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.

Hemostats in Spine Surgery: Literature Review and Expert Panel Recommendations.

Bleeding in spine surgery is a common occurrence but when bleeding is uncontrolled the consequences can be severe due to the potential for spinal cord compression and damage to the central nervous system. There are many factors that influence bleeding during spine surgery including patient factors and those related to the type of surgery and the surgical approach to bleeding. There are a range of methods that can be employed to both reduce the risk of bleeding and achieve hemostasis, one of which is the adjunct use of hemostatic agents. Hemostatic agents are available in a variety of forms and materials and with considerable variation in cost, but specific evidence to support their use in spine surgery is sparse. A literature review was conducted to identify the pre-, peri-, and postsurgical considerations around bleeding in spine surgery. The review generated a set of recommendations that were discussed and ratified by a wider expert group of spine surgeons. The results are intended to provide a practical guide to the selection of hemostats for specific bleeding situations that may be encountered in spine surgery.

Security and reliability of CUSTOMBONE cranioplasties: A prospective multicentric study.

BACKGROUND: Repairing bone defects generated by craniectomy is a major therapeutic challenge in terms of bone consolidation as well as functional and cognitive recovery. Furthermore, these surgical procedures are often grafted with complications such as infections, breaches, displacements and rejections leading to failure and thus explantation of the prosthesis. OBJECTIVE: To evaluate cumulative explantation and infection rates following the implantation of a tailored cranioplasty CUSTOMBONE prosthesis made of porous hydroxyapatite. One hundred and ten consecutive patients requiring cranial reconstruction for a bone defect were prospectively included in a multicenter study constituted of 21 centres between December 2012 and July 2014. Follow-up lasted 2 years. RESULTS: Mean age of patients included in the study was 42±15 years old (y.o), composed mainly by men (57.27%). Explantations of the CUSTOMBONE prosthesis were performed in 13/110 (11.8%) patients, significantly due to infections: 9/13 (69.2%) (p<0.0001), with 2 (15.4%) implant fracture, 1 (7.7%) skin defect and 1 (7.7%) following the mobilization of the implant. Cumulative explantation rates were successively 4.6% (SD 2.0), 7.4% (SD 2.5), 9.4% (SD 2.8) and 11.8% (SD 2.9%) at 2, 6, 12 and 24 months. Infections were identified in 16/110 (14.5%): 8/16 (50%) superficial and 8/16 (50%) deep. None of the following elements, whether demographic characteristics, indications, size, location of the implant, redo surgery, co-morbidities or medical history, were statistically identified as risk factors for prosthesis explantation or infection. CONCLUSION: Our study provides relevant clinical evidence on the performance and safety of CUSTOMBONE prosthesis in cranial procedures. Complications that are difficulty incompressible mainly occur during the first 6 months, but can appear at a later stage (>1 year). Thus assiduous, regular and long-term surveillances are necessary.

Impact of malpractice liability among spine surgeons: A national survey of French private neurosurgeons.

PURPOSE: In the general context of medical judicialization, spine surgeons are impacted by the part that medical responsibility and the risk of malpractice play in their actions and decisions. Our aim was to evaluate possible shifts in practices among private neurosurgeons who are highly exposed to this judicial risk and detect alterations in their pleasure in exercising their profession. We present the first national survey on French physicians' perception of surgical judicialization and consequences on their practice. METHODS: An online survey was submitted to the 121 members of the French Society of Private Neurosurgery, who represent 29.1% of the total number of spine surgeons and perform 36.0% of the national total spine surgery activity. The French law (no-fault out-of-court scheme) significantly impacts these surgeons in the event of litigation. RESULTS: A total of 78 surveys were completed (64.5% response rate): 89.7% of respondents experienced alteration of doctor-patient relationship related to judicialization and 60.2% had already refused to perform risky surgeries. Fear of being sued added negative pressure during surgery for 55.1% of respondents and 37.2% of them had already considered stopping their practice because of this litigation context. CONCLUSION: The increasing impact of medical liability is prompting practitioners to change their practice and perceptions. The doctor-patient relationship appears to be altered, negative pressure is placed on physicians and defensively, some neurosurgeons may refuse high-risk patients and procedures. This situation causes professional disenchantment and can ultimately prove disadvantageous for both doctors and patients.

Towards a European health research and innovation cloud (HRIC).

