RESUMEN
The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8+ T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules. This subset also expressed genes for granzymes, perforin, interferon-γ, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumulation. Leukocyte-restricted STAT3 GOF was sufficient and CD8+ T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8+ T cell oligoclonal accumulation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.
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Enfermedades Autoinmunes , Leucemia Linfocítica Granular Grande , Animales , Ratones , Enfermedades Autoinmunes/genética , Enfermedades Autoinmunes/patología , Linfocitos T CD8-positivos , Mutación con Ganancia de Función , Leucemia Linfocítica Granular Grande/genética , Leucemia Linfocítica Granular Grande/patología , Mutación , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismoRESUMEN
BACKGROUND: No approved treatment for peanut allergy exists for children younger than 4 years of age, and the efficacy and safety of epicutaneous immunotherapy with a peanut patch in toddlers with peanut allergy are unknown. METHODS: We conducted this phase 3, multicenter, double-blind, randomized, placebo-controlled trial involving children 1 to 3 years of age with peanut allergy confirmed by a double-blind, placebo-controlled food challenge. Patients who had an eliciting dose (the dose necessary to elicit an allergic reaction) of 300 mg or less of peanut protein were assigned in a 2:1 ratio to receive epicutaneous immunotherapy delivered by means of a peanut patch (intervention group) or to receive placebo administered daily for 12 months. The primary end point was a treatment response as measured by the eliciting dose of peanut protein at 12 months. Safety was assessed according to the occurrence of adverse events during the use of the peanut patch or placebo. RESULTS: Of the 362 patients who underwent randomization, 84.8% completed the trial. The primary efficacy end point result was observed in 67.0% of children in the intervention group as compared with 33.5% of those in the placebo group (risk difference, 33.4 percentage points; 95% confidence interval, 22.4 to 44.5; P<0.001). Adverse events that occurred during the use of the intervention or placebo, irrespective of relatedness, were observed in 100% of the patients in the intervention group and 99.2% in the placebo group. Serious adverse events occurred in 8.6% of the patients in the intervention group and 2.5% of those in the placebo group; anaphylaxis occurred in 7.8% and 3.4%, respectively. Serious treatment-related adverse events occurred in 0.4% of patients in the intervention group and none in the placebo group. Treatment-related anaphylaxis occurred in 1.6% in the intervention group and none in the placebo group. CONCLUSIONS: In this trial involving children 1 to 3 years of age with peanut allergy, epicutaneous immunotherapy for 12 months was superior to placebo in desensitizing children to peanuts and increasing the peanut dose that triggered allergic symptoms. (Funded by DBV Technologies; EPITOPE ClinicalTrials.gov number, NCT03211247.).
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Anafilaxia , Desensibilización Inmunológica , Hipersensibilidad al Cacahuete , Preescolar , Humanos , Lactante , Alérgenos/efectos adversos , Anafilaxia/etiología , Arachis/efectos adversos , Desensibilización Inmunológica/efectos adversos , Desensibilización Inmunológica/métodos , Hipersensibilidad al Cacahuete/complicaciones , Hipersensibilidad al Cacahuete/terapia , Administración CutáneaRESUMEN
BACKGROUND: In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. METHODS AND FINDINGS: OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). CONCLUSIONS: Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. TRIAL REGISTRATION: Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).
