It takes a village to skew a lymph node.

Unconventional T cells (UTCs) play important roles in protecting barrier tissues. In this issue of Immunity, Ataide and colleagues show an additional function for these cells: populating downstream lymph nodes and skewing their cytokine profiles. This process allows tissues to adjust the function of draining lymph nodes through imprinting UTC cytokine production, subsequently influencing the immune responses that are triggered.

Secondary influenza challenge triggers resident memory B cell migration and rapid relocation to boost antibody secretion at infected sites.

Resident memory B (BRM) cells develop and persist in the lungs of influenza-infected mice and humans; however, their contribution to recall responses has not been defined. Here, we used two-photon microscopy to visualize BRM cells within the lungs of influenza -virus immune and reinfected mice. Prior to re-exposure, BRM cells were sparsely scattered throughout the tissue, displaying limited motility. Within 24 h of rechallenge, these cells increased their migratory capacity, localized to infected sites, and subsequently differentiated into plasma cells. Alveolar macrophages mediated this process, in part by inducing expression of chemokines CXCL9 and CXCL10 from infiltrating inflammatory cells. This led to the recruitment of chemokine receptor CXCR3-expressing BRM cells to infected regions and increased local antibody concentrations. Our study uncovers spatiotemporal mechanisms that regulate lung BRM cell reactivation and demonstrates their capacity to rapidly deliver antibodies in a highly localized manner to sites of viral replication.

Immune microniches shape intestinal Treg function.

The intestinal immune system is highly adapted to maintaining tolerance to the commensal microbiota and self-antigens while defending against invading pathogens1,2. Recognizing how the diverse network of local cells establish homeostasis and maintains it in the complex immune environment of the gut is critical to understanding how tolerance can be re-established following dysfunction, such as in inflammatory disorders. Although cell and molecular interactions that control T regulatory (Treg) cell development and function have been identified3,4, less is known about the cellular neighbourhoods and spatial compartmentalization that shapes microorganism-reactive Treg cell function. Here we used in vivo live imaging, photo-activation-guided single-cell RNA sequencing5-7 and spatial transcriptomics to follow the natural history of T cells that are reactive towards Helicobacter hepaticus through space and time in the settings of tolerance and inflammation. Although antigen stimulation can occur anywhere in the tissue, the lamina propria-but not embedded lymphoid aggregates-is the key microniche that supports effector Treg (eTreg) cell function. eTreg cells are stable once their niche is established; however, unleashing inflammation breaks down compartmentalization, leading to dominance of CD103+SIRPα+ dendritic cells in the lamina propria. We identify and validate the putative tolerogenic interaction between CD206+ macrophages and eTreg cells in the lamina propria and identify receptor-ligand pairs that are likely to govern the interaction. Our results reveal a spatial mechanism of tolerance in the lamina propria and demonstrate how knowledge of local interactions may contribute to the next generation of tolerance-inducing therapies.

Parent-Youth Attachment Insecurity and Informant Discrepancies of Intrafamilial Aggression.

This study investigated how youth attachment anxiety and avoidance are associated with informant discrepancies of intrafamilial aggression within families where youth have clinically significant mental health challenges (N = 510 youth-parent dyads). Using polynomial regressions, we tested whether youth attachment avoidance and anxiety moderated the absolute magnitude of the association between youth- and parent-reports of aggression toward each other. Furthermore, difference scores were computed to test whether youth attachment was associated with the direction of youths' reports of the frequency of aggression relative to parents (i.e., did youth under- or over-report). Dyads' reports of youth-to-parent aggression were more strongly related at high than low levels of attachment anxiety. Results also revealed that youth attachment anxiety was associated with youth over-reporting of youth-to-parent and parent-to-youth aggression (relative to parents), whereas attachment avoidance was associated with youth over-reporting parent-to-youth aggression (relative to parents). These findings highlight the importance of understanding the source of informant discrepancies in social-emotional development and family functioning.

Chitin activates parallel immune modules that direct distinct inflammatory responses via innate lymphoid type 2 and γδ T cells.

