Heterozygous RPA2 variant as a novel genetic cause of telomere biology disorders.

Premature telomere shortening or telomere instability is associated with a group of rare and heterogeneous diseases collectively known as telomere biology disorders (TBDs). Here we identified two unrelated individuals with clinical manifestations of TBDs and short telomeres associated with the identical monoallelic variant c.767A>G; Y256C in RPA2 Although the replication protein A2 (RPA2) mutant did not affect ssDNA binding and G-quadruplex-unfolding properties of RPA, the mutation reduced the affinity of RPA2 with the ubiquitin ligase RFWD3 and reduced RPA ubiquitination. Using engineered knock-in cell lines, we found an accumulation of RPA at telomeres that did not trigger ATR activation but caused short and dysfunctional telomeres. Finally, both patients acquired, in a subset of blood cells, somatic genetic rescue events in either POT1 genes or TERT promoters known to counteract the accelerated telomere shortening. Collectively, our study indicates that variants in RPA2 represent a novel genetic cause of TBDs. Our results further support the fundamental role of the RPA complex in regulating telomere length and stability in humans.

Congenital microcoria deletion in mouse links Sox21 dysregulation to disease and suggests a role for TGFB2 in glaucoma and myopia.

Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present a 3D architecture model of the 13q32.1 region, demonstrating that MCOR-related deletions consistently disrupt the boundary between two topologically associating domains (TADs). Deleting the critical MCOR-causing region in mice reveals ectopic Sox21 expression precisely aligning with Dct, each located in one of the two neighbor TADs. This observation is consistent with the TADs' boundary alteration and adoption of Dct regulatory elements by the Sox21 promoter. Additionally, we identify Tgfb2 as a target gene of SOX21 and show TGFΒ2 accumulation in the aqueous humor of an MCOR-affected subject. Accumulation of TGFB2 is recognized for its role in glaucoma and potential impact on axial myopia. Our results highlight the importance of SOX21-TGFB2 signaling in iris development and control of eye growth and IOP. Insights from MCOR studies may provide therapeutic avenues for this condition but also for glaucoma and high myopia conditions, affecting millions of people.

Cluster B personality disorders and psychotropic medications: a focused analysis of trends and patterns across sex and age groups.

PURPOSE: This study investigated sex and age differences in patterns of psychotropic medication use before and after the initial diagnosis of Cluster B personality disorders (PDs) and analyzed trends over time. METHODS: Analyzing data from the Quebec Integrated Chronic Disease Surveillance System for individuals newly diagnosed with Cluster B PD (≥ 14 years) between 2002 and 2018 and under the provincial public drug plan, we calculated yearly and monthly proportions of individuals exposed to psychotropic medications during the year before and after their diagnosis by sex and age. Robust Poisson regression models assessed the association between sex and exposure to psychotropic medications after the diagnosis of Cluster B PD. RESULTS: Among 87,778 individuals with a first Cluster B PD diagnosis (mean age: 44.5 years; 57.5% women), the proportion of users increased post-diagnosis. Notably, after diagnosis, females were more likely to receive psychiatric medications (between 78.9% and 83.7% during the study period vs. 72.8% and 76.8%). Males were less likely than females to receive antidepressants (adjusted prevalence ratio (aPR): 0.83; 99% confidence interval (CI): 0.82-0.85) and anxiolytics (aPR: 0.86; 99%CI: 0.84-0.88), whereas they had higher exposure to antipsychotics (aPR: 1.04; 99%CI: 1.02-1.06) and ADHD medications (aPR: 1.14; 99%CI: 1.07-1.2). Age-specific trends showed increased ADHD medication use among younger patients (14-24 years), and anxiolytic use predominated in those aged ≥ 65 years. CONCLUSIONS: Psychotropic medication use was high among Cluster B PD patients, with differences in medication classes according to age and sex. The marked sex and age differences in psychotropic medication use among Cluster B PD patients underscore the need for a sex-sensitive and age-specific approach in psychiatric care.

Tweaking algorithms. Technopolitical issues associated with artificial intelligence based tuberculosis detection in global health.

