Safety and pharmacokinetics of VRC07-523LS administered via different routes and doses (HVTN 127/HPTN 087): A Phase I randomized clinical trial.

BACKGROUND: Broadly neutralizing antibodies (bnAbs) are a promising approach for HIV-1 prevention. In the Antibody Mediated Prevention (AMP) trials, a CD4-binding site targeting bnAb, VRC01, administered intravenously (IV), demonstrated 75% prevention efficacy against highly neutralization-sensitive viruses but was ineffective against less sensitive viruses. VRC07-523LS is a next-generation bnAb targeting the CD4-binding site and was engineered for increased neutralization breadth and half-life. We conducted a multicenter, randomized, partially blinded Phase I clinical trial to evaluate the safety and serum concentrations of VRC07-523LS, administered in multiple doses and routes to healthy adults without HIV. METHODS AND FINDINGS: Participants were recruited between 2 February 2018 and 9 October 2018. A total of 124 participants were randomized to receive 5 VRC07-523LS administrations via IV (T1: 2.5 mg/kg, T2: 5 mg/kg, T3: 20 mg/kg), subcutaneous (SC) (T4: 2.5 mg/kg, T5: 5 mg/kg), or intramuscular (IM) (T6: 2.5 mg/kg or P6: placebo) routes at 4-month intervals. Participants and site staff were blinded to VRC07-523LS versus placebo for the IM group, while all other doses and routes were open-label. Safety data were collected for 144 weeks following the first administration. VRC07-523LS serum concentrations were measured by ELISA through Day 112 in all participants and by binding antibody multiplex assay (BAMA) thereafter in 60 participants (10 per treatment group) through Day 784. Compartmental population pharmacokinetic (PK) analyses were conducted to evaluate the VRC07-523LS serum PK. Neutralization activity was measured in a TZM-bl assay and antidrug antibodies (ADAs) were assayed using a tiered bridging assay testing strategy. Injections and infusions were well tolerated, with mild pain or tenderness reported commonly in the SC and IM groups, and mild to moderate erythema or induration reported commonly in the SC groups. Infusion reactions reported in 3 of 20 participants in the 20 mg/kg IV group. Peak geometric mean (GM) concentrations (95% confidence intervals [95% CIs]) following the first administration were 29.0 µg/mL (25.2, 33.4), 58.5 µg/mL (49.4, 69.3), and 257.2 µg/mL (127.5, 518.9) in T1-T3 with IV dosing; 10.8 µg/mL (8.8, 13.3) and 22.8 µg/mL (20.1, 25.9) in T4-T5 with SC dosing; and 16.4 µg/mL (14.7, 18.2) in T6 with IM dosing. Trough GM (95% CIs) concentrations immediately prior to the second administration were 3.4 µg/mL (2.5, 4.6), 6.5 µg/mL (5.6, 7.5), and 27.2 µg/mL (23.9, 31.0) with IV dosing; 0.97 µg/mL (0.65, 1.4) and 3.1 µg/mL (2.2, 4.3) with SC dosing, and 2.6 µg/mL (2.05, 3.31) with IM dosing. Peak VRC07-523LS serum concentrations increased linearly with the administered dose. At a given dose, peak and trough concentrations, as well as serum neutralization titers, were highest in the IV groups, reflecting the lower bioavailability following SC and IM administration. A single participant was found to have low titer ADA at a lone time point. VRC07-523LS has an estimated mean half-life of 42 days across all doses and routes (95% CI: 40.5, 43.5), over twice as long as VRC01 (15 days). CONCLUSIONS: VRC07-523LS was safe and well tolerated across a range of doses and routes and is a promising long-acting bnAb for inclusion in HIV-1 prevention regimens. TRIAL REGISTRATION: ClinicalTrials.gov/ NCT03387150 (posted on 21 December 2017).

Measurement invariance of the Coparenting Relationship Scale (CRS) across 10 countries.

