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BackgroundIndividuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21.MethodsWe examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ40, Aβ42, tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ40, Aβ42, tau, ptau181, and NfL) and amyloid and tau PET data.FindingsFor both cohorts, the prevalence of mosaicism was

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs. This imbalance necessitates LMIC-focused research to ensure that characterization of dementia accurately reflects the involvement and specificities of diverse populations. Development of effective preventive, diagnostic, and therapeutic approaches for dementia in LMICs requires targeted, personalized, and harmonized efforts. Our article represents timely discussions at the 2022 Symposium on Dementia and Brain Aging in LMICs that identified the foremost opportunities to advance dementia research, differential diagnosis, use of neuropsychometric tools, awareness, and treatment options. We highlight key topics discussed at the meeting and provide future recommendations to foster a more equitable landscape for dementia prevention, diagnosis, care, policy, and management in LMICs. HIGHLIGHTS: Two-thirds of persons with dementia live in LMICs, yet research and costs are skewed toward HICs. LMICs expect dementia prevalence to more than double, accompanied by socioeconomic disparities. The 2022 Symposium on Dementia in LMICs addressed advances in research, diagnosis, prevention, and policy. The Nairobi Declaration urges global action to enhance dementia outcomes in LMICs.

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

IntroductionPeople with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers could be used to track the early stages of AD in DS or to inform inclusion criteria for clinical AD treatment trials.MethodsThis large cross-sectional cohort study investigated the associations between plasma biomarkers of amyloid beta (Aβ)42/40, total tau, and neurofilament light chain (NfL) and cognitive (episodic memory, visual-motor integration, and visuospatial abilities) and functional (adaptive behavior) impairments in 260 adults with DS without dementia (aged 25-81 years).ResultsIn general linear models lower plasma Aβ42/40 was related to lower visuospatial ability, higher total tau was related to lower episodic memory, and higher NfL was related to lower visuospatial ability and lower episodic memory.DiscussionPlasma biomarkers may have utility in tracking AD pathology associated with early stages of cognitive decline in adults with DS, although associations were modest.HighlightsPlasma Alzheimer's disease (AD) biomarkers correlate with cognition prior to dementia in Down syndrome.Lower plasma amyloid beta 42/40 was related to lower visuospatial abilities.Higher plasma total tau and neurofilament light chain were associated with lower cognitive performance.Plasma biomarkers show potential for tracking early stages of AD symptomology.

The chemokine CCL28 is highly expressed in mucosal tissues, but its role during infection is not well understood. Here, we show that CCL28 promotes neutrophil accumulation in the gut of mice infected with Salmonella and in the lung of mice infected with Acinetobacter. Neutrophils isolated from the infected mucosa expressed the CCL28 receptors CCR3 and, to a lesser extent, CCR10, on their surface. The functional consequences of CCL28 deficiency varied between the two infections: Ccl28-/- mice were highly susceptible to Salmonella gut infection but highly resistant to otherwise lethal Acinetobacter lung infection. In vitro, unstimulated neutrophils harbored pre-formed intracellular CCR3 that was rapidly mobilized to the cell surface following phagocytosis or inflammatory stimuli. Moreover, CCL28 stimulation enhanced neutrophil antimicrobial activity, production of reactive oxygen species, and formation of extracellular traps, all processes largely dependent on CCR3. Consistent with the different outcomes in the two infection models, neutrophil stimulation with CCL28 boosted the killing of Salmonella but not Acinetobacter. CCL28 thus plays a critical role in the immune response to mucosal pathogens by increasing neutrophil accumulation and activation, which can enhance pathogen clearance but also exacerbate disease depending on the mucosal site and the infectious agent.

The mammalian orthoreovirus (reovirus) σNS protein is required for formation of replication compartments that support viral genome replication and capsid assembly. Despite its functional importance, a mechanistic understanding of σNS is lacking. We conducted structural and biochemical analyses of a σNS mutant that forms dimers instead of the higher-order oligomers formed by wildtype (WT) σNS. The crystal structure shows that dimers interact with each other using N-terminal arms to form a helical assembly resembling WT σNS filaments in complex with RNA observed using cryo-EM. The interior of the helical assembly is of appropriate diameter to bind RNA. The helical assembly is disrupted by bile acids, which bind to the same site as the N-terminal arm. This finding suggests that the N-terminal arm functions in conferring context-dependent oligomeric states of σNS, which is supported by the structure of σNS lacking an N-terminal arm. We further observed that σNS has RNA chaperone activity likely essential for presenting mRNA to the viral polymerase for genome replication. This activity is reduced by bile acids and abolished by N-terminal arm deletion, suggesting that the activity requires formation of σNS oligomers. Our studies provide structural and mechanistic insights into the function of σNS in reovirus replication.

Acute high-altitude (HA) exposure can induce several pathologies. Dexamethasone (DEX) can be taken prophylactically to prevent HA disease, but the mechanism by which it acts in this setting is unclear. We studied the transcriptome of peripheral blood mononuclear cells (PBMCs) from 16 subjects at low altitude (LA, 225 m) and then 3 days after acute travel to HA (3500 m) during the India-Leh-Dexamethasone-Expedition-2020 (INDEX2020). Half of the participants received oral DEX prophylaxis 4 mg twice daily in an unblinded manner, starting 1 day prior to travel to HA, and 12 h prior to the first PBMC collection. PBMC transcriptome data were obtained from 16 subjects, half of whom received DEX. The principal component analysis demonstrated a clear separation of the groups by altitude and treatment. HA exposure resulted in a large number of gene expression changes, particularly in pathways of inflammation or the regulation of cell division, translation, or transcription. DEX prophylaxis resulted in changes in fewer genes, particularly in immune pathways. The gene sets modulated by HA and DEX were distinct. Deconvolution analysis to assess PBMC subpopulations suggested changes in B-cell, T-cell, dendritic cell, and myeloid cell numbers with HA and DEX exposures. Acute HA travel and DEX prophylaxis induce significant changes in the PBMC transcriptome. The observed benefit of DEX prophylaxis against HA disease may be mediated by suppression of inflammatory pathways and changing leukocyte population distributions.

Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for translational research. Using an impressive array of in vitro and in vivo preclinical HNSCC models, Smith and colleagues demonstrated the efficacy of alpelisib and tipifarnib combination therapy through sustained mTOR inhibition in PIK3CA/HRAS-dysregulated HNSCC, including preliminary evidence of robust antitumor activity in a patient enrolled in a precision medicine trial. This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers. See related article by Smith et al., p. 3252.

BackgroundPre-treatment biomarkers for outcome of repetitive Transcranial Magnetic Stimulation (rTMS) treatment of Major Depressive Disorder (MDD) have proven elusive. One promising family of biomarkers involves the autonomic nervous system (ANS), which is dysregulated in individuals with MDD.MethodsWe examined the relationship between the pre-treatment pupillary light reflex (PLR) and rTMS outcome in 51 MDD patients. Outcome was measured as the percent change in the 30-item Inventory of Depressive Symptomatology Self Rated (IDS-SR) score from baseline to treatment 30.ResultsPatients showed significant improvement with rTMS treatment. There was a significant correlation between baseline pupillary Constriction Amplitude (CA) and clinical improvement over the treatment course (R = 0.41, p = 0.003).LimitationsWe examined a limited number of subjects who received heterogeneous treatment protocols. Almost all patients in the study received psychotropic medications concomitant with rTMS treatment.ConclusionPLR measured before treatment may be a predictive biomarker for clinical improvement from rTMS in subjects with MDD.

The IMPACC cohort, composed of >1,000 hospitalized COVID-19 participants, contains five illness trajectory groups (TGs) during acute infection (first 28 days), ranging from milder (TG1-3) to more severe disease course (TG4) and death (TG5). Here, we report deep immunophenotyping, profiling of >15,000 longitudinal blood and nasal samples from 540 participants of the IMPACC cohort, using 14 distinct assays. These unbiased analyses identify cellular and molecular signatures present within 72 h of hospital admission that distinguish moderate from severe and fatal COVID-19 disease. Importantly, cellular and molecular states also distinguish participants with more severe disease that recover or stabilize within 28 days from those that progress to fatal outcomes (TG4 vs. TG5). Furthermore, our longitudinal design reveals that these biologic states display distinct temporal patterns associated with clinical outcomes. Characterizing host immune responses in relation to heterogeneity in disease course may inform clinical prognosis and opportunities for intervention.

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with "neoantigen-like" NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.

PurposeThe purpose of this systematic review was to summarize the available data on how surgical management of injuries to the thumb ulnar collateral ligament (UCL) complex affects athletes and their return-to-play (RTP) and postinjury performance metrics in addition to evaluating rehabilitation guidelines.MethodsA systematic search was performed on PubMed and Embase databases for articles on outcomes of surgical treatment of thumb UCL injuries in athletes. Articles with expert recommendations on postoperative management and RTP guidelines were also included separately. Study characteristics were recorded, including sport, RTP rates, and data on performance. Recommendations were summarized by sport. The Methodological Index for Non-Randomized Studies (MINORS) criteria was used to assess methodological quality. The authors also present their recommended return-to-sport algorithm.ResultsTwenty-three articles were included, including 11 with reports on patients and 12 expert opinions on guiding RTP. The mean MINORS score for the applicable studies was 9.4. In the 311 patients included, RTP was 98.1% in aggregate. No performance detriments were noted in athletes after surgery. Thirty-two (10.3%) patients had postoperative complications. The recommendations on timing to RTP vary by sport and author, but all recommended initial thumb protection when returning to sport. Newer techniques, such as suture tape augmentation, suggest the permission for earlier motion.ConclusionsReturn-to-play rates after surgical treatment of thumb UCL injuries are high, with reassuring return to preinjury level of play with few complications. Recommendations for surgical technique have trended toward suture anchors and, now, suture tape augmentation with earlier motion protocols, although rehabilitation guidelines vary by sport and author. Current information on thumb UCL surgery in athletes is limited by the low quality of evidence and expert recommendations.Type of study/level of evidencePrognostic IV.

BackgroundPulmonary hypertension (PH) can occur as a complication of schistosomiasis. In humans, schistosomiasis-PH persists despite antihelminthic therapy and parasite eradication. We hypothesized that persistent disease arises as a consequence of exposure repetition.MethodsFollowing intraperitoneal sensitization, mice were experimentally exposed to Schistosoma eggs by intravenous injection, either once or three times repeatedly. The phenotype was characterized by right heart catheterization and tissue analysis.ResultsFollowing intraperitoneal sensitization, a single intravenous Schistosoma egg exposure resulted in a PH phenotype that peaked at 7-14 days, followed by spontaneous resolution. Three sequential exposures resulted in a persistent PH phenotype. Inflammatory cytokines were not significantly different between mice exposed to one or three egg doses, but there was an increase in perivascular fibrosis in those who received three egg doses. Significant perivascular fibrosis was also observed in autopsy specimens from patients who died of this condition.ConclusionsRepeatedly exposing mice to schistosomiasis causes a persistent PH phenotype, accompanied by perivascular fibrosis. Perivascular fibrosis may contribute to the persistent schistosomiasis-PH observed in humans with this disease.

BackgroundImportant insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down syndrome. We aimed to directly compare amyloid changes between these two groups of people.MethodsIn this cross-sectional study, we included participants (aged ≥25 years) with Down syndrome and sibling controls who had MRI and amyloid PET scans in the first data release (January, 2020) of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. We also included carriers of autosomal dominant Alzheimer's disease genetic mutations and non-carrier familial controls who were within a similar age range to ABC-DS participants (25-73 years) and had MRI and amyloid PET scans at the time of a data freeze (December, 2020) of the Dominantly Inherited Alzheimer Network (DIAN) study. Controls from the two studies were combined into a single group. All DIAN study participants had genetic testing to determine PSEN1, PSEN2, or APP mutation status. APOE genotype was determined from blood samples. CSF samples were collected in a subset of ABC-DS and DIAN participants and the ratio of amyloid β42 (Aβ42) to Aβ40 (Aβ42/40) was measured to evaluate its Spearman's correlation with amyloid PET. Global PET amyloid burden was compared with regards to cognitive status, APOE ɛ4 status, sex, age, and estimated years to symptom onset. We further analysed amyloid PET deposition by autosomal dominant mutation type. We also assessed regional patterns of amyloid accumulation by estimated number of years to symptom onset. Within a subset of participants the relationship between amyloid PET and CSF Aβ42/40 was evaluated.Findings192 individuals with Down syndrome and 33 sibling controls from the ABC-DS study and 265 carriers of autosomal dominant Alzheimer's disease mutations and 169 non-carrier familial controls from the DIAN study were included in our analyses. PET amyloid centiloid and CSF Aβ42/40 were negatively correlated in carriers of autosomal dominant Alzheimer's disease mutations (n=216; r=-0·565; p

