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Background: Aspirin is frequently used in pregnancy to decrease the risk of developing pre-eclampsia. Studies have highlighted this potential benefit which in theory happens by inhibition of platelet function. However, questions remain on the appropriate dosing and the reliability of serum markers in determining aspirin responsiveness in pregnancy (ARP)., Objective: review the literature on ARP and identify the gaps, followed by investigating the objective biomarkers used to assess ARP. This includes the factors associated such as aspirin formulations, doses, and patient comorbidities., Methods: A comprehensive search was conducted using keywords such as 'aspirin', 'pregnancy', and 'responsiveness' in relevant databases such as PubMed, SCOPUS, Cochrane from inception to March 2024. Our inclusion criteria enrolled pregnant women aged 18 years old and above, irrespective of their trimester status, who were prescribed aspirin for any medical indication., Results: The research findings encompass three key areas. Firstly, examination of the impact of different aspirin formulations on responsiveness revealed no significant differences between different formulations. Secondly, nine papers were identified with varied dosages of administered aspirin, highlighting a need for standardized approach to dosing, and investigating higher dosing and its impact. Thirdly, there is a lack of consensus on biomarkers used to assess ARP. Finally, this synthesis sheds light on prognostic factors of developing aspirin non-responsiveness, such as medical comorbidities., Conclusion: This scoping review identifies several residual uncertainties on ARP. The main gaps are validation of serum markers, understanding the influence of underlying morbidity on ARP, and determining appropriate aspirin dosing in pregnancy., Competing Interests: Declaration of Competing Interest We declare that we have no known competing financial interests or personal relationship that could have appeared to influence the work reported in the paper titled “Sensitive Objective Markers for Measuring Aspirin Responsiveness in Pregnancy: An Explorative Scoping Review”., (Copyright © 2024. Published by Elsevier B.V.)

Background: Patients with heart failure are living longer with the inevitable morbidity of rising medication counts. It remains uncertain what fraction of this ensuing polypharmacy exactly predicts adverse clinical outcomes., Methods: This prospective study examined records of patients admitted to a Weill Cornell-affiliated tertiary medical institution with a confirmed diagnosis of heart failure between January 2018 to January 2022. Each patient's medications for the past four months were tallied, and a definitional threshold of ≤4, ≥5, ≥10 medications was established. The primary outcome was all-cause mortality within the study period., Results: Out of a total of 7354 patients included in the study, 70 % were males with a median age of 59 years IQR (48-71). The median (IQR) age-adjusted Charlson Comorbidity Index (CCI) was 2 1-5 . A total of 1475 (20 %) participants died within the study period. Patient cohorts with excessive polypharmacy (≥9 medications) had the highest probability of survival up to 1.6 years compared to those with lower medication thresholds (≤4); the mortality rate decreased by 18 % for patients with excessive polypharmacy [HR = 0.82, 95 % CI: 0.71-0.94]). Conversely, patients with non-heart failure-related polypharmacy had increased risks of ICU admissions (aOR = 1.78, 95 % CI: 1.13-2.70)., Conclusion: In an examination of a database of patients with chronic heart failure, major non-heart failure-related polypharmacy was associated with increased risks in intensive care admissions. Excessive polypharmacy was associated with increased rates of survival., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Background and Aims: As part of the COVID-19 control strategy, a growing number of vaccine portfolios evolved and got fast-tracked through regulatory agencies, with a limited examination of their efficacy and safety in vulnerable populations, such as patients with chronic conditions and immunocompromised states. Patients with chronic liver disease (CLD), and cohorts post liver transplant (LT) in particular, were underrepresented in the determinant trials of vaccine development, hence the paucity of data on their efficacy and safety in published literature. This systematic review aims to examine the available evidence and ascertain the effectiveness and safety of Covid-19 vaccination in patients with CLD and those with LT., Methods: A systematic review of PubMed (Medline), Google Scholar, Cochrane Library, and ScienceDirect from inception until 1 st March 2022 was conducted. We included observational studies and assessed vaccine efficacy regarding seroconversion or immunological rate, whereas serious or significant adverse effects have been considered safety outcomes when reported., Results: Studies comprised 45275 patients, performed in 11 different countries. Seroconversion or immunological rate after Covid-19 vaccination was mostly the primary endpoint, whereas other endpoints like covid-19 related adverse effects were also reported. Twenty-four of the final analyzed studies are prospective cohort studies, while four are retrospective cohort studies. Twenty-one studies included patients who underwent LT and received the Covid vaccine; nine included patients who had CLD due to various etiologies. The median age range of all included patients varied from 43-69 years. All patients with LT who received at least two doses of Covid vaccine had a seroconversion rate of around 60%. Patients with CLD had a seroconversion rate of about 92% post two doses of Covid vaccination. The average seroconversion rate in post-transplant recipients was around 45% after two doses of the significant Covid vaccines: Pfizer, AstraZeneca, Moderna, and Jansen. Only two studies have reported a higher seroconversion rate of 75% and 73% after the third dose of Covid vaccine. No significant adverse effects were reported in all studies; the most commonly reported negative effect was local injection site pain., Conclusion: The present systematic review, comprising real-world observational data studies, concludes that Covid-19 vaccination was associated with 92% and 60% seroconversion rates in patients with CLD and LT, respectively. No significant side effects were reported in all studies. This finding helps to resolve the uncertainty associated with Covid-19 vaccination in this cohort of patients., Competing Interests: The authors declared no conflicts of interest relevant to this review or its publication., (© 2023 Elzouki, Elshafei, Aziz, Elzouki, Waheed, Farooqui, Azad, Habas, Danjuma, Licensee HBKU Press.)