The purpose of this study was to assess the factor structure and the measurement invariance of the Coparenting Relationship Scale (CRS) across 10 countries based on the seven-factor coparenting model (i.e., Coparenting Agreement, Coparenting Closeness, Exposure to Conflict, Coparenting Support, Endorsement of Partner's Parenting; Division of Labor) proposed by Feinberg (2003). The results of research on coparenting from numerous countries have documented its foundational importance for parent mental health, family relationship quality, child development, and psychopathology. Yet, a cross-country perspective is still lacking. Such a perspective can provide insight into which dimensions of coparenting are universally recognized and which are especially prone to variation. A unique multinational data set, comprised of 15 individual studies collected across 10 countries (Belgium, Brazil, China, Israel, Italy, Japan, Portugal, Switzerland, Turkey, USA) in nine languages was established (N = 9,292; 51.1% mothers). Measurement invariance analyses were conducted. A six-factor structure (original seven factors minus Division of Labor) of the measure was consistent across the different contexts and measurement invariance was achieved at the configural level. There was no support for metric or scalar invariance. These findings provide a basis for the CRS to be used across countries and should inspire future quantitative and qualitative research in cross-country coparenting research to understand what aspects are universal and what aspects of coparenting are linked to specific material, relational, or ideational conditions that underlie high-quality coparenting. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Immune profiling of age and adjuvant-specific activation of human blood mononuclear cells in vitro.

Vaccination reduces morbidity and mortality due to infections, but efficacy may be limited due to distinct immunogenicity at the extremes of age. This raises the possibility of employing adjuvants to enhance immunogenicity and protection. Early IFNγ production is a hallmark of effective vaccine immunogenicity in adults serving as a biomarker that may predict effective adjuvanticity. We utilized mass cytometry (CyTOF) to dissect the source of adjuvant-induced cytokine production in human blood mononuclear cells (BMCs) from newborns (~39-week-gestation), adults (~18-63 years old) and elders (>65 years of age) after stimulation with pattern recognition receptors agonist (PRRa) adjuvants. Dimensionality reduction analysis of CyTOF data mapped the BMC compartment, elucidated age-specific immune responses and profiled PRR-mediated activation of monocytes and DCs upon adjuvant stimulation. Furthermore, we demonstrated PRRa adjuvants mediated innate IFNγ induction and mapped NK cells as the key source of TLR7/8 agonist (TLR7/8a) specific innate IFNγ responses. Hierarchical clustering analysis revealed age and TLR7/8a-specific accumulation of innate IFNγ producing γδ T cells. Our study demonstrates the application of mass cytometry and cutting-edge computational approaches to characterize immune responses across immunologically distinct age groups and may inform identification of the bespoke adjuvantation systems tailored to enhance immunity in distinct vulnerable populations.

Heterologous SARS-CoV-2 booster vaccine for individuals with hematological malignancies after a primary SARS-CoV-2 mRNA vaccine series.

Heterologous COVID-19 vaccine boosters have not been evaluated for patients with hematological malignancies. A Novavax booster was administered for 56 individuals with hematological malignancies who had received a primary COVID-19 series and prior boosters with mRNA vaccines only. Blood specimens were obtained at baseline (pre-vaccine), 28 days, and 168 days after vaccination with the Novavax booster. The median fold change of anti-Spike IgG was 1.02 (IQR 0.79, 1.3) between baseline and Day 28. Circulating Spike protein-specific B cells increased 1.4-fold at Day 28 (p < 0.05). Increases in antibody and T cell responses were modest without significance, with a waning of humoral and cellular responses at 168 days after vaccination.

Elevated nuclear TDP-43 induces constitutive exon skipping.

BACKGROUND: Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. METHODS: We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. RESULTS: Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. CONCLUSIONS: Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.

A lateral approach allows accurate and stable total elbow replacement in dogs.

