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.

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.

Systemic cytokines related to memory function 6-9 months and 12-15 months after SARS-CoV-2 infection.

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 IL1ß, 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-1ß, 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-1ß 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.

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.

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.

[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.

[Acute Q fever, antiphopholipid antibodies and renal artery thrombosis: case report and literature review]. / Fièvre Q aiguë, antiphospholipides et thrombose artérielle rénale : à propos d'un cas et revue de la littérature.

INTRODUCTION: Antiphospholipid antibodies (aPL) can be associated with numerous infectious and particularly Q fever. Data on the pathogenicity of aPL in the course of acute Q fever are scarce. CASE REPORT: We report the case an acute Coxiella burnetii infection associated with clinical and biological manifestations of the aPL syndrome, including a renal infarction. Along with antibiotic treatment, anticoagulation and intravenous immunoglobulins, the clinical outcome was favourable. Antiphospholipid antibodies and Q fever antibody titers had a closely related evolution. CONCLUSION: Arterial thrombosis associated with Q fever and aPL is exceptional. The nosology and potential mechanisms are discussed.

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.

[Medical treatment in peripheral arterial disease: a professional practice study in 262 patients]. / Traitement médical de l'artériopathie oblitérante des membres inférieurs: étude de pratique professionnelle chez 262 patients.

PURPOSE: Antiplatelet agents (APA), statins and angiotensin converting enzyme inhibitors (ACEI) are effective to reduce the risk of cardio-vascular events in patients with peripheral arterial disease (PAD). Few data are available on the actual prescription of these drugs in outpatients and on the effect of hospital care on the level of prescription. METHODS: Retrospective study of patients hospitalized with a confirmed diagnosis of PAD over a one-year period. Comparison of medical treatments on admission and on discharge. RESULTS: 262 patients were included. Mean age was 73 +/- 11 years, and 29% of the patients were women. APA were present in 64% on admission and in 83% when discharged (P < 0.0001). A statin was present in 29% on admission and in 38% when discharged (P = 0.001). ACEI were present in 27% on admission and in 32% when discharged (P= 0.02). A vasodilator was present in 47% on admission and 52% when discharged (P = 0.1). 35% of the patients had isolated PAD. Compared to the patients with associated clinical coronary or cerebro-vascular disease, they were less frequently discharged on statins (respectively 26 and 45%, p = 0.003) and on ACEI (respectively 23 et 38%, P = 0.016) whereas APA were equally prescribed (respectively 82 and 84%, P= 0.7). CONCLUSION: APA were prescribed to a majority of outpatients and the level of prescription was further improved when patients were discharged from the hospital. Statins and ACEI were insufficiently prescribed. On the other hand, vasodilator therapy remained still largely prescribed, despite the lack of any strong effect on morbidity and survival.

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.

[Haemostasis. Aspirin and clopidogrel platelet resistances]. / Hémostase. Résistances plaquettaires à l'aspirine et au clopidogrel.

Articles on antiplatelet "resistance" or "nonresponder" subjects now appear in the medical literature or in the media on a regular basis. The clinical consequences of such biological resistances are yet uncertain. In this review, we describe the concepts of specific and non specific resistances according to the tests used and summarize the main studies up to now. If antiplatelet drug resistances are shown to be predictive of cardiovascular events in large prospective studies, tailoring antiplatelet drugs could be beneficial and, therefore, warranted. New compounds with a more potent effect are emerging and might be useful in clinically relevant resistances.

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.

The specific thromboxane receptor antagonist S18886: pharmacokinetic and pharmacodynamic studies.

OBJECTIVES AND PATIENTS: We conducted a multicenter double-blind pharmacokinetic/pharmacodynamic (PK/PD) study of the new oral thromboxane receptor antagonist S18886 in 30 patients with peripheral artery disease, who were randomized to receive five different oral dosages of S18886 (1, 2.5, 5, 10 or 30 mg) for 12 weeks (83 days). Primary objective was to determine the effect of S18886 on platelet aggregation ex vivo. RESULTS: Pharmacokinetics of S18886 was linear, with peak plasma levels being reached between 30 min and 2 h and a terminal half-life of 5.8-10 h. No significant accumulation of S18886 in plasma was observed after repeated dosing. The relationship between the S18886 concentration and platelet inhibition was examined in terms of U46619-induced platelet aggregation. Over the range of doses studied, there was a predictable relation between the plasma drug concentration and the degree of platelet inhibition at each dose. Maximal inhibition of U46619-induced platelet aggregation was achieved within 1 h with all oral doses of S18886, and this effect was maintained for at least 12 h. The PK/PD relationship was direct, and U46619-induced platelet aggregation was strongly inhibited by S18886 plasma concentrations above 10 ng mL(-1). This concentration was thus the minimal effective antiplatelet level in this population, and was maintained only by the dosages of 10 and 30 mg. The safety profile of S18886 was excellent, whatever the unit dose, with no attributable adverse events. CONCLUSION: The results of this study, which included modeling and simulation, help identify the minimal effective plasma concentration of S18886 required for potent antiplatelet efficacy in patients with stable peripheral arterial disease.

[Pharmacogenetics and antiplatelet drugs]. / Pharmacogénétique et médicaments antiplaquettaires.