Computer-aided detection algorithms based on artificial intelligence are increasingly being tested and used as a means for detecting tuberculosis in countries where the epidemic is still present. Computer-aided detection tools are often presented as a global solution that can be deployed in all the geographical areas concerned by tuberculosis, but at the same time, they need to be adjusted and calibrated according to local populations' characteristics. The aim of this article is to analyze the tensions between the standardization of computer-aided detection algorithms and their local adaptation and the political issues associated with these tensions. We undertook a qualitative analysis of practices associated with tuberculosis detection algorithms in different contexts, contrasting the perspectives of various stakeholders. Algorithms embed the promise of standardization through automation and the bypassing of variable human expertise such as that of radiologists, they are nonetheless objects of local practices that we have characterized as "tweaking." This work of tweaking reveals how the technology is situated but also the many concerns of the users and workers (insertion in care, control over infrastructure, and political ownership). This should be better considered to truly make computer-aided detection innovative tools for tuberculosis management in global health.

Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.

De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and -2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.

Understanding drug exceptional access programs (DEAPs) in Canada, and their associated social and political issues.

Drug exceptional access programs (DEAPs) exist across Canada to address gaps in access to pharmaceuticals. These programs circumvent standard procedures, raising epistemic, economic, social and political issues. This commentary provides insights into these issues by revealing the context and procedures on which these programs depend.

AI for Detection of Tuberculosis: Implications for Global Health.

Tuberculosis, which primarily affects developing countries, remains a significant global health concern. Since the 2010s, the role of chest radiography has expanded in tuberculosis triage and screening beyond its traditional complementary role in the diagnosis of tuberculosis. Computer-aided diagnosis (CAD) systems for tuberculosis detection on chest radiographs have recently made substantial progress in diagnostic performance, thanks to deep learning technologies. The current performance of CAD systems for tuberculosis has approximated that of human experts, presenting a potential solution to the shortage of human readers to interpret chest radiographs in low- or middle-income, high-tuberculosis-burden countries. This article provides a critical appraisal of developmental process reporting in extant CAD software for tuberculosis, based on the Checklist for Artificial Intelligence in Medical Imaging. It also explores several considerations to scale up CAD solutions, encompassing manufacturer-independent CAD validation, economic and political aspects, and ethical concerns, as well as the potential for broadening radiography-based diagnosis to other nontuberculosis diseases. Collectively, CAD for tuberculosis will emerge as a representative deep learning application, catalyzing advances in global health and health equity. Keywords: Computer-aided Diagnosis (CAD), Conventional Radiography, Thorax, Lung, Machine Learning Supplemental material is available for this article. © RSNA, 2024.

Psychotropic medication use pre and post-diagnosis of cluster B personality disorder: a Quebec's health services register cohort.

Background: Cluster B personality disorders (PDs) are considered some of the most severe mental health conditions. Scarce evidence exists about the real-world utilization of psychotropics for cluster B PD individuals. Objective: We aimed to uncover trends and patterns of psychotropic medication use among individuals diagnosed with cluster B PD in the year before and after their diagnosis and to identify factors associated with medication use in a large cohort of individuals newly diagnosed with cluster B PDs. Methods: We conducted a population-based observational study using Quebec's health services register. We identified Quebec residents aged ≥14 years and insured with the provincial drug plan with a first diagnosis of cluster B PD recorded between April 1, 2002, and March 31, 2019. Cluster B PD was defined with ICD-9/10 diagnostic codes. We retrieved all claims for the main psychotropic medication classes: antipsychotics, antidepressants, anxiolytics, mood stabilizers, and attention-deficit/hyperactivity disorder (ADHD) medications. We calculated the proportion of individuals exposed to these medication classes and analyzed trends over the years using robust Poisson regression models, adjusting for potential confounders. We used robust Poisson regression to identify factors associated with medication class use. Results: We identified 87,778 new cases of cluster B PD, with a mean age of 44.5 years; 57.5% were women. Most frequent psychiatric comorbidities in the five years before cluster B PD diagnosis were depression (50.9%), anxiety (49.7%), and psychotic disorders (37.5%). Most individuals (71.0%) received at least one psychotropic during the year before cluster B PD diagnosis, and 78.5% received at least one of these medications in the subsequent year. The proportion of users increased after the diagnosis for antidepressants (51.6-54.7%), antipsychotics (35.9-45.2%), mood stabilizers (14.8-17.0%), and ADHD medications (5.1-5.9%), and remained relatively stable for anxiolytics (41.4-41.7%). Trends over time showed statistically significant increased use of antipsychotics and ADHD medications, decreased use of anxiolytics and mood stabilizers, and a stable use of antidepressants. Conclusion: Psychotropic medication use is highly prevalent among cluster B PD individuals. We observed an increase in medication use in the months following the diagnosis, particularly for antipsychotics, antidepressants, and mood stabilizers.

