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Abstract Objectives To evaluate literature from a 12-year period (2010–2021) on the antimicrobial resistance profile of Pseudomonas aeruginosa from the Arabian Gulf countries (Bahrain, Kuwait, Oman, Qatar, Saudi Arabia, and the United Arab Emirates). Methods An electronic literature search was conducted for articles on antimicrobial resistance in P. aeruginosa and associated phenotypes, covering the period of 1st January 2010 to 1st December 2021. Results Antimicrobial resistance in the Arabian Gulf was highest to meropenem (10.3–45.7%) and lowest to colistin (0.0–0.8%), among the agents tested. Annual data showed that ceftazidime resistance (Kuwait), piperacillin-tazobactam non-susceptibility (Qatar), and aztreonam, imipenem, and meropenem resistance (Saudi Arabia) increased by 12–17%. Multiple mechanisms of carbapenem resistance were identified and multiple clones were detected, including high-risk clones such as ST235. The most common carbapenemases detected were the VIM-type metallo-β-lactamases. Conclusions Among P. aeruginosa in the Arabian Gulf countries, resistance to meropenem was higher than to the other agents tested, and meropenem resistance increased in Saudi Arabia during the study period. Resistance to colistin, a classic antibiotic used to treat Pseudomonas spp. infections, remained low. The VIM-type β-lactamase genes were dominant. We recommend local and regional antimicrobial resistance surveillance programs to detect the emergence of resistance genes and to monitor antimicrobial resistance trends in P. aeruginosa.

The emergence of multidrug-resistant (MDR) Mycobacterium tuberculosis (Mtb) strains, identified as resistant to at least isoniazid and rifampin, these two drugs form the backbone of the first line drug which is used for tuberculosis (TB) treatment, unresponsive has hampered TB control. As a result of the nearly universal calculation of with half a million new cases of MDR/first line drug TB per year, it is important to keep the database up to date awareness of the processes that contribute to the emergence of MDR Mtb. This resistance is produced for a variety of reasons, including genetic, microbiological factors, non-adherence to treatment by patients and/or failures in therapy administration by some referrer medical centre for TB. This review offers a detailed summary of genetic mechanisms that lead to resistant to first line drug therapy used in management of TB as well as up-to-date information on some new aspects lead to such problem. Keywords: Mycobacterium tuberculosis, first line drug, anti-TB treatment, World Health Organization, isoniazid and rifampin Citation: Hassan JS, Al-Tamimi BJ, Abdulrahman TR, Jamal QW. Resistance mechanisms to first line drug in Mycobacterium tuberculosis: A review. Iraqi JMS. 2022; 20(1): 35-43. doi: 10.22578/IJMS.20.1.5

Background: Prostate cancer is one of the major medical problems in male population. Chronic inflammation has an important role in many human cancers and could be involved in the etiology of prostate cancer. Toll-like receptors are important tolls in innate immunity to pathogens. Many environmental factors could predispose for this cancer, however, genetic background of the population cannot be neglected. Objective: To explore the hypothesis that genetic variation in TLR4 gene can influence the individual's susceptibility to prostate cancer. Patients and Methods: A total of 95 outpatient men with histologically-proven prostate cancer as well as 45 apparently healthy men were recruited for this study. Blood samples were taken from each participant from which genomic DNA was extracted and TLR4 gene was PCR-amplified, using specific primers. PCR products were genotyped by direct sequencing. Results: Asp299gly and Thr399Ile SNPs had only two genotypes; the distributions of these genotypes were statistically not significant between prostate cancer patients and controls. At allele levels, the control group had significantly higher frequency in the mutant allele of Thr399Ile SNP (allele T) than prostate cancer patients. On the other hand, the rs11536889 had three genotypes with the mutant homozygous genotype (CC) and the mutant allele were more prevalent in PCa than controls with significant difference (OR=3.433, 95%CI=1.107-10.645, P= 0.033 and OR=2.730, 95%CI= 1.095-6.803, P=0.031 respectively). Conclusion: Allele T of Thr399Ile SNP may have a protective role, while allele C of rs11536889 SNP might increase the risk of prostate cancer.

