Chlamydia trachomatis induces disassembly of the primary cilium to promote the intracellular infection.

Chlamydia trachomatis is a clinically important bacterium that infects epithelial cells of the genitourinary and respiratory tracts and the eye. These differentiated cells are in a quiescent growth state and have a surface organelle called a primary cilium, but the standard Chlamydia cell culture infection model uses cycling cells that lack primary cilia. To investigate if these differences are relevant, we performed infections with host cells that have a primary cilium. We found that C. trachomatis caused progressive loss of the primary cilium that was prevented by disrupting Aurora A (AurA), HDAC6 or calmodulin, which are components of the cellular cilia disassembly pathway. Stabilization of the primary cilium by targeting this pathway caused a large reduction in infectious progeny although there were no changes in chlamydial inclusion growth, chlamydial replication or the ultrastructural appearance of dividing and infectious forms (RBs and EBs, respectively). Thus, the presence of a primary cilium interfered with the production of infectious EBs at a late step in the developmental cycle. C. trachomatis infection also induced quiescent cells to re-enter the cell cycle, as detected by EdU incorporation in S-phase, and Chlamydia-induced cilia disassembly was necessary for cell cycle re-entry. This study therefore describes a novel host-pathogen interaction in which the primary cilium limits a productive Chlamydia infection, and the bacterium counteracts this host cell defense by activating the cellular cilia disassembly pathway.

'I need to understand so we can decide together': Difficult conversations about alopecia areata.

The management of alopecia areata (AA) in pediatric patients poses unique challenges, particularly regarding treatment discussions and decision making involving both patients and their families. This commentary presents findings from unpublished research on treatment-discontinuation discussions between AA patients and their treating providers, shedding light on the hopes, expectations, and disappointments of individuals with severe AA. The study explored patient and guardian satisfaction with these discussions, emphasizing the importance of addressing psychosocial concerns, facilitating contact with support groups, and demonstrating empathy. The role of dermatologists in conversations about treatment, prognosis, and quality of life is examined, emphasizing the need for honesty, empathy, and realistic expectations. The authors propose a patient-centered approach to initiating and guiding discussions, focusing on understanding the impact of AA on patients and their families and collaboratively deciding on treatment options. The mantra: 'I need to understand how this is affecting all of you, so we can decide together what to do next' is central to this proposed approach. Special considerations for different scenarios are discussed, highlighting the importance of individualized care and effective communication. Overall, the commentary emphasizes the significance of actively listening, acknowledging emotions, and prioritizing patient and family goals to optimize care for pediatric AA patients.

A holistic approach to fragile X syndrome integrated guidance for person-centred care.

BACKGROUND: The Fragile X community has expressed a desire for centralised, national guidelines in the form of integrated guidance for Fragile X Syndrome (FXS). METHODS: This article draws on existing literature reviews, primary research and clinical trials on FXS, a Fragile X Society conference workshop and first-hand experience of clinicians who have worked with those living with FXS over many years. RESULTS: The article scopes proposed integrated guidance over the life course, including appendices of symptoms, comorbidities and referral options for FXS and Fragile X Premutation Associated Conditions. CONCLUSION: Integrated guidance would provide an authoritative source for doctors, health professionals, therapists, care workers, social workers, educators, employers, families and those living with FXS, so that a holistic, person-centred approach can be taken across the United Kingdom to garner the best outcomes for those with FXS.

A rare case of cutaneous myxoma with trichofolliculoma-like features.

Carney complex is a rare genetic disorder associated with a number of cutaneous lesions, especially cutaneous myxomas. We present a rare case of cutaneous myxoma (superficial angiomyxoma) with trichofolliculoma-like features in a patient with Carney complex, and explore how the associated histopathology provides critical context for elucidating the etiology of this benign neoplasm.

Role for the EWS domain of EWS/FLI in binding GGAA-microsatellites required for Ewing sarcoma anchorage independent growth.