Vaccine promotion strategies in community pharmacy addressing vulnerable populations: a scoping review.

CONTEXT: Social determinants of health are drivers of vaccine inequity and lead to higher risks of complications from infectious diseases in under vaccinated communities. In many countries, pharmacists have gained the rights to prescribe and administer vaccines, which contributes to improving vaccination rates. However, little is known on how they define and target vulnerable communities. OBJECTIVE: The purpose of this study is to describe how vulnerable communities are targeted in community pharmacies. METHODS: We performed a systematic search of the Embase and MEDLINE database in August 2021 inspired by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocols (PRISMA ScR). Articles in English, French or Spanish addressing any vaccine in a community pharmacy context and that target a population defined as vulnerable were screened for inclusion. RESULTS: A total of 1039 articles were identified through the initial search, and 63 articles met the inclusion criteria. Most of the literature originated from North America (n = 54, 86%) and addressed influenza (n = 29, 46%), pneumococcal (n = 14, 22%), herpes zoster (n = 14, 22%) or human papilloma virus vaccination (n = 14, 22%). Lifecycle vulnerabilities (n = 48, 76%) such as age and pregnancy were most often used to target vulnerable patients followed by clinical factors (n = 18, 29%), socio-economical determinants (n = 16, 25%) and geographical vulnerabilities (n = 7, 11%). The most frequently listed strategy was providing a strong recommendation for vaccination, promotional posters in pharmacy, distributing leaflet/bag stuffers and providing staff training. A total of 24 barriers and 25 facilitators were identified. The main barriers associated to each vulnerable category were associated to effective promotional strategies to overcome them. CONCLUSION: Pharmacists prioritize lifecycle and clinical vulnerability at the expense of narrowing down the definition of vulnerability. Some vulnerable groups are also under targeted in pharmacies. A wide variety of promotional strategies are available to pharmacies to overcome the specific barriers experienced by various groups.

Supporting Reassigned Hospital Staff During the COVID-19 Pandemic in the Montreal Region: What Does it say About Leadership Styles?

Globally, the COVID-19 pandemic took a high toll on health human resources, especially in contexts where these resources were already fragile. In Quebec, to make up for the shortage of health human resources, and to contain the COVID-19 outbreaks in long-term care facilities, many hospital staff (including a majority of nurses) were sent to those facilities, with varying degrees of support. Building on the body of evidence linking leadership style and resilience, we conducted a qualitative comparative analysis of two hospitals in the Montreal Metropolitan Area, Quebec. We explored respondents' experience of psychosocial support tools provided to hospital staff reassigned to COVID-affected facilities. Data from 27 in-depth interviews with high- and mid-level managers, and front-line workers, was analyzed through the lens of leadership styles. Our findings highlighted how the design and implementation of support tools revealed major differences across the two hospitals' leadership styles (i.e., one hospital expressing leader-centered styles vs. the other expressing follower-centered leadership styles). The expression of these leadership styles was largely shaped by recent policies, notably a major political reform of 2015, which enforced more centralized decision-making. Our study offered additional empirical evidence that leadership styles fostering the recovery of health human resources may be a key indicator of successful response to crises.

