Astrocytic interleukin-3 programs microglia and limits Alzheimer's disease.

Communication within the glial cell ecosystem is essential for neuronal and brain health1-3. The influence of glial cells on the accumulation and clearance of ß-amyloid (Aß) and neurofibrillary tau in the brains of individuals with Alzheimer's disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aß deposits, microglia increase their expression of IL-3Rα-the specific receptor for IL-3 (also known as CD123)-making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aß and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte-microglia cross-talk and a node for therapeutic intervention in AD.

Gene burden analysis identifies genes associated with increased risk and severity of adult-onset hearing loss in a diverse hospital-based cohort.

Loss or absence of hearing is common at both extremes of human lifespan, in the forms of congenital deafness and age-related hearing loss. While these are often studied separately, there is increasing evidence that their genetic basis is at least partially overlapping. In particular, both common and rare variants in genes associated with monogenic forms of hearing loss also contribute to the more polygenic basis of age-related hearing loss. Here, we directly test this model in the Penn Medicine BioBank-a healthcare system cohort of around 40,000 individuals with linked genetic and electronic health record data. We show that increased burden of predicted deleterious variants in Mendelian hearing loss genes is associated with increased risk and severity of adult-onset hearing loss. As a specific example, we identify one gene-TCOF1, responsible for a syndromic form of congenital hearing loss-in which deleterious variants are also associated with adult-onset hearing loss. We also identify four additional novel candidate genes (COL5A1, HMMR, RAPGEF3, and NNT) in which rare variant burden may be associated with hearing loss. Our results confirm that rare variants in Mendelian hearing loss genes contribute to polygenic risk of hearing loss, and emphasize the utility of healthcare system cohorts to study common complex traits and diseases.

Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes.

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

Impact of natural selection on global patterns of genetic variation and association with clinical phenotypes at genes involved in SARS-CoV-2 infection.

Human genomic diversity has been shaped by both ancient and ongoing challenges from viruses. The current coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had a devastating impact on population health. However, genetic diversity and evolutionary forces impacting host genes related to SARS-CoV-2 infection are not well understood. We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (angiotensin converting enzyme 2 [ACE2], transmembrane protease serine 2 [TMPRSS2], dipeptidyl peptidase 4 [DPP4], and lymphocyte antigen 6 complex locus E [LY6E]). We analyzed data from 2,012 ethnically diverse Africans and 15,977 individuals of European and African ancestry with electronic health records and integrated with global data from the 1000 Genomes Project. At ACE2, we identified 41 nonsynonymous variants that were rare in most populations, several of which impact protein function. However, three nonsynonymous variants (rs138390800, rs147311723, and rs145437639) were common among central African hunter-gatherers from Cameroon (minor allele frequency 0.083 to 0.164) and are on haplotypes that exhibit signatures of positive selection. We identify signatures of selection impacting variation at regulatory regions influencing ACE2 expression in multiple African populations. At TMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage compared with the chimpanzee genome. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19. Our study provides insights into global variation at host genes related to SARS-CoV-2 infection, which have been shaped by natural selection in some populations, possibly due to prior viral infections.

A genome-first approach to rare variants in hypertrophic cardiomyopathy genes MYBPC3 and MYH7 in a medical biobank.

'Genome-first' approaches to analyzing rare variants can reveal new insights into human biology and disease. Because pathogenic variants are often rare, new discovery requires aggregating rare coding variants into 'gene burdens' for sufficient power. However, a major challenge is deciding which variants to include in gene burden tests. Pathogenic variants in MYBPC3 and MYH7 are well-known causes of hypertrophic cardiomyopathy (HCM), and focusing on these 'positive control' genes in a genome-first approach could help inform variant selection methods and gene burdening strategies for other genes and diseases. Integrating exome sequences with electronic health records among 41 759 participants in the Penn Medicine BioBank, we evaluated the performance of aggregating predicted loss-of-function (pLOF) and/or predicted deleterious missense (pDM) variants in MYBPC3 and MYH7 for gene burden phenome-wide association studies (PheWAS). The approach to grouping rare variants for these two genes produced very different results: pLOFs but not pDM variants in MYBPC3 were strongly associated with HCM, whereas the opposite was true for MYH7. Detailed review of clinical charts revealed that only 38.5% of patients with HCM diagnoses carrying an HCM-associated variant in MYBPC3 or MYH7 had a clinical genetic test result. Additionally, 26.7% of MYBPC3 pLOF carriers without HCM diagnoses had clear evidence of left atrial enlargement and/or septal/LV hypertrophy on echocardiography. Our study shows the importance of evaluating both pLOF and pDM variants for gene burden testing in future studies to uncover novel gene-disease relationships and identify new pathogenic loss-of-function variants across the human genome through genome-first analyses of healthcare-based populations.