Ewing sarcoma usually expresses the EWS/FLI fusion transcription factor oncoprotein. EWS/FLI regulates myriad genes required for Ewing sarcoma development. EWS/FLI binds GGAA-microsatellite sequences in vivo and in vitro. These sequences provide EWS/FLI-mediated activation to reporter constructs, suggesting that they function as EWS/FLI-response elements. We now demonstrate the critical role of an EWS/FLI-bound GGAA-microsatellite in regulation of the NR0B1 gene as well as for Ewing sarcoma proliferation and anchorage-independent growth. Clinically, genomic GGAA-microsatellites are highly variable and polymorphic. Current data suggest that there is an optimal "sweet-spot" GGAA-microsatellite length (of 18-26 GGAA repeats) that confers maximal EWS/FLI-responsiveness to target genes, but the mechanistic basis for this remains unknown. Our biochemical studies, using recombinant Δ22 (a version of EWS/FLI containing only the FLI portion), demonstrate a stoichiometry of one Δ22-monomer binding to every two consecutive GGAA-repeats on shorter microsatellite sequences. Surprisingly, the affinity for Δ22 binding to GGAA-microsatellites significantly decreased, and ultimately became unmeasureable, when the size of the microsatellite was increased to the sweet-spot length. In contrast, a fully functional EWS/FLI mutant (Mut9, which retains approximately half of the EWS portion of the fusion) showed low affinity for smaller GGAA-microsatellites but instead significantly increased its affinity at sweet-spot microsatellite lengths. Single-gene ChIP and genome-wide ChIP-sequencing (ChIP-seq) and RNA-seq studies extended these findings to the in vivo setting. Together, these data demonstrate the critical requirement of GGAA-microsatellites as EWS/FLI activating response elements in vivo and reveal an unexpected role for the EWS portion of the EWS/FLI fusion in binding to sweet-spot GGAA-microsatellites.

A Fully Integrated CMOS Fluorescence Biochip for DNA and RNA Testing.

Design and successful implementation of a fully-integrated CMOS fluorescence biochip for DNA/RNA testing in molecular diagnostics (MDx) is presented. The biochip includes a 32×32 array of continuous wave fluorescence detection biosensing elements. Each biosensing element is capable of having unique DNA probe sequences, wavelength-selective multi-dielectric emission filter (OD of 3.6), resistive heater for thermal cycling, and a high performance and programmable photodetector. The dimension of each biosensor is 100µm×100µm with a 50µm×50µm Nwell-Psub photodiode acting as the optical transducer, and a ΣΔ modulator based photocurrent sensor. The measured photodetector performance shows ~116 dB detection dynamic range (10fA - 10nA) over the 25°C - 100°C temperature range, while being ~1 dB away from the fundamental shot-noise limit. To empirically demonstrate the compatibility of this biochip with MDx applications, we have successfully utilized the array and its thermal cycling capability to adopt a 7-plex panel for detection of 6 human upper respiratory viruses.

Rhodium-Catalyzed Enantioselective Intramolecular Hydroacylation of Trisubstituted Alkenes.

We report the first examples of transition metal-catalyzed enantioselective alkene hydroacylations with 1,1,2-trisubstituted alkenes. DFT and mechanistic studies are consistent with a reaction pathway for these rhodium-catalyzed processes including intramolecular alkene hydroacylation and α-epimerization to generate highly enantioenriched, polycyclic architectures. This reaction sequence enables the hydroacylation of 2-(cyclohex-1-en-1-yl)benzaldehydes to form hexahydro-9H-fluoren-9-ones in moderate to high yields (68-91 %) with high enantioselectivities (up to 99 % ee) and diastereoselectivities (typically >20:1).

CPAF: a Chlamydial protease in search of an authentic substrate.

Bacteria in the genus Chlamydia are major human pathogens that cause an intracellular infection. A chlamydial protease, CPAF, has been proposed as an important virulence factor that cleaves or degrades at least 16 host proteins, thereby altering multiple cellular processes. We examined 11 published CPAF substrates and found that there was no detectable proteolysis when CPAF activity was inhibited during cell processing. We show that the reported proteolysis of these putative CPAF substrates was due to enzymatic activity in cell lysates rather than in intact cells. Nevertheless, Chlamydia-infected cells displayed Chlamydia-host interactions, such as Golgi reorganization, apoptosis resistance, and host cytoskeletal remodeling, that have been attributed to CPAF-dependent proteolysis of host proteins. Our findings suggest that other mechanisms may be responsible for these Chlamydia-host interactions, and raise concerns about all published CPAF substrates and the proposed roles of CPAF in chlamydial pathogenesis.

