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BACKGROUND: The biological response to antiplatelet drugs has repeatedly been shown to predict the recurrence of major adverse cardiovascular events (MACEs). However, most studies involved coronary artery disease patients with recent vessel injury shortly after the initiation of antiplatelet therapy. Data on stable cardiovascular patients are scarce, and the added predictive value of specific assays (the vasodilator phosphoprotein assay for the clopidogrel response and serum thromboxane B2 for the aspirin response) and aggregation-based assays relative to common predictors has rarely been addressed. METHODS AND RESULTS: Stable cardiovascular outpatients participating in the Antiplatelet Drug Resistances and Ischemic Events (ADRIE) study (n=771) were tested twice, at 2 separate visits, with specific and aggregation-based assays. Follow-up lasted 3 years, and <1% of patients were lost to follow-up. MACEs were adjudicated by an independent committee. Multivariate survival analyses included relevant variables identified in univariate analysis and platelet function test results. The C-index was used to express the prognostic value of various multivariate models. MACEs, the primary end point, occurred in 16% of patients. Hypertension, smoking, older age, and elevated low-density lipoprotein cholesterol were predictive of MACE recurrence, with a C-index of 0.63 (P<0.001). Neither the specific nor the aggregation-based assays added significant predictive value for the primary end point. CONCLUSIONS: Biological antiplatelet drug responsiveness, measured with specific or aggregation-based assays, has no incremental predictive value over common cardiovascular risk factors for MACE recurrence in stable cardiovascular outpatients. These results do not support platelet function testing for MACE risk evaluation in stable cardiovascular patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00501423. [ABSTRACT FROM AUTHOR]

Cognitive symptoms persisting beyond the acute phase of COVID-19 infection are commonly described for up to 2 years after infection. The relationship between cognitive performance, in particular episodic memory processes observed chronically after infection, and cytokine levels in the acute phase of COVID-19 has not yet been identified in humans. To determine whether the levels of cytokines IL1β, IL-6 and TNFα secreted in the acute phase of SARS-CoV-2 infection are associated and predict verbal and visuospatial episodic memory performance in humans 6 to 9 months and 12 to 15 months post-infection. The associations and predictive value of the concentration of cytokines measured in acute phase (IL-1β, IL-6, TNFα) from plasma samples of N = 33 hospitalized COVID-19 patients (mean age 61 years, 39-78, 65% in intensive care) in relation to their verbal and visuospatial episodic memory performance measured at 6-9 months and 12-15 months post-infection were analyzed. To do this, we used Spearman correlations and generalised linear mixed models. IL-1β levels were associated with verbal episodic memory total recall scores 6-9 months post-infection. At 12-15 months post-infection IL-6 predicted verbal episodic memory score. This study demonstrated that the severity of inflammatory reaction at acute phase of SARS-CoV-2 infection predicts verbal episodic memory performance in the long-term post-infection., (© 2024. The Author(s).)

Importance: Thromboprophylaxis is recommended for medical inpatients at risk of venous thromboembolism (VTE). Risk assessment models (RAMs) have been developed to stratify VTE risk, but a prospective head-to-head comparison of validated RAMs is lacking., Objectives: To prospectively validate an easy-to-use RAM, the simplified Geneva score, and compare its prognostic performance with previously validated RAMs., Design, Setting, and Participants: This prospective cohort study was conducted from June 18, 2020, to January 4, 2022, with a 90-day follow-up. A total of 4205 consecutive adults admitted to the general internal medicine departments of 3 Swiss university hospitals for hospitalization for more than 24 hours due to acute illness were screened for eligibility; 1352 without therapeutic anticoagulation were included., Exposures: At admission, items of 4 RAMs (ie, the simplified and original Geneva score, the Padua score, and the IMPROVE [International Medical Prevention Registry on Venous Thromboembolism] score) were collected. Patients were stratified into high and low VTE risk groups according to each RAM., Main Outcomes and Measures: Symptomatic VTE within 90 days., Results: Of 1352 medical inpatients (median age, 67 years [IQR, 54-77 years]; 762 men [55.4%]), 28 (2.1%) experienced VTE. Based on the simplified Geneva score, 854 patients (63.2%) were classified as high risk, with a 90-day VTE risk of 2.6% (n = 22; 95% CI, 1.7%-3.9%), and 498 patients (36.8%) were classified as low risk, with a 90-day VTE risk of 1.2% (n = 6; 95% CI, 0.6%-2.6%). Sensitivity of the simplified Geneva score was 78.6% (95% CI, 60.5%-89.8%) and specificity was 37.2% (95% CI, 34.6%-39.8%); the positive likelihood ratio of the simplified Geneva score was 1.25 (95% CI, 1.03-1.52) and the negative likelihood ratio was 0.58 (95% CI, 0.28-1.18). In head-to-head comparisons, sensitivity was highest for the original Geneva score (82.1%; 95% CI, 64.4%-92.1%), while specificity was highest for the IMPROVE score (70.4%; 95% CI, 67.9%-72.8%). After adjusting the VTE risk for thromboprophylaxis use and site, there was no significant difference between the high-risk and low-risk groups based on the simplified Geneva score (subhazard ratio, 2.04 [95% CI, 0.83-5.05]; P = .12) and other RAMs. Discriminative performance was poor for all RAMs, with an area under the receiver operating characteristic curve ranging from 53.8% (95% CI, 51.1%-56.5%) for the original Geneva score to 58.1% (95% CI, 55.4%-60.7%) for the simplified Geneva score., Conclusions and Relevance: This head-to-head comparison of validated RAMs found suboptimal accuracy and prognostic performance of the simplified Geneva score and other RAMs to predict hospital-acquired VTE in medical inpatients. Clinical usefulness of existing RAMs is questionable, highlighting the need for more accurate VTE prediction strategies.

Background: Despite numerous observations of neuropsychological deficits immediately following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, little is known about what happens to these deficits over time and whether they are affected by changes in fatigue and any psychiatric symptoms. We aimed to assess the prevalence of neuropsychological deficits at 6-9 months and again at 12-15 months after coronavirus disease 2019 (COVID-19) and to explore whether it was associated with changes in fatigue and psychiatric symptoms., Methods: We administered a series of neuropsychological tests and psychiatric questionnaires to 95 patients (mean age = 57.12 years, standard deviation (SD) = 10.68; 35.79% women) 222 (time point 1 (T1)) and 441 (time point 2 (T2)) days on average after infection. Patients were categorised according to the severity of their respiratory COVID-19 symptoms in the acute phase: mild (no hospitalisation), moderate (conventional hospitalisation), and severe (hospitalisation in intensive care unit (ICU) plus mechanical ventilation). We ran Monte-Carlo simulation methods at each time point to generate a simulated population and then compared the cumulative percentages of cognitive disorders displayed by the three patient subgroups with the estimated normative data. We calculated generalised estimating equations for the whole sample to assess the longitudinal associations between cumulative neuropsychological deficits, fatigue, and psychiatric data (anxiety, depressive symptoms, posttraumatic stress disorder, and apathy)., Results: Most participants (>50%) exhibited a decrease in their neuropsychological impairments, while approximately 25% showed an escalation in these cognitive deficits. At T2, patients in the mild subgroup remained free of accumulated neuropsychological impairments. Patients with moderate severity of symptoms displayed a decrease in the magnitude of cumulative deficits in perceptual and attentional functions, a persistence of executive, memory and logical reasoning deficits, and the emergence of language deficits. In patients with severe symptoms, perceptual deficits emerged and executive deficits increased, while attentional and memory deficits remained unchanged. Changes in executive functions were significantly associated with changes in depressive symptoms, but the generalised estimating equations failed to reveal any other significant effect., Conclusion: While most cumulative neuropsychological deficits observed at T1 persisted and even worsened over time in the subgroups of patients with moderate and severe symptoms, a significant proportion of patients, mainly in the mild subgroup, exhibited improved performances. However, we identified heterogeneous neuropsychological profiles both cross-sectionally and over time, suggesting that there may be distinct patient phenotypes. Predictors of these detrimental dynamics have yet to be identified., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and disclose no relevant interests., (Copyright © 2024 by the Journal of Global Health. All rights reserved.)

