T cell-intrinsic ASC critically promotes T(H)17-mediated experimental autoimmune encephalomyelitis.

Interleukin 1ß (IL-1ß) is critical for the in vivo survival, expansion and effector function of IL-17-producing helper T (T(H)17) cells during autoimmune responses, including experimental autoimmune encephalomyelitis (EAE). However, the spatiotemporal role and cellular source of IL-1ß during EAE pathogenesis are poorly defined. In the present study, we uncovered a T cell-intrinsic inflammasome that drives IL-1ß production during T(H)17-mediated EAE pathogenesis. Activation of T cell antigen receptors induced expression of pro-IL-1ß, whereas ATP stimulation triggered T cell production of IL-1ß via ASC-NLRP3-dependent caspase-8 activation. IL-1R was detected on T(H)17 cells but not on type 1 helper T (T(H)1) cells, and ATP-treated T(H)17 cells showed enhanced survival compared with ATP-treated T(H)1 cells, suggesting autocrine action of T(H)17-derived IL-1ß. Together these data reveal a critical role for IL-1ß produced by a T(H)17 cell-intrinsic ASC-NLRP3-caspase-8 inflammasome during inflammation of the central nervous system.

Clustered de novo start-loss variants in GLUL result in a developmental and epileptic encephalopathy via stabilization of glutamine synthetase.

Glutamine synthetase (GS), encoded by GLUL, catalyzes the conversion of glutamate to glutamine. GS is pivotal for the generation of the neurotransmitters glutamate and gamma-aminobutyric acid and is the primary mechanism of ammonia detoxification in the brain. GS levels are regulated post-translationally by an N-terminal degron that enables the ubiquitin-mediated degradation of GS in a glutamine-induced manner. GS deficiency in humans is known to lead to neurological defects and death in infancy, yet how dysregulation of the degron-mediated control of GS levels might affect neurodevelopment is unknown. We ascertained nine individuals with severe developmental delay, seizures, and white matter abnormalities but normal plasma and cerebrospinal fluid biochemistry with de novo variants in GLUL. Seven out of nine were start-loss variants and two out of nine disrupted 5' UTR splicing resulting in splice exclusion of the initiation codon. Using transfection-based expression systems and mass spectrometry, these variants were shown to lead to translation initiation of GS from methionine 18, downstream of the N-terminal degron motif, resulting in a protein that is stable and enzymatically competent but insensitive to negative feedback by glutamine. Analysis of human single-cell transcriptomes demonstrated that GLUL is widely expressed in neuro- and glial-progenitor cells and mature astrocytes but not in post-mitotic neurons. One individual with a start-loss GLUL variant demonstrated periventricular nodular heterotopia, a neuronal migration disorder, yet overexpression of stabilized GS in mice using in utero electroporation demonstrated no migratory deficits. These findings underline the importance of tight regulation of glutamine metabolism during neurodevelopment in humans.

Transplantation Outcomes with Donor Hearts after Circulatory Death.

BACKGROUND: Data showing the efficacy and safety of the transplantation of hearts obtained from donors after circulatory death as compared with hearts obtained from donors after brain death are limited. METHODS: We conducted a randomized, noninferiority trial in which adult candidates for heart transplantation were assigned in a 3:1 ratio to receive a heart after the circulatory death of the donor or a heart from a donor after brain death if that heart was available first (circulatory-death group) or to receive only a heart that had been preserved with the use of traditional cold storage after the brain death of the donor (brain-death group). The primary end point was the risk-adjusted survival at 6 months in the as-treated circulatory-death group as compared with the brain-death group. The primary safety end point was serious adverse events associated with the heart graft at 30 days after transplantation. RESULTS: A total of 180 patients underwent transplantation; 90 (assigned to the circulatory-death group) received a heart donated after circulatory death and 90 (regardless of group assignment) received a heart donated after brain death. A total of 166 transplant recipients were included in the as-treated primary analysis (80 who received a heart from a circulatory-death donor and 86 who received a heart from a brain-death donor). The risk-adjusted 6-month survival in the as-treated population was 94% (95% confidence interval [CI], 88 to 99) among recipients of a heart from a circulatory-death donor, as compared with 90% (95% CI, 84 to 97) among recipients of a heart from a brain-death donor (least-squares mean difference, -3 percentage points; 90% CI, -10 to 3; P<0.001 for noninferiority [margin, 20 percentage points]). There were no substantial between-group differences in the mean per-patient number of serious adverse events associated with the heart graft at 30 days after transplantation. CONCLUSIONS: In this trial, risk-adjusted survival at 6 months after transplantation with a donor heart that had been reanimated and assessed with the use of extracorporeal nonischemic perfusion after circulatory death was not inferior to that after standard-care transplantation with a donor heart that had been preserved with the use of cold storage after brain death. (Funded by TransMedics; ClinicalTrials.gov number, NCT03831048.).