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Vacuna contra Difteria, Tétanos y Tos Ferina , Esquemas de Inmunización , Inmunoglobulina E , Humanos , Lactante , Método Doble Ciego , Inmunoglobulina E/inmunología , Inmunoglobulina E/sangre , Femenino , Masculino , Vacuna contra Difteria, Tétanos y Tos Ferina/inmunología , Vacuna contra Difteria, Tétanos y Tos Ferina/administración & dosificación , Vacuna contra Difteria, Tétanos y Tos Ferina/efectos adversos , Australia , Vacunas Combinadas/inmunología , Vacunas Combinadas/efectos adversos , Vacunas Combinadas/administración & dosificación , Vacuna contra la Tos Ferina/inmunología , Vacuna contra la Tos Ferina/efectos adversos , Vacuna contra la Tos Ferina/administración & dosificación , Hipersensibilidad a los Alimentos/inmunología , Hipersensibilidad a los Alimentos/prevención & control , Vacuna Antipolio de Virus Inactivados/inmunología , Vacuna Antipolio de Virus Inactivados/efectos adversos , Vacuna Antipolio de Virus Inactivados/administración & dosificación , Vacunas contra Haemophilus/inmunología , Vacunas contra Haemophilus/efectos adversos , Vacunas contra Haemophilus/administración & dosificación , Tos Ferina/prevención & control , Tos Ferina/inmunología , Inmunogenicidad Vacunal , Anticuerpos Antibacterianos/sangre , Anticuerpos Antibacterianos/inmunologíaRESUMEN
B cells and their secreted antibodies are fundamental for host-defense against pathogens. The generation of high-affinity class switched antibodies results from both somatic hypermutation (SHM) of the immunoglobulin (Ig) variable region genes of the B-cell receptor and class switch recombination (CSR) which alters the Ig heavy chain constant region. Both of these processes are initiated by the enzyme activation-induced cytidine deaminase (AID), encoded by AICDA. Deleterious variants in AICDA are causal of hyper-IgM syndrome type 2 (HIGM2), a B-cell intrinsic primary immunodeficiency characterised by recurrent infections and low serum IgG and IgA levels. Biallelic variants affecting exons 2, 3 or 4 of AICDA have been identified that impair both CSR and SHM in patients with autosomal recessive HIGM2. Interestingly, B cells from patients with autosomal dominant HIGM2, caused by heterozygous variants (V186X, R190X) located in AICDA exon 5 encoding the nuclear export signal (NES) domain, show abolished CSR but variable SHM. We herein report the immunological and functional phenotype of two related patients presenting with common variable immunodeficiency who were found to have a novel heterozygous variant in AICDA (L189X). This variant led to a truncated AID protein lacking the last 10 amino acids of the NES at the C-terminal domain. Interestingly, patients' B cells carrying the L189X variant exhibited not only greatly impaired CSR but also SHM in vivo, as well as CSR and production of IgG and IgA in vitro. Our findings demonstrate that the NES domain of AID can be essential for SHM, as well as for CSR, thereby refining the correlation between AICDA genotype and SHM phenotype as well as broadening our understanding of the pathophysiology of HIGM disorders.
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Citidina Desaminasa , Síndrome de Inmunodeficiencia con Hiper-IgM , Cambio de Clase de Inmunoglobulina , Humanos , Citidina Desaminasa/genética , Citidina Desaminasa/metabolismo , Síndrome de Inmunodeficiencia con Hiper-IgM/genética , Inmunoglobulina A/genética , Cambio de Clase de Inmunoglobulina/genética , Inmunoglobulina G/genética , Fenotipo , Hipermutación Somática de InmunoglobulinaRESUMEN
BACKGROUND: Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells. METHODS: iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aß42 and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aß42. RESULTS: AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100ß and increased secretion and phagocytosis of Aß42 while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia. CONCLUSION: Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a 'primed' phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aß42 production and phagocytosis.
