The experience of an antimicrobial stewardship program and antibiotic consumption and resistance trends during the COVID-19 pandemic at a tertiary care center in Beirut.

BACKGROUND: Antimicrobial Resistance, a global concern, worsened with the COVID-19 pandemic that caused a surge of critically ill patients, increased antimicrobial consumption, and the spread of infections with multidrug-resistant organisms (MDROs). Antimicrobial Stewardship Programs (ASP) aim to optimize antimicrobial utilization to fight resistance. We aim to describe the ASP experience and to study antimicrobial consumption and MDRO rates among COVID-19 patients at a tertiary care center in Beirut. METHODS: We compiled the ASP interventions, defined as ASP team recommendations, from January 2019 until December 2021. Data on antimicrobial consumption, expressed as a defined daily dose (DDD) per 100 patient days, was collected per quarter for all antimicrobials and restricted antimicrobials per ASP guidance. Our primary objective was to report on the ASP experience, and the secondary objective was to reflect on the rates of MDROs among hospitalized COVID-19 patients with respiratory or bloodstream bacterial co-infections between March 2020 and September 2021. RESULTS: 9922 ASP interventions were documented during this study period, with a noticeable correlation between COVID-19 surges in Lebanon and the number of ASP interventions. Acceptance rates for these recommendations improved over time, with a noticeable decrease in the proportion of interventions related to de-escalation and discontinuation of broad-spectrum antimicrobials. We noted an increase in all antimicrobial consumption after the onset of the pandemic, peaking in Q4 2020 (142.8 DDD of anti-infectives/100 patient days) and Q1 2021 (79.1 DDD of restricted anti-infectives/100 patient days). As expected, MDROs, particularly ESKAPE organisms (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Carbapenem-resistant Enterobacteriaceae) accounted for 24% of isolates obtained from this cohort. CONCLUSION: This study highlights the experience of the ASP as we adapted to the COVID-19 pandemic. The ASP team maintained its operations and continued to monitor antibiotic consumption and provide recommendations to limit antibiotic misuse in an effort to mitigate the impact of the pandemic on antimicrobial resistance.

Blood Stream Infections in COVID-19 Patients From a Tertiary Care Center in Lebanon: Causative Pathogens and Rates of Multi-Drug Resistant Organisms.

Objective: To report the microbiological profile of the pathogens implicated in blood stream infections (BSI) in hospitalized coronavirus disease 2019 (COVID-19) patients and to examine the risk factors associated with multidrug-resistant organisms (MDROs) causing BSI. Patients and Methods: Between March 2020 and September 2021, 1647 patients were hospitalized with COVID-19 at the American University of Beirut. From 85 patients, 299 positive blood cultures were reported to the Infection Control and Prevention Program. The BSI was defined as 1 positive blood culture for bacterial or fungal pathogens. The following organisms were considered MDROs: methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp, carbapenem-resistant Enterobacterales spp., carbapenem-resistant Pseudomonas aeruginosa, MDR Acinetobacter baumannii only susceptible to colistin or tigecycline, and Candida auris. Results: We identified 99 true positive BSI events. Gram-negative bacteria accounted for 38.4 %, followed by Gram-positive bacteria (37.4%), and fungi (24.2%). The most isolated species were Candida spp. (23%), 3 of which were C. auris, followed by Enterobacterales spp. (13%), Enterococcus spp. (12%), S. aureus (9%), P. aeruginosa (9%), and A. baumannii (3%). The MDROs represented 26% of the events. The overall mortality rate was 78%. The time to acquisition of BSI in patients with MDROs was significantly longer compared with that of non-MDROs (20.2 days vs 11.2 days). And there was a significantly shorter time from acquisition of BSI to mortality between MDROs and non-MDROs (1.5 vs 8.3 days). Conclusion: Rigorous infection prevention and control measures and antimicrobial stewardship are important to prevent antimicrobial resistance progression, especially in low-resource settings.

