Time-resolved systems immunology reveals a late juncture linked to fatal COVID-19.

COVID-19 exhibits extensive patient-to-patient heterogeneity. To link immune response variation to disease severity and outcome over time, we longitudinally assessed circulating proteins as well as 188 surface protein markers, transcriptome, and T cell receptor sequence simultaneously in single peripheral immune cells from COVID-19 patients. Conditional-independence network analysis revealed primary correlates of disease severity, including gene expression signatures of apoptosis in plasmacytoid dendritic cells and attenuated inflammation but increased fatty acid metabolism in CD56dimCD16hi NK cells linked positively to circulating interleukin (IL)-15. CD8+ T cell activation was apparent without signs of exhaustion. Although cellular inflammation was depressed in severe patients early after hospitalization, it became elevated by days 17-23 post symptom onset, suggestive of a late wave of inflammatory responses. Furthermore, circulating protein trajectories at this time were divergent between and predictive of recovery versus fatal outcomes. Our findings stress the importance of timing in the analysis, clinical monitoring, and therapeutic intervention of COVID-19.

Immune dysregulation and autoreactivity correlate with disease severity in SARS-CoV-2-associated multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) is a life-threatening post-infectious complication occurring unpredictably weeks after mild or asymptomatic SARS-CoV-2 infection. We profiled MIS-C, adult COVID-19, and healthy pediatric and adult individuals using single-cell RNA sequencing, flow cytometry, antigen receptor repertoire analysis, and unbiased serum proteomics, which collectively identified a signature in MIS-C patients that correlated with disease severity. Despite having no evidence of active infection, MIS-C patients had elevated S100A-family alarmins and decreased antigen presentation signatures, indicative of myeloid dysfunction. MIS-C patients showed elevated expression of cytotoxicity genes in NK and CD8+ T cells and expansion of specific IgG-expressing plasmablasts. Clinically severe MIS-C patients displayed skewed memory T cell TCR repertoires and autoimmunity characterized by endothelium-reactive IgG. The alarmin, cytotoxicity, TCR repertoire, and plasmablast signatures we defined have potential for application in the clinic to better diagnose and potentially predict disease severity early in the course of MIS-C.

Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19.

Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood1-4. Here we use systems immunology approaches, including longitudinal multimodal single-cell analysis (surface proteins, transcriptome and V(D)J sequences) to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean, 151 days after diagnosis) and 40 age- and sex-matched control individuals who had never had COVID-19. At the baseline and independent of time after COVID-19, recoverees had elevated T cell activation signatures and lower expression of innate immune genes including Toll-like receptors in monocytes. Male individuals who had recovered from COVID-19 had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared with healthy male individuals and female individuals who had recovered from COVID-19, in part because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated prevaccination frequencies of 'virtual memory'-like CD8+ T cells poised to produce more IFNγ after IL-15 stimulation. Moreover, the expression of the repressed innate immune genes in monocytes increased by day 1 to day 28 after vaccination in recoverees, therefore moving towards the prevaccination baseline of the healthy control individuals. By contrast, these genes decreased on day 1 and returned to the baseline by day 28 in the control individuals. Our study reveals sex-dimorphic effects of previous mild COVID-19 and suggests that viral infections in humans can establish new immunological set-points that affect future immune responses in an antigen-agnostic manner.

Expanding the Immunology Toolbox: Embracing Public-Data Reuse and Crowdsourcing.

New technologies have been propelling dramatic increases in the volume and diversity of large-scale public data, which can potentially be reused to answer questions beyond those originally envisioned. However, this often requires computational and statistical skills beyond the reach of most bench scientists. The development of educational and accessible computational tools is thus critical, as are crowdsourcing efforts that utilize the community's expertise to curate public data for hypothesis generation and testing. Here we review the history of public-data reuse and argue for greater incorporation of computational and statistical sciences into the biomedical education curriculum and the development of biologist-friendly crowdsourcing tools. Finally, we provide a resource list for the reuse of public data and highlight an illustrative crowdsourcing exercise to explore public gene-expression data of human autoimmune diseases and corresponding mouse models. Through education, tool development, and community engagement, immunologists will be poised to transform public data into biological insights.

Early human B cell signatures of the primary antibody response to mRNA vaccination.

