Search

The types of immune cells that populate the trachea after ILTV vaccination and infection have not been assessed. The objective of this study was to quantify CD4+, CD8α+, CD8β+, TCRγδ+, and MRC1LB+ cells that infiltrate the trachea after vaccination with chicken embryo origin (CEO), tissue culture origin (TCO), and recombinant herpesvirus of turkey-laryngotracheitis (rHVT-LT) vaccines, and after challenge of vaccinated and non-vaccinated chickens with a virulent ILTV strain. Eye-drop vaccination with CEO, or TCO, or in ovo vaccination with rHVT-LT did not alter the number of CD4+, CD8α+, CD8β+, TCRγδ+, and MRC1LB+ cells in the trachea. After challenge, the CEO vaccinated group of chickens showed swift clearance of the challenge virus, the mucosa epithelium of the trachea remained intact, and a limited number of CD4+, CD8α+, and CD8β+ cells were detected in the upper trachea mucosa. The TCO and rHVT-LT vaccinated groups of chickens showed narrow viral clearance with moderate disruption of the trachea epithelial integrity, and a significant increase in CD4+, CD8α+, CD8β+, and TCRγδ+ cells infiltrated the upper trachea mucosa. Non-vaccinated challenged chickens showed high levels of viral replication, the epithelial organization of the upper trachea mucosa was heavily disrupted, and the predominant infiltrates were CD4+, TCRγδ+, and MRC1LB+ cells. Hence, the very robust protection provided by CEO vaccination was characterized by minimal immune cell infiltration to the trachea mucosa. In contrast, partial protection induced by the TCO and rHVT-LT vaccines requires a prolonged period of T cell expansion to overcome the established infection in the trachea mucosa.

Attachment-based family therapy (ABFT; Diamond G.S. et al., 2014 ) is an empirically supported treatment designed to capitalize on the innate, biologically based, caregiving instinct and adolescent need for attachment security. This therapy is grounded in attachment and emotional processing theory and provides an interpersonal, process-oriented, trauma-informed approach to treating adolescents struggling with suicide and associated problems such as depression and trauma. ABFT offers a clear structure and road map to help therapists quickly address the attachment ruptures that lie at the core of family conflict, which can fuel adolescent distress. Several clinical trials and process studies have demonstrated empirical support for the model and its proposed mechanisms of change. In this paper, we provide an overview of the theories underlying the model, the clinical strategies that guide the treatment, the outcome research that demonstrates efficacy, and the process research that explores the proposed mechanisms of change.

Acknowledgements: We would like to thank all members of the Gallego Romero and McCarthy groups for their helpful discussions and comments on the manuscript. We also wish to acknowledge all of the study participants who generously consented to genome sequencing in the original study, and the leadership of Herawati Sudoyo and Chelzie Crenna Darusalam (Eijkman Institute for Molecular Biology) in generating these datasets., Funder: Leakey Foundation; funder-id: http://dx.doi.org/10.13039/100005966, Funder: University of Melbourne; funder-id: http://dx.doi.org/10.13039/501100001782, Modern humans have admixed with multiple archaic hominins. Papuans, in particular, owe up to 5% of their genome to Denisovans, a sister group to Neanderthals whose remains have only been identified in Siberia and Tibet. Unfortunately, the biological and evolutionary significance of these introgression events remain poorly understood. Here we investigate the function of both Denisovan and Neanderthal alleles characterised within a set of 56 genomes from Papuan individuals. By comparing the distribution of archaic and non-archaic variants we assess the consequences of archaic admixture across a multitude of different cell types and functional elements. We observe an enrichment of archaic alleles within cis-regulatory elements and transcribed regions of the genome, with Denisovan variants strongly affecting elements active within immune-related cells. We identify 16,048 and 10,032 high-confidence Denisovan and Neanderthal variants that fall within annotated cis-regulatory elements and with the potential to alter the affinity of multiple transcription factors to their cognate DNA motifs, highlighting a likely mechanism by which introgressed DNA can impact phenotypes. Lastly, we experimentally validate these predictions by testing the regulatory potential of five Denisovan variants segregating within Papuan individuals, and find that two are associated with a significant reduction of transcriptional activity in plasmid reporter assays. Together, these data provide support for a widespread contribution of archaic DNA in shaping the present levels of modern human genetic diversity, with different archaic ancestries potentially affecting multiple phenotypic traits within non-Africans.