Basal cell adenoma and basal cell adenocarcinoma of the parotid gland: clinical findings and surgical outcomes in a single-institution study.

BACKGROUND: Basal cell adenoma (BCA) is a rare benign tumor within the salivary glands. Basal cell adenocarcinoma (BCAC), the malignant counterpart of BCA, is also an exceedingly rare tumor with very limited clinical studies conducted. This study aims to investigate the clinical characteristics, demographics, and surgical outcomes of patients diagnosed with BCA and BCAC within the parotid gland. METHODS: A retrospective analysis from May 2003 to August 2023 was performed for all patients undergoing parotidectomy for masses. Retrospective data on gender, age, tumor characteristics, and outcomes were collected. Surgical approaches, including negative margin attainment, capsule removal, and histological diagnosis, were also detailed. RESULTS: The study included 1268 patients who underwent parotidectomy, resulting in 81 cases of BCA and 7 cases of BCAC. BCA patients, with a mean age of 55.1 years, showed diverse age distribution and predominantly presented in the 50s. In BCAC cases, seven female patients exhibited a predominant location in the deep lobes. FNA revealed BCAC in three out of seven cases, and subsequent parotidectomy was performed, resulting in no observed recurrences or metastases. CONCLUSION: This study reports the largest number of BCA cases from a single institution and provides comprehensive insights into the demographics, tumor characteristics, and clinical outcomes of both BCA and BCAC. Although further research should be conducted, based on clinical follow-up results, appropriately including the capsule in the tumor excision indicates favorable outcomes, especially when the tumor size is not large.

Endothelial lipase mediates efficient lipolysis of triglyceride-rich lipoproteins.

Triglyceride-rich lipoproteins (TRLs) are circulating reservoirs of fatty acids used as vital energy sources for peripheral tissues. Lipoprotein lipase (LPL) is a predominant enzyme mediating triglyceride (TG) lipolysis and TRL clearance to provide fatty acids to tissues in animals. Physiological and human genetic evidence support a primary role for LPL in hydrolyzing TRL TGs. We hypothesized that endothelial lipase (EL), another extracellular lipase that primarily hydrolyzes lipoprotein phospholipids may also contribute to TRL metabolism. To explore this, we studied the impact of genetic EL loss-of-function on TRL metabolism in humans and mice. Humans carrying a loss-of-function missense variant in LIPG, p.Asn396Ser (rs77960347), demonstrated elevated plasma TGs and elevated phospholipids in TRLs, among other lipoprotein classes. Mice with germline EL deficiency challenged with excess dietary TG through refeeding or a high-fat diet exhibited elevated TGs, delayed dietary TRL clearance, and impaired TRL TG lipolysis in vivo that was rescued by EL reconstitution in the liver. Lipidomic analyses of postprandial plasma from high-fat fed Lipg-/- mice demonstrated accumulation of phospholipids and TGs harboring long-chain polyunsaturated fatty acids (PUFAs), known substrates for EL lipolysis. In vitro and in vivo, EL and LPL together promoted greater TG lipolysis than either extracellular lipase alone. Our data positions EL as a key collaborator of LPL to mediate efficient lipolysis of TRLs in humans and mice.

Squamous Cell Carcinoma Arising From Epidermal Cyst: A Case Series of 9 Patients With a Literature Review.

