mTOR inhibition attenuates cTfh cell dysregulation and chronic T-cell activation in multilineage immune cytopenias.

mTOR inhibitors such as sirolimus are increasingly used in the management of multilineage immune cytopenia (m-IC) in children. Although sirolimus is effective in improving IC, it is unclear how sirolimus affects the broader immune dysregulation associated with m-IC. We profiled T- and B-cell subsets longitudinally and measured cytokines and chemokines before and after sirolimus treatment. Eleven of the 12 patients with m-IC who tolerated sirolimus were followed for a median duration of 17 months. All patients had an improvement in IC, and sirolimus therapy did not result in significant decreases in T-, B- and NK-cell numbers. However, the expansion and activation of circulating T follicular helper and the Th1 bias noted before the initiation of sirolimus were significantly decreased. Features of chronic T-cell activation and exhaustion within effector memory compartments of CD4+ and CD8+ T cells decreased with sirolimus therapy. Corresponding to these changes, plasma levels of CXCL9 and CXCL10 also decreased. Interestingly, no significant improvement in the proportion of class-switched memory B cells or frequencies of CD4+ naive T cells were noted. Longer follow-up and additional studies are needed to validate these findings and evaluate the effect of sirolimus on B-cell maturation.

T-follicular helper cell expansion and chronic T-cell activation are characteristic immune anomalies in Evans syndrome.

Pediatric Evans syndrome (pES) is increasingly identified as the presenting manifestation of several inborn errors of immunity. Despite an improved understanding of genetic defects in pES, the underlying immunobiology of pES is poorly defined, and characteristic diagnostic immune parameters are lacking. We describe the immune characteristics of 24 patients with pES and compared them with 22 patients with chronic immune thrombocytopenia (cITP) and 24 healthy controls (HCs). Compared with patients with cITP and HC, patients with pES had increased circulating T-follicular helper cells (cTfh), increased T-cell activation, and decreased naïve CD4+ T cells for age. Despite normal or high immunoglobulin G (IgG) in most pES at presentation, class-switched memory B cells were decreased. Within the cTfh subset, we noted features of postactivation exhaustion with upregulation of several canonical checkpoint inhibitors. T-cell receptor ß chain (TCR-ß) repertoire analysis of cTfh cells revealed increased oligoclonality in patients with pES compared with HCs. Among patients with pES, those without a known gene defect had a similar characteristic immune abnormality as patients with defined genetic defects. Similarly, patients with pES with normal IgG had similar T-cell abnormalities as patients with low IgG. Because genetic defects have been identified in less than half of patients with pES, our findings of similar immune abnormalities across all patients with pES help establish a common characteristic immunopathology in pES, irrespective of the underlying genetic etiology.

Fostering belonging and social connectedness in nursing: Evidence-based strategies: A discussion paper for nurse students, faculty, leaders, and clinical nurses.

BACKGROUND: The phenomenon of loneliness among healthcare providers, particularly nurses, has garnered increasing attention due to its detrimental effects on individual well-being and professional retention. The isolation experienced by nurses has been linked to heightened turnover rates and intentions to leave the profession, posing significant challenges to healthcare systems globally. Recognizing loneliness as an epidemic in 2023, the U.S. Surgeon General highlighted the urgency of addressing this issue within the healthcare workforce. PURPOSE: This paper explores evidence-based strategies to mitigate loneliness and promote social connectedness among nurses, drawing insights from various stakeholders. It aims to offer actionable recommendations to enhance the nursing experience and retain professionals in the field. DISCUSSION: Strategies include peer support programs, mentorship initiatives, wellness activities, and fostering open communication. Leveraging technology for virtual connections is also highlighted, especially in remote work scenarios. CONCLUSION: A holistic approach is vital, combining individual, interpersonal, and systemic interventions to combat nurse loneliness. Prioritizing social connectedness fosters a supportive work environment, benefiting both nurses and patient care quality.

Germline IKAROS dimerization haploinsufficiency causes hematologic cytopenias and malignancies.

IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.

T Cell-Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis (HLH) Occurs in Non-Asians and Is Associated with a T Cell Activation State that Is Comparable to Primary HLH.