AbstractObjectives: To evaluate the performance of the Anoxomat, in comparison with the conventional anaerobic GasPak jar system, for the isolation of obligate anaerobes. Method: Anoxomat, model WS800, and anaerobic GasPak jar system (Oxoid) were evaluated. Anoxomat system utilized a gas mixture of 80% N2, 10% CO2 and 10% H2, while the GasPak used a gas mixture of 90% H2 and 10% CO2. An anaerobic indicator within the jars monitored anaerobiosis. A total of 227 obligate anaerobic bacteria comprising 116 stock strains, 5 ATCC reference strains and 106 fresh strains, representing different genera, were investigated for growth on anaerobic agar plates and scored for density, colony sizes, susceptibility zones of antibiotic inhibition and the speed of anaerobiosis (reducing the indicator). Results: The results demonstrate that the growth of anaerobic bacteria is faster inside the Anoxomat jar than in the anaerobic GasPak jar system. Of the 227 strains tested, the colonies of 152 (67%) were larger (by size range of 0.2–2.4 mm) in the Anoxomat at 48 h than in the GasPak jar compared with only 21% (range 0.1–0.3 mm) that were larger in the GasPak than in the Anoxomat. The remaining 12% were equal in their sizes. There was no measurable difference in the colony sizes of the reference strains. The Porphyromonas asaccharolytica strains failed to grow within the GasPak system but grew inside the Anoxomat. With the Anoxomat, anaerobiosis was achieved about 35 min faster than in the GasPak system. The density of growth recorded for 177 (78%) strains was heavier in the Anoxomat than in the GasPak jar. The zones of inhibition of the antibiotics tested were not different in the two systems. Conclusion: The Anoxomat system provided superior growth, in terms of density and colony size, and achieved anaerobiosis more rapidly. Evidently, the Anoxomat method is more reliable and appears to support the growth of strict anaerobes better.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Study Question: Does adjuvant growth hormone (GH) therapy in GnRH antagonist cycles improve reproductive outcomes in the general IVF population?, Summary Answer: Empiric adjuvant GH therapy in GnRH antagonist cycles does not improve IVF stimulation results or reproductive outcomes, including implantation, miscarriage, and clinical pregnancy rates., What Is Known Already: Previous evidence regarding the benefits of GH therapy in IVF cycles has been inconclusive due to the lack of well-designed, large-scale randomized controlled trials (RCTs) in the general IVF population., Study Design, Size, Duration: This is a phase III open-label RCT involving 288 patients undergoing antagonist IVF cycles at the Ovo clinic in Montreal, Canada, between June 2014 and January 2020. Patients were randomly assigned at a 1:1 ratio to either the GH or control group. The intervention group received daily 2.5 mg subcutaneous injections of GH from Day 1 of ovarian stimulation until the day of oocyte retrieval, while the control group received standard ovarian stimulation without any adjuvant therapy., Participants/materials, Setting, Methods: Patients were expected normal responders. All embryo transfers, both fresh and frozen, resulting from the studied IVF cycle were included in an intention-to-treat and per-protocol analyses. The primary outcome was the clinical pregnancy rate, while secondary outcomes included the number of retrieved oocytes, good-quality embryos, maturation, fertilization, implantation, and miscarriage rates., Main Results and the Role of Chance: A total of 288 patients were recruited and randomly assigned at a 1:1 ratio to either the GH or the control group. After excluding cycle cancellations and patients who did not undergo transfer, 105 patients remained in each group. The overall mean age was 38.0 years, the mean BMI was 25.11 kg/m2 and the mean anti-Müllerian hormone was 2.51 ng/ml. The cycle characteristics were similar between both groups. No differences were observed regarding the total dose of gonadotropins (4600 versus 4660 IU for the GH and control groups, respectively, P = 0.752), days of stimulation (11.4 versus 11.7 days, P = 0.118), and endometrial thickness (10.63 versus 10.94 mm, P = 0.372). Both the intention to treat (ITT) and per protocol analyses yielded similar results for stimulation outcomes. In the ITT analysis, no differences were found in the number of follicles ≥15 mm (7.8 versus 7.1, P = 0.212), retrieved oocytes (11.7 versus 11.2, P = 0.613), mature oocytes (8.5 versus 8.6, P = 0.851), maturation rate (73.8 versus 78.4%, P = 0.060), fertilization rate (64.3 versus 67.2%, P = 0.388), and good quality embryos (2.5 versus 2.6, P = 0.767). Reproductive outcomes in fresh embryo transfer showed no difference for implantation rate (38.2 versus 39.5%, P = 0.829), miscarriage rate (26.5 versus 31.1%, P = 0.653), clinical pregnancy rate (43.6 versus 50.0%, P = 0.406, rate difference, 95% CI: -0.06 [-0.22, 0.09]), and live birth rate (32.1 versus 33.3%, P = 0.860). The number of embryos needed to achieve a clinical pregnancy was 3.0 versus 2.5 in the GH and control groups, respectively. Similarly, reproductive outcomes in first frozen embryo transfer showed no difference for implantation rate (31.6 versus 45.3%, P = 0.178), miscarriage rate (28.6 versus 26.3%, P = 0.873), clinical pregnancy rate (35.1 versus 44.2%, P = 0.406, P = 0.356, rate difference, 95% CI: -0.09 [-0.28, 0.10]), and live birth rate (22.8 versus 32.6%, P = 0.277). The number of embryos needed to achieve a clinical pregnancy was 3.1 versus 2.4 in the GH and control groups, respectively., Limitations, Reasons for Caution: The study focused on expected normal responders, limiting its applicability to other patient populations such as poor responders., Wider Implications of the Findings: These findings suggest that adding GH therapy to ovarian stimulation in GnRH antagonist cycles may not benefit the general IVF population. Additional high-quality RCTs are warranted to identify subgroups of patients who might benefit from this treatment., Study Funding/competing Interest(s): EMD Serono Inc., Mississauga, Canada, supplied Saizen® for the study, free of charge. In addition, they provided funding for the statistical analysis. I-J.K. declares grants or contracts from Ferring Pharmaceuticals, consulting fees from Ferring Pharmaceuticals, honoraria from Ferring Pharmaceuticals and EMD Serono, support for attending meetings or travel from Ferring Pharmaceuticals and EMD Serono, participation on a Data Safety Monitoring Board or Advisory Board for Ferring Pharmaceuticals, and stock or stock options from The Fertility Partners; W.J. declares support for attending meetings or travel from EMD Serono; and S.P. declares stock or stock options from The Fertility Partners. All other authors have no conflicts of interest to disclose., Trial Registration Number: NCT01715324., Trial Registration Date: 25 October 2012., Date of First Patient’s Enrolment: 25 June 2014., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Introduction Sickle cell anemia (SCA) affects the Saudi Arabian population significantly, with 4.2% carriers and 0.26% affected. Vaso-occlusive crises cause severe pain due to blood vessel blockage by sickled cells, leading to frequent emergency visits, where treatment includes the use of nonsteroidal anti-inflammatory drugs (NSAIDs), oxygen, and opioids. This study examines opioid use in managing SCA crises in Saudi emergency departments. Method A retrospective cross-sectional study in western Saudi Arabia surveyed board-certified emergency physicians (consultants, fellows, specialists) via the Sickle Cell Disease Implementation Consortium (SCDIC). Non-board-certified physicians and general practitioners were excluded. Data were gathered through structured surveys and supplemented by interviews. Results The study included 53 emergency physicians, mostly specialists (60.4%), with one to three years' experience, primarily from King Abdul Aziz University Hospital (28.3%) and King Abdullah Medical Complex (22.6%). While more than half of the participants felt adequately trained for SCA management, 20.8% faced challenges referring patients to case management programs. Major barriers included department overcrowding and the opioid epidemic. Conclusion The study reveals challenges in managing SCA in Saudi emergency departments, particularly with opioid use. Despite physician training, gaps in administrative support, medication access, and follow-up care persist. Institutional policies and opioid epidemic concerns restrict Schedule-II opioid prescriptions. Implementing a comprehensive opioid administration tracking system and standardizing protocols are crucial for enhancing patient outcomes. Future efforts should focus on improving resources and inter-institutional collaboration., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Jeddah university issued approval UJ-REC-153. Declaration by Bioethics Committee of Scientific and Medical Research Bioethics Committee Registration Number: HAP-02-J-094 Application Number: UJ-REC-153 Research Project Tittle: "Opioids Control for patients with sickle cell anemia in emergency departments in the western region of Saudi Arabia" Applicant Names: Mansoor K Radwi Abrar Ahmed Aljubayri Adulrahman Safwat Hassan Haitham Suhaim Alamri Osama Abdulrahman alraddadi Saeed Khalid AL-ghamdi Abdualrahman Talal Alashari Hisham Rizk University of jeddah 0/50/4025 0124125 A Technical Review The committee has reviewed the proposed research project on technical foundation. It is found that the proposed research is designed adequately with considerations of technical aspects and the scientific common practices on the University of Jeddah. Ethical Review The committee has reviewed the proposed research project for compliance with the regulations and polices of bioethics scientific research of university of Jeddah in principles of national law of ethics of research on living things by Bureau of Experts at the Saudi Council of ministries and national committee of bioethics at King Abdulaziz City of Science and Technology. It is found that the project is in agreement with laws and regulations of research ethics adopted by the University of Jeddah. Beslara the technical and Ethical review of the proposed research project. The committee grants approval for this proposal to commence for one year from the issue of this letter. The committee considers the methodology, technical and ethical aspects of the proposal to be adequate for the involved research processes set out in the proposal. The committee considers that the applicants) expertise level is satisfying the purpose of this research proposal to conduct this research in compliance with the university of Jeddah regulations and polices of scientific research. committee chairman Dr. Shatha Khusaifan. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Radwi et al.)

Objective: This study aimed to evaluate antibiotic susceptibility and antimicrobial resistance trends among clinically significant anaerobes in Kuwait hospitals from 2013 to 2022, comparing these findings with data from 2002 to 2012. Methods: The study prospectively collected 2,317 anaerobic isolates from various body sites across four Kuwaiti hospitals between January 2013 and December 2022. The minimum inhibitory concentrations for 11 antianaerobic antibiotics were determined using E-test methodology. The study analyzed trends and resistance rates across two periods: 2013-2017 and 2018-2022, using statistical analysis for resistance comparison. Results: Of the 2,317 isolates, most were from wounds (42.2%), fluids (28.0%), and tissues (20.5%). Bacteroides fragilis was the most common pathogen (34.0%), followed by Prevotella bivia (13.4%). Over 90% of isolates were susceptible to imipenem, meropenem, tigecycline, and metronidazole, whereas lower susceptibility was observed for penicillin, amoxicillin-clavulanic acid, and clindamycin. Notable differences in resistance profiles since 2002 were observed, especially in amoxicillin-clavulanic acid, piperacillin, piperacillin-tazobactam, and clindamycin. Conclusion: Owing to detected resistance to all antibiotics, susceptibility testing for anaerobic isolates is recommended in severe infections to ensure effective antimicrobial therapy. Continuous surveillance is crucial for developing antibiotic policies to manage invasive anaerobic infections.