Chitin, a polysaccharide constituent of many allergens and parasites, initiates innate type 2 lung inflammation through incompletely defined pathways. We show that inhaled chitin induced expression of three epithelial cytokines, interleukin-25 (IL-25), IL-33, and thymic stromal lymphopoietin (TSLP), which nonredundantly activated resident innate lymphoid type 2 cells (ILC2s) to express IL-5 and IL-13 necessary for accumulation of eosinophils and alternatively activated macrophages (AAMs). In the absence of all three epithelial cytokines, ILC2s normally populated the lung but failed to increase IL-5 and IL-13. Although eosinophils and AAMs were attenuated, neutrophil influx remained normal without these epithelial cytokines. Genetic ablation of ILC2s, however, enhanced IL-1ß, TNFα, and IL-23 expression, increased activation of IL-17A-producing γδ T cells, and prolonged neutrophil influx. Thus, chitin elicited patterns of innate cytokines that targeted distinct populations of resident lymphoid cells, revealing divergent but interacting pathways underlying the tissue accumulation of specific types of inflammatory myeloid cells.

The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors.

Platelets are critical for haemostasis, thrombosis, and inflammatory responses, but the events that lead to mature platelet production remain incompletely understood. The bone marrow has been proposed to be a major site of platelet production, although there is indirect evidence that the lungs might also contribute to platelet biogenesis. Here, by directly imaging the lung microcirculation in mice, we show that a large number of megakaryocytes circulate through the lungs, where they dynamically release platelets. Megakaryocytes that release platelets in the lungs originate from extrapulmonary sites such as the bone marrow; we observed large megakaryocytes migrating out of the bone marrow space. The contribution of the lungs to platelet biogenesis is substantial, accounting for approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature megakaryocytes along with haematopoietic progenitors in the extravascular spaces of the lungs. Under conditions of thrombocytopenia and relative stem cell deficiency in the bone marrow, these progenitors can migrate out of the lungs, repopulate the bone marrow, completely reconstitute blood platelet counts, and contribute to multiple haematopoietic lineages. These results identify the lungs as a primary site of terminal platelet production and an organ with considerable haematopoietic potential.

Psychometric Evaluation of the Affect Regulation Checklist: Clinical and Community Samples, Parent-Reports and Youth Self-Reports.

The Affect Regulation Checklist (ARC) was designed to capture affect dysregulation, suppression, and reflection. Importantly, affect dysregulation has been established as a transdiagnostic mechanism underpinning many forms of psychopathology. We tested the ARC psychometric properties across clinical and community samples and through both parent-report and youth self-report information. Clinical sample: Participants included parents (n = 814; Mage = 43.86) and their child (n = 608; Mage = 13.98). Community sample: Participants included independent samples of parents (n = 578; Mage = 45.12) and youth (n = 809; Mage = 15.67). Exploratory structural equation modeling supported a three-factor structure across samples and informants. Dysregulation was positively associated with all forms of psychopathology. In general, suppression was positively associated with many forms of psychopathology, and reflection was negatively associated with externalizing problems and positively associated with internalizing problems.

Type 2 innate lymphoid cells control eosinophil homeostasis.

Eosinophils are specialized myeloid cells associated with allergy and helminth infections. Blood eosinophils demonstrate circadian cycling, as described over 80 years ago, and are abundant in the healthy gastrointestinal tract. Although a cytokine, interleukin (IL)-5, and chemokines such as eotaxins mediate eosinophil development and survival, and tissue recruitment, respectively, the processes underlying the basal regulation of these signals remain unknown. Here we show that serum IL-5 levels are maintained by long-lived type 2 innate lymphoid cells (ILC2) resident in peripheral tissues. ILC2 cells secrete IL-5 constitutively and are induced to co-express IL-13 during type 2 inflammation, resulting in localized eotaxin production and eosinophil accumulation. In the small intestine where eosinophils and eotaxin are constitutive, ILC2 cells co-express IL-5 and IL-13; this co-expression is enhanced after caloric intake. The circadian synchronizer vasoactive intestinal peptide also stimulates ILC2 cells through the VPAC2 receptor to release IL-5, linking eosinophil levels with metabolic cycling. Tissue ILC2 cells regulate basal eosinophilopoiesis and tissue eosinophil accumulation through constitutive and stimulated cytokine expression, and this dissociated regulation can be tuned by nutrient intake and central circadian rhythms.

The spatiotemporal cellular dynamics of lung immunity.