Purpose: To investigate real-world prescribing trends and clinical outcomes based on body mass index (BMI) categorization in patients who received rivaroxaban therapy., Methods: This was a retrospective cohort study involving all patients who received rivaroxaban therapy across all Hamad Medical Corporation (HMC) hospitals from 2015 to 2020., Results: The number of patients initiated on rivaroxaban therapy significantly increased from 152 (3.3%) in 2015 to 1342 (28.9%) in 2020 (p <0.001). Within BMI categories, a similar increasing trend was observed in underweight, normal, and overweight patients, while from 2018 to 2020, there was a decreasing trend in rivaroxaban prescribing in all obese classes. The prevalence rate of all-cause mortality differed significantly between the BMI groups, with the highest mortality being among morbidly obese patients (BMI ≥ 40 kg/m 2 ) (p< 0.001). On the other hand, no significant differences were found between the BMI groups in terms of bleeding, pulmonary embolism, deep vein thrombosis and stroke incidences. Multivariate logistic regression analyses showed that the likelihood of all-cause mortality was significantly higher in overweight and all categories of obese patients compared to underweight patients: overweight (OR: 5.3, 95% CI: 2.3-11.9, p< 0.001); obese class 1 (OR: 5.4, 95% CI: 2.3 - 12.2, p< 0.001); obese class 2 (OR: 6.5, 95% CI: 2.7 - 15.6, p< 0.001); and obese class 3 (OR: 3.7, 95% CI: 1.6 - 8.7, p = 0.003)., Conclusions: Rivaroxaban prescribing has significantly increased over the years across general population, with a noticeable decline in obese population during the last few years (from 2018 onwards). Furthermore, an appreciable association was evident between all-cause mortality and BMI of these patients., (© 2023. The Author(s).)

Purpose: Polypharmacy presents an increasing therapeutic challenge for physicians managing patients with chronic kidney disease (CKD). However, there is a lack of consensus regarding the specific medication count threshold that defines polypharmacy in this population. The objective of this review is to establish a unified definition of polypharmacy in the CKD population by examining the diverse definitions used in previously published studies., Methods: A comprehensive search was conducted in relevant databases (PubMed, SCOPUS, Cochrane, and disease-specific databases) from 2000 to May 2022 to identify studies with polypharmacy threshold definitions in patients with CKD. Studies meeting the inclusion criteria were included in this review, and their methodologic quality was assessed., Findings: Following the screening of the search results, duplicate records and studies that did not meet the inclusion criteria were removed, resulting in a total of 18 studies included in this review. Among these, 61.1% specified the polypharmacy definition to be a threshold of ≥5 medications. In addition, 22.2% specified a high polypharmacy definition at a threshold of ≥10 medications. However, none of the studies reported on the dichotomy between kidney-related and non-kidney-related polypharmacy., Implications: This review indicates that a numerical threshold of ≥5 medications is commonly used to define polypharmacy in patients with CKD. Nevertheless, it remains uncertain whether a kidney-related polypharmacy definition or a high polypharmacy definition would better identify patients with CKD at risk for polypharmacy-related complications., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Despite significant improvements in both treatment and prevention strategies, as well as multiple commissioned reviews, there remains uncertainty regarding the survival benefit of repurposed drugs such as colchicine in patients with Coronavirus Disease 2019 (COVID-19) clinical syndrome., Methods: In this umbrella review, we carried out a comprehensive search of PubMed, EMBASE, Cochrane Database of Systematic Reviews, Science Citation Index, and the Database of Abstracts of Reviews of Effectiveness between January 1, 2020 and January 31, 2023 for systematic reviews and meta-analyses evaluating the mortality-reducing benefits of colchicine in patients with COVID-19. This was to ascertain the exact relationship between colchicine exposure and mortality outcomes in these cohorts of patients. We utilized A Measurement Tool to Assess systematic Reviews-2 (AMSTAR-2) to conduct an exhaustive methodological quality and risk of bias assessment of the included reviews., Results: We included eighteen meta-analyses (n = 199,932 participants) in this umbrella review. Colchicine exposure was associated with an overall reduction of about 32% in the risk of mortality (odds ratio 0.68, confidence interval [CI] 0.58-0.78; I2 = 94%, p = 0.001). Further examination of pooled estimates of mortality outcomes by the quality effects model (corrected for the methodological quality and risk of bias of the constituent reviews) reported similar point estimates (OR 0.73; CI 0.59 to 0.91; I2 = 94%)., Conclusion: In a pooled umbrella evaluation of published meta-analyses of COVID-19 patient cohorts, exposure to colchicine was associated with a reduction in overall mortality. Although it remains uncertain if this effect could potentially be attenuated or augmented by COVID-19 vaccination., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Competing Interests: MD and IE were employed by Hamad Medical Corporation. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background: Despite its central role in drug metabolism, the exact prevalence estimates and factors affecting global trends of polypharmacy in patients with chronic liver disease (CLD) have remained unexamined. The aim of this systematic review and meta-analysis is to estimate the prevalence of polypharmacy in patients with CLD and to comprehensively synthesize the socio-demographic factors that drive this., Methods: We conducted a comprehensive search of relevant databases (PubMed, EMBASE, Science citation index, Cochrane Database of Systematic Reviews, and database of abstracts of reviews of effectiveness) for studies published from inception to May 30, 2022 that reported on prevalence estimates of polypharmacy in patients with CLD. The risk of bias was conducted utilizing Loney criteria. The primary outcome was the pooled prevalence of polypharmacy in patients with CLD. We subsequently performed a systematic review and weighted meta-analysis to ascertain the exact pooled prevalence of polypharmacy among patients with CLD., Results: We identified approximately 50 studies from the initial literature search, of which 7 (enrolling N = 521,435 patients) with CLD met the inclusion criteria; of these, 58.7% were male, with a mean age of 53.9 (SD ± 12.2) years. The overall pooled prevalence of polypharmacy among patients with CLD was 31% (95% confidence interval [CI]: 4%-66%, I2 = 100%, τ2 ≤ 0.001, P ≤ .0001). We found higher pooled prevalence estimates among patients aged 50 years and older compared to their younger cohorts (42%, [CI 10-77]; I2 = 100%, P = <.001 vs 21%, [CI 0-70]; I2 = 100%, P = <.001)., Conclusion: In an examination of multiple community- and hospital-based databases of patients with CLD, we found a pooled prevalence estimate of polypharmacy of approximately 31%. This represents a case burden within the range reported in the general population and will likely respond to mitigation strategies employed thus far for patients in that population., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background and Purpose: Uncertainty remains regarding the impact of enteric-coated aspirin (EC-ASA) on secondary prevention of ischemic stroke compared to plain aspirin (P-ASA). Hence, this study was designed to investigate the effect of EC formulation on ASA response via evaluating thromboxane B2 (TXB2) levels in patients with suspected or newly diagnosed stroke., Methods: A prospective cohort study on suspected or newly diagnosed ischemic stroke patients who are aspirin-naive was conducted. Patients were received either EC aspirin or plain aspirin for at least 3 days. The primary outcome was the proportion of aspirin non-responsiveness between two groups (level of residual serum TXB2 associated with elevated thrombotic risk (< 99.0% inhibition or TXB2 > 3.1 ng/ml) within 72 h after three daily aspirin doses, while secondary outcomes were the incidence of early gastrointestinal tract (GIT) bleeding with the various aspirin preparations. (Trial registration: Clinicaltrials.gov NCT04330872 registered on 02 April 2020)., Results: Of 42 patients, ischemic strokes were confirmed in both P-ASA (81%) and EC-ASA (67%) arms. ASA non-responsiveness showed no significant difference between the two formulations (P-ASA vs. EC-ASA; 28.6% vs 23.8%; P = 0.726). Univariate and multivariate logistic regression analysis showed that patients treated with EC-ASA were more likely to have a lower rate of non-responders compared to P-ASA (unadjusted OR 0.78; 95% CI 0.20, 3.11); with the risk highest in type 2 diabetic patients with HBA1c > 6.5% (adjusted OR 6; 95% CI 1.02, 35.27; P = 0.047). No incidence of GIT bleeding observed throughout the study., Conclusion: A significant proportion of ASA non-responsiveness was recorded regardless of ASA formulation administered. The increased risk of ASA non-responsiveness in diabetic patients needs further exploration by larger prospective studies., (© 2022. The Author(s).)