PURPOSE: T cell-Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (T cell-EBV-HLH) is prevalent in East Asia and has poor prognosis. Understanding of this disease is limited, and literature regarding prevalence in North America is scarce. Herein, we summarize our experience. METHODS: A retrospective analysis of T cell-EBV-HLH patients admitted to Children's Healthcare of Atlanta (GA, USA) from 2010 to 2020 was conducted. Additional immune studies were completed in a subset of patients. RESULTS: We report 15 patients (10 months-19 years of age) diagnosed with T cell-EBV-HLH. Nine patients were Hispanic, and the majority did not have primary HLH (p-HLH) gene defects. Soluble interleukin-2 receptor levels in T cell-EBV-HLH were significantly higher than other forms of secondary-HLH but comparable to p-HLH, and it correlated with disease severity at presentation. Natural killer cell function was decreased in most patients despite a negative workup for p-HLH. Depending on disease severity, initial therapy included dexamethasone or dexamethasone and etoposide. Refractory patients were managed with blended regimens that included one or more of the following therapies: combination chemotherapy, alemtuzumab, emapalumab, and nivolumab. Rituximab did not appreciably decrease EBV viremia in most patients. Non-critically ill patients responded well to immunosuppressive therapy and are long-term survivors without undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Alemtuzumab resulted in inflammation flare in two of the three patients. Three patients underwent allogeneic HSCT, with disease relapse noted in one. At a median follow-up of 3 years, 10 of the 15 patients are alive. CONCLUSION: T cell-EBV-HLH occurs in the USA among the non-Asian populations, especially in those who are Hispanic.

The host-defense peptide piscidin P1 reorganizes lipid domains in membranes and decreases activation energies in mechanosensitive ion channels.

The host-defense peptide (HDP) piscidin 1 (P1), isolated from the mast cells of striped bass, has potent activities against bacteria, viruses, fungi, and cancer cells and can also modulate the activity of membrane receptors. Given its broad pharmacological potential, here we used several approaches to better understand its interactions with multicomponent bilayers representing models of bacterial (phosphatidylethanolamine (PE)/phosphatidylglycerol) and mammalian (phosphatidylcholine/cholesterol (PC/Chol)) membranes. Using solid-state NMR, we solved the structure of P1 bound to PC/Chol and compared it with that of P3, a less potent homolog. The comparison disclosed that although both peptides are interfacially bound and α-helical, they differ in bilayer orientations and depths of insertion, and these differences depend on bilayer composition. Although Chol is thought to make mammalian membranes less susceptible to HDP-mediated destabilization, we found that Chol does not affect the permeabilization effects of P1. X-ray diffraction experiments revealed that both piscidins produce a demixing effect in PC/Chol membranes by increasing the fraction of the Chol-depleted phase. Furthermore, P1 increased the temperature required for the lamellar-to-hexagonal phase transition in PE bilayers, suggesting that it imposes positive membrane curvature. Patch-clamp measurements on the inner Escherichia coli membrane showed that P1 and P3, at concentrations sufficient for antimicrobial activity, substantially decrease the activating tension for bacterial mechanosensitive channels. This indicated that piscidins can cause lipid redistribution and restructuring in the microenvironment near proteins. We conclude that the mechanism of piscidin's antimicrobial activity extends beyond simple membrane destabilization, helping to rationalize its broader spectrum of pharmacological effects.

Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.

BACKGROUND: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing. OBJECTIVES: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles. METHODS: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants. RESULTS: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein. CONCLUSION: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity.

Hypogammaglobulinemia with decreased class-switched B-cells and dysregulated T-follicular-helper cells in IPEX syndrome.

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.

The psychological and social consequences of single-sided deafness in adulthood.

OBJECTIVES: This study examined the subjective psychological and social effects of highly asymmetric hearing loss (single-sided deafness [SSD]) in adults. DESIGN: Three group interviews were conducted using the critical incident technique and analysed using an inductive thematic analysis. STUDY SAMPLE: Eight adults with a clinical diagnosis of a moderately severe hearing loss or greater in one ear and normal or near-normal hearing in the other ear. RESULTS: A range of functional hearing difficulties associated with SSD including impaired speech in background noise and reduced spatial awareness were reported to affect social and psychological well-being. Social consequences of SSD resulted from activity limitations and participation restrictions including withdrawal from and within situations. Participants reported psychological effects including worrying about losing the hearing in their other ear, embarrassment related to the social stigma attached to hearing loss and reduced confidence and belief in their abilities to participate. CONCLUSIONS: Single-sided deafness can be associated with many negative consequences. Counselling may help overcome the psychological consequences of hearing loss regardless of whether technological support such as a hearing aid is prescribed. The audiological management of these individuals should support the development of listening strategies and set appropriate expectations for participation in everyday listening situations.