The role of species ecology in predicting Toxoplasma gondii prevalence in wild and domesticated mammals globally.

Macroecological approaches can provide valuable insight into the epidemiology of globally distributed, multi-host pathogens. Toxoplasma gondii is a protozoan that infects any warm-blooded animal, including humans, in almost every habitat worldwide. Toxoplasma gondii infects its hosts through oocysts in the environment, carnivory of tissue cysts within intermediate host prey and vertical transmission. These routes of infection enable specific predictions regarding the ecological and life history traits that should predispose specific taxa to higher exposure and, thus infection rates of T. gondii. Using T. gondii prevalence data compiled from 485 studies representing 533 free-ranging wild mammalian species, we examined how ecological (habitat type, trophic level) and life history (longevity, vagility, gestation duration and torpor) traits influence T. gondii infection globally. We also compared T. gondii prevalence between wild and domesticated species from the same taxonomic families using data compiled from 540 studies of domestic cattle, sheep, and pigs. Across free-ranging wildlife, we found the average T. gondii prevalence was 22%, which is comparable to the global human estimate. Among ecological guilds, terrestrial species had lower T. gondii prevalence than aquatic species, with freshwater aquatic taxa having an increased prevalence compared to marine aquatic species. Dietary niches were also influential, with carnivores having an increased risk compared to other trophic feeding groups that have reduced tissue cyst exposure in their diet. With respect to influential life history traits, we found that more vagile wildlife species had higher T. gondii infection rates, perhaps because of the higher cumulative risk of infection during movement through areas with varying T. gondii environmental loads. Domestic farmed species had a higher T. gondii prevalence compared to free-ranging confamilial wildlife species. Through a macroecological approach, we determined the relative significance of transmission routes of a generalist pathogen, demonstrating an increased infection risk for aquatic and carnivorous species and highlighting the importance of preventing pathogen pollution into aquatic environments. Toxoplasma gondii is increasingly understood to be primarily an anthropogenically-associated pathogen whose dissemination is enhanced by ecosystem degradation and human subsidisation of free-roaming domestic cats. Adopting an ecosystem restoration approach to reduce one of the world's most common parasites would synergistically contribute to other initiatives in conservation, feline and wildlife welfare, climate change, food security and public health.

Evaluation and Management of Kidney Dysfunction in Advanced Heart Failure: A Scientific Statement From the American Heart Association.

Early identification of kidney dysfunction in patients with advanced heart failure is crucial for timely interventions. In addition to elevations in serum creatinine, kidney dysfunction encompasses inadequate maintenance of sodium and volume homeostasis, retention of uremic solutes, and disrupted endocrine functions. Hemodynamic derangements and maladaptive neurohormonal upregulations contribute to fluctuations in kidney indices and electrolytes that may recover with guideline-directed medical therapy. Quantifying the extent of underlying irreversible intrinsic kidney disease is crucial in predicting whether optimization of congestion and guideline-directed medical therapy can stabilize kidney function. This scientific statement focuses on clinical management of patients experiencing kidney dysfunction through the trajectory of advanced heart failure, with specific focus on (1) the conceptual framework for appropriate evaluation of kidney dysfunction within the context of clinical trajectories in advanced heart failure, including in the consideration of advanced heart failure therapies; (2) preoperative, perioperative, and postoperative approaches to evaluation and management of kidney disease for advanced surgical therapies (durable left ventricular assist device/heart transplantation) and kidney replacement therapies; and (3) the key concepts in palliative care and decision-making processes unique to individuals with concomitant advanced heart failure and kidney disease.

