New therapies for highly sensitized patients on the waiting list.

PURPOSE: Exposure to HLA alloantigens through pregnancy, blood products and previous transplantations induce powerful immunologic responses that create an immunologic barrier to successful transplantation. This is commonly detected through screening for HLA antibodies using Luminex beads coated with HLA antigens at transplant evaluation. Currently accepted approaches to desensitization include plasmapheresis (PLEX)/low or high dose IVIg plus anti-CD20. However, these approaches are often unsuccessful due to the inability to remove high titer circulating HLA antibodies and limit rebound responses by long-lived anti-HLA antibody secreting plasma cells (PCs) and memory B-cells (BMEM). This is especially significant for patients with cPRA 99-100%. RECENT FINDINGS: Newer desensitization approaches such as imlifidase (IgG endopeptidase) rapidly inactivates IgG molecules and creates an "antibody-free zone" by cleaving IgG into F(ab'2) and Fc fragments, thus eliminating complement and cell-mediated injury to the graft. This represents an important advancement in desensitization. However, the efficacy of imlifidase is limited by pathogenic antibody rebound, increasing the potential for antibody-mediated rejection. Controlling antibody rebound requires new strategies that address the issues of antibody depletion and inhibition of BMEM & PC responses. This will likely require a combination of agents that effectively and rapidly deplete pathogenic antibodies and prevent immune cell activation pathways responsible for antibody rebound. Here, using anti-IL-6R (tocilizumab) or anti-IL-6 (clazakizumab) could offer long-term control of BMEM and PC DSA responses. Agents aimed at eliminating long-lived PCs (anti-CD38 & anti-BCMAxCD3) are likely to benefit HS patients. Complement inhibitors and novel agents aimed at inhibiting Fc neonatal receptor (FcRn) IgG recycling will be important in desensitization. CONCLUSIONS: Administering these agents alone or in combination will advance our ability to effectively desensitize patients and maintain durable suppression post-transplant. After many years of limited options, advanced therapeutics will likely improve efficacy of desensitization and improve access to kidney transplantation for highly-HLA sensitized patients.

Thirty-Day Readmissions After Hospitalization for Psoriatic Arthritis.

Background Psoriatic arthritis (PsA) is correlated with higher rates of major adverse cardiovascular events and autoimmune disorders than the general population, leading to more frequent hospitalizations. This study assessed the rates and characteristics of index and 30-day readmissions among adults hospitalized for PsA and evaluated the indications and predictors of 30-day readmissions across the United States. Methodology We analyzed the 2020 Nationwide Readmissions Database for adult PsA hospitalizations using the International Classification of Diseases, Tenth Revision, Clinical Modification codes. To compare baseline characteristics between index admissions and readmissions, we used chi-square tests. We used ranking commands to identify the most common indications for readmissions and multivariable Cox regression analysis to identify the predictors of readmissions. The primary endpoints were the rates and characteristics of index and 30-day readmissions. The secondary endpoint was the predictors of readmission within 30 days of index hospital discharge. Results Approximately 842 index hospitalizations for PsA were analyzed. Of these, 244 (29%) resulted in 30-day readmissions, with the primary causes being acute kidney failure, major depression, and heart failure. Readmitted patients had a mean age of 48.2 years (SD = 6.4 years) compared with 54.6 years (SD = 2.2 years) in index hospitalizations (p = 0.147). More readmitted patients were uninsured than index hospitalizations (18.6% vs. 4.4%; p = 0.015). The mean length of stay for readmissions was 7.2 days compared with 3.9 days for index admissions. The mean total hospital costs were US$31,424 for index admissions and US$60,147 for readmissions (p < 0.001). Significant differences in comorbidities such as hypertension (24.8% vs. 40.1%, p = 0.032), liver disease (29% vs. 7.9%, p = 0.020), uveitis (9.4% vs. 4.5%, p < 0.001), inflammatory bowel disease (8.6% vs. 3.8%, p < 0.001), and alcohol use disorder (29% vs. 7.8%, p = 0.002) were observed between readmissions and index admissions. Age <40 years (adjusted hazard ratio (AHR) = 2.35; p = 0.047), home healthcare (AHR = 5.87; p = 0.035), residence in the same state as the hospital (AHR = 1.24; p = 0.018), and secondary diagnoses of inflammatory bowel disease (AHR = 2.33; p < 0.001) or deep venous thrombosis (AHR = 3.80; p = 0.007) were correlated with an increased likelihood of readmission. Conclusions About one in three hospitalizations for PsA result in readmission within 30 days of initial discharge. Age <40 years, discharge to home healthcare, and a secondary diagnosis of inflammatory bowel disease or deep venous thrombosis were correlated with an increased likelihood of readmission.