Background: Empagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI)., Objectives: This study sought to evaluate the association of left ventricular ejection fraction (LVEF), congestion, or both, with outcomes and the impact of empagliflozin in reducing HF risk post-AMI., Methods: In the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both, to empagliflozin (10 mg daily) or placebo and were followed up for a median of 17.9 months., Results: Among 6,522 patients, the mean baseline LVEF was 41 ± 9%; 2,648 patients (40.6%) presented with LVEF <45% alone, 1,483 (22.7%) presented with congestion alone, and 2,181 (33.4%) presented with both. Among patients in the placebo arm of the trial, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (HR: 1.49; 95% CI: 1.31-1.69; P < 0.0001), first HF hospitalization (HR: 1.64; 95% CI: 1.37-1.96; P < 0.0001), and total HF hospitalizations (rate ratio [RR]: 1.89; 95% CI: 1.51-2.36; P < 0.0001). The presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR: 1.52, 1.94, and RR: 2.03, respectively). Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or congestion, or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status., Conclusions: In patients with AMI, the severity of left ventricular dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion. (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction [EMPACT-MI]; NCT04509674)., Competing Interests: Funding Support and Author Disclosures Funding support was provided by Boehringer Ingelheim and Eli Lilly and Company. Dr Udell has served on the advisory boards of Boehringer Ingelheim, Novavax, Novo Nordisk, and Sanofi; has received speaker honoraria from Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly; and has received research funding to his institution from Amgen, Bayer, Boehringer Ingelheim, and Novartis. Dr Petrie has received research funding from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and has served as a consultant and on trial committees for Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences. Dr Jones has received research grants from Bayer, Boehringer Ingelheim, Merck, Novartis, PCORI, and the National Institutes of Health (NIH). Dr Mattheus is an employee of Boehringer Ingelheim. Dr Seide is an employee of Boehringer Ingelheim. Dr Amir has served as a national principal investigator and as a steering committee member for the study; has participated in paid lectures and advisory board meetings and has clinical trials with Boehringer Ingelheim. Dr Bahit has received modest honoraria from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr Bauersachs has received honoraria for lectures or consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards Lifesciences, and Roche, unrelated to this work; and has received research support for the department from Zoll, CVRx, Abiomed, Norgine, and Roche, unrelated to this work. Dr Bayes-Genis has lectured and/or participated in advisory boards for Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche, and Vifor. Dr Goodman has received research grant support (steering committee or data and safety monitoring committee) and/or speaker or consulting honoraria (advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and has received salary support or honoraria from the Canadian Heart Failure Society, Canadian Heart Research Centre, and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Center for Clinical Research, Duke Clinical Research Institute, Jewish General Hospital, New York University Clinical Coordinating Centre, PERFUSE Research Institute, Peter Munk Cardiac Centre Clinical Trials and Translation Unit, and the TIMI Study Group (Brigham Health). Dr Goto has served on the advisory boards of Antos Therapeutic and Janssen; and has received honoraria from the American Heart Association (Associate Editor); and has served on the grant evaluation committee for the Nakatani Foundation and the Kaketsuken Foundation. Dr Gasior is an employee of Boehringer Ingelheim. Dr Jamal is an employee of Boehringer Ingelheim. Dr Januzzi has served as a trustee of the American College of Cardiology; has served as a board member of Imbria Pharmaceuticals; has served as director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, Bristol Myers Squibb, HeartFlow, Innolife, Medtronic, and Roche; has received consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer Ingelheim, Cytokinetics, Janssen, Merck, Novartis, Prevencio, Quidel/Ortho, and Roche; and has participated in clinical endpoint committees/data safety monitoring boards for Abbott, AbbVie, Axon, Bayer, CVRx, Medtronic, Pfizer, Roche, and Takeda. Dr Lopes has received research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi; has received funding for educational activities or lectures from Pfizer, Daiichi-Sankyo, and Novo Nordisk; and has received funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Martinez-Traba is an employee of Boehringer Ingelheim. Dr Parikh has served as a consultant for Medtronic; and has received institutional research grants from Abbott and Edwards Lifesciences. Dr Parkhomenko has received research grants and personal fees from Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squib/Pfizer, and Daiichi-Sankyo. Dr Schou has received lecture fees from Novartis, AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr van der Meer has received grant support from the European Research Council (ERC CoG 101045236, DISSECT-HF) and the University Medical Centre Groningen; and Dr van der Meer’s employer, has received consultancy fees and/or grants from Novartis, Pharmacosmos, Vifor Pharma, AstraZeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi-Sankyo, Boehringer Ingelheim, and Ionis. Dr Vinereanu has received research grants and consultancy fees from Boehringer Ingelheim; and has received research grants from Bayer Healthcare, Novartis, and Servier. Dr Zieroth has received research grant support, served on advisory boards for, or participated in speaker engagements with AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Salubrisbio, Servier, and Vifor Pharma; has served on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, and Pfizer; and has nonindustry relationships with the Canadian Medical and Surgical KT Group, CCS, CHFS, Charite, EOCI, Liv, Medscape, Ology, PACE-CME, Radcliffe, Reach MD, and the Translational Medicine Academy. Dr Brueckmann is an employee of Boehringer Ingelheim. Dr Sumin is an employee of Boehringer Ingelheim. Dr Bhatt has served on the advisory boards of Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, and Stasys; has served on the Board of Directors of the American Heart Association New York City, Angiowave (with stock options), Bristol Myers Squibb (with stock), DRS.LINQ (with stock options), and High Enroll (with stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic, Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi-Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute; and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from the American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), Wiley (steering committee); has served as Deputy Editor for Clinical Cardiology; has been named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, which assigned it to Lexicon; neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (Editor, Braunwald’s Heart Disease); has served as site co-investigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has served as a trustee of the American College of Cardiology; and has conducted unfunded research for FlowCo. Dr Hernandez has served as a consultant to Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intellia, Intercept, Myokardia, Novartis, Novo Nordisk, Prolaio, and TikkunLev; and has received research funding from American Regent, Amgen, Bayer, Boehringer Ingelheim, Eli Lilly, Merck, Novartis, Novo Nordisk, and Verily. Dr Butler has served as a consultant for Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Eli Lilly, LivaNova, Janssen, Medtronics, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown., Methods: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes., Results: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P =0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P =0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P <0.05)., Conclusions: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction., Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674., Competing Interests: Disclosures Dr Hernandez has served as a consultant for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intellia, Intercept, MyoKardia, Novartis, Novo Nordisk, Prolaio, and TikkunLev; and has received research funding from American Regent, Amgen, Bayer, Boehringer Ingelheim, Lilly, Merck, Novartis, Novo Nordisk, and Verily. Dr Bhatt has served on advisory boards for ANGIOWave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Stasys; on the board of directors for American Heart Association New York City, ANGIOWave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options), and High Enroll (stock); has served as a consultant for Broadview Ventures, GlaxoSmithKline, Hims, SFJ, and Youngene; has served on data monitoring committees for Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute, and Rutgers University (for the NIH-funded MINT Trial); has received honoraria from American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; chair, ACC accreditation oversight committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor-in-chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (AHA lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor-in-chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest editor; associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), WebMD (CME steering committees), and Wiley (steering committee); other: Clinical Cardiology (deputy editor); is named on a patent for sotagliflozin assigned to Brigham and Women’s Hospital, which was assigned to Lexicon (neither Dr Bhatt nor Brigham and Women’s Hospital receives any income from this patent); has received research funding from Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene, and 89Bio; has received royalties from Elsevier (editor, Braunwald’s Heart Disease); has served as site coinvestigator for Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte, and Vascular Solutions; has served as trustee for American College of Cardiology; and performed unfunded research for FlowCo. Dr Butler has served as a consultant to Abbott, American Regent, Amgen, Applied Therapeutic, AskBio, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiac Dimension, Cardiocell, Cardior, CSL Bearing, CVRx, Cytokinetics, Daxor, Edwards, Element Science, Faraday, Foundry, G3P, Innolife, Impulse Dynamics, Imbria, Inventiva, Ionis, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Owkin, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Prolaio, Regeneron, Renibus, Roche, Salamandra, Sanofi, SC Pharma, Secretome, Sequana, SQ Innovation, Tenex, Tricog, Ultromics, Vifor, and Zoll. Dr Goto reports serving as Associate Editor for Circulation and receipt of a steering committee fee from the Duke Clinical Research Institute for EMPACT-MI. Dr Lopes reports research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi-Aventis; funding for educational activities or lectures from Pfizer, Daiichi Sankyo, and Novo Nordisk; and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, and Novo Nordisk. Dr Amir reports serving as National PI-Steering committee member for the study and participated in paid lectures and advisory board meetings and clinical trials in Dr Amir’s department at Boehringer Ingelheim. Dr Beyes-Genis has lectured or participated in advisory boards for Abbott, AstraZeneca, Bayer, Boehringer-Ingelheim, Medtronic, Novartis, Novo Nordisk, Roche Diagnostics, and Vifor. Dr Bahit reports modest honorarium from MSD, Pfizer, Bristol Myers Squibb, CSL Behring, Janssen, Boehringer Ingelheim, and Anthos Therapeutics. Dr Bauersachs received honoraria for lectures/consulting from Novartis, Vifor, Bayer, Pfizer, Boehringer Ingelheim, AstraZeneca, Cardior, CVRx, BMS, Amgen, Corvia, Norgine, Edwards, and Roche not related to this article; and research support for Dr Bauersachs’ department from Zoll, CVRx, Abiomed, Norgine, and Roche, not related to this article. Dr Schou reports lecture fees from Novartis, Astra Zeneca, Bohringer, and Novo Nordisk. Dr Steg reports research grants from Amarin and Sanofi; clinical trial participation for Amarin, Amgen, AstraZeneca, Idorsia, Janssen, Novartis, Novo-Nordisk, and Sanofi; consulting or speaking for Amarin, Amgen, and Novo-Nordisk; and serving as senior associate editor at Circulation. Dr Parikh reports serving as a consultant for Medtronic, Inc and receipt of an institutional research grant from Abbott and Edwards Lifesciences. Dr Januzzi reports participation as a trustee of the American College of Cardiology, board member of Imbria Pharmaceuticals, and director at Jana Care; has received research support from Abbott, Applied Therapeutics, Bayer, BBMS, HeartFlow Inc, Innolife, and Roche Diagnostics, and consulting income from Abbott, AstraZeneca, Bayer, Beckman, Boehringer-Ingelheim, Janssen, Medtronic, Novartis, Prevencio, Quidel/Ortho, Roche Diagnostics, and Vascular Dynamics; and participates in clinical end point committees or data safety monitoring boards for Abbott, AbbVie, Bayer, CVRx, Medtronic, Pfizer, Roche Diagnostics, and Takeda. Dr Goodman reports research grant support (eg, steering committee or data and safety monitoring committee) or speaker or consulting honoraria (eg, advisory boards) from Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CSL Behring, CYTE Ltd, Daiichi-Sankyo/American Regent, Eli Lilly, Esperion, Ferring Pharmaceuticals, HLS Therapeutics, Idorsia, JAMP Pharma, Merck, Novartis, Novo Nordisk A/C, Pendopharm/Pharmascience, Pfizer, Regeneron, Sanofi, Servier, Tolmar Pharmaceuticals, and Valeo Pharma; and salary support or honoraria from the Heart and Stroke Foundation of Ontario/University of Toronto (Polo) Chair, Canadian Heart Failure Society, Canadian Heart Research Centre and MD Primer, Canadian VIGOUR Centre, Cleveland Clinic Coordinating Centre for Clinical Research, Duke Clinical Research Institute, New York University Clinical Coordinating Centre, PERFUSE Research Institute, and TIMI Study Group (Brigham Health). Dr van der Meer reports support from the European Research Council (ERC CoG 101045236, DISSECT-HF); the UMCG, which employs Dr van der Meer, received consultancy fees or grants from Novartis, Pharmacosmos, Vifor Pharma, Astra Zeneca, Pfizer, Pharma Nord, BridgeBio, Novo Nordisk, Daiichi Sankyo, Boehringer Ingelheim, and Ionis. Dr Petrie reports research funding from Boehringer Ingelheim, Roche, SQ Innovations, Astra Zeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos; and consultancy or trial committee participation from Akero, Applied Therapeutics, Amgen, AnaCardio, Biosensors, Boehringer Ingelheim, Novartis, Astra Zeneca, Novo Nordisk, AbbVie, Bayer, Horizon Therapeutics, Takeda, Cardiorentis, Pharmacosmos, Siemens, Eli Lilly, Vifor, New Amsterdam, Moderna, Teikoku, LIB Therapeutics, and 3R Lifesciences. Dr Parkhomenko reports research grants and personal fees from Bayer, Amgen, Astra Zeneca, Boehringer Ingelheim, BMS/Pfizer, and Daiichi-Sankyo. Dr Vinereanu reports research grants and consultancy fees from Boehringer Ingelheim and research grants from Bayer Healthcare, Novartis, and Servier Pharmaceuticals LLC. Dr Zieroth reports research grant support, served on advisory boards for, or had speaker engagements with AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Cytokinetics, Eli Lilly, GSK, Janssen, Medtronic, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Roche, Salubrisbio, Servier, and Vifor Pharma; and serves on a clinical trial committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis and Pfizer; nonindustry participation includes Canadian Medical and Surgical KT Group, CCS, CHFS, Charite, EOCI, Liv, Medscape, Ology, PACE-CME, Radcliffe, Reach MD, and Translational Medicine Academy. Dr Jones reports research grants from Bayer, Boehringer Ingelheim, Merck, Novartis, PCORI, and the National Institutes of Health. Drs Seide, Mattheus, Zwiener, Sumin, Gasior, Jamal, and Brueckmann are employees of Boehringer Ingelheim.