Messenger RNA (mRNA) vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are highly effective at inducing protective immunity. However, weak antibody responses are seen in some individuals, and cellular correlates of immunity remain poorly defined, especially for B cells. Here we used unbiased approaches to longitudinally dissect primary antibody, plasmablast, and memory B cell (MBC) responses to the two-dose mRNA-1273 vaccine in SARS-CoV-2-naive adults. Coordinated immunoglobulin A (IgA) and IgG antibody responses were preceded by bursts of spike-specific plasmablasts after both doses but earlier and more intensely after dose 2. While antibody and B cell cellular responses were generally robust, they also varied within the cohort and decreased over time after a dose-2 peak. Both antigen-nonspecific postvaccination plasmablast frequency after dose 1 and their spike-specific counterparts early after dose 2 correlated with subsequent antibody levels. This correlation between early plasmablasts and antibodies remained for titers measured at 6 months after vaccination. Several distinct antigen-specific MBC populations emerged postvaccination with varying kinetics, including two MBC populations that correlated with 2- and 6-month antibody titers. Both were IgG-expressing MBCs: one less mature, appearing as a correlate after the first dose, while the other MBC correlate showed a more mature and resting phenotype, emerging as a correlate later after dose 2. This latter MBC was also a major contributor to the sustained spike-specific MBC response observed at month 6. Thus, these plasmablasts and MBCs that emerged after both the first and second doses with distinct kinetics are potential determinants of the magnitude and durability of antibodies in response to mRNA-based vaccination.

Enzymatic control of intermolecular interactions for generating synthetic nanoarchitectures in cellular environment.

Nanoarchitectonics, as a technology to arrange nano-sized structural units such as molecules in a desired configuration, requires nano-organization, which usually relies on intermolecular interactions. This review briefly introduces the development of using enzymatic reactions to control intermolecular interactions for generating artificial nanoarchitectures in a cellular environment. We begin the discussion with the early examples and uniqueness of enzymatically controlled self-assembly. Then, we describe examples of generating intracellular nanostructures and their relevant applications. Subsequently, we discuss cases of forming nanostructures on the cell surface via enzymatic reactions. Following that, we highlight the use of enzymatic reactions for creating intercellular nanostructures. Finally, we provide a summary and outlook on the promises and future direction of this strategy. Our aim is to give an updated introduction to the use of enzymatic reaction in regulating intermolecular interactions, a phenomenon ubiquitous in biology but relatively less explored by chemists and materials scientists. Our goal is to stimulate new developments in this simple and versatile approach for addressing societal needs.

Enzymatic reactions in cells create precise nanoarchitectures, offering insights into cell biology through controllable nanoarchitectonics, as shown by numerous examples in this review.

Evaluating Predictors of Patient Satisfaction With Facial Appearance After Mohs Micrographic Surgery Using the FACE-Q.

BACKGROUND: Although patient satisfaction with reconstructive outcomes after facial skin cancer resection is an important consideration in Mohs surgery, there is limited information evaluating this concern using validated patient-reported outcome tools. OBJECTIVE: To characterize predictors that may be associated with increased postoperative patient satisfaction with facial appearance after Mohs surgery using the FACE-Q/Skin Cancer survey, a patient-reported outcome tool that has been validated in various studies. METHODS: A total of 202 patients who underwent Mohs surgery for facial skin cancer at the Brigham and Women's Faulkner Hospital between April 2017 and November 2021 were included after completing the postoperative Satisfaction with Facial Appearance scale (FACE-Q scale). RESULTS: Male patients were significantly more likely to have higher satisfaction scores compared with female patients (aOR 2.4, 95% CI 1.1-5.1). Increased preoperative facial satisfaction scores was directly correlated with increased postoperative facial satisfaction scores ( p < .01). Patients with tumors on the lower face/neck (aOR 3.88; 95% CI 1.4-10.7) had significantly greater satisfaction scores compared with those with tumors on their nose/nasolabial folds. CONCLUSION: Potential interventions and counseling methods can be tailored toward specific patient populations with lower satisfaction scores to increase their overall satisfaction with reconstructive outcomes.

Humoral Fingerprinting of Immune Responses: 'Super-Resolution', High-Dimensional Serology.

In a recent study, Chung et al. report the development of a high-dimensional approach to assess humoral responses to immune perturbation that goes beyond antibody neutralization and titers. This approach enables the identification of potentially novel correlates and mechanisms of protective immunity to HIV vaccination, thus offering a glimpse of how dense phenotyping of serological responses coupled with bioinformatics analysis could lead to much-sought-after markers of protective vaccination responses.

Robust Hadley Circulation changes and increasing global dryness due to CO2 warming from CMIP5 model projections.