Myocarditis and Pericarditis Post-mRNA COVID-19 Vaccination: Insights from a Pharmacovigilance Perspective.

Concerns remain regarding the rare cardiovascular adverse events, myocarditis and pericarditis (myo/pericarditis), particularly in younger individuals following mRNA COVID-19 vaccination. Our study aimed to comprehensively assess potential safety signals related to these cardiac events following the primary and booster doses, with a specific focus on younger populations, including children as young as 6 months of age. Using the Vaccine Adverse Events Reporting System (VAERS), the United States national passive surveillance system, we conducted a retrospective pharmacovigilance study analyzing spontaneous reports of myo/pericarditis. We employed both frequentist and Bayesian methods and conducted subgroup analyses by age, sex, and vaccine dose. We observed a higher reporting rate of myo/pericarditis following the primary vaccine series, particularly in males and mainly after the second dose. However, booster doses demonstrated a lower number of reported cases, with no significant signals detected after the fourth or fifth doses. In children and young adults, we observed notable age and sex differences in the reporting of myo/pericarditis cases. Males in the 12-17 and 18-24-year-old age groups had the highest number of cases, with significant signals for both males and females after the second dose. We also identified an increased reporting for a spectrum of cardiovascular symptoms such as chest pain and dyspnea, which increased with age, and were reported more frequently than myo/pericarditis. The present study identified signals of myo/pericarditis and related cardiovascular symptoms after mRNA COVID-19 vaccination, especially among children and adolescents. These findings underline the importance for continued vaccine surveillance and the need for further studies to confirm these results and to determine their clinical implications in public health decision-making, especially for younger populations.

Risk of myocarditis and pericarditis in mRNA COVID-19-vaccinated and unvaccinated populations: a systematic review and meta-analysis.

OBJECTIVE: To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated individuals in the absence of COVID-19 infection. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases (Medline, Embase, Web of Science and WHO Global Literature on Coronavirus Disease), preprint repositories (medRxiv and bioRxiv), reference lists and grey literature were searched from 1 December 2020 until 31 October 2022. STUDY SELECTION: Epidemiological studies of individuals of any age who received at least one dose of an mRNA COVID-19 vaccine, reported a risk of myo/pericarditis and compared the risk of myo/pericarditis to individuals who did not receive any dose of an mRNA COVID-19 vaccine. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently conducted screening and data extraction. The rate of myo/pericarditis among vaccinated and unvaccinated groups was recorded, and the rate ratios were calculated. Additionally, the total number of individuals, case ascertainment criteria, percentage of males and history of SARS-CoV-2 infection were extracted for each study. Meta-analysis was done using a random-effects model. RESULTS: Seven studies met the inclusion criteria, of which six were included in the quantitative synthesis. Our meta-analysis indicates that within 30-day follow-up period, vaccinated individuals were twice as likely to develop myo/pericarditis in the absence of SARS-CoV-2 infection compared to unvaccinated individuals, with a rate ratio of 2.05 (95% CI 1.49-2.82). CONCLUSION: Although the absolute number of observed myo/pericarditis cases remains quite low, a higher risk was detected in those who received mRNA COVID-19 vaccinations compared with unvaccinated individuals in the absence of SARS-CoV-2 infection. Given the effectiveness of mRNA COVID-19 vaccines in preventing severe illnesses, hospitalisations and deaths, future research should focus on accurately determining the rates of myo/pericarditis linked to mRNA COVID-19 vaccines, understanding the biological mechanisms behind these rare cardiac events and identifying those most at risk.

The Impact of Antimicrobial Stewardship and Infection Control Interventions on Acinetobacter baumannii Resistance Rates in the ICU of a Tertiary Care Center in Lebanon.

