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Background: In 2020, people living with HIV (PLHIV) in France were worried that the COVID-19 health crisis would lead to long-term changes in their HIV care. Using data from the anonymous, online, cross-sectional survey ACOVIH, which was completed by PLHIV between July and September 2020, this study explored factors associated with worry about long-term changes to HIV care after the end of the first lockdown (17 March-11 May 2020). Methods: Using multivariate logistic regression, we compared participants who declared they were worried about long-term changes with those who did not, in terms of their demographic, behavioral, and socioeconomic characteristics, as well as their experience of the COVID-19 crisis and access to care. Results: Among the 249 respondents, 61.5% (n = 153) declared having worries about long-term changes to HIV care. Specifically, after adjustment for gender and age, PLHIV born outside of France (adjusted odds ratios (aOR) [95%CI] = 2.57[1.44;6.76]), those whose financial situation deteriorated since the beginning of the pandemic (4.87[1.97;13.20]), those with a history of HIV opportunistic infections (3.27[1.53;7.32]), and respondents who took psychotropic drugs (3.21[1.50;7.22]) were all more likely to declare having worries. In terms of related determinants, a deterioration in communication with their HIV medical team (3.47[1.61;7.94]), having worries about COVID-19 (1.36[1.14;1.62]), and believing that HIV treatment increased the risk of COVID-19 infection (1.52[1.15;2.03]), were all significantly associated with having worries about long-term changes to HIV care. Conclusion: In the context of future disease epidemics, taking into account the profiles of individual PLHIV, and providing clearer, targeted information on HIV care, could help reduce worry in this population about the continuity of HIV care and could foster efficient communication with care providers. Plain Language Summary: People living with HIV's worry that the COVID-19 health crisis could impact long-term HIV care: lessons from the French context for future disease epidemics During the first COVID-19 lockdown in France, people living with HIV were worried about the potential long-term changes to their HIV care. This study, based on data from the ACOVIH survey, found that experiencing financial difficulties since the beginning of the pandemic, a history of HIV opportunistic infections, and taking psychotropic drugs, were all associated with increased worry. Factors like a deterioration in communication with their HIV medical team and the belief that HIV treatment increased the risk of COVID-19 infection, also contributed to having worries. Addressing these factors and providing clear, targeted information could reduce worry about HIV care continuity in future epidemics. [ABSTRACT FROM AUTHOR]

In this article, we present a novel and sustainable approach for recycling printed circuit boards (PCBs), potentially enabling the complete transformation of collected waste into reusable raw materials. Our methodology starts with the disassembly of PCBs for the extraction of all electronic components (ECs). These ECs are then subjected to a classification process using advanced sorting techniques, including machine vision and multi-energy X-ray transmission spectroscopy powered by artificial intelligence, which allows ECs with similar elemental composition to be accurately sorted together. This sorting approach can effectively enrich the target elements up to 10,000 times their original content, enabling their subsequent recovery through dedicated physico-hydrometallurgical processes. These tailored methods offer enhanced efficiency and improved environmental sustainability for recycling valuable and critical elements such as rare earth elements, tantalum, and platinum group metals. Notably, our approach not only demonstrates superior sustainability but also offers increased economic viability, making it a more financially profitable solution.

Recent evidence has demonstrated that disability from musculoskeletal disorders is a multifactorial problem that is not only due to workers' characteristics but also closely related to environmental factors, such as the workplace, the health care system, the compensation system, and the interactions among all stakeholders regarding the disability problem. The Work Disability Diagnosis Interview (WoDDI) was developed following a systematic method in order to help clinicians detect possible disability prognostic factors in subacute or chronic musculoskeletal pain patients. A structured literature review, followed by expert input and a second round of revisions after 4-year's usage led to the current version. The WoDDI is composed of open-ended questions on physical, psychosocial, occupational, and administrative factors, collated into an interview form used at the first encounter with the disabled worker. It enables clinicians to develop a rehabilitation plan and focus on disability resolution in patients absent from work due to a musculoskeletal disorder. Initial application demonstrated a high prevalence of sociodemographic, work-related, and psychosocial factors that may contribute to prolonged work absence. [ABSTRACT FROM AUTHOR]

