One-year follow-up of COVID-19 recoverees with impaired pulmonary function: A prospective cohort study.

Decreased diffusion capacity for carbon monoxide (DLCO) is the most prevalent pulmonary testing abnormality among COVID-19 recoverees. We prospectively followed 51 individuals with impaired DLCO at an average of ∼3 months following COVID-19 and re-examined them at one year. At follow-up, mean DLCO increased from 68.0 % to 72.6 % (p = 0.002); while 33 % of the cohort experienced a clinically significant rise (>10 points) in DLCO, only 29 % normalized their values. While DLCO change did not correlate with symptoms, lack of improvement was more prevalent among individuals with obesity. Regardless of COVID-19 severity, a substantial proportion continued to exhibit DLCO impairment at 1-year.

Disparities in Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitor Prescription and Dispensing in the Israeli Population-A Retrospective Cohort Study.

OBJECTIVE: To describe disparities in prescribing and dispensing sodium-glucose cotransporter 2 inhibitors (SGLT2i) in Israel. RESEARCH DESIGN AND METHODS: This was a population-based retrospective cohort study of adults with type 2 diabetes eligible for SGLT2i treatment from 2017 to 2023. The primary outcome was the time between initial eligibility and the first prescription of SGLT2i. RESULTS: Among 32,742 eligible patients, only 53% were prescribed SGLT2i. Multivariable analyses, adjusting for death as a competing risk, revealed delays in prescription were associated with older age, Arab or Bedouin ethnicity, neoplasms, acute kidney failure, falls, previous hospitalization, urinary tract infections, and dementia. Factors associated with shorter time intervals to prescription were sex (men), medium/high socioeconomic status, and residing in an intermediate or central area of Israel. CONCLUSIONS: Disparities in drug prescription exist, even in a country with universal health coverage. Addressing these disparities requires improvements in health care systems, education, and alert systems to overcome barriers to evidence-based interventions.

The effect of obligatory Padua prediction scoring in hospitalized medically ill patients: A retrospective cohort study.

BACKGROUND: Venous thromboembolism (VTE) is considered a preventable cause of mortality. The evidence for the benefit of VTE prophylaxis in acute medical patients is non-conclusive. Meta-analysis of RCTs failed to demonstrate reduction of all-cause mortality, while showing higher risk of bleeding. The Israeli Ministry of Health has instructed to assess all acute medical patients for the risk for VTE using the Padua Prediction Score, without mandating prophylaxis. AIM: To evaluate the effect of filling the Padua score on clinical outcomes and VTE prophylaxis rates. METHODS: Retrospective Study was performed in Israel during the years 2014-2017. The participants were divided to Padua compliance vs non-compliance group. Primary outcome: 30-day mortality. Secondary outcomes: 90-day incidence of VTE and suspected major bleeding. A propensity-weighted logistic multiple regression was performed. RESULTS: 18,890 patients were included in the study. The fulfillment of the Padua score was associated with an increased use of VTE prophylaxis, OR 1.66 (95% CI 1.49-1.84). However, there was no reduction of mortality or VTE events, OR 1.13 (95% CI 0.97-1.31) and OR 1.22 (95% CI 0.79-1.8) respectively. Hospitalizations related to hemoglobin decrease were not statistically different between the two groups. CONCLUSIONS: Padua score for the assessment of VTE risk in medical wards was associated with higher administration of pharmacological prophylaxis without reduction in VTE or mortality rate. Its usage should be reassessed as a performance measure.

Universal Risk Factors for Mortality in Bloodstream Infections (UNIFORM): a systematic review and Delphi survey.

