The NLRP6 Inflammasome Recognizes Lipoteichoic Acid and Regulates Gram-Positive Pathogen Infection.

The activator and composition of the NLRP6 inflammasome remain poorly understood. We find that lipoteichoic acid (LTA), a molecule produced by Gram-positive bacteria, binds and activates NLRP6. In response to cytosolic LTA or infection with Listeria monocytogenes, NLRP6 recruited caspase-11 and caspase-1 via the adaptor ASC. NLRP6 activation by LTA induced processing of caspase-11, which promoted caspase-1 activation and interleukin-1ß (IL-1ß)/IL-18 maturation in macrophages. Nlrp6-/- and Casp11-/- mice were less susceptible to L. monocytogenes infection, which was associated with reduced pathogen loads and impaired IL-18 production. Administration of IL-18 to Nlrp6-/- or Casp11-/- mice restored the susceptibility of mutant mice to L. monocytogenes infection. These results reveal a previously unrecognized innate immunity pathway triggered by cytosolic LTA that is sensed by NLRP6 and exacerbates systemic Gram-positive pathogen infection via the production of IL-18.

Vaccination with prefusion-stabilized respiratory syncytial virus fusion protein induces genetically and antigenically diverse antibody responses.

An effective vaccine for respiratory syncytial virus (RSV) is an unrealized public health goal. A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) substantially increases serum-neutralizing activity in healthy adults. We sought to determine whether DS-Cav1 vaccination induces a repertoire mirroring the pre-existing diversity from natural infection or whether antibody lineages targeting specific epitopes predominate. We evaluated RSV F-specific B cell responses before and after vaccination in six participants using complementary B cell sequencing methodologies and identified 555 clonal lineages. DS-Cav1-induced lineages recognized the prefusion conformation of F (pre-F) and were genetically diverse. Expressed antibodies recognized all six antigenic sites on the pre-F trimer. We identified 34 public clonotypes, and structural analysis of two antibodies from a predominant clonotype revealed a common mode of recognition. Thus, vaccination with DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.

Activation Dynamics and Immunoglobulin Evolution of Pre-existing and Newly Generated Human Memory B cell Responses to Influenza Hemagglutinin.

Vaccine-induced memory B cell responses to evolving viruses like influenza A involve activation of pre-existing immunity and generation of new responses. To define the contribution of these two types of responses, we analyzed the response to H7N9 vaccination in H7N9-naive adults. We performed comprehensive comparisons at the single-cell level of the kinetics, Ig repertoire, and activation phenotype of established pre-existing memory B cells recognizing conserved epitopes and the newly generated memory B cells directed toward H7 strain-specific epitopes. The recall response to conserved epitopes on H7 HA involved a transient expansion of memory B cells with little observed adaptation. However, the B cell response to newly encountered epitopes was phenotypically distinct and generated a sustained memory population that evolved and affinity matured months after vaccination. These findings establish clear differences between newly generated and pre-existing memory B cells, highlighting the challenges in achieving long-lasting, broad protection against an ever-evolving virus.

Efficacy and Safety of an mRNA-Based RSV PreF Vaccine in Older Adults.