Background: Limited data exists regarding the safety of the COVID-19 2023-2024 vaccine formulations and whether the safety profiles differ from the original formulations. We evaluated the association between the BNT162b2 XBB COVID-19 vaccine and the risk of 20 pre-specified adverse events of special interest (AESIs)., Methods: We identified commercially-insured individuals in the US age ≥ 6 months who received the BNT162b2 XBB COVID-19 vaccine between September 11, 2023 and January 15, 2024 within the Optum pre-adjudicated database. The self-controlled risk interval design was used to compare the incidence of 20 pre-specified AESIs during a risk period following vaccination to a control period. Relative incidence and 95 % confidence intervals (CI) were estimated using exact conditional Poisson regression., Results: The analysis included 113,459 individuals who received the BNT162b2 XBB COVID-19 vaccine (median [interquartile range] age: 47.1 [33.0-59.1] years). Relative incidence was calculated when ≥1 event occurred in either the risk or control period. For these 10 AESIs, there was no significant association between receipt of the BNT162b2 XBB COVID-19 vaccine and the incidence of any of these AESIs. Point estimates were higher in the risk period compared to the control period for ischemic stroke (relative incidence: 1.52; 95 % CI: 0.44-5.94), myocarditis/pericarditis (relative incidence: 1.50; 95 % CI: 0.22-12.61), immune-mediated myositis (relative incidence: 1.44; 95 % CI: 0.83-2.52), herpes zoster (relative incidence: 1.24; 95 % CI: 0.69-2.28), and non-febrile convulsions/seizures (relative incidence: 1.22; 95 % CI: 0.86-1.73). These estimates were not statistically significant, though most were based on few events. Results were generally similar in subgroup analyses of individuals administered a concomitant seasonal influenza vaccine., Conclusions: There was no increased risk of 20 pre-specified AESIs following receipt of the BNT162b2 XBB COVID-19 vaccine among US commercially insured individuals aged ≥6 months. Findings are consistent with the current evidence on the safety of BNT162b2 COVID-19 vaccines. Public registration: EUPAS108135., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jenny W Sun reports a relationship with Pfizer that includes: employment and equity or stocks. Laura E Dodge reports a relationship with Optum that includes: employment and equity or stocks. Eric J Kim reports a relationship with Optum that includes: employment and equity or stocks. Li Zhou reports a relationship with Optum that includes: employment and equity or stocks. Susan Mather reports a relationship with Pfizer that includes: employment and equity or stocks. Henry Goebe reports a relationship with Pfizer that includes: employment and equity or stocks. Nicola Charpentier reports a relationship with BioNTech SE that includes: employment and equity or stocks. Kirsten Nespithal reports a relationship with BioNTech SE that includes: employment and equity or stocks. Kofi Asomaning reports a relationship with Pfizer Inc that includes: employment and equity or stocks. Florence T Wang reports a relationship with Optum that includes: employment and equity or stocks. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) led to urgent actions by innovators, vaccine developers, regulators, and other stakeholders to ensure public access to protective vaccines while maintaining regulatory agency standards. Although development timelines for vaccines against SARS-CoV-2 were much quicker than standard vaccine development timelines, regulatory requirements for efficacy and safety evaluations, including the volume and quality of data collected, were upheld. Rolling review processes supported by sponsors and regulatory authorities enabled rapid assessment of clinical data as well as emergency use authorization. Post-authorization and pharmacovigilance activities enabled the quantity and breadth of post-marketing safety information to quickly exceed that generated from clinical trials. This paper reviews safety and reactogenicity data for the BNT162 vaccine candidates, including BNT162b2 (Comirnaty, Pfizer/BioNTech COVID-19 vaccine) and bivalent variant-adapted BNT162b2 vaccines, from preclinical studies, clinical trials, post-marketing surveillance, and real-world studies, including an unprecedentedly large body of independent evidence.

