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.

Risk Factors for Neonatal Clavicular Fractures: A Population-Based Case-Control Study.

BACKGROUND: Neonatal clavicular fractures represent the most common fracture during delivery. We aimed to define risk factors associated with these fractures in a large population-based database. METHODS: Data were extracted from Clalit Health Services' electronic health records from 2000 to 2020. Newborns with clavicular fractures were compared with a healthy control group. The following parameters were compared-for the newborns: sex, birth weight, birth height, and head circumference; for the delivery process: assisted delivery, cesarean section, use of epidural, birth week, and number of fetuses; and for the mother: age at delivery, socioeconomic status, height, weight, and body mass index (BMI). RESULTS: We found a rate of 0.28% for neonatal clavicular fractures (5015 clavicular fractures/1 755 660 deliveries). Male gender and heavier birth weight were found to be significantly associated with clavicular fractures (P < .001). Increased risk was also associated with lower socioeconomic status, baseline weight, and maternal BMI (P < .001 for all). Assisted delivery increased the risk of clavicular fracture (OR = 2.274; 95% CI, 1.661-3.115; P < .0001), while cesarean section and use of epidural were found to be protective (OR = 0.149; 95% CI, 0.086-0.26; P < .0001; and OR = 0.687; 95% CI, 0.0531-0.89; P < .004, respectively). CONCLUSIONS: This study provides insight into the risk factors associated with neonatal clavicular fractures on the largest group of patients reported to date.

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.

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 enterococcal urinary tract infections: a multinational, retrospective cohort study.

Complicated urinary tract infection (cUTI) is a frequent cause of morbidity. In this multinational retrospective cohort study, we aimed to demonstrate risk factors for enterococcal UTI. Univariate and multivariate analyses of risk factors for enterococcal infection were performed. Among 791 hospitalized patients with cUTI, enterococci accounted for approximately 10% of cases (78/791). Risk factors for enterococcal UTI in multivariable analysis were male gender, age range of 55-75 years, catheter-associated UTI, and urinary retention. This information may assist treating physicians in their decision-making on prescribing empiric anti-enterococcus treatment to hospitalized patients presenting with cUTI and thus improve clinical outcomes.

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.

Seven Versus 14 Days of Antibiotic Therapy for Uncomplicated Gram-negative Bacteremia: A Noninferiority Randomized Controlled Trial.

BACKGROUND: Gram-negative bacteremia is a major cause of morbidity and mortality in hospitalized patients. Data to guide the duration of antibiotic therapy are limited. METHODS: This was a randomized, multicenter, open-label, noninferiority trial. Inpatients with gram-negative bacteremia, who were afebrile and hemodynamically stable for at least 48 hours, were randomized to receive 7 days (intervention) or 14 days (control) of covering antibiotic therapy. Patients with uncontrolled focus of infection were excluded. The primary outcome at 90 days was a composite of all-cause mortality; relapse, suppurative, or distant complications; and readmission or extended hospitalization (>14 days). The noninferiority margin was set at 10%. RESULTS: We included 604 patients (306 intervention, 298 control) between January 2013 and August 2017 in 3 centers in Israel and Italy. The source of the infection was urinary in 411 of 604 patients (68%); causative pathogens were mainly Enterobacteriaceae (543/604 [90%]). A 7-day difference in the median duration of covering antibiotics was achieved. The primary outcome occurred in 140 of 306 patients (45.8%) in the 7-day group vs 144 of 298 (48.3%) in the 14-day group (risk difference, -2.6% [95% confidence interval, -10.5% to 5.3%]). No significant differences were observed in all other outcomes and adverse events, except for a shorter time to return to baseline functional status in the short-course therapy arm. CONCLUSIONS: In patients hospitalized with gram-negative bacteremia achieving clinical stability before day 7, an antibiotic course of 7 days was noninferior to 14 days. Reducing antibiotic treatment for uncomplicated gram-negative bacteremia to 7 days is an important antibiotic stewardship intervention. CLINICAL TRIALS REGISTRATION: NCT01737320.

Desert cyanobacteria prepare in advance for dehydration and rewetting: The role of light and temperature sensing.

Cyanobacteria inhabiting desert biological soil crusts must prepare towards dehydration, or their revival after rewetting is severely impaired. The mechanisms involved are unknown but signalling of forthcoming dehydration by dawn illumination was demonstrated. Accurate and reproducible simulation of desert conditions enabled examination of physiological activities and transcript profiles in a model organism, Leptolyngbya ohadii, in response to specific conditions. Exposure to far red light or lack of ground warming during dawn severely reduced revival after rewetting and altered the network of gene expression. The data implicated phytochromes in light and temperature sensing. Many genes were up- or down-regulated before water content decline, while others were strongly affected by the progression of dehydration and desiccation. Transcription continues during the desiccated phase but only barely during early rewetting, although photosynthetic activity was regained. Application of rifampicin with or without a preceding dehydration phase demonstrated that RNA is stabilized/protected during desiccation, possibly by intrinsically disordered proteins. We conclude that increasing light and temperature at dawn activates a network of genes that prepare the cells towards dehydration. Quick resumption of photosynthesis upon rewetting in contrast to the slow change in the transcript profile suggested that in addition to preparing towards dehydration the cells also prepare for forthcoming rewetting, during dehydration. Unravelling the presently unknown function of many responding genes will help to clarify the networks involved.

CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and the Circadian Control of Stomatal Aperture.

