002; I²=96%), IL-6 (WMD, ?0.84 [95% CI, ?1.03 to ?0.64]; P<.001; I²=0%), and TNF-α (WMD, ?12.75 [95% CI, ?17.20 to ?8.29]; P<.001; I²=99%). Moreover, ARBs showed a significant reduction only in IL-6 (WMD, ?1.34 [95% CI, ?2.65 to ?0.04]; P=.04; I²=85%) and did not significantly affect CRP (P=.15) or TNF-α (P=.97) levels. The lowering effect of ACEIs on CRP levels remained significant with enalapril (P=.006) and perindopril (P=.01) as well as with a treatment duration of less than 24 weeks (WMD, -0.67 [95% CI, ?1.07 to -0.27]; P=.001; I²=94%) and in patients with coronary artery disease (WMD, ?0.75 [95% CI, ?1.17 to ?0.33]; P<.001; I²=96%).ConclusionBased on this meta-analysis, ACEIs showed a beneficial lowering effect on CRP, IL-6, and TNF-α, whereas ARBs were effective as a class in reduction of IL-6 only.     

Indirect Comparison of Glucocorticoid-Sparing Agents for Remission Maintenance in Giant Cell Arteritis: A Network Meta-analysis

ObjectiveTo compare and rank the effect of glucocorticoid-sparing agents in giant cell arteritis (GCA), for which several drugs have been evaluated but with a benefit-risk balance that remains uncertain.MethodsThe MEDLINE and Clinical Trials databases were searched up to November 2021; all randomized controlled trials investigating glucocorticoids in GCA were included. The glucocorticoid regimen was dichotomized into short (≤6 months) or prolonged (>6 months) use. Risk of relapse and safety were estimated using network meta-analysis with frequentist random effects models.ResultsOf the 96 records screened, 8 trials were included (572 patients). The trials compared glucocorticoids and a sparing agent: tocilizumab (2 trials), oral methotrexate (3 trials), infliximab (1 trial), etanercept (1 trial), and adalimumab (1 trial). The pooled prevalence of GCA relapse was 52.6% (95% CI, 38.1 to 66.9). The risk of relapse was significantly lower with tocilizumab compared with methotrexate (relative risk [RR], 0.41; 95% CI, 0.17 to 0.97) and prolonged (RR, 0.41; 95% CI, 0.20 to 0.83) and short (RR, 0.32; 95% CI, 0.16 to 0.66) glucocorticoid use. The risk of relapse was not significantly different with methotrexate compared with short (RR, 0.79; 95% CI, 0.48 to 1.31) and prolonged (RR, 0.95; 95% CI, 0.31 to 2.89) glucocorticoid use. The frequency of serious adverse events and serious infection was comparable between the different drugs. The certainty of the evidence was low to very low.ConclusionThis meta-analysis suggests that tocilizumab may be superior to other sparing agents to prevent GCA relapse, but with a low to very low certainty of evidence, and that safety is comparable to the other drugs.RegistrationThe protocol of the meta-analysis is registered in the international prospective register of systematic reviews PROSPERO (https://www.crd.york.ac.uk/prospero/; registration CRD42020112387).     

Polyhexamethylene biguanide discs versus unmedicated dressings for prevention of central venous catheter–associated infection in the intensive care unit: A pilot randomised controlled trial to assess protocol safety and feasibility