Understanding the interplay between the inherent disorder and the correlated fluctuating-spin ground state is a key element in the search for quantum spin liquids. H3LiIr2O6 is considered to be a spin liquid that is proximate to the Kitaev-limit quantum spin liquid. Its ground state shows no magnetic order or spin freezing as expected for the spin liquid state. However, hydrogen zero-point motion and stacking faults are known to be present. The resulting bond disorder has been invoked to explain the existence of unexpected low-energy spin excitations, although data interpretation remains challenging. Here, we use resonant X-ray spectroscopies to map the collective excitations in H3LiIr2O6 and characterize its magnetic state. In the low-temperature correlated state, we reveal a broad bandwidth of magnetic excitations. The central energy and the high-energy tail of the continuum are consistent with expectations for dominant ferromagnetic Kitaev interactions between dynamically fluctuating spins. Furthermore, the absence of a momentum dependence to these excitations are consistent with disorder-induced broken translational invariance. Our low-energy data and the energy and width of the crystal field excitations support an interpretation of H3LiIr2O6 as a disordered topological spin liquid in close proximity to bond-disordered versions of the Kitaev quantum spin liquid.

There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.

BackgroundUreteral obstruction after percutaneous nephrolithotomy (PCNL) may require prolonged drainage with a nephrostomy tube (NT) or ureteral stent, but it is not well understood how and why this occurs. The goal of this study was to identify risk factors associated with postoperative ureteral obstruction to help guide drainage tube selection.MethodsProspective data from adult patients enrolled in the Registry for Stones of the Kidney and Ureter (ReSKU) who underwent PCNL from 2016 to 2020 were used. Patients who had postoperative NTs with antegrade imaging-based flow assessment on postoperative day one (POD1) were included. Patients with transplanted kidneys or those without appropriate preoperative imaging were excluded. We assessed the association between patient demographics, stone characteristics, and intraoperative factors using POD1 antegrade flow, a proxy for ureteral patency, as the primary outcome. Stepwise selection was used to develop a multivariate logistic regression model controlling for BMI, stone location, stone burden, ipsilateral ureteroscopy (URS), access location, estimated blood loss, and operative time.ResultsWe analyzed 241 cases for this study; 204 (84.6%) had a visual clearance of stone. Antegrade flow on POD1 was absent in 76 cases (31.5%). A multivariate logistic regression model found that stones located anywhere other than in the renal pelvis (OR 2.63, 95% CI 1.29-5.53; p = 0.01), non-lower pole access (OR 2.81, 95% CI 1.42-5.74; p

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia-related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS. Participants from the Alzheimer's disease in Down syndrome (ADDS) study with magnetic resonance imaging (MRI) scans and blood biomarker data were included. Support vector machine (SVM) analyses examined the relationship of blood-based proteomic biomarkers with MRI-defined cerebrovascular disease among participants characterized as having cognitive decline (n = 36, mean age ± SD = 53 ± 6.2) and as being cognitively stable (n = 78, mean age = 49 ± 6.4). Inflammatory and AD markers were associated with cerebrovascular disease, particularly among symptomatic individuals. The pattern suggested relatively greater inflammatory involvement among cognitively stable individuals and greater AD involvement among those with cognitively decline. The findings help to generate hypotheses that both inflammatory and AD markers are implicated in cerebrovascular disease among those with DS and point to potential mechanistic pathways for further examination.

Public access to genetic information is increasing, and community dermatologists may progressively encounter patients interested in genetic testing for melanoma risk. Clarifying potential utility will help plan for this inevitability. We determined interest and uptake of genetic risk feedback based on melanocortin receptor gene (MC1R) variants, immediate (two weeks) responses to risk feedback, and test utility at three months in patients (age ≥ 18, with a history of nonmelanoma skin cancer). Participants (N = 50) completed a baseline survey and were invited to consider MC1R testing via the study website. Testing interest and uptake were assessed through registration of test decision, request of a saliva test kit, and kit return (all yes/no). Immediate responses to risk feedback included feedback-relevant thoughts, emotions, communication, and information seeking after result receipt; test utility outcomes included family and physician communication and information seeking. Results indicated good retention at both time points (76%; 74%). Half (48%) logged onto the study website, and of these, most (92%) chose testing and (95%) returned a saliva sample. After two weeks, most (94%) had read all the risk feedback information and distress was low (M = 8.81, 7-28, SD = 2.23). Many (69%) had talked with their family about the results. By three months, most had spoken with family (92%) and physicians (80%) about skin cancer risk. Physician communication was higher (70%) in those tested versus those not tested (40%, p = 0.02). The substantial interest and promising outcomes associated with MC1R genetic testing in dermatology patients inform intervention strategies to enhance benefits and minimize risks of skin cancer genetic testing.

AimThe Cass Clinic is a student-run free clinic in Detroit, Michigan that treats chronic diseases including hypertension (HTN), diabetes mellitus (DM), and obesity. Our study aims to quantify the effectiveness of our clinic in managing chronic diseases.Subject and methodsThis study assessed selected health outcomes for 137 patients who visited our clinic between September 1, 2017 and August 31, 2018 based on initial and most recent surrogate markers including manual blood pressure, hemoglobin A1c (HbA1c), and body mass index (BMI) recorded in the clinic's medical record system dating back to 2012.ResultsPatients were divided into two groups: occasionally seen patients (OSP) and frequently seen patients (FSP). FSP with HTN had systolic blood pressure (SBP) decreased by an average of 14.1 mmHg and diastolic blood pressure (DBP) decreased by 9.8 mmHg, which were statistically associated with the number of clinic visits. Additionally, all patients treated at Cass Clinic saw a decrease in their HbA1c and BMI. HbA1c in OSP decreased by 0.50%. HbA1c in the FSP decreased by 1.7%. Patients with at least two recorded BMIs (n=73) saw a decrease of 0.13 kg/m2.ConclusionThe data from our analysis support that a student-run free clinic model like Cass Clinic provides long-term value for patients who frequently utilize the clinic. These clinics also act as an important resource for the community by making positive strides toward better health in multiple measurable outcomes, including HTN and DM management.