The lung is a complex structure that is interdigitated with immune cells. Understanding the 4D process of normal and defective lung function and immunity has been a centuries-old problem. Challenges intrinsic to the lung have limited adequate microscopic evaluation of its cellular dynamics in real time, until recently. Because of emerging technologies, we now recognize alveolar-to-airway transport of inhaled antigen. We understand the nature of neutrophil entry during lung injury and are learning more about cellular interactions during inflammatory states. Insights are also accumulating in lung development and the metastatic niche of the lung. Here we assess the developing technology of lung imaging, its merits for studies of pathophysiology and areas where further advances are needed.

Coaching of patients with an isolated minimally displaced fracture of the radial head immediately increases range of motion.

STUDY DESIGN: Prospective cohort. INTRODUCTION: Elbow stiffness is the most common adverse event after isolated radial head fractures. PURPOSE OF THE STUDY: To assess the effect of coaching on elbow motion during the same office visit in patients with such fractures. METHODS: We enrolled 49 adult patients with minimally displaced radial head fractures, within 14 days of injury. After diagnosis, we measured demographics, catastrophic thinking, health anxiety, symptoms of depression, upper extremity-specific symptoms and disability, pain, and elbow and wrist motion. The patient was taught to apply an effective stretch in spite of the pain to limit stiffness, and elbow motion was measured again. RESULTS: With the exception of radial deviation and pronation, motion measures improved slightly but significantly on average immediately after coaching. Elbow flexion improved from 79% (110° ± 22°) of the uninjured side to 88% (122° ± 18°) after coaching (P < .001); elbow extension improved from 71% (29° ± 14°) to 78% (22° ± 15°) (P = .0012). DISCUSSION: Instruction that stretching exercises are healthy even when painful resulted in immediate improvements in motion. Prospective studies comparing different strategies for coaching patients regarding painful stretches might help clarify the optimal approach. LEVEL OF EVIDENCE: Therapeutic level 4.

Time Seeing a Hand Surgeon Is Not Associated With Patient Satisfaction.

BACKGROUND: Previous studies, predominantly in the primary care setting, identified time spent with the physician as an important predictor of satisfaction. It is unknown if the same holds true in hand surgery. QUESTIONS/PURPOSES: Is patient satisfaction measured immediately after an office visit associated with the duration of time spent with the hand surgeon? What other factors are associated with satisfaction directly after the visits and 2 weeks after the appointment? METHODS: We prospectively enrolled 81 patients visiting our hand and upper extremity surgery outpatient clinic. We recorded their demographics and measured physical function, pain behavior, symptoms of depression, time spent in the waiting room, time spent with the physician, and patient satisfaction. Office times were measured using our patient ambulatory tracking system and by a research assistant outside the clinic room. To assess satisfaction we used items from the Consumer Assessment of Healthcare Providers and Systems survey (a federally developed standardized survey instrument) relevant to our study. Two weeks later, 51 (64%) patients were available for telephone followup and the same measures were completed. Mean time spent with the hand surgeon was 8 ± 5 minutes and mean in-office wait time to see the hand surgeon was 32 ± 18 minutes. A priori power analyses indicated that 77 patients would provide 80% power to detect an effect size f(2) = 0.18 for a regression with five predictors. This means that we would detect time spent with the physician as a significant factor if it accounted for 7% or more of the variability in satisfaction. RESULTS: Time spent with the hand surgeon was not associated with patient satisfaction measured directly after the visit (r = -0.023; p = 0.84). Longer time waiting to see the physician correlated with decreased patient satisfaction (r = -0.30; p = 0.0057). The final multivariable model for increased satisfaction directly after the office visit included shorter waiting time (regression coefficient [ß] -0.0014; partial R(2) 0.094; 95% confidence interval [CI], -0.0024 to -0.00042; p = 0.006) and being married/living with a partner (ß 0.057; partial R(2) 0.11; 95% CI, 0.021-0.093; p = 0.002 [adjusted R(2) 0.18; p < 0.001]). Similarly, multivariable analysis found higher patient satisfaction 2 weeks after the visit to be independently associated with shorter waiting time (ß -0.0037; partial R(2) 0.10; 95% CI, -0.0070 to -0.00054; p = 0.023) and being married/living with a partner (ß 0.15; partial R(2) 0.12; 95% CI, 0.033-0.26; p = 0.012 [adjusted R(2) 0.16; p = 0.0052]). CONCLUSIONS: Patient satisfaction among patients undergoing hand surgery may relate more to shorter time in the waiting room and to the quality more than the quantity of time spent with the patient. LEVEL OF EVIDENCE: Level II, prognostic study.

