STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation.

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.

Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy.

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.).

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

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).

A Novel Heterozygous Variant in AICDA Impairs Ig Class Switching and Somatic Hypermutation in Human B Cells and is Associated with Autosomal Dominant HIGM2 Syndrome.

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.

Ultrasound-guided deployment of ProGlide™ device in transfemoral transcatheter aortic valve implantation and risk reduction of vascular complications: A propensity-matched cohort study.

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.

Widespread seasonal compensation effects of spring warming on northern plant productivity.

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.

Network analysis of neuropsychiatric, cognitive, and functional complications of stroke: implications for novel treatment targets.

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.

Gluteal Tendinopathy Is Associated With Lower Patient-Reported Outcome Measures in Total Hip Arthroplasty With a Posterior Approach: A Prospective Cohort Study of 1,538 Patients.

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).

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

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.

Cognitive Recovery After Stroke: Memory.

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.

White matter microstructure is associated with the precision of visual working memory.

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.

Rhinovirus infection induces secretion of endothelin-1 from airway epithelial cells in both in vitro and in vivo models.

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.

Isolation of casein for stable isotope ratio analysis of butter, cheese, and milk powder.

RATIONALE: Stable isotope ratio analysis (SIRA) is commonly used for the authentication of dairy commodities, providing evidence to support the geographical origin and production background of products. We set out to optimise methods for the isolation of a common constituent (casein) from three dairy commodities, which would permit easier inter- and intra-commodity comparisons following SIRA. METHODS: Three published methods for isolation of protein (from cheese, milk, and butter) were adapted to yield protein (casein) fractions from commercial cheddar cheese, whole milk powder (WMP), and butter samples with a high degree of purity for subsequent SIRA. The casein fractions isolated underwent elemental analysis (H, C, and N), protein determination, and some also underwent SIRA of O and S. Two-way analysis of variance and Tukey post hoc comparisons tested differences between methods. RESULTS: For each product, an optimised casein isolation method was chosen based on the C/N ratio and protein content. An optimum solvent lipid extraction (petroleum spirit-diethyl ether (2:1)) and casein precipitation method was chosen for cheddar cheese casein. A final solvent lipid extraction (heptane-isopropanol (3:2)) was necessary for WMP and butter casein extraction. δ13 C and δ2 H values validated the methods' abilities to remove contaminating lipid and isolate pure casein. CONCLUSIONS: Casein of high purity, for subsequent SIRA, can be isolated from cheddar cheese, WMP, and butter following modifications of previously published methods.

Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke.

Spontaneous recovery of motor and cognitive function occurs in many individuals after stroke. The mechanisms are incompletely understood, but may involve neurotransmitter systems that support neural plasticity, networks that are involved in learning and regions of the brain that are able to flexibly adapt to demand (such as the 'multiple-demand system'). Forty-two patients with first symptomatic ischaemic stroke were enrolled in a longitudinal cohort study of cognitive function after stroke. High-resolution volumetric, diffusion MRI and neuropsychological assessment were performed at a mean of 70 ± 18 days after stroke. Cognitive assessment was repeated 1 year after stroke, using parallel test versions to avoid learning effects, and change scores were computed for long-term episodic, short-term and working memory. Structural MRI features that predicted change in cognitive scores were identified by a two-stage analysis: a discovery phase used whole-brain approaches in a hypothesis-free unbiased way; and an independent focused phase, where measurements were derived from regions identified in the discovery phase, using targeted volumetric measurements or tractography. Evaluation of the cholinergic basal forebrain, based on a validated atlas-based approach, was included given prior evidence of a role in neural plasticity. The status of the fornix, cholinergic basal forebrain and a set of hippocampal subfields were found to predict improvement in long-term memory performance. In contrast to prior expectation, the same pattern was found for short-term and working memory, suggesting that these regions are part of a common infrastructure that supports recovery across cognitive domains. Associations between cholinergic basal forebrain volume and cognitive recovery were found primarily in subregions associated with the nucleus basalis of Meynert, suggesting that it is the cholinergic outflow to the neocortex that enables recovery. Support vector regression models derived from baseline measurements of fornix, cholinergic basal forebrain and hippocampal subfields were able to explain 62% of change in long-term episodic and 41% of change in working memory performance over the subsequent 9 months. The results suggest that the cholinergic system and extended hippocampal network play key roles in cognitive recovery after stroke. Evaluation of these systems early after stroke may inform personalized therapeutic strategies to enhance recovery.

Effect of reduced-calcium and high-calcium cheddar cheese consumption on the excretion of faecal fat: a 2-week cross-over dietary intervention study.