Cell-free DNA for the detection of kidney allograft rejection.

Donor-derived cell-free DNA (dd-cfDNA) is an emerging noninvasive biomarker that has the potential to detect allograft injury. The capacity of dd-cfDNA to detect kidney allograft rejection and its added clinical value beyond standard of care patient monitoring is unclear. We enrolled 2,882 kidney allograft recipients from 14 transplantation centers in Europe and the United States in an observational population-based study. The primary analysis included 1,134 patients. Donor-derived cell-free DNA levels strongly correlated with allograft rejection, including antibody-mediated rejection (P < 0.0001), T cell-mediated rejection (P < 0.0001) and mixed rejection (P < 0.0001). In multivariable analysis, circulating dd-cfDNA was significantly associated with allograft rejection (odds ratio 2.275; 95% confidence interval (CI) 1.902-2.739; P < 0.0001) independently of standard of care patient monitoring parameters. The inclusion of dd-cfDNA to a standard of care prediction model showed improved discrimination (area under the curve 0.777 (95% CI 0.741-0.811) to 0.821 (95% CI 0.784-0.852); P = 0.0011) and calibration. These results were confirmed in the external validation cohorts (n = 1,748) including a cohort of African American patients (n = 439). Finally, dd-cfDNA showed high predictive value to detect subclinical rejection in stable patients. Our study provides insights on the potential value of assessing dd-cfDNA, in addition to standard of care monitoring, to improve the detection of allograft rejection. ClinicalTrials.gov registration: NCT05995379 .

Impact of Post Manufacturing Handling of Protein-Based Biologic Drugs on Product Quality and User Centricity.

This article evaluates the current gaps around the impact of post-manufacturing processes on the product qualities of protein-based biologics, with a focus on user centricity. It includes the evaluation of the regulatory guidance available, describes a collection of scientific literature and case studies to showcase the impact of post-manufacturing stresses on product and dosing solution quality. It also outlines the complexity of clinical handling and the need for communication, and alignment between drug providers, healthcare professionals, users, and patients. Regulatory agencies provide clear expectations for drug manufacturing processes, however, guidance supporting post-product manufacturing handling is less defined and often misaligned. This is problematic as the pharmaceutical products experience numerous stresses and processes which can potentially impact drug quality, safety and efficacy. This article aims to stimulate discussion amongst pharmaceutical developers, health care providers, device manufacturers, and public researchers to improve these processes. Patients and caregivers' awareness can be achieved by providing relevant educational material on pharmaceutical product handling.

Enhancing HIV positivity yield in southern Mozambique: The effect of a Ministry of Health training module in targeted provider-initiated testing and counselling

