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Abstract Background The Clinical Dementia Rating (CDR) scale allows to detect the presence of dementia and to assess its severity, however its evaluation requires a significant time (45 min). We evaluated the agreement between two methods of collection of the CDR: face-to-face interview or based on the information available in the patient’s medical record. Methods The CLIMER study was conducted among patients attending a memory center. The CDR scale was evaluated during face-to-face interviews between neuropsychologists and patients and their caregivers and based on blind analysis of the information of the patients’ medical record by neuropsychologists. The agreement of the CDR sum of boxes (CDR-SB), the 5-point scale CDR and the different domains of the CDR evaluated between the different methods was measured using intraclass correlation (ICC) coefficient, Bland and Altman method, and linearly weighted Kappa. Results The study included 139 patients (means ± SD age 80.1 ± 6, 58.3% women, 71.9% with dementia). The ICC for the CDR-SB score assessed by face-to-face and with all the information available in the patient’s medical record was 0.95 (95% CI: 0.93–0.97). The mean difference between the CDR-SB score assessed by face-to-face and with the medical record was 0.098 ± 1.036, and 92.4% of the patients lay within the 95% limits of agreement. The ICC for the 5-point scale CDR assessed by face-to-face and with the patient’s medical record was 0.92 (95% CI: 0.88–0.95) when all the available information of the patient’s medical record was used. The linear weighted Kappa coefficients was 0.79 (95% CI: 0.68–0.91) for the 5-point scale CDR comparison between the two evaluation methods. The analysis by domain of the CDR showed ICC ranging from 0.65 to 0.91 depending of the domains and the methods of evaluation. Conclusion This study showed an excellent level of agreement of the evaluation of the CDR- SB and the 5-point scale CDR when using all the information of the patient’s medical record compared to the face-to-face interview. Trial registration https//clinicaltrials.gov/ct2/show/NCT04763941 Registration Date 02/17/2021.

Abstract Since 2014, sacubitril/valsartan (Entresto®) is widely prescribed for heart failure. Despite neprilysin inhibition’s benefits in heart failure, concerns about potential amyloid-beta (Aβ) accumulation and Alzheimer’s disease (AD) risk have persisted. This narrative review, a decade post-approval, evaluates the risk of amyloid pathology and neurocognitive disorders in long-term sacubitril/valsartan use. Clinical trials, real-world studies, and pharmacovigilance data do not indicate an increased risk of cognitive decline. In patients treated with sacubitril/valsartan blood-based amyloid biomarkers show perturbations, while neuroimaging biomarkers reveal no significant increase in amyloid load. Despite a theoretical risk of amyloid accumulation and AD under treatment with sacubitril/valsartan, current clinical data appears reassuring, and there is no signal indicating an increased risk of cognitive decline, but a perturbation of amyloid blood-based biomarkers, which implies great caution when interpreting biomarkers in this context.

Abstract Background Long-term exposure to anticholinergic and sedative drugs could be a modifiable risk factor for cognitive decline. The objective of this study was to measure the association between previous cumulative anticholinergic and sedative drug exposure (Drug Burden Index) and cognitive decline. Methods A cohort study (MEMORA cohort) was conducted in a French memory clinic for patients attending a consultation between November 2014 and December 2020, with at least 2 Mini-Mental State Examination (MMSE) measurements (≥ 6 months apart) and available medication data from the local Primary Health Insurance Fund database (n = 1,970). Drug Burden Index was linearly cumulated until each MMSE measurement and was used to categorise patients according to their level of exposure (no exposure, moderate, or high). The longitudinal association between Drug Burden Index and MMSE was assessed using a multivariate linear mixed model, adjusted for age, education level, anxiety disorders, depressive disorders, functional autonomy, and behavioural disorders. Results Overall, 1,970 patients were included with a mean follow-up duration of 2.78 years (± 1.54) and 2.99 visits per patients (5,900 MMSE + Drug Burden Index measurements collected). At baseline, 68.0% of patients had moderate cumulative anticholinergic and sedative drug exposure and a mean MMSE of 21.1. MMSE decrease was steeper in patients with moderate and high Drug Burden Index ( -1.74 and -1.70/year, respectively) than in patients with no exposure (-1.26/year) after adjusting for age, education, anxiety and depressive disorders, functional autonomy, and behavioural disorders (p