Payday, ponchos, and promotions: a qualitative analysis of perspectives from non-governmental organization programme managers on community health worker motivation and incentives.

BACKGROUND: Community health workers (CHWs) have been central to broadening the access and coverage of preventative and curative health services worldwide. Much has been debated about how to best remunerate and incentivize this workforce, varying from volunteers to full time workers. Policy bodies, including the WHO and USAID, now advocate for regular stipends. METHODS: This qualitative study examines the perspective of health programme managers from 16 international non-governmental organizations (NGOs) who directly oversee programmes in resource-limited settings. It aimed to explore institutional guidelines and approaches to designing CHW incentives, and inquire about how NGO managers are adapting their approaches to working with CHWs in this shifting political and funding climate. Second, it meant to understand the position of stakeholders who design and manage non-governmental organization-run CHW programmes on what they consider priorities to boost CHW motivation. Individuals were recruited using typical case sampling through chain referral at the semi-annual CORE Group meeting in the spring of 2012. Semi-structured interviews were guided by a peer reviewed tool. Two reviewers analyzed the transcripts for thematic saturation. RESULTS: Six key factors influenced programme manager decision-making: National-level government policy, donor practice, implicit organizational approaches, programmatic, cultural, and community contexts, experiences and values of managers, and the nature of the work asked of CHWs. Programme managers strongly relied on national government to provide clear guidance on CHW incentives schemes. Perspectives on remuneration varied greatly, from fears that it is unsustainable, to the view that it is a basic human right, and a mechanism to achieve greater gender equity. Programme managers were interested in exploring career paths and innovative financing schemes for CHWs, such as endowment funds or material sales, to heighten local ownership and sustainability of programmes. Participants also supported the creation of both national-level and global interfaces for sharing practical experience and best practices with other CHW programmes. CONCLUSION: Prescriptive recommendations for monetary remuneration, aside from those coming from national governments, will likely continue to meet resistance by NGOs, as contexts are nuanced. There is growing consensus that incentives should reflect the nature of the work asked of CHWs, and the potential for motivation through sustainable financial schemes other than regular salaries. Programme managers advocate for greater transparency and information sharing among organizations.

Development of an evaluation framework suitable for assessing humanitarian workforce competencies during crisis simulation exercises.

The need to provide a professionalization process for the humanitarian workforce is well established. Current competency-based curricula provided by existing academically affiliated training centers in North America, the United Kingdom, and the European Union provide a route toward certification. Simulation exercises followed by timely evaluation is one way to mimic the field deployment process, test knowledge of core competences, and ensure that a competent workforce can manage the inevitable emergencies and crises they will face. Through a 2011 field-based exercise that simulated a humanitarian crisis, delivered under the auspices of the World Health Organization (WHO), a competency-based framework and evaluation tool is demonstrated as a model for future training and evaluation of humanitarian providers.

Global emergency medicine: four part series : Paper 4: Global EM education and professionalization.

In 2018, the Canadian Association of Emergency Physicians (CAEP) academic symposium included developing recommendations on supporting global emergency medicine (EM) in Canadian departments and divisions. Members of CAEP's Global EM committee created a four-part series to be published in CJEM that would build upon the symposium recommendations. The objective is to offer practical tools to EM physicians interested in becoming involved in Global EM, as well as provide departments with successful Canadian case examples that foster, facilitate, and grow Global EM efforts. This submission is the fourth paper of the series which focuses on education and continuing professional development for Global EM. It includes resources for resident global EM electives, fellowship training and ongoing or additional CPD training for practicing EM physicians. It also highlights the importance of pre-departure training and other required elements of engaging responsibly in Global EM work.

RéSUMé: En 2018, le symposium universitaire de l'Association canadienne des médecins d'urgence (ACMU) comprenait l'élaboration de recommandations sur le soutien de la médecine d'urgence mondiale (MU) dans les départements et divisions canadiens. Les membres du comité mondial de la GU de l'ACMU proposent une série de quatre articles qui seront publiés dans la MCEM et qui s'appuieront sur les recommandations du symposium. L'objectif est d'offrir des outils pratiques aux médecins en GU qui souhaitent s'impliquer dans la GU mondiale, ainsi que de fournir aux départements des exemples de cas canadiens réussis qui favorisent, facilitent et développent les efforts en GU mondiale. Ce mémoire est le quatrième article de la série qui se concentre sur l'éducation et le développement professionnel continu pour Global EM. Il comprend des ressources pour les cours au choix internationaux de GU des résidents, la formation de fellowship et la formation continue ou supplémentaire de DPC pour les médecins praticiens de GU. Il souligne également l'importance de la formation préalable au départ et d'autres éléments requis pour s'engager de manière responsable dans le travail de gestion des urgences à l'échelle mondiale.