OBJECTIVE: Evaluate whether total elbow replacement (TER) through a lateral approach is accurate and stable. ANIMALS: 12 skeletally mature large-breed dog cadavers were used. METHODS: Limb alignment, elbow joint motion, and collateral ligament laxity were evaluated preoperatively. The order of surgery (left or right) and the approach (lateral or medial) were randomly selected for TER in each dog. The other approach was used in the contralateral elbow. Intraoperative technical difficulties, duration of surgery, and anatomic complications were recorded. Limb alignment, elbow joint motion, collateral ligament laxity, and prosthetic component alignment were evaluated after surgery. Data were collected from June 11 to 15, 2023. RESULTS: The duration of surgery using a lateral or medial approach did not differ (P = .499). Anatomic complications were not observed. The lateral approach resulted in 8° more elbow extension (P = .003), 1.58° less lateral collateral ligament constraint (P = .033), 2.80° less medial collateral ligament constraint (P = .002), 4.38° less frontal plane constraint (P = .004), 8° greater humeral component inclination (P = .033), and 5.6° greater radioulnar component varus (P = .001) than the medial approach. Varus of the radius, mechanical axis deviation, limb supination, elbow flexion, mediolateral humeral component and craniocaudal radioulnar component orientation did not differ among joints operated using a lateral or medial approach. In normal cadaveric elbows, a lateral approach for TER appears feasible, producing equivalent limb alignment, joint laxity, and joint motion to normal elbows and to TER placed using a medial approach. CLINICAL RELEVANCE: In dogs, TER can be performed using a lateral surgical approach.

Health Care Utilization by Patients With Chronic Pelvic Pain.

OBJECTIVE: To describe the patterns of health care utilization among patients with chronic pelvic pain. METHODS: Deidentified administrative claims data from the OptumLabs Data Warehouse were used. Adult female patients who had their first medical claim for chronic pelvic pain between January 1, 2016, and December 31, 2019, were included. Utilization was examined for 12 months after the index diagnosis. The greedy nearest neighbor matching method was used to identify a control group of individuals without chronic pelvic pain. Comparisons were made between those with and those without chronic pelvic pain using χ 2 tests for categorical data and Wilcoxon rank-sum tests for continuous data. RESULTS: In total, 18,400 patients were analyzed in the chronic pelvic pain cohort. Patients with chronic pelvic pain had a higher rate of chronic overlapping pain conditions. Patients with chronic pelvic pain had higher rates of health care utilization across all queried indices. They had more outpatient office visits; 55.5% had 10 or more office visits. Patients with chronic pelvic pain showed higher utilization of the emergency department (ED) (6.3 visits vs 1.9 visits; P <.001). Urine culture and pelvic ultrasonography were the most utilized tests. One-third of patients with chronic pelvic pain utilized physical therapy (PT), and 13% utilized psychological or behavioral therapy. Patients with chronic pelvic pain had higher rates of hysterectomy (8.9% vs 0.6%). The average total health care costs per patient with chronic pelvic pain per year was $12,254. CONCLUSION: Patients with chronic pelvic pain have higher rates of chronic overlapping pain conditions and undergo more ED visits, imaging tests, and hysterectomies than patients without chronic pelvic pain. Improving access to multidisciplinary care, increasing utilization of interventions such as PT and psychological or behavioral therapy, and reducing ED utilization may be possible targets to help reduce overall health care costs and improve patient care.

Identification and characterization of zinc importers in Corynebacterium diphtheriae.