Hearing Instruments for Unilateral Severe-to-Profound Sensorineural Hearing Loss in Adults: A Systematic Review and Meta-Analysis.

OBJECTIVES: A systematic review of the literature and meta-analysis was conducted to assess the nature and quality of the evidence for the use of hearing instruments in adults with a unilateral severe to profound sensorineural hearing loss. DESIGN: The PubMed, EMBASE, MEDLINE, Cochrane, CINAHL, and DARE databases were searched with no restrictions on language. The search included articles from the start of each database until February 11, 2015. Studies were included that (a) assessed the impact of any form of hearing instrument, including devices that reroute signals between the ears or restore aspects of hearing to a deaf ear, in adults with a sensorineural severe to profound loss in one ear and normal or near-normal hearing in the other ear; (b) compared different devices or compared a device with placebo or the unaided condition; (c) measured outcomes in terms of speech perception, spatial listening, or quality of life; (d) were prospective controlled or observational studies. Studies that met prospectively defined criteria were subjected to random effects meta-analyses. RESULTS: Twenty-seven studies reported in 30 articles were included. The evidence was graded as low-to-moderate quality having been obtained primarily from observational before-after comparisons. The meta-analysis identified statistically significant benefits to speech perception in noise for devices that rerouted the speech signals of interest from the worse ear to the better ear using either air or bone conduction (mean benefit, 2.5 dB). However, these devices also degraded speech understanding significantly and to a similar extent (mean deficit, 3.1 dB) when noise was rerouted to the better ear. Data on the effects of cochlear implantation on speech perception could not be pooled as the prospectively defined criteria for meta-analysis were not met. Inconsistency in the assessment of outcomes relating to sound localization also precluded the synthesis of evidence across studies. Evidence for the relative efficacy of different devices was sparse but a statistically significant advantage was observed for rerouting speech signals using abutment-mounted bone conduction devices when compared with outcomes after preoperative trials of air conduction devices when speech and noise were colocated (mean benefit, 1.5 dB). Patients reported significant improvements in hearing-related quality of life with both rerouting devices and following cochlear implantation. Only two studies measured health-related quality of life and findings were inconclusive. CONCLUSIONS: Devices that reroute sounds from an ear with a severe to profound hearing loss to an ear with minimal hearing loss may improve speech perception in noise when signals of interest are located toward the impaired ear. However, the same device may also degrade speech perception as all signals are rerouted indiscriminately, including noise. Although the restoration of functional hearing in both ears through cochlear implantation could be expected to provide benefits to speech perception, the inability to synthesize evidence across existing studies means that such a conclusion cannot yet be made. For the same reason, it remains unclear whether cochlear implantation can improve the ability to localize sounds despite restoring bilateral input. Prospective controlled studies that measure outcomes consistently and control for selection and observation biases are required to improve the quality of the evidence for the provision of hearing instruments to patients with unilateral deafness and to support any future recommendations for the clinical management of these patients.

Improving health-related quality of life in single-sided deafness: a systematic review and meta-analysis.

Unilateral severe-to-profound hearing loss, or single-sided deafness (SSD), impairs listening abilities supported by the use of two ears, including speech perception in background noise and sound localisation. Hearing-assistive devices can aid listening by re-routing sounds from the impaired to the non-impaired ear or by restoring input to the impaired ear. A systematic review of the literature examined the impact of hearing-assistive devices on the health-related quality of life (HRQoL) of adults with SSD as measured using generic and disease-specific instruments. A majority of studies used observational designs, and the quality of the evidence was low to moderate. Only two studies used generic instruments. A mixed-effect meta-analysis of disease-specific measures suggested that hearing-assistive devices have a small-to-medium impact on HRQoL. The Speech, Spatial and Qualities of Hearing Scale and the Health Utilities Index Mark 3 (HUI3) were identified as instruments that are sensitive to device-related changes in disease-specific and generic HRQoL, respectively.

Trial protocol for the Building Resilience through Socio-Emotional Training (ReSET) programme: a cluster randomised controlled trial of a new transdiagnostic preventative intervention for adolescents.

BACKGROUND: Adolescence is a period of heightened vulnerability to developing mental health problems, and rates of mental health disorder in this age group have increased in the last decade. Preventing mental health problems developing before they become entrenched, particularly in adolescents who are at high risk, is an important research and clinical target. Here, we report the protocol for the trial of the 'Building Resilience through Socioemotional Training' (ReSET) intervention. ReSET is a new, preventative intervention that incorporates individual-based emotional training techniques and group-based social and communication skills training. We take a transdiagnostic approach, focusing on emotion processing and social mechanisms implicated in the onset and maintenance of various forms of psychopathology. METHODS: A cluster randomised allocation design is adopted with randomisation at the school year level. Five-hundred and forty adolescents (aged 12-14) will be randomised to either receive the intervention or not (passive control). The intervention is comprised of weekly sessions over an 8-week period, supplemented by two individual sessions. The primary outcomes, psychopathology symptoms and mental wellbeing, will be assessed pre- and post-intervention, and at a 1-year follow-up. Secondary outcomes are task-based assessments of emotion processing, social network data based on peer nominations, and subjective ratings of social relationships. These measures will be taken at baseline, post-intervention and 1-year follow-up. A subgroup of participants and stakeholders will be invited to take part in focus groups to assess the acceptability of the intervention. DISCUSSION: This project adopts a theory-based approach to the development of a new intervention designed to target the close connections between young people's emotions and their interpersonal relationships. By embedding the intervention within a school setting and using a cluster-randomised design, we aim to develop and test a feasible, scalable intervention to prevent the onset of psychopathology in adolescence. TRIAL REGISTRATION: ISRCTN88585916. Trial registration date: 20/04/2023.

The role of language in mental health during the transition from primary to secondary education.

We report a preregistered analysis to test whether children meeting diagnostic criteria for language disorder (LD) have higher self-reported and/or parent-reported mental health symptoms during the transition from primary to secondary education. Data are from a UK-based longitudinal cohort study, The Surrey Communication and Language in Education Study (SCALES). SCALES oversampled children at risk of LD at school entry. Language was measured using a battery of standardised assessments in Year 1 (age 5-6 years, n = 529), and mental health symptoms were measured using self and parent report in Year 6 (age 10-11 years, n = 384) and Year 8 (age 12-13 years, n = 246). Social experiences were also measured using self-report measures in Year 6. Mental health symptoms were stable during the transition from primary to secondary school. Symptom rates did not differ between children with and without LD based on self-report, but children with LD had higher parent-reported mental health symptoms than their peers with typical language. Similarly, early language was negatively associated with parent-reported but not self-reported mental health symptoms. Early language was associated with fewer child-reported positive social experiences in Year 6, but social experiences did not mediate the association between language and mental health. We found poor agreement between parent and self-reported child mental health symptoms across language groups. Future studies should aim to determine sources of disagreement between parent and child report, particularly for children with communication difficulties who may struggle to accurately self-report mental health symptoms.

Birth Companions: Teaching Nursing Students to Become Doulas.

The benefits of continuous labor support have been repeatedly discussed in the literature and supported by professional obstetric organizations. At the Johns Hopkins University School of Nursing, students are offered the unique opportunity to learn how to be a doula. The Birth Companions program provides nursing students the opportunity to develop knowledge and skills to provide continuous labor support to women of Baltimore and surrounding areas. This faculty-led, student-run program also supports student engagement in service learning, and practice regarding leadership skills and interprofessional collaboration as a student nurse.

Nursing students' reflections on vaccine administration during the COVID-19 global pandemic.

BACKGROUND: During the COVID-19 pandemic, many nursing schools limited in-person clinical instruction to lower the risk of student exposure to SARS-CoV-2. Some U.S. state boards of nursing authorized virtual learning experiences to attempt to fill this void. The effects of restricting such hands-on training are not fully understood, but we believed it could be detrimental to student development and saw partnering with local COVID-19 vaccination clinic as a promising alternative. Between January and April 2021, second semester pre-licensure nursing students assisted at the clinic and submitted reflections on the experience. The aim of this study was to assess the effectiveness of this educational encounter. METHODS: One hundred seventy-one students submitted reflections on their experience, which were de-identified and uploaded to a HIPAA- and FERPA-compliant cloud storage system using SAFE desktop and coded for thematic analysis. RESULTS: Analysis revealed five major themes: community, socializing, perceived confidence, impact, and professional role. CONCLUSION: This study demonstrated the viability of instruction at a COVID-19 vaccination clinic as an alternative learning experience for nursing students encountering restricted face-to-face clinical training. It suggests that schools can develop other novel clinical experiences to increase students' perceived confidence, provide opportunities to practice skills, and gain insights into nursing practice.

Nursing Students with Disabilities: A Guide to Providing Accommodations.

The number of nursing students with disabilities entering nursing school continues to rise along with the critical need for nurses. According to federal law, accommodations must be implemented in the classroom and clinical area for nursing students with disabilities. Faculty and administrators must protect the civil rights of those with disabilities by addressing barriers to student success and establishing accommodations. By using adaptive equipment, service animals, and other accommodations, nursing students with disabilities can be successful in providing safe and effective care to patients and add to diversity and inclusion in the nursing profession.

HSCT using carrier donors for CD40L deficiency results in excellent immune function and higher CD40L expression in cTfh.

Data are limited regarding the immune status of CD40 ligand (CD40L)-deficient carriers and hematopoietic stem cell transplantation (HSCT) outcomes using them as donors for CD40L-deficient patients. Therefore, we studied the immune profiles of 7 carriers, 4 of whom were HSCT donors for family members with CD40L deficiency, and we characterized their HSCT outcomes. Immunoglobulin profiles, CD4, CD8, circulating T-follicular helper (cTfh) cells, and regulatory T cells (Tregs) in carriers were comparable to those in healthy controls. CD40L expression in carriers ranged from 37% to 78%. cTfh cells from carriers expressed higher CD40L compared with total CD4 cells or the memory CD4 compartment, suggesting a potential advantage to CD40L-expressing cTfh cells. Tregs had minimal CD40L expression in carriers and healthy controls. So we postulated that HSCT using donors who were CD40L carriers may result in excellent immune reconstitution without immune dysregulation. Four CD40L-deficient patients underwent HSCT from carriers who had CD40L expression from 37% to 63%. All patients engrafted, achieved excellent immune reconstitution with lack of opportunistic infections, graft-versus-host disease, and immune dysregulation; stable CD40L expression mimicked that of donors 1 to 5 years after HSCT. Immunoglobulin independence was achieved in 3 of the 4 patients. We demonstrated higher CD40L expression in the cTfh compartment of carriers and excellent immune reconstitution using donors who were CD40L carriers in CD40L-deficient patients.

Relationship between early language competence and cognitive emotion regulation in adolescence.

Cognitive emotion regulation improves throughout adolescence and promotes good mental health. Here, we test whether language skills at school entry predict success in emotion regulation in an experimental task at age 10-11, using longitudinal data from the Surrey Communication and Language in Education Study. We additionally compared the performance of children with and without language disorder (LD). Across the whole sample (N = 344), language skills at school entry predicted emotion regulation success in Year 6 (ß = 0.23), over and above the concurrent association between language and regulation success. There was no evidence that children with LD that could engage in the task were less successful regulators compared to peers with typical language. However, a quarter of children with LD were unable to complete the task. These children had more severe language difficulties, lower non-verbal IQ and more comorbid conditions. This has implications for clinicians addressing mental health needs for children with neurodevelopmental conditions that affect language, as conversations about emotions and emotion regulation are an integral part of therapy. The longitudinal relationship between language skills and the capacity to use temporal distancing for emotion regulation in early adolescence suggests that language may drive improvements in emotion regulation.

Federal, state, and institutional regulations regarding a nursing student with a service animal.

Several universities are reporting increasing numbers of students using a service animal. Understanding the three types of assistance animals-service animal, therapy animal, and emotional support animal-will assist nursing educators in determining which animals are trained to provide a specific service to the student. Students with conditions as varied as diabetes, anxiety disorder, and seizures may benefit from a service animal. Reviewing the types of support these animals provide and federal, state, and local regulations related to service animal use will guide faculty members in preparing for a high quality learning experience for students who use a service animal. Query: Embase, CINAHL, PubMed.