Identification of small-molecule protein-protein interaction inhibitors for NKG2D.

NKG2D (natural-killer group 2, member D) is a homodimeric transmembrane receptor that plays an important role in NK, γδ+, and CD8+ T cell-mediated immune responses to environmental stressors such as viral or bacterial infections and oxidative stress. However, aberrant NKG2D signaling has also been associated with chronic inflammatory and autoimmune diseases, and as such NKG2D is thought to be an attractive target for immune intervention. Here, we describe a comprehensive small-molecule hit identification strategy and two distinct series of protein-protein interaction inhibitors of NKG2D. Although the hits are chemically distinct, they share a unique allosteric mechanism of disrupting ligand binding by accessing a cryptic pocket and causing the two monomers of the NKG2D dimer to open apart and twist relative to one another. Leveraging a suite of biochemical and cell-based assays coupled with structure-based drug design, we established tractable structure-activity relationships with one of the chemical series and successfully improved both the potency and physicochemical properties. Together, we demonstrate that it is possible, albeit challenging, to disrupt the interaction between NKG2D and multiple protein ligands with a single molecule through allosteric modulation of the NKG2D receptor dimer/ligand interface.

Taurolidine and Heparin as Catheter Lock Solution for Central Venous Catheters in Hemodialysis.

BACKGROUND: Chronic kidney disease can lead to end-stage renal disease, and the prevalence is increasing. Many patients starting hemodialysis require central venous catheters (CVCs). Catheter-related bloodstream infections (CRBSIs) are a common complication and lead to significant morbidity and mortality. Interventions to prevent CRBSI include antimicrobial lock therapy but concern for the development of antimicrobial resistance and adverse effects. Nonantimicrobial antiseptics as catheter lock solutions have also been used. Taurolidine and heparin catheter lock solution is first approved by the Food and Drug Administration for the prevention of CRBSI in patients on hemodialysis. Taurolidine has a unique mechanism of action and favorable safety profile. MECHANISM OF ACTION, PHARMACODYNAMICS, AND PHARMACOKINETICS: Taurolidine and heparin catheter lock solution have both antimicrobial and anticoagulant properties. Taurolidine is derivative of the amino acid taurine, and heparin is derived from porcine intestinal mucosa. Taurolidine not only damages microbial cell walls but also prevents the adherence of microorganisms to biological surfaces, preventing biofilm formation. Taurolidine and heparin catheter lock solution is intended to be used intraluminally within the catheter and should be aspirated. Because it is used locally, limited pharmacokinetic and pharmacodynamic data are available. CLINICAL TRIALS: The LOCK-IT-100 trial is a randomized, double-blind, phase 3 study, which included 795 end-stage renal disease patients on hemodialysis with CVC. Taurolidine and heparin was compared with the control heparin alone. The results of the study showed a 71% risk reduction in CRBSI for taurolidine and heparin arm (95% confident interval, 38%-86%, P = 0.0006). Other studies have also shown that taurolidine lock solution leads to decreased CRBSI episodes. Several systematic reviews and meta-analysis consisted of taurolidine in adult, and pediatric populations also showed reduction in the incidence of CRBSIs. THERAPEUTIC ADVANCE: Taurolidine and heparin lock solution represents a novel preventive strategy for those undergoing hemodialysis through a CVC by reducing the risk of CRBSI. This is significant progress because there are no other similar options available for patients for whom catheters are the only options for their life-saving treatment.

Public health surveillance and the data, information, knowledge, intelligence and wisdom paradigm.

This article points out deficiencies in present-day definitions of public health surveillance, which include data collection, analysis, interpretation and dissemination, but not public health action. Controlling a public health problem of concern requires a public health response that goes beyond information dissemination. It is undesirable to have public health divided into data generation processes (public health surveillance) and data use processes (public health response), managed by two separate groups (surveillance experts and policy-makers). It is time to rethink the need to modernize the definition of public health surveillance, inspired by the authors' enhanced Data, Information, Knowledge, Intelligence and Wisdom model. Our recommendations include expanding the scope of public health surveillance beyond information dissemination to comprise actionable knowledge (intelligence); mandating surveillance experts to assist policy-makers in making evidence-informed decisions; encouraging surveillance experts to become policy-makers; and incorporating public health literacy training - from data to knowledge to wisdom - into the curricula for all public health professionals. Work on modernizing the scope and definition of public health surveillance will be a good starting point.