The endogenous circadian (∼24 h) system allows plants to anticipate and adapt to daily environmental changes. Stomatal aperture is one of the many processes under circadian control; stomatal opening and closing occurs under constant conditions, even in the absence of environmental cues. To understand the significance of circadian-mediated anticipation in stomatal opening, we have generated SGC (specifically guard cell) Arabidopsis (Arabidopsis thaliana) plants in which the oscillator gene CIRCADIAN CLOCK ASSOCIATED1 (CCA1) was overexpressed under the control of the guard-cell-specific promoter, GC1. The SGC plants showed a loss of ability to open stomata in anticipation of daily dark-to-light changes and of circadian-mediated stomatal opening in constant light. We observed that under fully watered and mild drought conditions, SGC plants outperform wild type with larger leaf area and biomass. To investigate the molecular basis for circadian control of guard cell aperture, we used large-scale qRT-PCR to compare circadian oscillator gene expression in guard cells compared with the "average" whole-leaf oscillator and examined gene expression and stomatal aperture in several lines of plants with misexpressed CCA1 Our results show that the guard cell oscillator is different from the average plant oscillator. Moreover, the differences in guard cell oscillator function may be important for the correct regulation of photoperiod pathway genes that have previously been reported to control stomatal aperture. We conclude by showing that CONSTANS and FLOWERING LOCUS T, components of the photoperiod pathway that regulate flowering time, also control stomatal aperture in a daylength-dependent manner.

Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial.

Importance: The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI). Objective: To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis. Design, Setting, and Participants: Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel. Interventions: Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection. Main Outcomes and Measures: The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events. Results: Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively). Conclusions and Relevance: Among women with uncomplicated UTI, 5-day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion. Trial Registration: ClinicalTrials.gov Identifier: NCT01966653.

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 (LSS) 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 LSS in diabetic patients, substantial epidemiological research on the likelihood of LSS diagnosis in individuals with diabetes is scarce. MATERIALS AND METHODS: Using nationwide data, a total of 49,576 patients diagnosed with LSS based on International Classification of Diseases-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 LSS diagnosis in diabetic patients [odds ratio (OR) 1.39, 95% CI: 1.36 - 1.43, P <0.001]. Those with hemoglobin A1c ≥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 nonstenosis patients; spinal stenosis diagnosis alone minimally impacted survival. Relative to individuals diagnosed with diabetes mellitus at the age of 65 or older, the OR for developing LSS were 1.22 (95% CI: 1.18-1.27, P <0.001) when DM was diagnosed at 50 to 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 (hazard ratio: 1.36, 95% CI: 1.29-1.44, P <0.001) and those with DM without stenosis (hazard ratio: 1.49, 95% CI: 1.41-1.57, P <0.001) compared with controls. CONCLUSIONS: Diabetic patients with prolonged disease, poor glycemic control, and diabetes-related complications face an elevated risk of developing LSS. 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.

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.

Comparative Analysis of First-Line Antihypertensive Treatment Classes.

BACKGROUND: The best first-line monotherapy for hypertension remains uncertain, as current guidelines suggest that thiazides, angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB) are appropriate in the absence of specific comorbidities. We aimed to compare the outcomes of first-line antihypertensive classes in a real-life setting with a long follow-up period. METHODS: This nationwide retrospective new-user cohort study included patients insured by the largest health maintenance organization in Israel. We included patients with a new diagnosis of hypertension between 2008 and 2021 who initiated treatment with a single first-line drug for hypertension. Outcomes were assessed with and without propensity score matching for confounding factors. The primary composite outcome was the first occurrence of myocardial infarction (MI), acute coronary syndrome (ACS), stroke, or heart failure (HF). RESULTS: A total of 97,639 patients initiated antihypertensive treatment with a single drug as first-line therapy. The most commonly prescribed class was ACEi/ARB (66,717, 68.3%), followed by CCBs (15,922, 16.3%), beta-blockers (BBs, 12,869, 13.2%), and thiazides (2,131, 2.2%). For the primary outcome, the hazard ratios (HRs) for BBs, CCBs, and ACEi/ARBs were 1.44 (95% CI 1.25 - 1.66), 1.10 (95% CI 0.96 - 1.27), and 1.13 (95% CI 0.99 - 1.29), respectively, when compared to thiazides. CONCLUSION: When initiating pharmacotherapy for hypertension with a single drug, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers were associated with similar risk of MI, ACS, stroke, or HF when compared to thiazides, while beta-blockers were associated with increased risk.

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.

Genome-wide screening reveals essential roles for HOX genes and imprinted genes during caudal neurogenesis of human embryonic stem cells.

Mapping the essential pathways for neuronal differentiation can uncover new therapeutics and models for neurodevelopmental disorders. We thus utilized a genome-wide loss-of-function library in haploid human embryonic stem cells, differentiated into caudal neuronal cells. We show that essential genes for caudal neurogenesis are enriched for secreted and membrane proteins and that a large group of neurological conditions, including neurodegenerative disorders, manifest early neuronal phenotypes. Furthermore, essential transcription factors are enriched with homeobox (HOX) genes demonstrating synergistic regulation and surprising non-redundant functions between HOXA6 and HOXB6 paralogs. Moreover, we establish the essentialome of imprinted genes during neurogenesis, demonstrating that maternally expressed genes are non-essential in pluripotent cells and their differentiated germ layers, yet several are essential for neuronal development. These include Beckwith-Wiedemann syndrome- and Angelman syndrome-related genes, for which we suggest a novel regulatory pathway. Overall, our work identifies essential pathways for caudal neuronal differentiation and stage-specific phenotypes of neurological disorders.

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.

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.

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.