The European Union (EU) initiative on the Digital Transformation of Health and Care (Digicare) aims to provide the conditions necessary for building a secure, flexible, and decentralized digital health infrastructure. Creating a European Health Research and Innovation Cloud (HRIC) within this environment should enable data sharing and analysis for health research across the EU, in compliance with data protection legislation while preserving the full trust of the participants. Such a HRIC should learn from and build on existing data infrastructures, integrate best practices, and focus on the concrete needs of the community in terms of technologies, governance, management, regulation, and ethics requirements. Here, we describe the vision and expected benefits of digital data sharing in health research activities and present a roadmap that fosters the opportunities while answering the challenges of implementing a HRIC. For this, we put forward five specific recommendations and action points to ensure that a European HRIC: i) is built on established standards and guidelines, providing cloud technologies through an open and decentralized infrastructure; ii) is developed and certified to the highest standards of interoperability and data security that can be trusted by all stakeholders; iii) is supported by a robust ethical and legal framework that is compliant with the EU General Data Protection Regulation (GDPR); iv) establishes a proper environment for the training of new generations of data and medical scientists; and v) stimulates research and innovation in transnational collaborations through public and private initiatives and partnerships funded by the EU through Horizon 2020 and Horizon Europe.

Consequences of the new zolpidem prescription regulations: a cohort study from the French national healthcare database.

PURPOSE: To determine changes in the prevalence of zolpidem consumption since the change in the regulations of prescription. Formulations containing zolpidem were subject to the regulations of narcotics by the French decree of April 7, 2017. METHODS: Longitudinal cohort study using data from the representative French healthcare database. The main outcome was the prevalence of oral hypnotic drug reimbursement before and after April 2017. The secondary outcome was the change in prescription habits for zolpidem since the decree in long-term users and excessive users. RESULTS: A total of 81,174 individuals had at least one hypnotic drug reimbursement; among, whom 2143 had at least one reimbursement of zolpidem. Before the decree, 26% had at least one reimbursement of zolpidem, whereas it dropped to 18.4% after the decree. Among the 545 long-term users, the reimbursement of zolpidem was discontinued after the decree for 60.4% and 24.2% retained zolpidem as a treatment. The main replacement drug was zopiclone for 6.4% of them. Among the 1598 excessive users, the reimbursement of zolpidem was stopped after the decree for 16.5% and 56.3% retained zolpidem as a treatment. The main replacement drug was zopiclone for 12.1% of them. CONCLUSIONS: The French decree had a major impact on the reimbursement of oral zolpidem. Indeed, prescription of the hypnotic was discontinued for half of the long-term users of zolpidem, and just over one-sixth of the excessive users discontinued the prescription of zolpidem after the decree.

New insights on lake sediment DNA from the catchment: importance of taphonomic and analytical issues on the record quality.

Over the last decade, an increasing number of studies have used lake sediment DNA to trace past landscape changes, agricultural activities or human presence. However, the processes responsible for lake sediment formation and sediment properties might affect DNA records via taphonomic and analytical processes. It is crucial to understand these processes to ensure reliable interpretations for "palaeo" studies. Here, we combined plant and mammal DNA metabarcoding analyses with sedimentological and geochemical analyses from three lake-catchment systems that are characterised by different erosion dynamics. The new insights derived from this approach elucidate and assess issues relating to DNA sources and transfer processes. The sources of eroded materials strongly affect the "catchment-DNA" concentration in the sediments. For instance, erosion of upper organic and organo-mineral soil horizons provides a higher amount of plant DNA in lake sediments than deep horizons, bare soils or glacial flours. Moreover, high erosion rates, along with a well-developed hydrographic network, are proposed as factors positively affecting the representation of the catchment flora. The development of open and agricultural landscapes, which favour the erosion, could thus bias the reconstructed landscape trajectory but help the record of these human activities. Regarding domestic animals, pastoral practices and animal behaviour might affect their DNA record because they control the type of source of DNA ("point" vs. "diffuse").

Late Holocene volcanic and anthropogenic mercury deposition in the western Central Andes (Lake Chungará, Chile).