Background: Empagliflozin improves cardiovascular outcomes in patients with heart failure, patients with type 2 diabetes who are at high cardiovascular risk, and patients with chronic kidney disease. The safety and efficacy of empagliflozin in patients who have had acute myocardial infarction are unknown., Methods: In this event-driven, double-blind, randomized, placebo-controlled trial, we assigned, in a 1:1 ratio, patients who had been hospitalized for acute myocardial infarction and were at risk for heart failure to receive empagliflozin at a dose of 10 mg daily or placebo in addition to standard care within 14 days after admission. The primary end point was a composite of hospitalization for heart failure or death from any cause as assessed in a time-to-first-event analysis., Results: A total of 3260 patients were assigned to receive empagliflozin and 3262 to receive placebo. During a median follow-up of 17.9 months, a first hospitalization for heart failure or death from any cause occurred in 267 patients (8.2%) in the empagliflozin group and in 298 patients (9.1%) in the placebo group, with incidence rates of 5.9 and 6.6 events, respectively, per 100 patient-years (hazard ratio, 0.90; 95% confidence interval [CI], 0.76 to 1.06; P = 0.21). With respect to the individual components of the primary end point, a first hospitalization for heart failure occurred in 118 patients (3.6%) in the empagliflozin group and in 153 patients (4.7%) in the placebo group (hazard ratio, 0.77; 95% CI, 0.60 to 0.98), and death from any cause occurred in 169 (5.2%) and 178 (5.5%), respectively (hazard ratio, 0.96; 95% CI, 0.78 to 1.19). Adverse events were consistent with the known safety profile of empagliflozin and were similar in the two trial groups., Conclusions: Among patients at increased risk for heart failure after acute myocardial infarction, treatment with empagliflozin did not lead to a significantly lower risk of a first hospitalization for heart failure or death from any cause than placebo. (Funded by Boehringer Ingelheim and Eli Lilly; EMPACT-MI ClinicalTrials.gov number, NCT04509674.)., (Copyright © 2024 Massachusetts Medical Society.)

Competing Interests: The authors have no conflicts of interest to declare.

The effectiveness of intravenous immunoglobulin (IVIg) for patients with unexplained recurrent implantation failure (uRIF) remains debated. We retrospectively analysed outcomes of uRIF patients treated with IVIg compared to a separate control uRIF cohort within our center (01/2014-12/2021). Primary outcomes included live birth, miscarriage, or transfer failure. We documented IVIg side effects and maternal/fetal outcomes. Logistic regression analysis was used to assess for association of IVIg exposure with outcomes and adjust for confounders. The study included 143 patients, with a 2:1 ratio of controls to patients receiving IVIg treatment. Patient characteristics were similar between groups. There was higher live birth rate (LBR) in patients receiving IVIg (32/49; 65.3%) compared to controls (32/94; 34%); p < 0.001). When stratifying patients into moderate and severe uRIF (respectively 3-4 and [Formula: see text] 5 previous good quality blastocyst transfer failures), only patients with severe uRIF benefited from IVIg (LBR (20/29 (69%) versus 5/25 (20%) for controls, p = 0.0004). In the logistic regression analysis, IVIg was associated with higher odds of live birth (OR 3.64; 95% CI 1.78-7.67; p = 0.0004). There were no serious adverse events with IVIg. IVIg can be considered in well selected patients with [Formula: see text] 5 previous unexplained, high quality blastocyst transfer failures. A randomized controlled trial is needed to confirm these findings., (© 2024. Crown.)