Global emergency medicine: four part series on best practices : Paper 1: Introduction and overview of global emergency medicine.

The Canadian Association of Emergency Physicians' (CAEP) Global Emergency Medicine committee presents a four-part series that builds upon the Academic Symposium recommendations from the CAEP 2018 meeting (Collier et al. in CJEM 21(5):600-606, 2019). This series presents best practices and offers practical tools for the development and practice of Global EM. This is the first paper of the series which provides an overview of current Global EM systems and development. The breadth and scope of the field is described, and key definitions are outlined. International efforts, initiatives, and organizations relating to public health and humanitarian response are introduced. Other key aspects of Global EM are explored in papers 2-4 including: developing partnerships, supporting centers of research and practice, and education and training.

RéSUMé: Le Comité mondial de la médecine d'urgence de l'Association canadienne des médecins d'urgence (ACMU) présente une série en quatre parties qui s'appuie sur les recommandations du Symposium universitaire de la réunion de 2018 de l'ACMU [1]. Cette série présente les meilleures pratiques et propose des outils pratiques pour le développement et la pratique de la ME mondiale. Il s'agit du premier article de la série qui donne un aperçu des systèmes et du développement actuels de la ME mondiale. L'étendue et la portée du domaine sont décrites, ainsi que les définitions clés. Les efforts, les initiatives et les organisations internationales en matière de santé publique et d'intervention humanitaire sont présentés. D'autres aspects clés de la GU mondiale sont explorés dans les documents 2 à 4, notamment : le développement de partenariats, le soutien des centres de recherche et de pratique, et l'éducation et la formation.

Panic attack history and anxiety sensitivity in relation to cognitive-based smoking processes among treatment-seeking daily smokers.

INTRODUCTION: Empirical research has found that panic attacks are related to increased risk of more severe nicotine withdrawal and poor cessation outcome. Anxiety sensitivity (AS; fear of anxiety and related sensations) has similarly been found to be related to an increased risk of acute nicotine withdrawal and poorer cessation outcome. However, research has yet to examine the relative contributions of panic attacks and AS in terms of cognitive-based smoking processes (e.g., negative reinforcement smoking expectancies, addictive and negative affect-based reduction smoking motives, barriers to cessation, problem symptoms experienced while quitting). METHOD: Participants (n = 242; 57.4% male; M (age) = 38.1) were daily smokers recruited as a part of a larger randomized control trial for smoking cessation. It was hypothesized that both panic attacks and AS would uniquely and independently predict the studied cognitive-based smoking processes. RESULTS: As hypothesized, AS was uniquely and positively associated with all smoking processes after controlling for average number of cigarettes smoked per day, current Axis I diagnosis, and participant sex. However, panic attack history was only significantly related to problem symptoms experienced while quitting smoking. CONCLUSIONS: Although past research has demonstrated significant associations between panic attacks and certain aspects of cigarette smoking (e.g., severity of nicotine withdrawal; lower abstinence rates, and negative affect reduction motives), the present findings suggest that AS may be more relevant to understanding beliefs about and motives for smoking behavior as well as perceptions of cessation-related difficulties.

A mixed-methods assessment of sexual and gender-based violence in eastern Democratic Republic of Congo to inform national and international strategy implementation.