En este artículo se señalan las deficiencias de las definiciones actuales de la vigilancia de salud pública, que incluyen la recopilación, el análisis, la interpretación y la difusión de los datos, pero no las medidas de salud pública. El control de un problema de salud pública de interés exige una respuesta de salud pública que vaya más allá de la difusión de información. No es deseable que la salud pública esté dividida por un lado en procesos de generación de datos (vigilancia de salud pública) y por otro en procesos de uso de datos (respuesta de salud pública), gestionados por dos grupos diferentes (expertos en vigilancia y responsables de la formulación de políticas). Ha llegado el momento de replantear la necesidad de modernizar la definición de la vigilancia de salud pública tomando como referencia el modelo mejorado de Datos, Información, Conocimiento, Inteligencia y Sabiduría de los autores. Entre las recomendaciones que se proponen se encuentran las de ampliar el alcance de la vigilancia de salud pública más allá de la difusión de información para que incluya también el conocimiento aplicable (inteligencia); instar a los expertos en vigilancia a que presten ayuda a los responsables de la formulación de políticas en la toma de decisiones basadas en la evidencia; alentar a los expertos en vigilancia a que se conviertan en responsables de la formulación de políticas; e incorporar la formación en conocimientos básicos de salud pública (desde los datos hasta los conocimientos y la sabiduría) en los planes de estudio de todos los profesionales de la salud pública. Un buen punto de partida será trabajar en la modernización del alcance y la definición de la vigilancia de salud pública.

Este artigo aponta deficiências nas definições atuais de vigilância em saúde pública, que incluem coleta, análise, interpretação e disseminação de dados, mas não ações de saúde pública. O controle de um problema preocupante de saúde pública exige uma resposta de saúde pública que vá além da disseminação de informações. A saúde pública não deve ser dividida em processos de geração de dados (vigilância em saúde pública) e processos de uso de dados (resposta de saúde pública) gerenciados por dois grupos distintos (especialistas em vigilância e formuladores de políticas). É hora de repensar a necessidade de modernizar a definição de vigilância em saúde pública, inspirada no modelo aprimorado de Dados, Informações, Conhecimento, Inteligência e Sabedoria dos autores. Nossas recomendações incluem: expansão do escopo da vigilância em saúde pública para além da disseminação de informações, de modo a abranger conhecimentos acionáveis (inteligência); obrigatoriedade de que os especialistas em vigilância auxiliem os formuladores de políticas na tomada de decisões baseadas em evidências; incentivo para que os especialistas em vigilância se tornem formuladores de políticas; e incorporação de capacitação em letramento em saúde pública (partindo dos dados para o conhecimento e em seguida para a sabedoria) nos currículos de todos os profissionais de saúde pública. O trabalho de modernizar o escopo e a definição de vigilância em saúde pública será um bom ponto de partida.

Resonant Acoustic Rheometry to Measure Coagulation Kinetics in Hemophilia A and Healthy Plasma: A Novel Viscoelastic Method.

Compared with conventional coagulation tests and factor-specific assays, viscoelastic hemostatic assays (VHAs) can provide a more thorough evaluation of clot formation and lysis but have several limitations including clot deformation. In this proof-of-concept study, we test a noncontact technique, termed resonant acoustic rheometry (RAR), for measuring the kinetics of human plasma coagulation. Specifically, RAR utilizes a dual-mode ultrasound technique to induce and detect surface oscillation of blood samples without direct physical contact and measures the resonant frequency of the surface oscillation over time, which is reflective of the viscoelasticity of the sample. Analysis of RAR results of normal plasma allowed defining a set of parameters for quantifying coagulation. RAR detected a flat-line tracing of resonant frequency in hemophilia A plasma that was corrected with the addition of tissue factor. Our RAR results captured the kinetics of plasma coagulation and the newly defined RAR parameters correlated with increasing tissue factor concentration in both healthy and hemophilia A plasma. These findings demonstrate the feasibility of RAR as a novel approach for VHA, providing the foundation for future studies to compare RAR parameters to conventional coagulation tests, factor-specific assays, and VHA parameters.