Corynebacterium diphtheriae is the causative agent of diphtheria, a severe respiratory disease in humans. C. diphtheriae colonizes the human upper respiratory tract, where it acquires zinc, an essential metal required for survival in the host. While the mechanisms for zinc transport by C. diphtheriae are not well characterized, four putative zinc ABC-type transporter loci were recently identified in strain 1737: iutABCD/E (iut), znuACB (znu), nikABCD1 (nik1), and nikABCD2 (nik2). A mutant deleted for all four loci (Δ4) exhibited similar growth to that of the wild-type strain in a zinc-limited medium, suggesting there are additional zinc transporters. Two additional gene loci predicted to be associated with metal import, mntABCD (mnt) and sidAB (sid), were deleted in the Δ4 mutant to construct a new mutant designated Δ6. The C. diphtheriae Δ6 mutant exhibited significantly reduced growth under zinc limitation relative to the wild type, suggesting a deficiency in zinc acquisition. Strains retaining the iut, znu, mnt, or sid loci grew to near-wild-type levels in the absence of the other five loci, indicating that each of these transporters may be involved in zinc uptake. Plasmid complementation with cloned iut, znu, mnt, or nik1 loci also enhanced the growth of the Δ6 mutant. Quantification of intracellular zinc content by inductively coupled plasma mass spectrometry was consistent with reduced zinc uptake by Δ6 relative to the wild type and further supports a zinc uptake function for the transporters encoded by iut, znu, and mnt. This study demonstrates that C. diphtheriae zinc transport is complex and involves multiple zinc uptake systems.IMPORTANCEZinc is a critical nutrient for all forms of life, including human bacterial pathogens. Thus, the tools that bacteria use to acquire zinc from host sources are crucial for pathogenesis. While potential candidates for zinc importers have been identified in Corynebacterium diphtheriae from gene expression studies, to date, no study has clearly demonstrated this function for any of the putative transporters. We show that C. diphtheriae encodes at least six loci associated with zinc import, underscoring the extent of redundancy for zinc acquisition. Furthermore, we provide evidence that a previously studied manganese-regulated importer can also function in zinc import. This study builds upon our knowledge of bacterial zinc transport mechanisms and identifies potential targets for future diphtheria vaccine candidates.

Vaccine induction of heterologous HIV-1-neutralizing antibody B cell lineages in humans.

A critical roadblock to HIV vaccine development is the inability to induce B cell lineages of broadly neutralizing antibodies (bnAbs) in humans. In people living with HIV-1, bnAbs take years to develop. The HVTN 133 clinical trial studied a peptide/liposome immunogen targeting B cell lineages of HIV-1 envelope (Env) membrane-proximal external region (MPER) bnAbs (NCT03934541). Here, we report MPER peptide-liposome induction of polyclonal HIV-1 B cell lineages of mature bnAbs and their precursors, the most potent of which neutralized 15% of global tier 2 HIV-1 strains and 35% of clade B strains with lineage initiation after the second immunization. Neutralization was enhanced by vaccine selection of improbable mutations that increased antibody binding to gp41 and lipids. This study demonstrates proof of concept for rapid vaccine induction of human B cell lineages with heterologous neutralizing activity and selection of antibody improbable mutations and outlines a path for successful HIV-1 vaccine development.

Utilization of long-acting injectable monthly depot buprenorphine for opioid use disorder (OUD) in Kentucky, before and after COVID-19 related buprenorphine access policy changes.

INTRODUCTION: Long-acting injectable buprenorphine (LAI-bup) formulations have advantages over transmucosal buprenorphine (TM-bup), but barriers may limit their utilization. Several policies shifted during the COVID-19 pandemic to promote buprenorphine access. The federal government expanded telemedicine treatment for opioid use disorder and Kentucky (KY) Medicaid lifted prior authorization requirements (PAs) for LAI-bup (i.e., Sublocade®). This retrospective cohort study evaluated changes in LAI-bup access, utilization, and retention before and after these policy changes in KY. METHODS: Individual-level TM-bup and LAI-bup dispensing record data from KY's prescription drug monitoring program examined LAI-bup utilization and retention, without a >30-day gap in coverage, for patients starting a new episode of LAI-bup treatment. Two key time periods were examined: pre-policy changes (Apr 1, 2019 - Dec 31, 2019) and post-policy changes (Apr 1, 2020 - Dec 31, 2020). Data on PA requests among Medicaid managed care organizations and availability of LAI-bup Risk Evaluation and Mitigation Strategy (REMS)-certified pharmacies were also obtained. A multivariable Cox proportional hazard regression model analysis compared pre- versus post-policy period treatment discontinuation. RESULTS: The number of patients initiating LAI-bup increased from 211 to 481 over the two periods. By the end of the post-policy period, 24.3 % of eligible patients were retained on LAI-bup, versus 12.5 % in the pre-policy change period. The adjusted hazard ratio, comparing discontinuation during the post- versus pre-policy change periods, was 0.70 (95 % confidence interval: 0.55-0.89). There were also more REMS-certified pharmacies and providers in the post-policy change period. CONCLUSIONS: LAI-bup access, utilization, and retention increased after several policy changes.

