A data-driven pipeline to extract potential adverse drug reactions through prescription, procedures and medical diagnoses analysis: application to a cohort study of 2,010 patients taking hydroxychloroquine with an 11-year follow-up.

CONTEXT: Real-life data consist of exhaustive data which are not subject to selection bias. These data enable to study drug-safety profiles but are underused because of their temporality, necessitating complex models (i.e., safety depends on the dose, timing, and duration of treatment). We aimed to create a data-driven pipeline strategy that manages the complex temporality of real-life data to highlight the safety profile of a given drug. METHODS: We proposed to apply the weighted cumulative exposure (WCE) statistical model to all health events occurring after a drug introduction (in this paper HCQ) and performed bootstrap to select relevant diagnoses, drugs and interventions which could reflect an adverse drug reactions (ADRs). We applied this data-driven pipeline on a French national medico-administrative database to extract the safety profile of hydroxychloroquine (HCQ) from a cohort of 2,010 patients. RESULTS: The proposed method selected eight drugs (metopimazine, anethole trithione, tropicamide, alendronic acid & colecalciferol, hydrocortisone, chlormadinone, valsartan and tixocortol), twelve procedures (six ophthalmic procedures, two dental procedures, two skin lesions procedures and osteodensitometry procedure) and two medical diagnoses (systemic lupus erythematous, unspecified and discoid lupus erythematous) to be significantly associated with HCQ exposure. CONCLUSION: We provide a method extracting the broad spectrum of diagnoses, drugs and interventions associated to any given drug, potentially highlighting ADRs. Applied to hydroxychloroquine, this method extracted among others already known ADRs.

Impact of medical and pharmaceutical interventions on anti-infective prescriptions: an observational study.

Appropriate prescribing of anti-infectives is a public health challenge. In our hospital, clinical microbiologists (clinical microbiology mobile unit, UMMc) and clinical pharmacists (clinical pharmacy, PHAc) carry out interventions on anti-infective prescriptions to improve practices. Our main objective was to evaluate the acceptance of UMMc and PHAc interventions on anti-infective prescriptions by quantifying the rate of prescription change 24 h after intervention. The secondary objective was to characterize the type of intervention and associate the rate of change for each. All prescriptions are computerized, and interventions traced via DxCare® software, which feeds a local data warehouse (HEGP-CDW). This descriptive, retrospective, single-center, uncontrolled study was conducted from January 2015 to December 2018. The data were extracted over this period from the data warehouse and analyzed using R software. UMMc interventions were accepted 72.2% of the time and PHA interventions 87.3%. The types of interventions found were mostly dose adjustments (61.1% for the UMMc and 54.2% for the PHAc) and proposals to change or stop a drug. Interventions have an impact on anti-infective prescriptions and are generally followed by clinicians. For the category "discontinuation of a molecule", almost half of the advice from the UMMc was refused. The collaboration between the UMMc and PHAc should be reinforced to improve acceptance.

Evolution of the nutritional status of COVID-19 critically-ill patients: A prospective observational study from ICU admission to three months after ICU discharge.