BACKGROUND: Respiratory syncytial virus (RSV) can cause substantial morbidity and mortality among older adults. An mRNA-based RSV vaccine, mRNA-1345, encoding the stabilized RSV prefusion F glycoprotein, is under clinical investigation. METHODS: In this ongoing, randomized, double-blind, placebo-controlled, phase 2-3 trial, we randomly assigned, in a 1:1 ratio, adults 60 years of age or older to receive one dose of mRNA-1345 (50 µg) or placebo. The two primary efficacy end points were the prevention of RSV-associated lower respiratory tract disease with at least two signs or symptoms and with at least three signs or symptoms. A key secondary efficacy end point was the prevention of RSV-associated acute respiratory disease. Safety was also assessed. RESULTS: Overall, 35,541 participants were assigned to receive the mRNA-1345 vaccine (17,793 participants) or placebo (17,748). The median follow-up was 112 days (range, 1 to 379). The primary analyses were conducted when at least 50% of the anticipated cases of RSV-associated lower respiratory tract disease had occurred. Vaccine efficacy was 83.7% (95.88% confidence interval [CI], 66.0 to 92.2) against RSV-associated lower respiratory tract disease with at least two signs or symptoms and 82.4% (96.36% CI, 34.8 to 95.3) against the disease with at least three signs or symptoms. Vaccine efficacy was 68.4% (95% CI, 50.9 to 79.7) against RSV-associated acute respiratory disease. Protection was observed against both RSV subtypes (A and B) and was generally consistent across subgroups defined according to age and coexisting conditions. Participants in the mRNA-1345 group had a higher incidence than those in the placebo group of solicited local adverse reactions (58.7% vs. 16.2%) and of systemic adverse reactions (47.7% vs. 32.9%); most reactions were mild to moderate in severity and were transient. Serious adverse events occurred in 2.8% of the participants in each trial group. CONCLUSIONS: A single dose of the mRNA-1345 vaccine resulted in no evident safety concerns and led to a lower incidence of RSV-associated lower respiratory tract disease and of RSV-associated acute respiratory disease than placebo among adults 60 years of age or older. (Funded by Moderna; ConquerRSV ClinicalTrials.gov number, NCT05127434.).

Control of pathogens and pathobionts by the gut microbiota.

A dense resident microbial community in the gut, referred as the commensal microbiota, coevolved with the host and is essential for many host physiological processes that include enhancement of the intestinal epithelial barrier, development of the immune system and acquisition of nutrients. A major function of the microbiota is protection against colonization by pathogens and overgrowth of indigenous pathobionts that can result from the disruption of the healthy microbial community. The mechanisms that regulate the ability of the microbiota to restrain pathogen growth are complex and include competitive metabolic interactions, localization to intestinal niches and induction of host immune responses. Pathogens, in turn, have evolved strategies to escape from commensal-mediated resistance to colonization. Thus, the interplay between commensals and pathogens or indigenous pathobionts is critical for controlling infection and disease. Understanding pathogen-commensal interactions may lead to new therapeutic approaches to treating infectious diseases.

A Seed Mismatch Enhances Argonaute2-Catalyzed Cleavage and Partially Rescues Severely Impaired Cleavage Found in Fish.

The RNAi pathway provides both innate immunity and efficient gene-knockdown tools in many eukaryotic species, but curiously not in zebrafish. We discovered that RNAi is less effective in zebrafish at least partly because Argonaute2-catalyzed mRNA slicing is impaired. This defect is due to two mutations that arose in an ancestor of most teleost fish, implying that most fish lack effective RNAi. Despite lacking efficient slicing activity, these fish have retained the ability to produce miR-451, a microRNA generated by a cleavage reaction analogous to slicing. This ability is due to a G-G mismatch within the fish miR-451 precursor, which substantially enhances its cleavage. An analogous G-G mismatch (or sometimes also a G-A mismatch) enhances target slicing, despite disrupting seed pairing important for target binding. These results provide a strategy for restoring RNAi to zebrafish and reveal unanticipated opposing effects of a seed mismatch with implications for mechanism and guide-RNA design.

Safety, Tolerability and Immunogenicity of a mRNA-based RSV Vaccine in Healthy Young Adults in a Phase 1 Clinical Trial.