Background: Drug induced liver injury (DILI) is a rising morbidity amongst patients with COVID-19 clinical syndrome. The updated RUCAM causality assessment scale is validated for use in the general population, but its utility for causality determination in cohorts of patients with COVID-19 and DILI remains uncertain., Methods: This retrospective study was comprised of COVID-19 patients presenting with suspected DILI to the emergency department of Weill Cornell medicine-affiliated Hamad General Hospital, Doha, Qatar. All cases that met the inclusion criteria were comparatively adjudicated by two independent rating pairs (2 clinical pharmacist and 2 physicians) utilizing the updated RUCAM scale to assess the likelihood of DILI., Results: A total of 72 patients (mean age 48.96 (SD ± 10.21) years) were examined for the determination of DILI causality. The majority had probability likelihood of "possible" or "probable" by the updated RUCAM scale. Azithromycin was the most commonly reported drug as a cause of DILI. The median R-ratio was 4.74 which correspond to a mixed liver injury phenotype. The overall Krippendorf's kappa was 0.52; with an intraclass correlation coefficient (ICC) of 0.79 (IQR 0.72-0.85). The proportion of exact pairwise agreement and disagreement between the rating pairs were 64.4%, kappa 0.269 (ICC 0.28 [0.18, 0.40]) and kappa 0.45 (ICC 0.43 [0.29-0.57]), respectively., Conclusion: In a cohort of patients with COVID-19 clinical syndrome, we found the updated RUCAM scale to be useful in establishing "possible" or "probable" DILI likelihood as evident by the respective kappa values; this results if validated by larger sample sized studies will extend the clinical application of this universal tool for adjudication of DILI., Competing Interests: The authors have declared that no competing interests exist.

Background: There has been a rising prevalence of polypharmacy among people living with HIV (PLWH). Uncertainty however remains regarding the exact estimates of polypharmacy among these cohorts of patients., Methods: We conducted a systematic search of PubMed; EMBASE, CROI, Cochrane Database of Systematic Reviews; Science Citation Index and Database of Abstracts of Reviews of Effects for studies between 1 January 2000 and 30 June 2021 that reported on the prevalence of polypharmacy (ingestion of > 5 non-ART medications) among PLWH on antiretroviral therapy regimen (ART). Prevalence of polypharmacy among HIV-positive patients on ART with Clopper-Pearson 95% confidence intervals were presented. The heterogeneity between studies was evaluated using I 2 and τ 2 statistics., Results: One hundred ninety-seven studies were initially identified, 23 met the inclusion criteria enrolling 55,988 PLWH, of which 76.7% [95% confidence interval (CI): 76.4-77.1] were male. The overall pooled prevalence of polypharmacy among PLWH was 33% (95% CI: 25-42%) ( I 2  = 100%, τ 2  = 0.9170, p  < 0.0001). Prevalence of polypharmacy is higher in the Americas (44%, 95% CI: 27-63%) ( I 2  = 100%, τ 2  = 1.0886, p  < 0.01) than Europe (29%, 95% CI: 20-40%) ( I 2  = 100%, τ 2  = 0.7944, p  < 0.01)., Conclusion: The pooled prevalence estimates from this synthesis established that polypharmacy is a significant and rising problem among PLWH. The exact interventions that are likely to significantly mitigate its effect remain uncertain and will need exploration by future prospective and systematic studies., Registration: PROSPERO: CRD42020170071 ., Plain Language Summary: Background: In people living with HIV (PLWH), what is the prevalence of polypharmacy and is this influenced by sociodemographic factors? Methods and Results: In this systematic review and meta-analysis of 23 studies comprising 55,988 participants, we have for the first time found an estimated polypharmacy pooled prevalence of 33% among PLWH. There was a relatively higher pooled prevalence of polypharmacy among the America's compared with European cohorts of PLWH. Conclusion: Polypharmacy among PLWH is a rising morbidity that needs urgent intervention both at policy and patient levels of care., Competing Interests: Competing interests: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s), 2022.)

Polypharmacy in people living with HIV/AIDS (PLWHA) is a rising morbidity that exacts hefty economic burden on health budgets in addition to other adverse clinical outcomes. Despite recent advances, uncertainty remains around its exact definition in PLWHA. In this systematic review and Meta-analysis, we explored relevant databases (PUBMED, EMBASE, CROI) for studies evaluating polypharmacy in PLWHA from January 2000 to August 2021 to ascertain the exact numerical threshold that defines this morbidity. Two independent reviewers extracted and reviewed relevant variables for analyses. The review included a total of 31 studies involving n = 53,347 participants with a mean age of 49.5 (SD ± 17.0) years. There was a total of 36 definitions, with 93.5% defining polypharmacy as the concomitant use of 5 or more medications. We found significant variation in the numerical definition of polypharmacy, with studies reporting it as "minor" (N = 3); "major" (N = 29); "severe" (N = 2); "excessive" (N = 1); and "higher" (N = 1). Most studies did not incorporate a duration (84%) in their definition and excluded ART medications (67.7%). A plurality of studies in PLWHA have established that polypharmacy in this cohort of patients is the intake of ≥ 5 medications (including both ART and non-ART). To standardize the approach to addressing this rising morbidity, we recommend incorporation of this definition into national and international PLWHA treatment guidelines., (© 2022. The Author(s).)