Lessons Learned from Field Experiences on Hospitals' Resilience to the COVID-19 Pandemic: A Systematic Approach.

In this concluding article of the special issue, we examine lessons learned from hospitals' resilience to the COVID-19 pandemic in Brazil, Canada, France, Japan, and Mali. A quality lesson learned (QLL) results from a systematic process of collecting, compiling, and analyzing data derived ideally from sustained effort over the life of a research project and reflecting both positive and negative experiences. To produce QLLs as part of this research project, a guide to their development was drafted. The systematic approach we adopted to formulate quality lessons, while certainly complex, took into account the challenges faced by the different stakeholders involved in the fight against the COVID-19 pandemic. Here we present a comparative analysis of the lessons learned by hospitals and their staff with regard to four common themes that were the subject of empirical analyses: 1) infrastructure reorganization; 2) human resources management; 3) prevention and control of infection risk; and 4) logistics and supply. The lessons learned from the resilience of the hospitals included in this research indicate several factors to consider in preparing for a health crisis: 1) strengthening the coordination and leadership capacities of hospital managers and health authorities; 2) improving communication strategies; 3) strengthening organizational capacity; and 4) adapting resources and strategies, including for procurement and infection risk management.

Communication and Information Strategies Implemented by Four Hospitals in Brazil, Canada, and France to Deal with COVID-19 Healthcare-Associated Infections.

During the COVID-19 pandemic outbreak, COVID-19 healthcare-associated infections (HAI) and risk management became major challenges facing hospitals. Using evidence from a research project, this commentary presents: 1) various communication and information strategies implemented by four hospitals and their staff in Brazil, Canada and France to reduce the risks of COVID-19 HAIs, and how they were perceived by hospital staff; 2) the flaws in communication in the hospitals; and 3) a proposed agenda for research on and action to improve institutional communications for future pandemics. By analyzing "top-down" strategies at the organizational level and spontaneous strategies initiated by and between professionals, this study shows that during the first waves of the pandemic, reliable information and clear communication about guidelines and health protocols' changes can help alleviate fears among staff and avoid misapplication of protocols, thereby reducing infection risks. There was a lack of a "bottom-up" communication channel, while, when making decisions, it is crucial to listen to and fully take into account staff's voices, experiences, and feelings. More balanced communication between hospital administrators and staff could strengthen team cohesion and lead to better enforcement of protocols, which in turn will reduce the risk of contamination, alleviate the potential impacts on staff health, and improve the quality of care provided to patients.

Hospital Governance During the COVID-19 Pandemic: A Multiple-Country Case Study.

In response to the disruptions caused by COVID-19, hospitals around the world proactively or reactively developed and/or re-organized their governance structures to manage the COVID-19 response. Hospitals' governance played a crucial role in their ability to reorganize and respond to the pressing needs of their staff. We discuss and compare six hospital cases from four countries on different continents: Brazil, Canada, France, and Japan. Our study examined how governance strategies (e.g., special task forces, communications management tools, etc.) were perceived by hospital staff. Key findings from a total of 177 qualitative interviews with diverse hospital stakeholders were analyzed using three categories drawn from the European Observatory on Health Systems and Policies framework on health systems resilience during the COVID-19 pandemic: 1) delivering a clear and timely COVID-19 response strategy; 2) coordinating effectively within (horizontally) and across (vertically) levels of decision-making; and 3) communicating clearly and transparently with the hospital's diverse stakeholders. Our study gleaned rich accounts for these three categories, highlighting significant variations across settings. These variations were primarily determined by the hospitals' environment prior to the COVID-19 crisis, namely whether there already existed a culture of managerial openness (including spaces for social interactions among hospital staff) and whether preparedness planning and training had been routinely integrated into their activities.

Artificial intelligence-based computer aided detection (AI-CAD) in the fight against tuberculosis: Effects of moving health technologies in global health.