Undiagnosed sub-valvular aortic stenosis with an associated Ventricular Septal Defect (VSD) presenting late in a multi-parous woman.

BACKGROUND: Sub-valvular aortic stenosis is a rare disorder that has a prevalence of 6.5% of all adult congenital heart diseases. The hemodynamic changes that occur in pregnancy with the resultant increase in cardiac output may not well be tolerated by a pregnant woman with sub-valvular aortic stenosis. CASE PRESENTATION: We report the case of a 34-year-old para 7 (6 alive + 1 dead) who has been experiencing intermittent episodes of easy fatigability on moderate exertion since childhood and had survived 6 prior pregnancies. During her last pregnancy, she started experiencing chest pain, palpitations, dyspnea, orthopnea, and pre-syncope at 36 weeks and had a caesarean section at 37 weeks on account of fetal distress. The post-delivery cardiac evaluation showed severe sub-valvular Aortic stenosis and a ventricular septal defect. CONCLUSION: Sub-valvular Aortic stenosis may progress slowly in adults and may be tolerated during pregnancy. Despite the rare presentation and contraindication of pregnancy in such a patient, she extraordinarily survived the pregnancy with a healthy baby. Routine cardiovascular assessment during prenatal, ante-natal and post-natal care is highly advocated particularly so in resource-poor settings.

Evaluation of health service outcomes for an audiology first point of contact retrocochlear clinic: a 6-year retrospective cohort study.

OBJECTIVE: Although existing studies of audiology first point of contact clinics which screen for retrocochlear pathology have demonstrated positive clinical outcomes, they have provided limited information regarding service impacts. Thus, this study aimed to evaluate both the clinical and health service outcomes of an audiology first point of contact (FPOC) clinic for adults referred to ENT services with suspected retrocochlear pathology. DESIGN: Retrospective cohort study. STUDY SAMPLE: All 1123 patients referred to the clinic over a 6-year period (2013-2019). RESULTS: Most (73.7%) of the 1123 patients referred to the Retrocochlear Clinic were managed and discharged by the audiologist and did not require ENT appointment. Almost half (43.1%) were directly referred for MRI imaging, of which 4 (1.1%) were diagnosed with Vestibular Schwannoma. Waiting times for first appointments significantly (p < 0.001) reduced from a median of 748 days to 63.5 days over the 6-year period. Attendance rates also significantly (p < 0.001) improved over this time (from 52.2% to 90%). There were no adverse events reported. Of those discharged without attending an ENT appointment, 1.8% were rereferred to ENT within 12 months of discharge. CONCLUSIONS: This audiology FPOC Retrocochlear Clinic was shown to be a safe and effective alternative service model.

Outcomes of a first point of contact speech language therapy clinic for patients requiring vocal cord check pre and post thyroid/parathyroid surgery.