Background: Acute pulmonary embolism (PE) is a common and potentially life-threatening condition. This comprehensive study from a Gulf Cooperation Council (GCC) country aimed to evaluate the clinical, radiological, and outcome characteristics associated with acute PE., Methods: This retrospective observational study analyzed data of patients with confirmed acute PE who were admitted to the largest academic tertiary center in the State of Qatar from January 1, 2014, to December 31, 2018. Data on the clinical presentation, radiologic, and echocardiographic findings, as well as outcomes were collected., Results: A total of 436 patients were diagnosed with acute PE during the study period (male, 53%). Approximately 56% of the patients were < 50 years old at presentation, with a median age of 47 years. In approximately 69% of cases, the PE occurred outside the hospital. The main associated comorbidities were obesity (34.6%), hypertension (29.4%), and diabetes (25%). Immobilization (25.9%) and recent surgery (20.6%) were the most common risk factors. The most frequent presenting symptom was dyspnea (39.5%), and the most frequent signs were tachycardia (49.8%) and tachypnea (45%). Cardiac arrest was the initial presentation in 2.2% of cases. Chest X-ray findings were normal in 41%. On computed tomography pulmonary angiography (CTPA), 41.3% of the patients had segmental PE, 37.1% had central PE, and 64.1% had bilateral PE. The main electrocardiographic (ECG) abnormality was sinus tachycardia (98%). In patients who underwent echocardiography, right ventricular (RV) enlargement was the main echocardiographic finding (36.4%). Low-, intermediate-, and high-risk PE constituted 49.8%, 31.4%, and 18.8% of the cases, respectively. Thrombolysis was prescribed in 8.3% of the total and 24.4% of the high-risk PE cases. Complications of PE and its treatment (from admission up to 6 months post-discharge) included minor bleeding (14%), major bleeding (5%), PE recurrence (4.8%), and chronic thromboembolic pulmonary hypertension (CTEPH) (5%). A total of 15 (3.4%) patients died from PE., Conclusions: Acute PE can manifest with complex and variable clinical and radiological syndromes. Striking findings in this study are the younger age of acute PE occurrence and the low PE-related mortality rate., (© 2022 Ibrahim, Al-Shokri, Hussein, Abu Afifeh, Karuppasamy, Parambil, Elasad, Faris, Abdelghani, Abdellah, Kamel, Ghazouani, Ahmad, Aladab, Danjuma, Raza, licensee HBKU Press.)

Background: Obesity is associated with increased prevalence of gastroesophageal reflux disease, with recent reports suggesting improvement in gastroesophageal reflux disease symptoms and weight loss following bariatric surgical intervention. However, the exact impact of the type of bariatric surgery on the evolution of gastroesophageal reflux disease symptoms has remained unexamined., Methods: We systematically searched electronic databases (PubMed, EMBASE, Web of Science, and the Cochrane Library from inception to December 2018) for eligible studies that satisfy prespecified inclusion criteria. We included clinical trials of all designs that reported on gastroesophageal reflux disease outcomes following laparoscopic sleeve gastrectomy or laparoscopic Roux-en-Y gastric bypass. Two independent reviewers extracted relevant data based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. Data were pooled using a random-effects model. Main outcomes were symptomatic improvement in gastroesophageal reflux disease symptoms following bariatric surgery., Results: A total of 31 studies were analyzed, and a robust-error meta-regression model was used to conduct a dose-response meta-analysis synthesizing data on 31 studies that reported gastroesophageal reflux disease outcomes after bariatric surgery. Of 5,295 patients who underwent either laparoscopic sleeve gastrectomy ( n  = 4,715 patients) or laparoscopic Roux-en-Y gastric bypass ( n  = 580 patients), 63.4% experienced improvement in gastroesophageal reflux disease symptoms (95% CI 32.46-72.18). The dose-response meta-analysis demonstrated a window period of 2 years for sustained improvement after which symptoms began to recur in those that were asymptomatic., Conclusion: Bariatric surgery may improve gastroesophageal reflux disease symptoms in obese patients who underwent laparoscopic sleeve gastrectomy; however, the most favorable effect is likely to be found after Roux-en-Y gastric bypass surgery. The effects were not sustained and returned to baseline within 4 years., (© 2021 The Authors.)

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rising morbidity amongst hospitalized patients. Whilst clinical protocols for the management of individual DRESS cases have been well established, determination of potential prevention of these cases by utilizing novel "avoidability" tools has remained unexplored. This retrospective study reviewed records of patients who presented to the emergency department of Weill Cornell Medicine-affiliated Hamad General Hospital, Doha Qatar with suspected DRESS syndrome. These cases were independently adjudicated (utilizing the RegiSCAR, and JSCAR tools) as DRESS-drug pairs by a team of two clinical pharmacists and two General Physicians. They were then rated for potential avoidability with the Liverpool adverse drug reactions avoidability tool (LAAT) by the same team of raters. A total of 16 patients satisfied RegiSCAR criteria for DRESS syndrome. The mean age of the study population was 41.5 years (SD ± 13.3). The study population was predominantly male (n = 12; [75%]). The median latent period from drug ingestion to clinical presentation was 14 days (interquartile range [IQR] 6.5, 29). The median RegiSCAR and J-SCAR scores were 6 (IQR 5, 6.8), 5 (IQR 4, 5.8) respectively. Utilizing the LAAT, about 60% of the DRESS syndrome-drug pairs were rated as "avoidable" ("probable" or "definite"). The overall Krippendorf's alpha with the LAAT was 0.81 (SE 0.10, CI 0.59-1.00); with an intraclass correlation coefficient (ICC) of 0.90 (CI 0.77, 0.96.). In a randomly selected cohort of DRESS syndrome-drug pairs, a significant proportion was potentially avoidable ("possibly" and "definitely") utilizing the LAAT. This will need validation by larger sample-sized prospective studies utilizing the updated LAAT proposed by this study., (© 2021. The Author(s).)