BACKGROUND: Significant variations in the variables collected in clinical studies focusing on bacteraemia lead to inconsistency in the evaluation of risk factors for mortality. OBJECTIVE: We aimed to define a minimum set of risk factors that should be assessed and reported in all studies assessing survival in bacteraemia. STUDY ELIGIBILITY: We conducted a systematic review including observational prospective and retrospective cohort studies that assessed all-cause mortality among patients with bacteraemia. We included only studies computing an adjusted analysis for mortality, with >500 participants. EXPOSURES: Independently significant risk factors for all-cause, preferably 30-day, mortality. DATA SOURCES: PubMed was used to identify eligible studies published between 2000 and 2020. A Delphi survey among experts was used to evaluate and prioritize the factors identified by the systematic review. RISK OF BIAS: SIGN checklist complemented by risk of bias assessment of the adjusted analysis. DATA SYNTHESIS: Definite universal risk factors were defined as those assessed in >50% of all included studies and significant in >50% of those. Potential universal risk factors were defined as those significant in >50% of studies evaluating the factor and a subgroup analysis was performed for studies of Staphylococcus aureus bacteraemia. RESULTS: We included in the systematic review 62 studies, comprising more than 300,000 patients, from which a list of 17 risk factors was derived, whose association with all-cause mortality was statistically significant in most studies. The factors address baseline patient variables, the setting of infection acquisition, factors associated with the specific infection, the inflammatory response at onset of sepsis and management parameters where relevant. There were 14 risk factors for S. aureus bacteraemia. CONCLUSION: We identified a minimum set of universal factors to be collected, reported, and assessed, in all future studies evaluating factors associated with mortality in bacteraemia to improve study quality and harmonization.

Graves' Disease Following COVID-19 Vaccination: A Population-based, Matched Case-control Study.

OBJECTIVE: Multiple cases and case series reported Graves' disease (GD) following coronavirus disease 2019 (COVID-19) vaccination. We aimed to determine whether COVID-19 vaccination was associated with the incidence of GD. METHODS: We analyzed data from Clalit Health Services, the largest healthcare organization in Israel, which insures 4.7 million patients. A population-based, matched, case-control study was performed. Cases were defined as adult patients diagnosed with GD between December 2020 and November 2022. Each case was matched with controls in a 1:2 ratio. Each control was assigned an index date, which was identical to that of their matched case, defined as the date of GD diagnosis. Time between vaccination date and the diagnosis of GD or index date was assessed. RESULTS: A total of 726 patients with GD were matched with 1452 controls. The study patients and controls have received similar proportions of the COVID-19 vaccine [at least 1 dose: 80% (581/726) vs 77.8% (1129/1452), P = .22, respectively]. In a univariate analysis, at least 1 dose of the COVID-19 vaccine was not associated with the incidence of GD [odds ratio 95% confidence interval: 1.15 (.92-1.43)]. The mean time between first COVID-19 vaccination and the diagnosis of GD for cases or index date for controls was not significantly different [275.69 days (SD 144.37) for cases compared to 275.45 days (SD 145.76) for controls]. CONCLUSION: Our study found no association between COVID-19 vaccination and the incidence of GD.

Impact of the 2019 Food and Drug Administration Guidance for Uncomplicated Urinary Tract Infection on Treatment Response Rates: A Reanalysis of a Clinical Trial of Nitrofurantoin vs Fosfomycin.

Background: Current US Food and Administration (FDA) guidance recommends that the primary efficacy endpoint for uncomplicated urinary tract infection (uUTI) clinical trials be a composite of clinical and microbiological responses. We applied these criteria to a previous clinical trial to determine the impact on treatment outcomes. Methods: We conducted a patient-level reanalysis of a randomized clinical trial of nitrofurantoin versus fosfomycin for treatment of uUTI in nonpregnant adult women. Women were included in the reanalysis if they had 2 or more signs/symptoms of uUTI and a single bacterial species isolated from baseline urine culture at ≥105 colony-forming units (CFU)/mL. The applied primary efficacy endpoint-therapeutic response-required both clinical resolution of signs/symptoms and reduction of the infecting bacterial pathogen to <103 CFU/mL at day 14 post-treatment completion. Results: Two hundred eleven of 513 (41%) patients were eligible for inclusion in the reanalysis. Among these patients, 74% (76/103) and 69% (75/108) in the nitrofurantoin and fosfomycin groups, respectively, achieved clinical resolution by day 14. Similarly, 70% (72/103) and 67% (72/108) in each group achieved microbiological success at day 14. As such, 59% (61/103) and 57% (62/108) of women in each group met the primary efficacy endpoint-therapeutic success-at day 14. In comparison, 75% and 66% of patients in each group achieved clinical resolution at day 14 in the initial clinical trial. Conclusions: Applying current FDA guidance resulted in lower composite efficacy rates than clinical resolution alone as observed in the initial clinical trial. This may limit the ability to compare antibiotic treatment effects between historical and future clinical trials.