In this selective overview of articles, we describe new concepts, therapeutic measures and pharmacological agents that may modify current practice in clinical internal medicine. Novelties for the management of cardiovascular disease, such as heart failure, hypoxemic respiratory failure, nosocomial pneumonia and certain allergies are discussed., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

When used in real-world conditions, substantial interindividual variations in direct oral anticoagulant (DOAC) plasma concentrations are observed for a given dose, leading to a risk of over- or under-exposure and clinically significant adverse events. Physiologically-based pharmacokinetic (PBPK) models could help physicians to tailor DOAC prescriptions in vulnerable patient populations, such as those in the hospital setting. The present study aims to validate prospectively PBPK models for rivaroxaban and apixaban in a large cohort of elderly, polymorbid, and hospitalized patients. In using a model of geriatric population integrating appropriate physiological parameters into models first optimized with healthy volunteer data, observed plasma concentration collected in hospitalized patients on apixaban (n = 100) and rivaroxaban (n = 100) were adequately predicted (ratio predicted/observed area under the concentration curve for a dosing interval [AUC tau ] = 0.97 [0.96-0.99] geometric mean, 90% confidence interval, ratio predicted/observed AUC tau  = 1.03 [1.02-1.05]) for apixaban and rivaroxaban, respectively. Validation of the present PBPK models for rivaroxaban and apixaban in in-patients represent an additional step toward the feasibility of bedside use., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

This study aimed to characterize apixaban pharmacokinetics (PKs) and its variability in a real-world clinical setting of hospitalized patients using a population PK (PopPK) approach. Model-based simulations helped to identify factors that affect apixaban exposure and their clinical significance. A classic stepwise strategy was applied to determine the best PopPK model for describing typical apixaban PKs in hospitalized patients from the OptimAT study (n = 100) and evaluating the associated variability and influencing factors. Apixaban exposure under specific conditions was assessed using the final model. A two-compartment model with first-order absorption and elimination best described the data. The developed PopPK model revealed a major role of renal function and a minor role of P-glycoprotein phenotypic (P-gp) activity in explaining apixaban variability. The final model indicated that a patient with stage 4 chronic kidney disease (creatinine clearance [CLcr] = 15-29 mL/min) would have a 45% higher drug exposure than a patient with normal renal function (CLcr >90 mL/min), with a further 12% increase if the patient was also a poor metabolizer of P-gp. A high interindividual variability in apixaban PKs was observed in a real-life setting, which was partially explained by renal function and by P-gp phenotypic activity. Target apixaban concentrations are reached under standard dosage regimens, but overexposure can rapidly occur in the presence of cumulative factors warranting the development of a predictive tool for tailoring apixaban exposure and its clinical utility in at-risk patients., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Thromboprophylaxis (TPX) prescription is recommended in medical inpatients categorized as high risk of venous thromboembolism (VTE) by validated risk assessment models (RAMs), but how various RAMs differ in categorizing patients in risk groups, and whether the choice of RAM influences estimates of appropriate TPX use is unknown., Objectives: To determine the proportion of medical inpatients categorized as high or low risk according to validated RAMs, and to investigate the appropriateness of TPX prescription., Methods: This is a prospective cohort study of acutely ill medical inpatients from 3 Swiss university hospitals. Participants were categorized as high or low risk of VTE by validated RAMs (ie, the Padua, the International Medical Prevention Registry on Venous Thromboembolism , simplified, and original Geneva scores). We assessed prescription of any TPX at baseline. We considered TPX prescription in high-risk and no TPX prescription in low-risk patients as appropriate., Results: Among 1352 medical inpatients, the proportion categorized as high risk ranged from 29.8% with the International Medical Prevention Registry on Venous Thromboembolism score to 66.1% with the original Geneva score. Overall, 24.6% were consistently categorized as high risk, and 26.3% as low risk by all 4 RAMs. Depending on the RAM used, TPX prescription was appropriate in 58.7% to 63.3% of high-risk (ie, 36.7%-41.3% underuse) and 52.4% to 62.8% of low-risk patients (ie, 37.2%-47.6% overuse)., Conclusion: The proportion of medical inpatients considered as high or low VTE risk varied widely according to different RAMs. Only half of patients were consistently categorized in the same risk group by all RAMs. While TPX remains underused in high-risk patients, overuse in low-risk patients is even more pronounced., (© 2023 The Author(s).)

BACKGROUND: Admission to the hospital is a major risk factor for the development of venous thromboembolism (VTE). Whether thromboprophylaxis with low-molecular-weight heparin prevents symptomatic VTE in medically ill, hospitalized older adults remains debated. METHODS: In a prospective, randomized, placebo-controlled, double-blind, multicenter trial, older adults (>70 years of age) hospitalized for acute medical conditions were randomly assigned to receive 40 mg a day of low-molecular-weight heparin (enoxaparin) or placebo for 6 to 14 days. The primary efficacy outcome was the cumulative incidence of symptomatic VTE (distal or proximal deep vein thrombosis, fatal or nonfatal pulmonary embolism) at 30 days. The primary safety outcome was major bleeding. Secondary outcomes included efficacy and safety outcomes at 90 days. RESULTS: The trial was prematurely discontinued in September 2020, 5 years after enrollment began, because of drug supply issues. By the time of trial discontinuation, 2559 patients had been randomly assigned at 47 centers. Median age was 82 years and 60% of patients were female. In the intention-to-treat population, the primary efficacy outcome occurred in 22 out of 1278 (cumulative incidence, 1.8%) patients in the enoxaparin group and in 27 out of 1263 (cumulative incidence, 2.2%) patients in the placebo group (cumulative incidence difference, −0.4 percentage points; 95% confidence interval, −1.5 to 0.7), with no significant difference in time to VTE (P=0.46). The incidence of major bleeding was 0.9% in the enoxaparin group and 1.0% in the placebo group. At 90 days there were 14 symptomatic pulmonary emboli in the enoxaparin group and 25 in the placebo group; all 39 pulmonary embolism events resulted in hospital readmission and/or death, with 5 deaths from pulmonary embolism in the enoxaparin group and 11 deaths in the placebo group. CONCLUSIONS: This trial of thromboprophylaxis in medically ill, hospitalized older adults did not demonstrate that enoxaparin reduced the risk of symptomatic VTE after 1 month. Because the trial was prematurely discontinued, larger trials are needed to definitively address this question. (Funded by the French Ministry of Health Programme Hospitalier de Recherche Clinique, grant number PHRC-N-13-0283; ClinicalTrials.gov number, NCT02379806.)