A prospective randomized clinical trial of prescription of full-time versus as-desired splint wear for de Quervain tendinopathy.

PURPOSE: There is no consensus on the best protocol for splint wear in the non-operative management of de Quervain tendinopathy. This study aimed to determine if there is a difference between prescription of strict splint wear compared to selective splint wear in patients with de Quervain tendinopathy. We tested the primary null hypothesis that there is no difference in upper-extremity disability eight weeks after initiating splinting between patients prescribed full-time or as-desired splint wear. Secondary study questions addressed differences in grip strength, pain intensity, and treatment satisfaction. Additionally, we evaluated the influence of psychological factors on disability. METHODS: Eighty-three patients diagnosed with de Quervain tendinopathy were randomly allocated into two different splint-wearing instructions: full-time wear (N = 43) or as-desired wear (N = 40). At enrollment, patients had grip strength measured and completed measures of upper-extremity disability, pain intensity, and psychological distress. An average of 7.5 weeks later, patients returned for a second visit. Analysis was by intention-to-treat and with use of mean imputation for missing data. RESULTS: Fifty-eight patients (70 %; 26 in the full-time cohort and 32 in the as-desired cohort) completed the study. There were no statistically significant differences in disability (p = 0.77), grip strength (p = 0.82), pain intensity (p = 0.36), and treatment satisfaction (p = 0.91) between patients instructed to wear the splint full-time and those instructed to use it as desired. Disability at final evaluation correlated significantly with baseline levels of pain anxiety (p = 0.008), catastrophic thinking (p = 0.001), and symptoms of depression (p < 0.001). The best multivariable linear regression model included symptoms of depression alone and accounted for 32 % of the variability in disability (p < 0.001). CONCLUSION: There is no difference in patient-reported outcomes and grip strength with prescription of full-time or as-desired splinting, and patients can wear the splint as they prefer. These results suggest that splinting for de Quervain tendinopathy is palliative at best and strict rest is not disease modifying.

Polycystic Ovarian Syndrome: A Primer.

Polycystic ovary syndrome (PCOS) affects 8-10 percent of reproductive-aged females, making it the most common state of endocrine dysfunction in women. Patients with PCOS are often treated for the signs and symptoms of the condition without consideration for the underlying syndrome, causing frustration for many affected patients. Abnormal uterine bleeding, endometrial hyperplasia and cancer, hirsutism and other skin changes, obesity, glucose intolerance, hypertension, and hyperlipidemia often accompany the syndrome, making it imperative to address these issues. The keys to diagnosis and treatment are understanding the diagnostic criteria of hyperandrogenism, ovulatory dysfunction, polycystic ovaries and the metabolic syndrome, while aiming treatment at controlling the symptoms and causes of the syndrome. In 2013, the Endocrine Society released its clinical guidelines, Diagnosis and Treatment of Polycystic Ovary Syndrome: An Endocrine Society Clinical Practice Guideline. This gives clear diagnostic criteria, and treatment goals aimed at the etiology of the syndrome: to decrease hyperandrogenic symptoms, management of underlying metabolic abnormalities, prevention of endometrial hyperplasia and carcinoma, and improvement of ovulation.

Stabilized imaging of immune surveillance in the mouse lung.

Real-time imaging of cellular and subcellular dynamics in vascularized organs requires image resolution and image registration to be simultaneously optimized without perturbing normal physiology. This problem is particularly pronounced in the lung, in which cells may transit at speeds >1 mm s(-1) and in which normal respiration results in large-scale tissue movements that prevent image registration. Here we report video-rate, two-photon imaging of a physiologically intact preparation of the mouse lung that is stabilizing and nondisruptive. Using our method, we obtained evidence for differential trapping of T cells and neutrophils in mouse pulmonary capillaries, and observed neutrophil mobilization and dynamic vascular leak in response to stretch and inflammatory models of lung injury in mice. The system permits physiological measurement of motility rates of >1 mm s(-1), observation of detailed cellular morphology and could be applied in the future to other organs and tissues while maintaining intact physiology.