HIV BG505 SOSIP.664 trimer with 3M-052-AF/alum induces human autologous tier-2 neutralizing antibodies.

Stabilized trimers preserving the native-like HIV envelope structure may be key components of a preventive HIV vaccine regimen to induce broadly neutralizing antibodies (bnAbs). We evaluated trimeric BG505 SOSIP.664 gp140, formulated with a novel TLR7/8 signaling adjuvant, 3M-052-AF/Alum, for safety, adjuvant dose-finding and immunogenicity in a first-in-healthy adult (n=17), randomized, placebo-controlled trial (HVTN 137A). The vaccine regimen appeared safe. Robust, trimer-specific antibody, B-cell and CD4+ T-cell responses emerged post-vaccination. Five vaccinees developed serum autologous tier-2 nAbs (ID50 titer, 1:28-1:8647) after 2-3 doses targeting C3/V5 and/or V1/V2/V3 Env regions by electron microscopy and mutated pseudovirus-based neutralization analyses. Trimer-specific, B-cell-derived monoclonal antibody activities confirmed these results and showed weak heterologous neutralization in the strongest responder. Our findings demonstrate the clinical utility of the 3M-052-AF/alum adjuvant and support further improvements of trimer-based Env immunogens to focus responses on multiple broad nAb epitopes. KEY TAKEAWAY/TAKE-HOME MESSAGES: HIV BG505 SOSIP.664 trimer with novel 3M-052-AF/alum adjuvant in humans appears safe and induces serum neutralizing antibodies to matched clade A, tier 2 virus, that map to diverse Env epitopes with relatively high titers. The novel adjuvant may be an important mediator of vaccine response.

Barriers to Buprenorphine Dispensing by Medicaid-Participating Community Retail Pharmacies.

Importance: Controlled substances have regulatory requirements under the US Federal Controlled Substance Act that must be met before pharmacies can stock and dispense them. However, emerging evidence suggests there are pharmacy-level barriers in access to buprenorphine for treatment for opioid use disorder even among pharmacies that dispense other opioids. Objective: To estimate the proportion of Medicaid-participating community retail pharmacies that dispense buprenorphine, out of Medicaid-participating community retail pharmacies that dispense other opioids and assess if the proportion dispensing buprenorphine varies by Medicaid patient volume or rural-urban location. Design, Setting, and Participants: This serial cross-sectional study included Medicaid pharmacy claims (2016-2019) data from 6 states (Kentucky, Maine, North Carolina, Pennsylvania, Virginia, West Virginia) participating in the Medicaid Outcomes Distributed Research Network (MODRN). Community retail pharmacies serving Medicaid-enrolled patients were included, mail-order pharmacies were excluded. Analyses were conducted from September 2022 to August 2023. Main Outcomes and Measures: The proportion of pharmacies dispensing buprenorphine approved for opioid use disorder among pharmacies dispensing an opioid analgesic or buprenorphine prescription to at least 1 Medicaid enrollee in each state. Pharmacies were categorized by median Medicaid patient volume (by state and year) and rurality (urban vs rural location according to zip code). Results: In 2016, 72.0% (95% CI, 70.9%-73.0%) of the 7038 pharmacies that dispensed opioids also dispensed buprenorphine to Medicaid enrollees, increasing to 80.4% (95% CI, 79.5%-81.3%) of 7437 pharmacies in 2019. States varied in the percent of pharmacies dispensing buprenorphine in Medicaid (range, 73.8%-96.4%), with significant differences between several states found in 2019 (χ2 P < .05), when states were most similar in the percent of pharmacies dispensing buprenorphine. A lower percent of pharmacies with Medicaid patient volume below the median dispensed buprenorphine (69.1% vs 91.7% in 2019), compared with pharmacies with above-median patient volume (χ2 P < .001). Conclusions and Relevance: In this serial cross-sectional study of Medicaid-participating pharmacies, buprenorphine was not accessible in up to 20% of community retail pharmacies, presenting pharmacy-level barriers to patients with Medicaid seeking buprenorphine treatment. That some pharmacies dispensed opioid analgesics but not buprenorphine suggests that factors other than compliance with the Controlled Substance Act influence pharmacy dispensing decisions.