Antimicrobial resistance is a serious threat to global health, causing increased mortality and morbidity especially among critically ill patients. This toll is expected to rise following the COVID-19 pandemic. Carbapenem-resistant Acinetobacter baumannii (CRAb) is among the Gram-negative pathogens leading antimicrobial resistance globally; it is listed as a critical priority pathogen by the WHO and is implicated in hospital-acquired infections and outbreaks, particularly in critically ill patients. Recent reports from Lebanon describe increasing rates of infection with CRAb, hence the need to develop concerted interventions to control its spread. We set to describe the impact of combining antimicrobial stewardship and infection control measures on resistance rates and colonization pressure of CRAb in the intensive care units of a tertiary care center in Lebanon before the COVID-19 pandemic. The antimicrobial stewardship program introduced a carbapenem-sparing initiative in April 2019. During the same period, infection control interventions involved focused screening, monitoring, and tracking of CRAb, as well as compliance with specific measures. From January 2018 to January 2020, we report a statistically significant decrease in carbapenem consumption and a decrease in resistance rates of isolated A. baumannii. The colonization pressure of CRAb also decreased significantly, reaching record low levels at the end of the intervention period. The results indicate that a multidisciplinary approach and combined interventions between the stewardship and infection control teams can lead to a sustained reduction in resistance rates and CRAb spread in ICUs.

Evaluation of Carbapenem Use Before and After Implementation of an Antimicrobial Stewardship-Led Carbapenem-Sparing Strategy in a Lebanese Tertiary Hospital: A Retrospective Study.

Purpose: The use of carbapenem before and after implementation of an antimicrobial stewardship-led carbapenem-sparing strategy at a tertiary care center in Lebanon was evaluated. Methods: A retrospective, observational chart review was performed on all hospitalized pediatric and adult patients who received carbapenem therapy during January 2019 and January 2020. Patients who started their regimen before January or received carbapenems for less than 24 hours were excluded. Primary outcomes included the appropriateness of physician prescribing patterns and pharmacists' interventions, as well as appropriateness and response rates of the latter. Secondary outcomes included the carbapenem defined daily dose (DDD) and days of therapy (DOT). Descriptive statistics were used in the analysis and a p-value < 0.05 was considered to be statistically significant. Results: A total of 157 and 150 patients charts were reviewed in January 2019 and January 2020, respectively. There was no difference in baseline characteristics except for inpatient services and rates of isolated multidrug-resistant organisms. When comparing the two timelines, the appropriateness of physicians' prescribing patterns increased in terms of empirical therapy, targeted therapy, and duration of therapy but the results were not statistically significant. Pharmacists' interventions significantly increased with regards to the duration of therapy (p= <0.001), dose adjustment (p<0.001), de-escalation to a narrower spectrum antibiotic (p=0.007), and use of extended infusion (p=0.042). The DDD and DOT were higher for ertapenem and lower for anti-pseudomonal carbapenems in January 2020. Conclusion: The carbapenem-sparing strategy adopted by the antimicrobial stewardship program contributed to an increase in the number of interventions made by pharmacists on carbapenem therapy, including their appropriateness, and response rate. Despite an improvement in the physician-prescribing patterns, more awareness and education may be needed to achieve a better impact.

Challenges to Antimicrobial Stewardship in the Countries of the Arab League: Concerns of Worsening Resistance during the COVID-19 Pandemic and Proposed Solutions.

The COVID-19 pandemic is expected to worsen the global problem of antimicrobial resistance (AMR). There is a heightened interest in understanding this effect and to develop antimicrobial stewardship (AMS) interventions accordingly to curb this threat. Our paper aims to evaluate the potential magnitude of COVID-19 on AMR and AMS with a focus on the countries of the Arab league, given the social, political, and economic environments. We also evaluate obstacles in applying the rational use of antibiotics, monitoring resistance trends in the midst of the pandemic, and evaluating the impact of the economic crisis in some countries. We aim to raise awareness about the potential effects of antibiotic overuse during the pandemic and to propose practical approaches to tackle this issue.

