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.

Glucagon-like Peptide 1 Receptor Agonists and Cardiovascular Outcomes in Solid Organ Transplant Recipients With Diabetes Mellitus.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in type 2 diabetes. Limited data are available on diabetes treatment after solid organ transplantation. We aimed to explore the effect of GLP1-RAs on cardiovascular outcomes in transplanted recipients with diabetes. METHODS: We extracted data on adult transplant recipients (kidney, lungs, liver, heart) insured in a large health maintenance organization. Death-censored patients with diabetes treated with GLP1-RAs were matched with nonusers. The primary outcome was a composite of major cardiovascular events (MACEs): a nonfatal cardiac event (myocardial infarction, stable/unstable angina, coronary bypass, and coronary angiography), ischemic stroke and all-cause mortality. Secondary outcomes were MACE or peripheral vascular disease (MACE-PVD), and all-cause mortality. Safety outcomes included biliopancreatic adverse events. RESULTS: We included 318 patients (69% males, average age 58.3 ±â€…11.0 y) with a 3.1-y median follow-up. The incidence of MACE was 101 of 1000 patient-years in GLP1-RAs users compared with 134 of 1000 in controls (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.27-0.78). GLP1-RAs similarly reduced the risk of MACE-PVD (HR 0.53; 95% CI, 0.33-0.88) and the risk of all-cause mortality (HR 0.39; 95% CI, 0.18-0.84). Biliopancreatic adverse events occurred less in GLP1-RA users. CONCLUSIONS: Transplant recipients with diabetes who used GLP1-RAs had lower risks for MACE and all-cause mortality. These results may profoundly implicate the daily management of posttransplant recipients with diabetes, a population with a high prevalence of cardiometabolic risk factors and cardiovascular death. Transplant patients are usually excluded from randomized controlled trials and, hence might be undertreated with disease-modifying drugs. Larger prospective studies are needed in this unique population.

Cabergoline treatment for surgery-naïve non-functioning pituitary macroadenomas.

PURPOSE: The treatment strategy of non-functioning pituitary adenomas (NFPAs) includes surgery, radiotherapy, medical therapy, or observation without intervention. Cabergoline, a dopaminergic agonist, was suggested for the treatment of NFPA remnants after trans-sphenoidal surgery. This study investigates the efficacy of cabergoline in surgery-naive patients with NFPA. METHODS: Retrospective cohort study including surgery-naive patients with NFPA ≥ 10 mm, treated with cabergoline at a dose of ≥ 1 mg/week for at least 24 months. Patients with chiasmal damage were excluded. Data collected included symptoms, in particular visual disturbances, hormonal levels, tumor characteristics and size evaluated by MRI. Tumor growth was defined as an increase in maximal diameter of ≥ 2 mm, and shrinkage as reduction of ≥ 2 mm. RESULTS: Our cohort included 25 patients treated with cabergoline as primary therapy. Mean age was 63.3 ± 17.3 years, 56% (14/25) were males. Mean tumor size at diagnosis was 18.6 ± 6.3 mm (median 17 mm, range 10-36), and the average follow-up period with cabergoline was 4.6 ± 3.4 years. Out of the 25 tumors, five tumors (20%) decreased in size (mean decrease of 5.0 ± 3.0 mm), 12 tumors (48%) remained stable, and eight (32%) increased in size (mean growth of 5.0 ± 3.3 mm) with cabergoline treatment. During the first two years of cabergoline treatment, the median tumor size exhibited a reduction of 0.5 mm. Patients with an increase in tumor size had larger adenomas at diagnosis and a longer follow-up. Two patients (8%) underwent surgery due to tumor enlargement. CONCLUSION: Primary treatment with cabergoline is a reasonable approach for selected patients with NFPAs without visual threat.

Mortality and Hospitalization Risks in Patients With Cancer and the SARS-CoV-2 Omicron Variant.

This cohort study compares the mortality and hospitalization risks among patients with vs without solid cancer and diagnosed with COVID-19 during the period when the Omicron variant was dominant.

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.

Diabetes Mellitus and Poor Glycemic Control are Associated with a Higher Risk of Lumbar Spinal Stenosis: An Analysis of a Large Nationwide Database.