BACKGROUND & AIMS: Malnutrition following intensive care unit (ICU) stay is frequent and could be especially prominent in critically ill Coronavirus Disease 2019 (COVID-19) patients as they present prolonged inflammatory state and long length stay. We aimed to determine the prevalence of malnutrition in critically ill COVID-19 patients both at the acute and recovery phases of infection. METHODS: We conducted a prospective observational study including critically ill COVID-19 patients requiring invasive mechanical ventilation discharged alive from a medical ICU of a university hospital. We collected demographic, anthropometric and ICU stay data (SAPS2, recourse to organ support and daily energy intake). Nutritional status and nutritional support were collected at one month after ICU discharge (M1) by phone interview and at 3 months after ICU discharge (M3) during a specialized and dedicated consultation conducted by a dietitian. Malnutrition diagnosis was based on weight loss and body mass index (BMI) criteria following the Global Leadership Initiative on Malnutrition. Primary outcome was the prevalence of malnutrition at M3 and secondary outcomes were the evolution of nutritional status from ICU admission to M3 and factors associated with malnutrition at M3. RESULTS: From march 13th to may 15th, 2020, 38 patients were discharged alive from the ICU, median [IQR] age 66 [59-72] years, BMI 27.8 [25.5-30.7] kg/m2 and SAPS2 47 [35-55]. Thirty-three (86%) patients were followed up to M3. Prevalence of malnutrition increased during the ICU stay, from 18% at ICU admission to 79% at ICU discharge and then decreased to 71% at M1 and 53% at M3. Severe malnutrition prevailed at ICU discharge with a prevalence of 55% decreasing 32% at M3. At M3, the only factors associated with malnutrition in univariate analysis were the length of invasive mechanical ventilation and length of ICU stay (28 [18-44] vs. 13 [11-24] days, P = 0.011 and 32 [22-48] vs. 17 [11-21] days, P = 0.006, respectively), while no ICU preadmission and admission factors, nor energy and protein intakes distinguished the two groups. Only 35% of undernourished patients at M3 had benefited from a nutritional support. CONCLUSION: Malnutrition is frequent, protracted and probably underrecognized among critically ill Covid-19 patients requiring invasive mechanical ventilation with more than half patients still being undernourished three months after ICU discharge. A particular attention should be paid to the nutritional status of these patients not only during their ICU stay but also following ICU discharge.

Interobserver agreement issues in radiology.

Agreement between observers (i.e., inter-rater agreement) can be quantified with various criteria but their appropriate selections are critical. When the measure is qualitative (nominal or ordinal), the proportion of agreement or the kappa coefficient should be used to evaluate inter-rater consistency (i.e., inter-rater reliability). The kappa coefficient is more meaningful that the raw percentage of agreement, because the latter does not account for agreements due to chance alone. When the measures are quantitative, the intraclass correlation coefficient (ICC) should be used to assess agreement but this should be done with care because there are different ICCs so that it is important to describe the model and type of ICC being used. The Bland-Altman method can be used to assess consistency and conformity but its use should be restricted to comparison of two raters.

Preoperative evaluation of small bowel complications in Crohn's disease: comparison of diffusion-weighted and contrast-enhanced MR imaging.

PURPOSE: To compare the accuracy of MR enterography (MRE) using combined T2-weighted and contrast-enhanced (CE) sequences with that of combined T2- and diffusion-weighted (DW) sequences for the detection of complex enteric Crohn's disease (CD). MATERIALS: Thirty-eight patients who underwent surgery for CD complications and preoperative MRE from 2011 to 2016 were included. MRE examinations were blindly analyzed independently by one junior and one senior abdominal radiologist for the presence of fistula, stenosis and abscesses. During a first reading session, T2-weighted images (WI), steady-state sequences and DW-MRE were reviewed (set 1). During a separate distant session, T2-WI, True-FISP and CE-MRE were reviewed (set 2). Performance of each reader was evaluated by comparison with the standard of reference established using intraoperative and pathological findings. RESULTS: Forty-eight fistulas, 43 stenoses and 11 abscesses were found. For the senior radiologist, sensitivity for the detection of fistula, stenosis and abscess ranged from 80% to 100% for set 1 and 88% to 100% for set 2 and specificity ranged from 56% to 70% for set 1 and 53% to 93% for set 2, with no significant difference between the sets (p = 0.342-0.429). For the junior radiologist, sensitivity ranged from 53% to 63% for set 1 and 64% to 88% for set 2 and specificity ranged from 0% to 25% for set 1 and 17% to 40% for set 2 (p = 0.001 and 0.007, respectively). CONCLUSION: For a senior radiologist, DW-MRE has similar sensitivity as CE-MRE for the detection of CD complications. For a junior radiologist, CE-MRE yields the best results compared with DW-MRE. KEY POINTS: • For experienced readers, DWI has similar diagnostic capability as contrast-enhanced MR imaging for the diagnosis of Crohn's disease complications. • For senior radiologists, gadolinium chelate injection could be waived for the diagnosis of Crohn's disease complications. • The interpretation of DWI for Crohn's disease complications requires some experience.

Knowledge of medical students on National Health Care System: A French multicentric survey.