In this paper, we investigate changes in the Hadley Circulation (HC) and their connections to increased global dryness (suppressed rainfall and reduced tropospheric relative humidity) under CO2 warming from Coupled Model Intercomparison Project Phase 5 (CMIP5) model projections. We find a strengthening of the HC manifested in a "deep-tropics squeeze" (DTS), i.e., a deepening and narrowing of the convective zone, enhanced ascent, increased high clouds, suppressed low clouds, and a rise of the level of maximum meridional mass outflow in the upper troposphere (200-100 hPa) of the deep tropics. The DTS induces atmospheric moisture divergence and reduces tropospheric relative humidity in the tropics and subtropics, in conjunction with a widening of the subsiding branches of the HC, resulting in increased frequency of dry events in preferred geographic locations worldwide. Among various water-cycle parameters examined, global dryness is found to have the highest signal-to-noise ratio. Our results provide a physical basis for inferring that greenhouse warming is likely to contribute to the observed prolonged droughts worldwide in recent decades.

Missed Opportunities for HIV Prophylaxis Among Emergency Department Patients With Occupational and Nonoccupational Body Fluid Exposures.

STUDY OBJECTIVE: Exposures to HIV are frequently managed in the emergency department (ED) for assessment and potential initiation of HIV postexposure prophylaxis. Despite established guidelines, it is unclear whether patients with a nonoccupational exposure are managed similarly to patients with an occupational exposure. METHODS: This retrospective study used an administrative database to identify consecutive patients at a single ED with a discharge diagnosis of "blood or body fluid exposure" without sexual assault from April 1, 2007 to June 30, 2013. Patient exposure details and physician management were ascertained according to predefined guidelines. The primary outcome was the proportion of patients with high-risk exposures who were correctly given HIV prophylaxis; the secondary outcome was the proportion of patients with low-risk exposures who were correctly not given HIV prophylaxis. Other outcomes included the proportion of patients who had a baseline HIV test in the ED, the proportion who followed up with an HIV test within 6 months, and the number of seroconversions in this group. All outcomes were compared between nonoccupational and occupational exposure. RESULTS: Of 1,972 encounters, 1,358 patients (68.9%) had an occupational exposure and 614 (31.1%) had a nonoccupational exposure. In the occupational exposure group, 190 patients (14.0%) were deemed high risk, with 160 (84.2%; 95% confidence interval [CI] 78.1% to 88.9%) appropriately given prophylaxis. In the nonoccupational exposure group, 287 patients (46.7%) had a high-risk exposure, with 208 (72.5%; 95% CI 66.8% to 77.5%) given prophylaxis, for a difference of 11.7% (95% CI 3.8% to 19.1%). For low-risk exposures, appropriate management of both occupational and nonoccupational exposure was similar (92.4% versus 93.0%). At the index ED visit, 90.5% of occupational exposure patients and 76.7% of nonoccupational exposure patients received HIV testing, for a difference of 13.8% (95% CI 10.1% to 17.7%). At 6 months, 25.4% of patients with an occupational exposure and 35.0% of patients with a nonoccupational exposure had a follow-up test, for a difference of -9.6% (95% CI -14.2% to -5.1%). Of patients who had follow-up testing within 6 months, 4 of 215 (1.9%) in the nonoccupational exposure group tested newly positive for HIV, whereas 0 of 345 (0%) in the occupational exposure group tested positive. CONCLUSION: For ED patients with blood or body fluid exposures, those with high-risk nonoccupational exposures were not given HIV prophylaxis nearly twice as often as those with high-risk occupational exposure. Although 6-month follow-up testing rates were low, 1.9% of high-risk nonoccupational exposure patients seroconverted.

FOCUS: the Society of Cardiovascular Anesthesiologists' initiative to improve quality and safety in the cardiovascular operating room.