Abstract Background The identification of factors involved in the conversion across the different Alzheimer’s disease (AD) stages is crucial to prevent or slow the disease progression. We aimed to assess the factors and their combination associated with the conversion across the AD stages, from mild cognitive impairment to dementia, at a mild, moderate or severe stage and to identify profiles associated with earliest/latest conversion across the AD stages. Methods In this study conducted on the real-life MEMORA cohort data collected from January 1, 2013, and December 31, 2019, three cohorts were selected depending on the baseline neurocognitive stage from a consecutive sample of patients attending a memory center, aged between 50 and 90 years old, with a diagnosis of AD during the follow-up, and with at least 2 visits at 6 months to 1 year of interval. A machine learning approach was used to assess the relationship between factors including socio-demographic characteristics, comorbidities and history of diseases, prescription of drugs, and geriatric hospitalizations, and the censored time to conversion from mild cognitive impairment to AD dementia, from the mild stage of dementia to the moderate or severe stages of AD dementia, and from the moderate stage of AD dementia to the severe stage. Profiles of earliest/latest conversion compared to median time to conversion across stages were identified. The median time to conversion was estimated with a Kaplan-Meier estimator. Results Overall, 2891 patients were included (mean age 77±9 years old, 65% women). The median time of follow-up was 28 months for mild cognitive impairment (MCI) patients, 33 months for mild AD dementia and 30 months for moderate AD dementia. Among the 1264 patients at MCI stage, 61% converted to AD dementia (median time to conversion: 25 months). Among the 1142 patients with mild AD dementia, 59% converted to moderate/severe stage (median time: 23 months) and among the 1332 patients with moderate AD dementia, 23% converted to severe stage (Q3 time to conversion: 22 months). Among the studied factors, cardiovascular comorbidities, anxiety, social isolation, osteoporosis, and hearing disorders were identified as being associated with earlier conversion across stages. Symptomatic treatment i.e. cholinesterase inhibitors for AD was associated with later conversion from mild stage of dementia to moderate/severe stages. Conclusion This study based on a machine learning approach allowed to identify potentially modifiable factors associated with conversion across AD stages for which timely interventions may be implemented to delay disease progression.

Objective: Frailty has been extensively studied in end-stage kidney disease (ESKD) and kidney transplant (KT) patients. The identification of frailty is useful to predict adverse outcomes among ESKD and KT patients. The recent concept of intrinsic capacity (IC) appears as a good and easy-to-understand tool to screen for and monitor frailty in older adults with ESKD. This study aims to assess the relationships between frailty and IC in older adults with ESKD awaiting KT. Design: Cross-sectional study Setting and participants: 236 patients from a day-care geriatric unit undergoing pre-KT geriatric assessment between 2017 and 2022 were included in the main sample, and 151 patients in an independent multicentric replication sample. Measurements: Frailty was evaluated using the physical frailty phenotype (PFP) and IC measures using the World Health Organization’s screening (step 1) and diagnostic (step 2) tools for five IC domains (vitality, locomotion, audition, cognition, psychology). Multivariate regressions were run to assess relationships between PFP and IC domains, adjusted for age, sex, and comorbidities. Analyses were replicated using another independent multicenter cohort including 151 patients with ESKD to confirm the results. Results: Impairments in the locomotion, psychology, and vitality IC domains according to WHO screening tools were associated with frailty (odds ratio 9.62 [95% CI 4.09−24.99], 3.19 [95% CI 1.11–8.88], and 3.11 [95% CI 1.32–7.29], respectively). When IC were measured linearly with z-scores, all IC domains except hearing were inversely associated with frailty. In the replication cohort, results were overall similar, with a greater association between psychology domain and frailty. Conclusion: This study highlights the relationship between frailty and IC in ESKD patients. We assume that IC may be assessed and monitored in ESKD patients, to predict and prevent future frailty, and post-KT adverse outcomes.