STUDY DESIGN: A large-scale retrospective case-control study. OBJECTIVE: Examine diabetes as a risk factor for lumbar spinal stenosis development and evaluate the impact of diabetes duration, glycemic control, and associated complications on this risk. SUMMARY OF BACKGROUND DATA: Diabetes mellitus, a multiorgan disorder impacting various connective tissues, induces histological changes in spinal structures, particularly the ligamentum flavum. While clinical studies suggest a higher incidence of lumbar spinal stenosis in diabetic patients, substantial epidemiological research on the likelihood of lumbar spinal stenosis diagnosis in individuals with diabetes is scarce. MATERIALS AND METHODS: Using nationwide data, a total of 49,576 patients diagnosed with lumbar spinal stenosis based on ICD-10 codes were matched with controls of the same number based on age and sex. Employing a multivariable logistic regression model, the study assessed for the association between spinal stenosis and diabetes, while adjusting for confounders. RESULTS: We found a higher likelihood of lumbar spinal stenosis diagnosis in diabetic patients (OR 1.39, 95% CI 1.36 - 1.43, P<0.001). Those with HbA1c ≥7% and ≥1 diabetes-related complication also had an elevated likelihood (OR 1.19, 95% CI 1.08 - 1.31, P=0.001). Prolonged diabetes exposure increased the risk. Diabetes diagnosis reduced median survival by around 4.5 years for both stenosis and non-stenosis patients; spinal stenosis diagnosis alone minimally impacted survival. Relative to individuals diagnosed with diabetes mellitus (DM) at the age of 65 or older, the odds ratio (OR) for developing lumbar spinal stenosis (LSS) were 1.22 (95% CI 1.18 - 1.27, P<0.001) when DM was diagnosed at 50-65 years old and 1.67 (95% CI 1.56 - 1.79, P<0.001) for those under 50 years old. Multivariate analysis revealed a significantly increased risk of all-cause mortality in patients with DM and spinal stenosis (HR 1.36, 95% CI 1.29 - 1.44, P<0.001) and those with DM without stenosis (HR 1.49, 95% CI 1.41 - 1.57, P<0.001), compared to controls. CONCLUSION: Diabetic patients with prolonged disease, poor glycemic control, and diabetes-related complications face an elevated risk of developing lumbar spinal stenosis. Recognizing the reciprocal adverse relationship between these conditions is crucial in clinical practice and designing public health measures for managing both conditions. LEVEL OF EVIDENCE: 4.

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.

Underrepresentation of women in randomized controlled trials: a systematic review and meta-analysis.

BACKGROUND: Although regulatory changes towards correcting the underrepresentation of women in randomized controlled trials (RCTs) occurred (National Institutes of Health 1994), concerns exist about whether an improvement is taking place. In this systematic review and meta-analysis, we aimed to assess the inclusion rates of women in recent RCTs and to explore the potential barriers for the enrollment of women. METHODS: RCTs published in 2017 examining any type of intervention in adults were searched in PubMed and Cochrane Library. The following predefined medical fields were included: cardiovascular diseases, neoplasms, endocrine system diseases, respiratory tract diseases, bacterial and fungal infections, viral diseases, digestive system diseases, and immune system diseases. Studies were screened independently by two reviewers, and an equal number of studies was randomly selected per calendric month. The primary outcome was the enrollment rate of women, calculated as the number of randomized women patients divided by the total number of randomized patients. Rates were weighted by their inverse variance; statistical significance was tested using general linear models (GLM). RESULTS: Out of 398 RCTs assessed for eligibility, 300 RCTs were included. The enrollment rate of women in all the examined fields was lower than 50%, except for immune system diseases [median enrollment rate of 68% (IQR 46 to 81)]. The overall median enrollment rate of women was 41% (IQR 27 to 54). The median enrollment rate of women decreased with older age of the trials' participants [mean age of trials' participants ≤ 45 years: 47% (IQR 30-64), 46-55 years: 46% (IQR 33-58), 56-62 years: 38% (IQR 27-50), ≥ 63 years: 33% (IQR 20-46), p < 0.001]. Methodological quality characteristics showed no significant association with the enrollment rates of women. Out of the 300 included RCTs, eleven did not report on the number of included women. There was no significant difference between these studies and the studies included in the analysis. CONCLUSIONS: Women are being inadequately represented, in the selected medical fields analyzed in our study, in recent RCTs. Older age is a potential barrier for the enrollment of women in clinical trials. Low inclusion rates of elderly women might create a lack of crucial knowledge in the adverse effects and the benefit/risk profile of any given treatment. Factors that might hinder the participation of women should be sought and addressed in the design of the study.