The Cancer Genome Atlas (TCGA) classification of genetic alterations in uveal melanoma is widely used for prognostication. We present novel observations on the impact of TCGA Group specifically for iris melanoma.This was a retrospective cohort study at a tertiary referral ocular oncology center. All patients with a diagnosis of iris melanoma who underwent genetic evaluation and assessment for TCGA classification between 20 November 1995 and 5 April 2021 were included. The main outcome measures were visual acuity, secondary glaucoma, tumor recurrence, melanoma-related metastasis and death per TCGA group.There were a total of 78 patients included. The mean patient age was 49.6 years (median 53.0, range 3.0-85.0), mean tumor basal diameter was 6.7 mm (median 6.0, range 1.5-22.0), and mean tumor thickness was 2.6 mm (median 2.5, range 0.5-8.5). Cytology results confirmed iris melanoma (93%) or were inconclusive (7%). The TCGA groups included Group A (n = 36, 46%), Group B (n = 7, 9%), Group C (n = 34, 44%), and Group D (n = 1, 1%). There was no statistically significant difference in outcomes of visual acuity, tumor thickness reduction, secondary glaucoma, tumor recurrence, melanoma-related metastasis or death per individual TCGA group (A vs. B vs. C vs. D) and per bimodal comparison (A/B vs. C/D).In this analysis, iris melanoma was classified as TCGA group A or B in 55% and as C or D in 45%. The TCGA classification was not predictive of melanoma-related metastasis or death.

Close relationships are consequential for youth depressive symptoms and suicide risk, but nuanced research examining intersecting factors is needed to improve identification and intervention. This study examines a clinical, residential sample of 939 adolescents and young adults ages 10 to 23 years old (M = 15.84, SD = 1.53; 97.7% white, 99.5% non-Hispanic, 55% female). The final model found that family conflict, parental criticism, verbal bullying, and interactions with friends were associated with depressive symptoms in the expected directions, and there were significant interactions with family, peer, and demographic variables. However, most associations with suicide risk were indirect. Associations involving family factors, peer factors, depressive symptoms, and suicide are not always straightforward, and should be understood within a microsystemic context.

In a sample of suicidal adolescents (N = 117), we sought to identify how adolescents' attachment to their parents related to a key mechanism of suicide from the Interpersonal Theory of Suicide (IPTS). We tested both attachment-anxiety and attachment-avoidance, to both mother- and father-figures as correlates of the IPTS construct, perceived burdensomeness (PB). In addition, we tested PB as a mediator between these attachment variables and adolescent suicide ideation in a path analysis. Our path analysis indicated both mother- and father-related attachment anxiety were associated with PB and PB was related to suicide ideation. We also found an indirect effect of father-related attachment anxiety on suicide ideation. This study provides empirical support for earlier systemic work that proposes how family relationships may influence an adolescent's suicidal ideation. Finally, we provide practical clinical suggestions for how therapists may implement a systemic framework to address a suicidal adolescent and their family relationships.

OBJECTIVES To determine survival outcomes following enucleation for uveal melanoma. To compare these outcomes with the 8th edition AJCC classification and determine the influence of cytogenetics, using Fluorescent in situ Hybridisation (FISH), on survival. To determine whether failure to gain sufficient sample for cytogenetics using Fine Needle Aspiration Biopsy (FNAB) correlates with survival. SUBJECTS/METHODS All patients undergoing primary enucleation for uveal melanoma at Moorfields Eye Hospital between 2012 and 2015 were included. Clinical, pathological, cytological and survival data were analysed for all patients. RESULTS In total, 155 subjects were included. Mean age at enucleation was 65.9 years (SD 14.13). 88 (56.8%) patients died at a mean of three (SD 1.9) years following enucleation. Of these, 52 (33.5%) died from metastatic melanoma, 16 (10.3%) from other causes and 20 (12.9%) causes of death were unknown. Cumulative incidence analysis demonstrated AJCC grade, chromosome 8q gain and monosomy three all predict metastatic mortality. The greatest 5-year mortality rate (62%, SD10.1%) was in those with both chromosome abnormalities and AJCC stage III (Stage IV patients excluded due to low numbers). Largest basal diameter and chromosome status, both independently (p = 0.02 and p