In Mozambique, targeted provider-initiated HIV testing and counselling (PITC) is recommended where universal PITC is not feasible, but its effectiveness depends on healthcare providers' training. This study aimed to evaluate the effect of a Ministry of Health training module in targeted PITC on the HIV positivity yield, and identify factors associated with a positive HIV test. We conducted a single-group pre-post study between November 2018 and November 2019 in the triage and emergency departments of four healthcare facilities in Manhiça District, a resource-constrained semi-rural area. It consisted of two two-month phases split by a one-week targeted PITC training module ("observation phases"). The HIV positivity yield of targeted PITC was estimated as the proportion of HIV-positive individuals among those recommended for HIV testing by the provider. Additionally, we extracted aggregated health information system data over the four months preceding and following the observation phases to compare yield in real-world conditions ("routine phases"). Logistic regression analysis from observation phase data was conducted to identify factors associated with a positive HIV test. Among the 7,102 participants in the pre- and post-training observation phases (58.5% and 41.5% respectively), 68% were women, and 96% were recruited at triage. In the routine phases with 33,261 individuals (45.8% pre, 54.2% post), 64% were women, and 84% were seen at triage. While HIV positivity yield between pre- and post-training observation phases was similar (10.9% (269/2470) and 11.1% (207/1865), respectively), we observed an increase in yield in the post-training routine phase for women in triage, rising from 4.8% (74/1553) to 7.3% (61/831) (Yield ratio = 1.54; 95%CI: 1.11-2.14). Age (25-49 years) (OR = 2.43; 95%CI: 1.37-4.33), working in industry/mining (OR = 4.94; 95%CI: 2.17-11.23), unawareness of partner's HIV status (OR = 2.50; 95%CI: 1.91-3.27), and visiting a healer (OR = 1.74; 95%CI: 1.03-2.93) were factors associated with a positive HIV test. Including these factors in the targeted PITC algorithm could have increased new HIV diagnoses by 2.6%. In conclusion, providing refresher training and adapting the current targeted PITC algorithm through further research can help reach undiagnosed PLHIV, treat all, and ultimately eliminate HIV, especially in resource-limited rural areas.

Long-term Safety in Epstein-Barr Virus-Seropositive Kidney-only Transplant Recipients Treated With Belatacept in Clinical Practice: Final Study Results From the ENLiST Registry.

Background: Belatacept, a selective T-cell costimulation blocker, was associated with improved survival and renal function but also with a risk of posttransplant lymphoproliferative disorder (PTLD) in adult kidney transplant recipients in phase 3 trials. This registry examined long-term safety in Epstein-Barr virus (EBV)-seropositive kidney transplant recipients treated with belatacept. Methods: This US-based, prospective, voluntary, multicenter registry (Evaluating Nulojix Long-Term Safety in Transplant [ENLiST]) included adult EBV-seropositive kidney-only transplant recipients treated de novo (within 14 d of transplantation) with belatacept. Primary objectives were to estimate incidence rates of confirmed PTLD, central nervous system (CNS) PTLD, and progressive multifocal encephalopathy (PML). The minimum follow-up was 2 y. Results: Of 985 enrolled transplant recipients, 933 EBV-seropositive patients received belatacept, with 523 (56.1%) receiving concomitant tacrolimus at transplant (for up to 12 mo). By study end, 3 cases of non-CNS PTLD (incidence rate, 0.08/100 person-years), 1 case of CNS PTLD (0.03/100 person-years), and no cases of PML had been reported. Two patients with non-CNS PTLD received concomitant belatacept and tacrolimus and 1 received belatacept and lymphocyte-depleting therapy. Incidence rates were comparable between patients who received concomitant belatacept and tacrolimus and those who did not receive tacrolimus (0.09/100 person-years and 0.07/100 person-years, respectively; P = 0.96). Two of 4 patients with PTLD died, and 2 were alive at the end of the study. Cumulatively, 131 graft losses or deaths were reported by study end. Conclusions: Our results from the ENLiST registry, a large, prospective real-world study, showed that the incidence rates of PTLD and CNS PTLD in belatacept-treated EBV-seropositive transplant recipients were consistent with findings from previous phase 3 trials.

Enhancing HIV positivity yield in southern Mozambique: The effect of a Ministry of Health training module in targeted provider-initiated testing and counselling.