Re-Admission of COVID-19 Patients Hospitalized with Omicron Variant-A Retrospective Cohort Study.

In accordance with previous publications, re-admission rates following hospitalization of patients with COVID-19 is 10%. The aim of the current study was to describe the rates and risk factors of hospital re-admissions two months following discharge from hospitalization during the fifth wave due to the dominant Omicron variant. A retrospective cohort study was performed in Rabin Medical Center, Israel, from November 2021 to February 2022. The primary outcome was re-admissions with any diagnosis; the secondary outcome was mortality within two months of discharge. Overall, 660 patients were hospitalized with a diagnosis of COVID-19. Of the 528 patients discharged from a primary hospitalization, 150 (28%) were re-admitted. A total of 164 patients (25%) died throughout the follow-up period. A multi-variable analysis determined that elevated creatinine was associated with a higher risk of re-admissions. Rates of re-admissions after discharge during the Omicron wave were considerably higher compared to previous waves. A discharge plan for surveillance and treatment following hospitalization is of great importance in the management of pandemics.

Lower serum alpha 1 antitrypsin levels in patients with severe COVID-19 compared with patients hospitalized due to non-COVID-19 pneumonia.

INTRODUCTION: Alpha 1 antitrypsin (A1AT) is the major human blood serine protease inhibitor. Transmembrane serine protease 2 (TMPRSS2), which is crucial for SARS-CoV-2 cell entry, is inhibited by A1AT. Therefore, we hypothesized that individuals with diminished levels of A1AT may be more prone to SARS-CoV-2 infection and severe COVID-19 disease. Our aim in this study was to evaluate the level of A1AT in hospitalized COVID-19 patients in comparison to hospitalized patients with non-COVID-19 pneumonia. METHODS: We conducted an observational prospective study between October 2020 and April 2021 in Rabin Medical Centre in Israel. A1AT levels were measured from the routine serum samples of hospitalized patients with COVID-19 and non-COVID-19 pneumonia (control group). The primary outcome was A1AT level, secondary outcomes were clinical outcomes and predictors of morality. RESULTS: Overall, 145 patients were included in the study, 98 in the COVID-19 group and 47 in the control group. The median A1AT level was 222 mg/dL (interquartile range (IQR) 188-269) and 258 mg/dL (IQR 210-281) in the COVID-19 and control groups, respectively (p = .045). Multivariate analysis for independent risk factors for mortality among COVID-19 patients showed that diabetes mellitus (p = .02), older age (p = .04), and high A1AT levels (p = .04) were all associated with increased mortality. CONCLUSION: Patients admitted due to severe COVID-19 had lower A1AT levels in comparison to patients admitted due to non-COVID pneumonia. This observation may suggest an association between mildly diminished A1AT and higher risk of SARS-CoV-2 infection with severe COVID-19 disease.

Predicting In-Hospital Antibiotic Use in the Medical Department: Derivation and Validation Study.

BACKGROUND: The rise of multi-drug-resistant pathogens and nosocomial infections among hospitalized patients is partially attributed to the increased use of antibiotic therapy. A prediction model for in-hospital antibiotic treatment could be valuable to target preventive strategies. METHODS: This was a retrospective cohort study, including patients admitted in 2018 to medical departments and not treated with antibiotics during the first 48 h. Data available at hospital admission were used to develop a logistic model to predict the probability of antibiotic treatment during hospitalization. The performance of the model was evaluated in two independent validation cohorts. RESULTS: In the derivation cohort, antibiotic treatment was initiated in 454 (8.1%) out of 5592 included patients. Male gender, lower functional capacity, prophylactic antibiotic treatment, medical history of atrial fibrillation, peripheral vascular disease, solid organ transplantation, chronic use of a central venous catheter, urinary catheter and nasogastric tube, albumin level, mental status and vital signs at presentation were identified as predictors for antibiotic use during hospitalization and were included in the prediction model. The area under the ROC curve (AUROC) was 0.72 (95% CI 0.70-0.75). In the highest probability group, the percentage of antibiotic treatment was 18.2% (238/1,307). In the validation cohorts, the AUROC was 0.73 (95% CI 0.68-0.77) and 0.75 (95% CI 0.72-0.78). In the highest probability group, the percentage of antibiotic treatment was 12.5% (66/526) and 20.7% (244/1179) of patients. CONCLUSIONS: Our prediction model performed well in the validation cohorts and was able to identify a subgroup of patients at high risk for antibiotic treatment.