Right ventricular (RV) failure is the primary cause of death in pulmonary hypertension (PH), but the mechanisms of RV failure are not well understood. We hypothesized macrophages in the RV contribute to the RV response in PH. We induced PH in mice with hypoxia (FiO2 10%) and Schistosoma mansoni exposure, and in rats with SU5416-hypoxia. We quantified cardiac macrophages in mice using flow cytometry. Parabiosis between congenic CD45.1/.2 mice or Cx3cr1-green fluorescent protein and wild-type mice was used to quantify circulation-derived macrophages in experimental PH conditions. We administered clodronate liposomes to Sugen hypoxia (SU-Hx) exposed rats to deplete macrophages and evaluated the effect on the extracellular matrix (ECM) and capillary network in the RV. In hypoxia exposed mice, the overall number of macrophages did not significantly change but two macrophage subpopulations increased. Parabiosis identified populations of RV macrophages that at steady state is derived from the circulation, with one subpopulation that significantly increased with PH stimuli. Clodronate treatment of SU-Hx rats resulted in a change in the RV ECM, without altering the RV vasculature, and correlated with improved RV function. Populations of RV macrophages increase and contribute to RV remodeling in PH, including through regulation of the RV ECM.

Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH) worldwide, but the prevalence and risk factors for schistosomiasis-associated PAH (SchPAH) development are not well understood. Schistosomiasis-associated hepatosplenic disease (SchHSD) is thought to be a major risk factor for PAH development. Herein, we describe our plans for prospectively screening SchHSD subjects for clinical evidence of PAH at two major academic medical centers and national referral hospitals in Addis Ababa, Ethiopia and Lusaka, Zambia. The screening study will primarily be conducted by echocardiography, in addition to clinical assessments. Plasma samples will be drawn and banked for subsequent analysis based on preclinical animal model rationale. If successful, this study will demonstrate feasibility of conducting prospective cohort studies of SchPAH screening in schistosomiasis-endemic regions of Africa, and provide initial data on clinic-based disease prevalence and potential mechanistic biomarkers underlying disease pathogenesis.

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer's disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer's Disease in Down Syndrome (ADDS) study were included given available research MRI (n = 116; 50 ± 8 years; 42% women) and amyloid PET scans (n = 71; 50 ± 7 years; 39% women) at the time of analysis. Participants were characterized as cognitively stable (CS; 64%), with mild cognitive impairment-DS (MCI-DS; 23%), with possible AD dementia (5%), or with definite AD dementia (8%). OSA was determined via medical records and interviews. Models tested the effect of OSA on MRI-derived cerebrovascular biomarkers and PET-derived amyloid burden, and the moderating effect of OSA and AD diagnosis on biomarkers. OSA was reported in 39% of participants, which did not differ by clinical AD diagnostic group. OSA was not associated with cerebrovascular biomarkers but was associated with greater cortical amyloid burden. White matter hyperintensity (WMH) volume (primarily in the parietal lobe), enlarged perivascular spaces, and cortical and striatal amyloid burden were greater across clinical AD diagnostic groups (CS

Pulmonary arterial hypertension is an incurable disease marked by dysregulated metabolism, both at the cellular level in the pulmonary vasculature, and at the whole-body level characterized by impaired exercise oxygen consumption. Though both altered pulmonary vascular metabolism and abnormal exercise physiology are key markers of disease severity and pulmonary arterial remodeling, their precise interactions are relatively unknown. Herein we review normal pulmonary vascular physiology and the current understanding of pulmonary vascular cell metabolism and cardiopulmonary response to exercise in Pulmonary arterial hypertension. We additionally introduce a newly developed international collaborative effort aimed at quantifying exercise-induced changes in pulmonary vascular metabolism, which will inform about underlying pathophysiology and clinical management. We support our investigative approach by presenting preliminary data and discuss potential future applications of our research platform.

Treatment of obesity, an ongoing global epidemic, is challenging, as weight-loss efforts require a multidisciplinary approach addressing both behavioral and biologic needs that are not completely understood. Recent studies of the gut microbiome may provide better insight into the condition, and ultimately serve to advance more effective therapies. Research in this field has shifted from analyzing microbiome compositional differences to investigating functional changes that affect disease pathophysiology and outcome. Bacteria-derived metabolites are a way to bridge compositional changes to functional consequences. Through the production of metabolites, such as short chain fatty acids, tryptophan derivatives and bile acids, and interactions with peripheral and central signaling pathways, the gut microbiome may alter the body's metabolic and behavioral responses to food. Here, we summarize these mechanisms driven by gut-derived metabolites, through which the microbiome is thought to contribute to obesity, as well as review recent investigations of interventions related to these metabolites. Limitations of existing research, primarily due to paucity of causal studies in humans, are also discussed in this review.

High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.

ObjectiveThe purpose of this study was to evaluate the utility of ICD-O-3-classified local tumor behavior as a prognosticator of head and neck paraganglioma (HNP) outcomes.Study designRetrospective cohort study.SettingNational Cancer Database between 2004 and 2016.MethodsThis study included patients aged ≥18 years who were diagnosed with HNP. Clinical outcomes and clinicopathologic features were compared with regard to local tumor behavior.ResultsOur study included 525 patients, of which the majority had HNP classified as locally invasive (45.9%) or borderline (37.9%). The most common anatomic sites involved were the carotid body (33.7%), intracranial regions (29.0%), or cranial nerves (25.5%). Carotid body tumors were exclusively locally invasive, whereas intracranial and cranial nerve HNP were overwhelmingly benign or borderline (94% and 91%, respectively). One-fourth of patients underwent pathologic analysis of regional lymph nodes, of which the majority were positive for metastasis (80.6%). Metastasis to distant organs was twice as common in patients with locally invasive tumors vs benign (15% vs 7.1). For benign disease, surgery with radiotherapy (adjusted hazard ratio [aHR], 40.45; P = .006) and active surveillance (aHR, 24.23; P = .008) were associated with worse survival when compared with surgery alone. For locally invasive tumors, greater age (aHR, 1.07; P < .0001) and positive surgical margins (aHR, 4.13; P = .010) were predictors of worse survival, while combined surgery and radiotherapy were predictors of improved survival vs surgery alone (aHR, 0.31; P = .027).ConclusionWhile criteria for tumor behavior could not be defined, our results suggest that such a classification system could be used to enhance HNP risk stratification and guide clinical management decisions.