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High adherence to the Mediterranean diet (MD) has been associated with lower incidence of cardiovascular disease, increased HDL-cholesterol levels, and decreased triglycerides (TG), and total and LDL cholesterol levels. We aimed to assess the association of MD adherence at baseline with the lipid profile both cross-sectionally and prospectively in a sample of apparently healthy community-dwelling subjects. We conducted three cross-sectional studies using data from follow-ups 1 (FU1, 2009–2012), 2 (FU2, 2014–2017), and 3 (FU3, 2018–2021) of CoLaus|PsyCoLaus, a population-based sample from Lausanne, Switzerland. Dietary intake was assessed with a food frequency questionnaire. Two MD scores (Trichopoulou and Vormund) were computed, ranging from 0 (low) to 9 (high). In total, LDL and HDL cholesterol and TG were assessed. Incident dyslipidemia was defined as hypolipidemic treatment at FU2 or FU3. Overall, 4249 participants from FU1 (53.7% women, 57.6 ± 10.5 years, Trichopoulou 4.0 ± 1.5, Vormund 4.7 ± 1.9) were included. Neither MD score correlated significantly with the lipid markers and similar results were obtained according to the hypolipidemic status. Among the 3092 untreated FU1 participants with FU2 and FU3 data, 349 (11.3%) developed dyslipidemia by FU2 or FU3. No difference in MD scores was found between participants who developed dyslipidemia and those who did not (4.1 ± 1.5 vs. 4.0 ± 1.5 and 4.8 ± 1.8 vs. 4.8 ± 1.9 for Trichopoulou and Vormund, respectively, p > 0.05). Finally, no associations were found between MD score and lipid changes at 5 or 10 years. Contrary to other studies, adherence to MD at baseline did not show any significant effects on lipid composition/incident dyslipidemia in Colaus|PsyCoLaus participants.

BackgroundWhite matter hyperintensities (WMH), a biomarker of small vessel disease, are often found in Alzheimer’s disease (AD) and their advanced detection and quantification can be beneficial for research and clinical applications. To investigate WMH in large-scale multicenter studies on cognitive impairment and AD, appropriate automated WMH segmentation algorithms are required. This study aimed to compare the performance of segmentation tools and provide information on their application in multicenter research.MethodsWe used a pseudo-randomly selected dataset (n = 50) from the DZNE-multicenter observational Longitudinal Cognitive Impairment and Dementia Study (DELCODE) that included 3D fluid-attenuated inversion recovery (FLAIR) images from participants across the cognitive continuum. Performances of top-rated algorithms for automated WMH segmentation [Brain Intensity Abnormality Classification Algorithm (BIANCA), lesion segmentation toolbox (LST), lesion growth algorithm (LGA), LST lesion prediction algorithm (LPA), pgs, and sysu_media] were compared to manual reference segmentation (RS).ResultsAcross tools, segmentation performance was moderate for global WMH volume and number of detected lesions. After retraining on a DELCODE subset, the deep learning algorithm sysu_media showed the highest performances with an average Dice’s coefficient of 0.702 (±0.109 SD) for volume and a mean F1-score of 0.642 (±0.109 SD) for the number of lesions. The intra-class correlation was excellent for all algorithms (>0.9) but BIANCA (0.835). Performance improved with high WMH burden and varied across brain regions.ConclusionTo conclude, the deep learning algorithm, when retrained, performed well in the multicenter context. Nevertheless, the performance was close to traditional methods. We provide methodological recommendations for future studies using automated WMH segmentation to quantify and assess WMH along the continuum of cognitive impairment and AD dementia.

