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PurposeThis study reports on a prospective, multicenter, single-arm, clinical trial utilizing the SonoMotion (San Mateo, California) Break Wave lithotripsy (BWL) device to fragment urinary stones.Materials and methodsPatients with a urinary stone underwent a single treatment of 30 minutes and peak negative pressure of 4.5 to 8 MPa. Subjects were contacted and outcomes assessed at 7, 14, and 35 days after treatment, with clinical follow-up and CT imaging 70 ± 14 days postprocedure. The primary objectives were to assess the safety (hematomas, complications, etc) and effectiveness of BWL (any fragmentation, residual fragments ≤4 mm or ≤2 mm, and completely stone-free rate) as assessed via noncontrast CT-kidneys, ureters, and bladder.ResultsForty-four patients with a ureteral (43%) or renal (57%) stone were treated across 5 centers. Stone fragmentation occurred in 88% of cases; 70% had fragments ≤ 4 and 51% ≤ 2 mm, while 49% were completely stone free on CT; no serious adverse events were reported. Eighty-six percent of patients received either no analgesic medication at all (50%) or minor analgesia (36%). After determining optimal therapy settings, 36 patients were treated and the effectiveness improved exhibiting fragmentation in 92% (33/36), residual fragments ≤ 4 mm in 75% and 58% with fragments ≤ 2 mm with 58% completely stone free. Effectiveness was less in subjects with lower pole stones with 81% fragmentation, 71% having fragments ≤ 4 mm, 29% with fragments ≤ 2 mm, and 29% completely stone free; of distal ureteral stone patients, 89% were completely stone free.ConclusionsBWL offered safe and effective noninvasive stone therapy requiring little to no anesthesia and was carried out successfully in nonoperative environments.Trial registrationClinicalTrials.gov identifier: NCT03811171.

We identify a population of Protogenin-positive (PRTG+ve) MYChigh NESTINlow stem cells in the four-week-old human embryonic hindbrain that subsequently localizes to the ventricular zone of the rhombic lip (RLVZ). Oncogenic transformation of early Prtg+ve rhombic lip stem cells initiates group 3 medulloblastoma (Gr3-MB)-like tumors. PRTG+ve stem cells grow adjacent to a human-specific interposed vascular plexus in the RLVZ, a phenotype that is recapitulated in Gr3-MB but not in other types of medulloblastoma. Co-culture of Gr3-MB with endothelial cells promotes tumor stem cell growth, with the endothelial cells adopting an immature phenotype. Targeting the PRTGhigh compartment of Gr3-MB in vivo using either the diphtheria toxin system or chimeric antigen receptor T cells constitutes effective therapy. Human Gr3-MBs likely arise from early embryonic RLVZ PRTG+ve stem cells inhabiting a specific perivascular niche. Targeting the PRTGhigh compartment and/or the perivascular niche represents an approach to treat children with Gr3-MB.

Aberrant expression of the E26 transformation-specific (ETS) transcription factors characterizes numerous human malignancies. Many of these proteins, including EWS:FLI1 and EWS:ERG fusions in Ewing sarcoma (EwS) and TMPRSS2:ERG in prostate cancer (PCa), drive oncogenic programs via binding to GGAA repeats. We report here that both EWS:FLI1 and ERG bind and transcriptionally activate GGAA-rich pericentromeric heterochromatin. The respective pathogen-like HSAT2 and HSAT3 RNAs, together with LINE, SINE, ERV, and other repeat transcripts, are expressed in EwS and PCa tumors, secreted in extracellular vesicles (EVs), and are highly elevated in plasma of patients with EwS with metastatic disease. High human satellite 2 and 3 (HSAT2,3) levels in EWS:FLI1- or ERG-expressing cells and tumors were associated with induction of G2/M checkpoint, mitotic spindle, and DNA damage programs. These programs were also activated in EwS EV-treated fibroblasts, coincident with accumulation of HSAT2,3 RNAs, proinflammatory responses, mitotic defects, and senescence. Mechanistically, HSAT2,3-enriched cancer EVs induced cGAS-TBK1 innate immune signaling and formation of cytosolic granules positive for double-strand RNAs, RNA-DNA, and cGAS. Hence, aberrantly expressed ETS proteins derepress pericentromeric heterochromatin, yielding pathogenic RNAs that transmit genotoxic stress and inflammation to local and distant sites. Monitoring HSAT2,3 plasma levels and preventing their dissemination may thus improve therapeutic strategies and blood-based diagnostics.

IL-17C is an epithelial cell-derived proinflammatory cytokine whose transcriptional regulation remains unclear. Analysis of the IL17C promoter region identified TCF4 as putative regulator, and siRNA knockdown of TCF4 in human keratinocytes (KCs) increased IL17C. IL-17C stimulation of KCs (along with IL-17A and TNF-α stimulation) decreased TCF4 and increased NFKBIZ and ZC3H12A expression in an IL-17RA/RE-dependent manner, thus creating a feedback loop. ZC3H12A (MCPIP1/Regnase-1), a transcriptional immune-response regulator, also increased following TCF4 siRNA knockdown, and siRNA knockdown of ZC3H12A decreased NFKBIZ, IL1B, IL36G, CCL20, and CXCL1, revealing a proinflammatory role for ZC3H12A. Examination of lesional skin from the KC-Tie2 inflammatory dermatitis mouse model identified decreases in TCF4 protein concomitant with increases in IL-17C and Zc3h12a that reversed following the genetic elimination of Il17c, Il17ra, and Il17re and improvement in the skin phenotype. Conversely, interference with Tcf4 in KC-Tie2 mouse skin increased Il17c and exacerbated the inflammatory skin phenotype. Together, these findings identify a role for TCF4 in the negative regulation of IL-17C, which, alone and with TNF-α and IL-17A, feed back to decrease TCF4 in an IL-17RA/RE-dependent manner. This loop is further amplified by IL-17C-TCF4 autocrine regulation of ZC3H12A and IL-17C regulation of NFKBIZ to promote self-sustaining skin inflammation.