INTRODUCTION: Speech Language Therapy First Point of Contact Clinic (SLT-FPOCC) models can assist assessment of low-risk patient populations referred to ear, nose and throat (ENT) services. To further improve ENT waitlist management and compliance with best-practice care, consideration of other low-risk populations that could be safely managed through this service model is needed. The aims of this paper are to evaluate the clinical and service outcomes of completing vocal cord check (VCC) assessments for patients' pre and post thyroid/parathyroid surgery within an SLT-FPOCC model and examine consumer perceptions. METHODS & PROCEDURES: The service followed existing SLT-FPOCC procedures, with ENT triaging referrals, then SLT completing pre- and postoperative VCC assessment (interview, perceptual assessment, flexible nasendoscopy), with assessment data later reviewed by ENT to diagnose laryngeal pathology. Clinical and service outcomes were collected prospectively. Patients completed an anonymous post-service satisfaction survey. RESULTS: Of the first 100 patients referred for preoperative VCCs, SLT assessment identified 42 with dysphonia and 30 reporting dysphagia, while ENT confirmed 9 with significant preoperative anatomical findings. Eighty-three underwent surgery, with 63 (95 nerves at surgical risk) returning for a postoperative VCC. Postoperative VCC identified three temporary neuropraxias (3.2%) and three unilateral vocal fold paresis (3.2%). Patients were highly satisfied with the service. All 163 pre-/postoperative VCCs were completed with no adverse events. CONCLUSION & IMPLICATIONS: The current data support SLT-FPOCC service expansion to include pre and post thyroid/parathyroid surgery VCC checks, with positive consumer perception. The model supports delivery of best practice management (i.e., pre- and postoperative VCC) for patients receiving surgery for thyroid/parathyroid dysfunction, and associated efficiencies for ENT services. WHAT THIS PAPER ADDS: What is already known Assessment of laryngeal function via flexible nasoendoscopy is recommended best practice for patients pre and postthyroid/parathyroid surgery, as recurrent laryngeal nerve injury is a low incidence (<10%), yet well-recognised risk of these surgeries. Traditionally, general surgeons refer presurgical patients to ear, nose and throat (ENT) for vocal cord check (VCC) assessment. However, with access to specialist outpatient services under increasing pressure, there is growing support for utilisation of other health professionals, such as speech-language therapists working in first point of contact (FPOCC) models, to assist with the administration of pre- and postsurgical assessments of such low-risk populations. What this study adds This work expands on the emerging body of evidence for speech language therapy (SLT) led FPOCC models within ENT outpatient services, providing clinical and service outcomes to support the safety of a new model designed to administer VCCs for patients pre and post thyroid/parathyroid surgery. Adopting a similar model to a prior published SLT-led FPOCC model, the trained SLT completes the pre- and postsurgical VCC including flexible nasoendoscopy and videostroboscopy, with images and clinical information then presented to ENT for diagnosis and management planning. This study also provides the first data on consumer perceptions of this type of service model. Clinical implications of this study Data on 100 consecutive presurgical patients revealed positive service findings, supporting the safety of this model. Nature and incidence of clinical findings pre and post surgery were consistent with previously published studies using traditional models of care (i.e., ENT completing the flexible nasendoscopy). Consumer perception was positive. This model enables delivery of pre-and postsurgical assessments for patients receiving thyroid/parathyroid surgery, consistent with best practice care, and reduces burden on ENT services. In total 163 ENT appointments were avoided with this model, with positive implications for ENT waitlist management.

Epithelial sodium transport and its control by aldosterone: the story of our internal environment revisited.

Transcription and translation require a high concentration of potassium across the entire tree of life. The conservation of a high intracellular potassium was an absolute requirement for the evolution of life on Earth. This was achieved by the interplay of P- and V-ATPases that can set up electrochemical gradients across the cell membrane, an energetically costly process requiring the synthesis of ATP by F-ATPases. In animals, the control of an extracellular compartment was achieved by the emergence of multicellular organisms able to produce tight epithelial barriers creating a stable extracellular milieu. Finally, the adaptation to a terrestrian environment was achieved by the evolution of distinct regulatory pathways allowing salt and water conservation. In this review we emphasize the critical and dual role of Na(+)-K(+)-ATPase in the control of the ionic composition of the extracellular fluid and the renin-angiotensin-aldosterone system (RAAS) in salt and water conservation in vertebrates. The action of aldosterone on transepithelial sodium transport by activation of the epithelial sodium channel (ENaC) at the apical membrane and that of Na(+)-K(+)-ATPase at the basolateral membrane may have evolved in lungfish before the emergence of tetrapods. Finally, we discuss the implication of RAAS in the origin of the present pandemia of hypertension and its associated cardiovascular diseases.

Gut microbiota and systemic immunity in health and disease.

The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. Although the influence of the gut microbiota on intestinal physiology and immunity is well known, mounting evidence suggests a key role for intestinal symbionts in controlling immune cell responses and development outside the gut. Although the underlying mechanisms by which the gut symbionts influence systemic immune responses remain poorly understood, there is evidence for both direct and indirect effects. In addition, the gut microbiota can contribute to immune responses associated with diseases outside the intestine. Understanding the complex interactions between the gut microbiota and the host is thus of fundamental importance to understand both immunity and human health.