Background: A neurocognitive phenotype of post-COVID-19 infection has recently been described that is characterized by a lack of awareness of memory impairment (i.e., anosognosia), altered functional connectivity in the brain's default mode and limbic networks, and an elevated monocyte count. However, the relationship between these cognitive and brain functional connectivity alterations in the chronic phase with the level of cytokines during the acute phase has yet to be identified., Aim: Determine whether acute cytokine type and levels is associated with anosognosia and functional patterns of brain connectivity 6-9 months after infection., Methods: We analyzed the predictive value of the concentration of acute cytokines (IL-1RA, IL-1β, IL-6, IL-8, IFNγ, G-CSF, GM-CSF) (cytokine panel by multiplex immunoassay) in the plasma of 39 patients (mean age 59 yrs, 38-78) in relation to their anosognosia scores for memory deficits via stepwise linear regression. Then, associations between the different cytokines and brain functional connectivity patterns were analyzed by MRI and multivariate partial least squares correlations for the whole group., Results: Stepwise regression modeling allowed us to show that acute TNFα levels predicted (R 2 = 0.145; β = -0.38; p = .017) and were associated (r = -0.587; p < .001) with scores of anosognosia for memory deficits observed 6-9 months post-infection. Finally, high TNFα levels were associated with hippocampal, temporal pole, accumbens nucleus, amygdala, and cerebellum connectivity., Conclusion: Increased plasma TNFα levels in the acute phase of COVID-19 predict the presence of long-term anosognosia scores and changes in limbic system functional connectivity., Competing Interests: Conflict of interest The authors report no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Alterations of the limbic system may be present in the chronic phase of SARS-CoV-2 infection. Our aim was to study the long-term impact of this disease on limbic system-related behaviour and its associated brain functional connectivity, according to the severity of respiratory symptoms in the acute phase. To this end, we investigated the multimodal emotion recognition abilities of 105 patients from the Geneva COVID-COG Cohort 223 days on average after SARS-CoV-2 infection (diagnosed between March 2020 and May 2021), dividing them into three groups (severe, moderate or mild) according to respiratory symptom severity in the acute phase. We used multiple regressions and partial least squares correlation analyses to investigate the relationships between emotion recognition, olfaction, cognition, neuropsychiatric symptoms and functional brain networks. Six to 9 months following SARS-CoV-2 infection, moderate patients exhibited poorer recognition abilities than mild patients for expressions of fear ( P = 0.03 corrected), as did severe patients for disgust ( P = 0.04 corrected) and irritation ( P < 0.01 corrected). In the whole cohort, these performances were associated with decreased episodic memory and anosmia, but not with depressive symptoms, anxiety or post-traumatic stress disorder. Neuroimaging revealed a positive contribution of functional connectivity, notably between the cerebellum and the default mode, somatosensory motor and salience/ventral attention networks. These results highlight the long-term consequences of SARS-Cov-2 infection on the limbic system at both the behavioural and neuroimaging levels., Competing Interests: The authors report no competing interests., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Two successive COVID-19 flares occurred in Switzerland in spring and autumn 2020. During these periods, therapeutic strategies have been constantly adapted based on emerging evidence. We aimed to describe these adaptations and evaluate their association with patient outcomes in a cohort of COVID-19 patients admitted to the hospital. Consecutive patients admitted to the Geneva Hospitals during two successive COVID-19 flares were included. Characteristics of patients admitted during these two periods were compared as well as therapeutic management including medications, respiratory support strategies and admission to the ICU and intermediate care unit (IMCU). A mutivariable model was computed to compare outcomes across the two successive waves adjusted for demographic characteristics, co-morbidities and severity at baseline. The main outcome was in-hospital mortality. Secondary outcomes included ICU admission, Intermediate care (IMCU) admission, and length of hospital stay. A total of 2'983 patients were included. Of these, 165 patients (16.3%, n = 1014) died during the first wave and 314 (16.0%, n = 1969) during the second (p = 0.819). The proportion of patients admitted to the ICU was lower in second wave compared to first (7.4 vs. 13.9%, p < 0.001) but their mortality was increased (33.6% vs. 25.5%, p < 0.001). Conversely, a greater proportion of patients was admitted to the IMCU in second wave compared to first (26.6% vs. 22.3%, p = 0.011). A third of patients received lopinavir (30.7%) or hydroxychloroquine (33.1%) during the first wave and none during second wave, while corticosteroids were mainly prescribed during second wave (58.1% vs. 9.1%, p < 0.001). In the multivariable analysis, a 25% reduction of mortality was observed during the second wave (HR 0.75; 95% confidence interval 0.59 to 0.96). Among deceased patients, 82.3% (78.2% during first wave and 84.4% during second wave) died without beeing admitted to the ICU. The proportion of patients with therapeutic limitations regarding ICU admission increased during the second wave (48.6% vs. 38.7%, p < 0.001). Adaptation of therapeutic strategies including corticosteroids therapy and higher admission to the IMCU to receive non-invasive respiratory support was associated with a reduction of hospital mortality in multivariable analysis, ICU admission and LOS during the second wave of COVID-19 despite an increased number of admitted patients. More patients had medical decisions restraining ICU admission during the second wave which may reflect better patient selection or implicit triaging., (© 2023. The Author(s).)

Background: Despite the widespread use of glucocorticoids in inflammatory and autoimmune disorders, there is uncertainty about the safe cessation of long-term systemic treatment, as data from prospective trials are largely missing. Due to potential disease relapse or glucocorticoid-induced hypocortisolism, the drug is often tapered to sub-physiological doses rather than stopped when the underlying disease is clinically stable, increasing the cumulative drug exposure. Conversely, the duration of exposure to glucocorticoids should be minimized to lower the risk of side effects., Methods: We designed a multicenter, randomized, triple-blinded, placebo-controlled trial to test the clinical noninferiority of abrupt glucocorticoid stop compared to tapering after ≥28 treatment days with ≥420 mg cumulative and ≥7.5 mg mean daily prednisone-equivalent dose. 573 adult patients treated systemically for various disorders will be included after their underlying disease has been stabilized. Prednisone in tapering doses or matching placebo is administered over 4 weeks. A 250 mg ACTH-test, the result of which will be revealed a posteriori, is performed at study inclusion; all patients are instructed on glucocorticoid stress cover dosing. Follow-up is for 6 months. The composite primary outcome measure is time to hospitalization, death, initiation of unplanned systemic glucocorticoid therapy, or adrenal crisis. Secondary outcomes include the individual components of the primary outcome, cumulative glucocorticoid doses, signs and symptoms of hypocortisolism, and the performance of the ACTH test in predicting the clinical outcome. Cox proportional hazard, linear, and logistic regression models will be used for statistical analysis., Conclusion: This trial aims to demonstrate the clinical noninferiority and safety of abrupt treatment cessation after ≥28 days of systemic glucocorticoid therapy in patients with stabilized underlying disease., Trial Registration: ClinicalTrials.gov Identifier: NCT03153527; EUDRA-CT: 2020-005601-48 https://clinicaltrials.gov/ct2/show/NCT03153527?term=NCT03153527&draw=2&rank=1., Competing Interests: No competing interests., (Copyright: © 2023 Komminoth et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Neuropsychological deficits and brain damage following SARS-CoV-2 infection are not well understood. Then, 116 patients, with either severe, moderate, or mild disease in the acute phase underwent neuropsychological and olfactory tests, as well as completed psychiatric and respiratory questionnaires at 223 ± 42 days postinfection. Additionally, a subgroup of 50 patients underwent functional magnetic resonance imaging. Patients in the severe group displayed poorer verbal episodic memory performances, and moderate patients had reduced mental flexibility. Neuroimaging revealed patterns of hypofunctional and hyperfunctional connectivities in severe patients, while only hyperconnectivity patterns were observed for moderate. The default mode, somatosensory, dorsal attention, subcortical, and cerebellar networks were implicated. Partial least squares correlations analysis confirmed specific association between memory, executive functions performances and brain functional connectivity. The severity of the infection in the acute phase is a predictor of neuropsychological performance 6-9 months following SARS-CoV-2 infection. SARS-CoV-2 infection causes long-term memory and executive dysfunctions, related to large-scale functional brain connectivity alterations., (© 2022 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