Respectful Maternity Care : A Systematic Review.

BACKGROUND: Severe maternal morbidity and mortality are worse in the United States than in all similar countries, with the greatest effect on Black women. Emerging research suggests that disrespectful care during childbirth contributes to this problem. PURPOSE: To conduct a systematic review on definitions and valid measurements of respectful maternity care (RMC), its effectiveness for improving maternal and infant health outcomes for those who are pregnant and postpartum, and strategies for implementation. DATA SOURCES: Systematic searches of Ovid Medline, CINAHL, Embase, Cochrane Central Register of Controlled Trials, PsycInfo, and SocINDEX for English-language studies (inception to July 2023). STUDY SELECTION: Randomized controlled trials and nonrandomized studies of interventions of RMC versus usual care for effectiveness studies; additional qualitative and noncomparative validation studies for definitions and measurement studies. DATA EXTRACTION: Dual data abstraction and quality assessment using established methods, with resolution of disagreements through consensus. DATA SYNTHESIS: Thirty-seven studies were included across all questions, of which 1 provided insufficient evidence on the effectiveness of RMC to improve maternal outcomes and none studied RMC to improve infant outcomes. To define RMC, authors identified 12 RMC frameworks, from which 2 main concepts were identified: disrespect and abuse and rights-based frameworks. Disrespect and abuse components focused on recognizing birth mistreatment; rights-based frameworks incorporated aspects of reproductive justice, human rights, and antiracism. Five overlapping framework themes include freedom from abuse, consent, privacy, dignity, communication, safety, and justice. Twelve tools to measure RMC were validated in 24 studies on content validity, construct validity, and internal consistency, but lack of a gold standard limited evaluation of criterion validity. Three tools specific for RMC had at least 1 study demonstrating consistency internally and with an intended construct relevant to U.S. settings, but no single tool stands out as the best measure of RMC. LIMITATIONS: No studies evaluated other health outcomes or RMC implementation strategies. The lack of definition and gold standard limit evaluation of RMC tools. CONCLUSION: Frameworks for RMC are well described but vary in their definitions. Tools to measure RMC demonstrate consistency but lack a gold standard, requiring further evaluation before implementation in U.S. settings. Evidence is lacking on the effectiveness of implementing RMC to improve any maternal or infant health outcome. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42023394769).

Dual transcriptional characterization of spinach and Peronospora effusa during resistant and susceptible race-cultivar interactions.