BACKGROUND: Education on national health care policy and costs is part of our medical curriculum explaining how our health care system works. Our aim was to measure French medical students' knowledge about national health care funding, costs and access and explore association with their educational and personal background. METHODS: We developed a web-based survey exploring knowledge on national health care funding, access and costs through 19 items and measured success score as the number of correct answers. We also collected students' characteristics and public health training. The survey was sent to undergraduate medical students and residents from five medical universities between July and November 2015. RESULTS: A total of 1195 students from 5 medical universities responded to the survey. Most students underestimated the total amount of annual medical expenses, hospitalization costs and the proportion of the general population not benefiting from a complementary insurance. The knowledge score was not associated with medical education level. Three students' characteristics were significantly associated with a better knowledge score: male gender, older age, and underprivileged status. CONCLUSION: Medical students have important gaps in knowledge regarding national health care funding, coverage and costs. This knowledge was not associated with medical education level but with some of the students' personal characteristics. All these results are of great concern and should lead us to discussion and reflection about medical and public health training.

Evaluation of the peritoneal carcinomatosis index with CT and MRI.

BACKGROUND: The aim was to determine the incremental value of MRI compared with CT in the preoperative estimation of the peritoneal carcinomatosis index (PCI). METHODS: CT and MRI examinations of patients with peritoneal carcinomatosis were evaluated. CT images were first analysed by two observers who determined a first PCI (PCICT ). Then, the two observers reviewed MRI examinations in combination with CT and determined a second PCI (PCICT+MRI ). The sensitivity and negative predictive value of the two imaging sets were determined using surgery as a reference standard (PCIRef ). RESULTS: CT plus MRI was more accurate in predicting the surgical PCI than CT alone. The absolute difference between PCICT+MRI and PCIRef was lower than that between PCICT and PCIRef (mean(s.d.) 3·96(4·10) versus 4·89(4·73); P = 0·010). The number of true-positive findings increased from 106 to 125 for reader 1 and from 117 to 132 for reader 2 with the adjunct of MRI. For both readers, an increased sensitivity was obtained when both MRI and CT were used (from 63 to 81 per cent for reader 1; from 44 to 81 per cent for reader 2). The increase in sensitivity was greater for patients with a moderate volume of disease. CONCLUSION: The combination of CT and MRI improved the preoperative estimation of PCI compared with CT alone.

Kidney transplant recipients carrying the CYP3A4*22 allelic variant have reduced tacrolimus clearance and often reach supratherapeutic tacrolimus concentrations.

CYP3A4*22 is an allelic variant of the cytochrome P450 3A4 associated with a decreased activity. Carriers of this polymorphism may require reduced tacrolimus (Tac) doses to reach the target residual concentrations (Co). We tested this hypothesis in a population of kidney transplant recipients extracted from a multicenter, prospective and randomized study. Among the 186 kidney transplant recipients included, 9.3% (18 patients) were heterozygous for the CYP3A4*22 genotype and none were homozygous (allele frequency of 4.8%). Ten days after transplantation (3 days after starting treatment with Tac), 11% of the CYP3A4*22 carriers were within the target range of Tac Co (10-15 ng/mL), whereas among the CYP3A4*1/*1 carriers, 40% were within the target range (p = 0.02, OR = 0.19 [0.03; 0.69]). The mean Tac Co at day 10 in the CYP3A4*1/*22 group was 23.5 ng/mL (16.6-30.9) compared with 15.1 ng/mL (14-16.3) in the CYP3A4*1/*1 group, p < 0.001. The Tac Co/dose significantly depended on the CYP3A4 genotype during the follow-up (random effects model, p < 0.001) with the corresponding equivalent dose for patients heterozygous for CYP3A4*22 being 0.67 [0.54; 0.84] times the dose for CYP3A4*1/*1 carriers. In conclusion, the CYP3A4*22 allelic variant is associated with a significantly altered Tac metabolism and carriers of this polymorphism often reach supratherapeutic concentrations.

Perceived usefulness of nine quality improvement tools among Swiss physicians.