Problem: Recurrent pregnancy loss (RPL) affects up to 4% of couples attempting to conceive. RPL is unexplained in over 50% of cases and no effective treatments exist. Due to the immune system's pivotal role during implantation and pregnancy, immune-mediated RPL may be suspected and immunomodulatory treatments like intravenous immunoglobulin (IVIg) have been administered but remain controversial. The goal of our study was to evaluate our center's 6 year-outcomes and to develop a framework for IVIg use in RPL., Method of the Study: Retrospective, single-center cohort study. All patients having received IVIg for unexplained RPL at the McGill Reproductive Immunology Clinic (MRIC) from January 2014 to December 2020 were included if maternal age was <42 years, body mass index (BMI) < 35 kg/m 2 , non-smoker and having had ≥3 consecutive RPL despite previous treatment with aspirin and progesterone. IVIg 0.6-0.8 g/kg was given prior to conception and monthly during pregnancy until 16-20 weeks' gestation. We compared IVIg treated patient's outcomes to a separate "natural history cohort". This cohort was composed of patients consulting at the McGill recurrent pregnancy loss clinic and the MRIC over a 2-year period (January 2020 to December 2021) with similar inclusion criteria as the treatment cohort but did not receive IVIg or other immunomodulatory treatments. The association of IVIg with outcomes (compared to no IVIg) was evaluated among the groups of patients with primary RPL and secondary RPL. The primary outcome was live birth rate (LBR), secondary outcomes included IVIg safety, obstetrical, and neonatal complications., Results: Among 169 patients with unexplained RPL that were included in the study, 111 had primary RPL (38 exposed to IVIg and 83 controls) and 58 had secondary RPL (nine exposed to IVIG and 49 controls). Among patients with primary RPL (n = 111), the LBR was 64.3% (18/28) among patient exposed to IVIg compared to 43.4% (36/83) in controls (p = 0.079); regression analysis adjusting for BMI and number of previous miscarriages showed benefit favoring the use of IVIg (OR = 3.27, CI 95% (1.15-10.2), p = 0.03) when evaluating for live birth. In the subgroup of patients with ≥5 previous RPL and primary RPL (n = 31), IVIg was associated with higher LBR compared to control (10/15 (66.7%) vs. 3/16 (18.8%); p = 0.0113) but not the in the sub-group of patients with <5 miscarriages and primary RPL (8/13 (61.5%) vs. 33/67 (49.3%); p = 0.548). IVIG treatment did not improve LBR in patients with secondary RPL in our study (3/9 (33.3%) vs. 23/49 (47%); p = 0.495). There were no serious adverse events in the IVIg treatment group, obstetrical/neonatal complications were similar between groups., Conclusion: IVIg may be an effective treatment for patients with RPL if appropriately used in specific groups of patients. IVIg is a blood product and subject to shortages especially with unrestricted off-label use. We propose considering IVIg in well-selected patients with high order RPL who have failed standard medical therapy. Further mechanistic studies are needed to understand immune-mediated RPL and IVIg's mode of action. This will enable further refinement of treatment criteria and the development of standardized protocol for its use in RPL., (© 2023 The Authors. American Journal of Reproductive Immunology published by John Wiley & Sons Ltd.)

Selenium is one of the compounds belonging to the trace minerals group, which needs less than 100 mg/day. This element is one of the main constituents of selenoproteins, and the function of selenoproteins is to help make DNA and protect cells from damage and infection. This experiment aimed to evaluate the effect of different sources of selenium on some mineral elements in the blood serum of lambs. This experiment was conducted using twenty 4-month-old lambs with an average weight of 37±2.2 kg, 4 treatments, and 5 replications in a completely randomized design (CRD). The treatments tested included control, sodium selenite, nano selenium, and VitEsel. The experiment duration was 30 days, and blood sampling of lambs was performed at the beginning of the experiment (zero), 15, and 30 days. Different sources of selenium significantly affected the concentrations of iron, copper, and zinc ( P <0.05). Different sources of selenium in this experiment decreased the concentration of iron and copper and increased the concentration of zinc and plasma selenium in different periods ( P <0.05). Using different sources of selenium changed the concentration of the studied elements and showed the difference in their bioavailability., Competing Interests: The authors declare that they have no conflict of interest.

Objective: This paper provides a systematic review of evidence of government purchase of health services from private providers through stand-alone contracting-out (CO) initiatives and CO insurance schemes (CO-I) on health service utilisation in Eastern Mediterranean Region (EMR) to inform universal health coverage 2030 strategies., Design: Systematic review., Data Sources: Electronic search of published and grey literature on Cochrane Central Register of Controlled Trials, PubMed, CINHAL, Google Scholar and web, including websites of ministries of health from January 2010 to November 2021., Eligibility Criteria: Randomised controlled trials, quasi-experimental studies, time series, before-after and endline with comparison group reporting quantitative utilisation of data across 16 low-income and middle-income states of EMR. Search was limited to publications in English or English translation., Data Extraction and Synthesis: We planned for meta-analysis, but due to limited data and heterogeneous outcomes, descriptive analysis was performed., Results: Several initiatives were identified but only 128 studies were eligible for full-text screening and 17 met the inclusion criteria. These included CO (n=9), CO-I (n=3) and a combination of both (n=5) across seven countries. Eight studies assessed interventions at national level and nine at subnational level. Seven studies reported on purchasing arrangements with non-governmental organisations, 10 on private hospitals and clinics. Impact on outpatient curative care utilisation was seen in both CO and CO-I, positive evidence of improved maternity care service volumes was seen mainly from CO interventions and less reported from CO-I, whereas data on child health service volume was only available for CO and indicated negative impact on service volumes. The studies also suggest pro-poor effect for CO initiatives, whereas there was scarce data for CO-I., Conclusion: Purchasing involving stand-alone CO and CO-I interventions in EMR positively impact general curative care utilisation, but lacks conclusive evidence for other services. Policy attention is needed for embedded evaluations within programmes, standardised outcome metrics and disaggregated utilisation data., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

In Brief: Immune dysfunction may contribute to or cause recurrent implantation failure. This article summarizes normal and pathologic immune responses at implantation and critically appraises currently used immunomodulatory therapies., Abstract: Recurrent implantation failure (RIF) may be defined as the absence of pregnancy despite the transfer of ≥3 good-quality blastocysts and is unexplained in up to 50% of cases. There are currently no effective treatments for patients with unexplained RIF. Since the maternal immune system is intricately involved in mediating endometrial receptivity and embryo implantation, both insufficient and excessive endometrial inflammatory responses during the window of implantation are proposed to lead to implantation failure. Recent strategies to improve conception rates in RIF patients have focused on modulating maternal immune responses at implantation, through either promoting or suppressing inflammation. Unfortunately, there are no validated, readily available diagnostic tests to confirm immune-mediated RIF. As such, immune therapies are often started empirically without robust evidence as to their efficacy. Like other chronic diseases, patient selection for immunomodulatory therapy is crucial, and personalized medicine for RIF patients is emerging. As the literature on the subject is heterogenous and rapidly evolving, we aim to summarize the potential efficacy, mechanisms of actions and side effects of select therapies for the practicing clinician.

Toxocariasis is a worldwide helminthic infection which is transmitted from infected dogs and cats and has been associated with peripheral blood eosinophilia. The Centers for Disease Control and Prevention (CDC) placed toxocariasis among the top 6 parasitic diseases in the USA which are prioritized for public health action. To our knowledge, there are no reports on human toxocariasis in Kuwait or in the other Gulf Cooperation Council (GCC) countries. This study aims at investigating the seroprevalence of toxocariasis among allergic patients in Kuwait and its association with eosinophilia, age, gender, nationality, and history of direct contact with dogs or cats. From September to December 2021, the laboratory records of allergic patients referred to Al-Rashed Allergy Hospital, Kuwait were reviewed and a total of 400 serum samples were selected: 200 samples from patients with normal eosinophil count (< 500 cells/μl) and 200 samples from patients with eosinophilia (> 500 cells/μl). The sera were screened for anti- Toxocara canis IgG antibodies via antibody enzyme-linked immunosorbent assay (Ab-ELISA). The seropositive patients were asked about their history of direct contact with dogs or cats. Statistical analyses were performed using Microsoft Excel® Analysis ToolPak software. Toxocariasis seropositivity was detected in 10 out of 400 (2.5%) allergic patients. Five patients had eosinophilia while 5 had normal eosinophil count. There was no difference in mean age or gender between Toxocara -seropositive and seronegative patients ( p  > 0.05). The seroprevalence rate was lower-than-expected among Kuwaiti patients (2/307, 0.7%) in comparison with non-Kuwaiti patients (8/57, 14.0%) (χ2 = 33.603, df  = 1, p  < 0.001) who originated from endemic South/Southeast Asian countries. Seven out of 8 (87.5%) seropositive patients had a history of direct contact with cats, dogs, or both. The seroprevalence rate of toxocariasis among allergic patients in Kuwait was 2.5%. Raising awareness and early deworming treatment/prophylaxis for juvenile dogs and cats remain crucial for toxocariasis prevention., Competing Interests: The authors declare that they have no conflict of interest., (© 2022 The Authors.)