BACKGROUND: Spinach downy mildew, caused by the obligate oomycete pathogen, Peronospora effusa remains a major concern for spinach production. Disease control is predominantly based on development of resistant spinach cultivars. However, new races and novel isolates of the pathogen continue to emerge and overcome cultivar resistance. Currently there are 20 known races of P. effusa. Here we characterized the transcriptomes of spinach, Spinacia oleracea, and P. effusa during disease progression using the spinach cultivar Viroflay, the near isogenic lines NIL1 and NIL3, and P. effusa races, R13 and R19, at 24 h post inoculation and 6 days post inoculation. A total of 54 samples were collected and subjected to sequencing and transcriptomic analysis. RESULTS: Differentially expressed gene (DEG) analysis in resistant spinach interactions of R13-NIL1 and R19-NIL3 revealed spinach DEGs from protein kinase-like and P-loop containing families, which have roles in plant defense. The homologous plant defense genes included but were not limited to, receptor-like protein kinases (Spiol0281C06495, Spiol06Chr21559 and Spiol06Chr24027), a BAK1 homolog (Spiol0223C05961), genes with leucine rich repeat motifs (Spiol04Chr08771, Spiol04Chr01972, Spiol05Chr26812, Spiol04Chr11049, Spiol0084S08137, Spiol03Chr20299) and ABC-transporters (Spiol02Chr28975, Spiol06Chr22112, Spiol06Chr03998 and Spiol04Chr09723). Additionally, analysis of the expression of eight homologous to previously reported downy mildew resistance genes revealed that some are differentially expressed during resistant reactions but not during susceptible reactions. Examination of P. effusa gene expression during infection of susceptible cultivars identified expressed genes present in R19 or R13 including predicted RxLR and Crinkler effector genes that may be responsible for race-specific virulence on NIL1 or NIL3 spinach hosts, respectively. CONCLUSIONS: These findings deliver foundational insight to gene expression in both spinach and P. effusa during susceptible and resistant interactions and provide a library of candidate genes for further exploration and functional analysis. Such resources will be beneficial to spinach breeding efforts for disease resistance in addition to better understanding the virulence mechanisms of this obligate pathogen.

Detection of viral RNA and DNA and immune response following administration of live attenuated measles and varicella vaccines in children with chronic liver disease.

Infections preventable by live virus vaccines are surging in the setting of decreased herd immunity. Many children with chronic liver diseases (CLDs) are unimmunized and at increased risk for infection due to guidelines recommending against live vaccines within 4 weeks pretransplant. This prospective study of 21 children with CLD and 13 healthy controls defined the timing of measles virus and varicella-zoster virus (VZV) RNA- and DNA-emia following vaccination and compared immune responses to measles and varicella vaccines in both groups. Measles virus RNA and VZV DNA real-time PCR were measured weekly following vaccination; measles virus RNA was undetectable in all by 14 days postvaccination, but VZV DNA, which can be managed with antivirals, was detected in 1 child in the CLD group at 21 days and 1 control at 28 days postvaccination. Humoral or cell-mediated vaccine response was 100% to measles virus and 94% to VZV in the CLD group postvaccination, whereas it was 100% to both vaccines in controls. Our pilot study suggests that both live vaccines can be safely and effectively administered up to 14 days prior to transplantation in children with CLD. We anticipate this will improve vaccination rates and thus decrease rates of vaccine-preventable infections in vulnerable children with CLD.

Health Expenditures After Bariatric Surgery: A Retrospective Cohort Study.

OBJECTIVE: Bariatric surgery leads to substantial improvements in weight and weight-related conditions, but prior literature on post-surgical health expenditures is equivocal. In a retrospective cohort study, we compared expenditures between surgical and matched non-surgical patients. SUMMARY BACKGROUND DATA AND METHODS: In a retrospective study, total, outpatient, inpatient and medication expenditures 3 years before and 5.5 years after surgery were compared between 22,698 bariatric surgery (n=7,127 RYGB, 15,571 sleeve gastrectomy) patients from 2012-2019 and 66,769 matched non-surgical patients, using generalized estimating equations. We also compared expenditures between patients receiving the two leading surgical procedures in weighted analyses. RESULTS: Surgical and non-surgical cohorts were well matched, 80-81% female, with mean body mass index (BMI) of 44, and mean age of 47 (RYGB) and 44 (SG) years. Estimated total expenditures were similar between surgical and non-surgical groups 3 years before surgery ($27 difference, 95% confidence interval (CI): -42, 102)), increased 6 months prior to surgery for surgical patients, and decreased below pre-period levels for both groups after 3-5.5 years to become similar (difference at 5.5 y=-$61, 95% CI: -166, 52). Long-term outpatient expenditures were similar between groups. Surgical patients' lower long-term medication expenditures ($314 lower at 5.5 y, 95% CI: -419, -208) were offset by a higher risk of hospitalization. Total expenditures were similar between RYGB and SG patients 3.5 to 5.5 years after surgery. CONCLUSIONS: Bariatric surgery translated into lower medication expenditures than matched controls, but not lower overall long-term expenditures. Expenditure trends appear similar for the two leading bariatric operations.