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Enfermedad de Alzheimer , Células Madre Pluripotentes Inducidas , Humanos , Astrocitos/metabolismo , Microglía/metabolismo , Células Madre Pluripotentes Inducidas/metabolismo , Interleucina-8/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/metabolismo , Citocinas/metabolismo , Fenotipo , Péptidos beta-Amiloides/metabolismo , Presenilina-2/genética , Presenilina-2/metabolismoRESUMEN
RATIONALE & OBJECTIVE: Females have a higher prevalence of chronic kidney disease (CKD) than males but are less likely to be treated with kidney replacement therapy (KRT). We studied the interaction between sex and the association of cardiometabolic risk factors for the decline in kidney function over time. STUDY DESIGN: A population-based cohort study. SETTING & PARTICIPANTS: 1,127,731 adults living in Wales, United Kingdom, within the Secure Anonymised Information Linkage Databank. EXPOSURE: Sex and risk factors including age, estimated glomerular filtration rate (eGFR), cardiometabolic conditions, smoking, and socioeconomic deprivation. These risk factors were defined using primary care records. OUTCOME: The yearly declines in eGFR and the risk of incident kidney failure defined as long-term KRT and/or sustained eGFR<15mL/min/1.73m2. ANALYTICAL APPROACH: Linear mixed effects models and Cox proportional hazards analysis. RESULTS: The average decline in eGFR at age≤73 years was equal in males and females. After age 73 years, eGFR decline was faster in males than females, particularly for males with heart failure (males-1.22mL/min/1.73m2 per year [95% CI, -1.25 to-1.20] vs females-0.87mL/min/1.73m2 per year [95% CI, -0.89 to-0.85]) and current smokers (males-1.58mL/min/1.73m2 per year [95% CI, -1.60 to-1.55] vs females-1.27mL/min/1.73m2 per year [95% CI, -1.29 to-1.25]). Socioeconomic deprivation was one of the most impactful risk factors on eGFR decline among females aged>73 years, whereas cardiometabolic risk factors were more important among males. Older females at baseline were less likely to develop incident kidney failure than older males (P for age<0.001). LIMITATIONS: Study of people who were almost exclusively White and who had blood laboratory test data. Reliance on creatinine-based eGFR. Albuminuria and body mass index data were incomplete. CONCLUSIONS: The eGFR decline was faster in males than in females, especially in the setting of heart failure and smoking. Socioeconomic deprivation was an important risk factor associated with eGFR decline, particularly for females. further work is required to explore less well-recognized risk factors, but these findings may inform clinical management strategies of CKD overall and within sex-specific groups. PLAIN-LANGUAGE SUMMARY: Kidney function is known to decline at a faster rate among males than females. This study incorporated blood laboratory test results from the routine care of 1.1 million adults living in the United Kingdom and found that the decline in kidney function associated with risk factors varied by sex. Before and at the age of 73 years, the decline in kidney function was similar between males and females. After age 73, cardiometabolic risk factors were associated with faster decline in kidney function among males than females, specifically heart failure and smoking. Socioeconomic deprivation was also associated with the decline in kidney function for both sexes, but it was a stronger risk factor among females. These findings may inform the management of kidney disease overall and within sex-specific groups.
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BACKGROUND: Few studies have examined long-term outcomes following oral immunotherapy (OIT); none have examined long-term risks and benefits associated with distinct clinical outcomes (desensitization, remission). METHODS: Participants completing the probiotic and peanut oral immunotherapy (PPOIT) -003 randomized trial were enrolled in a follow-on study, PPOIT-003LT. Peanut ingestion, reactions, and health-related quality of life (HRQOL) were monitored prospectively. Outcomes at 1-year and 2-years post-treatment were examined by treatment group and by post-OIT clinical outcome (remission, desensitization without remission [DWR], allergic). RESULTS: 86% (151/176) of eligible children enrolled. Post-treatment peanut ingestion at 2-years post-treatment were similar for PPOIT (86.7%) and OIT (78.7%) groups, both higher than placebo (10.3%). Reactions reduced over time for all treatment and clinical outcome groups (PPOIT 31.7% to 23.3%, OIT 37.7% to 19.7%, placebo 13.8% to 6.9%; remission 27.5% to 15.9%; DWR 57.9% to 36.8%; allergic 11.6% to 7%). At 2-years post-treatment, similar proportions of remission and allergic participants reported reactions (RD 0.09 (95%CI -0.03, 0.20), p = .127), whereas more DWR participants reported reactions than remission (remission vs DWR: RD -0.21 (95%CI -0.39; -0.03), p = .02) and allergic (DWR vs allergic: RD 0.30 (95%CI 0.13, 0.47), p = .001) participants. At 2-years post-treatment, 0% remission versus 5.3% DWR versus 2.3% allergic participants reported adrenaline injector usage. Remission participants had significantly greater HRQOL improvement (adjusted for baseline) compared with both DWR (MD -0.54 (95%CI -0.99, -0.10), p = .017) and allergic (MD -0.82 (95%CI -1.25, -0.38), p < .001). CONCLUSION: By 2-years post-treatment, remission participants reported fewer reactions, less severe reactions and greater HRQOL improvement compared with DWR and allergic participants, indicating that remission is the patient-preferred treatment outcome over desensitization or remaining allergic.