Colistin Monotherapy versus Combination Therapy for Carbapenem-Resistant Organisms.

BACKGROUND: Pneumonia and bloodstream infections (BSI) due to extensively drug-resistant (XDR) Acinetobacter baumannii, XDR Pseudomonas aeruginosa, and carbapenem-resistant Enterobacterales (CRE) are associated with high mortality rates, and therapeutic options remain limited. This trial assessed whether combination therapy with colistin and meropenem was superior to colistin monotherapy for the treatment of these infections. METHODS: The OVERCOME (Colistin Monotherapy versus Combination Therapy) trial was an international, randomized, double-blind, placebo-controlled trial. We randomly assigned participants to receive colistin (5 mg/kg once followed by 1.67 mg/kg every 8 hours) in combination with either meropenem (1000 mg every 8 hours) or matching placebo for the treatment of pneumonia and/or BSI caused by XDR A. baumannii, XDR P. aeruginosa, or CRE. The primary outcome was 28-day mortality, and secondary outcomes included clinical failure and microbiologic cure. RESULTS: Between 2012 and 2020, a total of 464 participants were randomly assigned to treatment, and 423 eligible patients comprised the modified intention-to-treat population. A. baumannii was the predominant trial pathogen (78%) and pneumonia the most common index infection (70%). Most patients were in the intensive care unit at the time of enrollment (69%). There was no difference in mortality (43 vs. 37%; P=0.17), clinical failure (65 vs. 58%; difference, 6.8 percentage points; 95% confidence interval [CI], -3.1 to 16.6), microbiologic cure (65 vs. 60%; difference, 4.8 percentage points; 95% CI, -5.6 to 15.2), or adverse events (acute kidney injury, 52 vs. 49% [P=0.55]; hypersensitivity reaction, 1 vs. 3% [P=0.22]; and neurotoxicity, 5 vs. 2% [P=0.29]) between patients receiving monotherapy and combination therapy, respectively. CONCLUSIONS: Combination therapy with colistin and meropenem was not superior to colistin monotherapy for the treatment of pneumonia or BSI caused by these pathogens. (Funded by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases protocol 10-0065; ClinicalTrials.gov number, NCT01597973.).

Safety and efficacy of non-insulin therapy in non-critically ill hospitalized patients with type 2 diabetes mellitus.

INTRODUCTION: Clinical guidelines recommend insulin as the mainstay of therapy for hospitalized patients with diabetes mellitus. The aim of the current study is to evaluate safety and efficacy of non-insulin anti-hyperglycemic therapy in hospitalized patients. MATERIALS AND METHODS: Systematic review and meta-analysis of randomized controlled trials (RCTs) examining treatment of hospitalized patients with type 2 diabetes with insulin vs non-insulin therapy. We searched PubMed and the Cochrane Library for RCTs published from inception to November 30, 2022. Primary outcomes were 30-day mortality and hypoglycemic events during hospitalization. This meta-analysis includes two parts, the first is a comparison between insulin and non-insulin therapy and the second is a comparison between insulin only and a combination of insulin+non-insulin therapy. RESULTS: A total of 14 randomized control studies and 1570 patients were included. There was a lower incidence of 30-day mortality in the insulin+non-insulin group compared with the insulin group without statistical significance, RR 0.64 (95%CI 0.30-1.35). Hypoglycemic events were significantly lower with the non-insulin therapies compared to insulin therapy, RR 0.23 (95%CI 0.09-0.55). Mean daily glucose levels were significantly lower in the insulin+non-insulin group compared to the insulin group by 10.83 mg/dL (95%CI -14.78-(-6.87)). CONCLUSIONS: Non-insulin either with or without insulin, results in lower rates of hypoglycemia. Non-insulin+insulin is more effective than insulin alone in reducing blood glucose levels. Non-insulin-based therapy is safe and effective for control of hyperglycemia. Insulin combined with non-insulin drugs seems to be the preferred treatment option for the majority of hospitalized patients with type 2 DM in the non-critical care setting.