In Mozambique, targeted provider-initiated HIV testing and counselling (PITC) is recommended where universal PITC is not feasible, but its effectiveness depends on healthcare providers' training. This study aimed to evaluate the effect of a Ministry of Health training module in targeted PITC on the HIV positivity yield, and identify factors associated with a positive HIV test. We conducted a single-group pre-post study between November 2018 and November 2019 in the triage and emergency departments of four healthcare facilities in Manhiça District, a resource-constrained semi-rural area. It consisted of two two-month phases split by a one-week targeted PITC training module ("observation phases"). The HIV positivity yield of targeted PITC was estimated as the proportion of HIV-positive individuals among those recommended for HIV testing by the provider. Additionally, we extracted aggregated health information system data over the four months preceding and following the observation phases to compare yield in real-world conditions ("routine phases"). Logistic regression analysis from observation phase data was conducted to identify factors associated with a positive HIV test. Among the 7,102 participants in the pre- and post-training observation phases (58.5% and 41.5% respectively), 68% were women, and 96% were recruited at triage. In the routine phases with 33,261 individuals (45.8% pre, 54.2% post), 64% were women, and 84% were seen at triage. While HIV positivity yield between pre- and post-training observation phases was similar (10.9% (269/2470) and 11.1% (207/1865), respectively), we observed an increase in yield in the post-training routine phase for women in triage, rising from 4.8% (74/1553) to 7.3% (61/831) (Yield ratio = 1.54; 95%CI: 1.11-2.14). Age (25-49 years) (OR = 2.43; 95%CI: 1.37-4.33), working in industry/mining (OR = 4.94; 95%CI: 2.17-11.23), unawareness of partner's HIV status (OR = 2.50; 95%CI: 1.91-3.27), and visiting a healer (OR = 1.74; 95%CI: 1.03-2.93) were factors associated with a positive HIV test. Including these factors in the targeted PITC algorithm could have increased new HIV diagnoses by 2.6%. In conclusion, providing refresher training and adapting the current targeted PITC algorithm through further research can help reach undiagnosed PLHIV, treat all, and ultimately eliminate HIV, especially in resource-limited rural areas.

Gilteritinib as Post-Transplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3.

PURPOSE: Allogeneic hematopoietic cell transplantation (HCT) improves outcomes for patients with AML harboring an internal tandem duplication mutation of FLT3 (FLT3-ITD) AML. These patients are routinely treated with a FLT3 inhibitor after HCT, but there is limited evidence to support this. Accordingly, we conducted a randomized trial of post-HCT maintenance with the FLT3 inhibitor gilteritinib (ClinicalTrials.gov identifier: NCT02997202) to determine if all such patients benefit or if detection of measurable residual disease (MRD) could identify those who might benefit. METHODS: Adults with FLT3-ITD AML in first remission underwent HCT and were randomly assigned to placebo or 120 mg once daily gilteritinib for 24 months after HCT. The primary end point was relapse-free survival (RFS). Secondary end points included overall survival (OS) and the effect of MRD pre- and post-HCT on RFS and OS. RESULTS: Three hundred fifty-six participants were randomly assigned post-HCT to receive gilteritinib or placebo. Although RFS was higher in the gilteritinib arm, the difference was not statistically significant (hazard ratio [HR], 0.679 [95% CI, 0.459 to 1.005]; two-sided P = .0518). However, 50.5% of participants had MRD detectable pre- or post-HCT, and, in a prespecified subgroup analysis, gilteritinib was beneficial in this population (HR, 0.515 [95% CI, 0.316 to 0.838]; P = .0065). Those without detectable MRD showed no benefit (HR, 1.213 [95% CI, 0.616 to 2.387]; P = .575). CONCLUSION: Although the overall improvement in RFS was not statistically significant, RFS was higher for participants with detectable FLT3-ITD MRD pre- or post-HCT who received gilteritinib treatment. To our knowledge, these data are among the first to support the effectiveness of MRD-based post-HCT therapy.

SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys.

The steps governing healing with or without fibrosis within the same microenvironment are unclear. After acute kidney injury (AKI), injured proximal tubular epithelial cells activate SOX9 for self-restoration. Using a multimodal approach for a head-to-head comparison of injury-induced SOX9 lineages, we identified a dynamic SOX9 switch in repairing epithelia. Lineages that regenerated epithelia silenced SOX9 and healed without fibrosis (SOX9on-off). By contrast, lineages with unrestored apicobasal polarity maintained SOX9 activity in sustained efforts to regenerate, which were identified as a SOX9on-on Cadherin6pos cell state. These reprogrammed cells generated substantial single-cell WNT activity to provoke a fibroproliferative response in adjacent fibroblasts, driving AKI to chronic kidney disease. Transplanted human kidneys displayed similar SOX9/CDH6/WNT2B responses. Thus, we have uncovered a sensor of epithelial repair status, the activity of which determines regeneration with or without fibrosis.