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BACKGROUND: ProGlide is a percutaneous suture-mediated closure device used in arterial and venous closure following percutaneous intervention. Risk of vascular complications from use, particularly related to failure in hemostasis, or acute vessel closure, remains significant and often related to improper suture deployment. We describe a technique of ultrasound-guided ProGlide deployment in transfemoral transcatheter aortic valve implantation (TF-TAVI). AIMS: The aim of this study is to assess vascular outcomes for ultrasound-guided deployment of ProGlide vascular closure devices in patients undergoing TF-TAVI. METHODS: We collected relevant clinical data of patients undergoing TAVI in a large volume centre. PRIMARY OUTCOME: main access Valve Academic Research Consortium 3 (VARC-3) major vascular complication. SECONDARY OUTCOME: any major/minor VARC-3 vascular complication, its type (bleed or ischemia), and treatment required (medical, percutaneous, or surgical). We performed inverse weighting propensity score analysis to compare the population undergoing ultrasound-guided versus conventional ProGlide deployment for main TAVI access. Ultrasound technique for ProGlide insertion was performed as described below. RESULTS: Five hundred and seventeen patients undergoing TF-TAVI were included. PRIMARY OUTCOME: In 126 (ultrasound-guided) and 391 (conventional ProGlide insertion), 0% versus 1.8% (p < 0.001) had a major VARC-3 vascular complication, respectively. SECONDARY OUTCOME: 0.8% (one minor VARC-3 bleed) vs 4.1% (13 bleeds and three occlusions) had any VARC-3 vascular complication (major and minor) (p < 0.001). Surgical treatment of vascular complication was required in 0.8% versus 1.3% (p = NS). CONCLUSIONS: Ultrasound-guided deployment of ProGlide for vascular closure reduced the risk of major vascular complications in a large population undergoing TAVI.
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Estenosis de la Válvula Aórtica , Reemplazo de la Válvula Aórtica Transcatéter , Dispositivos de Cierre Vascular , Humanos , Estenosis de la Válvula Aórtica/diagnóstico por imagen , Estenosis de la Válvula Aórtica/cirugía , Estenosis de la Válvula Aórtica/complicaciones , Estudios de Cohortes , Arteria Femoral/diagnóstico por imagen , Arteria Femoral/cirugía , Resultado del Tratamiento , Hemorragia/etiología , Conducta de Reducción del Riesgo , Ultrasonografía Intervencional/efectos adversos , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugíaRESUMEN
BACKGROUND AND HYPOTHESIS: People with chronic kidney disease (CKD) have increased incidence and mortality from most cancer types. We hypothesised that odds of presenting with advanced cancer may vary according to differences in eGFR, that this could contribute to increased all-cause mortality and that sex differences may exist. METHODS: Data were from Secure Anonymised Information Linkage Databank, including people with de-novo cancer diagnosis (2011-2017) and two kidney function tests within two years prior to diagnosis to determine baseline eGFR (mL/min/1.73m2). Logistic regression models determined odds of presenting with advanced cancer by baseline eGFR. Cox proportional hazards models tested associations between baseline eGFRcr and all-cause mortality. RESULTS: eGFR < 30 was associated with higher odds of presenting with advanced cancer of prostate, breast and female genital organs, but not other cancer sites. Compared to eGFR > 75-90, eGFR < 30 was associated with greater hazards of all-cause mortality in both sexes, but the association was stronger in females (female: HR 1.71, 95%CI 1.56-1.88; male versus female comparison HR 0.88, 95%CI 0.78-0.90). CONCLUSIONS: Lower or higher eGFR was not associated with substantially higher odds of presenting with advanced cancer across most cancer sites, but was associated with reduced survival. A stronger assocation with all-cause mortality in females compared to males with eGFR < 30 is concerning and warrants further scrutiny.
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International and national oncofertility networks, including the US-led Oncofertility Consortium, FertiProtekt, and the Danish Network, have played pivotal roles in advancing the discipline of oncofertility over the last decade. Many other countries lack a shared approach to pediatric oncofertility health service delivery. This study aims to describe baseline oncofertility practices at Australian New Zealand Children's Haematology/Oncology Group centers in 2019-2021, describe binational priorities for care, and propose a 5-year action plan for best practice to be implemented by the newly formed Australian New Zealand Consortium in Children, Adolescents, and Young Adults (CAYA) Oncofertility (ANZCO).