Prevalence and Clinical Consequences of Colistin Heteroresistance and Evolution into Full Resistance in Carbapenem-Resistant Acinetobacter baumannii.

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings.

Assessment of Exercise Capacity of Individuals with Long COVID: A Cross-sectional Study.

BACKGROUND: Clinical investigations of long-term effects of coronavirus disease 2019 (COVID-19) are rarely translated to objective findings. OBJECTIVES: To assess the functional capacity of individuals reported on deconditioning that hampered their return to their pre-COVID routine. METHODS: Assessment included the 6-minute walk test (6MWT) and the 30-second sit-to-stand test (30-STST). We compared the expected and observed scores using the Wilcoxon signed-rank test. Predictors of test scores were identified using linear regression models. RESULTS: We included 49 individuals, of whom 38 (77.6%) were recovering from mild COVID-19. Twenty-seven (55.1%) individuals had a 6MWT score lower than 80% of expected. The average 6MWT scores were 129.5 ± 121.2 meters and 12.2 ± 5.0 repeats lower than expected scores, respectively (P < 0.001 for both). The 6MWT score was 107.3 meters lower for individuals with severe COVID-19 (P = 0.013) and rose by 2.7 meters per each 1% increase in the diffusing capacity of carbon monoxide (P = 0.007). The 30-STST score was 3.0 repeats lower for individuals who reported moderate to severe myalgia (P = 0.038). CONCLUSIONS: Individuals with long COVID who report on deconditioning exhibit significantly decreased physical capacity, even following mild acute illness. Risk factors include severe COVID-19 and impaired diffusing capacity or myalgia during recovery.

External Validity of a Randomized Controlled Trial on Duration of Antibiotics for the Treatment of Gram-Negative Bacteremia.

INTRODUCTION: Reports regarding the external validity of randomized controlled trials (RCTs) are scarce. We aimed to assess the population external validity of an investigator-initiated RCT on the duration of antibiotics for the treatment of Gram-negative bacteremia by comparing patients included in the RCT to patients that were not included in the trial. METHODS: Hospitalized patients with Gram-negative bacteremia were recruited into an RCT and randomized to receive 7 or 14 days of covering antibiotic therapy in Israel and Italy from 2013 to 2017. In a concomitant observational study, RCT participants were compared with patients who fulfilled the inclusion criteria but were not included in the trial due to participation in other trials, discharge before approached by researchers, refusal to participate, or unwillingness of the treating physician to allow participants' recruitment. RESULTS: Six hundred and four RCT patients were compared with 613 nonincluded patients. Almost 50% of nonincluded patients (288/613) were dependent on others for activities of daily living at baseline compared to 37.7% of RCT participants (228/604). Dementia was nearly 2-fold more frequent in nonincluded patients than those included (5.9% [36/613] versus 3.6% [22/604], p = 0.07). Patients who were not included in the RCT were more likely to acquire their infection in the hospital (53.3% [327/613] versus 29.1% [176/604], p < 0.001). The primary composite outcome of mortality, clinical failure, readmissions, or extended hospitalization at 90 days occurred in 353 of 613 nonincluded patients (57.6%) compared to 299 of 604 RCT participants (49.6%), p = 0.005. However, on multivariate analysis noninclusion in the RCT was not an independent risk factor for clinical failure and mortality. CONCLUSIONS: RCTs, even with broad eligibility criteria, do not represent the whole spectrum of patients and leave out a population with more severe illness for whom the evidence is lacking.

Assessing the impact of coronavirus disease 2019 on mortality: a population-based, matched case-control study.