BACKGROUND: Respiratory syncytial virus (RSV) presents a global health concern. A lipid nanoparticle-encapsulated mRNA-based RSV vaccine (mRNA-1345) encoding the membrane-anchored RSV prefusion stabilised F glycoprotein (preF) is under clinical investigation. METHODS: This phase 1, randomized, observer-blind, placebo-controlled dose escalation study assessed safety and immunogenicity of mRNA-1345 in healthy adults aged 18-49 years (NCT04528719). Participants were randomized to receive one dose of mRNA-1345 (50, 100, or 200 µg) or placebo, or 3 doses of mRNA-1345 (100 µg) or placebo 56 days apart. RESULTS: mRNA-1345 was well-tolerated at all dose levels. The most common solicited adverse reactions were pain, headache, fatigue, myalgia, or chills, which were all generally mild to moderate. A single injection of mRNA-1345 boosted RSV neutralizing antibody titers (geometric mean fold rise [GMFR]: RSV-A, 20.0 to 23.5; RSV-B, 11.7 to 16.0) and RSV preF binding antibody concentrations (GMFR: 16.1 to 21.8) at 1 month post injection, with no apparent dose response. Antibody levels remained above baseline through 6 months. Sequential doses of 100 µg were well tolerated but did not further boost antibody levels. CONCLUSIONS: A single mRNA-1345 injection demonstrated an acceptable safety profile in younger adults and induced a durable neutralizing antibody response, supporting its continued development.

Safety and Immunogenicity of an mRNA-Based RSV Vaccine Including a 12-Month Booster in a Phase I Clinical Trial in Healthy Older Adults.

BACKGROUND: An mRNA-based RSV vaccine, mRNA-1345, is under clinical investigation to address RSV disease burden in older adults. METHODS: This phase 1, randomized, observer-blind, placebo-controlled, dose-ranging study evaluated safety, reactogenicity, and immunogenicity of mRNA-1345 in adults 65-79 years (NCT04528719). Participants were randomized to receive 1-dose of mRNA-1345 (12.5, 25, 50, 100, or 200-µg) or placebo and matched mRNA-1345 booster or placebo at 12-months. RESULTS: Overall, 298 participants received the first injection; 247 received the 12-month booster injection. mRNA-1345 was generally well-tolerated after both injections, with the most frequently reported solicited adverse reactions being injection-site pain, fatigue, headache, arthralgia, and myalgia. Reactogenicity was higher after the booster injection than the first injection but similar severity, time-to-onset, and duration. A single mRNA-1345 injection boosted RSV-A and RSV-B neutralizing antibody titers (nAb) and prefusion-F-binding antibody (preF-bAb) concentrations at 1-month (geometric mean-fold rises: RSV-A, 10.2-16.5; RSV-B, 5.3-12.5; preF-bAb, 7.2-12.1). RSV antibody levels remained above baseline through 12-months, indicating immune persistence. A 12-month booster injection also increased RSV-A and RSV-B nAb titers and preF-bAb concentrations; titers post-booster injection were numerically lower compared to titers after the first-dose, with overlapping 95% CIs. CONCLUSIONS: mRNA-1345 was well-tolerated and immunogenic following a single injection and a 12-month booster. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04528719.

A Monoclonal Antibody for Malaria Prevention.

BACKGROUND: Additional interventions are needed to reduce the morbidity and mortality caused by malaria. METHODS: We conducted a two-part, phase 1 clinical trial to assess the safety and pharmacokinetics of CIS43LS, an antimalarial monoclonal antibody with an extended half-life, and its efficacy against infection with Plasmodium falciparum. Part A of the trial assessed the safety, initial side-effect profile, and pharmacokinetics of CIS43LS in healthy adults who had never had malaria. Participants received CIS43LS subcutaneously or intravenously at one of three escalating dose levels. A subgroup of participants from Part A continued to Part B, and some received a second CIS43LS infusion. Additional participants were enrolled in Part B and received CIS43LS intravenously. To assess the protective efficacy of CIS43LS, some participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying P. falciparum sporozoites 4 to 36 weeks after administration of CIS43LS. RESULTS: A total of 25 participants received CIS43LS at a dose of 5 mg per kilogram of body weight, 20 mg per kilogram, or 40 mg per kilogram, and 4 of the 25 participants received a second dose (20 mg per kilogram regardless of initial dose). No safety concerns were identified. We observed dose-dependent increases in CIS43LS serum concentrations, with a half-life of 56 days. None of the 9 participants who received CIS43LS, as compared with 5 of 6 control participants who did not receive CIS43LS, had parasitemia according to polymerase-chain-reaction testing through 21 days after controlled human malaria infection. Two participants who received 40 mg per kilogram of CIS43LS and underwent controlled human malaria infection approximately 36 weeks later had no parasitemia, with serum concentrations of CIS43LS of 46 and 57 µg per milliliter at the time of controlled human malaria infection. CONCLUSIONS: Among adults who had never had malaria infection or vaccination, administration of the long-acting monoclonal antibody CIS43LS prevented malaria after controlled infection. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 612 ClinicalTrials.gov number, NCT04206332.).