In response to infection or sterile insults, inflammatory programmed cell death is an essential component of the innate immune response to remove infected or damaged cells. PANoptosis is a unique innate immune inflammatory cell death pathway regulated by multifaceted macromolecular complexes called PANoptosomes, which integrate components from other cell death pathways. Growing evidence shows that PANoptosis can be triggered in many physiological conditions, including viral and bacterial infections, cytokine storms, and cancers. However, PANoptosomes at the single cell level have not yet been fully characterized. Initial investigations have suggested that key pyroptotic, apoptotic, and necroptotic molecules including the inflammasome adaptor protein ASC, apoptotic caspase-8 (CASP8), and necroptotic RIPK3 are conserved components of PANoptosomes. Here, we optimized an immunofluorescence procedure to probe the highly dynamic multiprotein PANoptosome complexes across various innate immune cell death-inducing conditions. We first identified and validated antibodies to stain endogenous mouse ASC, CASP8, and RIPK3, without residual staining in the respective knockout cells. We then assessed the formation of PANoptosomes across innate immune cell death-inducing conditions by monitoring the colocalization of ASC with CASP8 and/or RIPK3. Finally, we established an expansion microscopy procedure using these validated antibodies to image the organization of ASC, CASP8, and RIPK3 within the PANoptosome. This optimized protocol, which can be easily adapted to study other multiprotein complexes and other cell death triggers, provides confirmation of PANoptosome assembly in individual cells and forms the foundation for a deeper molecular understanding of the PANoptosome complex and PANoptosis to facilitate therapeutic targeting.

GUY’s forceful personality and abounding energy were a source of continual wonder and inspiration to his staff throughout his time as turbine designer. But he drove himself too hard; these great gifts were beginning to fail in the last phase of his career. In Guy’s boyhood locomotive work was the field most clearly offering scope for talent in mechanical engineering. Guy trained as a pupil under the Chief Mechanical Engineer of the Taff Vale Railway. He received his technical education at the University College of South Wales from 1907 to 1910. He was a hard worker and academically brilliant. He obtained the college diplomas in Mechanical and Electrical Engineering. He did not take a degree as he had not matriculated. In later life the honorary degree of D.Sc. was conferred on him by the University of Wales.

n/a

n/a

A series of patients with late reconstruction of the anterior cruciate ligament is presented. Seven patients were treated by the Jones method of reconstruction, but, because of certain difficulties with this procedure, a modified technique was developed. Six patients were treated by this modified procedure, and their results two or more years after surgery were reviewed. The number of patients in each group is small, a reflection of the relative infrequency with which anterior cruciate reconstruction is indicated. However, the modified procedure described is believed to result in greater security of anterior-cruciate reconstruction and greater knee flexion following surgery in the occasional patients who have genuine disability and in whom surgical reconstruction of this ligament is indicated.