The study of brain-to-brain synchrony has a burgeoning application in the brain-computer interface (BCI) research, offering valuable insights into the neural underpinnings of interacting human brains using numerous neural recording technologies. The area allows exploring the commonality of brain dynamics by evaluating the neural synchronization among a group of people performing a specified task. The growing number of publications on brain-to-brain synchrony inspired the authors to conduct a systematic review using the PRISMA protocol so that future researchers can get a comprehensive understanding of the paradigms, methodologies, translational algorithms, and challenges in the area of brain-to-brain synchrony research. This review has gone through a systematic search with a specified search string and selected some articles based on pre-specified eligibility criteria. The findings from the review revealed that most of the articles have followed the social psychology paradigm, while 36% of the selected studies have an application in cognitive neuroscience. The most applied approach to determine neural connectivity is a coherence measure utilizing phase-locking value (PLV) in the EEG studies, followed by wavelet transform coherence (WTC) in all of the fNIRS studies. While most of the experiments have control experiments as a part of their setup, a small number implemented algorithmic control, and only one study had interventional or a stimulus-induced control experiment to limit spurious synchronization. Hence, to the best of the authors' knowledge, this systematic review solely contributes to critically evaluating the scopes and technological advances of brain-to-brain synchrony to allow this discipline to produce more effective research outcomes in the remote future., Competing Interests: WJ was employed by BrainCo Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Nazneen, Islam, Sajal, Jamal, Amin, Vaidyanathan, Chau and Mamun.)

Introduction: Mortality rates and clinical characteristics of patients with coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU) vary significantly., Objectives: To describe the data of patients with pulmonary comorbidities who were admitted to the ICU with COVID-19 in Qatar in terms of demographic characteristics, coexisting conditions, imaging findings, and outcomes., Methods: We conducted a retrospective study of the outcomes with regard to mortality and requirement of invasive ventilation, demographic characteristics, coexisting conditions, secondary infections, and imaging findings for critical care patients with COVID-19 in Qatar who had pulmonary comorbidities between March and June 2020., Results: A total of 923 patients were included, 29 (3.14%) were found to have pulmonary disease. All these 29 patients' respiratory disease was noted to be asthma. Among these, three patients (10.3%) died in the ICU within 28 days of ICU admission. They were all above 50 years old. Nineteen (66%) patients required intubation and mechanical ventilation. Twenty-one (72.4%) patients were males. The most common comorbidities included diabetes mellitus (55.1%) and hypertension (62%). Eighteen (62%) patients developed secondary infections in the ICU. Five (17.24%) patients developed renal impairment. Twenty (69%) patients received tocilizumab as part of their COVID-19 management, and out of these 16 (80%) patients developed a coinfection., Conclusion: Patients with pulmonary disorders had higher mortality rates than other patients admitted to ICU during the same time frame with similar comorbidities; these patients require extra consideration and care to avoid disease progression and death., Competing Interests: The authors declare that they have no competing interests., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Introduction: Pneumatocele formation in COVID-19 pneumonia is arguably a common occurrence., Case Presentation: We present a case of pneumatoceles, developing as a sequel of COVID-19 infection. We argue that pneumatocele formation in COVID-19 pneumonia is a common occurrence. Importantly pneumothorax, which can lead to a raised morbidity and mortality in these patients, can be a complication of a pneumatocele rupture., Conclusion: As pneumatocele in COVID-19 pneumonia patients can lead to life-threatening complications, we emphasize the need to formulate appropriate and standardized monitoring and management guidelines. Our literature review also discusses various plausible mechanisms leading to pneumatocele formation and points to management strategies that may prevent pneumatocele formation and its complications., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Objective: The aim of this study was to determine the bacterial profile and prevalence of antibiotic resistance patterns of uropathogens, as well as to evaluate the problem with extended-spectrum β-lactamases (ESBLs)-producing isolates, causing urinary tract infections (UTIs) in children in Al-Amiri Hospital, Kuwait, over a 5-year period., Materials and Methods: Significant isolates from symptomatic pediatric patients with UTIs from January 2017 to December 2021 were identified by conventional methods and by the VITEK 2 identification card system. Antimicrobial susceptibility testing was performed by the disk diffusion method for Gram-positive organisms and an automated VITEK 2 system for Gram-negative organisms. ESBL-producing Enterobacterales were detected by the double-disk diffusion method and VITEK 2 system., Results: Significant bacteriuria was detected in 13.7% of the 9,742 urine samples. Escherichia coli accounted for 67.3% of these, followed by Klebsiella pneumoniae (8.9%), Proteus spp. (5.7%), and Enterococcus spp. (7.4%), respectively. High resistance rates were observed among the Enterobacterales against ampicillin, cephalothin, nitrofurantoin, amoxicillin/clavulanic acid, and trimethoprim-sulfamethoxazole. The prevalence of ESBL-producing E. coli and K. pneumoniae was 26% and 55%, respectively. The most sensitive among the antibiotics tested for Gram-negative organisms were meropenem, amikacin, gentamicin, and piperacillin/tazobactam, while the antibiotics tested for Gram-positive organisms were vancomycin, ampicillin, linezolid, and nitrofurantoin., Conclusion: E. coli remains the most common uropathogen. A high percentage of uropathogens causing UTI in children were highly resistant to the first- and second-line antibiotics for the therapy of UTI. ESBL-producing bacteria were highly prevalent in children in our hospital. Local antibiograms should be used to assist with empirical UTI treatment., (© 2022 The Author(s). Published by S. Karger AG, Basel.)