Predictors of MOUD referral among persons with involvement in the criminal legal system.

INTRODUCTION: Opioid use disorder (OUD) is a significant cause of opioid-related fatality, and while medications to treat OUD (MOUD) are effective, disparities remain in the access and uptake of such medications. This study investigated factors that may influence referral to and initiation of MOUD treatment. METHODS: Data from electronic medical records of 677 patients with a history of criminal legal system involvement in a recovery program were used to examine the flow of MOUD referral. RESULTS: Among patients identified as potentially eligible for MOUD treatment, about 38.0 percent were referred and 18.8 percent were confirmed to initiate MOUD treatment. Logistic regression analyses highlighted female gender and unemployment due to incarceration as positive and negative predictors of referral, respectively. The Chi-square test revealed that women and uninsured patients were more likely to initiate referred MOUD treatment. CONCLUSIONS: Data highlight the need for greater connection between referral agencies and MOUD treatment providers, considering factors that may influence referral.

SARS-CoV-2 Viral Load in the Nasopharynx at Time of First Infection Among Unvaccinated Individuals: A Secondary Cross-Protocol Analysis of 4 Randomized Trials.

Importance: SARS-CoV-2 viral load (VL) in the nasopharynx is difficult to quantify and standardize across settings, but it may inform transmission potential and disease severity. Objective: To characterize VL at COVID-19 diagnosis among previously uninfected and unvaccinated individuals by evaluating the association of demographic and clinical characteristics, viral variant, and trial with VL, as well as the ability of VL to predict severe disease. Design, Setting, and Participants: This secondary cross-protocol analysis used individual-level data from placebo recipients from 4 harmonized, phase 3 COVID-19 vaccine efficacy trials sponsored by Moderna, AstraZeneca, Janssen, and Novavax. Participants were SARS-CoV-2 negative at baseline and acquired COVID-19 during the blinded phase of the trials. The setting included the US, Brazil, South Africa, Colombia, Argentina, Peru, Chile, and Mexico; start dates were July 27, 2020, to December 27, 2020; data cutoff dates were March 26, 2021, to July 30, 2021. Statistical analysis was performed from November 2022 to June 2023. Main Outcomes and Measures: Linear regression was used to assess the association of demographic and clinical characteristics, viral variant, and trial with polymerase chain reaction-measured log10 VL in nasal and/or nasopharyngeal swabs taken at the time of COVID-19 diagnosis. Results: Among 1667 participants studied (886 [53.1%] male; 995 [59.7%] enrolled in the US; mean [SD] age, 46.7 [14.7] years; 204 [12.2%] aged 65 years or older; 196 [11.8%] American Indian or Alaska Native, 150 [9%] Black or African American, 1112 [66.7%] White; 762 [45.7%] Hispanic or Latino), median (IQR) log10 VL at diagnosis was 6.18 (4.66-7.12) log10 copies/mL. Participant characteristics and viral variant explained only 5.9% of the variability in VL. The independent factor with the highest observed differences was trial: Janssen participants had 0.54 log10 copies/mL lower mean VL vs Moderna participants (95% CI, 0.20 to 0.87 log10 copies/mL lower). In the Janssen study, which captured the largest number of COVID-19 events and variants and used the most intensive post-COVID surveillance, neither VL at diagnosis nor averaged over days 1 to 28 post diagnosis was associated with COVID-19 severity. Conclusions and Relevance: In this study of placebo recipients from 4 randomized phase 3 trials, high variability was observed in SARS-CoV-2 VL at the time of COVID-19 diagnosis, and only a fraction was explained by individual participant characteristics or viral variant. These results suggest challenges for future studies of interventions seeking to influence VL and elevates the importance of standardized methods for specimen collection and viral load quantitation.

