Showing papers by "Rappaport Faculty of Medicine published in 2019"

International Consensus Guidelines for the Optimal Use of the Polymyxins: Endorsed by the American College of Clinical Pharmacy (ACCP), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Infectious Diseases Society of America (IDSA), International Society for Anti-infective Pharmacology (ISAP), Society of Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP).

Abstract: The polymyxin antibiotics colistin (polymyxin E) and polymyxin B became available in the 1950s and thus did not undergo contemporary drug development procedures. Their clinical use has recently resurged, assuming an important role as salvage therapy for otherwise untreatable gram-negative infections. Since their reintroduction into the clinic, significant confusion remains due to the existence of several different conventions used to describe doses of the polymyxins, differences in their formulations, outdated product information, and uncertainties about susceptibility testing that has led to lack of clarity on how to optimally utilize and dose colistin and polymyxin B. We report consensus therapeutic guidelines for agent selection and dosing of the polymyxin antibiotics for optimal use in adult patients, as endorsed by the American College of Clinical Pharmacy (ACCP), Infectious Diseases Society of America (IDSA), International Society of Anti-Infective Pharmacology (ISAP), Society for Critical Care Medicine (SCCM), and Society of Infectious Diseases Pharmacists (SIDP). The European Society for Clinical Microbiology and Infectious Diseases (ESCMID) endorses this document as a consensus statement. The overall conclusions in the document are endorsed by the European Committee on Antimicrobial Susceptibility Testing (EUCAST). We established a diverse international expert panel to make therapeutic recommendations regarding the pharmacokinetic and pharmacodynamic properties of the drugs and pharmacokinetic targets, polymyxin agent selection, dosing, dosage adjustment and monitoring of colistin and polymyxin B, use of polymyxin-based combination therapy, intrathecal therapy, inhalation therapy, toxicity, and prevention of renal failure. The treatment guidelines provide the first ever consensus recommendations for colistin and polymyxin B therapy that are intended to guide optimal clinical use.

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

Abstract: 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.

Collagenase Nanoparticles Enhance the Penetration of Drugs into Pancreatic Tumors.

Abstract: Overexpressed extracellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDAC) limits drug penetration into the tumor and is associated with poor prognosis. Here, we demonstrate that a pretreatment based on a proteolytic-enzyme nanoparticle system disassembles the dense PDAC collagen stroma and increases drug penetration into the pancreatic tumor. More specifically, the collagozome, a 100 nm liposome encapsulating collagenase, was rationally designed to protect the collagenase from premature deactivation and prolonged its release rate at the target site. Collagen is the main component of the PDAC stroma, reaching 12.8 ± 2.3% vol in diseased mice pancreases, compared to 1.4 ± 0.4% in healthy mice. Upon intravenous injection of the collagozome, ∼1% of the injected dose reached the pancreas over 8 h, reducing the level of fibrotic tissue to 5.6 ± 0.8%. The collagozome pretreatment allowed increased drug penetration into the pancreas and improved PDAC treatment. PDAC tumors, pretreated with the collagozome followed by paclitaxel micelles, were 87% smaller than tumors pretreated with empty liposomes followed by paclitaxel micelles. Interestingly, degrading the ECM did not increase the number of circulating tumor cells or metastasis. This strategy holds promise for degrading the extracellular stroma in other diseases as well, such as liver fibrosis, enhancing tissue permeability before drug administration.

Fecal microbiome signatures of pancreatic cancer patients.

Abstract: Pancreatic cancer (PC) is a leading cause of cancer-related death in developed countries, and since most patients have incurable disease at the time of diagnosis, developing a screening method for early detection is of high priority. Due to its metabolic importance, alterations in pancreatic functions may affect the composition of the gut microbiota, potentially yielding biomarkers for PC. However, the usefulness of these biomarkers may be limited if they are specific for advanced stages of disease, which may involve comorbidities such as biliary obstruction or diabetes. In this study we analyzed the fecal microbiota of 30 patients with pancreatic adenocarcinoma, 6 patients with pre-cancerous lesions, 13 healthy subjects and 16 with non-alcoholic fatty liver disease, using amplicon sequencing of the bacterial 16S rRNA gene. Fourteen bacterial features discriminated between PC and controls, and several were shared with findings from a recent Chinese cohort. A Random Forest model based on the microbiota classified PC and control samples with an AUC of 82.5%. However, inter-subject variability was high, and only a small part of the PC-associated microbial signals were also observed in patients with pre-cancerous pancreatic lesions, implying that microbiome-based early detection of such lesions will be challenging.