Computer Aided Detection software based on Artificial Intelligence (AI-CAD), combined with chest X-rays have recently been promoted as an easy fix for a complex problem: ending TB by 2030. WHO has recommended the use of such imaging devices in 2021 and many partnerships have helped propose benchmark analysis and technology comparisons to facilitate their "market access". Our aim is to examine the socio-political and health issues that stem from using AI-CAD technology in a global health context conceptualized as a set of practice and ideas organizing global intervention "in the life of others". We also question how this technology, which is not yet fully implemented in routine use, may limit or amplify some inequalities in the care of tuberculosis. We describe AI-CAD through Actor-Network-Theory framework to understand the global assemblage and composite activities associated with detection through AI-CAD, and interrogate how the technology itself may consolidate a specific configuration of "global health". We explore the various dimensions of AI-CAD "health effects model": technology design, development, regulation, institutional competition, social interaction and health cultures. On a broader level, AI-CAD represents a new version of global health's accelerationist model centered on "moving and autonomous-presumed technologies". We finally present key aspects in our research which help discuss the theories mobilized: AI-CAD ambivalent insertion in global health, the social lives of its data: from efficacy to markets and AI-CAD human care and maintenance it requires. We reflect on the conditions that will affect AI-CAD use and its promises. In the end, the risk of new detection technologies such as AI-CAD is indeed that the fight against TB could be reduced to one that is purely technical and technological, with neglect to its social determinants and effects.

How resilience affected public health research during COVID-19 and why we should abandon it.

Resilience has accompanied the COVID-19 pandemic as a rallying motto, with calls by governments for a resilient society, resilient families and schools, and, of course, resilient healthcare systems in the face of this unprecedented pandemic shock. Resilience had already gained traction as an analytical concept in public health research for approximately a decade. It became a key concept despite the recognition of its lack of conceptual consistency. The COVID-19 pandemic presented itself as a perfect test-case and encouraged a multiplicity of studies on resilience and health care systems. In this commentary, we add to the existing critiques of resilience in the social sciences by reflecting on the effects of resilience when used to frame empirical inquiries and to draw lessons from the crisis. Resilience as a concept is unable to address crucial structural issues that health systems already faced throughout the world, and it remains a non-neutral political notion. We argue that we need to resist a generalised view of resilience and work with alternative imaginaries.

Adapting Hospital Work During COVID-19 in Quebec (Canada).

Among hospital responses to the COVID19 pandemic worldwide, service reorganization and staff reassignment have been some of the most prominent ways of adapting hospital work to the expected influx of patients. In this article, we examine work reorganization induced by the pandemic by identifying the operational strategies implemented by two hospitals and their staff to contend with the crisis and then analyzing the implications of those strategies. We base our description and analysis on two hospital case studies in Quebec. We used a multiple case study approach, wherein each hospital is considered a unique case. In both cases, work adaptation through staff reassignment was one of the critical measures undertaken to ensure absorption of the influx of patients into the hospitals. Our results showed that this general strategy was designed and applied differently in the two cases. More specifically, the reassignment strategies revealed numerous healthcare resource disparities not only between health territories, but also between different types of facilities within those territories. Comparing the two hospitals' adaptation strategies showed that past reforms in Quebec determined what these reorganizations could achieve, as well as how they would affect workers and the meaning they gave to their work.

How Did an Integrated Health and Social Services Center in the Quebec Province Respond to the COVID-19 Pandemic? A Qualitative Case Study.

During the first and second waves of the pandemic, Quebec was among the Canadian provinces with the highest COVID-19 mortality rates. Facing particularly large COVID-19 outbreaks in its facilities, an integrated health and social services center in the province of Quebec (Canada), developed resilience strategies. To explore these diverse responses to the crisis, we conducted a case study analysis of a Quebec integrated health and social services center, building on a conceptualization of resilience strategies using "configurations" of effects, strategies, and impacts. Qualitative data from 14 indepth interviews conducted in the summer and fall of 2020 with managers and frontline practitioners were analyzed through the lens of situations of "anticipation," "reaction," or "inaction." The findings were discussed in three results dissemination workshops, two with practitioners and one with managers, to discern lessons they learned. Three major configurations emerged: 1) reorganization of services and spaces to accommodate more COVID-19 patients; 2) management of contamination risks for patients and professionals; and 3) management of personal protective equipment (PPE), supplies, and medications. Within these configurations, the responses to the crisis were strongly shaped by the 2015 health care system reforms in Quebec and were constrained by organizational challenges that included a centralized model of governance, a history of substantial budget cuts to longterm care facilities, and a systematic lack of human resources.