BackgroundCentral venous catheters are prone to infectious complications, affecting morbidity, mortality and healthcare costs. Polyhexamethylene biguanide-impregnated discs at the catheter insertion site may prevent local and bloodstream infection; however, efficacy has not been established in a critical care setting.ObjectiveThe objective of this study was to pilot test polyhexamethylene biguanide–impregnated discs compared to standard unmedicated dressings for central venous catheter infection prevention in critically ill patients.MethodsThis was a single-centre pilot randomised controlled trial. Adults admitted to intensive care requiring a central venous catheter for >72 h were eligible. Patients with a current bloodstream infection, concurrent central venous catheter, chlorhexidine or polyhexamethylene biguanide allergy, or sensitive skin were excluded. Patients were randomised to receive standard central venous catheter dressings with/without polyhexamethylene biguanide discs.Outcome measuresThe primary outcome was feasibility, defined by patient eligibility, recruitment, retention, protocol adherence, missing data, and staff satisfaction. Secondary outcomes included: central line–associated infection; primary bloodstream infection; local infection; skin complications; device/dressing dwell time; serious adverse events, and cost-effectiveness.ResultsOf 309 patients screened, 80 participants were recruited with 98% (n = 78) receiving an internal jugular catheter which dwelled for a median of 5 days (interquartile range = 4.0, 6.0). Feasibility criteria were predominantly met (recruitment 88%; retention 100%; protocol fidelity 91%); however, eligibility criteria were not met (32%; most commonly owing to short predicted catheter dwell). Staff acceptability criteria were met, with 83% of staff scoring dressing application and removal ≥7 on a numerical rating scale. There were no central line–associated bloodstream infections and no local infections. Insertion site itch occurred in 4% (control [n = 0], intervention [n = 3]) of participants, while 32% (24/76) reported pain, and 46% (35/76) tenderness.ConclusionsPolyhexamethylene biguanide discs appear safe for central venous catheter infection prevention. Feasibility of a large efficacy trial was established with some modifications to screening processes. Large, adequately powered randomised controlled trials are needed to test the infection prevention hypotheses.     

Assessment of anti-inflammatory efficacy of acupuncture in patients with inflammatory bowel disease: A systematic review and meta-analysis

BackgroundInflammation has a significant role in the onset and progression of inflammatory bowel disease (IBD). Increasing attention has been paid to the use of acupuncture in IBD patients; however, its regulatory effects on inflammatory factors in IBD still require validation. Here, we systematically evaluated the effects of acupuncture on inflammatory factors in IBD patients.MethodsEight electronic databases were searched for studies that met the inclusion criteria. After evaluating the quality of the studies selected by two reviewers, the meta-analysis was performed to assess the efficacy of acupuncture in IBD patients and the impact on inflammatory factors (TNF-α, IL-1, IL-8 and IL-10).ResultsFour randomized controlled trials with a total of 228 patients satisfied the inclusion criteria. Acupuncture has a positive therapeutic impact on IBD (MD = 1.22, 95% CI [1.07, 1.39], P = 0.003). Moreover, it regulates the levels of TNF-α (MD =−60.58, 95% CI [−100.30, −20.89], P = 0.003), IL-8 (MD =−56.40, 95% CI [−60.02, −52.14], P < 0.00001) and IL-10 (MD =35.96, 95% CI [11.02, 60.91], P = 0.005) in IBD patients. However, the P value of meta-analysis in IL-1 great than 0.05.(MD =−27.90, 95% CI [−97.82, 42.02], P = 0.11).ConclusionAcupuncture has a positive therapeutic impact on IBD and can effectively regulate inflammatory factors in IBD patients. TNF-α, IL-8 and IL-10 are more appropriate inflammatory indicators for clinically evaluating the anti-inflammatory response in the blood of IBD patients by acupuncture.     

Multiple comorbidities increase the risk of death from invasive pneumococcal disease under the age of 65 years

IntroductionRisk factors for death from invasive pneumococcal disease (IPD) have not been clearly established in patients aged under 65 years. We aimed to evaluate contributions of host and bacterial factors to the risk of death from IPD in patients aged under 65 years in Japan.MethodsIn this prospective, observational, multicenter cohort study, patients with IPD (n = 581) aged 6–64 years were enrolled between 2010 and 2017. We investigated the role of host and bacterial factors in 28-day mortality.ResultsThe mortality rate increased from 3.4% to 6.2% in patients aged 6–44 years to 15.5%–19.5% in those aged 45–64 years. Multivariable analysis identified the following risk factors for mortality: age 45–64 years (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6–6.8, p = 0.001), bacteremia with unknown focus (HR, 2.0; 95% CI, 1.1–3.7, p = 0.024), meningitis (HR, 2.1; 95% CI, 1.1–4.0, p = 0.019), underlying multiple non-immunocompromising conditions (HR, 2.6; 95% CI, 1.1–7.4, p = 0.023), and immunocompromising conditions related to malignancy (HR, 2.4; 95% CI, 1.0–5.2, p = 0.039). Pneumococcal serotype was not associated with poor outcomes.ConclusionsHost factors, including age of 45–64 years and underlying multiple non-immunocompromising conditions, are important for the prognosis of IPD. Our results will contribute to the development of targeted pneumococcal vaccination strategies in Japan.     