Objectives: To report antimicrobial resistance data for Gram-positive and Gram-negative pathogens isolated from paediatric patients in three hospitals in Kuwait during 2012-19., Methods: In vitro activity of antimicrobials against isolates from documented infections was determined using CLSI broth microdilution method and breakpoints at a central laboratory. Enterobacterales and Pseudomonas aeruginosa isolates were screened for β-lactamases using multiplex PCR assays. Phenotypic determination of resistance in Haemophilus influenzae and Gram-positive isolates was performed using standard methodologies., Results: Among 515 Enterobacterales isolates, 29.3% were ESBL-positive; susceptibility was highest to amikacin, ceftazidime/avibactam and meropenem (≥97.4%), regardless of ESBL status. CTX-M-15 was identified in 87.1% of ESBL-positive Escherichia coli and 84.2% of ESBL-positive Klebsiella pneumoniae isolates. Of 111 P. aeruginosa isolates, 9.9% were MDR and 12.6% meropenem-resistant (MEM-R). Amikacin and ceftazidime/avibactam had the highest susceptibility rates in the overall group (≥92.8%), with reduced rates among MDR and MEM-R isolates. All 269 MRSA and 180 MSSA isolates were susceptible to daptomycin, linezolid, teicoplanin, tigecycline and vancomycin. All MSSA and 99.3% of MRSA were ceftaroline susceptible. All 168 pneumococcal isolates were susceptible to ceftaroline, linezolid, tigecycline and vancomycin. H. influenzae and Streptococcus pyogenes ceftaroline susceptibility rates were ≥93.3% and ≥95.6%., Conclusions: Most isolates of Enterobacterales (including resistant phenotypes) and P. aeruginosa from Kuwait during 2012-19 were susceptible to ceftazidime/avibactam. Ceftaroline was active against most Gram-positive isolates, including resistant phenotypes, and ESBL-negative Enterobacterales. These results indicate that novel antibiotics such as ceftazidime/avibactam and ceftaroline represent valuable treatment options for paediatric infections, including those caused by MDR organisms., (© Pfizer and The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: The aim of the study was to investigate the changing pattern in serogroup distribution and antimicrobial resistance of all Salmonella spp. isolated from patients attending the Mubarak Al Kabeer Hospital (MAK), Kuwait from 2006 to 2020., Patients and Methods: A retrospective study of all enrolled patients attending the MAK with culture-positive Salmonella spp. was undertaken. Data on age, gender, culture sample and serogroup were obtained from the laboratory information system. A prospective antimicrobial susceptibility of all stock isolates was carried out using E test. The trend rates of Salmonella serogroups and antimicrobial resistance were compared among 5 periods: 2006-2008, 2009-2011, 2012-2014, 2015-2017, and 2018-2020., Results: A total of 700 isolates were identified. The majority of the isolates were from the stool (77.6%), followed by the blood (16.4%). The most common serogroups were serogroup D (37.6%) and B (23.4%). There was a significant rise in ciprofloxacin resistance from 32.2% during 2006-2008 to 54.3% during 2018-2020 and from 32.5% during 2009-2011 to 54.3% during 2018-2020 ( P =0.0001, respectively). The resistance trend to cefotaxime was at relatively low levels ranging from 0% to 3.4% through 2006-2008 to 2018-2020. There was a significant drop of the resistance to ampicillin from 23.6% in 2015-2017 to 12.3% in 2006-2008 to 2018-2020 ( P =0.03). Trimethoprim/sulfamethoxazole resistance dropped significantly from 14.5 to 3.6% ( P =0.002) during 2006-2008 to 2018-2020 and then from 13.5 to 3.6% ( P =0.02) during 2015-2017 to 2018-2020. One hundred and seventeen (16.7%) isolates were multidrug-resistant., Conclusion: Continuous surveillance of Salmonella and its antimicrobial resistance is important for antibiotic policy formulation for invasive Salmonella infections., Competing Interests: All authors declare no competing interests in this work., (© 2021 Jamal et al.)

Purpose: The purpose of this review and meta-analysis is to standardize the practice of mosaic embryo transfer, based on the current available evidence., Methods: This is a systematic review and meta-analysis. Relevant studies published were comprehensively selected using PubMed, Medline, Embase, and CENTRAL until 5 March 2021. Prospective and retrospective studies reporting the genetic analysis and clinical outcomes of mosaic embryo transfer were included. Risk of bias assessment was based on the Newcastle-Ottawa scale for the non-randomized studies. The primary and secondary outcomes were combined ongoing pregnancy and live birth rate and miscarriage rate, respectively., Results: There were no differences between low and high mosaic embryos when a cut-off of 40% was used in terms of OP/LBR and SAB. However, low mosaics with a cut-off of 50% compared to high mosaics showed a significantly higher OP/LBR in the NGS but not in the a-CGH group, and a significantly lower risk of SAB. No differences were noted between mosaic monosomies versus trisomies and single versus double mosaics for both OP/LBR and SAB. Finally, segmental mosaics showed a higher OP/LBR and a lower SAB compared to whole chromosomes, and single and double mosaics had a higher OP/LBR compared to complex mosaics., Conclusions: A cut-off of 50% in defining low versus high mosaic embryos is preferable to a threshold of 40% when using NGS platform. No priority was established for mosaic trisomies over monosomies. Single and double mosaics must be preferred over complex mosaics and segmental mosaics must be preferred over whole chromosome mosaics. These results should be interpreted in the context of specific chromosomes involved in the mosaicism., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain., Methods: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure., Results: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin., Conclusions: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951)., (Copyright © 2021 Massachusetts Medical Society.)

Background: Empagliflozin reduces the risk of cardiovascular death or heart failure (HF) hospitalization in patients with reduced ejection fraction. Its interplay with systolic blood pressure (SBP) is not known., Objectives: The goal of this study was to evaluate the interplay of SBP and the effects of empagliflozin in EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction)., Methods: Study patients (N = 3,730) were randomly assigned to groups according to SBP at baseline (<110 mm Hg, n = 928; 110-130 mm Hg, n = 1,755; >130 mm Hg, n = 1,047). This study explored the influence of SBP on the effects of empagliflozin on cardiovascular death or HF hospitalization (primary outcome), as well as on total HF hospitalizations, rate of decline in estimated glomerular filtration rate, renal outcomes, and empagliflozin's effects and significance on SBP., Results: Over a median of 16 months considering only patients receiving placebo, baseline SBP and the risk of cardiovascular death or hospitalization for HF (P trend = 0.0015) were inversely related. Corrected for placebo, a slight early increase was observed in SBP at <110 mm Hg, no change at 110-130 mm Hg, and a slight reduction at >130 mm Hg. These between-group differences were of borderline significance (P for interaction trend = 0.05-0.10) after 4 and 12 weeks but were not significant later. SBP at baseline did not influence the effect of empagliflozin to reduce the risk of HF events or renal endpoints. When treated with empagliflozin, patients with SBP <110 mm Hg did not have an increased rate of symptomatic hypotension., Conclusions: Empagliflozin was effective and safe, with no meaningful interaction between SBP and the effects of empagliflozin in the EMPEROR-Reduced trial. (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction [EMPEROR-Reduced]; NCT03057977)., Competing Interests: Funding Support and Author Disclosures All authors were involved in the EMPEROR trial, which was funded by Boehringer Ingelheim and Eli Lilly. Dr Böhm is supported by the Deutsche Forschungsgemeinschaft (German Research Foundation; TTR 219, project number 322900939); and has received personal fees from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Medtronic, Novartis, Servier, and Vifor during the conduct of the study. Dr Anker has received grants and personal fees from Vifor Int and Abbott Vascular; has received personal fees from Bayer, Brahms GmbH, Boehringer Ingelheim, Cardiac Dimensions, Cordio, Novartis, and Servier; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Butler has received consulting fees from Abbott, Adrenomed, Amgen, Applied Therapeutics, Array, AstraZeneca, Bayer, BerlinCures, Boehringer Ingelheim, Cardior, CVRx, Foundry, G3 Pharma, Imbria, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Relypsa, Roche, Sanofi, Sequana Medical, Occlutech, and Vifor; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ferreira has received consulting fees from Boehringer Ingelheim during the conduct of the study. Dr Filippatos reports Committee Member contributions in trials; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Mahfoud has received grants and personal fees from Medtronic; and has received personal fees from ReCor, Boehringer Ingelheim, and Berlin Chemie, outside the submitted work. Dr Pocock has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Ponikowski has received personal fees from Boehringer Ingelheim, AstraZeneca, Servier, BMS, Amgen, Novartis, Merck, Pfizer, and Berlin Chemie; and has received grants and personal fees from Vifor Pharma. Drs Ofstad, Jamal, and Brueckmann are employees of Boehringer Ingelheim. Dipl Math Schüler is an employee of mainanalytics, contracted by Boehringer Ingelheim. Dr Wanner has received personal fees from Boehringer Ingelheim during the conduct of the study; and has received personal fees from Akebia, AstraZeneca, Bayer, Eli Lilly, GSK, Gilead, MSD, Mundipharma, Sanofi-Genzyme, and Vifor Fresenius outside the submitted work. Dr Zannad has received steering committee or advisory board fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cardior, CVRx, Janssen, LivaNova, Merck, Mundipharma, Novartis, Novo Nordisk, and Vifor Fresenius; and has received personal fees from Boehringer Ingelheim during the conduct of the study. Dr Packer has received consulting fees from Boehringer Ingelheim during the conduct of the study; and has received consulting fees from Abbvie, Actavis, Amgen, Amarin, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Casana, CSL Behring, Cytokinetics, Johnson & Johnson, Eli Lily & Company, Moderna, Novartis, ParatusRx, Pfizer, Relypsa, Salamandra, Synthetic Biologics, and Theravance, outside the submitted work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction. Carbapenem-resistant enterobacterales (CRE) are listed among the most urgent antibiotic resistance threats. Hypothesis. Previous studies on the mechanisms of CRE in Kuwait have focused on carbapenemases. There have been no studies on non-carbapenemase-producing CRE in Kuwait. Aim/Gap Statement. The aim of this study was to investigate the genetic characteristics of non-carbapenemase-producing carbapenem-resistant enterobacterales (NCPE) isolates using whole-genome sequencing (WGS). Methodology. Fourteen confirmed NCPE isolates that were negative for genes encoding carbapenemase production by polymerase chain reaction (PCR) assays using rectal swabs from intensive care unit patients were characterized using phenotypic, PCR and WGS methods. Susceptibility testing was performed via Etest and clonality via multi-locus sequence typing (MLST). Results. All of the isolates were resistant to ertapenem; 78.6 % were resistant to imipenem, meropenem and trimethoprim-sulfamethoxazole. Resistance to the other antibiotics was variable, ranging from 28.5 (colistin) through 50 (tigecycline) and 64.3 (amikacin) up to 85.7 % against both amoxicillin-clavulanic acid and ciprofloxacin. WGS detected several resistance genes mediating the production of β-lactamases, genes encoding an outer-membrane porin permeability mutation resulting in reduced susceptibility to β-lactams, including carbapenems, and genes for multidrug-resistant (MDR) efflux pumps. The isolates also possessed global activator protein MarA, which mediated reduced permeability to β-lactams. The existence of β-lactamase genes, overexpression of MDR efflux pumps and reduced permeability mediated by the porin genes were responsible for carbapenem resistance. Conclusions. This finding reflects the superior detection capabilities offered by WGS analysis, which can be used to complement traditional methods and overcome their limited resolution in clinical settings.