Immunosuppression-Free Life after Pediatric Liver Transplant: A Case-Control Study from the Society of Pediatric Liver Transplant (SPLIT) Registry.

OBJECTIVE: To compare long-term outcomes of pediatric liver transplant (LT) recipients off immunosuppression (IS) with matched controls on IS using data from the Society of Pediatric Liver Transplant (SPLIT) registry. STUDY DESIGN: This was a retrospective case-control study. SPLIT participants <18 years of age, ≥4 years after isolated LT, and off IS for ≥1 year (cases) were age- and sex-matched 1:2 to patients with the same primary diagnosis and post-LT follow-up duration (controls). Primary outcomes included retransplantation, allograft rejection, IS comorbidities, and prevalence of SPLIT-derived composite ideal outcome (c-IO) achieved at the end of the follow-up period. Differences were compared using multiple linear regression for continuous outcomes and logistic regression for dichotomous data. RESULTS: The study cohort was composed of 33 cases (42.4% male, 60.6% biliary atresia, median age at LT of 0.7 [P25, P75, 0.5, 1.6] years, median IS withdrawal time of 9 [P25, P75, 6, 12] years after LT) and 66 age- and sex-matched controls. No cases required retransplantation. Cases and controls had similar growth parameters, laboratory values, calculated glomerular filtration rates, rates of post-transplant lymphoproliferative disease, graft rejection, and attainment of c-IO. CONCLUSIONS: No differences in allograft rejection rates, IS complications, or c-IO prevalence were seen between SPLIT patients off IS and age- and sex-matched controls remaining on IS. Discontinuation of IS most commonly occurred in the context of rigorously designed IS withdrawal trials. The available sample size was small, affecting generalizability to the broader pediatric LT population.

Yosemite toad (Anaxyrus canorus) transcriptome reveals interplay between speciation genes and adaptive introgression.

Genomes are heterogeneous during the early stages of speciation, with small 'islands' of DNA appearing to reflect strong adaptive differences, surrounded by vast seas of relative homogeneity. As species diverge, secondary contact zones between them can act as an interface and selectively filter through advantageous alleles of hybrid origin. Such introgression is another important adaptive process, one that allows beneficial mosaics of recombinant DNA ('rivers') to flow from one species into another. Although genomic islands of divergence appear to be associated with reproductive isolation, and genomic rivers form by adaptive introgression, it is unknown whether islands and rivers tend to be the same or different loci. We examined three replicate secondary contact zones for the Yosemite toad (Anaxyrus canorus) using two genomic data sets and a morphometric data set to answer the questions: (1) How predictably different are islands and rivers, both in terms of genomic location and gene function? (2) Are the adaptive genetic trait loci underlying tadpole growth and development reliably islands, rivers or neither? We found that island and river loci have significant overlap within a contact zone, suggesting that some loci are first islands, and later are predictably converted into rivers. However, gene ontology enrichment analysis showed strong overlap in gene function unique to all island loci, suggesting predictability in overall gene pathways for islands. Genome-wide association study outliers for tadpole development included LPIN3, a lipid metabolism gene potentially involved in climate change adaptation, that is island-like for all three contact zones, but also appears to be introgressing (as a river) across one zone. Taken together, our results suggest that adaptive divergence and introgression may be more complementary forces than currently appreciated.

Superior Tumor Cell Uptake by Mono- and Tri-Nuclear Rhodamine-Gadolinium(III) Agents.

The synthesis and characterization of a novel trinuclear rhodamine-Gd(III) complex, along with two analogous mononuclear rhodamine-Gd(III) complexes, are reported. All complexes displayed good selectivity in a human glioma cell line (T98G) when compared to a glial cell line (SVG p12), with low cytotoxicities. Superior tumor cell uptake for these Gd(III) complexes was observed at lower incubation concentrations compared to previously-reported delocalized lipophilic cations such as a rhodamine-lanthanoid(III) probe and Gd(III)-arylphosphonium complexes, with ca. 150 % and 250 % increases in Gd uptake, respectively.