A pro-inflammatory gut mucosal cytokine response is associated with mild COVID-19 disease and superior induction of serum antibodies.

The relationship between gastrointestinal tract infection, the host immune response, and the clinical outcome of disease is not well understood in COVID-19. We sought to understand the effect of intestinal immune responses to SARS-CoV-2 on patient outcomes including the magnitude of systemic antibody induction. Combining two prospective cohort studies, International Severe Acute Respiratory and emerging Infections Consortium Comprehensive Clinical Characterisations Collaboration (ISARIC4C) and Integrated Network for Surveillance, Trials and Investigations into COVID-19 Transmission (INSTINCT), we acquired samples from 88 COVID-19 cases representing the full spectrum of disease severity and analysed viral RNA and host gut cytokine responses in the context of clinical and virological outcome measures. There was no correlation between the upper respiratory tract and faecal viral loads. Using hierarchical clustering, we identified a group of fecal cytokines including Interleukin-17A, Granulocyte macrophage colony-stimulating factor, Tumor necrosis factorα, Interleukin-23, and S100A8, that were transiently elevated in mild cases and also correlated with the magnitude of systemic anti-Spike-receptor-binding domain antibody induction. Receiver operating characteristic curve analysis showed that expression of these gut cytokines at study enrolment in hospitalised COVID-19 cases was associated negatively with overall clinical severity implicating a protective role in COVID-19. This suggests that a productive intestinal immune response may be beneficial in the response to a respiratory pathogen and a biomarker of a successful barrier response.

Mental Health During the First Year of the COVID-19 Pandemic: A Review and Recommendations for Moving Forward.

COVID-19 has infected millions of people and upended the lives of most humans on the planet. Researchers from across the psychological sciences have sought to document and investigate the impact of COVID-19 in myriad ways, causing an explosion of research that is broad in scope, varied in methods, and challenging to consolidate. Because policy and practice aimed at helping people live healthier and happier lives requires insight from robust patterns of evidence, this article provides a rapid and thorough summary of high-quality studies available through early 2021 examining the mental-health consequences of living through the COVID-19 pandemic. Our review of the evidence indicates that anxiety, depression, and distress increased in the early months of the pandemic. Meanwhile, suicide rates, life satisfaction, and loneliness remained largely stable throughout the first year of the pandemic. In response to these insights, we present seven recommendations (one urgent, two short-term, and four ongoing) to support mental health during the pandemic and beyond.

Policy stringency and mental health during the COVID-19 pandemic: a longitudinal analysis of data from 15 countries.

BACKGROUND: To date, public health policies implemented during the COVID-19 pandemic have been evaluated on the basis of their ability to reduce transmission and minimise economic harm. We aimed to assess the association between COVID-19 policy restrictions and mental health during the COVID-19 pandemic. METHODS: In this longitudinal analysis, we combined daily policy stringency data from the Oxford COVID-19 Government Response Tracker with psychological distress scores and life evaluations captured in the Imperial College London-YouGov COVID-19 Behaviour Tracker Global Survey in fortnightly cross-sections from samples of 15 countries between April 27, 2020, and June 28, 2021. The mental health questions provided a sample size of 432 642 valid responses, with an average of 14 918 responses every 2 weeks. To investigate how policy stringency was associated with mental health, we considered two potential mediators: observed physical distancing and perceptions of the government's handling of the pandemic. Countries were grouped on the basis of their response to the COVID-19 pandemic as those pursuing an elimination strategy (countries that aimed to eliminate community transmission of SARS-CoV-2 within their borders) or those pursuing a mitigation strategy (countries that aimed to control SARS-CoV-2 transmission). Using a combined dataset of country-level and individual-level data, we estimated linear regression models with country-fixed effects (ie, dummy variables representing the countries in our sample) and with individual and contextual covariates. Additionally, we analysed data from a sample of Nordic countries, to compare Sweden (that pursued a mitigation strategy) to other Nordic countries (that adopted a near-elimination strategy). FINDINGS: Controlling for individual and contextual variables, higher policy stringency was associated with higher mean psychological distress scores and lower life evaluations (standardised coefficients ß=0·014 [95% CI 0·005 to 0·023] for psychological distress; ß=-0·010 [-0·015 to -0·004] for life evaluation). Pandemic intensity (number of deaths per 100 000 inhabitants) was also associated with higher mean psychological distress scores and lower life evaluations (standardised coefficients ß=0·016 [0·008 to 0·025] for psychological distress; ß=-0·010 [-0·017 to -0·004] for life evaluation). The negative association between policy stringency and mental health was mediated by observed physical distancing and perceptions of the government's handling of the pandemic. We observed that countries pursuing an elimination strategy used different policy timings and intensities compared with countries pursuing a mitigation strategy. The containment policies of countries pursuing elimination strategies were on average less stringent, and fewer deaths were observed. INTERPRETATION: Changes in mental health measures during the first 15 months of the COVID-19 pandemic were small. More stringent COVID-19 policies were associated with poorer mental health. Elimination strategies minimised transmission and deaths, while restricting mental health effects. FUNDING: None.