Pneumococcal vaccination reduces in-hospital mortality,length of stay and medical expenditure in hospitalized elderly patients

Pneumococcal vaccination has been shown to reduce occurrence of invasive pneumococcal diseases in elderly patients. In this study, we investigated the real-world efficacy of pneumococcal vaccination implemented in elderly individuals in Japan. We reviewed the in-patient database of Juntendo University Hospital and selected elderly patients (≥65 years-old) who had received in-patient care in the general medicine department during 2014–2018. A total of 1355 patients were retrospectively enrolled and comprised of 1045 unvaccinated and 315 vaccinated elderly individuals. Prior vaccination was found associated with all-cause shorter hospital stays (adjusted RR = 0.66, 95% CI = 0.57 to 0.76) and less medical expenditure (adjusted RR = 0.76, 95% CI = 0.66 to 0.87) compared with no vaccination, as well as protection for all-cause in-hospital mortality (adjusted OR = 0.42, 95% CI = 0.22 to 0.83). The association of shorter hospital stays and less medical expenditure with vaccination was also observed in the context of pneumonia, although no altered risk in mortality was observed. In conclusion, this study is one of the first reporting real-world data after the initiation of pneumococcal vaccination program in 2014 in Japan. The national PPV23 vaccination program contributed to the reduction of all-cause in-patient days, mortality, and medical expenses in the elderly aged ≥65 years. Further data is warranted to evaluate the contribution from influenza vaccination and protein-conjugate based pneumococcal vaccine.     

Effectiveness of Physical Therapy Interventions in Reducing Fear of Falling Among Individuals With Neurologic Diseases: A Systematic Review and Meta-analysis

ObjectiveTo summarize the effectiveness of physical therapy interventions to reduce fear of falling (FOF) among individuals living with neurologic diseases.Data SourcesPubMed, Physiotherapy Evidence Database, Scopus, Web of Science, PsycINFO, Cumulative Index to Nursing and Allied Health, and SportDiscuss were searched from inception until December 2019.Study SelectionClinical trials with either the primary or secondary aim to reduce FOF among adults with neurologic diseases were selected.Data ExtractionPotential articles were screened for eligibility, and data were extracted by 2 independent researchers. Risk of bias was assessed by the Cochrane Risk of Bias tool for randomized controlled trials and the National Institutes of Health Quality Assessment Tool for pre-post studies. A meta-analysis was performed among trials presenting with similar clinical characteristics. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used to rate the overall quality of evidence.ResultsSixty-one trials with 3954 participants were included in the review and 53 trials with 3524 participants in the meta-analysis. The included studies presented, in general, with a low to high risk of bias. A combination of gait and balance training was significantly more effective compared with gait training alone in reducing FOF among individuals with Parkinson disease (PD) (mean difference [MD]=11.80; 95% CI, 8.22-15.38; P<.001). Home-based exercise and leisure exercise demonstrated significant improvement in reducing FOF over usual care in multiple sclerosis (MS) (MD=15.27; 95% CI, 6.15-24.38; P=.001). No statistically significant between-groups differences were reported among individuals with stroke and spinal cord injury. The overall quality of evidence presented in this review ranges from very low to moderate according to the assessment with the GRADE approach.ConclusionsGait with lower limb training combined with balance training is effective in reducing FOF in individuals with PD. Also, home-based or leisure exercise is effective among individuals with MS. However, because of several limitations of the included studies, further research is needed to examine the effectiveness of FOF intervention among individuals with neurologic diseases.     