Pulmonary artery (PA) pressure increases during lung growth after unilateral pneumonectomy (PNX). Mechanosensitive transcriptional co-activator, yes-associated protein (YAP1), in endothelial cells (ECs) is necessary for angiogenesis during post-PNX lung growth. We investigate whether increases in PA pressure following PNX control-angiogenesis through YAP1. When hydrostatic pressure is applied to human pulmonary arterial ECs (HPAECs), the expression of YAP1, transcription factor TEAD1, and angiogenic factor receptor Tie2 increases, while these effects are inhibited when HPAECs are treated with YAP1 siRNA or YAP1S94A mutant that fails to bind to TEAD1. Hydrostatic pressure also stimulates DNA synthesis, cell migration, and EC sprouting in HPAECs, while YAP1 knockdown or YAP1S94A mutant inhibits the effects. Gene enrichment analysis reveals that the levels of genes involved in extracellular matrix (ECM), cell adhesion, regeneration, or angiogenesis are altered in post-PNX mouse lung ECs, which interact with YAP1. Exosomes are known to promote tissue regeneration. Proteomics analysis reveals that exosomes isolated from conditioned media of post-PNX mouse lung ECs contain the higher levels of ECM and cell-adhesion proteins compared to those from sham-operated mouse lung ECs. Recruitment of host lung ECs and blood vessel formation are stimulated in the fibrin gel containing exosomes isolated from post-PNX mouse lung ECs or pressurized ECs, while YAP1 knockdown inhibits the effects. These results suggest that increases in PA pressure stimulate angiogenesis through YAP1 during regenerative lung growth.

The COVID-19 pandemic sparked the civic mobilization of various communities of color, including Asian Americans. This chapter discusses the corresponding role of Asian American Native American and Pacific Islander Serving Institutions (AANAPISIs) within this context, serving as critical sites in cultivating Asian American students’ civic engagement toward social justice agendas. Educational research, scholarship, and personal reflections of practitioners are integrated throughout the chapter to discuss how AANAPISIs at Sacramento State and Coastline College fulfill this call by providing culturally relevant and community responsive programs and practices influenced by an ethnic studies framework.

BackgroundSchistosomiasis, a major cause of pulmonary arterial hypertension (PAH) worldwide, is most clearly described complicating infection by one species, Schistosoma mansoni. Controlled exposure of mice can be used to induce Type 2 inflammation-dependent S. mansoni pulmonary hypertension (PH). We sought to determine if another common species, S. japonicum, can also cause experimental PH.MethodsSchistosome eggs were obtained from infected mice, and administered by intraperitoneal sensitization followed by intravenous challenge to experimental mice, which underwent right heart catheterization and tissue analysis.ResultsS. japonicum sensitized and challenged mice developed PH, which was milder than that following S. mansoni sensitization and challenge. The degree of pulmonary vascular remodeling and Type 2 inflammation in the lungs was similarly proportionate. Cross-sensitization revealed that antigens from either species are sufficient to sensitize for intravenous challenge with either egg, and the degree of PH severity depended on primarily the species used for intravenous challenge. Compared to a relatively uniform distribution of S. mansoni eggs, S. japonicum eggs were observed in clusters in the lungs.ConclusionsS. japonicum can induce experimental PH, which is milder than that resulting from comparable S. mansoni exposure. This difference may result from the distribution of eggs in the lungs, and is independent of which species is used for sensitization. This result is consistent with the clearer association between S. mansoni infection and the development of schistosomiasis-associated PAH in humans.

Radiologists in training draw from their early experiences in residency when choosing a fellowship. Once they have decided on an abdominal imaging fellowship, applicants must learn to navigate the interview process. During this challenging time, applicants explore the difference in clinical curricula and rotations, meet potential mentors and clinical faculty, consider potential academic interests and projects, and choose what location they would like to train for one year after residency. When in training, fellows undergo the challenge of finding employment while learning new skills and refining their abilities to become a well-rounded radiologist and clinician. This article summarizes key points potential applicants should consider when deciding on an abdominal imaging fellowship, how to prepare for the interview season, and how to plan their fellowship year before fellows take the next step to becoming attendings.

Stomatal pores close rapidly in response to low-air-humidity-induced leaf-to-air vapor pressure difference (VPD) increases, thereby reducing excessive water loss. The hydroactive signal-transduction mechanisms mediating high VPD-induced stomatal closure remain largely unknown. The kinetics of stomatal high-VPD responses were investigated by using time-resolved gas-exchange analyses of higher-order mutants in guard-cell signal-transduction branches. We show that the slow-type anion channel SLAC1 plays a relatively more substantial role than the rapid-type anion channel ALMT12/QUAC1 in stomatal VPD signaling. VPD-induced stomatal closure is not affected in mpk12/mpk4GC double mutants that completely disrupt stomatal CO2 signaling, indicating that VPD signaling is independent of the early CO2 signal-transduction pathway. Calcium imaging shows that osmotic stress causes cytoplasmic Ca2+ transients in guard cells. Nevertheless, osca1-2/1.3/2.2/2.3/3.1 Ca2+-permeable channel quintuple, osca1.3/1.7-channel double, cngc5/6-channel double, cngc20-channel single, cngc19/20crispr-channel double, glr3.2/3.3-channel double, cpk-kinase quintuple, cbl1/4/5/8/9 quintuple, and cbl2/3rf double mutants showed wild-type-like stomatal VPD responses. A B3-family Raf-like mitogen-activated protein (MAP)-kinase kinase kinase, M3Kδ5/RAF6, activates the OST1/SnRK2.6 kinase in plant cells. Interestingly, B3 Raf-kinase m3kδ5 and m3kδ1/δ5/δ6/δ7 (raf3/6/5/4) quadruple mutants, but not a 14-gene raf-kinase mutant including osmotic stress-linked B4-family Raf-kinases, exhibited slowed high-VPD responses, suggesting that B3-family Raf-kinases play an important role in stomatal VPD signaling. Moreover, high VPD-induced stomatal closure was impaired in receptor-like pseudokinase GUARD CELL HYDROGEN PEROXIDE-RESISTANT1 (GHR1) mutant alleles. Notably, the classical transient "wrong-way" VPD response was absent in ghr1 mutant alleles. These findings reveal genes and signaling mechanisms in the elusive high VPD-induced stomatal closing response pathway.