Neuropsychiatric Comorbidities and Psychotropic Medication Use in Medicare Beneficiaries With Dementia by Sex and Race.

BACKGROUND: Neuropsychiatric symptoms affect the majority of dementia patients. Past studies report high rates of potentially inappropriate prescribing of psychotropic medications in this population. We investigate differences in neuropsychiatric diagnoses and psychotropic medication prescribing in a local US cohort by sex and race. METHODS: We utilize Medicare claims and prescription fill records in a cohort of 100% Medicare North and South Carolina beneficiaries ages 50 and above for the year 2017 with a dementia diagnosis. We identify dementia and quantify diagnosis of anxiety, depression and psychosis using validated coding algorithms. We search Medicare claims for antianxiety, antidepressant and antipsychotic medications to determine prescriptions filled. RESULTS: Anxiety and depression were diagnosed at higher rates in White patients; psychosis at higher rates in Black patients. (P < .001) Females were diagnosed with anxiety, depression and psychosis at higher rates than males (P < .001) and filled more antianxiety and antidepressant medications than males. (P < .001) Black and Other race patients filled more antipsychotic medications for anxiety, depression and psychosis than White patients. (P < .001) Antidepressants were prescribed at higher rates than antianxiety or antipsychotic medications across all patients and diagnoses. Of patients with no neuropsychiatric diagnosis, 11.4% were prescribed an antianxiety medication, 22.8% prescribed an antidepressant and 7.6% prescribed an antipsychotic. CONCLUSIONS: The high fill rate of antianxiety (benzodiazepine) medications in dementia patients, especially females is a concern. Patients are prescribed psychotropic medications at high rates. This practice may represent potentially inappropriate prescribing. Patient/caregiver education with innovative community outreach and care delivery models may help decrease medication use.

Modern-era successful liver transplantation outcomes in children with hepatic undifferentiated embryonal sarcoma.

BACKGROUND: Hepatic undifferentiated embryonal sarcoma (HUES) is the third most common primary hepatic malignancy in children. If unresectable, liver transplantation (LT) is the only curative option. Historically, HUES LT outcomes were not favorable; however, modern-era data are lacking. We aimed to describe LT outcomes in children with HUES and compared with LT outcomes in children transplanted for hepatoblastoma (HBL) and non-malignancy indications. METHODS: Children 18 years or younger with HUES who underwent LT from 1987 to 2021 were identified from the Scientific Registry of Transplant Recipients database. Graft and patient survival were studied in HUES and LT recipients with HBL and non-malignancy indications using Kaplan-Meier analysis. Cox regression was used to compare patient and graft survival among groups, controlling for confounders. RESULTS: Twenty-one children with HUES underwent LT during the study period with a median age at LT of 10 years (IQR: 8-12 years). One and five-year patient survival for HUES recipients was not significantly different from that of recipients with HBL (p = .3) or non-malignancy diagnoses (p = .6). There were no deaths due to HUES recurrence. In multivariable Cox regression, HUES did not increase risk of either patient or graft loss as compared to HBL (HR 2.36, p = .2) or non-malignancy indications (HR 0.74, p = .7). CONCLUSION: LT outcomes are more favorable in patients with HUES than historically described, and similar to LT outcomes of patients with HBL and non-malignancy indications. Transplant should be considered for HUES patients with unresectable localized tumors.

Pediatric Learning Health Networks in Solid Organ Transplantation-Engaging all Stakeholders to Achieve Health for Children Who Require Transplantation.