The Brighton Collaboration Benefit-Risk Assessment of VAccines by TechnolOgy (BRAVATO) Working Group evaluates the safety and other key features of new platform technology vaccines, including nucleic acid (RNA and DNA) vaccines. This manuscript uses the BRAVATO template to report the key considerations for a benefit-risk assessment of the coronavirus disease 2019 (COVID-19) mRNA-based vaccine BNT162b2 (Comirnaty®, or Pfizer-BioNTech COVID-19 vaccine) including the subsequent Original/Omicron BA.1, Original/Omicron BA.4-5 and Omicron XBB.1.5 variant-adapted vaccines developed by BioNTech and Pfizer to protect against COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Initial Emergency Use Authorizations or conditional Marketing Authorizations for the original BNT162b2 vaccine were granted based upon a favorable benefit-risk assessment taking into account clinical safety, immunogenicity, and efficacy data, which was subsequently reconfirmed for younger age groups, and by real world evidence data. In addition, the favorable benefit-risk assessment was maintained for the bivalent vaccines, developed against newly arising SARS-CoV-2 variants, with accumulating clinical trial data., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The Brighton Collaboration BRAVATO authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. BioNTech authors are current employees of BioNTech, a for-profit organization, who may own stock or hold stock options. AM is an inventor on patents and/or patent applications related to RNA technology and COVID-19 vaccines., (Published by Elsevier Ltd.)

Background: This industry survey was conducted to gain insight into the ways structured Benefit-Risk assessment (sBRA) of medical products is approached across drug or medical device developing companies, including frameworks and methods that are currently used and areas where future work is being planned., Methods: A survey containing 28 questions covering five key areas of sBRA was set-up and shared with representatives from the participating companies. Each company was asked to complete a single survey response including inputs across the company's multidisciplinary key representatives involved in benefit-risk assessment., Results: Of the 26 participating companies, 21 (81%) are conducting sBRA. Considering these 21 qualitative frameworks were used by almost every company (19, 90%), while only 12 (57%) have used a quantitative method. Many companies have sBRA training (17, 81%), document templates (16,76%), Standard Operating Procedures (SOPs)/checklists (13, 62%), and /or best practice manuals/examples (12,57%) available. Considering all 26 companies Software tools (15, 58%) and BR planning documents (11,42%) were identified as areas into which many companies intend to put effort., Conclusions: The industry survey confirmed a wide usage of sBRA by many companies involved in research and development. Nevertheless, sBRA is evolving and several future opportunities like the implementation of visualization tools were identified by the representatives of the pharmaceutical companies. Finally, challenges like the cross-functional comprehension of the added value of sBRA are still seen., (© 2024. The Author(s), under exclusive licence to The Drug Information Association, Inc.)

Olo nutritional follow-up care offers vulnerable pregnant women food vouchers, multivitamin supplements, tools, and nutritional counselling to support healthy pregnancy outcomes. Purpose: To evaluate the contribution of Olo follow-up care to nutritional intakes and eating practices, as well as to assess the programme-related experience of participants. Methods: Participants (n = 30) responded to questionnaires and web-based 24-hour dietary recalls and participated in a semi-structured interview (n = 10). Results: Olo follow-up care reduced the proportion of participants below the recommended intake for groups for many micronutrients, with the greatest reduction for folate (by 96.7%), vitamin D (by 93.3%), iron (by 70.0%), calcium (by 50.0%), and zinc (by 30.0%), mainly due to the prenatal multivitamin supplements. Most participants (96.7%) did not follow Olo's typical recommendations but, if they had, hypothetically they would have consumed an average of 746 additional calories per day and be above the recommendations for excessive intakes of folic acid and iron (100% and 33.3%, respectively). More than half of the participants were moderately to severely food insecure. Olo contributed to reducing the impact of isolation and increased food accessibility and budget flexibility among participants. Conclusion: Olo follow-up care helped reduce the proportion of women below the recommended intake for micronutrients, but revising the food offered and strategies to address food insecurity may be necessary.