Diagnostic and management plan concordance across advanced audiologists, paediatric audiologists and non-specialist ENT doctors.

OBJECTIVE: To compare the concordance of advanced audiologists (AA), junior doctors (JD) and paediatric audiologists (PA) with an Ear, Nose and Throat (ENT) specialist on the diagnosis and management of children with middle ear or hearing concerns. DESIGN: A clinical equivalence (concordance) study. STUDY SAMPLE: Three AAs, five JDs, three PAs and one ENT specialist asynchronously reported diagnoses and management plans for ten, online paediatric cases consisting of video-otoscopic images and clinical findings. RESULTS: For medical diagnosis, significant agreement with the ENT specialist was observed at moderate and near-perfect levels for two AAs (k = 0.561 and 0.815), moderate levels for four JDs (k = 0.5 to 0.603) and near-perfect level for one PA (k = 0.815). For management decisions, significant agreement with the ENT specialist was observed at substantial (k = 0.636) and near-perfect (k = 0.818) levels for two AAs, and at a moderate level (k = 0.538) for one PA. Within group inter-rater agreement for management plans was substantial for AAs and JDs, and moderate for PAs. CONCLUSIONS: For children with middle ear disease or hearing concerns, AAs, JDs and PAs showed similar levels of agreement with an ENT specialist on diagnosis, but AAs were more likely than JDs or PAs to agree with an ENT specialist on management.

Parental satisfaction with an advanced audiology-led triage service in paediatric ENT outpatient clinics.

OBJECTIVE: The advanced audiology-led service is designed to triage and manage children who are referred to Ear Nose and Throat (ENT) outpatient services with middle ear or hearing concerns. This service has resulted in shorter waiting times for children to receive ENT treatment, and improved ENT capacity. The aim of this study was to explore parental satisfaction with the advanced audiology-led ENT service and to determine if there were cultural or process factors affecting satisfaction. DESIGN: Prospective cross-sectional study using a modified Visit-Specific Satisfaction Questionnaire (VSQ-9) survey. STUDY SAMPLE: One hundred and thirteen parents of children consecutively attending a first appointment in the advanced audiology-led service recruited between October 2016 and October 2017. RESULTS: There were a total of 100 valid responses (rate of 88.5%). The survey showed high levels of satisfaction. Satisfaction scores were significantly higher for items related to interactions with the audiologist compared to items related to waiting times. There were no differences in satisfaction across cultural groups. Parents were equally satisfied with the service whether their child was managed independently by the audiologist or required another appointment for medical input. CONCLUSIONS: The advanced audiology-led service had high levels of satisfaction from parents attending with their children.

Speech pathology prescribing in the outpatient setting: A review of requirements, considerations and barriers.

BACKGROUND: As health systems face increasing demands, non-medical prescribing is a workforce redesign strategy adopted within some services. Despite successful implementation in other professional groups, non-medical prescribing within speech pathology (SP) has not yet been described. AIMS: To provide a descriptive account of the development and planned implementation of two SP prescribing models. METHODS & PROCEDURES: The evolution of two SP-led prescribing models, including relevant training and credentialing, for use of (1) nystatin oral drops (100,000 units/mL); and (2) lidocaine (lignocaine) and phenylephrine nasal spray (5 mg/500 µg/spray), in the outpatient setting is detailed. Challenges to implementation are outlined. MAIN CONTRIBUTION: The development of relevant governance structures, a research evidenced-based project evaluation framework, and an overview of training pathways and credentialing was successfully completed. However, implementation of the models was unable to be achieved. A thorough review of the requirements and a discussion of contextual considerations that had a negative influence on the implementation of SP-led prescribing within this specific service context is provided. CONCLUSIONS & IMPLICATIONS: The successful implementation of SP-led prescribing is complex and highly context dependent. This work offers a discussion and review of the complexities of introducing a non-medical prescribing model in an outpatient hospital setting. WHAT THIS PAPER ADDS: What is already known on the subject Allied Health prescribing is an emerging practice area aiming to reduce current pressures on health services. SP-led prescribing has not been thoroughly investigated in the Australian context. What this study adds to existing knowledge This study describes the development of a SP-led prescribing process in the outpatient setting, and a thorough review and discussion of the drivers and barriers to the model's implementation. What are the potential or actual clinical implications of this work? The successful implementation of SP-led prescribing was identified to be complex from a legislative and operational perspective, as well as being highly context dependent. This study further highlights the importance of a thorough context evaluation and workflow mapping prior to full-scale implementation of SP prescribing trials.