BACKGROUND: Learning Health Networks (LHN) have evolved within medicine over the past two decades, but their integration into transplantation has been more recent. OBJECTIVES AND METHODS: In this paper, we describe three LHNs in end-stage organ disease/transplantation, their common and unique features, and how their "actor-oriented" architecture allowed for rapid adaptation to meet the needs of their patients and practitioners during the recent COVID-19 pandemic. RESULT: The structure and focus of the Improving Renal Outcomes Collaborative (IROC), Starzl Network for Excellence in Pediatric Transplantation (SNEPT), and the Advanced Cardiac Therapies Improving Outcomes Network (ACTION) are reviewed. We discuss the critical role of patient and family engagement, focusing on collaboration with Transplant Families. Finally, we review challenges common to the LHN concept and potential common areas of alignment to achieve the goal of more rapid and sustained progress to improve health in pediatric transplantation. CONCLUSION: LHN in transplantation are essential to accelerate knowledge dissemination and improve outcomes.

Anti-spike antibody durability after SARS-CoV-2 vaccination in adolescent solid organ transplant recipients.

BACKGROUND: Adolescent solid organ transplant recipients (aSOTRs) who received three doses of the COVID-19 mRNA vaccine experience high seroconversion rates and antibody persistence for up to 3 months. Long-term antibody durability beyond this timeframe following three doses of the SARS-CoV-2 mRNA vaccine remains unknown. We describe antibody responses 6 months following the third vaccine dose (D3) of the BNT162b2 mRNA vaccination among aSOTRs. METHODS: Participants in a multi-center, observational cohort who received the third dose of the vaccine were analyzed for antibodies to the SARS-CoV-2 spike protein receptor-binding domain (Roche Elecsys anti-SARS-CoV-2-S positive: ≥0.8, maximum: >2500 U/mL). Samples were collected at 1-, 3-, and 6-months post-D3. Participants were surveyed at each timepoint and at 12-months post-D3. RESULTS: All 34 participants had positive anti-RBD antibody titers 6 months post-D3. Variations in titers occurred between 3 and 6 months post-D3, with 8/28 (29%) having decreased antibody levels at 6 months compared to 3 months and 2/28 (7%) reporting increased titers at 6 months. The remaining 18/28 (64%) had unchanged antibody titers compared to 3-month post-D3 levels. A total of 4/34 (12%) reported breakthrough infection within 6 months and 3/32 (9%) reported infection after 6-12 months following the third dose of the SARS-CoV-2 mRNA vaccine. CONCLUSIONS: The results suggest that antibody durability persists up to 6 months following three doses of the SARS-CoV-2 mRNA in aSOTRs. Demography and transplant characteristics did not differ for those who experienced antibody weaning. Breakthrough infections did occur, reflecting immune-evasive nature of novel variants such as Omicron.

Impact of early immunosuppression on pediatric liver transplant outcomes within 1 year.

OBJECTIVES: The Starzl Network for Excellence in Pediatric Transplantation identified optimizing immunosuppression (IS) as a priority practice improvement area for patients, families, and providers. We aimed to evaluate associations between clinical characteristics, early IS, and outcomes. METHODS: We analyzed pediatric liver transplant (LT) data from 2013 to 2018 in the United Network for Organ Sharing (UNOS) and the Society of Pediatric Liver Transplantation (SPLIT) registries. RESULTS: We included 2542 LT recipients in UNOS and 1590 in SPLIT. IS choice varied between centers with steroid induction and mycophenolate mofetil (MMF) use each ranging from 0% to 100% across centers. Clinical characteristics associated with early IS choice were inconsistent between the two data sets. T-cell depleting antibody use was associated with improved 1-year graft (hazard ratio [HR] 0.50, 95% confidence interval [CI] 0.34-0.76) and patient (HR 0.40, 95% CI 0.20-0.79) survival in UNOS but decreased 1-year patient survival (HR 4.12, 95% CI 1.31-12.93) and increased acute rejection (HR 1.58, 95% CI 1.07-2.34) in SPLIT. Non-T-cell depleting antibody use was not associated with differential risk of survival nor rejection. MMF use was associated with improved 1-year graft survival (HR 0.73, 95% CI 0.54-0.99) in UNOS only. CONCLUSIONS: Variation exists in center choice of early IS regimen. UNOS and SPLIT data provide conflicting associations between IS and outcomes in multivariable analysis. These results highlight the need for future multicenter collaborative work to identify evidence-based IS best practices.