ImportanceNon–ventilator-associated hospital-acquired pneumonia (NV-HAP) is a common and deadly hospital-acquired infection. However, inconsistent surveillance methods and unclear estimates of attributable mortality challenge prevention.ObjectiveTo estimate the incidence, variability, outcomes, and population attributable mortality of NV-HAP.Design, Setting, and ParticipantsThis cohort study retrospectively applied clinical surveillance criteria for NV-HAP to electronic health record data from 284 US hospitals. Adult patients admitted to the Veterans Health Administration hospital from 2015 to 2020 and HCA Healthcare hospitals from 2018 to 2020 were included. The medical records of 250 patients who met the surveillance criteria were reviewed for accuracy.ExposuresNV-HAP, defined as sustained deterioration in oxygenation for 2 or more days in a patient who was not ventilated concurrent with abnormal temperature or white blood cell count, performance of chest imaging, and 3 or more days of new antibiotics.Main Outcomes and MeasuresNV-HAP incidence, length-of-stay, and crude inpatient mortality. Attributable inpatient mortality by 60 days follow-up was estimated using inverse probability weighting, accounting for both baseline and time-varying confounding.ResultsAmong 6 022 185 hospitalizations (median [IQR] age, 66 [54-75] years; 1 829 475 [26.1%] female), there were 32 797 NV-HAP events (0.55 per 100 admissions [95% CI, 0.54-0.55] per 100 admissions and 0.96 per 1000 patient-days [95% CI, 0.95-0.97] per 1000 patient-days). Patients with NV-HAP had multiple comorbidities (median [IQR], 6 [4-7]), including congestive heart failure (9680 [29.5%]), neurologic conditions (8255 [25.2%]), chronic lung disease (6439 [19.6%]), and cancer (5,467 [16.7%]); 24 568 cases (74.9%) occurred outside intensive care units. Crude inpatient mortality was 22.4% (7361 of 32 797) for NV-HAP vs 1.9% (115 530 of 6 022 185) for all hospitalizations; 12 449 (8.0%) were discharged to hospice. Median [IQR] length-of-stay was 16 (11-26) days vs 4 (3-6) days. On medical record review, pneumonia was confirmed by reviewers or bedside clinicians in 202 of 250 patients (81%). It was estimated that NV-HAP accounted for 7.3% (95% CI, 7.1%-7.5%) of all hospital deaths (total hospital population inpatient death risk of 1.87% with NV-HAP events included vs 1.73% with NV-HAP events excluded; risk ratio, 0.927; 95% CI, 0.925-0.929).Conclusions and RelevanceIn this cohort study, NV-HAP, which was defined using electronic surveillance criteria, was present in approximately 1 in 200 hospitalizations, of whom 1 in 5 died in the hospital. NV-HAP may account for up to 7% of all hospital deaths. These findings underscore the need to systematically monitor NV-HAP, define best practices for prevention, and track their impact.

Supplemental material, sj-pdf-1-smm-10.1177_09622802221094133 for Unbiased and robust analysis of co-localization in super-resolution images by Xueyan Liu, Clifford S. Guy, Emilio Boada-Romero, Douglas R. Green, Margaret E. Flanagan, Cheng Cheng, and Hui Zhang in Statistical Methods in Medical Research

T follicular helper (TFH) cells are crucial for B cell-mediated humoral immunity1. Although transcription factors such as BCL6 drive the differentiation of TFH cells2,3, it is unclear whether and how post-transcriptional and metabolic programs enforce TFH cell programming. Here we show that the cytidine diphosphate (CDP)–ethanolamine pathway co-ordinates the expression and localization of CXCR5 with the responses of TFH cells and humoral immunity. Using in vivo CRISPR–Cas9 screening and functional validation in mice, we identify ETNK1, PCYT2, and SELENOI—enzymes in the CDP–ethanolamine pathway for de novo synthesis of phosphatidylethanolamine (PE)—as selective post-transcriptional regulators of TFH cell differentiation that act by promoting the surface expression and functional effects of CXCR5. TFH cells exhibit unique lipid metabolic programs and PE is distributed to the outer layer of the plasma membrane, where it colocalizes with CXCR5. De novo synthesis of PE through the CDP–ethanolamine pathway co-ordinates these events to prevent the internalization and degradation of CXCR5. Genetic deletion of Pcyt2, but not of Pcyt1a (which mediates the CDP–choline pathway), in activated T cells impairs the differentiation of TFH cells, and this is associated with reduced humoral immune responses. Surface levels of PE and CXCR5 expression on B cells also depend on Pcyt2. Our results reveal that phospholipid metabolism orchestrates post-transcriptional mechanisms for TFH cell differentiation and humoral immunity, highlighting the metabolic control of context-dependent immune signalling and effector programs. Enzymes in the cytidine diphosphate–ethanolamine metabolic pathway, which promotes de novo synthesis of phosphatidylethanolamine, are shown to act as post-transcriptional mediators of the differentiation of T follicular helper (TFH) cells, by regulating the chemokine receptor CXCR5.