Digital Therapies (DTx) as New Tools within Physicians' Therapeutic Arsenal: Key Observations to Support their Effective and Responsible Development and Use.

In recent years, there has been a swift rise in the development of digital therapies (DTx). As a result of various technological advances and accessibility to patients, it is now possible to develop and offer therapeutic interventions in a digital manner. These take the form of an evidence-based intervention that is administered in digital form to prevent, manage, or treat a medical condition. What makes DTx significantly different from other types of digital applications or services (e.g., wellness applications) is that they are interventions authorised by regulatory agencies for the treatment, like a drug, of a health condition. Yielding actual therapeutic benefits and being at the crossroads of health and digital means that DTx are subject to both the upsides and downsides of both sectors. Thus, it is of particular interest to look at the facilitators and barriers to be foreseen in the development, assessment, and implementation of DTx. In this article, we will present key observations and outline the main challenges that may be faced in the development and integration of DTx into practice. It is certain that DTx can represent an interesting avenue for physicians to bring their prescribing role into the 21st century. We conclude with broad lessons that the emerging field of DTx can learn from decades of drug industry practice to avoid history repeating itself and to fast-track the development and ethical and optimal use of DTx.

Impact of individualized feedback letters on adherence to surgical antibiotic prophylaxis guidelines: an interrupted time series study (FEEDBACK-ASAP).

BACKGROUND: Surgical antibiotic prophylaxis (SAP) has been proved to decrease the rate of surgical site infections (SSI), but compliance to SAP guidelines remains suboptimal. AIM: This study evaluated the impact of periodically sending individualized feedback letters to surgeons and anesthesiologists on their compliance rate to SAP guidelines. METHODS: A total of 1491 surgeries were evaluated by retrospective chart review during the pre-intervention period and 668 surgeries were evaluated by prospective chart review during the per-intervention period. Finally, 295 letters were sent to 64 surgeons and 45 anesthesiologists. Compliance rate was assessed as an outcome composed of: indication for SAP, choice of antibiotic agent, antibiotic dose, postoperative duration, timing of the preoperative dose and intraoperative redosing. An interrupted time series design was used to assess a difference on compliance rates before and during the intervention period. FINDINGS: Sending individualized feedback letters to surgeons and anesthesiologists did not significantly improve the overall compliance to local SAP guidelines. CONCLUSION: Individualized feedback letters could be part of future interventions directed at improving compliance to SAP guidelines, but are likely insufficient by themselves to provide significant results.

Structuring and organizing interprofessional healthcare in partnership with patients with diabetes: the INterprofessional Management and Education in Diabetes care (INMED) pathway.

Type 2 diabetes is a complex chronic disease that requires ongoing monitoring by an interprofessional team to prevent complications. The INMED (INterprofessional Management and Education in Diabetes) care pathway was developed by our team to optimize primary care services for these patients and their families. The objective of this study is to describe the preliminary results of its adoption and implementation. The INMED care pathway is organized into four axes: (a) continuing professional education, (b) self-management support, (c) case management, and (d) ongoing evaluation of the quality of diabetes care and services. A multiple-case study is underway to document its effects on practice change using the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework. Preliminary results on the adoption and implementation revealed some strengths: (a) regular patient follow-up by the case manager, (b) scheduling of physician appointments when required, and (c) regular screening for risk factors. Barriers were also identified: (a) lack of clear understanding of the case manager role, (b) lack of referrals to team members, and (c) lack of use of the motivational interview approach. The INMED care pathway is being adopted by primary care teams but challenges need to be overcome to improve its reach and effectiveness.