Parameterization of Physiologically Based Biopharmaceutics Models: Workshop Summary Report.

This Article shares the proceedings from the August 29th, 2023 (day 1) workshop "Physiologically Based Biopharmaceutics Modeling (PBBM) Best Practices for Drug Product Quality: Regulatory and Industry Perspectives". The focus of the day was on model parametrization; regulatory authorities from Canada, the USA, Sweden, Belgium, and Norway presented their views on PBBM case studies submitted by industry members of the IQ consortium. The presentations shared key questions raised by regulators during the mock exercise, regarding the PBBM input parameters and their justification. These presentations also shed light on the regulatory assessment processes, content, and format requirements for future PBBM regulatory submissions. In addition, the day 1 breakout presentations and discussions gave the opportunity to share best practices around key questions faced by scientists when parametrizing PBBMs. Key questions included measurement and integration of drug substance solubility for crystalline vs amorphous drugs; impact of excipients on apparent drug solubility/supersaturation; modeling of acid-base reactions at the surface of the dissolving drug; choice of dissolution methods according to the formulation and drug properties with a view to predict the in vivo performance; mechanistic modeling of in vitro product dissolution data to predict in vivo dissolution for various patient populations/species; best practices for characterization of drug precipitation from simple or complex formulations and integration of the data in PBBM; incorporation of drug permeability into PBBM for various routes of uptake and prediction of permeability along the GI tract.

NOD1 and NOD2 in inflammatory and infectious diseases.

It has been long recognized that NOD1 and NOD2 are critical players in the host immune response, primarily by their sensing bacterial peptidoglycan-conserved motifs. Significant advances have been made from efforts that characterize their upstream activators, assembly of signaling complexes, and activation of downstream signaling pathways. Disruption in NOD1 and NOD2 signaling has also been associated with impaired host defense and resistance to the development of inflammatory diseases. In this review, we will describe how NOD1 and NOD2 sense microbes and cellular stress to regulate host responses that can affect disease pathogenesis and outcomes.

Medical management of male infertility: now and future.

PURPOSE OF REVIEW: Medical therapy for idiopathic male infertility has historically been empiric and based on small observational studies rather than larger well designed clinical trials. This review is timely and relevant because of the recent publication of several studies that are less susceptible to bias because of being placebo-controlled and more highly powered. RECENT FINDINGS: The largest proportion of recent publications covered antioxidants, with eight randomized controlled trials (RCTs) included in this review. The Males, Antioxidants, and Infertility (MOXI) trial is of particular interest, being a large multicenter RCT, which demonstrated no improvement in semen parameters or live-birth rates with antioxidant use. In addition, phosphodiesterase-5 inhibitors (PDE5i) have been shown to improve semen parameters, while duloxetine use was not associated with any adverse effects on sperm. Progress was also made in the realm of regenerative medicine, with the realization of the first successful primate model of sperm production from pluripotent stem cells. SUMMARY: It may be time to stop recommending antioxidants for idiopathic male infertility given recent studies suggesting lack of efficacy, but given their relative safety, it is reasonable to continue their use until the evidence is overwhelming. Otherwise, stem cell therapy is another anticipated area of research interest.