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Preservación de la Fertilidad , Neoplasias , Humanos , Adolescente , Nueva Zelanda , Preservación de la Fertilidad/métodos , Niño , Neoplasias/terapia , Neoplasias/complicaciones , Adulto Joven , Femenino , Australia , Masculino , AdultoRESUMEN
Climate change is shifting the phenological cycles of plants1, thereby altering the functioning of ecosystems, which in turn induces feedbacks to the climate system2. In northern (north of 30° N) ecosystems, warmer springs lead generally to an earlier onset of the growing season3,4 and increased ecosystem productivity early in the season5. In situ6 and regional7-9 studies also provide evidence for lagged effects of spring warmth on plant productivity during the subsequent summer and autumn. However, our current understanding of these lagged effects, including their direction (beneficial or adverse) and geographic distribution, is still very limited. Here we analyse satellite, field-based and modelled data for the period 1982-2011 and show that there are widespread and contrasting lagged productivity responses to spring warmth across northern ecosystems. On the basis of the observational data, we find that roughly 15 per cent of the total study area of about 41 million square kilometres exhibits adverse lagged effects and that roughly 5 per cent of the total study area exhibits beneficial lagged effects. By contrast, current-generation terrestrial carbon-cycle models predict much lower areal fractions of adverse lagged effects (ranging from 1 to 14 per cent) and much higher areal fractions of beneficial lagged effects (ranging from 9 to 54 per cent). We find that elevation and seasonal precipitation patterns largely dictate the geographic pattern and direction of the lagged effects. Inadequate consideration in current models of the effects of the seasonal build-up of water stress on seasonal vegetation growth may therefore be able to explain the differences that we found between our observation-constrained estimates and the model-constrained estimates of lagged effects associated with spring warming. Overall, our results suggest that for many northern ecosystems the benefits of warmer springs on growing-season ecosystem productivity are effectively compensated for by the accumulation of seasonal water deficits, despite the fact that northern ecosystems are thought to be largely temperature- and radiation-limited10.
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Desarrollo de la Planta , Fenómenos Fisiológicos de las Plantas , Estaciones del Año , Temperatura , Simulación por Computador , Mapeo Geográfico , Transpiración de Plantas , PlantasRESUMEN
BACKGROUND: Little is known about why patients with low back pain (LBP) respond differently to treatment, and more specifically, to a lumbar stabilization exercise program. As a first step toward answering this question, the present study evaluates how subgroups of patients who demonstrate large and small clinical improvements differ in terms of physical and psychological changes during treatment. METHODS: Participants (n = 110) performed the exercise program (clinical sessions and home exercises) over eight weeks, with 100 retained at six-month follow-up. Physical measures (lumbar segmental instability, motor control impairments, range of motion, trunk muscle endurance and physical performance tests) were collected twice (baseline, end of treatment), while psychological measures (fear-avoidance beliefs, pain catastrophizing, psychological distress, illness perceptions, outcome expectations) were collected at four time points (baseline, mid-treatment, end of treatment, follow-up). The participants were divided into three subgroups (large, moderate and small clinical improvements) based on the change of perceived disability scores. ANOVA for repeated measure compared well-contrasted subgroups (large vs. small improvement) at different times to test for SUBGROUP × TIME interactions. RESULTS: Statistically significant interactions were observed for several physical and psychological measures. In all these interactions, the large- and small-improvement subgroups were equivalent at baseline, but the large-improvement subgroup showed more improvements over time compared to the small-improvement subgroup. For psychological measures only (fear-avoidance beliefs, pain catastrophizing, illness perceptions), between-group differences reached moderate to strong effect sizes, at the end of treatment and follow-up. CONCLUSIONS: The large-improvement subgroup showed more improvement than the small-improvement subgroup with regard to physical factors typically targeted by this specific exercise program as well as for psychological factors that are known to influence clinical outcomes.