Gain-of-function mutation of microRNA-140 in human skeletal dysplasia

Abstract: MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression. Heterozygous loss-of-function point mutations of miRNA genes are associated with several human congenital disorders1-5, but neomorphic (gain-of-new-function) mutations in miRNAs due to nucleotide substitutions have not been reported. Here we describe a neomorphic seed region mutation in the chondrocyte-specific, super-enhancer-associated MIR140 gene encoding microRNA-140 (miR-140) in a novel autosomal dominant human skeletal dysplasia. Mice with the corresponding single nucleotide substitution show skeletal abnormalities similar to those of the patients but distinct from those of miR-140-null mice6. This mutant miRNA gene yields abundant mutant miR-140-5p expression without miRNA-processing defects. In chondrocytes, the mutation causes widespread derepression of wild-type miR-140-5p targets and repression of mutant miR-140-5p targets, indicating that the mutation produces both loss-of-function and gain-of-function effects. Furthermore, the mutant miR-140-5p seed competes with the conserved RNA-binding protein Ybx1 for overlapping binding sites. This finding may explain the potent target repression and robust in vivo effect by this mutant miRNA even in the absence of evolutionary selection of miRNA-target RNA interactions, which contributes to the strong regulatory effects of conserved miRNAs7,8. Our study presents the first case of a pathogenic gain-of-function miRNA mutation and provides molecular insight into neomorphic actions of emerging and/or mutant miRNAs.

Inhibitors of MAO-B and COMT: their effects on brain dopamine levels and uses in Parkinson's disease.

Abstract: MAO-B and COMT are both enzymes involved in dopamine breakdown and metabolism. Inhibitors of these enzymes are used in the treatment of Parkinson’s disease. This review article describes the scientific background to the localization and function of the enzymes, the physiological changes resulting from their inhibition, and the basic and clinical pharmacology of the various inhibitors and their role in treatment of Parkinson’s disease.

Implementations of 3D printing in ophthalmology

Abstract: The purpose of this paper is to provide an in-depth understanding of how to best utilize 3D printing in medicine, and more particularly in ophthalmology in order to enhance the clinicians’ ability to provide out-of-the-box solutions for unusual challenges that require patient personalization. In this review, we discuss the main applications of 3D printing for diseases of the anterior and posterior segments of the eye and discuss their current status and implementation. We aim to raise awareness among ophthalmologists and report current and future developments. A computerized search from inception up to 2018 of the online electronic database PubMed was performed, using the following search strings: “3D,” “printing,” “ophthalmology,” and “bioprinting.” Additional data was extracted from relevant websites. The reference list in each relevant article was analyzed for additional relevant publications. 3D printing first appeared three decades ago. Nevertheless, the implementation and utilization of this technology in healthcare became prominent only in the last 5 years. 3D printing applications in ophthalmology are vast, including organ fabrication, medical devices, production of customized prosthetics, patient-tailored implants, and production of anatomical models for surgical planning and educational purposes. The potential applications of 3D printing in ophthalmology are extensive. 3D printing enables cost-effective design and production of instruments that aid in early detection of common ocular conditions, diagnostic and therapeutic devices built specifically for individual patients, 3D-printed contact lenses and intraocular implants, models that assist in surgery planning and improve patient and medical staff education, and more. Advances in bioprinting appears to be the future of 3D printing in healthcare in general, and in ophthalmology in particular, with the emerging possibility of printing viable tissues and ultimately the creation of a functioning cornea, and later retina. It is expected that the various applications of 3D printing in ophthalmology will become part of mainstream medicine.