Clinical characteristics and prognosis of immunosuppressed inpatients with COVID-19 in Japan

IntroductionWe aimed to analyze the clinical characteristics and outcomes of immunosuppressed inpatients with coronavirus disease 2019 (COVID-19).MethodsIn this observational study, we utilized a large nationwide registry of hospitalized patients with COVID-19 in Japan. Patients’ baseline characteristics and outcomes were compared according to the immunosuppressed states of the patients. The impact of different therapeutic agents on the clinical courses of the patients was evaluated.ResultsData of 14,760 patients were included, and 887 (5.9%) were immunosuppressed. The immunosuppressed state of the patient resulted from solid tumor (43.3%, n = 384), chemotherapy within 3 months (15.6%, n = 138), collagen disease (16.9%, n = 150), use of immunosuppressive agents (16.0%, n = 142), and metastatic solid tumor (13.5%, n = 120). Immunosuppressed patients were older and had a higher severity of illness at admission and during hospitalization than non-immunosuppressed patients. The mortality rates for major diseases causing immunosuppression were as follows: solid tumor, 12.5% (48/384; P < 0.001; relative risk [RR], 3.41); metastatic solid tumor, 31.7% (38/120; P < 0.001; RR, 8.43); leukemia, 23.1% (9/39; P < 0.001; RR, 5.87); lymphoma, 33.3% (20/60; P < 0.001; RR, 8.63); and collagen disease, 15.3% (23/150; P < 0.001; RR 3.97). Underlying diseases with high mortality rates were not necessarily associated with high rates of invasive supportive care.ConclusionsThe prognosis of immunosuppressed COVID-19 inpatients varied according to the different immunosuppressed states. Multiple factors, including the severity of the underlying diseases, might have affected their invasive supportive care indications.     

Janus Kinase Inhibitors and Risk of Venous Thromboembolism: A Systematic Review and Meta-analysis

ObjectiveTo assess the risk of venous thromboembolism (VTE) in patients treated with Janus kinase (JAK) inhibitors in clinical trials.Patients and MethodsWe performed a literature search of Ovid MEDLINE and ePub Ahead of Print, In-Process & Other Non-Indexed Citations, and Daily; Ovid EMBASE; Ovid Cochrane Central Register of Controlled Trials; Ovid Cochrane Database of Systematic Reviews; and Scopus, from inception to December 4, 2019, for randomized, placebo-controlled trials with JAK inhibitors as an intervention and reported adverse events. Odds ratio with 95% CI was calculated to estimate the VTE risk using a random effects model. Two independent reviewers screened and extracted data. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to assess certainty in estimated VTE risk.ResultsWe included 29 trials (13,910 patients). No statistically significant association was found between use of JAK inhibitors and risk of VTE (odds ratio, 0.91; 95% CI, 0.57 to 1.47; P=.70; I²=0; low certainty because of serious imprecision). Results using Bayesian analysis were consistent with those of the primary analysis. Results of stratified and meta-regression analyses suggested no interaction by dose of drug, indication for treatment, or length of follow-up.ConclusionWe found insufficient evidence to support an increased risk of JAK inhibitor–associated VTE based on currently available data.     

Effect of renal clearance on vancomycin area under the concentration–time curve deviations in critically ill patients

IntroductionAugmented renal clearance (ARC) increases vancomycin (VCM) clearance. Therefore, higher VCM doses are recommended in patients with ARC; however, impacts of ARC on the area under the concentration–time curve (AUC) discrepancies between initial dosing design and therapeutic drug monitoring (TDM) period remains unclear.MethodsWe retrospectively collected data from critically ill patients treated with VCM. The primary endpoint was the association between ARC and AUC_24–48h deviations. ARC and AUC deviation were defined as a serum creatinine clearance (CCr) ≥130 mL/min/1.73 m² and an AUC at TDM 30% or more higher than the AUC at the initial dosing design, respectively. The pharmacokinetic profiles of VCM were analyzed with the trough levels or peak/trough levels using the Bayesian estimation software Practical AUC-guided TDM (PAT).ResultsAmong 141 patients (median [IQR]; 66 [58–74] years old; 30% women), 35 (25%) had ARC. AUC deviations were significantly more frequent in the ARC group than in the non-ARC group (20/35 [57.1%] and 17/106 [16.0%] patients, respectively, p < 0.001). Age- and sex-adjusted multivariate analyses revealed that the number of VCM doses before TDM ≥5 (odds ratio, 2.56; 95% confidence interval [CI]: 1.01–6.44, p = 0.047) and CCr ≥130 mL/min/1.73 m² were significantly associated with AUC deviations (odds ratio, 7.86; 95%CI: 2.91–21.19, p < 0.001).ConclusionOur study clarifies that the AUC of VCM in patients with ARC is higher at the time of TDM than at the time of dosage design.     