Abstract Some of the behavioral disorders observed in Parkinson’s disease (PD) may be related to an altered processing of social messages, including emotional expressions. Emotions conveyed by whole body movements may be difficult to generate and be detected by PD patients. The aim of the present study was to compare valence judgments of emotional whole body expressions in individuals with PD and in healthy controls matched for age, gender and education. Twenty-eight participants (13 PD patients and 15 healthy matched control participants) were asked to rate the emotional valence of short movies depicting emotional interactions between two human characters presented with the “Point Light Displays” technique. To ensure understanding of the perceived scene, participants were asked to briefly describe each of the evaluated movies. Patients’ emotional valence evaluations were less intense than those of controls for both positive (p

Aim: To assess whether the Mediterranean diet (MD) is associated with lower levels of type 2 diabetes (T2D) in a non-Mediterranean population. Methods: Cross-sectional analysis of follow-ups 1 (FU1, 2009–2012, n = 4398, 45.7% men, 57.7 ± 10.5 years), 2 (FU2, 2014–2017, n = 3154, 45.0% men, 61.7 ± 9.9 years), and 3 (FU3, 2018–2021, n = 2394, 45.2% men, 65.0 ± 9.6 years) of the Colaus|PsyCoLaus study (Lausanne, Switzerland). Two MD scores (Trichopoulou, noted MD1, and Sofi, noted MD2) were calculated using participants’ dietary data. T2D was defined as a fasting plasma glucose ≥7 mmol/L and/or the presence of an antidiabetic drug treatment. Results: Participants with the highest MD adherence had a higher educational level, a lower BMI, were less frequent smokers, presented less frequently with hypertension, and were more frequent alcohol consumers. After multivariable adjustment, no differences were found between participants with and without T2D regarding MD scores: 3.93 ± 0.07 vs. 3.97 ± 0.02; 4.08 ± 0.10 vs. 3.98 ± 0.03, and 3.83 ± 0.11 vs. 3.97 ± 0.03, respectively, for the MD1 score in FU1, FU2, and FU3. In addition, no association was found between adherence to MD and T2D: odds ratio (and 95% confidence interval) for medium and high relative to low adherence to MD1: 0.87 (0.68–1.10) and 0.89 (0.64–1.24) in FU1, 1.04 (0.76–1.42) and 1.07 (0.68–1.67) in FU2, and 0.73 (0.53–1.03) and 0.61 (0.37–1.02) in FU3, respectively. Corresponding results for MD2 were 0.90 (0.70–1.15) and 1.03 (0.69–1.53) in FU1, 1.16 (0.82–1.63) and 1.40 (0.81–2.41) in FU2, and 0.93 (0.65–1.34) and 0.55 (0.28–1.08) in FU3. Conclusion: We found no association between Mediterranean diet adherence and T2D in a non-Mediterranean population.

AIM OF THE STUDY: While hospitals are adopting strategies designed to increase the overall efficiency of the healthcare system, physicians are facing expanding requirements. Such changes in work environment add new psychosocial and physical stressors. Building on a previous quantitative time-motion study, we conducted a qualitative study to better understand the work experience of internal medicine residents. METHODS: The study used a qualitative description approach, and was based on focus group discussions with residents. Data were analysed using reflexive thematic analysis. The study was conducted among all residents of the Internal Medicine division of a tertiary university hospital in Switzerland. RESULTS: Time emerged as the major determinant of residents’ daily experience, which residents want to waste on no account. Shifts are perceived as a constraining succession of distinct periods, with little room for adjustments. Moreover, residents feel held back and distracted in their progression toward the end of the shift. Under time pressure, some essential professional activities, such as caring for patients and families, dealing with medical complications and talking with consultants, may be experienced as unexpected undesirable bumps on the road. Residents describe “running through” a structured day, scattered with obstacles, and resorting to “tricks of the trade” in an attempt to influence the course of the shift. CONCLUSIONS: Time constraints are not new to medicine. However, our findings outline how time has become a constant preoccupation for internal medicine residents, permeating their daily work experience. This changing relationship with time carries the risk of undermining the foundations of clinical medicine and challenges the ability of hospitals to preserve the “sense of the profession”.