PURPOSE: Studies show that dairy fat consumed in the form of cheese reduce LDL-cholesterol concentration (LDL-c) compared to butter and mechanistic suggestions include the calcium content of cheese leading to enhanced faecal fat excretion. The aim of this study was to test the effect of varying the calcium content within a cheese, on faecal fat excretion as a primary outcome, and blood lipid markers, fasting glucose and calcium excretion as secondary outcomes. METHODS: 7 healthy males (BMI 18-25) participated in this randomized, cross-over control intervention, of 3 × 2 week periods. Diets contained 240 g/day cheese; a High Calcium Cheese (HCC) diet, a Reduced Calcium Cheese (RCC) diet, and a control arm: Reduced Calcium Cheese + CaCO3 Supplement (RCC + Supp) diet. Diets differed in calcium content and form but were otherwise controlled for energy and key macronutrients. Blood and 5-day faecal samples were collected. RESULTS: There was no significant difference in faecal fat excretion (g/day) between the diets (P = 0.066). Percent fat of faecel excretion was higher after RCC + Supp (P = 0.016). None of the individual fatty acids were different. Fasting LDL-c was significantly lower following the HCC diet vs. the other arms (P = 0.002). Faecal Ca was different across all diets (P = 0.001), lowest after RCC, and greatest after RCC + Supp. No differences were observed for fasting blood parameters or changes in anthropometry. CONCLUSION: Varying the calcium content within a cheese matrix significantly affected fasting LDL-c values. Results did not support higher faecal fat excretion as an underlying mechanism, but the high attrition rate was a limitation. Trial registerer Trial Registered at ISRCTN.org, registration number ISRCTN11663659 on 12.07.2022. Retrospectively registered.

Factors associated with suicide in people who use drugs: a scoping review.

BACKGROUND: Suicide is a significant contributor to global mortality. People who use drugs (PWUD) are at increased risk of death by suicide relative to the general population, but there is a lack of information on associated candidate factors for suicide in this group. The aim of this study was to provide a comprehensive overview of existing evidence on potential factors for death by suicide in PWUD. METHODS: A scoping review was conducted according to the Arksey and O'Malley framework. Articles were identified using Medline, CINAHL, PsycINFO, SOCIndex, the Cochrane Database of Systematic Reviews and the Campbell Collaboration Database of Systematic Reviews; supplemented by grey literature, technical reports, and consultation with experts. No limitations were placed on study design. Publications in English from January 2000 to December 2021 were included. Two reviewers independently screened full-text publications for inclusion. Extracted data were collated using tables and accompanying narrative descriptive summaries. The review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines. RESULTS: The initial search identified 12,389 individual publications, of which 53 met the inclusion criteria. The majority (87%) of included publications were primary research, with an uncontrolled, retrospective study design. The most common data sources were drug treatment databases or national death indexes. Eleven potential factors associated with death by suicide among PWUD were identified: sex; mental health conditions; periods of heightened vulnerability; age profile; use of stimulants, cannabis, or new psychoactive substances; specific medical conditions; lack of dual diagnosis service provision; homelessness; incarceration; intravenous drug use; and race or ethnicity. Opioids, followed by cannabis and stimulant drugs were the most prevalent drugs of use in PWUD who died by suicide. A large proportion of evidence was related to opioid use; therefore, more primary research on suicide and explicit risk factors is required. CONCLUSIONS: The majority of studies exploring factors associated with death by suicide among PWUD involved descriptive epidemiological data, with limited in-depth analyses of explicit risk factors. To prevent suicide in PWUD, it is important to consider potential risk factors and type of drug use, and to tailor policies and practices accordingly.

Prosthetic femoral interposition arthroplasty with adult humeral implant, for children with cerebral palsy and symptomatic hips.

BACKGROUND: Immobile patients with cerebral palsy can suffer with painful dislocated hips. Decision-making and surgical management can prove challenging in this cohort of patients, with hips that cannot be reconstructed. METHODS: We conduced a retrospective chart review of all patients who underwent prosthetic femoral interposition arthroplasty (PFIA) by two surgeons from 2013 to 2021, for unreconstructable hips. We compared pain and range of motion in preoperative period to the postoperative period. Caregiver reported outcomes were used to assess satisfaction post operatively. During the follow up, radiographs of the PFIA were obtained to assess for proximal migration, heterotopic ossification and loosening of implants. RESULTS: Eleven index surgeries, which met the inclusion criteria, were included in this study. These were performed in eleven patients with an average follow up of 45 months. Regarding pain and range of motion post-operatively an excellent or good result was seen in nine cases. Two patients were classified as having a fair result with none having a poor result. Most caregivers reported being satisfied or very satisfied with the post-operative outcomes. CONCLUSION: A prescriptive operative solution to the painful dislocated hip in children with spastic cerebral palsy remains elusive. In this study, we have demonstrated both clinically and radiologically satisfactory results post proximal femoral interposition arthroplasty, for those patients with unreconstructable hips. Patient caregiver reported outcomes, show that the majority of caregivers were satisfied or very satisfied with the outcome of the surgery.