During Switzerland's first wave of COVID-19, clinical pharmacy activities during medical rounds in Geneva University Hospitals were replaced by targeted remote interventions. We describe using the electronic PharmaCheck system to screen high-risk situations of adverse drug events (ADEs), particularly targeting prescriptions of lopinavir/ritonavir (LPVr) and hydroxychloroquine (HCQ) in the presence of contraindications or prescriptions outside institutional guidelines. Of 416 patients receiving LPVr and/or HCQ, 182 alerts were triggered for 164 (39.4%) patients. The main associated risk factors of ADEs were drug-drug interactions, QTc interval prolongation, electrolyte disorder and inadequate LPVr dosage. Therapeutic optimisation recommended by a pharmacist or proposals for additional monitoring were accepted in 80% (n=36) of cases. Combined with pharmacist contextualisation to the clinical context, PharmaCheck made it possible to successfully adapt clinical pharmacist activities by switching from a global to a targeted analysis mode in an emergency context., Competing Interests: Competing interests: None declared., (© European Association of Hospital Pharmacists 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Hospital based internal medicine has been strongly solicited for over two years with the SARS-CoV-2 epidemic. This epidemic continues to evolve and represents a strain for public health. Numerous studies have addressed issues concerning this epidemic, and multiple novelties concerning other frequent pathologies have also been published. Management strategies of cardiovascular, pulmonary, gastro-intestinal and metabolic diseases are discussed., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Objective: Several studies have reported poor long-term neuropsychological performances in patients following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but none has yet considered the effect of administering multiple intercorrelated neuropsychological tests and assessed the frequency of cognitive deficits in a normative population. Our aim was therefore to assess the presence of cumulative neuropsychological deficits in an actual post-coronavirus disease of 2019 (COVID-19) comparison group versus one simulated using Monte-Carlo methods., Method: Validated neuropsychological Monte-Carlo simulation methods were applied to scores from a battery of neuropsychological tests (memory, executive, attentional, perceptual, logical reasoning, language, and ideomotor praxis) administered to 121 patients who had had mild, moderate, or severe COVID-19 (mean age: 56.70 years; 32% women), 222 ± 43 days post-infection. The cumulative percentages of the three severity subgroups were compared with the results of a false discovery rate-corrected probability analysis based on normative data., Results: The cumulative percentages of deficits in memory and executive functions among the severe and moderate patients were significantly higher than those estimated for the normative population. Moderate patients also had significantly more deficits in perception and logical reasoning. In contrast, the mild group did not have significantly more cumulative deficits., Conclusions: Moderate and severe forms of COVID-19 cause greater long-term neuropsychological deficits than those that would be found in a normative population, reinforcing the hypothesis of long-term effects of SARS-CoV-2 on cognitive function, independent of the severity of the initial infection., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Healthcare workers have potentially been among the most exposed to SARS-CoV-2 infection as well as the deleterious toll of the pandemic. This study has the objective to differentiate the pandemic toll from post-acute sequelae of SARS-CoV-2 infection in healthcare workers compared to the general population. The study was conducted between April and July 2021 at the Geneva University Hospitals, Switzerland. Eligible participants were all tested staff, and outpatient individuals tested for SARS-CoV-2 at the same hospital. The primary outcome was the prevalence of symptoms in healthcare workers compared to the general population, with measures of COVID-related symptoms and functional impairment, using prevalence estimates and multivariable logistic regression models. Healthcare workers (n = 3083) suffered mostly from fatigue (25.5 %), headache (10.0 %), difficulty concentrating (7.9 %), exhaustion/burnout (7.1 %), insomnia (6.2 %), myalgia (6.7 %) and arthralgia (6.3 %). Regardless of SARS-CoV-2 infection, all symptoms were significantly higher in healthcare workers than the general population (n = 3556). SARS-CoV-2 infection in healthcare workers was associated with loss or change in smell, loss or change in taste, palpitations, dyspnea, difficulty concentrating, fatigue, and headache. Functional impairment was more significant in healthcare workers compared to the general population (aOR 2.28; 1.76-2.96), with a positive association with SARS-CoV-2 infection (aOR 3.81; 2.59-5.60). Symptoms and functional impairment in healthcare workers were increased compared to the general population, and potentially related to the pandemic toll as well as post-acute sequelae of SARS-CoV-2 infection. These findings are of concern, considering the essential role of healthcare workers in caring for all patients including and beyond COVID-19., 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., (© 2022 The Author(s).)