Drastic reduction in pneumococcal meningitis in children owing to the introduction of pneumococcal conjugate vaccines: Longitudinal analysis from 2002 to 2016 in Japan

IntroductionThe characteristics of pneumococcal isolates and their associations with outcomes in pediatric meningitis are unclear. This study aimed to clarify serotypes and resistance genotypes of Streptococcus pneumoniae from children with meningitis and evaluate the patient prognoses and backgrounds.MethodsLarge-scale surveillance was conducted from 2002 to 2016 through periods I–V. Serotypes and penicillin (PEN) resistance genotypes were analyzed for pneumococcal isolates (n = 459) and cerebrospinal fluid (CSF) samples (n = 25). Furthermore, underlying diseases (n = 251), prognoses (n = 202), and laboratory data were evaluated.ResultsThe number of meningitis cases decreased drastically after the introduction of 7-valent pneumococcal conjugate vaccine (PCV7) to ?53.6% and after switching to PCV13 to ?70.2%. In particular, this reduction was apparent at ≤3 years of age. The proportion of the PCV7 serotype decreased sharply from 70.1% before introduction to 2.6% during period V; however, the non-vaccine type increased from 17.5% to 87.2%. The PEN resistance rate (gPRSP) was decreased from approximately 49% to 12.2% during period V. Among cases revealed prognosis, sequelae and mortality rates were 16.3% and 5.4%, respectively. The rate of the patients with underlying diseases was 26.3% and relatively high in ≥6 years. Laboratory data associated with a poor prognosis were low white blood cell count (<12.7 × 10³/μL), low platelet count (<28.1 × 10⁴/μL), low CSF-glucose (<36 mg/dL), and high CSF-protein (≥142 mg/dL).ConclusionsChanges in serotype prevalence warrant continuous monitoring to observe future trends of pneumococcal meningitis, and further developments in multivalent conjugate vaccines are required.     

Usefulness of β-lactam and macrolide combination therapy for treating community-acquired pneumonia patients hospitalized in the intensive care unit: Propensity score analysis of a prospective cohort study

IntroductionWhether β-lactam and macrolide combination therapy reduces mortality in severe community-acquired pneumonia (SCAP) patients hospitalized in the intensive care unit (ICU) is controversial. The aim of the present study was to evaluate the usefulness of β-lactam and macrolide combination therapy for SCAP patients hospitalized in the ICU.MethodsA prospective, observational, cohort study of hospitalized pneumonia patients was performed. Hospitalized SCAP patients admitted to the ICU within 24 h between October 2010 and October 2017 were included for analysis. The primary outcome was 30-day mortality, and secondary outcomes were 14-day mortality and ICU mortality. Inverse probability of treatment weighting (IPTW) analysis as a propensity score analysis was used to reduce biases, including six covariates: age, sex, C-reactive protein, albumin, Pneumonia Severity Index score, and APACHE II score.ResultsA total of 78 patients were included, with 48 patients in the non-macrolide-containing β-lactam therapy group and 30 patients in the macrolide combination therapy group. β-lactam and macrolide combination therapy significantly decreased 30-day mortality (16.7% vs. 43.8%; P = 0.015) and 14-day mortality (6.7% vs. 31.3%; P = 0.020), but not ICU mortality (10% vs 27.1%, P = 0.08) compared with non-macrolide-containing β-lactam therapy. After adjusting by IPTW, macrolide combination therapy also decreased 30-day mortality (odds ratio, 0.29; 95%CI, 0.09–0.96; P = 0.04) and 14-day mortality (odds ratio, 0.19; 95%CI, 0.04–0.92; P = 0.04), but not ICU mortality (odds ratio, 0.34; 95%CI, 0.08–1.36; P = 0.13).ConclusionsCombination therapy with β-lactam and macrolides significantly improved the prognosis of SCAP patients hospitalized in the ICU compared with a non-macrolide-containing β-lactam regimen.     