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Catastrofización , Evaluación de la Discapacidad , Terapia por Ejercicio , Dolor de la Región Lumbar , Humanos , Dolor de la Región Lumbar/psicología , Dolor de la Región Lumbar/terapia , Dolor de la Región Lumbar/rehabilitación , Masculino , Femenino , Terapia por Ejercicio/métodos , Adulto , Persona de Mediana Edad , Resultado del Tratamiento , Catastrofización/psicología , Vértebras Lumbares , Dimensión del Dolor , Estudios de Seguimiento , Rango del Movimiento Articular , Miedo/psicologíaRESUMEN
AIM: Recovery from stroke is adversely affected by neuropsychiatric complications, cognitive impairment, and functional disability. Better knowledge of their mutual relationships is required to inform effective interventions. Network theory enables the conceptualization of symptoms and impairments as dynamic and mutually interacting systems. We aimed to identify interactions of poststroke complications using network analysis in diverse stroke samples. METHODS: Data from 2185 patients were sourced from member studies of STROKOG (Stroke and Cognition Consortium), an international collaboration of stroke studies. Networks were generated for each cohort, whereby nodes represented neuropsychiatric symptoms, cognitive deficits, and disabilities on activities of daily living. Edges characterized associations between them. Centrality measures were used to identify hub items. RESULTS: Across cohorts, a single network of interrelated poststroke complications emerged. Networks exhibited dissociable depression, apathy, fatigue, cognitive impairment, and functional disability modules. Worry was the most central symptom across cohorts, irrespective of the depression scale used. Items relating to activities of daily living were also highly central nodes. Follow-up analysis in two studies revealed that individuals who worried had more densely connected networks than those free of worry (CASPER [Cognition and Affect after Stroke: Prospective Evaluation of Risks] study: S = 9.72, P = 0.038; SSS [Sydney Stroke Study]: S = 13.56, P = 0.069). CONCLUSION: Neuropsychiatric symptoms are highly interconnected with cognitive deficits and functional disabilities resulting from stroke. Given their central position and high level of connectedness, worry and activities of daily living have the potential to drive multimorbidity and mutual reinforcement between domains of poststroke complications. Targeting these factors early after stroke may have benefits that extend to other complications, leading to better stroke outcomes.
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Trastornos del Conocimiento , Disfunción Cognitiva , Accidente Cerebrovascular , Humanos , Depresión/psicología , Actividades Cotidianas/psicología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Trastornos del Conocimiento/complicaciones , Disfunción Cognitiva/complicaciones , CogniciónRESUMEN
BACKGROUND: Gluteal tendinopathy (GT) is found in 20 to 25% of patients undergoing total hip arthroplasty (THA). Despite this, there is a scarcity of literature assessing the association between GT and THA outcomes. The aim of this study was to evaluate whether intraoperative diagnosis of GT negatively affected postoperative outcomes. METHODS: Consecutive patients undergoing primary THA for osteoarthritis via a posterior approach over 5 years were recruited in a prospective study. Gluteal tendinopathy was assessed and graded at the time of surgery, but not repaired. A total of 1,538 (93%) completed the patient-reported outcome measures (PROMs) at 1 year after surgery and were included in the analysis. The PROMs included the Oxford Hip Score (OHS), Hip Disability and Osteoarthritis Outcome Score Joint Replacement (HOOS JR), and EuroQol 5-Dimension, and were collected preoperatively and one year after THA. RESULTS: The gluteal tendons were graded as 4 distinct grades: normal (n = 1,023, 66%), tendinopathy but no tear (n = 337, 22%), partial thickness tear (n = 131, 9%), and full thickness tear (n = 47, 3%). The occurrence of GT was associated with age, body mass index, and sex. There was no significant difference in baseline OHS or HOOS JR scores according to GT grade. As GT grade increased, lower median 1-year OHS (P = .001) and HOOS JR (P = .016) were observed. This association was confirmed by linear regression analysis with 1-year OHS (B = 0.5, 95% CI = -0.9 to -0.1, P = .011) when controlled for age and sex. CONCLUSIONS: Gluteal tendinopathy was commonly observed and was associated with inferior 1-year PROMs in patients undergoing THA via posterior approach. Increasing degree of tendinopathy was a negative prognostic factor for outcomes and patient satisfaction. LEVEL OF EVIDENCE: Level 2 (High quality prospective cohort study).