CONTEXT: National and international strategies were implemented in eastern Democratic Republic of Congo (DRC) to address sexual and gender-based violence (SGBV). OBJECTIVES: The objective was to assess community attitudes of SGBV and health facility capacity to address SGBV in eastern DRC. DESIGN AND SETTING: The design and setting are as follows: a cross-sectional, population-based cluster survey of 998 adults in eastern DRC territories, a convenience sample of 27 adults using semi-structured directed interviews, qualitative data from 37 focus groups conducted in three health zones, assessment of 64 health facilities and a comparative analysis of SGBV strategies. MAIN OUTCOME MEASURES: The main outcome measures opinions regarding SGBV prevention and justice and health facility capacity to address SGBV. RESULTS: The majority of respondents favored the legal system over community mediation to obtain justice for SGBV. However, 61.1% (95% CI, 51.8-70.5%) of SGBV survivors reported being forced to accept community mediation. Among SGBV survivors, 81.2% (95% CI, 74.5-87.8%) reported no available mental health care. Less than half of all respondents reported access to a hospital, clinic or pharmacy. The analyses and facility assessment reinforce the need to improve SGBV care. CONCLUSIONS: Mixed methodologies point to the complexities of addressing SGBV, assess key elements of SGBV prevention, justice and response, and may ultimately inform national and international strategies.

Academic affiliated training centers in humanitarian health, Part I: program characteristics and professionalization preferences of centers in North America.

The collaborative London based non-governmental organization network ELRHA (Enhancing Learning and Research for Humanitarian Assistance) supports partnerships between higher education institutions and humanitarian organizations worldwide with the objective to enhance the professionalization of the humanitarian sector. While coordination and control of the humanitarian sector has plagued the response to every major crisis, concerns highlighted by the 2010 Haitian earthquake response further catalyzed and accelerated the need to ensure competency-based professionalization of the humanitarian health care work force. The Harvard Humanitarian Initiative sponsored an independent survey of established academically affiliated training centers in North America that train humanitarian health care workers to determine their individual training center characteristics and preferences in the potential professionalization process. The survey revealed that a common thread of profession-specific skills and core humanitarian competencies were being offered in both residential and online programs with additional programs offering opportunities for field simulation experiences and more advanced degree programs. This study supports the potential for the development of like-minded academic affiliated and competency-based humanitarian health programs to organize themselves under ELRHA's regional "consultation hubs" worldwide that can assist and advocate for improved education and training opportunities in less served developing countries.

Former combatants in Liberia: the burden of possible traumatic brain injury among demobilized combatants.

OBJECTIVE: To provide a better understanding of any associations between Disarmament, Demobilization, and Reintegration, previous head injury, and mental health symptoms among former combatants in Liberia. METHODS: A cluster-sampled national survey of the adult household-based Liberian population. FINDINGS: Former combatants with reported head injury were more likely to experience major depressive disorder symptoms, suicidal ideation and attempts, and current substance abuse. Former combatants with head injury are 2.83 times more likely to have major depressive disorder symptoms, and those with suspected traumatic brain injury are five times more likely to have post-traumatic stress disorder. INTERPRETATION: The poor mental health of former combatants in Liberia, both child and adult, might be mitigated if Disarmament, Demobilization, and Reintegration programming assessed participants for head trauma and traumatic brain injury using simple screening methods. The specific health and mental health needs of ex-combatants--a highly vulnerable group--will need to be addressed by Liberia. If left untreated, ex-combatants with high rates of suicidal ideation and post-traumatic stress disorder might be susceptible to re-recruitment into new conflicts in the region.

The Use of "Retardation" in FRAXA, FMRP, FMR1 and Other Designations.

The European Fragile X Network met in Wroclaw, Poland, November 2021, and agreed to work towards the eradication of the word "retardation" in regard to the naming of the fragile X gene (FRAXA) and protein (FMRP). There are further genes which have "retardation" or abbreviations for "retardation" in their names or full designations, including FMR1, FMR2, FXR1, FXR2, NUFIP1, AFF1, CYFIP1, etc. "Retardation" was commonly used as a term in years past, but now any reference, even in an abbreviation, is offensive. This article discusses the stigmatisation associated with "retardation", which leads to discrimination; the inaccuracy of using "retardation" in these designations; and the breadth of fragile X syndrome being beyond that of neurodiversity. A more inclusive terminology is called for, one which ceases to use any reference to "retardation". Precedents for offensive gene names being altered is set out. The proposal is to approach the HGNC (HUGO [Human Genome Organisation] Gene Nomenclature Committee) for new terminology to be enacted. Ideas from other researchers in the field are welcomed.

Priority strategies to improve gender equity in Canadian emergency medicine: proceedings from the CAEP 2021 Academic Symposium on leadership.