Retrospective evaluation of intravenous fosfomycin in multi-drug resistant infections at a tertiary care hospital in Lebanon.

INTRODUCTION: Fosfomycin has re-emerged as a possible therapeutic alternative for the treatment of resistant bacterial pathogens. Its main mechanism of action is the inhibition of the initial step of cell wall synthesis and is active against both Gram-positive and Gram-negative bacteria. However, its clinical effectiveness against multidrug resistant bacteria remains largely unknown. Therefore, we aim to evaluate the clinical and microbiological effectiveness of intravenous fosfomycin as well as its safety in a tertiary care teaching hospital in Lebanon. METHODOLOGY: This is a retrospective chart review of adult patients who had presented to the hospital and were treated with intravenous fosfomycin for at least 24 hours for any type of infection between 2014 and 2019. RESULTS: Among 31 episodes treated with intravenous fosfomycin, 68% had an overall favorable clinical response. In 84% of the episodes, fosfomycin was administered in combination with other antibiotics, commonly tigecycline. Of those with available cultures at end of therapy, 73% achieved microbiological success. No relapse was documented within 30 days of completion of therapy. In the episodes secondary to resistant pathogens, the rates of favorable clinical outcome and microbiological success at the end of therapy were 71% and 73%, respectively. Fosfomycin resistance developed in two cases and mild adverse events occurred in 65% of the episodes during the course of treatment. CONCLUSIONS: Fosfomycin is a safe and effective option in the treatment of multi-drug resistant infections. Nevertheless, careful stewardship is important to maintain its efficacy and to reduce the risk of selection of antimicrobial resistance.

Antimicrobial stewardship in the ICU in COVID-19 times: the known unknowns.

Since the start of the COVID-19 pandemic, there has been concern about the concomitant rise of antimicrobial resistance. While bacterial co-infections seem rare in COVID-19 patients admitted to hospital wards and intensive care units (ICUs), an increase in empirical antibiotic use has been described. In the ICU setting, where antibiotics are already abundantly-and often inappropriately-prescribed, the need for an ICU-specific antimicrobial stewardship programme is widely advocated. Apart from essentially warning against the use of antibacterial drugs for the treatment of a viral infection, other aspects of ICU antimicrobial stewardship need to be considered in view of the clinical course and characteristics of COVID-19. First, the distinction between infectious and non-infectious (inflammatory) causes of respiratory deterioration during an ICU stay is difficult, and the much-debated relevance of fungal and viral co-infections adds to the complexity of empirical antimicrobial prescribing. Biomarkers such as procalcitonin for the decision to start antibacterial therapy for ICU nosocomial infections seem to be more promising in COVID-19 than non-COVID-19 patients. In COVID-19 patients, cytomegalovirus reactivation is an important factor to consider when assessing patients infected with SARS-CoV-2 as it may have a role in modulating the patient immune response. The diagnosis of COVID-19-associated invasive aspergillosis is challenging because of the lack of sensitivity and specificity of the available tests. Furthermore, altered pharmacokinetic/pharmacodynamic properties need to be taken into account when prescribing antimicrobial therapy. Future research should now further explore the 'known unknowns', ideally with robust prospective study designs.

Public health measures to reduce the risk of SARS-CoV-2 transmission in Canada during the early days of the COVID-19 pandemic: a scoping review.