Assessment of IgM DSAs in Transplant Recipients: Relationship to De Novo IgG DSAs and Risk for Antibody Rejection.

Background: The presence of anti-HLA donor-specific antibodies (DSAs) is associated with antibody-mediated rejection (AMR) and inferior graft survival. However, recent data suggest that ~50% of AMR episodes are IgG DSA negative and possibly related to non-HLA DSAs. After the initial activation of B cells to alloantigen, IgM is the first immunoglobulin produced. In addition, both IgM and IgG isotopes can activate the classic complement pathway and induce complement-dependent cytotoxicity to allograft targets. Current practices focus on the assessment of IgG DSAs with little concern for the assessment of IgM DSAs. Methods: Here, we examined anti-HLA IgM in a cohort of 22 patients who developed de novo IgG DSAs by a modified single-antigen bead-based test. Results: We found IgM HLA DSAs developed before IgG DSAs. The median time from the detection of IgM DSAs to the appearance of de novo IgG DSAs was 461 d. Most patients had IgM DSAs against the same HLA-DQ antigens, for which IgG de novo DSAs were also later detected. IgM DSAs were detected in patients with biopsies suspected of AMR. Conclusions: The detection of IgM DSAs could be an early indicator of alloimmune responses to allografts before IgG de novo DSAs appear.

Management of the sensitized pediatric renal transplant candidate.

Kidney transplantation is the treatment of choice for patients with ESRD as it is associated with improved patient survival and better quality of life, especially in children. There are several barriers to a successful transplant including organ shortage, anatomic barriers, and immunologic barriers. One of the biggest immunologic barriers that precludes transplantation is sensitization, when patients have antibodies prior to transplantation, resulting in positive crossmatches with donor. 30%-40% of adult patients on the wait list are sensitized. There is a growing number of pediatric patients on the wait list who are sensitized. This poses a unique challenge to the pediatric transplant community. Therefore, attempts to perform desensitization to remove or suppress pathogenic HLA antibodies resulting in acceptable crossmatches, and ultimately a successful transplant, while reducing the risk of acute rejection, are much needed in these children. This review article aims to address the management of such patients both prior to transplantation, with strategies to overcome sensitization, and after transplantation with monitoring for allograft rejection and other complications.

Reaction hijacking inhibition of Plasmodium falciparum asparagine tRNA synthetase.

Malaria poses an enormous threat to human health. With ever increasing resistance to currently deployed drugs, breakthrough compounds with novel mechanisms of action are urgently needed. Here, we explore pyrimidine-based sulfonamides as a new low molecular weight inhibitor class with drug-like physical parameters and a synthetically accessible scaffold. We show that the exemplar, OSM-S-106, has potent activity against parasite cultures, low mammalian cell toxicity and low propensity for resistance development. In vitro evolution of resistance using a slow ramp-up approach pointed to the Plasmodium falciparum cytoplasmic asparaginyl-tRNA synthetase (PfAsnRS) as the target, consistent with our finding that OSM-S-106 inhibits protein translation and activates the amino acid starvation response. Targeted mass spectrometry confirms that OSM-S-106 is a pro-inhibitor and that inhibition of PfAsnRS occurs via enzyme-mediated production of an Asn-OSM-S-106 adduct. Human AsnRS is much less susceptible to this reaction hijacking mechanism. X-ray crystallographic studies of human AsnRS in complex with inhibitor adducts and docking of pro-inhibitors into a model of Asn-tRNA-bound PfAsnRS provide insights into the structure-activity relationship and the selectivity mechanism.

Evaluating Clinical Safety and Analytical Impact of Subvisible Silicone Oil Particles in Biopharmaceutical Products.