Variability in SARS-CoV-2 susceptibility and COVID-19 disease severity between individuals is partly due to genetic factors. Here, we identify 4 genomic loci with suggestive associations for SARS-CoV-2 susceptibility and 19 for COVID-19 disease severity. Four of these 23 loci likely have an ethnicity-specific component. Genome-wide association study (GWAS) signals in 11 loci colocalize with expression quantitative trait loci (eQTLs) associated with the expression of 20 genes in 62 tissues/cell types (range: 1:43 tissues/gene), including lung, brain, heart, muscle, and skin as well as the digestive system and immune system. We perform genetic fine mapping to compute 99% credible SNP sets, which identify 10 GWAS loci that have eight or fewer SNPs in the credible set, including three loci with one single likely causal SNP. Our study suggests that the diverse symptoms and disease severity of COVID-19 observed between individuals is associated with variants across the genome, affecting gene expression levels in a wide variety of tissue types.

The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse-phase protein array molecular profiles from patient-derived xenograft (PDX) tumors and revealed 2 PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors according to cetuximab response with 88% accuracy. Next, a support vector machine classifier algorithm identified a minimalist biomarker signature consisting of 8 proteins - caveolin-1, Sox-2, AXL, STING, Brd4, claudin-7, connexin-43, and fibronectin - with expression that strongly predicted cetuximab response in PDXs using either protein or mRNA. A combination of caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in tumor samples from patients with HNSCC with known clinical response to cetuximab. These results support further investigation into the combined use of caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.

Fanconi anemia, the most frequent genetic cause of bone marrow failure, is characterized by an extreme predilection toward multiple malignancies, including a greater than 500-fold incidence of head and neck squamous cell carcinoma (HNSCC) relative to the general population. Fanconi anemia-associated HNSCC and esophageal SCC (FA-HNSCC) often present at advanced stages with poor survival. Surgical resection remains the primary treatment for FA-HNSCC, and there is often great reluctance to administer systemic agents and/or radiotherapy to these patients given their susceptibility to DNA damage. The paucity of FA-HNSCC case reports limits evidence-based management, and such cases have not been analyzed collectively in detail. We present a systematic review of FA-HNSCC treatments reported from 1966 to 2020, defining a cohort of 119 patients with FA-HNSCC including 16 esophageal SCCs (131 total primary tumors), who were treated with surgery, radiotherapy, systemic therapy (including cytotoxic agents, EGFR inhibitors, or immune checkpoint inhibitors), or a combination of modalities. We summarize the clinical responses and regimen-associated toxicities by treatment modality. The collective evidence suggests that when possible, surgical resection with curative intent should remain the primary treatment modality for FA-HNSCC. Radiation can be administered with acceptable toxicity in the majority of cases, including patients who have undergone stem cell transplantation. Although there is little justification for cytotoxic chemotherapy, EGFR inhibitors and tyrosine kinase inhibitors may be both safe and effective. Immunotherapy may also be considered. Most oncologists have little personal experience with FA-HNSCC. This review is intended as a comprehensive resource for clinicians.

The epidermal growth factor receptor (EGFR) inhibitor cetuximab is the only FDA-approved oncogene-targeting therapy for head and neck squamous cell carcinoma (HNSCC). Despite variable treatment response, no biomarkers exist to stratify patients for cetuximab therapy in HNSCC. Here, we applied unbiased hierarchical clustering to reverse phase protein array (RPPA) molecular profiles from patient-derived xenograft (PDX) tumors, which revealed two PDX clusters defined by protein networks associated with EGFR inhibitor resistance. In vivo validation revealed unbiased clustering to classify PDX tumors with 88% accuracy. Next, a support vector machine (SVM) classifier algorithm identified a minimalist biomarker signature consisting of eight proteins - Caveolin-1, Sox-2, AXL, STING, Brd4, Claudin-7, Connexin-43, and Fibronectin - whose expression strongly predicted cetuximab response in PDXs using either protein (AUC=0.95) or mRNA (AUC=0.97). A combination of Caveolin-1 and Sox-2 protein levels was sufficient to maintain high predictive accuracy, which we validated in HNSCC patient tumor samples with known clinical response to cetuximab. These results support further investigation into the combined use of Caveolin-1 and Sox-2 as predictive biomarkers for cetuximab response in the clinic.

BackgroundCompliance to periodontal maintenance therapy (PMT) is essential for long-term periodontal health. Between PMT visits, patients must maintain good oral hygiene. A dentifrice with demonstrable clinical benefits for use between PMT visits would be highly desirable. The aim of this clinical study was to investigate the effect of a novel dental gel on probing depths (PD) and inflammation when used as a home care dentifrice in Stage I and II periodontitis patients.MethodsThis double-blind clinical study randomized 65 subjects with Stage I and II periodontitis to the novel dental gel containing 2.6% EDTA, and a commercially available anti-gingivitis dentifrice with 0.454% stannous fluoride. Primary endpoint was PD at 6 months for those sites with baseline PD ≥ 4 mm and secondary endpoints included whole mouth mean scores of modified gingival index (MGI), modified sulcus bleeding index (mSBI) and plaque index (PI). No SRP was performed at baseline.ResultsSubjects using the novel dentifrice showed significant PD reductions of 1.18 mm (from 4.27 mm at baseline to 3.09 mm at 6 months) compared to 0.93 mm (from 4.23 mm at baseline to 3.30 mm at 6 months) shown for those using the positive control dentifrice. Difference between treatments at 6 months was 0.21 mm with P-value = 0.0126. Significant improvements in MGI (P = 0.0000), mSBI (P = 0.0000), and PI (P = 0.0102) were also observed in 6 months.ConclusionThe novel dentifrice showed significant reductions in PD and gingival inflammation over 6 months solely as a home care dentifrice without baseline SRP in Stage I and II periodontitis maintenance patients.