OBJECTIVE: The main objectives of this study were to synthesise and compare pandemic preparedness strategies issued by the federal and provincial/territorial (P/T) governments in Canada and to assess whether COVID-19 public health (PH) measures were tailored towards priority populations, as defined by relevant social determinants of health. METHODS: This scoping review searched federal and P/T websites on daily COVID-19 pandemic preparedness strategies between 30 January and 30 April 2020. The PROGRESS-Plus equity-lens framework was used to define priority populations. All definitions, policies and guidelines of PH strategies implemented by the federal and P/T governments to reduce risk of SARS-CoV-2 transmission were included. PH measures were classified using a modified Public Health Agency of Canada Framework for Canadian Pandemic Influenza Preparedness. RESULTS: A total of 722 COVID-19 PH measures were issued during the study period. Of these, home quarantine (voluntary) (n=13.0%; 94/722) and retail/commerce restrictions (10.9%; n=79/722) were the most common measures introduced. Many of the PH orders, including physical distancing, cancellation of mass gatherings, school closures or retail/commerce restrictions began to be introduced after 11 March 2020. Lifting of some of the PH orders in phases to reopen the economy began in April 2020 (6.5%; n=47/722). The majority (68%, n=491/722) of COVID-19 PH announcements were deemed mandatory, while 32% (n=231/722) were recommendations. Several PH measures (28.0%, n=202/722) targeted a variety of groups at risk of socially produced health inequalities, such as age, religion, occupation and migration status. CONCLUSIONS: Most PH measures centred on limiting contact between people who were not from the same household. PH measures were evolutionary in nature, reflecting new evidence that emerged throughout the pandemic. Although ~30% of all implemented COVID-19 PH measures were tailored towards priority groups, there were still unintended consequences on these populations.

HIV in Canada-surveillance report, 2019.

BACKGROUND: Human immunodeficiency virus (HIV) is a global public health issue. HIV has been nationally notifiable in Canada since 1985. The Public Health Agency of Canada (PHAC) monitors trends in new HIV diagnoses. OBJECTIVES: The objective of this surveillance report is to provide an overview of the epidemiology of reported HIV cases in 2019 in Canada. The report highlights 10-year trends (2010-2019). Data on HIV diagnosed through Immigration Medical Exams (IME) and trends in perinatal transmission of HIV are also presented. METHODS: PHAC monitors HIV through the HIV/AIDS Surveillance System, a passive, case-based system that collates non-nominal data submitted voluntarily by all Canadian provinces and territories. Descriptive analyses were conducted on national data. IME data were obtained from Immigration, Refugees and Citizenship Canada (IRCC), and data on HIV-exposed pregnancies were obtained through the Canadian Perinatal HIV Surveillance Program. RESULTS: In 2019, a total of 2,122 HIV diagnoses were reported in Canada (5.6 per 100,000 population). Saskatchewan reported the highest provincial diagnosis rate at 16.9 per 100,000 population. The 30 to 39-year age group had the highest HIV diagnosis rate at 12.7 per 100,000 population. While the rates for both males and females fluctuated in the past decade, since 2010 the rates among males decreased overall, while the rate among females increased slightly. As in previous years, the diagnosis rate for males in 2019 was higher than that for females (7.9 versus 3.4 per 100,000 population, respectively). The highest proportion of all reported adult cases with known exposure were gay, bisexual and other men who have sex with men (gbMSM, 39.7%), followed by cases attributed to heterosexual contact (28.3%) and among people who inject drugs (PWID, 21.5%). The number of migrants who tested positive for HIV during an IME conducted in Canada was 626. The one documented perinatal HIV transmission related to a mother who had not received antepartum or intrapartum antiretroviral therapy prophylaxis. CONCLUSION: The number and rate of reported HIV cases in Canada has remained relatively stable over the last decade, with minor year-to-year variations. As in previous years, the gbMSM and PWID populations represent a high proportion of HIV diagnoses, although a sizable number of cases were attributed to heterosexual contact. It is important to routinely monitor trends in HIV in light of pan-Canadian commitments to reduce the health impact of sexually transmitted and blood-borne infections by 2030.

Impact of pharmacist-conducted anticoagulation patient education and telephone follow-up on transitions of care: a randomized controlled trial.