A Desirability of Outcome Ranking Analysis of a Randomized Clinical Trial Comparing Seven Versus Fourteen Days of Antibiotics for Uncomplicated Gram-Negative Bloodstream Infection.

Background: Although a short course (7 days) of antibiotics has been demonstrated to be noninferior to a conventional course (14 days) in terms of mortality and infectious complications for patients with a Gram-negative bacterial bloodstream infection (GNB), it is unknown whether a shorter treatment duration can provide a better overall clinical outcome. Methods: We applied a bloodstream infection-specific desirability of outcome ranking (DOOR) analysis to the results of a previously completed, randomized controlled trial comparing short versus conventional course antibiotic therapy for hospitalized patients with uncomplicated GNB. We determined the probability that a randomly selected participant in the short course group would have a more desirable overall outcome than a participant in the conventional duration group. We performed (1) partial credit analyses allowing for calculated and variable weighting of DOOR ranks and (2) subgroup analyses to elucidate which patients may benefit the most from short durations of therapy. Results: For the 604 patients included in the original study (306 short course, 298 conventional course), the probability of having a more desirable outcome with a short course of antibiotics compared with a conventional course was 51.1% (95% confidence interval, 46.7% to 55.4%), indicating no significant difference. Partial credit analyses indicated that the DOOR results were similar across different patient preferences. Prespecified subgroup analyses using DOOR did not reveal significant differences between short and conventional courses of therapy. Conclusions: Both short and conventional durations of antibiotic therapy provide comparable clinical outcomes when using DOOR to consider benefits and risks of treatment options for GNB.

Frail Older Adults with Presymptomatic SARS-CoV-2 Infection: Clinical Course and Prognosis.

BACKGROUND/AIMS: The novel coronavirus SARS-CoV-2 has caused a pandemic threatening millions of people worldwide. This study aimed to describe clinical characteristics, outcomes, and risk factors of SARS-CoV-2-positive, asymptomatic, frail older adults. METHODS: A retrospective cohort study was conducted in 6 designated COVID-19 units, in skilled nursing homes. Subjects were severely frail older adults, positive for SARS-CoV-2, and asymptomatic at the time of their admission in these units. Residents' characteristics and symptoms were obtained via electronic medical records. The primary outcome was a composite of death or hospitalization by day 40. We looked at time to the primary outcome and used Cox regression for a multivariate analysis. RESULTS: During March-November 2020, 849 residents met inclusion criteria. Median age was 84 years. Most were completely dependent for basic activities of daily living and showed cognitive impairment. Six hundred forty-one (75.5%) residents were discharged after considered cured from COVID-19, 125 (14.7%) were hospitalized, and 82 (9.7%) died in the facilities. In survival analysis, 35% reached the primary outcome of death or hospitalization by day 40. Age (hazard ratio [HR] 1.23; 95% confidence interval [CI] 1.1-1.4), male gender (HR 1.41; 95% CI: 1.1-1.88), and COPD (HR 1.8; 95% CI: 1.23-2.67) were significant risk factors. CONCLUSIONS: In this large cohort, we report care and prognosis of asymptomatic older adults with major functional or cognitive impairments during the COVID-19 pandemic. Most presymptomatic patients do not develop severe infection, and age stays a predominant risk factor, even in the frailest older adults.

Risk factors for functional decline among survivors of Gram-negative bloodstream infection: A prospective cohort study.