Volcanism is one of the major natural processes emitting mercury (Hg) to the atmosphere, representing a significant component of the global Hg budget. The importance of volcanic eruptions for local-scale Hg deposition was investigated using analyses of Hg, inorganic elemental tracers, and organic biomarkers in a sediment sequence from Lake Chungará (4520 m a.s.l.). Environmental change and Hg deposition in the immediate vicinity of the Parinacota volcano were reconstructed over the last 2700 years, encompassing the pre-anthropogenic and anthropogenic periods. Twenty eruptions delivering large amounts of Hg (1 to 457 µg Hg m-2 yr-1 deposited at the timescale of the event) were locally recorded. Peaks of Hg concentration recorded after most of the eruptions were attributed to a decrease in sedimentation rate together with the rapid re-oxidation of gaseous elemental Hg and deposition with fine particles and incorporation into lake primary producers. Over the study period, the contribution of volcanic emissions has been estimated as 32% of the total Hg input to the lake. Sharp depletions in primary production occurred at each eruption, likely resulting from massive volcaniclastic inputs and changes in the lake-water physico-chemistry. Excluding the volcanic deposition periods, Hg accumulation rates rose from natural background values (1.9 ±â€¯0.5 µg m-2 yr-1) by a factor of 2.3 during the pre-colonial mining period (1400-900 yr cal. BP), and by a factor of 6 and 7.6, respectively, during the Hispanic colonial epoch (400-150 yr cal. BP) and the industrial era (~140 yr cal. BP to present). Altogether, the dataset indicates that lake primary production has been the main, but not limiting, carrier for Hg to the sediment. Volcanic activity and climate change are only secondary drivers of local Hg deposition relative to the magnitude of regional and global anthropogenic emissions.

Coupling indicators and lumped-parameter modeling to assess suspended matter and soluble phosphorus losses.

For ecological and economic issues, evaluating the environmental fate of dissolved and suspended matter in catchments and river ecosystems still remains a challenge for the preservation and management of natural resources. Models are useful tools and may help to cope with this challenge, and especially to define the relationships between the state of natural systems and land and river management/uses. As it is difficult - even impossible - to carry out experiments on natural systems such as catchments, models are also useful to test hypotheses about the underlying processes acting on dissolved and suspended losses. We propose an innovative approach to achieve these objectives. By coupling environmental indicators and lumped modeling, this study aims to develop a conceptual and general framework to evaluate and test the functions that drive particulate and dissolved matter flows at the catchment and landscape scales, while respecting the constraint of parsimony for the number of model parameters. Calculated suspended matter (SM) and soluble reactive phosphorus (SRP) losses agreed well with field data. 210Pbex (excess Pb) activities in core sediments were also compared to those of 210Pbex calculated from the filling of the reservoir. Our models are parsimonious and this does not impair their accuracy in reproducing recorded outflows or evaluating the sedimentation processes associated to particulate outflows. Considering the adequacy of our models, we validate the hypothesis that river bank erosion and water table behavior are the driving processes that govern losses of particulate and solute forms of P, in the studied extensive agriculture conditions.

[Evaluation of the nurse triage at the ophtalmology emergency department of Pierre-Paul-Riquet Hospital]. / Évaluation du questionnaire de tri infirmier aux urgences ophtalmologiques de l'hôpital Pierre-Paul-Riquet au CHU de Toulouse.

INTRODUCTION: The steady increase in the number of visits to the various emergency services combined with the decrease in medical demographics, make it necessary to optimize triage of patients to improve their care. The purpose of this study was to evaluate the pertinence of our triage questionnaire in the classification of ophthalmologic emergencies by severity. METHODS: We used a monocentric cross-sectional study. From September 5 through September 25 2017, 858 patients who had all been seen in the ophthalmology emergency department of Pierre Paul Riquet Hospital of Toulouse university medical center and had responded to the triage nurse questionnaire were included. According to the symptoms presented or not by the patient, a color code was attributed (GREEN, ORANGE or RED) in order of increasing level of emergency. For each patient, we compared the severity of the final diagnosis by Base Score with the level of emergency established by our questionnaire. RESULTS: There were 118 "GREEN" patients, 606 "ORANGE" patients and 134 "RED." We were able to analyze 822 patients. 21.65% of patients were correctly classified, 73.36% were overestimated (of which 87.06% by one level and 12.94% by two levels of severity), and 4.99% were underestimated (of which 90.24% by one level and 9.76% by two levels). CONCLUSION: Our current triage questionnaire is not sufficiently discriminating for effective triage of ophthalmologic emergencies. It often overestimates minor emergencies, causing a delay in treating other emergencies. We propose a new questionnaire modified according to the results obtained during our study.