Abstract Background White matter hyperintensities (WMH) are frequently found in Alzheimer’s disease (AD). Commonly considered as a marker of cerebrovascular disease, regional WMH may be related to pathological hallmarks of AD, including beta-amyloid (Aβ) plaques and neurodegeneration. The aim of this study was to examine the regional distribution of WMH associated with Aβ burden, glucose hypometabolism, and gray matter volume reduction. Methods In a total of 155 participants (IMAP+ cohort) across the cognitive continuum from normal cognition to AD dementia, FLAIR MRI, AV45-PET, FDG-PET, and T1 MRI were acquired. WMH were automatically segmented from FLAIR images. Mean levels of neocortical Aβ deposition (AV45-PET), temporo-parietal glucose metabolism (FDG-PET), and medial-temporal gray matter volume (GMV) were extracted from processed images using established AD meta-signature templates. Associations between AD brain biomarkers and WMH, as assessed in region-of-interest and voxel-wise, were examined, adjusting for age, sex, education, and systolic blood pressure. Results There were no significant associations between global Aβ burden and region-specific WMH. Voxel-wise WMH in the splenium of the corpus callosum correlated with greater Aβ deposition at a more liberal threshold. Region- and voxel-based WMH in the posterior corpus callosum, along with parietal, occipital, and frontal areas, were associated with lower temporo-parietal glucose metabolism. Similarly, lower medial-temporal GMV correlated with WMH in the posterior corpus callosum in addition to parietal, occipital, and fontal areas. Conclusions This study demonstrates that local white matter damage is correlated with multimodal brain biomarkers of AD. Our results highlight modality-specific topographic patterns of WMH, which converged in the posterior white matter. Overall, these cross-sectional findings corroborate associations of regional WMH with AD-typical Aß deposition and neurodegeneration.

BackgroundPoor vascular health may impede brain functioning in older adults, thus possibly increasing the risk of cognitive decline and Alzheimer’s disease (AD). The emerging link between vascular risk factors (VRF) and longitudinal decline in resting-state functional connectivity (RSFC) within functional brain networks needs replication and further research in independent cohorts.MethodWe examined 95 non-demented older adults using the IMAP+ cohort (Caen, France). VRF were assessed at baseline through systolic and diastolic blood pressure, body-mass-index, and glycated hemoglobin (HbA1c) levels. Brain pathological burden was measured using white matter hyperintensity (WMH) volumes, derived from FLAIR images, and cortical β-Amyloid (Aβ) deposition, derived from florbetapir-PET imaging. RSFC was estimated from functional MRI scans within canonical brain networks at baseline and up to 3 years of follow-up. Linear mixed-effects models evaluated the independent predictive value of VRF on longitudinal changes in network-specific and global RSFC as well as a potential association between these RSFC changes and cognitive decline.ResultsWe replicate that RSFC increased over time in global RSFC and in the default-mode, salience/ventral-attention and fronto-parietal networks. In contrast, higher diastolic blood pressure levels were independently associated with a decrease of RSFC over time in the default-mode, salience/ventral-attention, and fronto-parietal networks. Moreover, higher HbA1c levels were independently associated with a reduction of the observed RSFC increase over time in the salience/ventral-attention network. Both of these associations were independent of brain pathology related to Aβ load and WMH volumes. The VRF-related changes in RSFC over time were not significantly associated with longitudinal changes in cognitive performance.ConclusionOur longitudinal findings corroborate that VRF promote RSFC alterations over time within higher-order brain networks, irrespective of pathological brain burden. Altered RSFC in large-scale cognitive networks may eventually increase the vulnerability to aging and AD.