BackgroundCompliance to periodontal maintenance therapy (PMT) is essential for long-term periodontal health. Between PMT visits, patients must maintain good oral hygiene. A dentifrice with demonstrable clinical benefits for use between PMT visits would be highly desirable. The aim of this clinical study was to investigate the effect of a novel dental gel on probing depths (PD) and inflammation when used as a home care dentifrice in Stage I and II periodontitis patients.MethodsThis double-blind clinical study randomized 65 subjects with Stage I and II periodontitis to the novel dental gel containing 2.6% EDTA, and a commercially available anti-gingivitis dentifrice with 0.454% stannous fluoride. Primary endpoint was PD at 6 months for those sites with baseline PD ≥ 4 mm and secondary endpoints included whole mouth mean scores of modified gingival index (MGI), modified sulcus bleeding index (mSBI) and plaque index (PI). No SRP was performed at baseline.ResultsSubjects using the novel dentifrice showed significant PD reductions of 1.18 mm (from 4.27 mm at baseline to 3.09 mm at 6 months) compared to 0.93 mm (from 4.23 mm at baseline to 3.30 mm at 6 months) shown for those using the positive control dentifrice. Difference between treatments at 6 months was 0.21 mm with P-value = 0.0126. Significant improvements in MGI (P = 0.0000), mSBI (P = 0.0000), and PI (P = 0.0102) were also observed in 6 months.ConclusionThe novel dentifrice showed significant reductions in PD and gingival inflammation over 6 months solely as a home care dentifrice without baseline SRP in Stage I and II periodontitis maintenance patients.

BackgroundWomen with rare diseases, such as osteogenesis imperfecta, may consider pregnancy, although data regarding outcomes, specific risks, and management strategies are lacking.ObjectiveThe Brittle Bone Disorders Consortium of the National Institute of Health Rare Diseases Clinical Research Network established an Osteogenesis Imperfecta Pregnancy Registry to collect and evaluate pregnancy, maternal, and neonatal outcomes in women with osteogenesis imperfecta.Study designThis was a cross-sectional, survey-based study. Appropriate participants of the Brittle Bone Disorders Consortium Contact Registry were invited to participate in the study. Self-reported information regarding pregnancy characteristics and maternal and neonatal outcomes of women with osteogenesis imperfecta was compared with that of the general population, referenced by literature-based standards. Furthermore, compared with the general population, cohorts of women and fetuses with osteogenesis imperfecta were evaluated to determine whether the presence of osteogenesis imperfecta conveyed an increase in antepartum, intrapartum, and postpartum complications and an increase in adverse neonatal outcomes.ResultsHere, a total 132 participants completed the survey. Compared with the general population, women with osteogenesis imperfecta had higher rates of diabetes in pregnancy (13.3% vs 7%; 95% confidence interval, 7.0-19.6; P=.049), cesarean delivery (68.5% vs 32.7%; 95% confidence interval, 59.9-77.1; P

Very little research has been conducted on the second (and third, and thereafter) owners of new technologies. For light duty vehicles, the research has been focused on the first owners. In the case of plug-in electric vehicles (PEVs), understanding the secondary market is especially important for many reasons, including the vehicle market development and on-road usage. The second owner is also an adopter of new technology, many times taking greater risk than the original owner by purchasing a vehicle close to, or after, the end of the warranty. Data on vehicle ownership at the zip code level was used to explore the total number of vehicles, the number of electric vehicles (EVs) owned by the original owner, and the number of EVs owned by a second or third owner. Results suggest that in areas with few EVs overall, used PEVs make up a higher share of all PEVs, but a lower share of all vehicles. Used PEVs are slightly less spatially concentrated than new ones, possibly because of a weaker neighborhood effect and possibly because their lower cost makes them accessible to slightly more people. The study finds that at least in this phase of the market development, used PEVs are not trickling down at a high rate, but more research is needed to evaluate the reasons for this phenomenon. Policies that focus on the progression of used PEVs to secondary owners by improving the information provided to used car buyers, reducing the risk of purchasing a new technology, improving the availability of charging, and addressing other barriers, can help communities with low rates of PEV adoption and improve the market growth in the future.View the NCST Project Webpage

BackgroundThe origin of sex differences in prevalence and presentation of neuropsychiatric and behavioral traits is largely unknown. Given established genetic contributions and correlations, we tested for a sex-differentiated genetic architecture within and between traits.MethodsUsing European ancestry genome-wide association summary statistics for 20 neuropsychiatric and behavioral traits, we tested for sex differences in single nucleotide polymorphism (SNP)-based heritability and genetic correlation (rg < 1). For each trait, we computed per-SNP z scores from sex-stratified regression coefficients and identified genes with sex-differentiated effects using a gene-based approach. We calculated correlation coefficients between z scores to test for shared sex-differentiated effects. Finally, we tested for sex differences in across-trait genetic correlations.ResultsWe observed no consistent sex differences in SNP-based heritability. Between-sex, within-trait genetic correlations were high, although

PurposeHigh-dimensional image features that underlie COVID-19 pneumonia remain opaque. We aim to compare feature engineering and deep learning methods to gain insights into the image features that drive CT-based for COVID-19 pneumonia prediction, and uncover CT image features significant for COVID-19 pneumonia from deep learning and radiomics framework.MethodsA total of 266 patients with COVID-19 and other viral pneumonia with clinical symptoms and CT signs similar to that of COVID-19 during the outbreak were retrospectively collected from three hospitals in China and the USA. All the pneumonia lesions on CT images were manually delineated by four radiologists. One hundred eighty-four patients (n = 93 COVID-19 positive; n = 91 COVID-19 negative; 24,216 pneumonia lesions from 12,001 CT image slices) from two hospitals from China served as discovery cohort for model development. Thirty-two patients (17 COVID-19 positive, 15 COVID-19 negative; 7883 pneumonia lesions from 3799 CT image slices) from a US hospital served as external validation cohort. A bi-directional adversarial network-based framework and PyRadiomics package were used to extract deep learning and radiomics features, respectively. Linear and Lasso classifiers were used to develop models predictive of COVID-19 versus non-COVID-19 viral pneumonia.Results120-dimensional deep learning image features and 120-dimensional radiomics features were extracted. Linear and Lasso classifiers identified 32 high-dimensional deep learning image features and 4 radiomics features associated with COVID-19 pneumonia diagnosis (P  73% and specificity > 75% on external validation cohort with slight superior performance for radiomics Lasso classifier. Human expert diagnostic performance improved (increase by 16.5% and 11.6% in sensitivity and specificity, respectively) when using a combined deep learning-radiomics model.ConclusionsWe uncover specific deep learning and radiomics features to add insight into interpretability of machine learning algorithms and compare deep learning and radiomics models for COVID-19 pneumonia that might serve to augment human diagnostic performance.