Should rapid antigen tests be first-line for COVID-19 testing? Results of a prospective urban cohort study.

BACKGROUND: A highly accurate, rapid, and low-cost COVID-19 test is essential for guiding isolation measures. To date, the most widely used tests are either nucleic acid amplification tests or antigen tests. The objective of this study is to further assess the diagnostic performance of the Binax-CoV2 rapid antigen test in comparison to the current gold standard reverse transcription quantitative polymerase chain reaction (RT-qPCR), with additional analysis of symptomatology and cycle threshold utility. METHODS: This is a prospective cohort study performed between November and December 2020. Individuals who presented to COVID-19 testing events and received both RT-qPCR and a rapid antigent test were included. Testing occurred at the emergency department of an urban hospital and at a community mobile unit. No fees or appointments were required. Individuals self-reported the presence or absence of symptoms and history of positive COVID-19 test within the previous two weeks. Trained staff collected two subsequent nasopharyngeal swabs of both nares. One set of swabs underwent RT-qPCR and the other underwent Binax-CoV2 assay per manufacturer guidelines. RESULTS: A total of 390 patients were included, of which 302 were from the community site. Of these 302, 42 (14%) were RT-qPCR positive. Of the 42 RT-qPCR positive, 30 (71.4%) were also positive by Binax-CoV2. The Binax-CoV2 test had a sensitivity of 71.4% (95% CI: 55%-84%) and a specificity of 99.6% (95% CI: 98%-100%) in this population. Performance of the Binax-CoV2 test performed better in individuals with higher viral load. For symptomatic patients with cycle threshold < 20, sensitivity reached 100%. CONCLUSIONS: The Binax-CoV2 assay's specificity and sensitivity in individuals with high viral load makes it a suitable first-line test for detecting COVID-19. However, given the assay's measured sensitivity, a negative result on the Binax-CoV2 assay may warrant additional testing with more sensitive tests, such as the RT-qPCR. This is particularly the case with high clinical suspicion for an active SARS-CoV-2 infection even after a negative Binax-CoV2 result.

Skill transference and learning curves in novice learners: a randomized comparison of robotic and laparoscopic platforms.

BACKGROUND: While well-established protocols direct laparoscopic training, there remains a relative paucity of guidelines for robotic education. Furthermore, it is unknown how exposure to one platform influences trainees' proficiency in the other. This study aimed to compare and quantify (1) learning curves and (2) transference of skill between the two modalities in novice learners. METHODS: Thirty pre-clinical medical students were randomized into two groups. One group performed the peg-transfer task using the robot first, followed by laparoscopy, while the other group performed the same task laparoscopically first. Participants completed five repetitions with each methodology. Participants were timed and errors were recorded. We hypothesized that laparoscopic experience with the peg-transfer task would assist in completing the task robotically, and there would be a higher degree of skill transference from the laparoscopic to robotic platform. RESULTS: Peg-transfer task completion was consistently faster and more accurate with the robot compared to laparoscopy (p < 0.01). We observed a positive transference of skill from the laparoscopic to robotic platform. However, exposure to the robot-hindered students' ability to perform the task laparoscopically, evidenced by significantly increased time and errors when compared with baseline laparoscopic performance (p < 0.01). CONCLUSION: These findings encourage surgical residency programs to treat robotic and laparoscopic training as discrete entities and consider their unique learning curves and skill transference when designing an efficient curriculum. While these effects are observed in novices, future directions include uncovering the trends among resident trainees and practicing surgeons.

Beyond post-operative readmissions: analysis of the impact of unplanned readmissions during primary treatment of advanced-stage epithelial ovarian cancer on long-term oncology outcome.