The impact of intentional endometrial injury on reproductive outcomes: a systematic review and meta-analysis

Abstract: Background Endometrial injury is an intentional damage made to the endometrium, usually produced by a Pipelle catheter. Over the last two decades, endometrial injury has been studied to improve implantation rates and decrease the incidence of implantation failure in invitro fertilization (IVF) cycles. Recently, additional studies of endometrial injury, performed not only in patients with implantation failure but also in intrauterine insemination cycles, have been conducted, and the endometrial injury made by hysteroscopy has been researched. The evidence describing the impact of endometrial injury is controversial; therefore, we conducted a systematic review and meta-analysis to examine the issue. Objective and rationale Our objective is to review the research that has been done until now and perform a meta-analysis regarding endometrial injury and its influence on implantation success and pregnancy rates in patients with at least one failed IVF cycle. In particular, we aim to study the efficacy of the procedure and look for confounding factors, such as maternal age, in assessing the efficacy of endometrial injury. Search methods The systematic review of the literature was conducted according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) statement. Study protocol can be assessed at PROSPERO International prospective register of systematic reviews (registration number CRD42018092773). Searches were conducted by an experienced research librarian in the following databases: MEDLINE(R) using the OvidSP interface and PUBMED, Embase, Web of Science and Cochrane Library. This review considered for inclusion randomized-controlled trials examining the success of performing local endometrial injury on IVF outcomes in women with previous failed IVF cycles. Outcomes Ten studies, comprising a total of 1260 patients, were selected. Overall, when studying the effect of endometrial injury on clinical pregnancy rates (CPRs) and live birth rates (LBRs), higher rates were shown in the endometrial injury group. However, endometrial injury did not significantly improve CPRs and LBRs, when considering sub-group analyses of studies including patients with two or more failed IVF cycles, studies examining older patients or studies which did not include hysteroscopy. There was no significant difference found regarding multiple pregnancy rates, while a handful of studies showed an improvement in miscarriage rates. Wider implications Endometrial injury should be used restrictively and not routinely in clinics. Maternal age and number of previous failed treatment cycles may be contributing factors which can influence the results when studying the effect of endometrial local injury. It is possible that the relative contribution of endometrial receptivity to the chances of implantation decreases with any additional failed cycle. The optimal study to prove the efficacy of local endometrial injury on implantation and pregnancy rates, should be a random-controlled trial studying the effect of local endometrial injury in oocyte donation cycles, in recipients with repeated implantation failure. This kind of study will conclude whether local endometrial injury is an efficient procedure with minimum confounding factors, and may assist in defining the population, even outside of donation cycles, that will benefit from the procedure.

Leucocyte adhesion deficiency-A multicentre national experience.

Abstract: Leucocyte adhesion deficiency (LAD) is a rare, innate autosomal recessive immunodeficiency with three subtypes. Twenty-nine patients with LADs were diagnosed and treated in Israeli Medical Centers and in the Palestinian Authority. We discuss the phenotypic, genotypic and biochemical features of LAD-I, LAD-II and LAD-III diagnosed during the neonatal period and early infancy in 18, 6 and 5 patients, respectively. Consanguinity was frequent. Common features were severe infections of variable aetiology, excessive leukocytosis and delayed umbilical cord detachment. In LAD-I, the integrin CD18 expression varied from negligible to normal. However, CD11a expression was negligible in all tested patients, suggesting both CD11a and CD18 should be used to assess this subtype. LAD-II patients showed distinctive facial features, physical malformations, short stature and developmental delay. These patients show defective expression of SLeX (CD15a) on cell surface glycoproteins and lack of H antigen on erythroid cell surfaces resulting in Bombay blood group (hh). LAD-III showed intact but inactive β2 integrins associated with severe infections and significant bleeding disorders caused by defective platelet aggregation and thrombocytopenia. We report four patients with two new unpublished mutations: two LAD-I patients with c.1099delG in ITGB2 and two LAD-III patients with c.1069C>T in FERMT3. LAD-I patients harbouring the c.119_128 deletion in ITGB2 seemed to have better outcomes as compared to other LAD-I patients. Eight patients with LAD-I and -III underwent successful haematopoietic stem cell transplantation. Cumulative survival was 75%, 50% and 40% for LAD-I, LAD-II and LAD-III, with a median follow-up of 4 (0.08-19), 3.25 (1-32) and 6 (0.08-8) years, respectively. Prenatal diagnosis is recommended in families with LAD syndromes.