PurposeHigh-dimensional image features that underlie COVID-19 pneumonia remain opaque. We aim to compare feature engineering and deep learning methods to gain insights into the image features that drive CT-based for COVID-19 pneumonia prediction, and uncover CT image features significant for COVID-19 pneumonia from deep learning and radiomics framework.MethodsA total of 266 patients with COVID-19 and other viral pneumonia with clinical symptoms and CT signs similar to that of COVID-19 during the outbreak were retrospectively collected from three hospitals in China and the USA. All the pneumonia lesions on CT images were manually delineated by four radiologists. One hundred eighty-four patients (n = 93 COVID-19 positive; n = 91 COVID-19 negative; 24,216 pneumonia lesions from 12,001 CT image slices) from two hospitals from China served as discovery cohort for model development. Thirty-two patients (17 COVID-19 positive, 15 COVID-19 negative; 7883 pneumonia lesions from 3799 CT image slices) from a US hospital served as external validation cohort. A bi-directional adversarial network-based framework and PyRadiomics package were used to extract deep learning and radiomics features, respectively. Linear and Lasso classifiers were used to develop models predictive of COVID-19 versus non-COVID-19 viral pneumonia.Results120-dimensional deep learning image features and 120-dimensional radiomics features were extracted. Linear and Lasso classifiers identified 32 high-dimensional deep learning image features and 4 radiomics features associated with COVID-19 pneumonia diagnosis (P  73% and specificity > 75% on external validation cohort with slight superior performance for radiomics Lasso classifier. Human expert diagnostic performance improved (increase by 16.5% and 11.6% in sensitivity and specificity, respectively) when using a combined deep learning-radiomics model.ConclusionsWe uncover specific deep learning and radiomics features to add insight into interpretability of machine learning algorithms and compare deep learning and radiomics models for COVID-19 pneumonia that might serve to augment human diagnostic performance.

Wide-scale SARS-CoV-2 genome sequencing is critical to tracking viral evolution during the ongoing pandemic. Variants first detected in the United Kingdom, South Africa, and Brazil have spread to multiple countries. We developed the software tool, Variant Database (VDB), for quickly examining the changing landscape of spike mutations. Using VDB, we detected an emerging lineage of SARS-CoV-2 in the New York region that shares mutations with previously reported variants. The most common sets of spike mutations in this lineage (now designated as B.1.526) are L5F, T95I, D253G, E484K or S477N, D614G, and A701V. This lineage was first sequenced in late November 2020 when it represented

BACKGROUND: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). OBJECTIVE: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 -

Wide-scale SARS-CoV-2 genome sequencing is critical to tracking viral evolution during the ongoing pandemic. We develop the software tool, Variant Database (VDB), for quickly examining the changing landscape of spike mutations. Using VDB, we detect an emerging lineage of SARS-CoV-2 in the New York region that shares mutations with previously reported variants. The most common sets of spike mutations in this lineage (now designated as B.1.526) are L5F, T95I, D253G, E484K or S477N, D614G, and A701V. This lineage was first sequenced in late November 2020. Phylodynamic inference confirmed the rapid growth of the B.1.526 lineage. In concert with other variants, like B.1.1.7, the rise of B.1.526 appears to have extended the duration of the second wave of COVID-19 cases in NYC in early 2021. Pseudovirus neutralization experiments demonstrated that B.1.526 spike mutations adversely affect the neutralization titer of convalescent and vaccinee plasma, supporting the public health relevance of this lineage.

BackgroundThe need for diagnostic biomarkers of cognitive decline is particularly important among aging adults with Down syndrome (DS). Growing empirical support has identified the utility of plasma derived biomarkers among neurotypical adults with mild cognitive impairment (MCI) and Alzheimer's disease (AD); however, the application of such biomarkers has been limited among the DS population.ObjectiveThis study aimed to investigate the cross-sectional diagnostic performance of plasma neurofilament light chain (Nf-L) and total-tau, individually and in combination among a cohort of DS adults.MethodsPlasma samples were analyzed from n = 305 (n = 225 cognitively stable (CS); n = 44 MCI-DS; n = 36 DS-AD) participants enrolled in the Alzheimer's Biomarker Consortium -Down Syndrome.ResultsIn distinguishing DS-AD participants from CS, Nf-L alone produced an AUC of 90%, total-tau alone reached 74%, and combined reached an AUC of 86%. When age and gender were included, AUC increased to 93%. Higher values of Nf-L, total-tau, and age were all shown to be associated with increased risk for DS-AD. When distinguishing MCI-DS participants from CS, Nf-L alone produced an AUC of 65%, while total-tau alone reached 56%. A combined model with Nf-L, total-tau, age, and gender produced an AUC of 87%. Both higher values in age and total-tau were found to increase risk for MCI-DS; Nf-L levels were not associated with increased risk for MCI-DS.ConclusionAdvanced assay techniques make total-tau and particularly Nf-L useful biomarkers of both AD pathology and clinical status in DS and have the potential to serve as outcome measures in clinical trials for future disease-modifying drugs.

Zinc is an essential cofactor for bacterial metabolism, and many Enterobacteriaceae express the zinc transporters ZnuABC and ZupT to acquire this metal in the host. However, the probiotic bacterium Escherichia coli Nissle 1917 (or "Nissle") exhibits appreciable growth in zinc-limited media even when these transporters are deleted. Here, we show that Nissle utilizes the siderophore yersiniabactin as a zincophore, enabling Nissle to grow in zinc-limited media, to tolerate calprotectin-mediated zinc sequestration, and to thrive in the inflamed gut. We also show that yersiniabactin's affinity for iron or zinc changes in a pH-dependent manner, with increased relative zinc binding as the pH increases. Thus, our results indicate that siderophore metal affinity can be influenced by the local environment and reveal a mechanism of zinc acquisition available to commensal and pathogenic Enterobacteriaceae.