Managing spine surgery referrals: The consultation of neurosurgery and its nuances.

INTRODUCTION: Spinal disorders, particularly low back pain, are among the most common reasons for general practitioner (GP) consultation and can sometimes be a source of professional friction. Despite their frequency and published guidelines, many patients are still mistakenly referred by their GP to specialists for spinal surgery consultation which can create colleague relationship problems, suboptimal or unnessary delayed care, as well as the financial implications for patients. PURPOSE: To assess the management of GP lumbar spine referrals made to 4 neurosurgeons from 3 neurosurgical teams specialized in spinal surgery. METHODS: All patient's medical records relating to 672 primary consultants over a period of two months (January and February 2015) at three institutions were retrospectively reviewed. Medical referral letters, clinical evidence and imaging data were analyzed and the patients were classified according the accuracy of surgical assessment. The final decisions of the surgeons were also considered. RESULTS: Of the 672 patients analyzed, 198 (29.5%) were considered unsuitable for surgical assessment: no spinal pathology=10.6%, no surgical conditions=35.4%, suboptimal medical treatment=31.3%, suboptimal radiology=18.2% and asymptomatic patients=4.5%. CONCLUSION: Unnecessary referrals to our consultation centers highlight the gap between the reason for the consultation and the indications for spinal surgery. Compliance with the guidelines, the creation of effective multidisciplinary teams, as well as the "hands on" involvement of surgeons in primary and continuing education of physicians are the best basis for a reduction in inappropriate referrals and effective patient care management.

A 3500-year record of Hg and Pb contamination in a mediterranean sedimentary archive (the Pierre Blanche Lagoon, France).

A sediment core encompassing 3500 years of continuous sedimentation has been collected from a coastal lagoon located on the southwestern French Mediterranean coast. Lead concentrations and stable isotopes show that the sediments have recorded the three major periods of Pb pollution: the Etruscan-Greek-Roman period (650 BC to AD 50), the medieval period (AD 650 to AD 1450), and the modern period (from around AD 1850 to the present). These periods were separated by low pollution periods during the Dark Ages (between AD 50 and 650) and during the 16th century. From the end of the 19th century to the 1960s, Pb pollution increased exponentially. Coal combustion was the major source of Pb in the lagoon in the second half of the 20th century. Both the decrease in coal consumption and the ban on leaded gasoline resulted in a decrease in Pb pollution by a factor of 1.5 between 1973 and 1995. From 1991, sewage treatment plants and incinerators could be the major source of Pb. The average baseline Hg concentration from 1525 BC to AD 900 was 0.017 ± 0.003 µg g⁻¹ (n = 54). The Hg concentrations profile shows three major peaks: in AD 1150, AD 1660, and AD 1969, with the concentrations being respectively 8, 5, and 34 times higher than the baseline levels. The medieval peak (AD 1150) is attributed the medical use of Hg in the town of Montpellier and/or the burning of soil and vegetation. Noticeable Hg pollution was also detected during the 17th century in relation to gold and silver amalgamation in Europe. From the end of the 19th century, Hg concentrations increased exponentially until 1969. This modern pollution is attributed to the burning of coal.

Spread of West Nile virus in Iran: a cross-sectional serosurvey in equines, 2008-2009.

We report the first large-scale serosurvey for West Nile virus (WNV) conducted in the equine population in Iran. Blood samples were obtained in 2008-2009 from 1054 equines collected from 260 districts located in 27 provinces. The overall seroprevalence rate for WNV neutralizing antibodies was 23·7%. Marked geographical variations were observed as province-specific seroprevalence rates ranged from 1% to 88%, the highest values being observed in the southern and western parts of the country. The presence of IgM-positive animals (n=9) indicated a recent circulation of WNV in several provinces. Logistic modelling confirmed this result with a significant effect of age on seropositivity. This study revealed extensive circulation of WNV in Iran particularly in southwestern provinces where the virus probably circulates every year.

Risk factors for West Nile virus seropositivity of equids in Guadeloupe.