The Society of Cardiovascular Anesthesiologists (SCA) introduced the FOCUS initiative (Flawless Operative Cardiovascular Unified Systems) in 2005 in response to the need for a rigorous scientific approach to improve quality and safety in the cardiovascular operating room (CVOR). The goal of the project, which is supported by the SCA Foundation, is to identify hazards and develop evidence-based protocols to improve cardiac surgery safety. A hazard is anything that has the potential to cause a preventable adverse event. Specifically, the strategic plan of FOCUS includes 3 goals: (1) identifying hazards in the CVOR, (2) prioritizing hazards and developing risk-reduction interventions, and (3) disseminating these interventions. Collectively, the FOCUS initiative, through the work of several groups composed of members from different disciplines such as clinical medicine, human factors engineering, industrial psychology, and organizational sociology, has identified and documented significant hazards occurring daily in our CVORs. Some examples of frequent occurrences that contribute to reduce the safety and quality of care provided to cardiac surgery patients include deficiencies in teamwork, poor OR design, incompatible technologies, and failure to adhere to best practices. Several projects are currently under way that are aimed at better understanding these hazards and developing interventions to mitigate them. The SCA, through the FOCUS initiative, has begun this journey of science-driven improvement in quality and safety. There is a long and arduous road ahead, but one we need to continue to travel.

A unified metric of human immune health.

Immunological health has been challenging to characterize but could be defined as the absence of immune pathology. While shared features of some immune diseases and the concept of immunologic resilience based on age-independent adaptation to antigenic stimulation have been developed, general metrics of immune health and its utility for assessing clinically healthy individuals remain ill defined. Here we integrated transcriptomics, serum protein, peripheral immune cell frequency and clinical data from 228 patients with 22 monogenic conditions impacting key immunological pathways together with 42 age- and sex-matched healthy controls. Despite the high penetrance of monogenic lesions, differences between individuals in diverse immune parameters tended to dominate over those attributable to disease conditions or medication use. Unsupervised or supervised machine learning independently identified a score that distinguished healthy participants from patients with monogenic diseases, thus suggesting a quantitative immune health metric (IHM). In ten independent datasets, the IHM discriminated healthy from polygenic autoimmune and inflammatory disease states, marked aging in clinically healthy individuals, tracked disease activities and treatment responses in both immunological and nonimmunological diseases, and predicted age-dependent antibody responses to immunizations with different vaccines. This discriminatory power goes beyond that of the classical inflammatory biomarkers C-reactive protein and interleukin-6. Thus, deviations from health in diverse conditions, including aging, have shared systemic immune consequences, and we provide a web platform for calculating the IHM for other datasets, which could empower precision medicine.

Dermatologic toxicities of anti-neoplastic immunotherapy in United States hospitalizations.

A major side effect of anti-neoplastic immunotherapy is the onset of dermatologic toxicities following the administration of several different immunotherapy drugs. We sought to assess the incidence and mortality of anti-neoplastic immunotherapy-associated dermatologic toxicities using a nationally representative sample of United States (US) adults. The National Inpatient Sample database was queried for encounters undergoing anti-neoplastic immunotherapy. Multiple logistic regression models were constructed to analyze incidence of dermatologic toxicity and associated mortality as well as calculate adjusted odds ratios (aOR) after controlling for age, race, sex, household income, and cancer type. Immunotherapy patients demonstrated greater odds of developing pruritus (aOR = 7.59; 95% CI 5.17-11.2; P < 0.001), rash (aOR = 2.81; 95% CI 2.00-3.94, P < 0.001), generalized (aOR = 5.32; 95% CI 3.35-8.43; P < 0.001) and localized (aOR = 2.67; 95% CI 1.01-7.05; P < 0.001) skin eruptions, and vitiligo (aOR = 13.3; 95% CI 5.15-34.4; P < 0.001) compared to patients who did not receive anti-neoplastic immunotherapy. There were no significant differences observed in incidence of non-scarring alopecia (P = 0.7), psoriasis (P = 0.094), and dermatitis (P = 0.9) between the two groups. Patients who underwent immunotherapy were more likely to develop dermatologic toxicity (aOR = 3.93; 95% CI 3.12-4.94; P < 0.001), however, no significant differences in mortality were observed. Patients undergoing anti-neoplastic immunotherapy have an increased risk of developing dermatologic toxicity compared to patients who did not receive anti-neoplastic immunotherapy.

Intralesional cidofovir for the management of refractory cutaneous verrucae: a review of applications and opportunities.

Viral warts - manifestations of cutaneous infection by human papilloma virus - can be a significant physical and emotional burden for patients when common treatments fail, particularly for individuals who are immunocompromised or with multiple lesions. Cidofovir, an antiviral agent typically used for the treatment of cytomegalovirus infection, has emerged as an alternative treatment option for viral warts when administered topically or intralesionally. In this review, we highlight the scientific rationale, published evidence, and practical clinical uses of intralesional cidofovir for the management of cutaneous warts as well as ongoing questions requiring further research and exploration of this emerging therapy for refractory verrucae.