OBJECTIVES: Gender inequities are deeply rooted in our society and have significant negative consequences. Female physicians experience numerous gender-related inequities (e.g., microaggressions, harassment, violence). These inequities have far-reaching consequences on health, well-being and career longevity and may result in the devaluing of various strengths that female emergency physicians bring to the table. This, in turn, has an impact on patient healthcare experience and outcomes. During the 2021 Canadian Association of Emergency Physicians (CAEP) Academic Symposium, a national collaborative sought to understand gender inequities in emergency medicine in Canada. METHODS: We used a multistep stakeholder-engagement-based approach (harnessing both quantitative and qualitative methods) to identify and prioritize problems with gender equity in emergency medicine in Canada. Based on expert consultation and literature review, we developed recommendations to effect change for the higher priority problems. We then conducted a nationwide consultation with the Canadian emergency medicine community via online engagement and the CAEP Academic Symposium to ensure that these priority problems and solutions were appropriate for the Canadian context. CONCLUSION: Via the above process, 15 recommendations were developed to address five unique problem areas. There is a dearth of research in this important area and we hope this preliminary work will serve as a starting point to fuel further research. To facilitate these scholarly endeavors, we have appended additional documents identifying other key problems with gender equity in emergency medicine in Canada as well as proposed next steps for future research.

RéSUMé: OBJECTIFS: Les inégalités entre les sexes sont profondément ancrées dans notre société et ont des conséquences négatives importantes. Les femmes médecins subissent de nombreuses inégalités liées au genre (par exemple, microagressions, harcèlement, violence). Ces inégalités ont des conséquences considérables sur la santé, le bien-être et la longévité de la carrière et peuvent entraîner la dévalorisation des différents atouts que les femmes médecins urgentistes apportent à la table. Ceci, à son tour, a un impact sur l'expérience et les résultats des soins de santé des patients. Au cours du Symposium académique 2021 de l'Association canadienne des médecins d'urgence (ACMU), une collaboration nationale a cherché à comprendre les inégalités entre les sexes en médecine d'urgence au Canada. MéTHODES: Nous avons utilisé une approche en plusieurs étapes basée sur l'engagement des parties prenantes (en utilisant des méthodes quantitatives et qualitatives) pour identifier et classer par ordre de priorité les problèmes d'équité entre les sexes en médecine d'urgence au Canada. À partir d'une consultation d'experts et d'une revue de la littérature, nous avons élaboré des recommandations visant à apporter des changements aux problèmes les plus prioritaires. Nous avons ensuite mené une consultation nationale auprès de la communauté canadienne de médecine d'urgence par le biais d'un engagement en ligne et du symposium universitaire de l'ACMU afin de nous assurer que ces problèmes prioritaires et ces solutions étaient adaptés au contexte canadien. CONCLUSION: Grâce au processus ci-dessus, 15 recommandations ont été élaborées pour traiter 5 domaines problématiques uniques. Il existe un manque de recherche dans ce domaine important et nous espérons que ce travail préliminaire servira de point de départ pour alimenter d'autres recherches. Pour faciliter ces efforts de recherche, nous avons annexé d'autres documents identifiant d'autres problèmes clés en matière d'équité entre les sexes en médecine d'urgence au Canada, ainsi que des propositions d'étapes pour de futures recherches.

Chronic pain and marijuana use among a nationally representative sample of adults.

This study sought to examine the relations between chronic pain and marijuana use in a large nationally representative survey of adults (n = 5,672; 53% female; M(age) = 45.05, SD = 17.9) conducted in the United States. After controlling for sociodemographic variables, lifetime history of depression, and alcohol abuse/dependence, there was a significant association between lifetime chronic pain and lifetime and current marijuana use. Moreover, current chronic pain was significantly associated with lifetime marijuana use. There was no significant association between current chronic pain and current marijuana use, possibly owing to limited statistical power. Results suggest that there are generally consistent statistically significant relations between chronic pain and marijuana use. Future work is needed to explicate the developmental patterning between chronic pain and marijuana use. This paper presents the potential linkage between chronic pain and marijuana use. Results from this study suggest that it may be beneficial for clinicians to assess for marijuana use among patients suffering from chronic pain. Such patients may be using marijuana as a maladaptive coping strategy.