Objectives: Long-term mortality is increased in older patients with pneumonia. We aimed to test whether residual inflammation is predictive of one-year mortality after pneumonia., Methods: Inflammation biomarkers (C-reactive protein [CRP], interleukin [IL]-6 and IL-8, tumor necrosis factor-α, serum amyloid A, neopterin, myeloperoxidase, anti-apolipoprotein A-1, and anti-phosphorylcholine IgM) were measured at admission and discharge in older patients hospitalized for pneumonia in a prospective study. Univariate and multivariate analyses were conducted using absolute level at discharge and relative and absolute differences between admission and discharge for all biomarkers, along with usual prognostic factors., Results: In the 133 included patients (median age, 83 years [interquartile range: 78-89]), one-year mortality was 26%. In univariate analysis, the relative difference of CRP levels had the highest area under the receiver operating characteristic curve (0.70; 95% confidence interval [CI] 0.60-0.80). A decrease of CRP levels of more than 67% between admission and discharge had 68% sensitivity and 68% specificity to predict survival. In multivariate analysis, lower body mass index (hazard ratio=0.87 [CI 95% 0.79-0.96], P-value=0.01), higher IL-8 (hazard ratio=1.02 [CI 95% 1.00-1.04], P-value=0.02), and higher CRP (1.01 [95% CI 1.00-1.02], P=0.01) at discharge were independently associated with mortality., Conclusion: Higher IL-8 and CRP levels at discharge were independently associated with one-year mortality. The relative CRP difference during hospitalization was the best individual biomarker for predicting one-year mortality., Competing Interests: Declarations of competing interest The authors have no competing interests to declare., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: The SARS-CoV-2 pandemic led to a steep increase in hospital and intensive care unit (ICU) admissions for acute respiratory failure worldwide. Early identification of patients at risk of clinical deterioration is crucial in terms of appropriate care delivery and resource allocation. We aimed to evaluate and compare the prognostic performance of Sequential Organ Failure Assessment (SOFA), Quick Sequential Organ Failure Assessment (qSOFA), Confusion, Uraemia, Respiratory Rate, Blood Pressure and Age ≥65 (CURB-65), Respiratory Rate and Oxygenation (ROX) index and Coronavirus Clinical Characterisation Consortium (4C) score to predict death and ICU admission among patients admitted to the hospital for acute COVID-19 infection., Methods and Analysis: Consecutive adult patients admitted to the Geneva University Hospitals during two successive COVID-19 flares in spring and autumn 2020 were included. Discriminative performance of these prediction rules, obtained during the first 24 hours of hospital admission, were computed to predict death or ICU admission. We further exluded patients with therapeutic limitations and reported areas under the curve (AUCs) for 30-day mortality and ICU admission in sensitivity analyses., Results: A total of 2122 patients were included. 216 patients (10.2%) required ICU admission and 303 (14.3%) died within 30 days post admission. 4C score had the best discriminatory performance to predict 30-day mortality (AUC 0.82, 95% CI 0.80 to 0.85), compared with SOFA (AUC 0.75, 95% CI 0.72 to 0.78), qSOFA (AUC 0.59, 95% CI 0.56 to 0.62), CURB-65 (AUC 0.75, 95% CI 0.72 to 0.78) and ROX index (AUC 0.68, 95% CI 0.65 to 0.72). ROX index had the greatest discriminatory performance (AUC 0.79, 95% CI 0.76 to 0.83) to predict ICU admission compared with 4C score (AUC 0.62, 95% CI 0.59 to 0.66), CURB-65 (AUC 0.60, 95% CI 0.56 to 0.64), SOFA (AUC 0.74, 95% CI 0.71 to 0.77) and qSOFA (AUC 0.59, 95% CI 0.55 to 0.62)., Conclusion: Scores including age and/or comorbidities (4C and CURB-65) have the best discriminatory performance to predict mortality among inpatients with COVID-19, while scores including quantitative assessment of hypoxaemia (SOFA and ROX index) perform best to predict ICU admission. Exclusion of patients with therapeutic limitations improved the discriminatory performance of prognostic scores relying on age and/or comorbidities to predict ICU admission., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Available data have shown an association between direct oral anticoagulant (DOAC) plasma concentration and clinical, particularly bleeding, events. Factors that may influence DOAC plasma concentration are therefore the focus of particular attention. Population pharmacokinetic (PopPK) analyses can help in identifying such factors while providing predictive models. The main aim of the present study was to identify all the PopPK models to date for the four most frequently used DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban). The secondary aim was to use these models to simulate different DOAC plasma concentration-time profiles in relevant clinical scenarios. The results of our model-based simulations confirm the clinical relevance of the known major factors influencing DOAC exposure and support the current approved dose adaptation, at least for atrial fibrillation. They also highlight how the accumulation of covariates, not currently considered for dose adaptation due to their seemingly minor influence on DOAC exposure, lead to supratherapeutic blood concentrations and could thus enhance the risk of major bleeding. The present results therefore question DOAC dose adaptation in the presence of these covariates, such as drug-drug interaction or genotypes, alongside the known existing covariates. As the overall effect of accumulation of several covariates could be difficult to apprehend for the clinicians, PopPK modeling could represent an interesting approach for informed precision dosing and to improve personalized prescription of DOACs., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Lung ultrasonography (LUS) is an accurate method of estimating lung congestion but there is ongoing debate on the optimal number of scanning points. The aim of the present study was to compare the reproducibility (i.e. interobserver agreement) and the feasibility (i.e. time consumption) of the two most practiced protocols in patients hospitalized for acute heart failure (AHF). This prospective trial compared 8- and 28-point LUS protocols. Both were performed by an expert-novice pair of sonographers at admission and after 4 to 6 days on patients admitted for AHF. A structured bio-clinical evaluation was simultaneously carried out by the treating physician. The primary outcome was expert-novice interobserver agreement estimated by kappa statistics. Secondary outcomes included time spent on image acquisition and interpretation. During the study period, 43 patients underwent a total of 319 LUS exams. Expert-novice interobserver agreement was moderate at admission and substantial at follow-up for 8-point protocol (weighted kappa of 0.54 and 0.62, respectively) with no significant difference for 28-point protocol (weighted kappa of 0.51 and 0.41; P value for comparison 0.74 at admission and 0.13 at follow-up). The 8-point protocol required significantly less time for image acquisition at admission (mean time difference - 3.6 min for experts, - 5.1 min for novices) and interpretation (- 6.0 min for experts and - 6.3 min for novices; P value < 0.001 for all time comparisons). Similar differences were observed at follow-up. In conclusion, an 8-point LUS protocol was shown to be timesaving with similar reproducibility when compared with a 28-point protocol. It should be preferred for evaluating lung congestion in AHF inpatients., (© 2022. The Author(s).)

Background: Persistent symptoms of SARS-CoV-2 are prevalent weeks to months following the infection. To date, it is difficult to disentangle the direct from the indirect effects of SARS-CoV-2, including lockdown, social, and economic factors., Objective: The study aims to characterize the prevalence of symptoms, functional capacity, and quality of life at 12 months in outpatient symptomatic individuals tested positive for SARS-CoV-2 compared to individuals tested negative., Methods: From 23 April to 27 July 2021, outpatient symptomatic individuals tested for SARS-CoV-2 at the Geneva University Hospitals were followed up 12 months after their test date., Results: At 12 months, out of the 1447 participants (mean age 45.2 years, 61.2% women), 33.4% reported residual mild to moderate symptoms following SARS-CoV-2 infection compared to 6.5% in the control group. Symptoms included fatigue (16% vs. 3.1%), dyspnea (8.9% vs. 1.1%), headache (9.8% vs. 1.7%), insomnia (8.9% vs. 2.7%), and difficulty concentrating (7.4% vs. 2.5%). When compared to the control group, 30.5% of SARS-CoV-2 positive individuals reported functional impairment at 12 months versus 6.6%. SARS-CoV-2 infection was associated with the persistence of symptoms (adjusted odds ratio [aOR] 4.1; 2.60-6.83) and functional impairment (aOR 3.54; 2.16-5.80) overall, and in subgroups of women, men, individuals younger than 40 years, those between 40-59 years, and in individuals with no past medical or psychiatric history., Conclusion: SARS-CoV-2 infection leads to persistent symptoms over several months, including in young healthy individuals, in addition to the pandemic effects, and potentially more than other common respiratory infections. Symptoms impact functional capacity up to 12 months post infection., (© 2022 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