Effect of text message communication on patient presentation for an influenza vaccination in a community-based pharmacy setting.

BACKGROUND: Community pharmacies use text message communications for information regarding approaching refills and fill status. Patients can also be notified regarding annual influenza vaccine availability and schedule an appointment for the vaccine. OBJECTIVES: This study aimed to evaluate whether text message communications affected patient presentation and resulted in a percent increase of patients receiving an influenza vaccine compared with previous vaccine season and to determine whether additional vaccines are administered upon presentation. METHODS: Ambidirectional study retrospectively analyzed the impact, nationally, of a new text message communication on influenza vaccinations at a large community pharmacy chain and prospectively surveyed patients receiving an influenza vaccine at 2 geographically similar pharmacies of the chain in Southwest Virginia. Text message communications regarding vaccine and appointment availability were sent to patients at the age of 18 years and older who opted in to text message communications and received an influenza vaccine with the chain during the 2019-2020 influenza season. Vaccine data from consecutive seasons were compared. Eligible patients in Southwest Virginia were surveyed about how they were informed about availability, previous intent to receive an influenza vaccine, applicability to other vaccines, and effect of the coronavirus disease 2019 pandemic on vaccination. Results were analyzed using bivariate and multivariate analyses. RESULTS: Nationally, influenza vaccines administered increased by 17.45% in patients who permitted text message communication and overall by 13.22% after implementation. Decreases in co-administered pneumococcal vaccines and tetanus, diphtheria, and pertussis vaccines and an increase in co-administered zoster vaccines were observed. A total of 111 patients were surveyed; 4% presented owing to text message communication. A majority were intent on receiving the vaccine before being notified and reported that the pandemic did not affect presentation. Notably, 45.05% of patients were likely to receive routine vaccines if notified by text message. CONCLUSION: Text message communications are another viable way to increase vaccinations, but further studies should be conducted outside of a pandemic setting.

[Comparative analysis of the brain distribution of [18F]FDG in populations of patients with Alzheimer's disease with or without family history of dementia]. / Analyse comparative de la distribution cérébrale du [18F]FDG dans une population de patients souffrant de maladie d'Alzheimer présentant ou non des antécédents familiaux de démence.

Hereditary forms of Alzheimer's disease (AD) and early-onset forms have more brain damage than sporadic or late-onset forms at the time of diagnosis (1, 2). Data in the literature are contradictory concerning familial forms without known heredity or mutation. The aim of this study was to compare the brain distribution of FDG between two populations of patients with a clinical diagnosis of sporadic AD according to the presence or not of a first degree family history of dementia. We retrospectively included 243 patients with clinical diagnosis of AD who underwent brain FDG PET imaging between 2012 and 2017. SPM12 was used to compare the FDG brain distribution in 199 patients with AD and no familial history of dementia and 43 patients with AD and first degree familial history of dementia. Compared to a database of 22 healthy control subjects, both groups of AD patients showed a significant decrease of FDG distribution in temporo-parietal, posterior cingulate and posterior left frontal cortex with respect to the controls (p inferior to 0.05 corrected for the family-wise error, pFWE-corr). There were no significant differences between the two AD groups (pFWE-corr superior to 0.05 and p superior to 0.001 uncorrected for multiple comparisons) that present the same brain metabolic pathology.