Background: 3-methylmethcathinone (3-MMC) has been available on the European drug market for several years, but an increase in its availability seems to have occurred around 2020, associated with reports of harm and death. We aimed to analyze the composition of the supposed 3-MMC samples purchased and its concordance with the assumed composition of the drug., Methods: A prospective multicenter (n = 6) study was conducted between February 2021 and September 2021 in Auvergne-Rhone-Alpes, France. The inclusion criteria were: 3-MMC users over 18 years of age in contact with a community-based organization (CBO) called AIDES. Consumption was evaluated with an anonymized questionnaire and samples of 3-MMC powder were analyzed with a combination of qualitative (GC-MS) and quantitative methods (UPLC-MS/MS), to compare the assumed and real compositions of the products purchased., Results: We studied 45 samples provided by 33 users. The study population was predominantly male (91%), with a median age of 40 years, most were university graduates and regular users of 3-MMC. Intravenous drug use was reported by 15.2% of the population. Most of the users bought their 3-MMC online via the Clear Web. Drug testing was requested by 86% of the users, highlighting the need for this type of harm reduction strategy. The purity of the 3-MMC powder samples tested ranged from 21 to 98%. Other NPS drugs, such as 4-CEC (4-chloroethcathinone), 4-MMC, and 2-fluorodeschloroketamine (2-FDCK), supplied as methoxphenidine (MXP), were also detected., Conclusion: This prospective study shows that 3-MMC purity and dose vary considerably. It also describes the characteristics of 3-MMC users and their expectations of a drug-checking program. Our data suggest that drug-checking services may be useful in this population. Health associations and laboratories should work together to help increase access to such programs., (© 2023. The Author(s).)

Abstract: Surgery is often advised when conservative treatment fails in musculoskeletal pain conditions, but a substantial proportion still suffers chronic pain after surgery. Somatosensory processing system (SPS) signs were previously studied as potential predictors for chronic postsurgical pain, but results are inconsistent. Therefore, studying the evolution of SPS signs could be of added value. The aim was to summarize all studies that measured how SPS signs evolved after nociceptive targeted surgery in musculoskeletal disorders and to find preoperative, perioperative, and postoperative predictors for the evolution of these SPS signs. Data were summarized, and risk of bias and level of evidence and recommendation were determined. Twenty-one studies were included. Five scored a low, 3 a moderate, and 13 a high risk of bias. In general, no consistent evolution of SPS signs comparing preoperative and postoperative values and predictors for this evolution in musculoskeletal disorders could be found. In most cases, static quantitative sensory testing (QST) did not change or conflicting results were found. On the other hand, dynamic QST mostly improved after surgery. Worthfully mentioning is that worsening of SPS signs was only seen at a follow-up of <3 months after surgery, that conclusions are stronger when evaluating dynamic QST with a follow-up of ≥3 months after surgery, and that pain improvement postsurgery was an important predictor. Future high-quality research should focus on the evolution of SPS signs after nociceptive targeted surgery, accounting for pain improvement groups and focusing on preoperative, perioperative, and postoperative predictors of this evolution., (Copyright © 2023 International Association for the Study of Pain.)

Introduction: People living with HIV (PLHIV) who may have experienced biographical disruptions in their life trajectory may have a vulnerability to risk that differs from the general population, particularly in the context of an infectious health crisis. This study aimed to understand the factors associated with concerns about being infected with COVID-19 among PLHIV during the first period of the health crisis., Methods: This was an online cross-sectional study using an online self-administered questionnaire in the context of the COVID-19 epidemic in France among a population of PLHIV. The recruitment was done via social networks and through various actors in the fight against HIV. The self-questionnaire was available from July 2020 to September 2020., Results: The ACOVIH study collected 249 responses, 202 men and 47 women, with a mean age of 46.6 ± 12.9 years. The most represented socio-professional categories were employees (n=73.29%), followed by managers, professionals and artists (n=59.24%). The PLHIV most worried about being infected by COVID-19 had a level of education lower than or equal to the baccalaureate, family difficulties related to HIV and a deterioration in the relationship of trust with the HIV medical team., Conclusion: Feelings of anxiety can have a health and psychosocial impact on PLHIV. It is necessary to consider these negative factors by proposing adapted support and by carrying out preventive actions aiming in particular at improving the literacy of the PLHIV.