In Guadeloupe, West Nile virus (WNV) activity was first observed in equids in 2002, and a high seroprevalence was found in 2003. The objective of our study was to determine individual and environmental factors associated with the risk of WNV seropositivity during 2002-2003. Fieldwork was conducted to retrospectively determine the location of equids at the time of virus circulation and to collect information regarding environmental and individual variables. Sera were collected from 369 equids out of an estimated total population of less than 500. Thirty-four environmental and individual variables were investigated. Equids had a higher risk (p<0.001) for WNV seropositivity if they lived within the proximity "distance less than 1.5km" of marshes or swamp forests "a large freshwater formation behind mangroves" or if they remained outside after dusk. Equids living within the proximity of ouassous shrimp (Macrobrachium rosenbergii) basins or sugar cane fields had a lower risk (p<0.001) for WNV seropositivity. These results confirm that WNV circulation is more likely in the humid coastal areas of Guadeloupe. The identification of risk factors is useful for predicting future emergence sites of WNV in the archipelago and other Neotropical islands, and to better target sentinel surveillance in the region.

Adult human spinal cord harbors neural precursor cells that generate neurons and glial cells in vitro.

Adult human and rodent brains contain neural stem and progenitor cells, and the presence of neural stem cells in the adult rodent spinal cord has also been described. Here, using electron microscopy, expression of neural precursor cell markers, and cell culture, we investigated whether neural precursor cells are also present in adult human spinal cord. In well-preserved nonpathological post-mortem human adult spinal cord, nestin, Sox2, GFAP, CD15, Nkx6.1, and PSA-NCAM were found to be expressed heterogeneously by cells located around the central canal. Ultrastructural analysis revealed the existence of immature cells close to the ependymal cells, which display characteristics of type B and C cells found in the adult rodent brain subventricular region, which are considered to be stem and progenitor cells, respectively. Completely dissociated spinal cord cells reproducibly formed Sox2(+) nestin(+) neurospheres containing proliferative precursor cells. On differentiation, these generate glial cells and gamma-aminobutyric acid (GABA)-ergic neurons. These results provide the first evidence for the existence in the adult human spinal cord of neural precursors with the potential to differentiate into neurons and glia. They represent a major interest for endogenous regeneration of spinal cord after trauma and in degenerative diseases.

West Nile virus in wild resident birds, Southern France, 2004.

An equine West Nile virus (WNV) outbreak occurred in 2004 in the Camargue, a wetland area in the south of France where the virus was first reported in 1962 and re-emerged in 2000. WNV neutralizing antibodies were detected in resident birds and two isolates from a House Sparrow (Passer domesticus) and a Common Magpie (Pica pica) were completely sequenced. Phylogenetic analyses revealed that these isolates are closely related to strains previously found in horses in southern Europe and North Africa. More extensive investigation is required to determine whether WNV has been re-introduced or has become endemic in the Camargue.

West Nile virus outbreak detection using syndromic monitoring in horses.

Recent outbreaks of West Nile virus-associated (WNV) diseases, both in the old World and Americas, underline the importance for early warning systems that rapidly identify emerging and re-emerging diseases and thus help in their control. Traditional approaches of disease monitoring become less reliable and increasingly costly when used for rare health-related events, such as WNV outbreaks in southern France. The objective of this work was to discuss methodological issues related to syndromic monitoring of WNV-associated disease in Camargue horses by veterinary practitioners. Tracking cases of equine encephalitis by veterinarians is an example of such syndromic monitoring of an emerging disease. Signs of illness, observed prior diagnostic confirmation, can be of interest because they may provide an early warning for WNV circulation in a given area and allow authorities to take appropriate preventive measures for public health.

Bird species potentially involved in introduction, amplification, and spread of West Nile virus in a Mediterranean wetland, the Camargue (Southern France).

West Nile virus (WNV) is a mosquito-transmitted Flavivirus with a transmission cycle involving birds as amplifying hosts. Wild birds are also believed to carry WNV over large distances and are able to introduce it into new areas during migration and dispersal. In this paper, our objective is to provide lists of birds potentially involved in the introduction, the amplification and the spread of WNV in the Camargue, a Mediterranean wetland in the south of France where several WNV outbreaks have occurred since the 1960s. Bird species were classified according to the following ecological factors: migratory status and provenance area, used biotopes, abundance and period of presence in the Camargue. The obtained lists of bird species potentially involved in the introduction, amplification and spread of WNV should prove useful to determine target species on which further studies on WNV ecology in birds could be focused.