Acute TNFα levels predict cognitive impairment 6-9 months after COVID-19 infection.

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-1ß, 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 (R2 = 0.145; ß = -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.

Frequency of Abnormally Low Neuropsychological Scores in Post-COVID-19 Syndrome: the Geneva COVID-COG Cohort.

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.

Functional Independence Measure score is associated with mortality in critically ill elderly patients admitted to an intermediate care unit.

BACKGROUND: Age alone is not a robust predictor of mortality in critically ill elderly patients. Chronic health status and functional status before admission could be better predictors. This study aimed to determine whether functional status, assessed using the Functional Independence Measure (FIM), could be an independent predictor of mortality in a geriatric population admitted to an intermediate care unit (IMCU). METHODS: A monocentric, retrospective, observational study of all patients aged ≥75 years old admitted to Geneva University Hospitals' geriatric IMCU between 01.01.2012 and 31.05.2016. The study's primary outcome metrics were one-year mortality's associations with a pre-admission FIM score and other relevant prospectively recorded prognostic variables. RESULTS: A total of 345 patients were included (56% female, mean age 85 +/- 6.5 years). Mean FIM score was 66 +/- 26. One-year mortality was 57%. Dichotomized low (≤ 63) and high FIM (> 63) scores were associated with one-year mortalities of 68 and 44%, respectively. Logistic regression calculations found an association between pre-admission FIM score and one-year mortality (p <  0.0001), including variables usually associated with mortality (e.g., age, sex, comorbidities, mini-mental health state score, renal function). Multivariate survival analysis showed a significant difference between groups, with a hazard ratio of 0.29 (95% CI: 0.13-0.65) for patients with high FIM scores. CONCLUSIONS: In the present study, higher functional status, assessed using the FIM tool before admission to an IMCU, was significantly and independently associated with lower one-year mortality. This opens up perspectives on the potential value of FIM for establishing a finer prognosis and better triage of critically ill older patients.

Accuracy of comprehensive PCR analysis of nasopharyngeal and oropharyngeal swabs for CT-scan-confirmed pneumonia in elderly patients: a prospective cohort study.

OBJECTIVES: We aimed to assess the accuracy of PCR detection of viruses and bacteria on nasopharyngeal and oropharyngeal swabs (NPS) for the diagnosis of pneumonia in elderly individuals. METHODS: We included consecutive hospitalized elderly individuals suspected of having pneumonia. At inclusion, NPS were collected from all participants and tested by PCR for the presence of viral and bacterial respiratory pathogens (index test, defined as comprehensive molecular testing). Routine diagnostic tests (blood and sputum culture, urine antigen detection) were also performed. The reference standard was the presence of pneumonia on a low-dose CT scan as assessed by two independent expert radiologists. RESULTS: The diagnosis of pneumonia was confirmed in 127 of 199 (64%) included patients (mean age 83 years, community-acquired pneumonia in 105 (83%)). A pathogen was identified by comprehensive molecular testing in 114 patients (57%) and by routine methods in 22 (11%). Comprehensive molecular testing was positive for viruses in 62 patients (31%) and for bacteria in 73 (37%). The sensitivity and specificity were 61% (95% CI 53%-69%) and 50% (95% CI 39%-61%) for comprehensive molecular testing, and 14% (95% CI 82%-21%) and 94% (95% CI 86%-98%) for routine testing, respectively. Positive likelihood ratio was 2.55 for routine methods and 1.23 for comprehensive molecular testing. CONCLUSION: Comprehensive molecular testing of NPS increases the number of pathogens detected compared with routine methods, but results are poorly predictive of the presence of pneumonia. Hence, comprehensive molecular testing is unlikely to impact clinical decision-making (NCT02467192). CLINICAL TRIALS REGISTRATION: NCT02467192.

Why has model-informed precision dosing not yet become common clinical reality? lessons from the past and a roadmap for the future.