Euglycemic diabetic ketoacidosis (EuDKA) secondary to Sodium-glucose co-transporter-2 inhibitors (SGLT2i) in type 2 diabetes mellitus (T2D) is a rare but increasingly reported phenomenon. Not much is known about the burden of EuDKA in patients on SGLT2i or the associated factors. This retrospective cohort study tries to delineate the differences in factors associated with the development of EuDKA as compared to hyperglycemic DKA. We conducted a multicentre, retrospective study across three tertiary care centers under Weill Cornell affiliated-Hamad Medical Corporation, Qatar. The cohort comprised of T2D patients on SGLT2i who developed DKA between January 2015 to December 2020. The differences between the subjects who developed EuDKA or hyperglycaemic DKA (hDKA) were analyzed. A total of 9940 T2D patients were on SGLT2i during 2015-2020, out of which 43 developed DKA (0.43%). 25 developed EuKDA, whereas 18 had hDKA. The point prevalence of EuDKA in our cohort was 58.1%. EuDKA was most common in patients using canagliflozin, followed by empagliflozin and Dapagliflozin (100%, 77%, and 48.3%, respectively). Overall, infection (32.6%) was the most common trigger for DKA, followed by insulin non-compliance (13.7%). Infection was the only risk factor with a significant point estimate between the two groups, being more common in hDKA patients (p-value 0.006, RR 2.53, 95% CI 1.07-5.98). Canagliflozin had the strongest association with the development of EuDKA and was associated with the highest medical intensive care unit (MICU) admission rates (66.6%). In T2D patients on SGLT2i, infection is probably associated with an increased risk of developing EuDKA. The differential role of individual SGLT2i analogs is less clear and will need exploration by more extensive prospective studies.

End-stage liver disease and its related complications exert a huge disease burden and reduce the survival rates of many patients. Albumin administration for patients with decompensated liver cirrhosis has been a controversial topic of discussion. The aim of this study is to investigate whether albumin reduces the mortality and complications of liver cirrhosis compared to standard medical therapy (SMT) alone. Clinical trials in which albumin administration was compared to SMT in patients with liver cirrhosis were included in this meta-analysis. The primary outcome of this study was to evaluate the effect on reducing all-cause mortality. Ascites control, renal failure and hepatic encephalopathy were evaluated as secondary outcomes. Nine clinical trials with 1231 patients were recruited and analyzed using the quality effect model. Mortality rate was significantly reduced in the albumin group [relative risk (RR) 0.73, 95% confidence interval (CI) 0.56-0.96]. Heterogeneity was mild across all studies (I2 23.3%). Studies reporting long-term albumin (LTA) administration were found to have a significant decrease in mortality (RR 0.57, 95% CI 0.44-0.73). However, studies reporting short-term albumin administration were found to have no effect on mortality (RR 0.90, 95% CI 0.56-1.45). Furthermore, there was a significant decrease in the incidence of all secondary outcomes. This meta-analysis provides evidence that LTA administration is significantly effective in reducing the mortality of liver cirrhosis compared to SMT. Albumin administration was also shown to reduce the occurrence of ascites, renal failure and hepatic encephalopathy as complications of liver cirrhosis., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Cancer-associated thrombosis (CAT) carries significant morbidity and mortality. Low-molecular-weight heparin (LMWH) remains the standard of care, with recent systematic studies suggesting the efficacy and safety of rivaroxaban in the treatment of CAT. Uncertainty, however, remains regarding rivaroxaban efficacy and safety in real-world settings. We performed a systematic review and meta-analysis of studies comparing rivaroxaban to LMWH. We searched PubMed, MEDLINE, and EMBASE. The primary outcome was the net clinical benefit (NCB), while rates of major bleeding (MB), venous thromboembolism (VTE), clinically relevant nonmajor bleeding (CRNMB), and all-cause mortality events were secondary outcomes. Seventeen studies were included in the final analysis. Rivaroxaban had a better NCB (relative risk [RR] = 0.82; 95% CI = 0.75-0.89, Q = 10.51, I 2 = 0%), less VTE events (RR = 0.73, 95% CI = 0.65-0.82, Q = 6.76, I 2 = 0%), and lower all-cause mortality (RR = 0.72, 95% CI = 0.57-0.91, Q = 32.8, I 2 = 79%) compared to LMWH. Additionally, comparable MB events (RR = 1.07, 95% CI = 0.85-1.33, Q = 16.9, I 2 = 11%). However, CRNMB events were higher in the rivaroxaban group (RR = 2.02, 95% CI = 1.46-2.80, Q = 9.9, I 2 = 19%). Additional analyses demonstrated consistency of results. Our review encompassing data from randomized and real-world data suggested rivaroxaban superiority compared to LMWH in terms of a better NCB, fewer VTE events, lower all-cause mortality, and comparable MB risk while carrying a higher risk of CRNMB. These findings support the use of rivaroxaban in the treatment of CAT. Additionally, it warrants a sizable randomized controlled study testing the superiority of rivaroxaban versus LMWH formulation and ascertaining bleeding outcomes according to cancer type and site.

Background and Study Aims: Auditing of polypharmacy is particularly essential in patients with cirrhosis because of the crucial role of liver in drug metabolism. The aim of this study was to audit the drug prescribed in this group of patients and analyzed the quantity and severity of potential drug-drug interaction., Patients and Methods: In this cross-sectional study we analyzed the last prescription as recorded in the Electronic Medical Record at the time of discharge for cirrhotic patients who were hospitalized during 24-months study period. Data were also collected for age, gender, and diagnoses. The drugs were analyzed for cross interactions using the Lexicomp-online e-formulary. The drug interactions are classified as: class A: no known interaction, class B: no action needed, Class C: monitor therapy, class D: consider therapy modification, and Class X: the drug should be avoided., Results: A total of 333 patients with cirrhosis were audited, whereas complete and relevant data were available for 181 patients (134 males, 74%) with a mean age ± SD 59.7 ± 10.1. Out of these, 168 (92.8%) patients were using at least one medicine and the total number of medications used was 808 drugs. The observed average of utilization was 7.8 ± 3.1 drugs (range = 1-17) and 102 (56.3%) patients used polypharmacy. A total of 198 (24.5%) consumed drugs were related to cirrhosis and its complications. Six (3.3%), 30 (16.6%) and 65 (35.9%) patients had Class-X, Class D, and Class C, respectively. Utilization of polypharmacy was statistical significant in patients with class X (83.3%, p = 0.03), class D (16.6%, p = 0.01), and class C (35.9%, p = 0.02)., Conclusion: The findings highlight the importance of auditing for polypharmacy to recognize and prevent potential drug-related problems in patients with cirrhosis. Implementation of strategies to optimize medication use in patients with cirrhosis should be considered necessary as it can have a bearing on length of stay and morbidity., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