Autism is strongly associated with sensory processing difficulties. We investigate sensory habituation, given its relevance for understanding important phenotypic traits like hyper- and hypo-sensitivities. We collected electroencephalography data from 22 neuro-typical(NT) and 13 autistic(ASD) children during the presentation of visual and auditory sequences of repeated stimuli. Our data show that the ASD children have significantly reduced habituation relative to the NT children for both auditory and visual stimuli. These results point to impaired habituation as a modality-general phenomenon in ASD. Additionally, the rates of habituation are correlated with several clinical scores associated with competence along diverse phenotypic dimensions. These data suggest that the sensory difficulties in autism are likely to be associated with reduced habituation and are related to clinical symptomology., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Aims: Circulating troponin is an important measure of risk in patients with heart failure, but it has not been used to determine if disease severity influences the responses to drug treatments in randomized controlled trials., Methods and Results: In the EMPEROR-Reduced trial, patients with class II-IV heart failure and a reduced ejection fraction were randomly assigned to placebo or empagliflozin 10 mg daily and followed for the occurrence of serious heart failure and renal events. High-sensitivity cardiac troponin T (hs-cTnT) was measured in 3636 patients (>97%) at baseline, and patients were divided into four groups based on the degree of troponin elevation. With increasing concentrations of hs-cTnT, patients were progressively more likely to have diabetes and atrial fibrillation, to have New York Heart Association class III-IV symptoms and been hospitalized for heart failure within the prior year, and to have elevated levels of natriuretic peptides and worse renal function (P-trend < 0.0001 for all comparisons), but importantly, the troponin groups did not differ with respect to ejection fraction. A linear relationship was observed between the logarithm of hs-cTnT and the combined risk of cardiovascular death or hospitalization for heart failure (P = 0.0015). When treated with placebo, patients with the highest levels of hs-cTnT had risks of cardiovascular death and hospitalization for heart failure that were 3-5 fold greater than those with values in the normal range. Patients with higher levels of hs-cTnT were also more likely to experience worsening of renal function and serious adverse renal events and showed the least improvement in health status (as measured by the Kansas City Cardiomyopathy Questionnaire). When compared with placebo, empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure, regardless of the baseline level of hs-cTnT, whether the effects of treatment were analysed as hazard ratios or absolute risk reductions., Conclusions: Elevations in hs-cTnT reflect the clinical severity, stability and prognosis of patients with heart failure and a reduced ejection fraction, with biomarkers, comorbidities, clinical course and risks that are proportional to the magnitude of hs-cTnT elevation. Empagliflozin exerted favourable effects on heart failure and renal outcomes, regardless of the baseline concentration of hs-cTnT., (© 2021 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Objective: To investigate the effect of aspirin on IVF success rates when used as an adjuvant treatment for endometrial preparation., Data Sources: Relevant publications were comprehensively selected from PubMed, MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) up to November 15, 2020., Study Selection: Randomized controlled trials (RCTs) and retrospective cohort studies that used aspirin as an adjuvant treatment for endometrial preparation and reported subsequent pregnancy outcomes were included. Studies were excluded if aspirin was used before and/or during ovarian stimulation., Data Extraction and Synthesis: This systematic review and meta-analysis included a total of 7 studies. Risk of bias assessment was based on the methodology and categories listed in the Cochrane Handbook for the RCTs and the Newcastle-Ottawa scale for the retrospective studies. The primary outcome was live birth rate. Summary measures were reported as odds ratios (ORs) with 95% confidence intervals (CIs). There was significant evidence that aspirin for endometrial preparation improved live birth rates (OR  1.52; 95% CI   1.15-2.00). No effect was noted for clinical pregnancy rates (OR  1.37; 95% CI   1.00-1.87); however, aspirin was associated with improved pregnancy rates in a subgroup analysis of patients receiving oocyte donation (OR 2.53; 95% CI 1.30-4.92) and in the sensitivity analysis (OR 1.3; 95% CI   1.02-1.66). No effect of aspirin was found for implantation or miscarriage rates (OR 1.31; 95% CI  0.51-3.36 and OR 0.41; 95% CI  0.02-7.42, respectively)., Conclusion: These findings support a beneficial effect of aspirin for endometrial preparation on IVF success rates, mainly live birth rates, outside the context of ovarian stimulation. However, this evidence is based on poor quality data and needs to be confirmed with high-quality RCTs., (Copyright © 2021 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

It is estimated that nearly 90% of children on the autism spectrum exhibit sensory atypicalities. What aspects of sensory processing are affected in autism? Although sensory processing can be studied along multiple dimensions, two of the most basic ones involve examining instantaneous sensory responses and how the responses change over time. These correspond to the dimensions of 'sensitivity' and 'habituation'. Results thus far have indicated that autistic individuals do not differ systematically from controls in sensory acuity/sensitivity. However, data from studies of habituation have been equivocal. We have studied habituation in autism using two measures: galvanic skin response (GSR) and magneto-encephalography (MEG). We report data from two independent studies. The first study, was conducted with 13 autistic and 13 age-matched neurotypical young adults and used GSR to assess response to an extended metronomic sequence. The second study involved 24 participants (12 with an ASD diagnosis), different from those in study 1, spanning the pre-adolescent to young adult age range, and used MEG. Both studies reveal consistent patterns of reduced habituation in autistic participants. These results suggest that autism, through mechanisms that are yet to be elucidated, compromises a fundamental aspect of sensory processing, at least in the auditory domain. We discuss the implications for understanding sensory hypersensitivities, a hallmark phenotypic feature of autism, recently proposed theoretical accounts, and potential relevance for early detection of risk for autism.

Eleven metronidazole resistant Bacteroides and one newly classified Phocaeicola dorei strain from Kuwait were investigated for their resistance mechanisms and the emergence of their resistant plasmids. All but one strain harbored nimE genes on differently sized plasmids. Of the 11 nimE genes, 9 were preceded by full copies of the prototype ISBf6 insertion sequence element, one carried a truncated ISBf6 and one was activated by an additional copy of IS612B. Nucleotide sequencing results showed that the nimE ISBf6 distances were constant and all five different plasmids shared a common region, suggesting that (i) the nimE-ISBf6 configuration was inserted into an undisclosed common genetic element, (ii) over time, this common element was mutated by insertions and deletions, spreading the resultant plasmids. Of the 10 B. fragilis strains in this collection, 6 were also cfiA-positive, one with full imipenem resistance, indicating a tendency for multidrug resistance (MDR) among such isolates. The significant number of metronidazole resistant Bacteroides spp. and P. dorei strains with the MDR phenotype warns of difficulties in treatment and suggests promoting adherence to antibiotic stewardship recommendations in Kuwait., Competing Interests: Declaration of competing interest We declare no conflict of interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)