ABSTRACT: Epidermal cysts are among the most common benign subcutaneous tumors. However, malignant transformation of benign epidermal cysts into squamous carcinomas has been reported. Owing to its low incidence rate, the clinical and pathological features of this condition are not well understood. This study aimed to analyze the clinical and pathological characteristics of the malignant transformation of epidermal cysts, which could suggest an appropriate treatment strategy. We conducted a retrospective study of 9 patients diagnosed with squamous cell carcinoma arising from epidermal cysts. All patients underwent surgical excision, and clinical information regarding patient demographics, tumor characteristics, treatment, and outcomes was analyzed. The average age at diagnosis was 57.3 years, with an average latency period of 15.4 years. Five patients had undergone prior cyst excision or drainage, with an average of 2.3 episodes of recurrence. Surgical excision was the primary treatment in all cases, and 2 patients with margin involvement at the final pathology underwent re-excision with additional resection margins. No recurrence was observed during the follow-up period. Four patients had immune dysregulation due to an underlying chronic kidney disease or cancer. Our study emphasizes the need for increased awareness of squamous cell carcinoma arising from epidermal cysts in patients with a history of cyst existence or recurrence, especially those with immune deficiencies. We expect these findings to contribute to early suspicion of malignant transformation and guide adequate clinical decision-making.

Heterozygous variants in TBCK cause a mild neurologic syndrome in humans and mice.

TBCK-related encephalopathy is a rare pediatric neurodegenerative disorder caused by biallelic loss-of-function variants in the TBCK gene. After receiving anecdotal reports of neurologic phenotypes in both human and mouse TBCK heterozygotes, we quantified if TBCK haploinsufficiency causes a phenotype in mice and humans. Using the tbck+/- mouse model, we performed a battery of behavioral assays and mTOR pathway analysis to investigate potential alterations in neurophysiology. We conducted as well a phenome-wide association study (PheWAS) analysis in a large adult biobank to determine the presence of potential phenotypes associated to this variant. The tbck+/- mouse model demonstrates a reduction of exploratory behavior in animals with significant sex and genotype interactions. The concurrent PheWAS analysis of 10,900 unrelated individuals showed that patients with one copy of a TBCK loss-of-function allele had a significantly higher rate of acquired toe and foot deformities, likely indicative of a mild peripheral neuropathy phenotype. This study presents an example of what may be the underappreciated occurrence of mild neurogenic symptoms in heterozygote individuals of recessive neurogenetic syndromes.

Low frequency ambient noise dynamics and trends in the Indian Ocean, Cape Leeuwin, Australia.

Examination of 18 years of nearly continuous low frequency deep ocean ambient noise offshore Cape Leeuwin, Australia, finds evidence of a decreasing nonlinear trend suggestive of long-term cyclic dynamics. The nonlinear trend is found to be consistent with trends in oceanographic sea surface temperature, which are thought to drive changes in Antarctic sea ice extent. Assessment of oscillatory dynamics finds causal covariance between ambient noise levels and Indian Ocean sea surface temperature dipoles. Dynamics of annual ambient noise and Antarctic sea ice extent are examined suggesting a phase-locked relationship revealing nonlinear characteristics of the presumed dependence. Collectively, the hypotheses that deep water ambient noise dynamics in the Indian Ocean are influenced by Antarctic sea ice extent and melt dynamics and that linear models do not fully capture long-term ambient noise trends and dynamics are supported.

Utilization of Noncontrast Magnetic Resonance Lymphangiography for Selection of Effective Surgical Method in Breast Cancer-Related Lymphedema.