Introduction: The urban planning between France and Geneva leads us to target the local HIV epidemic dynamics in its cross-border dimension. We aim to assess its importance while taking into account cross-border movements.Purpose of research: This study aims to describe the HIV epidemic on a cross-border scale by comparing data with two other areas known for their HIV incidence, Lyon and Zurich, using epidemiological data available in France and Switzerland., Results: Available data demonstrate that the Geneva cross-border region HIV epidemics are similar in magnitude to those of the Lyon metropolitan area and Zurich canton. In addition, describing the target groups attending two NGO&#8217;s services allows us to understand the dynamics of cross&#8211;border mobility as well as target groups&#8217; health needs., Conclusion: The study shows that policy makers and experts need to focus on the cross-border dimension of the HIV epidemic dynamics in order to provide adequate responses around Geneva. We advocate for a sustained cross-border dialogue: to re-think the fight against HIV in the region, to take into account real life experiences, to make public policies and programs evolve on a cross-border basis, and to base our policies on a common set of good practices.

Acoustic shocks and traumas sometimes result in a cluster of debilitating symptoms, including tinnitus, hyperacusis, ear fullness and tension, dizziness, and pain in and outside the ear. The mechanisms underlying this large variety of symptoms remain elusive. In this article, we elaborate on the hypothesis that the tensor tympani muscle (TTM), the trigeminal nerve (TGN), and the trigeminal cervical complex (TCC) play a central role in generating these symptoms. We argue that TTM overuse (due to the acoustic shock), TTM overload (due to muscle tension), and ultimately, TTM injury (due to hypoxia and "energy crisis") lead to inflammation, thereby activating the TGN, TCC, and cortex. The TCC is a crossroad structure integrating sensory inputs coming from the head-neck complex (including the middle ear) and projecting back to it. The multimodal integration of the TCC may then account for referred pain outside the ear when the middle ear is inflamed and activates the TGN. We believe that our model proposes a synthetic and explanatory framework to explain the phenomena occurring postacoustic shock and potentially also after other nonauditory causes. Indeed, due to the bidirectional properties of the TCC, musculoskeletal disorders in the region of the head-neck complex, including neck injury due to whiplash or temporomandibular disorders, may impact the middle ear, thereby leading to otic symptoms. This previously unavailable model type is experimentally testable and must be taken as a starting point for identifying the mechanisms responsible for this particular subtype of tinnitus and its associated symptoms.

This study reports the case of an acoustic shock injury (ASI), which did not result in a significant hearing loss, but was followed by manifold chronic symptoms both within (tinnitus, otalgia, tingling in the ear, tension in the ear, and red tympanum) and outside the ears (blocked nose, pain in the neck/temporal region). We suggest that these symptoms may result from a loop involving injury to middle ear muscles, peripheral inflammatory processes, activation and sensitization of the trigeminal nerve, the autonomic nervous system, and central feedbacks. The pathophysiology of this ASI is reminiscent of that observed in post-traumatic trigeminal-autonomic cephalalgia. This framework opens new and promising perspectives on the understanding and medical management of ASI.

Two challenges were identified to improve the place of PEP in combined prevention: (1)&#160;improvement of healthcare professionals&#8217; knowledge, practices and attitudes; and (2)&#160;revision of the guidelines concerning first-line prescription, the conditions for access to PEP, and sexual health support..