During the latest pandemic, the RECOVERY study showed the benefits of dexamethasone (DEX) use in COVID-19 patients. Obesity has been proven to be an independent risk factor for severe forms of infection, but little information is available in the literature regarding DEX dose adjustment according to body weight. We conducted a prospective, observational, exploratory study at Geneva University Hospitals to assess the impact of weight on DEX pharmacokinetics (PK) in normal-weight versus obese COVID-19 hospitalized patients. Two groups of patients were enrolled: normal-weight and obese (body mass index [BMI] 18.5-25 and >30 kg/m 2 , respectively). All patients received the standard of care therapy of 6 mg DEX orally. Blood samples were collected, and DEX concentrations were measured. The mean DEX AUC 0-8 and C max were lower in the obese compared to the normal-weight group (572.02 ± 258.96 vs. 926.92 ± 552.12 ng h/ml and 138.67 ± 68.03 vs. 203.44 ± 126.30 ng/ml, respectively). A decrease in DEX AUC 0-8 of 4% per additional BMI unit was observed, defining a significant relationship between weight and DEX AUC 0-8 (p = 0.004, 95% CI 2-7%). In women, irrespective of the BMI, DEX AUC 0-8 increased by 214% in comparison to men (p < 0.001, 95% CI 154-298%). Similarly, the mean C max increased by 205% in women (p < 0.001, 95% CI 141-297%). Conversely, no significant difference between the obese and normal-weight groups was observed for exploratory treatment outcomes, such as the length of hospitalization. BMI, weight, and gender significantly affected DEX AUC. We conclude that dose adjustment would be needed if the aim is to achieve the same exposures in normal-weight and obese patients., (© 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background and Aims: Chronic kidney disease (CKD) confers a high risk for poor cardiovascular outcomes. We conducted a systematic review and meta-analysis to estimate the effects of revascularization as the initial management strategy compared with medical therapy among patients with CKD and coronary artery disease., Methods: A Medline/PubMed literature research was conducted to identify randomized studies comparing early coronary revascularization with optimal medical therapy or medical therapy alone in patients with CKD (estimated glomerular filtration rate <60 mL/min/1.73 m 2 or maintenance dialysis). The primary outcome was myocardial infarction. The secondary outcomes were all-cause mortality or progression to kidney failure. The risk ratio (RR) was estimated using a random-effects model., Results: Eleven randomized trials were included (3422 patients). Revascularization was associated with lower incidence of myocardial infarction compared with medical therapy in patients with CKD: RR 0.71 (95% confidence interval [CI] 0.54-0.94; p=0.02). This result was mainly driven from a significantly lower incidence of myocardial infarction with early revascularization among patients with stable coronary artery disease: RR 0.59; 95% CI 0.37-0.93. A similar incidence of all-cause mortality was observed with both treatment strategies: RR 0.88 (95% CI 0.72-1.08; p=0.22). A trend towards lower incidence of all-cause mortality was observed with revascularization in the subgroup of patients presenting with NSTE-ACS: RR 0.73 (95% CI 0.51-1.04; p=0.08) but not among patients with stable coronary disease. There was no difference in progression to kidney failure between the two strategies., Conclusions: Coronary revascularization may be superior to medical therapy among patients with CKD and coronary disease., (Copyright © 2022. Published by Elsevier B.V.)

Precision dosing strategies require accounting for between-patient variability in pharmacokinetics together with subsequent pharmacodynamic differences. Liquid biopsy is a valuable new approach to diagnose disease prior to the appearance of clinical signs and symptoms, potentially circumventing invasive tissue biopsies. However, the possibility of quantitative grading of biomarkers, as opposed to simply confirming their presence or absence, is relatively new. In this study, we aimed to verify expression measurements of cytochrome P450 (CYP) enzymes and the transporter P-glycoprotein (P-gp) in liquid biopsy against genotype and activity phenotype (assessed by the Geneva cocktail approach) in 30 acutely ill patients with cardiovascular disease in a hospital setting. After accounting for exosomal shedding, expression in liquid biopsy correlated with activity phenotype for CYP1A2, CYP2B6, CYP2C9, CYP3A, and P-gp (r = 0.44-0.70, P ≤ 0.05). Although genotype offered a degree of stratification, large variability (coefficient of variation (CV)) in activity (up to 157%) and expression in liquid biopsy (up to 117%) was observed within each genotype, indicating a mismatch between genotype and phenotype. Further, exosome screening revealed expression of 497 targets relevant to drug metabolism and disposition (159 enzymes and 336 transporters), as well as 20 molecular drug targets. Although there were no functional data available to correlate against these large-scale measurements, assessment of disease perturbation from healthy baseline was possible. Verification of liquid biopsy against activity phenotype is important to further individualize modeling approaches that aspire to achieve precision dosing from the start of drug treatment without the need for multiple rounds of dose optimization., (© 2022 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Adverse drug events (ADEs) can be prevented by deploying clinical decision support systems (CDSS) that directly assist physicians, via computerized order entry systems, and clinical pharmacists performing medication reviews as part of medical rounds. However, physicians using CDSS are known to be exposed to the alert-fatigue phenomenon. Our study aimed to assess the performance of PharmaCheck-a CDSS to help clinical pharmacists detect high-risk situations with the potential to lead to ADEs-and its impact on clinical pharmacists' activities., Methods: Twenty clinical rules, divided into four risk classes, were set for the daily screening of high-risk situations in the electronic health records of patients admitted to our General Internal Medicine Department. Alerts to clinical pharmacists encouraged them to telephone prescribers and suggest any necessary treatment adjustments. PharmaCheck's performance was assessed using the intervention's positive predictive value (PPV), which characterizes the proportion of interventions for each alert triggered. PharmaCheck's impact was assessed by considering clinical pharmacists as a filter for ruling out futile alerts and by comparing the final clinical PPV with a pharmacist (the proportion of interventions that led to a change in the medical regimen) to the final clinical PPV without a pharmacist., Results: Over 132 days, 447 alerts were triggered for 383 patients, leading to 90 interventions (overall intervention PPV = 20.1%). By risk class, intervention PPVs made up 26.9% (n = 65/242) of abnormal laboratory value alerts, 3.1% (4/127) of alerts for contraindicated medications or medications to be used with caution, 28.2% (20/71) of drug-drug interaction alerts, and 14.3% (1/7) of inadequate mode of administration alerts. Clinical PPVs reached 71.0% (64/90) when pharmacists filtered alerts and 14% (64/242) if they were not doing it., Conclusion: PharmaCheck enabled clinical pharmacists to improve their traditional processes and broaden their coverage by focusing on 20 high-risk situations. Alert management by pharmacists seemed to be a more effective way of preventing risky situations and alert-fatigue than a model addressing alerts to physicians exclusively. Some fine-tuning could enhance PharmaCheck's performance by considering the information quality of triggers, the variability of clinical settings, and the fact that some prescription processes are already highly secured., (© 2022. The Author(s).)

Background: Hospital-acquired venous thromboembolism (VTE) is one of the leading preventable causes of in-hospital mortality. However, its risk assessment in medically ill inpatients is complicated due to the patients' heterogeneity and complexity of currently available risk assessment models (RAMs). The simplified Geneva score provides simplicity but has not yet been prospectively validated. Immobility is an important predictor for VTE in RAMs, but its definition is inconsistent and based on subjective assessment by nurses or physicians. In this study, we aim to prospectively validate the simplified Geneva score and to examine the predictive performance of a novel and objective definition of in-hospital immobilization using accelerometry., Methods and Analysis: RISE is a multicenter prospective cohort study. The goal is to recruit 1350 adult inpatients admitted for medical illness in three Swiss tertiary care hospitals. We collect data on demographics, comorbidities, VTE risk and thromboprophylaxis. Mobility from admission to discharge is objectively measured using a wrist-worn accelerometer. Participants are followed for 90 days for the occurrence of symptomatic VTE (primary outcome). Secondary outcomes are the occurrence of clinically relevant bleeding, and mortality. The evolution of autonomy in the activities of daily living, the length of stay, and the occurrence of readmission are also recorded. Time-dependent area under the curve, sensitivity, specificity, and positive and negative predictive values are calculated for each RAM (i.e. the simplified and original Geneva score, Padua, and IMPROVE score) with and without the objective mobility measures to assess their accuracy in predicting hospital-acquired VTE at 90 days., Ethics and Expected Impact: The ethics committee approved the protocol and the study was registered on ClinicalTrials.gov as NCT04439383. RISE has the potential to optimize VTE risk stratification, and thus to improve the quality of care of medically hospitalized patients., Competing Interests: The authors have declared that no competing interests exist.