Les formes héréditaires de la maladie d'Alzheimer (MA) et les formes à début précoce présentent une atteinte cérébrale plus importante que les formes sporadiques ou celles à début tardif au moment du diagnostic (1, 2). Les données de la littérature sont contradictoires en ce qui concerne les formes familiales sans hérédité ni mutation connue. L'objectif de cette étude était de comparer la distribution cérébrale du [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) entre deux populations de patients présentant un diagnostic clinique de la MA sporadique selon la présence, ou non, d'une histoire familiale de démence au premier degré. Dans cette étude rétrospective, nous avons inclus 243 patients vus entre 2012 et 2017. Le logiciel SPM12 a été utilisé pour comparer la distribution cérébrale du FDG entre 199 patients souffrant de MA, sans histoire familiale et 43 patients souffrant de MA avec une histoire familiale de démence au premier degré. Comparés à une base de données de 22 sujets contrôles sains, chacun des deux groupes de patients présentait une réduction significative de la distribution du FDG au niveau du cortex temporo-pariétal, cingulaire postérieur et frontal postérieur gauche (p inf�rieur a 0,05 corrigé pour le family-wise error, pFWE-corr), caractéristique de la maladie. Il n'y avait pas de différence significative entre les deux groupes MA (pFWE-corr sup�rieur a 0,05 et p sup�rieur a 0,001 non corrigé, pour des comparaisons multiples) qui présentent donc la même altération métabolique cérébrale.

Effects of Age, Level of Education and HIV Status on Cognitive Performance in West African Older Adults: The West Africa IeDEA Cohort Collaboration.

An in-depth understanding of the impact of aging, cognitive reserve, and HIV status on cognitive function is needed in older West African adults. Ninety-nine HIV-negative and 334 HIV-positive adults aged ≥ 50 years were enrolled in three clinics (Senegal and Côte d'Ivoire) participating in the IeDEA West Africa collaboration. All subjects underwent the Free and Cued Selective Reminding Test (FCSRT) and the Isaacs Set Test (IST). Age (both linear and quadratic), education level, and HIV status effects on Z-scores were assessed using multivariate linear regression models. Interactions between HIV status and age or educational level were tested. In the present cohort of older West African adults, the role of age and educational level on episodic memory and verbal fluency was observed without revealing an interaction between HIV status and age effect. As age had quadratic effects, older HIV-positive adults should not be considered as a unique group irrespective of their age. Low-educated HIV-positive patients had the lowest verbal fluency performance compared to others. Further studies are needed to duplicate these results. In clinical settings, screening and adapted programs focusing on improving cognition in those patients are needed.

The Transcription Factor RORα Preserves ILC3 Lineage Identity and Function during Chronic Intestinal Infection.

Innate lymphoid cells (ILCs) are critical for host defense and tissue repair but can also contribute to chronic inflammatory diseases. The transcription factor RORα is required for ILC2 development but is also highly expressed by other ILC subsets where its function remains poorly defined. We previously reported that Rorasg/sg bone marrow chimeric mice (C57BL/6J) were protected from Salmonella-induced intestinal fibrosis due to defective ILC3 responses. In this study, single-cell RNA analysis of ILCs isolated from inflamed tissues indicates that RORα perturbation led to a reduction in ILC3 lineages. Furthermore, residual Rorasg/sg ILC3s have decreased expression of key signature genes, including Rorc and activating cytokine receptors. Collectively, our data suggest that RORα plays a key role in preserving functional ILC3s by modulating their ability to integrate environmental cues to efficiently produce cytokines.

IL-22 Preserves Gut Epithelial Integrity and Promotes Disease Remission during Chronic Salmonella Infection.

The cytokine IL-22 is rapidly induced at barrier surfaces where it regulates host-protective antimicrobial immunity and tissue repair but can also enhance disease severity in some chronic inflammatory settings. Using the chronic Salmonella gastroenteritis model, Ab-mediated neutralization of IL-22 impaired intestinal epithelial barrier integrity and, consequently, exaggerated expression of proinflammatory cytokines. As disease normally resolved, neutralization of IL-22 caused luminal narrowing of the cecum-a feature reminiscent of fibrotic strictures seen in Crohn disease patients. Corresponding to the exaggerated immunopathology caused by IL-22 suppression, Salmonella burdens in the gut were reduced. This enhanced inflammation and pathogen clearance was associated with alterations in gut microbiome composition, including the overgrowth of Bacteroides acidifaciens Our findings thus indicate that IL-22 plays a protective role by limiting infection-induced gut immunopathology but can also lead to persistent pathogen colonization.