Our study aimed to evaluate and validate according to standard NF EN ISO 15189 the original protocol ajustement of Hemoclot Protein C (PC) (Hyphen BioMed), clotting-based assay of PC on ACL TOP analyzer (Werfen/Instrumentation Laboratory). We evaluated the performance in terms of imprecision and we validate additional parameters in range B required by the SH GTA 04 (COFRAC): repeatability, reproducibility, detection and quantification limits, limits of linearity, stability, inter-samples and inter-reagents contamination, inaccuracy, evaluation of interferences (hemolysis, bilirubinemia and chyles). A comparison with Hemoclot PC on STA Compact analyzer (Stago) was performed. Coefficients of variation were lower than 5 %. Detection and quantification limits were respectively 8.3 % and 9.3 %. Superior limit of linearity was 140 %. The test didn't diplay any inter-samples and inter-reagents contamination. Reagent after reconstitution was stable 6 hours on ACL TOP. No interferences were observed for hemoglobin lower than 500 mg/dL, for bilirubin lower than and for chyles lower than 300 mg/dL. Comparison with Hemoclot PC on STA analyzer (Stago) was satisfactory. Hemoclot PC adjusted on ACL TOP analyzer showed satisfactory analytical performances with criteria chosen in our study. These data allow a better knowledge of the performances of this test and were useful to make a validation file in range B as recommended by SH GTA 04.

Aim: To evaluate whether the presence of diabetes-specific autoantibodies may predict the development of autoimmune thyroiditis (AIT) in children with type 1 diabetes (T1D)., Methods: Glutamic acid decarboxylase antibodies (GADA), tyrosine phosphatase IA2 antibodies (IA2A), and insulin autoantibodies (IAA) were determined at T1D onset in 341 children and adolescents. Thyroid antibodies (anti-TG, anti-TPO), thyroid stimulating hormone (TSH), T(3) and T(4) were measured in 335 patients at T1D onset and thereafter annually with a follow-up time of 1-15 yr. In case of thyroid antibody positivity and/or TSH elevation, thyroid gland sonography was performed. Treatment with l-thyroxine was started if persistent elevation of TSH and/or thyroid volume was present., Results: The majority of patients (92.1%) had at least one T1D antibody (71.6% GADA, 73.0% IA2A, and 44.9% IAA). GADA positive patients were older than those without GADA (p < 0.001). Thyroid autoimmunity was found in 15 of 335 patients (4.5%) at T1D onset with female preponderance (p = 0.013). At the end of follow-up, 70 patients (20.9%) had developed thyroid autoantibodies [cumulative incidence (CI) 0.36 ± 0.06 at 10 yr of T1D]. In 30 patients (9.0%), AIT was diagnosed up to 9.4 yr after T1D onset (CI 0.24 ± 0.06 at 10 yr). AIT incidence was not influenced by IAA or IA2A positivity. In multivariate analysis, GADA positive patients were estimated to have a 3.5-fold increased risk of AIT (CI 0.31 ± 0.11 at 10 yr) compared to those without GADA (p = 0.024)., Conclusion: Based on the present results, a special focus should be given to GADA positive patients concerning screening for AIT as they are at increased risk to develop autoimmune thyroiditis., (© 2010 John Wiley & Sons A/S.)

Aspirin (acetylsalicylic acid) and clopidogrel are two major antithrombogenic agents that are widely used for the treatment and prevention of cerebro- and cardiovascular conditions such as stroke. Combined use produces enhanced therapeutic effect. Aspirin and clopidogrel both are esters, and hydrolysis leads to decreased or inactivated therapeutic activity. The aim of the study was to determine whether aspirin and clopidogrel are hydrolyzed by the same enzyme(s), thus reciprocally prolonging the antithrombogenic activity. To test this possibility, microsomes from the liver and intestine were assayed for the hydrolysis of aspirin and clopidogrel. In contrary to the hypothesis, aspirin and clopidogrel were hydrolyzed in a tissue-differential manner. Liver microsomes hydrolyzed both drugs, whereas intestinal microsomes hydrolyzed aspirin only. Consistent with the tissue distribution of two carboxylesterases human carboxylesterase (HCE) 1 and HCE2, recombinant HCE1 hydrolyzed clopidogrel, whereas recombinant HCE2 hydrolyzed aspirin. In addition, hydrolysis of clopidogrel among liver samples was correlated well with the level of HCE1, and hydrolysis of aspirin with HCE2. Certain natural variants differed from the wild-type enzymes on the hydrolysis of aspirin or clopidogrel. In the presence of ethyl alcohol, clopidogrel is converted to ethyl clopidogrel. Carboxylesterases are important pharmacological determinants for drugs containing ester linkages and exhibit a large interindividual variation. The isoform-specific hydrolysis of aspirin and clopidogrel suggests that these two antithrombogenic agents may have pharmacokinetic interactions with different sets of ester drugs, and the altered hydrolysis by polymorphic mutants provides a molecular explanation to the interindividual variation.