There are increasing reports of antiretroviral therapy (ART) drug-related kidney dysfunction. Traditional markers of kidney dysfunction such as urine protein/creatinine ratio and estimated glomerular filtration rate (eGFR) have thus far proven ineffective at detecting some sub-clinical forms of ART-related kidney injury. This is a cross-sectional examination of 114 people living with HIV (PLWH), either naïve ( N =104) or treatment experienced ( N =10). Urinary kidney injury molecule-1 (KIM-1 ng/mg) thresholds were estimated using electrochemiluminescent assays from stored urine samples and normalised for urinary creatinine excretion (KIM-1/Cr). Correlation coefficients and predictors of kidney tubular injury were compared and derived for both adjusted and unadjusted urinary KIM-1/CR (ng/mg). In PLWH (both ART-naïve and treatment experienced) had a higher baseline unadjusted and adjusted median (≥3.7 ng/mg) and upper tertile (≥6.25 ng/mg) urinary KIM-1/Cr levels compared to either non-normal volunteers (0.39 ng/mg) or those with acute kidney injury in the general population (0.57 ng/mg). When upper tertile KIM-1/Cr (≥6.25 ng/mg) was utilised as a marker of kidney injury, eGFR (ml/min/1.73 m 2 ), white Caucasian ethnicity, and protease inhibitor exposure were significantly associated with increased risk of kidney injury in multivariate analyses (odds ratio 0.91, confidence interval [CI] 0.68-0.98, P = 0.02; odds ratio 8.9, CI 1.6-48.6, p = 0.01; and odds ratio 0.05, CI 0.03-0.9, p =0.04, respectively). We found a significant degree of sub-clinical kidney injury (high unadjusted and adjusted KIM-1/Cr) in PLWH with normal kidney function (eGFR ≥60 ml/min/1.73 m 2 ). We also found a higher baseline KIM-1/Cr (ng/mg) in our study cohort than reported both in normal volunteers and patients with kidney injury in the general population.

Background: Inflammatory bowel diseases (IBD) associated-chronic inflammation and autonomic dysregulation may predispose to arrhythmias. However, its exact prevalence is unknown. Thus, we aimed to ascertain the prevalence of arrhythmias in patients with IBD., Methods: We queried the Nationwide Inpatient Sample (the largest publicly available all-payer inpatient USA database) from 2012 to 2014. We used the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9 CM) discharge codes to identify adult patients (⩾18 years) with IBD and dysrhythmias (supraventricular tachycardia (SVT), atrial fibrillation, atrial flutter, ventricular tachycardia (VT), or ventricular fibrillation). Furthermore, we identified risk factors for cardiovascular disease. We divided patients into 2 cohorts, IBD cohorts, and non-IBD cohort. The independent effect of a diagnosis of IBD on the risk of dysrhythmias was examined using a multivariable logistic regression model controlling for multiple confounders., Results: We identified 847 235 and 84 757 349 weighted hospitalizations among patients with IBD and non-IBD cohorts, respectively. Patients with IBD were less likely to be hospitalized for dysrhythmias than the non-IBD (9.7% vs 14.2%, P  < .001). The hospitalization odds for dysrhythmias among patients with IBD were less than the general population (OR 0.87; 95% CI 0.85-0.88). However, the prevalence of SVT and VT was indifferent between the 2 groups. Male sex, age of over 60, and white race were risk factors for dysrhythmias., Conclusion: Despite prior reports of a higher prevalence of arrhythmias among patients with IBD, in a nationwide inpatient database, we found lower rates of hospitalization-related-arrhythmias in the IBD population compared to that of the general population., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2020.)

Background: Drug-induced liver injury (DILI) represents an increasing morbidity in the general population, but more so in the elderly cohort of patients. Despite this, the concept of its prevention through prospective analysis has largely remained unexamined. We evaluated the utility of recently validated adverse drug reactions (ADR) avoidability tool in a cohort of elderly patients with DILI., Methods: We examined 38 DILI-drug pairs from n=38 patients in a prospective cohort of patients presenting with adverse drug reactions to a Weill Cornell-affiliated tertiary hospital between February 2019 and January 2020. DILI outcomes were adjudicated by the updated Roussel Uclaf Causality Assessment Method (RUCAM). Two clinical pharmacologists and two general physicians utilized the Liverpool adverse drug reactions avoidability tool (LAAT) and the modified Hallas tools to rate the preventability of DILI-drug pairs. Inter-rater, exact agreement proportions, as well as intraclass correlation coefficients were generated and expressed as ordinal outcomes., Results: The cases examined for the determination of DILI avoidability had probability likelihood of "probable" or "highly probable" by the updated RUCAM scale. Examination of the 38 DILI-drug pairs (n= 38 patients) resulted in a total of 152 ordinal outcome decisions. We found about 32.3% (50/152) and 34.2% (52/152) of DILI-drug pairs were rated as "avoidable" ("probable" or "definite") by the LAAT and the modified Hallas tools respectively. The overall median Krippendorf's kappa with the LAAT was 0.61 (SE 0.12, CI 0.36, 0.85) and for modified Hallas tool was 0.53 (SE 0.18; CI 0.16, 0.89). The inter-rater correlation coefficient (ICC) for the LAAT and modified Hallas were 0.50 [0.32, 0.65] and 0.63 [0.48, 0.76] respectively. Exact pairwise agreement was present in 30/38 (IQR 29.5, 34.5), and 28/38 (IQR 27.5-35.5) of DILI-ADR pairs using the LAAT and modified Hallas tools respectively., Conclusion: We found a significant proportion of drug-induced liver injury adjudicated by the updated RUCAM scale in elderly hospitalized cohort of patients were avoidable with significant implication for therapeutic commissioning as well as cost effectiveness interventions in this cohort of patients.

The COVID-19 pandemic is caused by the severe acute-respiratory-syndrome-coronavirus-2 that uses ACE2 as its receptor. Drugs that raise serum/tissue ACE2 levels include ACE inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) that are commonly used in patients with hypertension, cardiovascular disease and/or diabetes. These comorbidities have adverse outcomes in COVID-19 patients that might result from pharmacotherapy. Increasing ACE2 could potentially increase the risk of infection, severity or mortality in COVID-19 or it might be protective as it forms angiotensin-(1-7) which exhibits anti-inflammatory/anti-oxidative effects and prevents diabetes- and/or hypertension-induced end-organ damage. Thus, there existed clinical uncertainty. Here, we review studies implicating 15 classes of drugs in increasing ACE2 levels in vivo and the available literature on the clinical safety of these drugs in COVID-19 patients. Further, in a re-analysis of clinical data from a meta-analysis of 9 studies, we show that ACEIs/ARBs usage was not associated with an increased risk of all-cause mortality. Literature suggests that ACEIs/ARBs usage generally appears to be clinically safe though their use in severe COVID-19 patients might increase the risk of acute renal injury. For definitive clarity, further clinical and mechanistic studies are needed in assessing the safety of all classes of ACE2 raising medications.