COVID-19 vaccine efficacy in participants with weakened immune systems from four randomized-controlled trials.

BACKGROUND: Although the SARS-CoV-2 vaccines are highly efficacious at preventing severe disease in the general population, current data are lacking regarding vaccine efficacy (VE) for individuals with mild immunocompromising conditions. METHODS: A post-hoc, cross-protocol analysis of participant-level data from the blinded phase of four randomized, placebo-controlled, COVID-19 vaccine phase 3 trials (Moderna, AstraZeneca, Janssen, and Novavax) was performed. We defined a "tempered immune system" (TIS) variable via a consensus panel based on medical history and medications to determine VE against symptomatic and severe COVID-19 cases in TIS participants versus non-TIS (NTIS) individuals starting at 14 days after completion of the primary series through the blinded phase for each of the four trials. An analysis of participants living with well-controlled HIV was conducted using the same methods. RESULTS: 3,852/30,351 (12.7%) Moderna participants, 3,088/29,868 (10.3%) Novavax participants, 3,549/32,380 (11.0%) AstraZeneca participants, and 5,047/43,788 (11.5%) Janssen participants were identified as having a TIS. Most TIS conditions (73.9%) were due to metabolism and nutritional disorders. Vaccination (versus placebo) significantly reduced the likelihood of symptomatic and severe COVID-19 for all participants for each trial. VE was not significantly different for TIS participants vs NTIS for either symptomatic or severe COVID-19 for each trial, nor was VE significantly different in the symptomatic endpoint for participants with HIV. CONCLUSIONS: For individuals with mildly immunocompromising conditions, there is no evidence of differences in VE against symptomatic or severe COVID-19 compared to those with non-tempered immune systems in the four COVID-19 vaccine randomized controlled efficacy trials.

Rapid Genome Sequencing Shows Diagnostic Utility In Infants With Congenital Heart Defects.

Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant mortality. CHD often has a genetic etiology and recent studies demonstrate utility in genetic testing. In clinical practice, decisions around genetic testing choices continue to evolve, and the incorporation of rapid genome sequencing (rGS) in CHD has not been well studied. Though smaller studies demonstrate the value of rGS, they also highlight the burden of results interpretation. We analyze genetic testing in CHD at two time-points, in 2018 and 2022-2023, across a change in clinical testing guidelines from chromosome microarray (CMA) to rGS. Analysis of 421 hospitalized infants with CHD demonstrated consistent genetic testing across time. Overall, after incorporation of rGS in 2022-2023, the diagnostic yield was 6.8% higher compared to 2018, and this pattern was consistent across all patient subtypes analyzed. In 2018, CMA was the most common test performed, with diagnostic results for CHD in 14.3%, while in 2022-2023, rGS was the most frequent test performed, with results diagnostic for CHD in 16.9%. Additionally, rGS identified 44% more unique genetic diagnoses than CMA. This is the largest study to highlight the value of rGS in CHD and has important implications for management.