Caspases are a family of enzymes that play roles in cell death and inflammation. It has been suggested that in the execution phase of the apoptotic pathway, caspase-3, -6 and -7 are involved. The substrate specificities of two proteases (caspases 3 and 7) are highly similar, which complicates the design of compounds that selectively interact with a single enzyme exclusively. The recognition of residues other than Asp in the P1 position of the substrate by caspase-3/-7 has been reported, promoting interest in the effects of phosphorylation of amino acids in the direct vicinity of the scissile bond. To evaluate conflicting reports on this subject, we synthesized a series of known caspase-3 and -7 substrates and phosphorylated analogs, performed enzyme kinetic assays and mapped the peptide cleavage sites using internally quenched fluorescent peptide substrates. Caspases 3 and 7 will tolerate pSer at the P1 position but only poorly at the P2′ position. Our investigation demonstrates the importance of peptide length and composition in interpreting sequence/activity relationships. Based on the results, we conclude that the relationship between caspase-3/-7 and their substrates containing phosphorylated amino acids might depend on the steric conditions and not be directly connected with ionic interactions. Thus, the precise effect of phospho-amino acid residues located in the vicinity of the cleaved bond on the regulation of the substrate specificity of caspases remains difficult to predict. Our observations allow to predict that natural phosphorylated proteins may be cleaved by caspases, but only when extended substrate binding site interactions are satisfied.

Objective Despite considerable evidence that supports perceived burdensomeness (PB) and thwarted belongingness (TB) as risk factors for suicidal ideation (SI), far less is known about the direction of effects between these constructs in treatments for suicidal adolescents. The present study examined bidirectional relations between PB, TB, and adolescents' suicidal ideation (SI) during a 16-week randomized clinical trial. Method 129 depressed and suicidal adolescents completed PB, TB, and SI measures at three time points: baseline (T1), mid-treatment (T2), and treatment completion (T3). Random-intercept cross-lagged panel models (RI-CLPM) examined within-subject direction of effects between interpersonal variables (PB & TB) and suicidal ideation (SI) in the first and second halves of treatment. Results Within-subjects, autoregressive paths indicated significant carryover in PB and SI. In the first half of treatment, a significant cross-lagged path indicated that T1 PB predicted change in T2 SI, and in the last half of treatment change in T2 SI predicted change in T3 PB. There were no significant auto-regressive or cross-lagged effects for TB. Conclusions In the first half of treatment, baseline PB predicted fewer reductions in SI suggesting that PB initially moderated adolescents' response to treatment. However, in the last half of treatment, initial reductions in SI predicted subsequent reductions in PB suggesting that adolescents' initial response to treatment decreased their perceptions of burdening others. The clinical and treatment implications of these bidirectional findings are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Schools have the unique opportunity to identify and refer youth at risk for suicide. School-based gatekeeper training programs aim to improve staff’s ability to talk to students about mental health concerns and refer them for an assessment. Unfortunately, progress in evaluating the available programs has been limited. In fact, the popular and widely used More Than Sad program has received no rigorous evaluation to date. This study sets out to evaluate the effectiveness of the More Than Sad program in a quasi-experimental, wait-list control design with a large number of school personnel, across geographically diverse communities. Fourteen school districts with over 1475 school personal received the training. A standardized assessment tool was used before and after the training and two months later. Half of the schools served as a wait list control before receiving the treatment. Results. Compared to wait-listed staff, school personal who received the training reported a significant increase in knowledge, preparedness, self-efficacy, and likelihood to refer. Self-reported and actual referral behavior also increased both for those that had made referrals in the past and those that had not. Gains were maintained at 2-month follow-up. More Than Sad can effectively improve suicide literacy and willingness to refer youth at risk for suicide to school mental health resources. With 90% of the training pre-recorded on DVDs, future research should explore implementation feasibility and effectiveness.

Background: Prior studies have demonstrated that patients with low left atrial pressure (LAP) undergoing transcatheter mitral valve repair (TMVr) have a high incidence of chronic lung disease, and ...

Patients with patent foramen ovale can manifest in a variety of ways. These presentations and their resolution are discussed in this article.

SARS-CoV-2 monoclonal antibodies (mAbs) have been proposed as a treatment for mild to moderate COVID-19, with favorable outcomes reported in clinical trials and an emergency use authorization granted by the Food and Drug Administration. Real-world data remain limited, however, and thus this analysis presents findings from over 6,500 outpatient administrations of mAb at facilities affiliated with a large healthcare organization in the United States. Within 48 hours of mAb infusion, 15.6% (1,043) of patients received a drug that was indicative of a possible reaction to the infusion; the majority of these were mild (e.g., acetaminophen). Approximately 5.2% of patients who received mAb (n=347) had a post-infusion emergency department visit or admission for COVID-19 disease progression. The results of this analysis indicate that patients who receive mAb have a low likelihood of both an immediate negative reaction to the treatment as well as future inpatient admission related to COVID-19 disease progression.