One Hundred Years of Seeking Respectful Maternity Care: History and Evolution.

Growing awareness of poor maternal health outcomes and maternal health disparities in the United States has heightened urgency around the need to promote Respectful Maternity Care (RMC) as a fundamental tenet of obstetric/midwifery care and standardize efforts to improve safety, eliminate obstetric violence and racism, and optimize health outcomes for all birthing people. The historical context of prior and contemporary perspectives around childbirth influences our understanding of RMC and are shaped by varying scholarly, clinical, and community standards (e.g., religion, human rights, government, public health, midwifery, ethics, activism, and the law), which have changed significantly since the mid-19th century. In this commentary, we share results of a contextual question scoped as part of a larger systematic review of RMC to help inform consensus around a shared definition and development of a metric to standardize delivery and evaluation of RMC. Synthesis of this literature identified landmark historical influences on RMC over the past 100 years, highlighting the multidisciplinary scholarship and historical context influencing the progress toward RMC. Further understanding of this history may also inform policies and guidance for ongoing efforts to center respect and accountability in all aspects of maternity care, with particular attention to populations who are disproportionally impacted by disrespectful care.

Applying Implementation Science to Advance Electronic Health Record-Driven Learning Health Systems: Case Studies, Challenges, and Recommendations.

With the widespread implementation of electronic health records (EHRs), there has been significant progress in developing learning health systems (LHSs) aimed at improving health and health care delivery through rapid and continuous knowledge generation and translation. To support LHSs in achieving these goals, implementation science (IS) and its frameworks are increasingly being leveraged to ensure that LHSs are feasible, rapid, iterative, reliable, reproducible, equitable, and sustainable. However, 6 key challenges limit the application of IS to EHR-driven LHSs: barriers to team science, limited IS experience, data and technology limitations, time and resource constraints, the appropriateness of certain IS approaches, and equity considerations. Using 3 case studies from diverse health settings and 1 IS framework, we illustrate these challenges faced by LHSs and offer solutions to overcome the bottlenecks in applying IS and utilizing EHRs, which often stymie LHS progress. We discuss the lessons learned and provide recommendations for future research and practice, including the need for more guidance on the practical application of IS methods and a renewed emphasis on generating and accessing inclusive data.

Transmission of Spinach Downy Mildew via Seed and Infested Leaf Debris.

Spinach downy mildew, caused by the obligate oomycete pathogen Peronospora effusa, is a worldwide constraint on spinach production. The role of airborne sporangia in the disease cycle of P. effusa is well established, but the role of the sexual oospores in the epidemiology of P. effusa is less clear and has been a major challenge to examine experimentally. To evaluate seed transmission of spinach downy mildew via oospores in this study, isolated glass chambers were employed in two independent experiments to grow out oospore-infested spinach seed and noninfested seeds mixed with oospore-infested crop debris. Downy mildew diseased spinach plants were observed 37 and 34 days after planting in the two isolator experiments, respectively, in the chambers that contained one of two oospore-infested seed lots or seeds coated with oospore-infested leaves. Spinach plants in isolated glass chambers initiated from seeds without oospores did not show downy mildew symptoms. Similar findings were obtained using the same seed lot samples in a third experiment conducted in a growth chamber. In direct grow out tests to examine oospore infection on seedlings performed in a containment greenhouse with oospore-infested seed of two different cultivars, characteristic Peronospora sporangiophores were observed growing from a seedling of each cultivar. The frequency of seedlings developing symptoms from 82 of these oospore-infested seed indicated that approximately 2.4% of seedlings from infested seed developed symptoms, and 0.55% of seedlings from total seeds assayed developed symptoms. The results provide evidence that oospores can serve as a source of inoculum for downy mildew and provide further evidence of direct seed transmission of the downy mildew pathogen to seedlings in spinach via seedborne oospores.