Chronic neuroangiostrongyliasis: case study of chronic presentations in Hawaii.

This paper describes chronic features of neuroangiostrongyliasis (NAS), a long-term outcome of the disease that has not been adequately described. Current and past literature is predominantly limited to acute manifestations of NAS, and mention of chronic, ongoing clinical symptoms is usually limited to brief notes in a discussion of severe cases. This study investigated the long-term outcomes in ten individuals who were diagnosed with acute neuroangiostrongyliasis in Hawaii between 2009 and 2017. The study demonstrates a significant number of persons in Hawaii sustain residual symptoms for many years, including troublesome sensory paresthesia (abnormal spontaneous sensations of skin experienced as 'burning, pricking, pins and needles'; also described as allodynia or hyperesthesia) and extremity muscle pains. As a consequence, employment and economic hardships, domestic relocations, and psychological impairments affecting personal relationships occurred. The study summarizes common features of chronic disease, sensory paresthesia and hyperesthesia, diffuse muscular pain, insomnia, and accompanying emotional distress; highlights the frequently unsuccessful endeavours of individuals struggling to find effective treatment; proposes pathogenic mechanisms responsible for prolonged illness including possible reasons for differences in disease presentation in Hawaii compared to Southeast Asia.

Neural changes following a body-oriented resilience therapy with elements of kickboxing for individuals with a psychotic disorder: a randomized controlled trial.

Individuals with a psychotic disorder are at an increased risk of becoming the victim of a crime. A body-oriented resilience therapy (BEATVIC) aimed at preventing victimization by addressing putatively underlying factors was developed. One of these factors is social cognition, particularly facial affect processing. The current study investigated neural effects of BEATVIC on facial affect processing using two face processing tasks. Participants were randomized to either BEATVIC or a 'Befriending' control group. Twenty-seven patients completed an Emotional Faces task and the Wall of Faces task during fMRI, pre- and post-intervention. General linear model analyses yielded no differences between groups over time. Independent component analyses revealed increased activation of the salience network to angry and fearful faces in BEATVIC compared to Befriending. Increased activation of the salience network may suggest an increased alertness for potentially dangerous faces.

EARLY RETINAL MICROVASCULAR ABNORMALITIES IN YOUNG ADULTS WITH TYPE 1 DIABETES MELLITUS WITHOUT CLINICALLY EVIDENT DIABETIC RETINOPATHY.

PURPOSE: To characterize the early retinal microvascular changes in young adults (age: 22.69 ± 3.50 years) with Type 1 diabetes mellitus without clinically detectable diabetic retinopathy using optical coherence tomography angiography and investigate the associated factors. METHODS: A total of 36 participants with Type 1 diabetes mellitus (70 eyes) and 34 healthy controls (57 eyes) were retrospectively reviewed. The analyzed optical coherence tomography angiography indices included capillary vessel density, foveal avascular zone area/perimeter/acircularity index, and foveal vascular density, acquired in the 6 × 6-mm2 area centered on the fovea. The generalized estimation equations model was applied to compare the mean values and to study the associated factors. RESULTS: In subjects with diabetes, statistically significant decreases were observed in parafoveal vessel density in both superficial and deep capillary plexuses, foveal avascular zone area/perimeter, and foveal vascular density when compared with controls (all P < 0.05). Higher glycated hemoglobin level was independently associated with the decrease of parafoveal vessel density as well as the increase of foveal avascular zone area/perimeter (all P < 0.05). Prepubescent onset of diabetes mellitus was also independently associated with the decrease of superficial parafoveal vessel density, foveal avascular zone area/perimeter, and foveal vascular density (P = 0.015, 0.011, 0.015, and 0.001, respectively). CONCLUSION: In young adults with Type 1 diabetes mellitus lacking clinical signs of diabetic retinopathy, optical coherence tomography angiography revealed alterations in retinal microvasculature that were associated with glycated hemoglobin level and onset of diabetes mellitus related to puberty.