Background: Hospitalized patients with COVID-19 suffered initially from high rates of venous thromboembolism (VTE), with possible associations between therapeutic anticoagulation and better clinical outcomes in observational studies., Objective: To test whether therapeutic anticoagulation improves clinical outcomes in severe COVID-19., Patients/methods: In this multicenter, open-label, randomized controlled trial, we recruited acutely ill medical COVID-19 patients with D-dimer >1000 ng/ml or critically ill COVID-19 patients in four Swiss hospitals, from April 2020 until June 2021, with a 30-day follow-up. Participants were randomized to in-hospital therapeutic anticoagulation versus low-dose anticoagulation in acutely ill participants/intermediate-dose anticoagulation in critically ill participants, with enoxaparin or unfractionated heparins. The primary outcome was a centrally adjudicated composite of 30-day all-cause mortality, VTE, arterial thrombosis, and disseminated intravascular coagulopathy (DIC), with screening for proximal deep vein thrombosis., Results: Among 159 participants, 55.3% were critically ill and 94.3% received corticosteroids. Before study inclusion, pulmonary embolism had been excluded in 71.7%. The primary outcome occurred in 4/79 participants randomized to therapeutic anticoagulation and 4/80 to low/intermediate anticoagulation (5.4% vs. 5.0%; risk difference +0.4%; adjusted hazard ratio 0.76, 95% confidence interval 0.18-3.21), including three deaths in each group. All primary outcomes and major bleeding ( n  = 3) occurred in critically ill participants. There was no asymptomatic proximal deep vein thrombosis and no difference in major bleeding., Conclusions: Among patients with severe COVID-19 treated with corticosteroids and with exclusion of pulmonary embolism at hospital admission for most, risks of mortality, thrombotic outcomes, and DIC were low at 30 days. The lack of benefit of therapeutic anticoagulation was too imprecise for definite conclusions., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Clinical Question: In adults with low density lipoprotein (LDL) cholesterol levels >1.8 mmol/L (>70 mg/dL) who are already taking the maximum dose of statins or are intolerant to statins, should another lipid-lowering drug be added, either a proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor or ezetimibe, to reduce the risk of major cardiovascular events? If so, which drug is preferred? Having decided to use one, should we add the other lipid-lowering drug?, Current Practice: Most guidelines emphasise LDL cholesterol targets in their recommendations for prescribing PCSK9 inhibitors and/or ezetimibe in adults at high risk of experiencing a major adverse cardiovascular event. However, to achieve these goals in very high risk patients with statins alone is almost impossible, so physicians are increasingly considering other lipid-lowering drugs solely for achieving LDL cholesterol treatment goals rather than for achieving important absolute cardiovascular risk reduction. Most guidelines do not systematically assess the cardiovascular benefits of adding PCSK9 inhibitors and/or ezetimibe for all risk groups across primary and secondary prevention, nor do they report, in accordance with explicit judgments of assumed patients' values and preferences, absolute benefits and harms and potential treatment burdens., Recommendations: The guideline panel provided mostly weak recommendations, which means we rely on shared decision making when applying these recommendations. For adults already using statins, the panel suggests adding a second lipid-lowering drug in people at very high and high cardiovascular risk but recommends against adding it in people at low cardiovascular risk. For adults who are intolerant to statins, the panel recommends using a lipid-lowering drug in people at very high and high cardiovascular risk but against adding it in those at low cardiovascular risk. When choosing to add another lipid-lowering drug, the panel suggests ezetimibe in preference to PCSK9 inhibitors. The panel suggests further adding a PCSK9 inhibitor to ezetimibe for adults already taking statins at very high risk and those at very high and high risk who are intolerant to statins., How This Guideline Was Created: An international panel including patients, clinicians, and methodologists produced these recommendations following standards for trustworthy guidelines and using the GRADE approach. The panel identified four risk groups of patients (low, moderate, high, and very high cardiovascular risk) and primarily applied an individual patient perspective in moving from evidence to recommendations, though societal issues were a secondary consideration. The panel considered the balance of benefits and harms and burdens of starting a PCSK9 inhibitor and/or ezetimibe, making assumptions of adults' average values and preferences. Interactive evidence summaries and decision aids accompany multi-layered recommendations, developed in an online authoring and publication platform (www.magicapp.org) that also allows re-use and adaptation., The Evidence: A linked systematic review and network meta-analysis (14 trials including 83 660 participants) of benefits found that PCSK9 inhibitors or ezetimibe probably reduce myocardial infarctions and stroke in patients with very high and high cardiovascular risk, with no impact on mortality (moderate to high certainty evidence), but not in those with moderate and low cardiovascular risk. PCSK9 inhibitors may have similar effects to ezetimibe on reducing non-fatal myocardial infarction or stroke (low certainty evidence). These relative benefits were consistent, but their absolute magnitude varied based on cardiovascular risk in individual patients (for example, for 1000 people treated with PCSK9 inhibitors in addition to statins over five years, benefits ranged from 2 fewer strokes in the lowest risk to 21 fewer in the highest risk). Two systematic reviews on harms found no important adverse events for these drugs (moderate to high certainty evidence). PCSK9 inhibitors require injections that sometimes result in injection site reactions (best estimate 15 more per 1000 in a 5 year timeframe), representing a burden and harm that may matter to patients. The MATCH-IT decision support tool allows you to interact with the evidence and your patients across the alternative options: https://magicevidence.org/match-it/220504dist-lipid-lowering-drugs/., Understanding the Recommendations: The stratification into four cardiovascular risk groups means that, to use the recommendations, physicians need to identify their patient's risk first. We therefore suggest, specific to various geographical regions, using some reliable risk calculators that estimate patients' cardiovascular risk based on a mix of known risk factors. The largely weak recommendations concerning the addition of ezetimibe or PCSK9 inhibitors reflect what the panel considered to be a close balance between small reductions in stroke and myocardial infarctions weighed against the burdens and limited harms.Because of the anticipated large variability of patients' values and preferences, well informed choices warrant shared decision making. Interactive evidence summaries and decision aids linked to the recommendations can facilitate such shared decisions. The strong recommendations against adding another drug in people at low cardiovascular risk reflect what the panel considered to be a burden without important benefits. The strong recommendation for adding either ezetimibe or PCSK9 inhibitors in people at high and very high cardiovascular risk reflect a clear benefit.The panel recognised the key uncertainty in the evidence concerning patient values and preferences, namely that what most people consider important reductions in cardiovascular risks, weighed against burdens and harms, remains unclear. Finally, availability and costs will influence decisions when healthcare systems, clinicians, or people consider adding ezetimibe or PCSK9 inhibitors., Competing Interests: Competing interests: All authors have completed the BMJ Rapid Recommendations interest disclosure form and a detailed, contextualised description of all disclosures is reported in web appendix 1. As with all BMJ Rapid Recommendations, the executive team and The BMJ judged that no panel member had any financial conflict of interest. Professional and academic interests were minimised as much as possible, while maintaining necessary expertise on the panel to make fully informed decisions., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Atypical pathogens (AP), present in some patients with community-acquired pneumonia (CAP), are intrinsically resistant to betalactam drugs, the mainstay of empirical antibiotic treatment. Adding antibiotic coverage for AP increases the risk of adverse effects and antimicrobial selection pressure, while withholding such coverage may worsen the prognosis if an AP is causative. A clinical model predicting the presence of AP would allow targeting atypical coverage for patients most likely to benefit., Methods: This is a secondary analysis of a multicentric randomized controlled trial that included 580 adults patients hospitalized for CAP. A predictive score was built using independent predictive factors for AP identified through multivariate analysis. Accuracy of the score was assessed using area under the receiver operating curve (AUROC), sensitivity, and specificity., Results: Prevalence of AP was 5.3%. Age < 75 years (OR 2.7, 95% CI 1.2-6.2), heart failure (OR 2.6, 95% CI 1.1-6.1), absence of chest pain (OR 3.0, 95% CI 1.1-8.2), natremia < 135 mmol/L (OR 3.0, 95% CI 1.4-6.6) and contracting the disease in autumn (OR 2.7, 95% CI 1.3-5.9) were independently associated with AP. A predictive score using these factors had an AUROC of 0.78 (95% CI 0.71-0.85). A score of 0 or 1 (present in 33% of patients) had 100% sensitivity and 35% specificity., Conclusion: Use of a score built on easily obtained clinical and laboratory data would allow safe withholding of atypical antibiotic coverage in a significant number of patients, with an expected positive impact on bacterial resistance and drug adverse effects., Trial Registration: NCT00818610., (© 2022. The Author(s).)