Rationale: There is an increasing and compelling need for early recognition of features of osmotic demyelination syndrome (ODS), and a further attempt at correcting this even where presentation is late., Patient Concerns: A 49-year-old male admitted into the emergency department with a complaint of lethargy and severe hyponatremia, with subsequent ODS supervening on initial attempts at correction., Diagnosis: Rapid rise in serum sodium concentration (121 mmol/L in 8 hours from a nadir of 101 mmol/L), concomitant deterioration in patient's conscious level support the diagnosis of ODS., Intervention: Concomitant administration of 5% dextrose water with desmopressin with a therapeutic objective of gradual relowering of serum sodium concentration., Outcomes: Significant improvement in patients' conscious level and motor function with the commencement of sodium relowering therapy. The patient was eventually discharged home., Lessons: Regardless of the temporal profile of neurologic sequelae following ODS due to hyponatremia, its worthwhile attempting initial sodium relowering with dextrose 5% and desmopressin and then monitoring of biochemical and neurologic markers.

Introduction: Uncertainty remains regarding the impact of enteric-coated (EC) aspirin as it relates to the reduction of cardiovascular risk. We hypothesize that EC formulation based on a previous report may blunt aspirin response as evidenced by reduced Thromboxane A2 (TXA 2) levels in diabetic patients. Thus, it was imperative to ascertain and validate the effect of the EC formulation of Aspirin on the Thromboxane B2 (TXB2) level., Methods/design: An open-label consecutive randomized interventional controlled trial. Patients with newly diagnosed ischemic stroke who are just about to start Aspirin were assessed for eligibility and inclusion in our trial. Consecutive patients (admitted to the stroke unit of Hamad General Hospital, Hamad Medical Corporation, Doha, Qatar) will be randomized to receive either EC aspirin or plain Aspirin. They will be required to continue taking them throughout the study (3 days). Demographics and laboratory records of the study participants will be abstracted from online records. Further study variables will be obtained manually in designated case record forms (CRF). The primary outcomes are the incidence of aspirin non-responders (level of residual serum TXB2 associated with elevated thrombotic risk (<99.0% inhibition or TXB2 >3.1 ng/mL) within 72 h after three daily aspirin doses). Whereas secondary outcomes are the incidence of GIT bleeding of various preparations of Aspirin. The study was approved by MRC and IRB of Hamad Medical Corporation (MRC number: 01-18-156)., Discussion: This trial will determine potential differences in the efficacy of EC Aspirin and plain Aspirin on the Thromboxane B2 level. Additionally, it will ascertain the tolerability and safety of both formulations of Aspirin in patients with newly diagnosed ischemic stroke. These results will either support the current notion of no difference between the two formulations. However, if a difference is found, this will invite for future trials exploring clinical outcomes occurrence between various formulations., Clinical Trial Registration: Clinicaltrials.gov NCT04330872 registered on April 2, 2020.

Background: There has been a significant improvement in both our understanding and therapeutic choices available to clinicians for the management of cancer associated thrombosis (CAT). Even with the recent publication of a systematic review and landmark trials demonstrating the non-inferiority of DOACS-based anticoagulation strategy compared to the standard of care in patients with CAT, there is unresolved uncertainty regarding the exact hierarchy of risks and effectiveness of various DOAC analogues in these cohorts of patients., Method: We will carry out a network meta-analyses, utilizing a novel generalized pairwise methodology to generate direct and indirect comparisons between the various DOAC analogues. We will search the following databases for studies that satisfies pre-specified inclusions criteria; these include PubMed, EMBASE, Cochrane library, Clinicaltrials.gov, conference abstracts among other sources. The primary efficacy and safety outcomes are recurrent VTE and major hemorrhagic events, respectively. Two reviewers will Search the databases independently with the view to identify studies that meet eligibility criteria. The methodological quality of the included studies will be determined using a recently validated risk of bias assessment tool., Results: We expect that the result of this review will ascertain the hierarchy of risks and effectiveness of various DOAC analogues in patients with CAT., Conclusion: Results of this review will assist in informed decisions making regarding therapeutic guidelines of DOAC in CAT.

BACKGROUND Lemierre's syndrome is a potential life-threatening disease commonly occurring in young, healthy individuals. It is often preceded by an oropharyngeal infection causing bacteremia. This may rapidly progress into thrombophlebitis of the internal jugular venous system, its branches, and septic embolization and often fulminant organ failure. CASE REPORT A previously healthy 31-year-old male with recent history of facial herpes zoster infection, presented with 1-week history of increasingly painful nasal, and periorbital swelling. Imaging confirmed superior ophthalmic vein thrombosis. Staphylococcus aureus was isolated in blood cultures and had an uncomplicated hospital course with full recovery. CONCLUSIONS Early recognition of Lemierre's syndrome contributes significantly in reducing morbidity and mortality associated with it. Staphylococcus aureus skin infection is a very rare cause of Lemierre's syndrome, and its association with superior ophthalmic vein thrombosis has not yet been reported in literature.

An adverse drug reactions avoidability tool called the Liverpool ADR avoidability assessment tool (LAAT) was recently developed (for research purposes), and subsequently validated with mixed interrater reliability (IRR). We investigated the comparative IRR of this tool in an inpatient cohort to ascertain its practical application in this setting.The patient population was comprised of 44 ADR drug pairs drawn from an observational prospective cohort of patents with ADR attending a Weill Cornell Medicine-affiliated tertiary medical Centre in Doha Qatar (Hamad General Hospital). Using the LAAT, and modified Hallas tools, 4 independent raters (2 Clinical Pharmacologists, and 2 General Physicians) assessed and scored the 44 ADR-drug pairs. Agreement proportions between the rating pairs were evaluated as well individual/overall kappa statistics and intraclass correlation coefficients. We evaluated the weight of each of the 7 questions on the LAAT tool to ascertain its determinative role.Across 44 ADR-drug pairs, the overall median Fleiss kappa using the LAAT, and modified Hallas tools were 0.67 (interquartile range (IQR) 0.55, 0.76), 0.36 (IQR, 0.23-0.71) respectively. The overall percentage pairwise agreement with the LAAT and modified Hallas tools were 78.5%, and 62.2% respectively. Exact pairwise agreement occurred in 37 out of 44 (range 0.71-1), and 27 of 44 (0.53-0.77) ADR-drug pairs using the LAAT and modified Hallas tools respectively. Using the LAAT tool, the overall intraclass correlation coefficient was 0.68 (CI 0.55, 0.79), and 0.37 (CI 0.22, 0.53) with the modified Hallas tool.We report a higher proportion of "possible" and "definite" avoidability outcomes of adverse drug reactions compared with the modified Hallas, or that reported by developers of the LAAT tool. Although initially developed for research purposes, our report has suggested for the first time a potential applicability of this tool in clinical environment as well.