OBJECTIVES: Estimating the isolated effect of coronavirus disease 2019 (COVID-19) on the risk of mortality is challenging. We aimed to determine whether COVID-19 was associated with high rates of mortality independently of age, sex and underlying disorders. METHODS: A population-based, matched, case-control study of adults insured by Clalit Health Services was performed. Cases were defined as patients who died of all causes between July and December 2020. Each case was matched in a ratio of 1:1 with a living control based on age, sex and co-morbidities. An unconditional logistic regression analysis was performed to identify independent risk factors for mortality. RESULTS: A total of 2874 patients who died were successfully matched with 2874 living controls. The prevalence of COVID-19 was higher among the patients who died than among the controls (13.5% [387/2874] vs. 4% [115/2874], respectively; OR, 3.73; 95% CI, 3.01-4.63; p < 0.001). A significantly increased odds of mortality was also observed in patients with COVID-19 without underlying diseases (OR, 3.67; 95% CI, 2.58-5.23) and in patients with COVID-19 and underlying diseases (OR, 3.77; 95% CI, 2.87-4.94). A multi-variate logistic analysis showed that COVID-19 (OR, 2.01; 95% CI, 1.07-3.77), low socio-economic status (OR, 1.36; 95% CI, 1.02-1.82), dementia (OR, 2.50; 95% CI, 2.10-3.01), smoking (OR, 1.35; 95% CI, 1.13-1.63) and an interaction variable of age >80 years and COVID-19 (OR, 2.27; 95% CI, 1.14-4.54) were independent risk factors for mortality, whereas influenza vaccination and high body mass index were associated with lower rates of mortality. CONCLUSION: Testing positive for COVID-19 increased the risk of death three folds, regardless of underlying disorders. These results emphasize the effect of COVID-19 on mortality during the early period of the COVID-19 outbreak, when no vaccines or effective therapeutics were available.

Duration of antibiotic treatment for Gram-negative bacteremia - Systematic review and individual participant data (IPD) meta-analysis.

Background: We aim to compare the effect of short versus long treatment duration in Gram-negative bacteremia on all-cause mortality in pre-specified sub-groups. Methods: Individual participant data meta-analysis of randomized controlled trials (RCTs) comparing short (≤7) versus longer (>7 days) antibiotic treatment for Gram-negative bacteremia. Participants were adults (≥18 years), with Gram-negative bacteremia during hospital stay. We searched PubMed, Cochrane Central Register of Controlled Trials, and Web of Science to identify trials conducted up to May 2022. Primary outcome was 90-day all-cause mortality. Secondary outcomes were 30-day mortality, relapse of bacteremia, length of hospital stay, readmission, local or distant infection complications, adverse events, and resistance emergence.Outcomes were assessed in pre-specified subgroups: women vs men; non-urinary vs urinary source; presence vs absence of hypotension on initial presentation; immunocompromised patients versus non-immunocompromised patients, and age (above/below 65). Fixed-effect meta-analysis model was used to estimate pooled odds ratio (OR) and 95% confidence interval (CI). All three trials had low risk of bias for allocation generation and concealment. Findings: Three RCTs (1186 patients) were included; 1121 with enterobacterales bacteremia. No significant difference in mortality was demonstrated between 7- and 14-days treatment (90-day mortality: OR 1.08, 95% CI 0.73-1.58; 30-day mortality: 1.08, 0.62-1.91). Relapse (1.00, 0.50-1.97); length of hospital stay (P = 0.78); readmission (0.96, 0.80-1.22); and infection complications (local: 1.62 0.76-3.47; distant: 2.00, 0.18-22.08), were without significant difference, and so were adverse events or resistance emergence.No significant difference in clinical outcomes between 7 and 14 days of antibiotics was demonstrated in the subgroups of gender, age, hemodynamic status, immune status, and source of infection. Interpretation: For patients hemodynamically stable and afebrile at 48 h prior to discontinuation, seven days of antibiotic therapy for enterobacterales bacteremia result in similar outcomes as 14 days, in terms of mortality, relapse, length of hospital stay, complications of infection, resistance emergence, and adverse events. These results apply for any adult age group, gender, source of infection, immune status, and hemodynamic status on presentation. Funding: There was no funding source for this study.