PURPOSE: The observation of inherited drug response variability gave rise to the field of pharmacogenetics. Pharmacogenetic research on drug targets, particularly platelet enzymes and receptors, is more recent and is becoming an emerging field. CURRENT KNOWLEDGE AND KEY POINTS: In the Framingham study, the heritability of platelet aggregation response ranges from 44 to 62%, depending on the agonists used. The gene coding for GPIIIa, a sub-unit of the fibrinogen receptor GPIIbIIIa, is one of the most extensively studied gene in relation with aggregation tests and antiplatelet drugs. The GPIIIa PLA1/PLA2 polymorphism has been associated with clopidogrel and orbofiban platelet response. However, data are more controversial concerning the association with aspirin response. Recently, Cox-1 and GPIa (part of the GPIaIIa collagen receptor) genetic variations have also been pointed out as possible candidates to explain part of the variability of the response to antiplatelet agents. Finally, the H1/H2 polymorphism of the platelet ADP receptor P2Y12 gene has been associated with ADP-induced platelet aggregation response and peripheral arterial disease. This polymorphism may modulate the effect of P2Y12 antagonists like clopidogrel and its clinical implication is currently under study. FUTURE PROSPECTS AND PROJECTS: Gene-expression profiling and proteomics may allow the identification of new candidate genes whose variations may be associated with the heritability of platelet aggregation response. In the next future, phenotypic or genotypic studies could be available to tailor the prescription of antiplatelet drugs.

Individual smallest detectable difference in bone mineral density measurements.

Bone mineral density (BMD) measurement is a major outcome measure in osteoporosis. The BMD changes observed must exceed the variability inherent in the measurement process to be considered related to disease progression. The objective of the study was to estimate short-term variability of BMD measurement and to propose a cut-off value for the smallest detectable BMD changes for an individual. To estimate the short-term variability, 70 healthy postmenopausal women aged 53 +/- 4 years (group 1) and 57 elderly osteoporotic postmenopausal women aged 80 +/- 6 years (group 2) had two repeated BMD measurements of the lumbar spine (L2-L4) and the proximal femur with dual-energy X-ray absorptiometry, with complete repositioning within 1 h. Cut-offs derived from short-term variability were either estimated from the coefficient of variation (CV) (which is a function of the measured value) or from the standard deviation (SD), and applied to 330 postmenopausal women (group 3) who had BMD measurements at baseline and 2 years later. The short-term intrasubject variability was greater at the lumbar spine in group 2 versus group 1 (0.0123 vs. 0.0059 g/cm2, p < 10-4), whereas it was not at the femoral neck (0.0098 vs. 0.0076 g/cm2, p = 0.28). There was no statistically significant correlation between short-term intrasubject variability (SD) and BMD as demonstrated with an analysis of covariance (p values ranging from 0.17 to 0.90). Cut-offs estimated with SD and CV were individually applied to group 3 patients. Using these two cut-offs, discrepancies in assessment of progression were observed in 1.7-8.6% of cases. Short-term BMD variability is constant in a wide range of BMD values. Consequently, to determine cut-off values for the smallest detectable differences in BMD at the individual level, precision errors should be based on SD (expressed in absolute units) rather than on CV (expressed in percentage).

Human serum does not contain a high affinity estrogen-binding glycoprotein different from sex hormone-binding globulin.

The mannoglycoprotein fraction obtained by Concanavalin-A chromatography of human serum binds both androgens and estrogens with high affinity. Sex hormone-binding globulin (SHBG) is a component of this fraction that binds both steroids, but the fraction may contain another component that binds only estrogen. We used several chromatographic methods to ascertain whether the estradiol-binding properties of the mannoglycoprotein fraction could be attributed to SHBG or to SHBG and the putative estrogen-binding protein. DEAE-trisacryl, chromatofocusing, and anti-SHBG-immunoglobulin Sepharose chromatography resulted in coelution of the androgen- and estrogen-binding activities. SHBG purified by ligand affinity chromatography as well as immunoaffinity-purified SHBG had estradiol-binding properties similar to those of the crude mannoglycoprotein preparation. These data strongly suggest that 1) SHBG is the only estradiol-binding protein in the mannoglycoprotein fraction obtained by Concanavalin-A chromatography of human serum, and 2) the putative estradiol-binding protein of serum is most likely SHBG.

Renal and metabolic clearance of N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) during angiotensin-converting enzyme inhibition in humans.

We investigated the contributions of angiotensin-converting enzyme (ACE) and glomerular filtration to creating the new metabolic balance of the hemoregulatory peptide N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) that occurs during acute and chronic ACE inhibition in healthy subjects. We also studied the effect of chronic renal failure on the plasma concentration of AcSDKP during long-term ACE inhibitor (ACEI) treatment or in its absence. In healthy subjects, a single oral dose of 50 mg captopril (n=32) and a 7-day administration of 50 mg captopril BID (n=10) resulted in a respective 42-fold (range, 18- to 265-fold) and 34-fold (range, 24-fold to 45-fold) increase in the ratio of urinary AcSDKP to creatinine accompanied by a 4-fold (range, 2- to 6.8-fold) and 4.8-fold (range, 2.6- to 11.8-fold) increase in plasma AcSDKP levels. Changes in plasma AcSDKP and in vitro ACE activity over time showed an intermittent reactivation of ACE between each captopril dose. In subjects with chronic renal failure (creatinine clearance<60 mL/min per 1.73 m2), plasma AcSDKP levels were 22 times higher (95% confidence interval, 15 to 33) in the ACEI group (n=35) than the control group (n=23); in subjects with normal renal function, they were only 4.1 times higher (95% confidence interval, 3.2 to 5.3) in the ACEI group (n=19) than the non-ACEI group (n=21). Renal failure itself led to a slight increase in plasma AcSDKP concentration. In conclusion, intermittent reactivation of ACE between doses of an ACEI is the major mechanism accounting for the lack of major AcSDKP accumulation during chronic ACE inhibition in subjects with normal renal function.