Association of Diabetes and Glycated Hemoglobin With the Risk of Intracerebral Hemorrhage: A Population-Based Cohort Study

Abstract: OBJECTIVE To examine the association of diabetes and glycated hemoglobin (HbA 1c ) with the risk of intracerebral hemorrhage (ICH) in a large population-based cohort. RESEARCH DESIGN AND METHODS The computerized database of the largest health care provider in Israel was used to identify adult members aged 40 years or older and alive at 1 January 2010 (297,486 with diabetes and 1,167,585 without diabetes). The cohort was followed until 31 December 2017 for incidence of ICH. Multivariable Cox proportional hazards regression models, adjusted for baseline disease risk score, were applied to estimate the hazard ratio (HR) of ICH. RESULTS Overall 4,170 ICH cases occurred during 10,730,915 person-years of follow-up. Diabetes was independently associated with increased ICH risk, with hazard ratio (HR) 1.36 (95% CI 1.27–1.45), and increased with longer diabetes duration: 1.23 (1.12–1.35) and 1.44 (1.34–1.56) for diabetes duration ≤5 years and >5 years, respectively. The increased ICH risk associated with diabetes was more pronounced in patients ≤60 years old ( P interaction 1c had a nonlinear J-shaped relationship with ICH ( P for nonlinearity = 0.0186). Compared to the fourth HbA 1c decile 6.5%–6.7% (48–50 mmol/mol), the HR for ICH was 1.27 (1.01–1.59) and 2.19 (1.75–2.73) in the lowest decile ≤ 6.0% (≤42mmol/mol) and highest HbA 1c decile >9.3% (>78mmol/mol), respectively. CONCLUSIONS Diabetes is associated with increased risk of ICH that is directly associated with diabetes duration. ICH and HbA 1c appear to have a J-shaped relationship, suggesting that both poor control as well as extreme intensive diabetes control might be associated with increased risk.

Frequent sugar feeding behavior by Aedes aegypti in Bamako, Mali makes them ideal candidates for control with attractive toxic sugar baits (ATSB).

Abstract: Background Current tools and strategies are not sufficient to reliably address threats and outbreaks of arboviruses including Zika, dengue, chikungunya, and yellow fever. Hence there is a growing public health challenge to identify the best new control tools to use against the vector Aedes aegypti. In this study, we investigated Ae. aegypti sugar feeding strategies in Bamako, Mali, to determine if this species can be controlled effectively using attractive toxic sugar baits (ATSB). Methodology We determined the relative attraction of Ae. aegypti males and females to a variety of sugar sources including flowers, fruits, seedpods, and honeydew in the laboratory and using plant-baited traps in the field. Next, we observed the rhythm of blood feeding versus sugar feeding activity of Ae. aegypti in vegetation and in open areas. Finally, we studied the effectiveness of spraying vegetation with ATSB on Ae. aegypti in sugar rich (lush vegetation) and in sugar poor (sparse vegetation) urban environments. Principal findings Male and female laboratory sugar feeding rates within 24 h, on 8 of 16 plants offered were over 80%. The survival rates of mosquitoes on several plant sources were nearly as long as that of controls maintained on sucrose solution. In the field, females were highly attracted to 11 of 20 sugar sources, and 8 of these were attractive to males. Peak periods of host attraction for blood-feeding and sugar feeding in open areas were nearly identical and occurred shortly after sunrise and around sunset. In shaded areas, the first sugar-seeking peak occurred between 11:30 and 12:30 while the second was from 16:30 to 17:30. In a 50-day field trial, ATSB significantly reduced mean numbers of landing / biting female Ae. aegypti in the two types of vegetation. At sugar poor sites, the mean pre-treatment catch of 20.51 females on day 14 was reduced 70-fold to 0.29 on day 50. At sugar rich sites, the mean pre-treatment catch of 32.46 females on day 14 was reduced 10-fold to a mean of 3.20 females on day 50. Conclusions This is the first study to show how the vector Ae. aegypti depends on environmental resources of sugar for feeding and survival. The demonstration that Ae. aegypti populations rapidly collapsed after ATSB treatment, in both sugar rich and sugar poor environments, is strong evidence that Ae. aegypti is sugar-feeding frequently. Indeed, this study clearly demonstrates that Ae. aegypti mosquitoes depend on natural sugar resources, and a promising new method for vector control, ATSB, can be highly effective in the fight against Aedes-transmitted diseases.