BACKGROUND: Multiple studies have assessed post-operative readmissions in advanced ovarian cancer. OBJECTIVE: To evaluate all unplanned readmissions during the primary treatment period of advanced epithelial ovarian cancer, and the impact of readmission on progression-free survival. METHODS: This was a single institution retrospective study from January 2008 to October 2018. Χ2/Fisher's exact and t-test, or Kruskal-Wallis test were used. Multivariable Cox proportional hazard models were used to assess the effect of covariates in progression-free survival analysis. RESULTS: A total of 484 patients (279 primary cytoreductive surgery, 205 neoadjuvant chemotherapy) were analyzed. In total, 272 of 484 (56%; 37% primary cytoreductive surgery, 32% neoadjuvant chemotherapy, p=0.29) patients were readmitted during the primary treatment period. Overall, 42.3% of the readmissions were surgery related, 47.8% were chemotherapy related, and 59.6% were cancer related but not related to surgery or chemotherapy, and each readmission could qualify for more than one reason. Readmitted patients had a higher rate of chronic kidney disease (4.1% vs 1.0%, p=0.038). Post-operative, chemotherapy, and cancer-related readmissions were similar between the two groups. However, the percentage of inpatient treatment days due to unplanned readmission was twice as high for primary cytoreductive surgery at 2.2% vs 1.3% for neoadjuvant chemotherapy (p<0.001). Despite longer readmissions in the primary cytoreductive surgery group, Cox regression analysis demonstrated that readmissions did not affect progression-free survival (HR=1.22, 95% CI 0.98 to 1.51; p=0.08). Primary cytoreductive surgery, higher modified Frailty Index, grade 3 disease, and optimal cytoreduction were associated with longer progression-free survival. CONCLUSIONS: In this study, 35% of the women with advanced ovarian cancer had at least one unplanned readmission during the entire treatment time. Patients treated by primary cytoreductive surgery spent more days during readmission than those with neoadjuvant chemotherapy. Readmissions did not affect progression-free survival and may not be valuable as a quality metric.

A qualitative analysis of pharmacists' attitudes towards provision of medication abortion.

BACKGROUND: 90% of United States' counties do not have a single clinic offering abortion care, and barriers to care disproportionately affect low-income families. Novel models of abortion care delivery, including provision of medication abortion in pharmacies, with pharmacists prescribing medication, have the potential to expand access to abortion care. Pharmacists are well-positioned to independently provide abortion care and are highly accessible to patients, however medication abortion provision by pharmacists is not currently legal or available in the United States. To assess the potential acceptability of pharmacist provision of medication abortion and to identify anticipated barriers and facilitators to this model of care, we explored pharmacists' attitudes towards providing medication abortion, inclusive of patient selection, counseling, and medication prescribing. METHODS: From May to October 2021, we conducted 20 semi-structured qualitative interviews with pharmacists across the United States, guided by the domains of the Consolidated Framework for Implementation Science Research. RESULTS: Major themes included there is a need for pharmacist provision of medication abortion and pharmacists perceive provision of medication abortion to be potentially acceptable if anticipated barriers are addressed. Anticipated barriers identified included personal, religious, and political beliefs of pharmacists and lack of space and systems to support the model. Ensuring adequate staffing with pharmacists willing to participate, private space, time for counseling, safe follow-up, training, and reimbursement mechanisms were perceived strategies to facilitate successful implementation. CONCLUSIONS: Pharmacist identified implementation strategies are needed to reduce anticipated barriers to pharmacist provision of medication abortion.

Specific Forms of Graphene Quantum Dots Induce Apoptosis and Cell Cycle Arrest in Breast Cancer Cells.