Background and Objectives: When considering surgery for patients with breast cancer-related lymphedema (BCRL), it is crucial to determine which surgery will be most effective for the patient and establish the indications for each surgery. Our study retrospectively compared the results of preoperative noncontrast MR lymphangiography (NMRL) performed on the lymphedematous limb of patients before surgery, with the aim of analyzing whether preoperative NMRL can be used as a criterion for determining the type of surgery. Materials and Methods: From January 2020 to June 2022, a total of 138 patients with lymphedema underwent surgery at Seoul National University Bundang Hospital. All patients underwent preoperative NMRL imaging and were classified into stages 1-3 based on the MRI severity index using the authors' previous reference. Three types of surgery, LVA, LVA + liposuction, and LVA + VLNT, were conducted on all patients. The effectiveness of the surgery was evaluated one year postoperatively using the interlimb volume difference before and after surgery, the fluid volume of the edematous limb measured by bioimpedance spectroscopy, and the subjective satisfaction of the patients through the Lymph Q questionnaire. Results: In this study, out of a total of 138 patients, 26 (19%) were MRI stage 1, 62 (45%) were stage 2, and 50 (36%) were stage 3. Of the 83 patients who underwent LVA surgery, the greatest decrease in interlimb volume difference was observed in stage 2 patients, and subjective satisfaction was also the most effective in stage 2. In the case of LVA + liposuction patients, a significant volume decrease and a high satisfaction were observed in stage 3 patients. In the case of LVA + VLNT patients, there was no difference in volume decrease according to the stage, but a greater decrease in body fluid volume was observed as the MRI severity index score increased through BIA. Conclusions: In conclusion, this study demonstrates that NMRL imaging is a useful modality for determining the most effective surgical method and predicting the surgical outcome in patients with lymphedema. This highlights the importance of using NMRL in the treatment planning of lymphedema patients.

Sotorasib for previously treated colorectal cancers with KRASG12C mutation (CodeBreaK100): a prespecified analysis of a single-arm, phase 2 trial.

BACKGROUND: Sotorasib, a specific, irreversible KRASG12C protein inhibitor, has shown monotherapy clinical activity in KRASG12C-mutated solid tumours, including colorectal cancer, in the CodeBreaK100 phase 1 trial. We aimed to investigate the activity and safety of sotorasib in phase 2 of the trial. METHODS: In this single-arm, phase 2 trial, adult patients with KRASG12C-mutated advanced solid tumours were enrolled, from 59 medical centres in 11 countries, if they were aged 18 years or older, had at least one measurable lesion according to the Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, and had an Eastern Cooperative Oncology Group performance status of 1 or lower. Only data for patients with colorectal cancer, enrolled at 33 medical centres in nine countries, are presented from this basket trial. To be enrolled, the patients had to have progressed after receiving fluoropyrimidine, oxaliplatin, and irinotecan treatment. These patients were administered 960 mg sotorasib orally once per day until disease progression, development of unacceptable side-effects, withdrawal of consent, or death. The primary endpoint was objective response (complete or partial response) as assessed by blinded independent central review. Response was evaluated in patients who received at least one dose of sotorasib and had at least one measurable lesion at baseline; safety was evaluated in patients who received at least one dose of sotorasib. This analysis is a prespecified analysis triggered by the phase 2 colorectal cancer cohort. This study is registered with ClinicalTrials.gov, NCT03600883, and is active but no longer recruiting. FINDINGS: On March 1, 2021, at data cutoff, 62 patients with KRASG12C-mutant colorectal cancer had been enrolled between Aug 14, 2019, and May 21, 2020, and had received at least one dose of sotorasib monotherapy. Objective response was observed in six (9·7%, 95% CI 3·6-19·9) of 62 patients, all with partial response. Treatment-related adverse events at grade 3 occurred in six (10%) patients, the most common of which was diarrhoea (two [3%] of 62 patients), and at grade 4 occurred in one (2%) patient (blood creatine phosphokinase increase); no fatal events were recorded. Serious treatment-related adverse events occurred in two (3%) patients (back pain and acute kidney injury). INTERPRETATION: Although the 9·7% overall response rate did not reach the benchmark, oral administration of sotorasib once per day showed modest anti-tumour activity and manageable safety in these heavily pretreated chemorefractory patients. Sotorasib is under evaluation in combination with other therapeutics to increase potential activity and overcome potential resistance mechanisms. FUNDING: Amgen.

Association of prior local therapy and outcomes with programmed-death ligand-1 inhibitors in advanced urothelial cancer.