Curcumin as Add-On to Antipsychotic Treatment in Patients With Chronic Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled Study.

Abstract: BackgroundIntroduction of old and new generations of antipsychotics leads to significant improvements in the positive symptoms of schizophrenia. However, negative symptoms remain refractory to conventional trials of antipsychotic therapy. Recently, there were several open clinical human trials with

Germline USP8 Mutation Associated With Pediatric Cushing Disease and Other Clinical Features: A New Syndrome.

Abstract: Background Somatic mutations in the ubiquitin-specific peptidase 8 (USP8) gene are common in corticotropinomas of children with Cushing disease (CD). We report a unique patient with a germline USP8 mutation who presented with CD and a constellation of other findings that constitute an intriguing genetic syndrome. Case description We describe a 16-year-old female with CD, developmental delay, dysmorphic features, ichthyosiform hyperkeratosis, chronic lung disease, chronic kidney disease, hyperglycemia, dilated cardiomyopathy with congestive heart failure, and previous history of hyperinsulinism and partial GH deficiency. She was diagnosed with CD at 14 years old and underwent transsphenoidal surgery. Despite initial improvement, she developed recurrent CD. Methods DNA was extracted from peripheral blood and tumor DNA; whole-exome and Sanger confirmatory sequencing were performed. Immunohistochemistry was performed on the resected adenoma. Results A de novo germline heterozygous USP8 mutation (c.2155T>C, p.S719P) in the critical 14-3-3 binding motif hot spot locus of the gene was identified in both the peripheral blood and tumor DNA. Histopathologic evaluation of the resected tumor confirmed an ACTH-secreting adenoma. Conclusion Somatic USP8 mutations are common in adenomas causing CD, but to date, no germline defects have been reported. We describe a patient with a de novo germline USP8 mutation with recurrent CD and multiple other medical problems. This unique patient informs us of the multitude of signaling events that may be controlled by USP8.

Association between urinary community-acquired fluoroquinolone-resistant Escherichia coli and neighbourhood antibiotic consumption: a population-based case-control study.

Abstract: Summary Background It is unknown whether increased use of antibiotics in a community increases the risk of acquiring antibiotic resistance by individuals living in that community, regardless of prior individual antibiotic consumption and other risk factors for antibiotic resistance. Methods We used a hierarchical multivariate logistic regression approach to evaluate the association between neighbourhood fluoroquinolone consumption and individual risk of colonisation or infection of the urinary tract with fluoroquinolone-resistant Escherichia coli. We did a population-based case-control study of adults (aged ≥22 years) living in 1733 predefined geographical statistical areas (neighbourhoods) in Israel. A multilevel study design was used to analyse data derived from electronic medical records of patients enrolled in the Clalit state-mandated health service. Findings 300 105 events with E coli growth and 1 899 168 cultures with no growth were identified from medical records and included in the analysis. 45 427 (16·8%) of 270 190 women and 8835 (29·5%) of 29 915 men had fluoroquinolone-resistant E coli events. We found an independent association between residence in a neighbourhood with higher antibiotic consumption and an increased risk of bacteriuria caused by fluoroquinolone-resistant E coli. Odds ratios (ORs) for the quintiles with higher neighbourhood consumption (compared with the lowest quintile) were 1·15 (95% CI 1·06–1·24), 1·31 (1·20–1·43), 1·41 (1·29–1·54), and 1·51 (1·38–1·65) for women, and 1·17 (1·02–1·35), 1·24 (1·06–1·45), 1·35 (1·15–1·59), and 1·50 (1·26–1·77) for men. Results remained significant when the analysis was restricted to patients who had not consumed fluoroquinolones themselves. Interpretation These data suggest that increased use of antibiotics in specific geographical areas is associated with an increased personal risk of acquiring antibiotic-resistant bacteria, independent of personal history of antibiotic consumption and other known risk factors for antimicrobial resistance. Funding None.

Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis.

Abstract: Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon.