Unleashing TNF cytotoxicity to enhance cancer immunotherapy.

Tumor necrosis factor (TNF) is a proinflammatory cytokine that is produced and secreted by cytotoxic lymphocytes upon tumor target recognition. Depending on the context, TNF can mediate either pro-survival or pro-death signals. The potential cytotoxicity of T cell-produced TNF, particularly in the context of T cell-directed immunotherapies, has been largely overlooked. However, a spate of recent studies investigating tumor immune evasion through the application of CRISPR-based gene-editing screens have highlighted TNF-mediated killing as an important component of the mammalian T cell antitumor repertoire. In the context of the current understanding of the role of TNF in antitumor immunity, we discuss these studies and touch on their therapeutic implications. Collectively, we provide an enticing prospect to augment immunotherapy responses through TNF cytotoxicity.

Comparing self-reported quality of life in youth with bipolar versus other disorders.

OBJECTIVES: This study benchmarks quality of life (QoL) of youth with bipolar disorder (BD) against healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. The relative impacts of depressive, (hypo)manic, mixed, and externalizing symptoms on QoL are tested for youth with BD. METHOD: In total, 657 youth completed the Schedule for Affective Disorders and Schizophrenia for Children (KSADS), the KSADS depression and mania scales, the Parent General Behavior Inventory (PGBI), and the Child Behavior Checklist (CBCL). Youth-reported QoL was determined by the Revised Children Quality of Life Questionnaire (KINDL) and was compared to healthy youth, youth with chronic medical conditions, and youth with other psychiatric disorders. RESULTS: Youth with BD reported poorer QoL overall and on most subscales compared to healthy youth, youth with chronic medical conditions, youth with behavior disorders, and youth with other non-behavior/non-mood disorders. QoL in youth with BD did not differ significantly from QoL in youth with unipolar depression. Parent-report and interview-rated depressive symptoms were associated with decreases in Total QoL and all QoL subscales except Family. Externalizing symptoms were associated with decreases in Family QoL and increases in Friend QoL, and (hypo)manic symptoms were associated with increases in Emotional Well-Being QoL. CONCLUSIONS: Depressive symptoms may drive the decline in QoL causing youth with BD to rate their QoL worse than healthy youth, youth with chronic medical conditions, and youth with behavior disorders, but not worse than youth with unipolar depression.

HOIP limits anti-tumor immunity by protecting against combined TNF and IFN-gamma-induced apoptosis.

The success of cancer immunotherapy is limited to a subset of patients, highlighting the need to identify the processes by which tumors evade immunity. Using CRISPR/Cas9 screening, we reveal that melanoma cells lacking HOIP, the catalytic subunit of LUBAC, are highly susceptible to both NK and CD8+ T-cell-mediated killing. We demonstrate that HOIP-deficient tumor cells exhibit increased sensitivity to the combined effect of the inflammatory cytokines, TNF and IFN-γ, released by NK and CD8+ T cells upon target recognition. Both genetic deletion and pharmacological inhibition of HOIP augment tumor cell sensitivity to combined TNF and IFN-γ. Together, we unveil a protective regulatory axis, involving HOIP, which limits a transcription-dependent form of cell death that engages both intrinsic and extrinsic apoptotic machinery upon exposure to TNF and IFN-γ. Our findings highlight HOIP inhibition as a potential strategy to harness and enhance the killing capacity of TNF and IFN-γ during immunotherapy.

Creating synergies among education/research, practice, and policy environments to build capacity for the scholar role in occupational therapy and physiotherapy in the Canadian context.

Scholarly practice (SP) is considered a key competency of occupational therapy and physiotherapy. To date, the three sectors-education/research, practice, and policy/regulation-that support SP have been working relatively independently. The goals of this project were to (a) understand how representatives of the three sectors conceptualize SP; (b) define each sector's individual and collective roles in supporting SP; (c) identify factors influencing the enactment of SP and the specific needs of how best to support SP; and (d) co-develop goals and strategies to support SP across all sectors. We used interpretive description methodology. Consistent with an integrated knowledge translation approach, partners representing the three sectors across Canada recruited individuals from each sector, developed the content and questions for three focus groups, and collected and analyzed the data. Inspired by the Consolidated Framework for Implementation Research, we developed the questions for the second focus group. We analyzed the data using an inductive thematic analysis method. Thirty-nine participants from the three sectors participated. Themes related to participants' conceptualization of SP included (a) ongoing process, (b) reflective process, (c) broad concept, and (d) collective effort. Themes describing factors influencing and supporting SP were (a) recognition, (b) appropriate conceptualization, (c) social network, (d) accessibility to resources, and (e) forces outside of practitioners' effort. Goals to support SP included (a) further recognizing SP, (b) sustaining SP competency, and (c) ensuring access to information. SP requires collaborative and integrated intersectoral support and further recognition of its importance through the collaboration of multiple stakeholders.

MCL internal brace does not fully recapitulate normal MCL function in valgus stress.

PURPOSE: The null hypothesis is that there would be no difference in medial gapping under valgus load between the intact MCL and the ruptured MCL with an internal brace in place. METHODS: Eight pairs of cadaver knees were used (16 knees). Alternating sides, one knee from each pair was used for one of two "internal brace" constructs. The constructs involved different methods of fixation for securing FiberTape (Arthrex, Naples, FL) to both the femur and tibia in an effort to brace the MCL. The knees were then subjected to valgus stress by applying 10 N m of torque with the knee at 20 degrees of flexion. The amount of medial joint space opening was measured on radiographs. The stress testing was conducted with three MCL states: intact, grade 2 tear, and grade 3 tear. RESULTS: In the Construct I specimens, gapping increased from 0.7 mm with the MCL intact to 1.1 mm with grade 2 tearing (p < 0.01), and to 1.3 mm with grade 3 tearing (p < 0.01). In the Construct II specimens, gapping increased from 0.7 mm with the MCL intact to 1.0 mm with grade 2 tearing (p < 0.01), and to 1.1 mm with grade 3 tearing (n.s.). Construct I specimens failed primarily at the femoral attachment. All Construct II specimens survived the valgus stress testing. CONCLUSION: Construct I did not maintain tension. Construct II did maintain tension during application of valgus load, but did not restore valgus opening to the intact state. It is important for clinicians who are considering using this commercially available technique to be aware of how the construct performs under valgus stress testing compared to the intact MCL.

Decreasing rate of inpatient pediatric bipolar disorder diagnosis in the US between 2004 and 2010.

OBJECTIVES: Diagnosis of bipolar disorder (BD) increased substantially among youth between the mid-1990s and mid-2000s in the United States. This dramatic increase in diagnosis resulted in concern regarding the potential for misdiagnosis of BD among youth. However, the rate of BD diagnosis in the United States had not been evaluated nationally since the mid-2000s. It was unclear whether changes in diagnostic rates continued to occur. Therefore, the present study aimed to assess the pattern of longitudinal trends in the rate of national inpatient BD diagnosis subsequent to 2004. METHODS: Data included a nationally representative dataset of inpatient hospitalizations between 1996 and 2010. De-identified data were obtained from the National Hospital Discharge Survey (NHDS) conducted annually by the National Center for Health Statistics. RESULTS: The proportion of BD diagnoses relative to all psychiatric diagnoses increased between 1996 and 2004 among children and adolescents. The proportion of BD diagnoses then decreased between 2004 and 2010 among children but continued to increase for adolescents. However, population-adjusted rates of BD diagnosis per 10,000 individuals in the general population initially increased until the mid-2000s and then decreased until 2010 for both children and adolescents. CONCLUSIONS: Rates of BD diagnosis substantially decreased for youth between the mid-2000s and 2010. This decline coincided with recommendations for more conservative diagnostic practices due to concerns about overdiagnosis and increasing awareness of the side effects of front-line medications used to treat BD in youth. Findings provide insight into changing trends in inpatient service utilization for BD in the United States.

Workers' compensation prescription medication patterns and associated outcomes.

BACKGROUND: Opioid use in the treatment of musculoskeletal injuries is a complex decision where benefits must be balanced with risk. Previous research has shown an association between higher opioid doses and adverse health effects. The study's objective was to investigate whether opioid prescriptions are associated with increased costs and deaths through an injury mechanism or as a direct result of the opioid prescription. METHODS: Data for 144,553 deidentified Ohio Bureau of Workers' Compensation claims from 2010 to 2014 with shoulder, knee, and low back injuries were obtained and followed until 2016. Each claim had associated prescription information. Injury claims were further classified using the allowed diagnoses by single or multiple body areas affected and injury severity ("simple" or "complex"). The outcome variables were medical and indemnity costs, lost days, MaxMED (maximum claim-prescribed daily morphine equivalent dose), and death status. Association between maximum opioid dose with deaths was determined by logistic regression analysis. RESULTS: Several outcome variables, including claim medical and indemnity costs, and the likelihood of claimant death, showed significant associations with the MaxMED. In the analysis of claim deaths, these associations held for all claim types (except complex), even after adjusting for age, gender, surgery, and lost time. CONCLUSION: The association between increasing opioid doses and deaths for low-severity diagnoses was disturbing given the lack of demonstrated efficacy of opioids for treatment of minor injuries. A focus on provider education, increased utilization of non-opioids, and early intervention for minor soft-tissue injuries could reduce claims costs, disability, and future deaths.

Transgender Youth Executive Functioning: Relationships with Anxiety Symptoms, Autism Spectrum Disorder, and Gender-Affirming Medical Treatment Status.

Executive function (EF) underlies broad health and adaptive outcomes. For transgender youth, navigating gender discernment and gender affirmation demand EF. Yet, factors associated with transgender youth EF are unknown. We investigate hypothesized predictors of EF: over-represented conditions among transgender youth (anxiety and depression symptoms, autism spectrum disorder [ASD]) and gender-affirming care. One-hundred twenty-four transgender 11-21-year-olds participated. Parents/caregivers completed EF and mental health report measures. ASD diagnostics and gender-affirming medication histories were collected. 21 % of non-autistic and 69 % of autistic transgender youth had clinically elevated EF problems. Membership in the gender-affirming hormone treatment group was associated with better EF. ASD, anxiety symptoms, and membership in the long-duration pubertal suppression group were associated with poorer EF. Given the importance of EF skills for multiple outcomes, and the unique and additional EF demands specific to transgender youths' experiences, EF skill monitoring-and when appropriate, supports-should be considered for transgender youth.

More stories to tell: NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1, a salicylic acid receptor.

Salicylic acid (SA) plays pivotal role in plant defense against biotrophic and hemibiotrophic pathogens. Tremendous progress has been made in the field of SA biosynthesis and SA signaling pathways over the past three decades. Among the key immune players in SA signaling pathway, NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1 (NPR1) functions as a master regulator of SA-mediated plant defense. The function of NPR1 as an SA receptor has been controversial; however, after years of arguments among several laboratories, NPR1 has finally been proven as one of the SA receptors. The function of NPR1 is strictly regulated via post-translational modifications and transcriptional regulation that were recently found. More recent advances in NPR1 biology, including novel functions of NPR1 and the structure of SA receptor proteins, have brought this field forward immensely. Therefore, based on these recent discoveries, this review acts to provide a full picture of how NPR1 functions in plant immunity and how NPR1 gene and NPR1 protein are regulated at multiple levels. Finally, we also discuss potential challenges in future studies of SA signaling pathway.

Injured recipients of low-titer group O whole blood have similar clinical outcomes compared to recipients of conventional component therapy: A single-center, retrospective study.

INTRODUCTION: Low-titer group O whole blood (LTOWB) is being increasingly transfused to injured patients. This study evaluated a range of clinical outcomes to determine if receipt of LTOWB predisposed recipients to worse outcomes compared to recipients of conventional component therapy (CCT). METHODS: A retrospective analysis of trauma patients who received at least 3 units of LTOWB (LTOWB group) versus those that received at least 3 units of RBCs, 1 unit of plasma and 1 unit of platelets but no LTOWB (CCT group) during the first 24 h of their admission was performed. Causal treatment effects were explored using propensity score matching (PSM) and coarsened exact matching (CEM). Important clinical outcomes were evaluated. RESULTS: There were 165 CCT and 155 LTOWB recipients eligible for matching. PSM and CEM reduced covariate imbalances between the CCT and LTOWB groups, with the exception that males remained over-represented in the LTOWB group due to the hospital's former resuscitation policy of not administering RhD-positive LTOWB to females <50. In both of the matched analyses, the LTOWB group received a median of 4 LTOWB units. There were no significant differences in 6-, 24-h mortality or 30-day mortality between groups, nor were there differences in the frequency of other clinical outcomes such as acute kidney injury, sepsis, venous/arterial thromboembolism; delta MODS was lower for the LTOWB recipients in the exact match group. CONCLUSION: In both matched analyses, administration of a median of four LTOWB units did not result in a different frequency of major clinical outcomes including mortality.

A Clinical Program for Transgender and Gender-Diverse Neurodiverse/Autistic Adolescents Developed through Community-Based Participatory Design.

Objective: A series of studies report elevated rates of autism and autistic characteristics among gender-diverse youth seeking gender services. Although youth with the co-occurrence present with complex care needs, existing studies have focused on co-occurrence rates. Further, clinical commentaries have emphasized provider-centered interpretations of clinical needs rather than key stakeholder-driven clinical approaches. This study aimed to employ community-based participatory research methodologies to develop a key stakeholder-driven clinical group program.Method: Autistic/neurodiverse gender-diverse (A/ND-GD) youth (N = 31), parents of A/ND-GD youth (N = 46), A/ND-GD self-advocates (N = 10), and expert clinical providers (N = 10) participated in a multi-stage community-based participatory procedure. Needs assessment data were collected repeatedly over time from A/ND-GD youth and their parents as the youth interacted with one another through ongoing clinical groups, the curriculum of which was developed progressively through the iterative needs assessments.Results: Separate adolescent and parent needs assessments revealed key priorities for youth (e.g., the importance of connecting with other A/ND-GD youth and the benefit of experiencing a range of gender-diverse role models to make gender exploration and/or gender affirmation more concrete) and parents (e.g., the need for A/ND-related supports for their children as well as provision of an A/ND-friendly environment that fosters exploration of a range of gender expressions/options). Integration and translation of youth and parent priorities resulted in 11 novel clinical techniques for this population.Conclusions: With generally high acceptability ratings for each component of the group program, this study presents a community-driven clinical model to support broad care needs and preferences of A/ND-GD adolescents.

Workers' compensation costs for healthcare caregivers: Home healthcare, long-term care, and hospital nurses and nursing aides.

BACKGROUND: Healthcare workers (nurses and nursing aides) often have different exposures and injury risk factors depending on their occupational subsector and location (hospital, long-term care, or home health care). METHODS: A total of 5234 compensation claims for nurses and nursing aides who suffered injuries to their lower back, knee, and/or shoulder over a 5-year period were obtained from the Ohio Bureau of Workers' Compensation and analyzed. Injury causation data was also collected for each claim. The outcome variables included indemnity costs, medical costs, total costs, and the number of lost work days. The highest prescribed morphine equivalent dose for opioid medications was also calculated for each claim. RESULTS: Home healthcare nurses and nursing aides had the highest average total costs per claim. Hospital nurses and nursing aides had the highest total claim costs, of $5 million/year. Shoulder injuries for home healthcare nursing aides (HHNAs) had the highest average total claim costs ($20,600/injury) for all occupation, setting, and body area combinations. Opioids were most frequently prescribed for home healthcare nurses (HHNs) and nursing aides (18.9% and 17.7% having been prescribed opioids, respectively). Overexertion was the most common cause for HHN and nursing aide claims. CONCLUSIONS: With the rapidly expanding workforce in the home healthcare sector, there is a potential health crisis from the continued expansion of home healthcare worker injuries and their associated costs. In addition, the potential for opioid drug usage places these workers at risk for future dependence, overdose, and prolonged disability. Future research is needed to investigate the specific and ideally reversible causes of injury in claims categorized as caused by overexertion.

Prevention and Reversal of Morbidity in Today's Cardiovascular Patient: Role of Lifestyle Modification and Nutrition in the Current Era.

PURPOSE OF REVIEW: The prevalence of cardiovascular disease despite good medical therapy is on the rise, driven by risk factors such as hypertension, diabetes, hypercholesterolemia, and obesity. As healthcare providers, we must seek to better advise patients on preventative strategies through lifestyle changes. RECENT FINDINGS: Guideline recommendations have been published by professional societies on the prevention of heart disease through lifestyle changes; however, limited education and experience with these lifestyle-modifying methods hinders appropriate counseling and treatment of patients. Robust data support the use of lifestyle medicine to reduce cardiovascular morbidity and risk. These include, a more plant-based whole food diet, regular exercise, stress relief, connectedness, and other lifestyle approaches. This review will help further the understanding of the front-line clinician in cardiovascular prevention.

Preliminary Psychometrics for the Executive Function Challenge Task: A Novel, "Hot" Flexibility, and Planning Task for Youth.

OBJECTIVE: Executive functions (EF) drive health and educational outcomes and therefore are increasingly common treatment targets. Most treatment trials rely on questionnaires to capture meaningful change because ecologically valid, pediatric performance-based EF tasks are lacking. The Executive Function Challenge Task (EFCT) is a standardized, treatment-sensitive, objective measure which assesses flexibility and planning in the context of provocative social interactions, making it a "hot" EF task. METHOD: We investigate the structure, reliability, and validity of the EFCT in youth with autism (Autism Spectrum Disorder; n = 129), or attention deficit hyperactivity disorder with flexibility problems (n = 93), and typically developing (TD; n = 52) youth. RESULTS: The EFCT can be coded reliably, has a two-factor structure (flexibility and planning), and adequate internal consistency and consistency across forms. Unlike a traditional performance-based EF task (verbal fluency), it shows significant correlations with parent-reported EF, indicating ecological validity. EFCT performance distinguishes youth with known EF problems from TD youth and is not significantly related to visual pattern recognition, or social communication/understanding in autistic children. CONCLUSIONS: The EFCT demonstrates adequate reliability and validity and may provide developmentally appropriate, treatment-sensitive, and ecologically valid assessment of "hot" EF in youth. It can be administered in controlled settings by masked administrators.

Consequences of Hypoxia for the Pulmonary Alveolar Epithelial Cell Innate Immune Response.

Pulmonary innate immune responses involve a highly regulated multicellular network to defend the enormous surface area of the lung. Disruption of these responses renders the host susceptible to pneumonia. Alveolar epithelial cells (AEC) are a critical source of innate immune molecules such as GM-CSF, which determine the functional maturation of alveolar macrophages. In many pulmonary diseases, heterogeneous ventilation leads to regional hypoxia in the lung. The effect of hypoxia on AEC innate immune function is unknown. We now report that exposure of primary murine AEC to hypoxia (1% oxygen) for 24 h results in significant suppression of key innate immune molecules, including GM-CSF, CCL2, and IL-6. This exposure did not cause toxicity but did induce stabilization of hypoxia-inducible factor 1α protein (HIF-1α) and shift to glycolytic metabolism. Focusing on GM-CSF, we found that hypoxia greatly decreased the rate of GM-CSF transcription. Hypoxia both decreased NF-κB signaling in AEC and induced chromosomal changes, resulting in decreased accessibility in the GM-CSF proximal promoter of target sequences for NF-κB binding. In mice exposed to hypoxia in vivo (12% oxygen for 2 d), lung GM-CSF protein expression was reduced. In vivo phagocytosis of fluorescent beads by alveolar macrophages was also suppressed, but this effect was reversed by treatment with GM-CSF. These studies suggest that in critically ill patients, local hypoxia may contribute to the susceptibility of poorly ventilated lung units to infection through complementary effects on several pathways, reducing AEC expression of GM-CSF and other key innate immune molecules.

Comparing the accuracy and speed of four data-checking methods.

Double entry locates and corrects more data-entry errors than does visual checking or reading the data out loud with a partner. However, many researchers do not use double entry, because it is substantially slower. Therefore, in this study we examined the speed and accuracy of solo read aloud, which has never before been examined and might be faster than double entry. To compare these four methods, we deliberately introduced errors while entering 20 data sheets and then asked 412 randomly assigned undergraduates to locate and correct these errors. Double entry was significantly and substantially more accurate than the other data-checking methods. However, the double-entry participants still made some errors. Close examination revealed that whenever double-entry participants made errors, they made the two sets of entries match, sometimes by introducing new errors into the dataset. This suggests that double entry can be improved by focusing attention on making entries match the original data sheets (rather than each other), perhaps by using a new person for mismatch correction. Solo read aloud was faster than double entry, but not as accurate. Double entry remains the gold standard in data-checking methods. However, solo read aloud was often substantially more accurate than partner read aloud and was more accurate than visual checking for one type of data. Therefore, when double entry is not possible, we recommend that researchers use solo read aloud or visual checking.

Medical Nutrition Education, Training, and Competencies to Advance Guideline-Based Diet Counseling by Physicians: A Science Advisory From the American Heart Association.

Growing scientific evidence of the benefits of heart-healthy dietary patterns and of the massive public health and economic burdens attributed to obesity and poor diet quality have triggered national calls to increase diet counseling in outpatients with atherosclerotic cardiovascular disease or risk factors. However, despite evidence that physicians are willing to undertake this task and are viewed as credible sources of diet information, they engage patients in diet counseling at less than desirable rates and cite insufficient knowledge and training as barriers. These data align with evidence of large and persistent gaps in medical nutrition education and training in the United States. Now, major reforms in undergraduate and graduate medical education designed to incorporate advances in the science of learning and to better prepare physicians for 21st century healthcare delivery are providing a new impetus and novel ways to expand medical nutrition education and training. This science advisory reviews gaps in undergraduate and graduate medical education in nutrition in the United States, summarizes reforms that support and facilitate more robust nutrition education and training, and outlines new opportunities for accomplishing this goal via multidimensional curricula, pedagogies, technologies, and competency-based assessments. Real-world examples of efforts to improve undergraduate and graduate medical education in nutrition by integrating formal learning with practical, experiential, inquiry-driven, interprofessional, and population health management activities are provided. The authors conclude that enhancing physician education and training in nutrition, as well as increasing collaborative nutrition care delivery by 21st century health systems, will reduce the health and economic burdens from atherosclerotic cardiovascular disease to a degree not previously realized.

Electrophysiologic testing for diagnostic evaluation and risk stratification in patients with suspected cardiac sarcoidosis with preserved left and right ventricular systolic function.

INTRODUCTION: While cardiac sarcoidosis (CS) carries a risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD), risk stratification of patients with CS and preserved left ventricular/right ventricular (LV/RV) systolic function remains challenging. We sought to evaluate the role of electrophysiologic testing and programmed electrical stimulation of the ventricle (EPS) in patients with suspected CS with preserved ventricular function. METHODS: One hundred twenty consecutive patients with biopsy-proven extracardiac sarcoidosis and preserved LV/RV systolic function underwent EPS. All patients had either probable CS defined by an abnormal cardiac positron emission tomography or cardiac magnetic resonance imaging, or possible CS with normal advanced imaging but abnormal echocardiogram (ECG), SAECG, Holter, or clinical factors. Patients were followed for 4.5 ± 2.6 years for SCD and VAs. RESULTS: Seven of 120 patients (6%) had inducible ventricular tachycardia (VT) with EPS and received an implantable cardioverter defibrillator (ICD). Three patients (43%) with positive EPS later had ICD therapies for VAs. Kaplan-Meier analysis stratified by EPS demonstrated a significant difference in freedom from VAs and SCD (P = 0.009), though this finding was driven entirely by patients within the cohort with probable CS (P = 0.018, n = 69). One patient with possible CS and negative EPS had unrecognized progression of the disease and unexplained death with evidence of CS at autopsy. CONCLUSIONS: EPS is useful in the risk stratification of patients with probable CS with preserved LV and RV function. A positive EPS was associated with VAs. While a negative EPS appeared to confer low risk, close follow-up is needed as EPS cannot predict fatal VAs related to new cardiac involvement or disease progression.

DOCK8 Drives Src-Dependent NK Cell Effector Function.

Mutations in the dedicator of cytokinesis 8 (DOCK8) gene cause an autosomal recessive form of hyper-IgE syndrome, characterized by chronic immunodeficiency with persistent microbial infection and increased incidence of malignancy. These manifestations suggest a defect in cytotoxic lymphocyte function and immune surveillance. However, how DOCK8 regulates NK cell-driven immune responses remains unclear. In this article, we demonstrate that DOCK8 regulates NK cell cytotoxicity and cytokine production in response to target cell engagement or receptor ligation. Genetic ablation of DOCK8 in human NK cells attenuated cytokine transcription and secretion through inhibition of Src family kinase activation, particularly Lck, downstream of target cell engagement or NKp30 ligation. PMA/Ionomycin treatment of DOCK8-deficient NK cells rescued cytokine production, indicating a defect proximal to receptor ligation. Importantly, NK cells from DOCK8-deficient patients had attenuated production of IFN-γ and TNF-α upon NKp30 stimulation. Taken together, we reveal a novel molecular mechanism by which DOCK8 regulates NK cell-driven immunity.

New understanding of primary health care nurse practitioner role optimisation: the dynamic relationship between the context and work meaning.

BACKGROUND: Optimising health professionals' contribution is an essential step in effective and efficient health human resources utilisation. However, despite the considerable efforts made to implement advanced practice nursing roles, including those in primary care settings (PHCNP), the optimisation of these roles remains variable. In this investigation, we report on the subjective work experience of a group of PHCNPs in the province of Quebec (Canada). METHODS: We used Giddens' structuration theory to guide our study given its' facilitation of the understanding of the dynamic between structural constraints and actors' actions. Using a qualitative descriptive study design, and specifically both individual and focus group interviews, we conducted our investigation within three health care regions in Quebec during 2016-2017. RESULTS: Forty-one PHCNPs participated. Their descriptions of their experience fell into two general categories. The first of these, their perception of others' inadequate understanding and valuing of their role, included the influence of certain work conditions, perceived restrictions on professional autonomy and the feeling of being caught between two professional paradigms. The second category, the PHCNPs' sense of engagement in their work, included perspectives associated with the specific conditions in which their work is situated, for example, the fragility of the role depending on the particular clinic/s in which they work or on the individuals with whom they work. This fragility was also linked with certain health care reforms that had been implemented in Quebec (e.g., legislation requiring greater physician productivity). CONCLUSION: Several new insights emerged, for example, the sense of role fragility being experienced by PHCNPs. The findings suggest an overarching link between the work context, the meaning attributed by PHCNPs to their work and their engagement. The optimisation of their role at the patient care level appears to be influenced by elements at the organisational and health system context levels. It appears that role optimisation must include the establishment of work environments and congruent health context structures that favour the implementation and deployment of new professional roles, work engagement, effective collaboration in interprofessional teams, and opportunities to exercise agency. Further research is necessary to evaluate initiatives that endeavour to achieve these objectives.