OBJECTIVES: To compare clinical outcomes with programmed-death ligand-1 immune checkpoint inhibitors (ICIs) in patients with advanced urothelial carcinoma (aUC) who have vs have not undergone radical surgery (RS) or radiation therapy (RT) prior to developing metastatic disease. PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment and outcomes data for patients with aUC receiving ICIs across 25 institutions. We compared outcomes (observed response rate [ORR], progression-free survival [PFS], overall survival [OS]) between patients with vs without prior RS, and by type of prior locoregional treatment (RS vs RT vs no locoregional treatment). Patients with de novo advanced disease were excluded. Analysis was stratified by treatment line (first-line and second-line or greater [second-plus line]). Logistic regression was used to compare ORR, while Kaplan-Meier analysis and Cox regression were used for PFS and OS. Multivariable models were adjusted for known prognostic factors. RESULTS: We included 562 patients (first-line: 342 and second-plus line: 220). There was no difference in outcomes based on prior locoregional treatment among those treated with first-line ICIs. In the second-plus-line setting, prior RS was associated with higher ORR (adjusted odds ratio 2.61, 95% confidence interval [CI]1.19-5.74]), longer OS (adjusted hazard ratio [aHR] 0.61, 95% CI 0.42-0.88) and PFS (aHR 0.63, 95% CI 0.45-0.89) vs no prior RS. This association remained significant when type of prior locoregional treatment (RS and RT) was modelled separately. CONCLUSION: Prior RS before developing advanced disease was associated with better outcomes in patients with aUC treated with ICIs in the second-plus-line but not in the first-line setting. While further validation is needed, our findings could have implications for prognostic estimates in clinical discussions and benchmarking for clinical trials. Limitations include the study's retrospective nature, lack of randomization, and possible selection and confounding biases.

Long-Term Effect of Intermediate Rhinoplasty in Unilateral Complete Cleft Lip Nasal Deformity.

BACKGROUND: Intermediate rhinoplasties are performed during preschool to reduce the patients' psychosocial burden. At our institution, limited dissection of the cartilages followed by suspension and interdomal sutures was performed through an alar rim incision on the cleft side to minimize the risk of iatrogenic nasal growth restriction. However, the long-term outcomes of "limited intermediate rhinoplasty" through skeletal growth are uncertain. MATERIALS AND METHODS: A retrospective review of all unilateral complete cleft lip and/or palate patients who underwent definitive rhinoplasty was performed. To avoid the confounding effect of primary rhinoplasty, only the patients who did not receive primary rhinoplasty were included in the analysis. The maneuvers performed during definitive rhinoplasty were analyzed and compared between patients who underwent intermediate rhinoplasty and those who did not. RESULTS: A total of 60 Korean patients (27 female and 33 male) underwent definitive rhinoplasty at the average age of 20.6 years old (17.1-25.5). Forty-three (71.6%) patients previously underwent intermediate rhinoplasty. A combination of 6 maneuvers was performed based on the deformity of each subunit (alar medialization, interdomal with suspension sutures, nostril sill depression correction, septoplasty, osteotomy, and hump rasping). The average number of maneuvers performed during definitive rhinoplasty was significantly higher in the intermediate group (3.31 versus 2.1, P=0.012). Alar medialization and nostril sill depression correction were more frequently performed in the intermediate group, while the frequencies of other maneuvers were not statistically different. CONCLUSION: While intermediate rhinoplasty improves the patients' psychosocial well-being, the effects of "limited intermediate rhinoplasty" manipulating only the cartilages do not seem to last until skeletal maturity. A more comprehensive dissection allowing the release of the lower lateral cartilage in the hinge area along with septoplasty may be more effective in providing longer-lasting effects.

The Safety of Operating on Breasts With a History of Prior Reduction Mammoplasty: Dynamic Magnetic Resonance Imaging Analysis of Angiogenesis.

BACKGROUND: The vascularity of the nipple-areolar complex (NAC) is altered after reduction mammoplasty, increasing the risk of complications after repeat reduction or nipple-sparing mastectomy. OBJECTIVES: The aim of this study was to evaluate angiogenesis of the NAC via serial analysis of magnetic resonance images. METHODS: Magnetic resonance images of breasts after reduction mammoplasty were analyzed for 35 patients (39 breasts) from 3-dimensional reconstructions of maximum-intensity projection images. All veins terminating at the NAC were classified as internal mammary, anterior intercostal, or lateral thoracic in origin. The vein with the largest diameter was considered the dominant vein. Images were classified based on the time since reduction: <6 months, 6 to 12 months, 12 to 24 months, >2 years. RESULTS: The average number of veins increased over time: 1.17 (<6 months), 1.56 (6-12 months), 1.64 (12-24 months), 1.73 (>2 years). Within 6 months, the pedicle was the only vein. Veins from other sources began to appear at 6 to 12 months. In most patients, at least 2 veins were available after 1 year. After 1 year, the internal mammary vein was the most common dominant vein regardless of the pedicle used. CONCLUSIONS: Repeat reduction mammoplasty or nipple-sparing mastectomy should be performed ≥1 year following the initial procedure. After 1 year, the superior or superomedial pedicle may represent the safest option when the previous pedicle is unknown.