Background: Recent systematic reviews have evaluated the efficacy of sodium-glucose co-transporter 2 inhibitors (SGLT2) inhibitors (SGLT2I) in improving glycaemic control and mortality in patients with type II diabetes mellitus. None have incorporated the most recent study or utilized the generalized pairwise modeling methodology network meta-analysis (NMA), as well as a novel bias risk assessment approach., Methods: We propose to conduct literature search of all randomized controlled clinical trials published in English language evaluating the efficacy of (SGLT2I) versus placebo or usual standard of care from the inception of following databases to September 30, 2019: Controlled Clinical Trials Cochrane Controlled Trials Register (CCTR), Cochrane Database of Systematic Reviews (CDSR), EMBASE, Database of Abstracts of Reviews of Effectiveness (DARE), PubMed. Two reviewers will independently search these databases to identify studies that satisfy pre-specified eligibility criteria. Study bias risk assessment amongst other methodology quality evaluation of the studies will be carried out using a novel risk bias assessment tool., Results: We anticipate that the result of this review will provide additional insight into the ranking of the efficacy of various (SGLT2I) in type II diabetic patients especially as it relates to mortality, glycemic control, and body weight reduction., Conclusion: The result of this review will be useful informing therapeutic decisions by policy makers with regards to commissioning of diabetic care.Prospero registration number: CRD42019139708.

Background: Drug induced liver injury (DILI) is an increasing cause of acute liver injury especially with increasing need for pharmacotherapy of widening comorbidities amongst our ever-aging population. Uncertainty however remains regarding both acceptable and widely agreeable diagnostic algorithms as well a clear understanding of mechanistic insights that most accurately underpins it. In this review, we have explored the potential role of emerging novel markers of DILI and how they could possibly be integrated into clinical care of patients., Methods: We explored PUBMED and all other relevant databases for scientific studies that explored potential utility of novel biomarkers of DILI, and subsequently carried out a narrative synthesis of this data. As this is a narrative review with no recourse to patient identifiable information, no ethics committee's approval was sought or required., Results: Novel biomarkers such as microRNA-122 (miR-122) profiles, high mobility group box-1 (HMGB1), glutamate dehydrogenase (GLDH), and cytokeratin-18 (K-18), amongst others do have the potential for reducing diagnostic uncertainties associated with DILI., Conclusion: With the increasing validation of some of the novel liver biomarkers such as K-18, mir-122, HMGB-1, and GLDH, there is the potential for improvement in the diagnostic uncertainty commonly associated with cases of DILI.

The association between single nucleotide polymorphisms of genes encoding transport proteins involved in the bio-disposition of tenofovir disoproxil fumarate (TDF) and kidney tubular dysfunction (KTD) in HIV-positive patients was examined in this study. Fifty-eight patients who received TDF were screened for KTD using retinol-binding protein (RBP) concentration in urine. We defined KTD as the top quartile of urinary RBP/creatinine ratio (>17 μg/mmol), regardless of estimated glomerular filtration rate (eGFR) or proteinuria. Genotyping of genes encoding transport proteins involved in the disposition of TDF was undertaken using validated Taqman 5' nuclease assays. Patients with KTD (N = 15) had higher current CD4 cell counts, lower eGFR and were less likely to possess the genotype CC at position 24 of the ABBC2 (MRP2, rs717620) gene. In multivariate analysis, genotype CC at position 24 of the ABBC2 gene was significantly associated with KTD (odds ratio =0.05, 95% confidence interval = 0.003-0.7, P = 0.027). Genotype CC at position 24 of the ABBC2 (MRP2 rs717620) gene was significantly associated with a reduced risk of elevated urinary RBP in HIV-positive patients exposed to TDF.

The potential for tenofovir to cause a range of kidney syndromes has been established from mechanistic and randomised clinical trials. However, the exact pattern of kidney involvement is still uncertain. We undertook a descriptive analysis of Yellow Card records of 407 HIV-positive persons taking tenofovir disoproxil fumarate (TDF) as part of their antiretroviral therapy regimen and submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) with suspected kidney adverse effects. Reports that satisfy defined criteria were classified as acute kidney injury, kidney tubular dysfunction and Fanconi syndrome. Of the 407 Yellow Card records analysed, 106 satisfied criteria for TDF-related kidney disease, of which 53 (50%) had features of kidney tubular dysfunction, 35 (33%) were found to have features of glomerular dysfunction and 18 (17%) had Fanconi syndrome. The median TDF exposure was 316 days (interquartile range 120-740). The incidence of hospitalisation for TDF kidney adverse effects was high, particularly amongst patients with features of Fanconi syndrome. The pattern of kidney syndromes in this population series mirrors that reported in randomised clinical trials. Cessation of TDF was associated with complete restoration of kidney function in up half of the patients in this report.

The converging clinical effectiveness of mineralocorticoid receptor antagonists (MRAs) Spironolactone and Eplerenone has made their safety profiles/cost-effectiveness key determinants of "agents of choice" across a broad range of clinical indications. The clinical biology of the aldosterone molecule and its range of effects in varied organ systems have been well elucidated from recent mechanistic and systematic studies. Clinical experience with Spironolactone is well established, as is its adverse effects profile. The range of adverse effects experienced with Spironolactone subsequently led to its modification and synthesis of Eplerenone. Recent published reports have confirmed lower prevalence rates of sex-related adverse effects attributable to Eplerenone compared to Spironolactone. There is, however, not much to choose between these agents in regards to other adverse effects including hyperkalemia and kidney failure. As was the experience with Spironolactone, as more robust observational data on Eplerenone accrues, it is possible that the real-life experience of its adverse profile may be discordant with that reported by randomized controlled clinical trials (RCTs). In addition, its metabolism by the vulnerable and highly polymorphic cytochrome dependent pathway also makes it susceptible to various drug interactions. The potential implication of the latter (including morbidity and mortality) may take years to evolve.