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Artroplastia de Reemplazo de Cadera , Osteoartritis de la Cadera , Medición de Resultados Informados por el Paciente , Tendinopatía , Humanos , Masculino , Femenino , Tendinopatía/cirugía , Tendinopatía/etiología , Estudios Prospectivos , Anciano , Persona de Mediana Edad , Nalgas/cirugía , Osteoartritis de la Cadera/cirugía , Anciano de 80 o más Años , Resultado del TratamientoRESUMEN
BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.
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Enfermedades del Sistema Inmune , Síndromes de Inmunodeficiencia , Niño , Humanos , Autoinmunidad/genética , Estudios de Cohortes , Mutación con Ganancia de Función , Síndromes de Inmunodeficiencia/genética , Mutación , Factor de Transcripción STAT3/genética , Proliferación Celular , LinfocitosRESUMEN
Memory impairment occurs in over a third of patients after symptomatic stroke. Memory deficits rarely occur in isolation but are an important component of the poststroke cognitive syndrome because of the strong relationship with the risk of poststroke dementia. In this review, we summarize available data on impairment of episodic memory, with a particular emphasis on the natural history of memory impairment after stroke and the factors influencing trajectory informed by an updated systematic review. We next discuss the pathophysiology of memory impairment and mechanisms of both decline and recovery of function. We then turn to the practical issue of measurement of memory deficits after stroke, emerging biomarkers, and therapeutic approaches. Our review identifies critical gaps, particularly in studies of the natural history that properly map the long-term trajectory of memory and the associations with factors that modulate prognosis. Few studies have used advanced neuroimaging and this, in conjunction with other biomarker approaches, has the potential to provide a much richer understanding of the mechanisms at play and promising therapeutic avenues.
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Trastornos del Conocimiento , Disfunción Cognitiva , Accidente Cerebrovascular , Humanos , Trastornos del Conocimiento/etiología , Trastornos del Conocimiento/psicología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/terapia , Pronóstico , Biomarcadores , Trastornos de la Memoria , Cognición , Pruebas Neuropsicológicas , Disfunción Cognitiva/complicacionesRESUMEN
Visual working memory is critical for goal-directed behavior as it maintains continuity between previous and current visual input. Functional neuroimaging studies have shown that visual working memory relies on communication between distributed brain regions, which implies an important role for long-range white matter connections in visual working memory performance. Here, we characterized the relationship between the microstructure of white matter association tracts and the precision of visual working memory representations. To that purpose, we devised a delayed estimation task which required participants to reproduce visual features along a continuous scale. A sample of 80 healthy adults performed the task and underwent diffusion-weighted MRI. We applied mixture distribution modelling to quantify the precision of working memory representations, swap errors, and guess rates, all of which contribute to observed responses. Latent components of microstructural properties in sets of anatomical tracts were identified by principal component analysis. We found an interdependency between fibre coherence in the bilateral superior longitudinal fasciculus (SLF) I, SLF II, and SLF III, on one hand, and the bilateral inferior fronto-occipital fasciculus (IFOF), on the other, in mediating the precision of visual working memory in a functionally specific manner. We also found that individual differences in axonal density in a network comprising the bilateral inferior longitudinal fasciculus (ILF) and SLF III and right SLF II, in combination with a supporting network located elsewhere in the brain, form a common system for visual working memory to modulate response precision, swap errors, and random guess rates.
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Memoria a Corto Plazo , Sustancia Blanca , Adulto , Humanos , Memoria a Corto Plazo/fisiología , Sustancia Blanca/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Imagen de Difusión por Resonancia Magnética , Mapeo Encefálico/métodosRESUMEN
BACKGROUND: In the United Kingdom (UK), cancer screening invitations are based on general practice (GP) registrations. We hypothesize that GP electronic medical records (EMR) can be utilised to calculate a lung cancer risk score with good accuracy/clinical utility. METHODS: The development cohort was Secure Anonymised Information Linkage-SAIL (2.3 million GP EMR) and the validation cohort was UK Biobank-UKB (N = 211,597 with GP-EMR availability). Fast backward method was applied for variable selection and area under the curve (AUC) evaluated discrimination. RESULTS: Age 55-75 were included (SAIL: N = 574,196; UKB: N = 137,918). Six-year lung cancer incidence was 1.1% (6430) in SAIL and 0.48% (656) in UKB. The final model included 17/56 variables in SAIL for the EMR-derived score: age, sex, socioeconomic status, smoking status, family history, body mass index (BMI), BMI:smoking interaction, alcohol misuse, chronic obstructive pulmonary disease, coronary heart disease, dementia, hypertension, painful condition, stroke, peripheral vascular disease and history of previous cancer and previous pneumonia. The GP-EMR-derived score had AUC of 80.4% in SAIL and 74.4% in UKB and outperformed ever-smoked criteria (currently the first step in UK lung cancer screening pilots). DISCUSSION: A GP-EMR-derived score may have a role in UK lung cancer screening by accurately targeting high-risk individuals without requiring patient contact.