OBJECTIVE: To identify risk factors for functional decline after hospitalization for Gram-negative bacteremia. PATIENTS AND METHODS: A prospective cohort study based on a randomized controlled trial conducted between January 1, 2013 and August 31, 2017 in Israel and Italy. Hospitalized patients with Gram-negative bacteremia who survived until day 90 and were not bedridden at baseline were included. The primary end point was functional decline at 90 days. RESULTS: Five hundred and nine patients were included. The median age of the cohort was 71 years (interquartile range [IQR], 60-80 years), 46.4% (236/509) were male and 352 of 509 (69%) patients were independent at baseline. Functional decline at 90 days occurred in 24.4% of patients (124/509). In multivariable analysis; older age (odds ratio [OR], 1.03; for an one-year increment, 95% confidence interval [CI] 1.01-1.05), functional dependence in instrumental activities of daily living at baseline (OR, 4.64; 95% CI 2.5-8.6), low Norton score (OR, 0.87; 95% CI 0.79-0.96) and underlying comorbidities: cancer (OR, 2.01; 95% CI 1.14-3.55) and chronic pulmonary disease (OR, 2.23 95% CI 1.12-4.42) and longer length of hospital stay (OR 1.09; for one-day increment, 95% CI 1.04-1.15) were associated with functional decline. Appropriate empirical antibiotic treatment was associated with lower rates of functional decline within 90 days (OR, 0.4; 95% CI 0.21-0.78). CONCLUSIONS: Patients surviving bloodstream infections have poor long term trajectories after clinical recovery and hospital discharge. This has vast implications for patients, their family members and health policy makers.

Inadequate reporting of participants eligible for randomized controlled trials - A systematic review and meta-analysis.

OBJECTIVE: to characterize randomized controlled trials (RCTs) that did not report the overall number of participants assessed for eligibility and to identify factors associated with higher enrollment rates. STUDY DESIGN AND SETTING: Systematic review and meta-analysis of RCTs in several pre-defined fields in internal medicine. We randomly extracted 360 articles that were published in 2017. Trials that reported numbers of assessed for eligibility patients were compared with those who did not. Recruitment rates were calculated in order to investigate whether they were associated with trial characteristics. RESULTS: A total of 360 RCTs were included. Only 2-thirds of the trials (242/360) reported the number of patients assessed for eligibility. Trials reporting eligibility data had better methodology, reported on the tested hypothesis, included a placebo arm, evaluated soft outcomes, published their findings in higher impact journals and recruited a higher number of randomized patients than those who did not. Recruitment rates in 225 (62.5%) trials enabling their calculation, were significantly higher in trials sponsored by industry, conducted in multiple centers and countries, including inpatients, tested non-inferiority hypothesis, included a placebo arm, and evaluated surrogate outcomes. CONCLUSIONS: Reporting of participant eligibility continues to be scarce. Inadequate reporting was associated with poor methodological characteristics in trials.

Risk factors for treatment failure in women with uncomplicated lower urinary tract infection.

Given rising antibiotic resistance and increasing use of delayed prescription for uncomplicated lower urinary tract infections (UTI), patients at risk for treatment failure should be identified early. We assessed risk factors for clinical and microbiological failure in women with lower UTI. This case-control study nested within a randomized clinical trial included all women in the per-protocol population (PPP), those in the PPP with microbiologically confirmed UTI, and those in the PPP with UTI due to Escherichia coli. Cases were women who experienced clinical and/or microbiologic failure; controls were those who did not. Risk factors for failure were assessed using multivariate logistic regression. In the PPP, there were 152 clinical cases for 307 controls. Among 340 women with microbiologically confirmed UTI, 126 and 102 cases with clinical and microbiological failure were considered with, respectively, 214 and 220 controls. Age ≥52 years was independently associated with clinical (adjusted OR 3.01; 95%CI 1.84-4.98) and microbiologic failure (aOR 2.55; 95%CI 1.54-4.25); treatment with fosfomycin was associated with clinical failure (aOR 2.35; 95%CI 1.47-3.80). The association with age persisted among all women, and women with E. coli-related UTI. Diabetes was not an independent risk factor, nor were other comorbidities. Postmenopausal age emerged as an independent risk factor for both clinical and microbiological treatment failure in women with lower UTI and should be considered to define women at-risk for non-spontaneous remission, and thus for delayed antibiotic therapy; diabetes mellitus was not associated with failure.

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity.

BACKGROUND: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study's population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. METHODS: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. RESULTS: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10-16) vs. 8.5 days (IQR 0-15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. CONCLUSION: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012.