Apixaban and rivaroxaban are the two most prescribed direct factor Xa inhibitors. With the increased use of DOACs in real-world settings, safety and efficacy concerns have emerged, particularly regarding their concomitant use with other drugs. Increasing evidence highlights drug−drug interactions with CYP3A/P-gp modulators leading to adverse events. However, current recommendations for dose adjustment do not consider CYP3A/P-gp genotype and phenotype. We aimed to determine their impact on apixaban and rivaroxaban blood exposure. Three-hundred hospitalized patients were included. CYP3A and P-gp phenotypic activities were assessed by the metabolic ratio of midazolam and AUC0−6h of fexofenadine, respectively. Relevant CYP3A and ABCB1 genetic polymorphisms were also tested. Capillary blood samples collected at four time-points after apixaban or rivaroxaban administration allowed the calculation of pharmacokinetic parameters. According to the developed multivariable linear regression models, P-gp activity (p < 0.001) and creatinine clearance (CrCl) (p = 0.01) significantly affected apixaban AUC0−6h. P-gp activity (p < 0.001) also significantly impacted rivaroxaban AUC0−6h. The phenotypic switch (from normal to poor metabolizer) of P-gp led to an increase of apixaban and rivaroxaban AUC0−6h by 16% and 25%, respectively, equivalent to a decrease of 38 mL/min in CrCl according to the apixaban model. CYP3A phenotype and tested SNPs of CYP3A/P-gp had no significant impact. In conclusion, P-gp phenotypic activity, rather than known CYP3A/P-gp polymorphisms, could be relevant for dose adjustment.

Internal medicine continues de evolve as a result of further insight and evidence for the efficacy of given interventions. Although numerous studies have addressed issues concerning the SARS-COV-2 epidemic, multiple novelties concerning other frequent pathologies have also been presented. Management strategies of cardiovascular disease, infectious diseases and venous thromboembolism are particularly concerned., Competing Interests: Les auteurs n’ont déclaré aucun conflit d’intérêts en relation avec cet article.

Physical examination (PE) has always been a corner stone of medical practice. The recent advances in imaging and fading of doctors' ability in performing it, however, raised doubts on PE usefulness. Point-of-care ultrasonography (POCUS) is gaining ground in medicine with the detection of free fluids being one of its main applications. To estimate physicians' confidence and use of PE and POCUS for the detection of abdominal or pleural free fluid, we conducted a cross-sectional survey. In all, 246 internal and emergency medicine physicians answered to the survey (197 in-hospital physicians and 49 general practitioners; response rate 28.5%). Almost all declared to perform PE in case of suspected ascites or pleural effusion (88% and 90%, respectively). The highest rates of confidence were observed in conventional PE signs (91% for diminished breath sounds, 80% for dullness to thorax percussion, and 66% for abdominal flank dullness). For the remaining signs, rates of confidence were less than 53%. Physicians with > 15 years of experience and POCUS-naïve doctors reported higher confidence in PE. Most of emergency and almost half of internal medicine physicians (78% and 44%, respectively) attended a structured POCUS course. POCUS use was higher among trained physicians for both ascites (84% vs 50%, p < 0.001) and pleural effusion (80% vs 34%, p < 0.001). Similarly, higher POCUS use was observed in younger physicians. In conclusion, PE is frequently performed and rates of confidence are low for most PE signs, especially among young doctors and POCUS users. This detailed inventory suggests an ongoing shift towards POCUS integration in clinical practice., (© 2021. The Author(s).)

Background: A hospitalization for community-acquired pneumonia results in a decrease in long-term survival in elderly patients. We assessed biomarkers at admission to predict one-year mortality in a cohort of elderly patients with pneumonia., Methods: A prospective observational study included patients >65 years hospitalized with pneumonia. Assessment of PSI, CURB-65, and biomarkers (C-reactive protein (CRP), procalcitonin (PCT), NT-pro-B-type natriuretic peptide (NT-proBNP), interleukin (IL)-6 and -8, tumor necrosis factor alpha (TNF-α), serum amyloid A (SAA), neopterin (NP), myeloperoxidase (MPO), anti-apolipoprotein A-1 IgG (anti-apoA-1), and anti-phosphorylcholine IgM (anti-PC IgM)) was used to calculate prognostic values for one-year mortality using ROC curve analyses. Post hoc optimal cutoffs with corresponding sensitivity (SE) and specificity (SP) were determined using the Youden index., Results: A total of 133 patients were included (median age 83 years [IQR: 78-89]). Age, dementia, BMI, NT-proBNP (AUROC 0.65 (95% CI: 0.55-0.77)), and IL-8 (AUROC 0.66 (95% CI: 0.56-0.75)) were significantly associated with mortality, with NT-proBNP (HR 1.01 (95% CI 1.00-1.02) and BMI (HR 0.92 (95% CI 0.85-1.000) being independent of age, gender, comorbidities, and PSI with Cox regression. At the cutoff value of 2200 ng/L, NT-proBNP had 67% sensitivity and 70% specificity. PSI and CURB-65 were not associated with mortality., Conclusions: NT-proBNP levels upon admission and BMI displayed the highest prognostic accuracy for one-year mortality and may help clinicians to identify patients with poor long-term prognosis.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, is a severe acute respiratory syndrome with an underlying inflammatory state. We have previously demonstrated that acute inflammation modulates cytochromes P450 (CYPs) activity in an isoform-specific manner. We therefore hypothesized that COVID-19 might also impact CYP activity, and thus aimed to evaluate the impact of acute inflammation in the context of SARS-CoV-2 infection on the six main human CYPs activity. This prospective observational study was conducted in 28 patients hospitalized at the Geneva University Hospitals (Switzerland) with a diagnosis of moderate to severe COVID-19. They received the Geneva phenotyping cocktail orally during the first 72 hours of hospitalization and after 3 months. Capillary blood samples were collected 2 hours after cocktail administration to assess the metabolic ratios (MRs) of CYP1A2, 2B6, 2C9, 2C19, 2D6, and 3A. C-reactive protein (CRP), interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) levels were also measured in blood. CYP1A2, CYP2C19, and CYP3A MRs decreased by 52.6% (P = 0.0001), 74.7% (P = 0.0006), and 22.8% (P = 0.045), respectively, in patients with COVID-19. CYP2B6 and CYP2C9 MRs increased by 101.1% (P = 0.009) and 55.8% (P = 0.0006), respectively. CYP2D6 MR variation did not reach statistical significance (P = 0.072). As expected, COVID-19 was a good acute inflammation model as mean serum levels of CRP, IL-6, and TNF-α were significantly (P < 0.001) higher during SARS-CoV-2 infection. CYP activity are modulated in an isoform-specific manner by SARS-CoV-2 infection. The pharmacokinetics of CYP substrates, whether used to treat the disease or as the usual treatment of patients, could be therefore clinically impacted., (© 2021 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)