Abstract Background White matter hyperintensities (WMH) are very frequent in older adults and associated with worse cognitive performance. Little is known about the links between WMH and vascular risk factors, cortical β-amyloid (Aβ) load, and cognition in cognitively unimpaired adults across the entire lifespan, especially in young and middle-aged adults. Methods One hundred and thirty-seven cognitively unimpaired adults from the community were enrolled (IMAP cohort). Participants underwent (i) a comprehensive neuropsychological assessment of episodic memory, processing speed, working memory, and executive functions; (ii) brain structural T1 and FLAIR MRI scans used for the automatic segmentation of total and regional (frontal, parietal, temporal, occipital, and corpus callosum) WMH; and (iii) a Florbetapir-PET scan to measure cortical Aβ. The relationships of total and regional WMH to age, vascular risk factors, cortical Aβ, and cognition were assessed within the whole sample, but also splitting the sample in two age groups (≤ or > 60 years old). Results WMH increased with age across the adult lifespan, i.e., even in young and middle-aged adults. Systolic blood pressure, diastolic blood pressure, and glycated hemoglobin were all associated with higher WMH before, but not after, adjusting for age and the other vascular risk factors. Higher frontal, temporal, and occipital WMH were associated with greater Aβ, but this association was no longer significant when adjusting for age and vascular risk factors. Higher total and frontal WMH were associated with worse performance in executive functions, with no interactive effect of the age group. In contrast, there was a significant interaction of the age group on the link between WMH and working memory, which was significant within the subgroup of young/middle-aged adults only. Adding cortical Aβ load in the models did not alter the results, and there was no interaction between WMH and Aβ on cognition. Conclusion WMH increased with age and were associated with worse executive functions across the adult lifespan and with worse working memory in young/middle-aged adults. Aβ load was weakly associated with WMH and did not change the relationship found between WMH and executive functions. This study argues for the clinical relevance of WMH across the adult lifespan, even in young and middle-aged adults with low WMH.

Introduction With the spread of COVID-19 epidemic, health plans must be adapted continuously. There is an urgent need to define the best care courses of patients with COVID-19, especially in intensive care units (ICUs), according to their individualised benefit/risk ratio. Since older age is associated with poorer short-term and long-term outcomes, prediction models are needed, that may assist clinicians in their ICU admission decision. Senior-COVID-Rea was designed to evaluate, in patients over 60 years old admitted in ICU for severe COVID-19 disease, the impact of age and geriatric and paraclinical parameters on their mortality 30 days after ICU admission.Methods and analysis This is a multicentre survey protocol to be conducted in seven hospitals of the Auvergne-Rhône-Alpes region, France. All patients over 60 years old admitted in ICU for severe COVID-19 infection (or their legally acceptable representative) will be proposed to enter the study and to fill in a questionnaire regarding their functional and nutritional parameters 1 month before COVID-19 infection. Paraclinical parameters at ICU admission will be collected: lymphocytes and neutrophils counts, high-fluorescent lymphoid cells and immature granulocytes percentages (Sysmex data), D-dimers, C-reactive protein, lactate dehydrogenase (LDH), creatinine, CT scan for lung extension rate as well as clinical resuscitation scores, and the delay between the first signs of infection and ICU admission. The primary outcome will be the overall survival at day 30 post-ICU admission. The analysis of factors predicting mortality at day 30 will be carried out using univariate and multivariate logistic regressions. Multivariate logistic regression will consider up to 15 factors.The ambition of this trial, which takes into account the different approaches of geriatric vulnerability, is to define the respective abilities of different operational criteria of frailty to predict patients’ outcomes.Ethics and dissemination The study protocol was ethically approved. The results of the primary and secondary objectives will be published in peer-reviewed journals.Trial registration number NCT04422340.

Environmental contaminations can sometimes be difficult to measure, particularly in complex matrices such as seawater. This is the case of organotin compounds (OSn) such as the monobutyltin (MBT), dibutyltin (DBT), and tributyltin (TBT), whose range of polarity is wide. These compounds, mostly coming from antifouling paints used on ship shell, can be found in water and sediments where they are stable and can persist for years. Passive sampling is gaining in interest to offer solutions to monitor these kinds of compounds even in low concentrations. However, due to the diversity of pollutants present in the environment nowadays, it is important to propose solutions that allow a specific sampling. This work aims to highlight the usability of molecularly imprinted polymers (MIPs) in passive sampling for the monitoring of OSn. MIPs were synthetized using three synthesis ways (bulk, suspension, and mini-emulsion processes) and kinetics were realized in order to estimate the retention of OSn by the solid MIP phase. Results highlighted a good retention of OSn with mean retention kinetic constants near 10−5, 10−6 and 10−7 L·ng·s−1 for DBT, TBT and MBT respectively. The synthesis mode showed no impact on retention kinetics, therefore, bulk synthesis is recommended because of its simplicity. If the elimination of OSn from MIPs is to be optimized, the retention of OSn on MIPs has been demonstrated, and is very promising for their use in specific passive samplers.