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Medicina General , Neoplasias Pulmonares , Humanos , Persona de Mediana Edad , Anciano , Registros Electrónicos de Salud , Detección Precoz del Cáncer , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/epidemiología , Factores de Riesgo , Medición de RiesgoRESUMEN
The CO2 electroreduction to fuels is a feasible approach to provide renewable energy sources. Therefore, it is necessary to conduct experimental and theoretical investigations on various catalyst design strategies, such as electronic metal-support interaction, to improve the catalytic selectivity. Here a solvent-free synthesis method is reported to prepare a copper (Cu)-based metal-organic framework (MOF) as the precursor. Upon electrochemical CO2 reduction in aqueous electrolyte, it undergoes in situ decomposition/redeposition processes to form abundant interfaces between Cu nanoparticles and amorphous carbon supports. This Cu/C catalyst favors the selective and stable production of CH4 with a Faradaic efficiency of ≈55% at -1.4 V versus reversible hydrogen electrode (RHE) for 12.5 h. The density functional theory calculation reveals the crucial role of interfacial sites between Cu and amorphous carbon support in stabilizing the key intermediates for CO2 reduction to CH4 . The adsorption of COOH* and CHO* at the Cu/C interface is up to 0.86 eV stronger than that on Cu(111), thus promoting the formation of CH4 . Therefore, it is envisioned that the strategy of regulating electronic metal-support interaction can improve the selectivity and stability of catalyst toward a specific product upon electrochemical CO2 reduction.
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BACKGROUND: Rhinovirus (RV) infection of airway epithelial cells triggers asthma exacerbations, during which airway smooth muscle (ASM) excessively contracts. Due to ASM contraction, airway epithelial cells become mechanically compressed. We previously reported that compressed human bronchial epithelial (HBE) cells are a source of endothelin-1 (ET-1) that causes ASM contraction. Here, we hypothesized that epithelial sensing of RV by TLR3 and epithelial compression induce ET-1 secretion through a TGF-ß receptor (TGFßR)-dependent mechanism. METHODS: To test this, we used primary HBE cells well-differentiated in air-liquid interface culture and two mouse models (ovalbumin and house dust mite) of allergic airway disease (AAD). HBE cells were infected with RV-A16, treated with a TLR3 agonist (poly(I:C)), or exposed to compression. Thereafter, EDN1 (ET-1 protein-encoding gene) mRNA expression and secreted ET-1 protein were measured. We examined the role of TGFßR in ET-1 secretion using either a pharmacologic inhibitor of TGFßR or recombinant TGF-ß1 protein. In the AAD mouse models, allergen-sensitized and allergen-challenged mice were subsequently infected with RV. We then measured ET-1 in bronchoalveolar lavage fluid (BALF) and airway hyperresponsiveness (AHR) following methacholine challenge. RESULTS: Our data reveal that RV infection induced EDN1 expression and ET-1 secretion in HBE cells, potentially mediated by TLR3. TGFßR activation was partially required for ET-1 secretion, which was induced by RV, poly(I:C), or compression. TGFßR activation alone was sufficient to increase ET-1 secretion. In AAD mouse models, RV induced ET-1 secretion in BALF, which positively correlated with AHR. CONCLUSIONS: Our data provide evidence that RV infection increased epithelial-cell ET-1 secretion through a TGFßR-dependent mechanism, which contributes to bronchoconstriction during RV-induced asthma exacerbations.