Patient groups prone to polypharmacy and special subpopulations are susceptible to suboptimal treatment. Refined dosing in special populations is imperative to improve therapeutic response and/or lowering the risk of toxicity. Model-informed precision dosing (MIPD) may improve treatment outcomes by achieving the optimal dose for an individual patient. There is, however, relatively little published evidence of large-scale utility and impact of MIPD, where it is often implemented as local collaborative efforts between academia and healthcare. This article highlights some successful applications of bringing MIPD to clinical care and proposes strategies for wider integration in healthcare. Considerations are brought up herein that will need addressing to see MIPD become "widespread clinical practice," among those, wider interdisciplinary collaborations and the necessity for further evidence-based efficacy and cost-benefit analysis of MIPD in healthcare. The implications of MIPD on regulatory policies and pharmaceutical development are also discussed as part of the roadmap.

Coadministration of ticagrelor and ritonavir: Toward prospective dose adjustment to maintain an optimal platelet inhibition using the PBPK approach.

Ticagrelor is a potent antiplatelet drug metabolized by cytochrome (CYP)3A. It is contraindicated in patients with human immunodeficiency virus (HIV) because of the expected CYP3A inhibition by most protease inhibitors, such as ritonavir and an increased bleeding risk. In this study, a physiologically based pharmacokinetic (PBPK) model was created for ticagrelor and its active metabolite (AM). Based on the simulated interaction between ticagrelor 180 mg and ritonavir 100 mg, a lower dose of ticagrelor was calculated to obtain, when coadministered with ritonavir, the same pharmacokinetic (PK) and platelet inhibition as ticagrelor administered alone. A clinical study was thereafter conducted in healthy volunteers. Observed PK profiles of ticagrelor and its AM were successfully predicted with the model. Platelet inhibition was nearly complete in both sessions despite administration of a fourfold lower dose of ticagrelor in the second session. This PBPK model could be prospectively used to broaden the usage of ticagrelor in patients with ritonavir-treated HIV regardless of the CYP3A inhibition.

Prothrombin G20210A mutation and lower extremity peripheral arterial disease: a systematic review and meta-analysis.

OBJECTIVE/BACKGROUND: Despite being an important risk factor for venous thromboembolism, the role of the prothrombin G20210A mutation in patients with arterial disease remains unclear. The aim of this review was to evaluate the association of prothrombin G20210A and lower extremity peripheral arterial disease (PAD). METHODS: This was a systematic review and meta-analysis of case-control studies. A systematic review of electronic databases, including MEDLINE and Embase, was conducted to assess the prevalence of prothrombin G20210A in patients with lower extremity PAD. The main outcome was the prevalence of prothrombin G20210A in patients with lower extremity PAD. The random effects model odds ratio (OR) was used as the primary outcome measure. RESULTS: The initial electronic search identified 168 relevant abstracts of which five studies evaluating 1,524 cases of PAD and 1,553 controls were included. Prothrombin G20210A was found in 70 of 1,524 patients with lower extremity PAD and 44 of 1,553 of the controls (random effects OR 1.68, 95% confidence interval [CI] 0.8-3.2). In those with critical limb ischemia (CLI), the prevalence of prothrombin G20210A was 23 of 302 compared with 31 of 1,253 of the controls (OR 3.2, 95% CI 1.6-6.1). CONCLUSION: Despite finding no significant association between lower extremity PAD and prothrombin G20210A, the meta-analysis suggests that the prevalence of prothrombin G20210A is significantly elevated in those with atherosclerotic occlusive disease of the lower extremities presenting with CLI. Well-designed prospective cohort studies evaluating the role of prothrombin G20210A as a predictor of disease progression or adverse vascular events are highly needed.

[My patient is too old for a lipid-lowering therapy: myths and reality]. / Mon patient est trop âgé pour une statine: mythes et réalités.

Lipid-lowering treatment in the elderly patient is conditioned by a high incidence and prevalence of cardiovascular disease in the setting of a limited remaining life span. The clinical benefit of statin therapy can be seen after a few months, thus supporting use in secondary prevention even when the lifespan is restricted to a few years. Recent guidelines propose the use of moderate doses in the elderly > 75 years. The evidence for treatment in primary prevention is weaker and the evaluation of the total cardiovascular risk is complicated by the high baseline risk of many elderly. Rational treatment decisions should be based on biologic rather than chronologic age. Statins are generally well tolerated in the elderly, requiring clinical monitoring only, with particular attention to pharmacokinetic interactions and renal failure.