Silicone oil is a commonly used lubricant in pre-filled syringes (PFSs) and can migrate over time into solution in the form of silicone oil particles (SiOPs). The presence of these SiOPs can result in elevated subvisible particle counts in PFS drug products compared to other drug presentations such as vials or cartridges. Their presence in products presents analytical challenges as they complicate quantitation and characterization of other types of subvisible particles in solution. Previous studies have suggested that they can potentially act as adjuvant resulting in potential safety risks for patients. In this paper we present several analytical case studies describing the impact of the presence of SiOPs in biotherapeutics on the analysis of the drug as well as clinical case studies examining the effect of SiOPs on patient safety. The analytical case studies demonstrate that orthogonal techniques, especially flow imaging, can help differentiate SiOPs from other types of particulate matter. The clinical case studies showed no difference in the observed patient safety profile across multiple drugs, patient populations, and routes of administration, indicating that the presence of SiOPs does not impact patient safety.

Advances in desensitization for human leukocyte antigen incompatible kidney transplantation.

PURPOSE OF REVIEW: Human leukocyte antigen (HLA) sensitization is a major barrier to kidney transplantation induced by exposure to alloantigens through pregnancy, blood product exposure and previous transplantations. Desensitization strategies are undertaken to improve the chances of finding compatible organ offers. Standard approaches to desensitization include the use of plasmapheresis/low dose intravenous immunoglobulin (IVIG) or high dose IVIG plus anti-CD20. However, current methods to reduce HLA antibodies are not always successful, especially in those with calculated panel reactive antibody 99-100%. RECENT FINDINGS: Newer desensitization strategies such as imlifidase [immunoglobulin G (IgG) endopeptidase] rapidly inactivates IgG molecules and creates an "antibody-free zone", representing an important advancement in desensitization. However, pathogenic antibodies rebound, increasing allograft injury that is not addressed by imlifidase. Here, use of anti-IL-6R (tocilizumab) or anti-interleukin-6 (clazakizumab) could offer long-term control of B-memory and plasma cell DSA responses to limit graft injury. Agents aimed at long-lived plasma cells (anti-CD38 and anti-BCMAxCD3) could reduce or eliminate HLA-producing plasma cells from marrow niches. Other agents such as complement inhibitors and novel agents inhibiting the Fc neonatal receptor (FcRn) mediated IgG recycling will likely find important roles in desensitization. SUMMARY: Use of these agents alone or in combination will likely improve the efficacy and durability of desensitization therapies, improving access to kidney transplantation for immunologically disadvantaged patients.

R-Loop Accumulation in Spliceosome Mutant Leukemias Confers Sensitivity to PARP1 Inhibition by Triggering Transcription-Replication Conflicts.

RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi), despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop-associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop-dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R-loops correlated with PARPi sensitivity, suggesting that R-loop-associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer. SIGNIFICANCE: Spliceosome-mutant leukemias accumulate R-loops and require PARP1 to resolve transcription-replication conflicts and genomic instability, providing rationale to repurpose FDA-approved PARP inhibitors for patients carrying spliceosome gene mutations.

Assessing the post hoc effectiveness of tixagevimab-cilgavimab for prevention of SARS-CoV-2 infections in solid organ transplant recipients.