A conserved population of MHC II-restricted, innate-like, commensal-reactive T cells in the gut of humans and mice.

Interactions with commensal microbes shape host immunity on multiple levels and play a pivotal role in human health and disease. Tissue-dwelling, antigen-specific T cells are poised to respond to local insults, making their phenotype important in the relationship between host and microbes. Here we show that MHC-II restricted, commensal-reactive T cells in the colon of both humans and mice acquire transcriptional and functional characteristics associated with innate-like T cells. This cell population is abundant and conserved in the human and murine colon and endowed with polyfunctional effector properties spanning classic Th1- and Th17-cytokines, cytotoxic molecules, and regulators of epithelial homeostasis. T cells with this phenotype are increased in ulcerative colitis patients, and their presence aggravates pathology in dextran sodium sulphate-treated mice, pointing towards a pathogenic role in colitis. Our findings add to the expanding spectrum of innate-like immune cells positioned at the frontline of intestinal immune surveillance, capable of acting as sentinels of microbes and the local cytokine milieu.

Mucosal immune responses in COVID19 - a living review.

COVID-19 was initially characterized as a disease primarily of the lungs, but it is becoming increasingly clear that the SARS-CoV2 virus is able to infect many organs and cause a broad pathological response. The primary infection site is likely to be a mucosal surface, mainly the lungs or the intestine, where epithelial cells can be infected with virus. Although it is clear that virus within the lungs can cause severe pathology, driven by an exaggerated immune response, infection within the intestine generally seems to cause minor or no symptoms. In this review, we compare the disease processes between the lungs and gastrointestinal tract, and what might drive these different responses. As the microbiome is a key part of mucosal barrier sites, we also consider the effect that microbial species may play on infection and the subsequent immune responses. Because of difficulties obtaining tissue samples, there are currently few studies focused on the local mucosal response rather than the systemic response, but understanding the local immune response will become increasingly important for understanding the mechanisms of disease in order to develop better treatments.

Assessing the validity of the Self versus other interest implicit association test.

There is great variability in the ways that humans treat one another, ranging from extreme compassion (e.g., philanthropy, organ donation) to self-interested cruelty (e.g., theft, murder). What underlies and explains this variability? Past research has primarily examined human prosociality using explicit self-report scales, which are susceptible to self-presentation biases. However, these concerns can be alleviated with the use of implicit attitude tests that assess automatic associations. Here, we introduce and assess the validity of a new test of implicit prosociality-the Self versus Other Interest Implicit Association Test (SOI-IAT)-administered to two samples in pre-registered studies: regular blood donors (Study 1; N = 153) and a nationally representative sample of Americans (Study 2; N = 467). To assess validity, we investigated whether SOI-IAT scores were correlated with explicit measures of prosociality within each sample and compared SOI-IAT scores of the control sample (representative sample of Americans) with the prosocial sample (blood donors). While SOI-IAT scores were higher in the prosocial blood donor sample, SOI-IAT scores were generally uncorrelated with explicit measures and actual prosocial behaviour. Thus, the SOI-IAT may be able to detect group differences in everyday prosociality, but future testing is needed for a more robust validation of the SOI-IAT. These unexpected findings underscore the importance of sharing null and mixed results to fill gaps in the scientific record and highlight the challenges of conducting research on implicit processes.