BACKGROUND: There is limited published data in Lebanon evaluating the impact of supplemental education for anticoagulants use, especially DOACs, on clinical outcomes such as bleeding. The study aims to assess the impact of pharmacist-conducted anticoagulation education and follow-up on bleeding and readmission rates. METHODS: This study was a randomized, non-blinded interventional study conducted between August 2017 and July 2019 in a tertiary care teaching Lebanese hospital. Participants were inpatients ≥18 years discharged on an oral anticoagulant for treatment. Block randomization was used. The control group received the standard nursing counseling while the intervention group additionally received pharmacy counseling. Phone call follow-ups were done on day 3 and 30 post-discharge. Primary outcomes included readmission rates and any bleeding event at day 3 and 30 post-discharge. Secondary outcomes included documented elements of education in the medical records and reported mortality upon day 30 post-discharge. RESULTS: Two hundred patients were recruited in the study (100 patients in each study arm) with a mean age of 73.9 years. In the pharmacist-counseled group, more patients contacted their physician within 3 days (14% versus 4%; p = 0.010), received explicit elements of education (p < 0.001) and documentation in the chart was better (p < 0.05). In the standard of care group, patients were more aware of their next physician appointment date (52% versus 31%, p < 0.001). No difference in bleeding rates at day 3 and 30 post-discharge was observed between the groups. CONCLUSIONS: Although pharmacist-conducted anticoagulation education did not appear to reduce bleeding or readmission rates at day 30, pharmacist education significantly increased patient communication with their providers in the early days post-discharge. TRIAL REGISTRATION: Lebanon Clinical Trial Registry LBCTR2020033424 . Retrospectively registered. Date of registration: 06/03/2020.

Risk of Adverse Cardiovascular Events Following a Myocardial Infarction in Patients Receiving Combined Clopidogrel and Proton Pump Inhibitor Treatment: A Nested Case-Control Study.

BACKGROUND: The clinical implications of potential interactions between proton pump inhibitors (PPIs) and clopidogrel have been debated for over a decade. OBJECTIVE: We assessed the association between combined clopidogrel-PPI treatment and the risk of recurrent myocardial infarction (MI) and three secondary outcomes. PATIENTS AND METHODS: A nested case-control study was conducted within Cerner Corporation's Health Facts® database. A retrospective cohort of patients who experienced a first MI and started clopidogrel treatment was created. Within this cohort, patients experiencing a second MI (cases) were matched with up to five controls. Logistic regression was used to estimate adjusted odds ratios (aORs). Findings were compared with those obtained from models with three negative control exposure drugs: H2 receptor antagonists, prasugrel, and ticagrelor. RESULTS: In total, 2890 recurrent MI cases were identified within 12 months following entry into the cohort of clopidogrel users (N = 52,006). aOR for PPI use versus non-use among clopidogrel users was 1.08 [95% confidence interval (CI) 0.95-1.23]. Similar ORs were obtained for secondary endpoints. A positive association between combined use of clopidogrel/PPIs and increased risk of MI was seen in the group aged 80-89 years (aOR 1.26; 95% CI 1.05-1.51). No associations with MI were observed for (1) H2 receptor antagonist use versus non-use among clopidogrel users or (2) PPI use versus non-use among prasugrel users or among ticagrelor users. CONCLUSIONS: Overall, our findings do not support a significant adverse clinical impact of concomitant clopidogrel/PPI use by patients with MI. Nonetheless, investigation of the possible association seen in those aged 80-89 years may be warranted.

Value of pharmacy services in an outpatient, preoperative, anesthesia clinic.