Perioperative Opioid Analgesics and Hallux Valgus Correction Surgery: Trends, Risk Factors for Prolonged Use and Complications.

In the setting of an opioid epidemic, this study aims to provide evidence on opioid use trends, risk factors for prolonged use, and complications from perioperative opioid consumption in hallux valgus surgery. A national database was queried for patients who underwent hallux valgus correction. Regression analysis identified: (1) risk factors for prolonged postoperative narcotic use; and (2) association between preoperative/prolonged postoperative narcotic use and postoperative complications. A linear regression analysis was used to determine trends. About 20,749 patients were included, of which 3464 patients were prescribed narcotics preoperatively and 4339 were identified as prolonged postoperative narcotic prescription users. Preoperative prescriptions were identified as risk factors for prolonged use. Perioperative narcotic use was observed to be a risk factor for poor outcomes. About 21% of patients were identified as prolonged postoperative narcotic prescription users. Patients undergoing hallux valgus corrective surgery should be counseled regarding their increased risk of complications when using narcotics.

Genome-first approach to rare EYA4 variants and cardio-auditory phenotypes in adults.

While newborns and children with hearing loss are routinely offered genetic testing, adults are rarely clinically tested for a genetic etiology. One clinically actionable result from genetic testing in children is the discovery of variants in syndromic hearing loss genes. EYA4 is a known hearing loss gene which is also involved in important pathways in cardiac tissue. The pleiotropic effects of rare EYA4 variants are poorly understood and their prevalence in a large cohort has not been previously reported. We investigated cardio-auditory phenotypes in 11,451 individuals in a large biobank using a rare variant, genome-first approach to EYA4. We filtered 256 EYA4 variants carried by 6737 participants to 26 rare and predicted deleterious variants carried by 42 heterozygotes. We aggregated predicted deleterious EYA4 gene variants into a combined variable (i.e. "gene burden") and performed association studies across phenotypes compared to wildtype controls. We validated findings with replication in three independent cohorts and human tissue expression data. EYA4 gene burden was significantly associated with audiometric-proven HL (p = [Formula: see text], Mobitz Type II AV block (p = [Formula: see text]) and the syndromic presentation of HL and primary cardiomyopathy (p = 0.0194). Analyses on audiogram, echocardiogram, and electrocardiogram data validated these associations. Prior reports have focused on identifying variants in families with severe or syndromic phenotypes. In contrast, we found, using a genotype-first approach, that gene burden in EYA4 is associated with more subtle cardio-auditory phenotypes in an adult medical biobank population, including cardiac conduction disorders which have not been previously reported. We show the value of using a focused approach to uncover human disease related to pleiotropic gene variants and suggest a role for genetic testing in adults presenting with hearing loss.

A streptococcal Fic domain-containing protein disrupts blood-brain barrier integrity by activating moesin in endothelial cells.

Streptococcus equi subsp. zooepidemicus (SEZ) is a zoonotic pathogen capable of causing meningitis in humans. The mechanisms that enable pathogens to traverse the blood-brain barrier (BBB) are incompletely understood. Here, we investigated the role of a newly identified Fic domain-containing protein, BifA, in SEZ virulence. BifA was required for SEZ to cross the BBB and to cause meningitis in mice. BifA also enhanced SEZ translocation across human Brain Microvascular Endothelial Cell (hBMEC) monolayers. Purified BifA or its Fic domain-containing C-terminus alone were able to enter into hBMECs, leading to disruption of monolayer barrier integrity. A SILAC-based proteomic screen revealed that BifA binds moesin. BifA's Fic domain was required for its binding to this regulator of host cell cytoskeletal processes. BifA treatment of hBMECs led to moesin phosphorylation and downstream RhoA activation. Inhibition of moesin activation or moesin depletion in hBMEC monolayers abrogated BifA-mediated increases in barrier permeability and SEZ's capacity to translocate across monolayers. Thus, BifA activation of moesin appears to constitute a key mechanism by which SEZ disrupts endothelial monolayer integrity to penetrate the BBB.