BACKGROUND: Doctors' opinions about quality improvement tools likely influence their uptake and eventual impact on patient care. Little is known about physicians' perception of the comparative utility of various quality improvement tools. METHODS: We conducted a mail survey of doctors in Geneva, Switzerland (2745 physicians, of whom 56% participated), to measure the perceived usefulness of 9 quality improvement tools. RESULTS: In decreasing order of perceived utility these tools were regular continuous education (rated as very or extremely useful by 75% of respondents), mortality and morbidity conferences (65%), quality circles (60%), patient satisfaction measurement (42%), assessment of the fulfillment of therapeutic objectives (41%), assessment of compliance with guidelines (36%), periodic evaluation of doctors' skills (14%), onsite visits with peer-review of medical records (11%), and certification of office practices (8%). CONCLUSION: Quality improvement tools seen as most useful by physicians are traditional methods such as continuous education and mortality and morbidity conferences. Methods that rely on the measurement of indicators or that have a judgmental component received less support.

Combined serum creatinine and cystatin C Schwartz formula predicts kidney function better than the combined CKD-EPI formula in children.

BACKGROUND: The combined serum creatinine (SCreat) and cystatin C (CysC) CKD-EPI formula constitutes a new advance for glomerular filtration rate (GFR) estimation in adults. Using inulin clearances (iGFRs), the revised SCreat and the combined Schwartz formulas, this study aims to evaluate the applicability of the combined CKD-EPI formula in children. METHOD: 201 iGFRs for 201 children were analyzed and divided by chronic kidney disease (CKD) stages (iGFRs ≥90 ml/min/1.73 m(2), 90 > iGFRs > 60, and iGFRs ≤59), and by age groups (<10, 10-15, and >15 years). Medians with 95% confidence intervals of bias, precision, and accuracies within 30% of the iGFRs, for all three formulas, were compared using the Wilcoxon signed-rank test. RESULTS: For the entire cohort and for all CKD and age groups, medians of bias for the CKD-EPI formula were significantly higher (p < 0.001) and precision was significantly lower than the solely SCreat and the combined SCreat and CysC Schwartz formulas. We also found that using the CKD-EPI formula, bias decreased and accuracy increased while the child age group increased, with a better formula performance above 15 years of age. However, the CKD-EPI formula accuracy is 58% compared to 93 and 92% for the SCreat and combined Schwartz formulas in this adolescent group. CONCLUSIONS: The performance of the combined CKD-EPI formula improves in adolescence compared with younger ages. Nevertheless, the CKD-EPI formula performs more poorly than the SCreat and the combined Schwartz formula in pediatric population.

[Hospital information system performance for road traffic accidents analysis in a hospital recruitment based area]. / Performance d'un système d'information hospitalier pour étudier l'accidentologie routière dans le bassin de recrutement d'un hôpital.

BACKGROUND: Road traffic accidents in France are mainly analyzed through reports completed by the security forces (police and gendarmerie). But the hospital information systems can also identify road traffic accidents via specific documentary codes of the International Classification of Diseases (ICD-10). The aim of this study was therefore to determine whether hospital stays consecutive to road traffic accident were truly identified by these documentary codes in a facility that collects data routinely and to study the consistency of results from hospital information systems and from security forces during the 2002-2008 period. METHODS: We retrieved all patients for whom a documentary code for road traffic accident was entered in 2002-2008. We manually checked the concordance of documentary code for road traffic accident and trauma origin in 350 patient files. The number of accidents in the Grenoble area was then inferred by combining with hospitalization regional data and compared to the number of persons injured by traffic accidents declared by the security force. RESULTS: These hospital information systems successfully report road traffic accidents with 96% sensitivity (95%CI: [92%, 100%]) and 97% specificity (95%CI: [95%, 99%]). The decrease in road traffic accidents observed was significantly less than that observed was significantly lower than that observed in the data from the security force (45% for security force data against 27% for hospital data). CONCLUSION: Overall, this study shows that hospital information systems are a powerful tool for studying road traffic accidents morbidity in hospital and are complementary to security force data.

Assessment of recurrence and complications following uncomplicated diverticulitis.