OBJECTIVE: This pilot study assessed the expansion of pharmacy services to a preoperative, anesthesia clinic. SETTING: Tertiary care academic medical center. PRACTICE DESCRIPTION: Medication histories were routinely obtained by clinic nurses, and pharmacy services were not available. PRACTICE INNOVATION: A prospective, single-center, pilot study enrolled English-speaking patients aged 65 years or older in a preoperative clinic before a scheduled surgery. Patient attributes including health literacy and preparatory activities were measured using verbal and written questionnaires. Home medication lists were obtained by both clinic nurses (routine care) and a pharmacist (research), and the 2 lists were compared to identify medication discrepancies for each patient. Discrepancies were categorized by type and severity. EVALUATION: This study evaluated the potential impact of medication histories obtained by pharmacists compared with those obtained by clinic nurses during geriatric preoperative clinic visits. RESULTS: Of the 44 patients who gave their consent and were included in this pilot study, 25% (n = 11) had limited/marginal written and verbal health literacy, and 20% (n = 9) had limited/marginal numerical health literacy. Of the 38 patients who completed the pharmacist medication history interview, only 21% (n = 8) brought a complete list of their current medications to the preoperative clinic, 95% (n = 36) had at least 1 medication discrepancy, and 61% (n = 23) had at least 1 clinically meaningful discrepancy. Clinically meaningful discrepancies were identified for 8% (35 of 459) of medications and occurred most commonly for blood pressure medications, nonsteroidal anti-inflammatory drugs, and beta blockers. CONCLUSION: In this study, medication history discrepancies identified by pharmacists suggest that the expansion of pharmacy services into the preoperative clinic is feasible and could potentially prevent meaningful medication errors among geriatric patients being admitted for a scheduled surgery.

Systematic review and meta-analysis of adverse cardiovascular events associated with proton pump inhibitors used alone or in combination with antiplatelet agents.

The potential association between major adverse cardiovascular events (MACE) and concomitant treatment with proton pump inhibitors (PPIs) and clopidogrel has been debated since 2009. Recent reports, however, suggest that PPIs may increase the risk of MACE independently of clopidogrel. This review evaluates epidemiological findings relevant to the association between PPIs, taken alone or concomitantly with antiplatelets, and the risk of MACE. A systematic review and meta-analysis were conducted. Relevant studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and then screened. Included studies were categorized into three groups: Group A: PPIs versus no PPIs; Group B: combined PPIs and clopidogrel versus clopidogrel alone; Group C: combined PPIs and other drugs versus other drugs. Pooled risk ratios (RRs) were calculated for each outcome of interest in each comparison group. Of the 1667 studies identified, 118 were included in the systematic review, of which 66 were included in the meta-analyses. Among Group A observational studies, RRs for MACE outcomes were statistically significant for some patient populations but not others. Pooled RRs from Group A RCTs were not statistically significant for any outcome. Pooled RRs for Group B observational studies were statistically significant for all-cause mortality and MI, but were diminished in magnitude when pooling was restricted to propensity score matched studies or post hoc analyses of RCTs. Group C studies did not demonstrate an association with MACE. Findings do not consistently support an association between MACE and PPIs when taken alone, or concomitantly with antiplatelets.

Trends in concomitant clopidogrel and proton pump inhibitor treatment among ACS inpatients, 2000-2016.

PURPOSE: The US Food and Drug Administration (FDA) issued three safety announcements between January 2009 and October 2010 warning against concomitant use of clopidogrel and proton pump inhibitors (PPIs) due to a potential drug-drug interaction that may attenuate clopidogrel's antiplatelet activity. This primary objective of this study was to examine trends in concomitant clopidogrel/PPI use among acute coronary syndrome (ACS) inpatients in the US between 2000 and 2016, in relation to the FDA safety communications. METHODS: Adult inpatients with a primary diagnosis of ACS were identified from the Cerner Health Facts® database. The standardized (age, sex, race, and census region) prevalence of clopidogrel use with PPIs was calculated yearly and quarterly. Findings were stratified by PPIs' potential to inhibit clopidogrel's activity and by age. RESULTS: A total of 204,533 inpatients were identified. In 2008, the prevalence of concomitant clopidogrel and PPI treatment was 34.9%, decreasing to 24.4 and 16.4% in 2009 and 2010, respectively, with the decline being similar across age groups. Treatment with inhibiting PPIs (omeprazole and esomeprazole) and clopidogrel has continued to decrease since 2010, with a prevalence of 0.8% in 2016. A similar reduction was not observed with clopidogrel and non-inhibiting PPIs (pantoprazole, lansoprazole, rabeprazole, and dexlansoprazole). During the FDA warning period, the combined treatment with clopidogrel and H2 receptor antagonists, an alternative to PPIs suggested by the FDA, temporarily increased from 7.8% in 2008 to 12.8 and 14.5% in 2009 and 2010, respectively. CONCLUSIONS: Findings suggest that clinical practice recommendations made by the FDA were followed. Further research is needed to determine how changes in drug labels and the availability of new drugs may have influenced the observed trends.