Immune checkpoint inhibitors in advanced upper and lower tract urothelial carcinoma: a comparison of outcomes.

OBJECTIVES: To compare clinical outcomes between patients with locally advanced (unresectable) or metastatic urothelial carcinoma (aUC) in the upper and lower urinary tract receiving immune checkpoint inhibitors (ICIs). PATIENTS AND METHODS: We performed a retrospective cohort study collecting clinicopathological, treatment, and outcome data for patients with aUC receiving ICIs from 2013 to 2020 across 24 institutions. We compared the objective response rate (ORR), overall survival (OS), and progression-free survival (PFS) between patients with upper and lower tract UC (UTUC, LTUC). Uni- and multivariable logistic and Cox regression were used to assess the effect of UTUC on ORR, OS, and PFS. Subgroup analyses were performed stratified based on histology (pure, mixed) and line of treatment (first line, subsequent line). RESULTS: Out of a total of 746 eligible patients, 707, 717, and 738 were included in the ORR, OS, and PFS analyses, respectively. Our results did not contradict the hypothesis that patients with UTUC and LTUC had similar ORRs (24% vs 28%; adjusted odds ratio [aOR] 0.73, 95% confidence interval [CI] 0.43-1.24), OS (median 9.8 vs 9.6 months; adjusted hazard ratio [aHR] 0.93, 95% CI 0.73-1.19), and PFS (median 4.3 vs 4.1 months; aHR 1.01, 95% CI 0.81-1.27). Patients with mixed-histology UTUC had a significantly lower ORR and shorter PFS vs mixed-histology LTUC (aOR 0.20, 95% CI 0.05-0.91 and aHR 1.66, 95% CI 1.06-2.59), respectively). CONCLUSION: Overall, patients with UTUC and LTUC receiving ICIs have comparable treatment response and outcomes. Subgroup analyses based on histology showed that those with mixed-histology UTUC had a lower ORR and shorter PFS compared to mixed-histology LTUC. Further studies and evaluation of molecular biomarkers can help refine patient selection for immunotherapy.

The incidence of thrombocytopenia in adult patients receiving chemotherapy for solid tumors or hematologic malignancies.

OBJECTIVES: To estimate the risk of thrombocytopenia in various cancers and chemotherapy regimens. METHODS: Structured patient-level data from the Flatiron Health Electronic Health Record database were used to identify adult patients who received chemotherapy for a solid tumor or hematologic malignancy from 2012 to 2017. Three-month cumulative incidence of thrombocytopenia was assessed based on platelet counts, overall and by grade of thrombocytopenia. Co-occurrence of anemia, neutropenia, and leukopenia was evaluated. RESULTS: Of 15,521 patients with solid tumors, 13% had thrombocytopenia within 3 months (platelet count < 100 × 109 /L); 4% had grade 3 (25 to < 50 × 109 /L), and 2% grade 4 (<25 × 109 /L) thrombocytopenia. Of 2537 patients with hematologic malignancies, 28% had any thrombocytopenia, 16% with grade 3, and 12% with grade 4. Among patients with thrombocytopenia, it occurred without another cytopenia in 18% of solid tumors and 7% of hematologic malignancies. CONCLUSIONS: In a large, US-representative sample of patients undergoing chemotherapy in clinical practice, thrombocytopenia incidence varied across tumor and regimen types. Despite recommendations to alter chemotherapy to avoid severe thrombocytopenia, 4% of patients with solid tumors and 16% with hematologic malignancies experienced grade 3 thrombocytopenia. Prediction and prevention of thrombocytopenia may help oncologists avoid dose modifications and their adverse effects on survival.