Geographic Inequalities in Cardiovascular Mortality in the United States: 1999 to 2018

ObjectiveTo evaluate the trends in cardiovascular, ischemic heart disease (IHD), stroke, and heart failure mortality in the stroke belt in comparison with the rest of the United States.Patients and MethodsWe evaluated the nationwide mortality data of all Americans from the Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research database from 1999 to 2018. Cause-specific deaths were identified in the stroke belt and nonstroke belt populations using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. The relative percentage gap was estimated as the absolute difference computed relative to nonstroke belt mortality. Piecewise linear regression and age-period-cohort modeling were used to assess, respectively, the trends and to forecast mortality across the 2 regions.ResultsThe cardiovascular mortality rate (per 100,000 persons) was 288.3 (95% CI, 288.0 to 288.6; 3,684,273 deaths) in the stroke belt region and 251.2 (95% CI, 251.0 to 251.3; 13,296,164 deaths) in the nonstroke belt region. In the stroke belt region, age-adjusted mortality rates due to all cardiovascular causes (average annual percentage change [AAPC] in mortality rates, ?2.4; 95% CI, ?2.8 to ?2.0), IHD (AAPC, ?3.8; 95% CI, ?4.2 to ?3.5), and stroke (AAPC, ?2.8; 95% CI, ?3.4 to ?2.1) declined from 1999 to 2018. A similar decline in cardiovascular (AAPC, ?2.5; 95% CI, ?3.0 to ?2.0), IHD (AAPC, ?4.0; 95% CI, ?4.3 to ?3.7), and stroke (AAPC, ?2.9; 95% CI, ?3.2 to ?2.2) mortality was seen in the nonstroke belt region. There was no overall change in heart failure mortality in both regions (P_AAPC>.05). The cardiovascular mortality gap was 11.8% in 1999 and 15.9% in 2018, with a modest reduction in absolute mortality rate difference (~7 deaths per 100,000 persons). These patterns were consistent across subgroups of age, sex, race, and urbanization status. An estimated 101,953 additional cardiovascular deaths need to be prevented from 2020 to 2025 in the stroke belt to ameliorate the gap between the 2 regions.ConclusionDespite the overall decline, substantial geographic disparities in cardiovascular mortality persist. Novel approaches are needed to attenuate the long-standing geographic inequalities in cardiovascular mortality in the United States, which are projected to increase.     

Daily practice and prognostic factors for pneumonia caused by methicillin-resistant Staphylococcus aureus in Japan: A multicenter prospective observational cohort study

Pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA) is associated with poor clinical outcomes. We surveyed clinical outcomes of MRSA pneumonia in daily practice to identify risk factors for the clinical failure and mortality in patients with MRSA pneumonia.This multicenter prospective observational study was performed across 48 Japanese medical institutions. Adult patients with culture-positive MRSA pneumonia were recruited and treated with anti-MRSA antibiotics. The relationships between clinical and microbiological characteristics and clinical outcomes at test of cure (TOC) or 30-day all-cause mortality were analyzed.In total, 199 eligible patients, including nursing and healthcare-associated pneumonia (n = 95), hospital-acquired pneumonia (n = 76), and community-acquired pneumonia (n = 25), received initial treatment with anti-MRSA agents such as vancomycin (n = 135), linezolid (n = 36), or teicoplanin (n = 22). Overall clinical failure rate at TOC and the 30-day mortality rate were 51.1% (48/94 patients) and 33.7% (66/196 patients), respectively. Multivariable logistic regression analyses for vancomycin-treated populations revealed that abnormal white blood cell count (odds ratio [OR] 4.34, 95% confidence interval [CI] 1.31–14.39) was a risk factor for clinical failure and that no therapeutic drug monitoring (OR 3.10, 95% CI 1.35–7.12) and abnormally high C-reactive protein level (OR 3.54, 95% CI 1.26–9.92) were risk factors for mortality.In conclusion, this study provides evidence that majority of MRSA pneumonia patients are initially treated with vancomycin in Japan, and the absence of therapeutic drug monitoring for vancomycin is significantly associated with the mortality in patients with MRSA pneumonia.