Background: The causes of prolonged disability due to back pain are multiply determined, involving medical, social, and environmental factors. Possible solutions to the problem of prolonged back pain disability have emerged from recent research but few efforts have been made to transfer evidence-based programs to large community settings., Objective: This article describes three phases of the process of transfer of evidence from rehabilitation research to community practice in the province of Quebec., Methods and Results: Phase A: Based on literature review and expert knowledge, the Sherbrooke model was developed and assessed through a population-based, randomized clinical trial. Results at 1-year follow-up showed quicker return to regular work and improvement of quality of life; the 6-year follow-up showed the cost-effectiveness of the method. Phase B: Based on the Sherbrooke model experience and recent evidence, a new program addressing the disability paradigm was developed and implemented in the province of Quebec (Canada). Results at 1- and 3-year follow-ups showed that only 24% of workers were not working owing to their musculoskeletal disorder. The program is presently being tested through a population-based, randomized clinical trial in a population of construction workers. Phase C: To implement the program at a provincial level, a network for management, research and education in work rehabilitation was developed. An external assessment is presently planned to evaluate return to work and economic outcomes and quality of implementation of the program in various settings.

The molecular basis of Muller's ratchet has been investigated using the important animal pathogen foot-and-mouth disease virus (FMDV). Clones from two FMDV populations were subjected to serial plaque transfers (repeated bottleneck events) on host BHK-21 cells. Relative fitness losses were documented in 11 out of 19 clones tested. Small fitness gains were observed in three clones. One viral clone attained an extremely low plating efficiency, suggesting that accumulation of deleterious mutations had driven the virus near extinction. Nucleotide sequence analysis revealed unique genetic lesions in multiply transferred clones that had never been seen in FMDVs isolated in nature or subjected to massive infections in cell culture. In particular, a frequent internal polyadenylate extension has identified a mutational hot spot on the FMDV genome. Furthermore, amino acid residue substitutions in internal capsid sites which are severely restricted during FMDV evolution, amounted to half of capsid replacements in the transferred clones. In addition, a striking dominance of non-synonymous replacements fixed upon large population infections of FMDV was not observed upon serial plaque transfers. The nucleotide sequence of the entire genome of a severely debilitated clone suggests that very few mutations may be sufficient to drive FMDV near extinction. The results provide an account of the molecular basis of Muller's ratchet for an RNA virus, and insight into the types of genetic variants which populate the mutant spectra of FMDV quasispecies.

In cultured striatal neurons, maximal [3H]GABA release stimulated by quisqualate (QA) or alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) was 10-20 times smaller than that stimulated by kainate (KA), and we have previously reported that QA or AMPA competitively inhibited KA-evoked GABA release. Since the lectin concanavalin A (Con A) has been shown to inhibit QA receptor desensitization, the interaction between QA and KA was further studied in Con A-treated neurons. Con A dose-dependently and specifically potentiated QA- or AMPA-evoked [3H]GABA release, so that maximal responses of QA or AMPA were half of that of KA. The responses of these agonists were inhibited by 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) with similar apparent Ki values, indicating that they resulted from non-NMDA receptor activation. In Con A-treated neurons, QA and AMPA competitively inhibited the KA-induced GABA release. The apparent affinities of QA and AMPA in inhibiting the KA response were identical to their affinities in stimulating GABA release. Moreover, the maximal KA response measured in the presence of QA or AMPA was identical to that measured with KA alone. These results clearly indicate that to stimulate GABA release from Con A-treated striatal neurons, QA and AMPA behave as partial agonists of a receptor fully activated by KA. These results further support the hypothesis that QA, AMPA and KA act on a common receptor type in striatal neurons.