Effects of heat shock on the distribution and expression levels of nuclear proteins in HeLa S3 cells.

Cumulating evidence has led to the idea that nuclear functions such as DNA replication, RNA transcription, RNA splicing and nucleocytoplasmic transport are facilitated by a proteinaceous architectural framework within the nuclear compartment and at the nuclear envelope. In the present study, we have used immunofluorescence microscopy and quantitative Western blotting to compare the distribution and expression levels of several nuclear proteins during the response of HeLa S3 cells to both mild and severe hyperthermia. Cells were exposed to mild (42 degrees C) or severe (45 degrees C) hyperthermia treatment for 90 min and left to recover at 37 degrees C for 1-25 h. The cell response was monitored immediately after the heat stress and at different time intervals during the recovery period. Our observations indicate that inner nuclear membrane proteins, LAP2beta and emerin, as well as major components of the nuclear lamina, lamins A/C and lamin B1, maintain an overall normal distribution at the nuclear periphery throughout the cell response to mild or severe hyperthermia. The response was nevertheless characterized by significant changes in the expression levels of emerin following recovery from a mild stress and of lamin B1 after recovery from a severe stress. Our results also provide evidence that the organization of functional domains within the nuclear interior such as nucleoli and splicing speckles differs between cells responding to a mild or a severe stress. Mild hyperthermia was accompanied by a significant decrease in the expression level of the nucleolar protein 2H12 whereas severe hyperthermia was characterized by a reduction in the expression of the nucleocytoplasmic shuttling protein 2A7. Our data underline the complexity of nuclear function/structure relationships and the needs for a better understanding of protein-protein interactions within the nuclear compartment.

Lamina-associated polypeptide 2 (LAP2) expression in fish and amphibians.

Somatic and germinal cells of 15 fish and 33 amphibian species were examined by SDS-PAGE followed by immunoblotting to determine the expression of LAP2 (lamina-associated polypeptide 2). LAP2 expression in frogs, salamanders and fish does not vary with the mode of reproduction. In fish and frog cells, a rim-like LAP2 positive region was detected around the nucleus by indirect immunofluorescence microscopy. The cell distribution and expression patterns of LAP2 in fish, frogs and salamanders are comparable with those found in Xenopus and zebrafish. The mammalian somatic cell pattern, which may also occur in gymnophione amphibians, includes LAP2alpha, beta and gamma as major isoforms, whereas LAP2alpha does not occur in cells of fish, frogs and salamanders. In fish, LAP2gamma is the major isoform of somatic cells, suggesting that LAP2gamma may be ancestral. However, in the rainbow trout, as in frogs and salamanders, LAP2beta was the major somatic isoform. Fish and frog sperm only express low molecular weight polypeptides. In contrast, fish and frog oocytes express an oocyte-specific LAP2 isoform of high molecular weight. In the toad Bufo marinus this isoform becomes upregulated in pre-vitellogenic oocytes of 150-200 microm in diameter. The absence of LAP2alpha and the differential expression of LAP2 isoforms in somatic and germ cells, as found in fish and frogs, may be ancestral vertebrate characters. In spite of differences in developmental time, the LAP2 isoforms of somatic cells are upregulated during gastrulation, suggesting that LAP2 may be implicated in the early development of fish and frog.