[Pneumonia in the elderly: are there any specificities? ]. / Pneumonie chez Le sujet âgé: y a-t-il des spécificités?

Pneumonia is one of the leading causes of death in the elderly. Streptococcus pneumoniae is the leading etiological agent, but the identification of a pathogen remains infrequent despite advances in microbiological methods. Antibiotic resistant organisms should be considered as potential causal agents in recently hospitalized patients and patients with recent antibiotic exposure and influenza during the flu season. The clinical diagnosis is difficult due to frequent atypical presentation. Prognostic scores are not always appropriate to predict the need for hospitalization in very old patients. Studies on the role of low-dose chest CT for the diagnosis, management and prevention should help improve the management of this disease in the future.

Antiplatelet therapy: targeting the TxA2 pathway.

The thromboxane (Tx) A2 pathway is a major contributor to the amplification of the initial platelet activation process. TxA2 mediates its effect through the thromboxane prostanoid (TP) receptor that is expressed not only in platelets, but also in endothelial cells, macrophages, and monocytes, and thus contributes to the development of atherosclerotic lesions. The TxA2 pathway is therefore a major target in the treatment of cardiovascular disease. Aspirin-the most widely used antiplatelet drug-is very effective at inhibiting platelet-derived TxA2 synthesis. However, aspirin's effects can be overcome by several other soluble agonists such as isoprostanes, which are aspirin-insensitive ligands of the TP receptor that are preferentially produced in diabetes mellitus. Other drugs, with either inhibitory effects on Tx synthase or antagonist effects on TP, have been developed with the hope of providing a better, more complete inhibition of the TxA2 pathway.

[Enteral nutrition: nasogastric tube or percutaneous endoscopic gastrostomy?]. / Nutrition entérale: sonde nasogastrique ou gastrostomie percutanée endoscopique?

When enteral nutrition is indicated to prevent or to treat a patient with denutrition choosing between a nasogastric tube (NGT) and a percutaneous endoscopic gastrostomy (PEG) is not always an easy decision. In neurological patients with swallowing disturbances or in patients with head and neck tumors, PEG is associated with lower rates of feeding tube dislodgement, while NGT has lower rates or morbidity. A meta-analysis showed that the interruption of nutrition is less frequent with PEG but there is no difference in terms of mortality and aspiration pneumonia between PEG and NGT. The European Society for Clinical Nutrition and Metabolism recommends PEG when enteral nutrition is expected to last more than 3 weeks.

[Practical implementation and usefulness of guidelines for the management of syncope: a professional practice study]. / Application pratique et intérêt des recommandations de prise en charge des syncopes : évaluation de pratiques professionnelles.

AIMS: To assess the practical implementation of international guidelines and their impact on syncope management in a 500-bed general hospital. PATIENTS AND METHODS: Three groups of 63 consecutive patients admitted for syncope to the emergency care unit (ECU) were studied: group 1, before the guidelines delivered to the practitioners, group 2 immediately after the diffusion of guidelines and group 3, one year later. The study evaluates the mean duration of stay (MDS) and the relevance of the diagnostic strategy. RESULTS: In group 1 compared to group 2, MDS were respectively 6.8±5.5 and 5.4±2.8 days (P=0.07) and the unexplained syncope number respectively 22% and 24% (P=0.8). The search of orthostatic hypotension became more systematic (13% versus 86% in group 1 and 2 respectively, P<0.001). The agreement (kappa coefficient) between initial and final diagnostic increased in 0.34 to 0.44. One year later MDS in group 3 was 7.1±4.7 days (P=0.8 versus group 1 and P=0.015 versus group 2) with only 6.3% systematic search for orthostatic hypotension (P<0.001). CONCLUSIONS: Guidelines optimize the syncope management in the ECU and the agreement between the emergency and discharge diagnostic without change of unexplained syncope and. MDS tend to be shorter when guidelines are actively implemented. Nevertheless, the positive impact of guidelines implementation is of limited duration.

Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis.