BACKGROUND: The natural history of sigmoid diverticulitis has been inferred from population-based or retrospective studies. This study assessed the risk of a recurrent attack following the first episode of uncomplicated diverticulitis. METHODS: Patients admitted between January 2007 and December 2011 with a first episode of uncomplicated sigmoid diverticulitis confirmed on computed tomography were enrolled in this prospective study. After successful medical management of the first episode, follow-up was conducted through yearly telephone interviews. Cox proportional hazards regression was performed to model the impact of various parameters on eventual recurrences and complications. RESULTS: During a median follow-up of 24 (range 3-63) months, 46 (16·4 per cent) of 280 patients experienced a second episode of diverticulitis. Six patients (2·1 per cent) subsequently developed complicated diverticulitis and four (1·4 per cent) underwent emergency surgery for peritonitis. In multivariable analysis, a raised serum level of C-reactive protein (over 240 mg/l) during the first attack was associated with early recurrence (hazard ratio 1·75, 95 per cent confidence interval 1·04 to 2·94; P = 0·035). CONCLUSION: Uncomplicated sigmoid diverticulitis follows a benign course with few recurrences and little need for emergency surgery. REGISTRATION NUMBER: NCT01015378 (http://www.clinicaltrials.gov).

Random modelling of contagious diseases.

Modelling contagious diseases needs to include a mechanistic knowledge about contacts between hosts and pathogens as specific as possible, e.g., by incorporating in the model information about social networks through which the disease spreads. The unknown part concerning the contact mechanism can be modelled using a stochastic approach. For that purpose, we revisit SIR models by introducing first a microscopic stochastic version of the contacts between individuals of different populations (namely Susceptible, Infective and Recovering), then by adding a random perturbation in the vicinity of the endemic fixed point of the SIR model and eventually by introducing the definition of various types of random social networks. We propose as example of application to contagious diseases the HIV, and we show that a micro-simulation of individual based modelling (IBM) type can reproduce the current stable incidence of the HIV epidemic in a population of HIV-positive men having sex with men (MSM).

Association in multifactorial traits: how to deal with rare observations?

To detect the role of a candidate gene for a trait in a sample of individuals, we may test SNP haplotype or diplotype effects. For a limited sample size, many haplotype or diplotype categories may contain few individuals. This involves a power decrease when testing the association between the trait and the haplotypes or diplotypes as these categories provide little additional information while increasing the degrees of freedom. The present paper proposes a new strategy to group rare categories based on a measure of similarity between haplotypes or diplotypes and compares it to two other possible strategies to deal with rare categories: a SNP selection strategy based on haplotype diversity, and a grouping strategy that pools all rare categories into a single baseline group. This comparison is performed by means of simulation under four scenarios. We show that this new strategy shows the largest increase in power irrespective of the model underlying the candidate gene in the studied trait. This strategy therefore provides a powerful alternative to currently used methods to reduce the number of rare categories.

Improved use of SNP information to detect the role of genes.

A topical question in genetic association studies is the optimal use of the information provided by genotyped single-nucleotide polymorphisms (SNPs) in order to detect the role of a candidate gene in a multifactorial disease. We propose a strategy called "combination test" that tests the association between a quantitative trait and all possible phased combinations of various numbers of SNPs. We compare this strategy to two alternative strategies: the association test that considers each SNP separately, and a multilocus genotype-based test that considers the phased combination of all SNPs together. To compare these three tests, a quantitative trait was simulated under different models of correspondence between phenotype and genotype, including the extreme case when two SNPs interact with no marginal effects of each SNP. The genotypes were taken from a sample of 290 independent individuals genotyped for three genes with various number of SNPs (from 5-8 SNPs). The results show that the "combination test" is the only one able to detect the association when the two SNPs involved in disease susceptibility interact with no marginal effects. Interestingly, even in the case of a single etiological SNP, the "combination test" performed well. We apply the three tests to Genetic Analysis Workshop 12 (Almasy et al. [2001] Genet. Epidemiol. 21:332-338) simulated data, and show that although there was no interactions between the etiological SNPs, the "combination test" was preferable to the two other compared methods to detect the role of the candidate gene.