Graphene quantum dots (GQDs), nanomaterials derived from graphene and carbon dots, are highly stable, soluble, and have exceptional optical properties. Further, they have low toxicity and are excellent vehicles for carrying drugs or fluorescein dyes. Specific forms of GQDs can induce apoptosis and could be used to treat cancers. In this study, three forms of GQDs (GQD (nitrogen:carbon = 1:3), ortho-GQD, and meta-GQD) were screened and tested for their potential to inhibit breast cancer cell (MCF-7, BT-474, MDA-MB-231, and T-47D) growth. All three GQDs decreased cell viability after 72 h of treatment and specifically affected breast cancer cell proliferation. An assay for the expression of apoptotic proteins revealed that p21 and p27 were up-regulated (1.41-fold and 4.75-fold) after treatment. In particular, ortho-GQD-treated cells showed G2/M phase arrest. The GQDs specifically induced apoptosis in estrogen receptor-positive breast cancer cell lines. These results indicate that these GQDs induce apoptosis and G2/M cell cycle arrest in specific breast cancer subtypes and could potentially be used for treating breast cancers.

The Impact of COVID-19, Mental Health Distress, and School-Based Sociocultural Protective Factors among Elementary-Aged Children and their Caregivers.

Given the individual and systemic stress endured by children and families during the COVID-19 pandemic, research examining culturally responsive school experiences and supports to enhance resilience is critical. This study examined the relationship between caregivers' perceptions of COVID-19 impact, mental health distress among children and caregivers, and school-based sociocultural protective factors, including culturally responsive practices in schools and the relationships between teachers and caregivers, concurrently and longitudinally. Data were collected from caregivers of elementary-aged children at two-time points from March to April 2020 (N = 174) and one year later in 2021 (N = 114). Regression analyses revealed that COVID-19 impact positively predicted and parent-teacher joining negatively predicted mental health concerns among children and families, concurrently and longitudinally. Furthermore, there was a positive relationship between caregivers' perceptions of teachers' social awareness and justice practices and mental health symptoms for children in 2020. Parent-teacher joining longitudinally moderated the relationship between COVID-19 impact and caregivers' mental health concerns. This study provides implications regarding sociocultural resilience factors that should be considered in schools amidst the COVID-19 pandemic.

Collaborative Cohort of Cohorts for COVID-19 Research (C4R) Study: Study Design.

The Collaborative Cohort of Cohorts for COVID-19 Research (C4R) is a national prospective study of adults comprising 14 established US prospective cohort studies. Starting as early as 1971, investigators in the C4R cohort studies have collected data on clinical and subclinical diseases and their risk factors, including behavior, cognition, biomarkers, and social determinants of health. C4R links this pre-coronavirus disease 2019 (COVID-19) phenotyping to information on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute and postacute COVID-related illness. C4R is largely population-based, has an age range of 18-108 years, and reflects the racial, ethnic, socioeconomic, and geographic diversity of the United States. C4R ascertains SARS-CoV-2 infection and COVID-19 illness using standardized questionnaires, ascertainment of COVID-related hospitalizations and deaths, and a SARS-CoV-2 serosurvey conducted via dried blood spots. Master protocols leverage existing robust retention rates for telephone and in-person examinations and high-quality event surveillance. Extensive prepandemic data minimize referral, survival, and recall bias. Data are harmonized with research-quality phenotyping unmatched by clinical and survey-based studies; these data will be pooled and shared widely to expedite collaboration and scientific findings. This resource will allow evaluation of risk and resilience factors for COVID-19 severity and outcomes, including postacute sequelae, and assessment of the social and behavioral impact of the pandemic on long-term health trajectories.

Gut microbiota and systemic immunity in health and disease.

The mammalian intestine is colonized by trillions of microorganisms that have co-evolved with the host in a symbiotic relationship. Although the influence of the gut microbiota on intestinal physiology and immunity is well known, mounting evidence suggests a key role for intestinal symbionts in controlling immune cell responses and development outside the gut. Although the underlying mechanisms by which the gut symbionts influence systemic immune responses remain poorly understood, there is evidence for both direct and indirect effects. In addition, the gut microbiota can contribute to immune responses associated with diseases outside the intestine. Understanding the complex interactions between the gut microbiota and the host is thus of fundamental importance to understand both immunity and human health.