Clinical and radiological outcomes following surgical hip dislocation for paediatric hip pathologies, a prospective cohort study.

BACKGROUND: Surgical Hip Dislocation (SHD) is a powerful tool in the armamentarium of any surgeon treating conditions affecting the hips of children presenting with sequelae of a number of common conditions including Legg-CalvéPerthes disease (LCPD) and slipped capital femoral epiphysis (SCFE). Risks associated with the procedure are well described. We investigated to assess if SHD is associated with significant surgical risk and if it improved clinical outcomes for patients. METHODS: We conducted a prospective cohort study. We reviewed 18 (11 males and 7 females; mean age 13.7 years (6-17) with symptomatic hip pathology, secondary to femoroacetabular impingement (FAI) between 2017 and 2021. All patients underwent a surgical hip dislocation approach and femoral head-neck osteochondroplasty, Head Split osteotomy or both. Clinical improvement was assessed using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. The minimum follow-up was 6 months (mean, 22 months; range, 6-42 months). RESULTS: WOMAC scores improved at final follow-up from 10 to 3 for pain, 33 to 10 for function, and 4 to 2 for the stiffness subscales. All radiographic measures improved significantly of the postoperative X-rays. No patients developed osteonecrosis, implant failure, deep infection, or nonunion. CONCLUSION: Surgical Hip Dislocation, in the short term, we found improvement in WOMAC scores and radiographic indices with a low complication rate.

Relationship between Protein Digestibility and the Proteolysis of Legume Proteins during Seed Germination.

Legume seed protein is an important source of nutrition, but generally it is less digestible than animal protein. Poor protein digestibility in legume seeds and seedlings may partly reflect defenses against herbivores. Protein changes during germination typically increase proteolysis and digestibility, by lowering the levels of anti-nutrient protease inhibitors, activating proteases, and breaking down storage proteins (including allergens). Germinating legume sprouts also show striking increases in free amino acids (especially asparagine), but their roles in host defense or other processes are not known. While the net effect of germination is generally to increase the digestibility of legume seed proteins, the extent of improvement in digestibility is species- and strain-dependent. Further research is needed to highlight which changes contribute most to improved digestibility of sprouted seeds. Such knowledge could guide the selection of varieties that are more digestible and also guide the development of food preparations that are more digestible, potentially combining germination with other factors altering digestibility, such as heating and fermentation. Techniques to characterize the shifts in protein make-up, activity and degradation during germination need to draw on traditional analytical approaches, complemented by proteomic and peptidomic analysis of mass spectrometry-identified peptide breakdown products.

Protocol for developing a dashboard for interactive cohort analysis of oral health-related data.

INTRODUCTION: A working knowledge of data analytics is becoming increasingly important in the digital health era. Interactive dashboards are a useful, accessible format for presenting and disseminating health-related information to a wide audience. However, many oral health researchers receive minimal data visualisation and programming skills. OBJECTIVES: The objective of this protocols paper is to demonstrate the development of an analytical, interactive dashboard, using oral health-related data from multiple national cohort surveys. METHODS: The flexdashboard package was used within the R Studio framework to create the structure-elements of the dashboard and interactivity was added with the Shiny package. Data sources derived from the national longitudinal study of children in Ireland and the national children's food survey. Variables for input were selected based on their known associations with oral health. The data were aggregated using tidyverse packages such as dplyr and summarised using ggplot2 and kableExtra with specific functions created to generate bar-plots and tables. RESULTS: The dashboard layout is structured by the YAML (YAML Ain't Markup Language) metadata in the R Markdown document and the syntax from Flexdashboard. Survey type, wave of survey and variable selector were set as filter options. Shiny's render functions were used to change input to automatically render code and update output. The deployed dashboard is openly accessible at https://dduh.shinyapps.io/dduh/ . Examples of how to interact with the dashboard for selected oral health variables are illustrated. CONCLUSION: Visualisation of national child cohort data in an interactive dashboard allows viewers to dynamically explore oral health data without requiring multiple plots and tables and sharing of extensive documentation. Dashboard development requires minimal non-standard R coding and can be quickly created with open-source software.