BACKGROUND: A poor biological response to clopidogrel is associated with an increased risk of major cardiovascular ischemic events (MACE). Paraoxonase 1 (PON1) enzyme activity is modulated by the PON1-Q192R variant (rs662) and was recently suggested to be strongly involved in clopidogrel bioactivation, but the influence of the PON1-Q192R variant on the risk of MACE in clopidogrel-treated patients is controversial. OBJECTIVES: To determine whether the PON1-Q192R variant influences clopidogrel biological responsiveness and the risk of MACE in patients treated with clopidogrel. METHODS: Systematic review and meta-analysis of studies of the association between the PON1-Q192R polymorphism and the biological response to clopidogrel and/or the risk of MACE during clopidogrel administration. RESULTS: Seventeen studies were included. In the 12 studies of the biological response to clopidogrel (n = 5302 patients), there was no significant difference between 192QQ and 192QR + 192RR subjects, whatever the laboratory method used (global mean standardized difference = 0.10 [-0.06; 0.25], P = 0.22). Eleven studies assessed the risk of MACE, four using a case-control design (n = 2739 patients) and seven a prospective design (n = 5353 patients). Overall, MACE occurred in 19% of patients in case-control studies and in 6% of patients in prospective cohort studies, with no significant difference between 192QQ and 192QR + 192RR patients (OR = 1.28 [0.97; 1.68], P = 0.08). Similar results were obtained when study design was taken into account. Heterogeneity was mainly driven by one publication. CONCLUSIONS: This meta-analysis suggests that the PON1-Q192R polymorphism has no major impact on the risk of MACE and does not alter the biological response to clopidogrel in clopidogrel-treated patients.

The paraoxonase-1 pathway is not a major bioactivation pathway of clopidogrel in vitro.

BACKGROUND AND PURPOSE: Clopidogrel is a prodrug bioactivated by cytochrome P450s (CYPs). More recently, paraoxonase-1 (PON1) has been proposed as a major contributor to clopidogrel metabolism. The purpose of this study was to assess the relative contribution of CYPs and PON1 to clopidogrel metabolism in vitro. EXPERIMENTAL APPROACH: Clopidogrel metabolism was studied in human serum, recombinant PON1 enzyme (rePON1), pooled human liver microsomes (HLMs), HLMs with the CYP2C19*1/*1 genotype and HLMs with the CYP2C19*2/*2 genotype. Inhibition studies were also performed using specific CYP inhibitors and antibodies. Clopidogrel and its metabolites were measured using LC/MS/MS method. KEY RESULTS: PON1 activity was highest in the human serum and there was no difference in PON1 activity between any of the HLM groups. The production of clopidogrel's active metabolite (clopidogrel-AM) from 2-oxo-clopidogrel in pooled HLMs was approximately 500 times that in serum. When 2-oxo-clopidogrel was incubated with rePON1, clopidogrel-AM was not detected. Clopidogrel-AM production from 2-oxo-clopidogrel was lower in CYP2C19*2/*2 HLMs compared with CYP2C19*1/*1 HLMs, while PON1 activity in HLMs with both genotypes was similar. Moreover, incubation with inhibitors of CYP3A, CYP2B6 and CYP2C19 significantly reduced clopidogrel bioactivation while a PON1 inhibitor, EDTA, had only a weak inhibitory effect. CONCLUSION AND IMPLICATIONS: This in vitro study shows that the contribution of PON1 to clopidogrel metabolism is limited at clinically relevant concentrations. Moreover, CYP2C19, CYP2B6 and CYP3A play important roles in the bioactivation of clopidogrel.

[Distal coronary thrombosis during L-asparaginase treatment for an acute lymphoblastic leukaemia]. / Thrombose coronaire distale compliquant une leucémie aiguë lymphoblastique traitée par asparaginase.

A 53-year-old man is treated by L-asparaginase for an acute lymphoblastic leukaemia. He received anti thrombin infusions. A systematic electrocardiogram showed an asymptomatic subepicardium ischemia without troponin elevation. Echocardiography and heart magnetic resonance imaging showed an apical thrombus facing a zone of myocardial necrosis. A thrombus regression was observed under anticoagulation. Atypical and asymptomatic coronary thrombosis may occur following L-asparaginase treatment. Regular electrocardiogram monitoring is proposed along this treatment. Arterial thrombosis associated with anti tumor chemotherapies are reviewed.