BACKGROUND: Tixagevimab-cilgavimab (Tix-Cil) was authorized for prophylaxis against COVID-19 in immunocompromised patients from December 2021 through January 2023. Real-world effectiveness for solid organ transplant (SOT) recipients has been unclear. METHODS: We enrolled 911 SOT recipients into a longitudinal COVID-19 serology study, of whom 381 (42%) received ≥1 dose of Tix-Cil. We collected and analyzed data on incident SARS-CoV-2 infections and antibody kinetics for all patients from January 2022 to March 2023, including periods dominated by Omicron BA and BQ subvariants. RESULTS: Over 253 ± 131 days of follow-up, there were 324 new-onset SARS-CoV-2 infections: 117 (31%) in Tix-Cil treated and 207 (39%) in Tix-Cil untreated patients (p = .012). In analyses adjusting for demographic, clinical, and COVID-19 exposure factors, any Tix-Cil treatment was associated with lower infection risk (OR 0.52, 95% CI 0.27-0.96, p = .039) throughout the surveillance period including when more resistant BQ.1 and BQ.1.1 subvariants had emerged (12/1/2022 onwards). Among treated patients, receiving a Tix-Cil dose was associated with substantial and sustained increase in anti-spike IgG antibody and angiotensin-converting enzyme 2 binding inhibition levels (Abbott Architect assay) that together also demonstrated association with lower infection risk (p = .042). During the full surveillance period, the frequency of infections requiring hospitalization was low overall (N = 26, 2.9% of the total cohort) and not significantly different between Tix-Cil recipients (N = 12, 3.2% of treated patients) and non-Tix-Cil recipients (N = 14, 2.6% of untreated patients) with unadjusted p = .31 for between-group difference. CONCLUSION: In a large cohort of SOT recipients, we found that Tix-Cil reduced infection risk even amidst emergent Omicron subvariants. Additionally, the extent of measurable humoral response to Tix-Cil may indicate relative effectiveness. Pre-exposure monoclonal antibody therapy may represent a strategy that will continue to offer clinical benefit for immunocompromised persons who are known to derive limited protection from vaccinations.

Who Gets Sick From COVID-19? Sociodemographic Correlates of Severe Adult Health Outcomes During Alpha- and Delta-Variant Predominant Periods: September 2020-November 2021.

BACKGROUND: Because COVID-19 case data do not capture most SARS-CoV-2 infections, the actual risk of severe disease and death per infection is unknown. Integrating sociodemographic data into analysis can show consequential health disparities. METHODS: Data were merged from September 2020 to November 2021 from 6 national surveillance systems in matched geographic areas and analyzed to estimate numbers of COVID-19-associated cases, emergency department visits, and deaths per 100 000 infections. Relative risks of outcomes per infection were compared by sociodemographic factors in a data set including 1490 counties from 50 states and the District of Columbia, covering 71% of the US population. RESULTS: Per infection with SARS-CoV-2, COVID-19-related morbidity and mortality were higher among non-Hispanic American Indian and Alaska Native persons, non-Hispanic Black persons, and Hispanic or Latino persons vs non-Hispanic White persons; males vs females; older people vs younger; residents in more socially vulnerable counties vs less; those in large central metro areas vs rural; and people in the South vs the Northeast. DISCUSSION: Meaningful disparities in COVID-19 morbidity and mortality per infection were associated with sociodemography and geography. Addressing these disparities could have helped prevent the loss of tens of thousands of lives.

BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state.

ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.

Nephroprotective effects of Datura stramonium leaves against methotrexate nephrotoxicity via attenuation of oxidative stress-mediated inflammation and apoptosis in rats.

Objective: Methotrexate (MTX) is a frontline antimetabolite anticancer drug which is used in different cancer treatments but its nephrotoxicity is a notable drawback that limits its clinical use. The present study was undertaken to examine whether Datura stramonium leaf extract (DSLE) could block MTX nephrotoxic side effect in rats. Materials and Methods: Animals were divided randomly into Control, Ethanol extract, MTX, and Extract + MTX groups. DSLE (200 mg/kg bw) was orally administered for 21 days, while MTX was injected intraperitoneally (ip) on the 18th day. Serum levels of urea, creatinine and uric acid were determined. Kidney samples were used to determine glutathione peroxidase (GPx), superoxide dismutase (SOD), and catalase (CAT) activities, and renal levels of malondialdehyde (MDA), reduced glutathione (GSH), nitric oxide (NO), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and caspase-3. Results: Injection of MTX resulted in considerable increases (p<0.05) in creatinine, urea, and uric acid levels as well as renal MDA, NO, IL-6, TNF-α and caspase-3 compared to the controls. SOD and GPx increased significantly, while GSH was significantly depleted. Interestingly, DSLE markedly reduced (p<0.05) levels of creatinine, urea, uric acid, TNF-α, NO, MDA and caspase-3, whereas renal GSH increased markedly compared to the MTX group. Conclusion: DSLE has nephroprotective activity against MTX toxicity. However, further mechanistic studies are needed.