ObjectivesThe vast majority of residents’ working time is spent away from patients. In hospital practice, many factors may influence the resident’s working day structure.Using an innovative method, we aimed to compare working time allocation among internal medicine residents using time-motion observations. The first study goal was to describe how the method could be used for inter-hospital comparison. The secondary goal was to learn about specific differences in the resident’s working day structure in university and non-university hospital settings.DesignTwo separate time-motion studies. Trained peer-observers followed the residents during weekday day shifts with a tablet, able to record 22 different activities and corresponding context (with patient, phone, colleague or computer).SettingInternal medicine residencies at a university (May–July 2015) and a non-university (September–October 2016) community hospital.Participants28 residents (mean age: 29 years, average postgraduate training: 30 months) at university hospital, 21 residents (mean age: 30 years, average postgraduate training: 17 months) at non-university hospital.OutcomesTime spent with patients and time dedicated to activities directly related to patients; description of main differences of time allocation between hospitals.ResultsCumulatively 1051 hours of observation (566 (university hospital)+486 (non-university hospital)) and 92 day shifts (49+43) were evaluated. Daily working time was 11.5 versus 11.3 hours. A median daily period of 195 min (IQR 179–211, 27.9%) and 116 min (IQR 98–134, 17.2%) (p

Chemokines and their receptors (members of the GPCR super-family) are involved in a wide variety of physiological processes and diseases; thus, understanding the specificity of the chemokine receptor family could help develop new receptor specific drugs. Here, we explore the evolutionary mechanisms that led to the emergence of the chemokine receptors. Based on GPCR hierarchical classification, we analyzed nested GPCR sets with an eigen decomposition approach of the sequence covariation matrix and determined three key residues whose mutation was crucial for the emergence of the chemokine receptors and their subsequent divergence into homeostatic and inflammatory receptors. These residues are part of the allosteric sodium binding site. Their structural and functional roles were investigated by molecular dynamics simulations of CXCR4 and CCR5 as prototypes of homeostatic and inflammatory chemokine receptors, respectively. This study indicates that the three mutations crucial for the evolution of the chemokine receptors dramatically altered the sodium binding mode. In CXCR4, the sodium ion is tightly bound by four protein atoms and one water molecule. In CCR5, the sodium ion is mobile within the binding pocket and moves between different sites involving from one to three protein atoms and two to five water molecules. Analysis of chemokine receptor evolution reveals that a highly constrained sodium binding site characterized most ancient receptors, and that the constraints were subsequently loosened during the divergence of this receptor family. We discuss the implications of these findings for the evolution of the chemokine receptor functions and mechanisms of action.

BACKGROUND:Recent implementation of electronic health records (EHR) has dramatically changed medical ward organization. While residents in general internal medicine use EHR systems half of their working time, whether computer usage impacts residents' workflow remains uncertain. We aimed to observe the frequency of task-switches occurring during resident's work and to assess whether computer usage was associated with task-switching. METHODS:In a large Swiss academic university hospital, we conducted, between May 26 and July 24, 2015 a time-motion study to assess how residents in general internal medicine organize their working day. RESULTS:We observed 49 day and 17 evening shifts of 36 residents, amounting to 697 working hours. During day shifts, residents spent 5.4 hours using a computer (mean total working time: 11.6 hours per day). On average, residents switched 15 times per hour from a task to another. Task-switching peaked between 8:00-9:00 and 16:00-17:00. Task-switching was not associated with resident's characteristics and no association was found between task-switching and extra hours (Spearman r = 0.220, p = 0.137 for day and r = 0.483, p = 0.058 for evening shifts). Computer usage occurred more frequently at the beginning or ends of day shifts and was associated with decreased overall task-switching. CONCLUSION:Task-switching occurs very frequently during resident's working day. Despite the fact that residents used a computer half of their working time, computer usage was associated with decreased task-switching. Whether frequent task-switches and computer usage impact the quality of patient care and resident's work must be evaluated in further studies.