IntroductionUrology residency prepares trainees for independent practice. The optimal operative chief resident year experience to prepare for practice is undefined. We analyzed the temporal arc of cases residents complete during their residency compared to their chief year in a multi-institutional cohort.MethodsAccreditation Council for Graduate Medical Education case logs of graduating residents from 2010 to 2022 from participating urology residency programs were aggregated. Resident data for 5 categorized index procedures were recorded: (1) general urology, (2) endourology, (3) reconstructive urology, (4) urologic oncology, and (5) pediatric urology. Interactions were tested between the trends for total case exposure in residency training relative to the chief resident year.ResultsFrom a sample of 479 resident graduates, a total of 1,287,433 total cases were logged, including 375,703 during the chief year (29%). Urologic oncology cases had the highest median percentage completed during chief year (56%) followed by reconstructive urology (27%), general urology (24%), endourology (17%), and pediatric urology (2%). Across the study period, all categories of cases had a downward trend in median percentage completed during chief year except for urologic oncology. However, only trends in general urology (slope of -0.68, P = .013) and endourology (slope of -1.71, P ≤ .001) were significant.ConclusionsOver 50% of cases completed by chief residents are urologic oncology procedures. Current declining trends indicate that residents are being exposed to proportionally fewer general urology and endourology cases during their chief year prior to entering independent practice.

BackgroundViruses impact nearly all organisms on Earth, including microbial communities and their associated biogeochemical processes. In soils, highly diverse viral communities have been identified, with a global distribution seemingly driven by multiple biotic and abiotic factors, especially soil temperature and moisture. However, our current understanding of the stability of soil viral communities across time and their response to strong seasonal changes in environmental parameters remains limited. Here, we investigated the diversity and activity of environmental soil DNA and RNA viruses, focusing especially on bacteriophages, across dynamics' seasonal changes in a snow-dominated mountainous watershed by examining paired metagenomes and metatranscriptomes.ResultsWe identified a large number of DNA and RNA viruses taxonomically divergent from existing environmental viruses, including a significant proportion of fungal RNA viruses, and a large and unsuspected diversity of positive single-stranded RNA phages (Leviviricetes), highlighting the under-characterization of the global soil virosphere. Among these, we were able to distinguish subsets of active DNA and RNA phages that changed across seasons, consistent with a "seed-bank" viral community structure in which new phage activity, for example, replication and host lysis, is sequentially triggered by changes in environmental conditions. At the population level, we further identified virus-host dynamics matching two existing ecological models: "Kill-The-Winner" which proposes that lytic phages are actively infecting abundant bacteria, and "Piggyback-The-Persistent" which argues that when the host is growing slowly, it is more beneficial to remain in a dormant state. The former was associated with summer months of high and rapid microbial activity, and the latter with winter months of limited and slow host growth.ConclusionTaken together, these results suggest that the high diversity of viruses in soils is likely associated with a broad range of host interaction types each adapted to specific host ecological strategies and environmental conditions. As our understanding of how environmental and host factors drive viral activity in soil ecosystems progresses, integrating these viral impacts in complex natural microbiome models will be key to accurately predict ecosystem biogeochemistry. Video Abstract.

BackgroundAutologous fat grafting is commonly used for soft-tissue repair (approximately 90,000 cases per year in the United States), but outcomes are limited by volume loss (20% to 80%) over time. Human allograft adipose matrix (AAM) stimulates de novo adipogenesis in vivo, but retention requires optimization. The extracellular matrix derived from superficial fascia, interstitial within the adipose layer, is typically removed during AAM processing. Thus, fascia, which contains numerous important proteins, might cooperate with AAM to stimulate de novo adipogenesis, improving long-term retention compared to AAM alone.MethodsHuman AAM and fascia matrix proteins (back and upper leg regions) were identified by mass spectrometry and annotated by gene ontology. A three-dimensional in vitro angiogenesis assay was performed. Finally, AAM and/or fascia (1 mL) was implanted into 6- to 8-week-old male Fischer rats. After 8 weeks, the authors assessed graft retention by gas pycnometry and angiogenesis (CD31) and adipocyte counts (hematoxylin and eosin) histologically.ResultsGene ontology annotation revealed an angiogenic enrichment pattern unique to the fascia, including lactadherin, collagen alpha-3(V) chain, and tenascin-C. In vitro, AAM stimulated 1.0 ± 0.17 angiogenic sprouts per bead. The addition of fascia matrix increased sprouting by 88% (2.0 ± 0.12; P < 0.001). A similar angiogenic response (CD31) was observed in vivo. Graft retention volume was 25% (0.25 ± 0.13) for AAM, significantly increasing to 60% (0.60 ± 0.14) for AAM/fascia ( P < 0.05). De novo adipogenesis was 12% (12.4 ± 7.4) for AAM, significantly increasing to 51% (51.2 ± 8.0) for AAM/fascia ( P < 0.001) by means of adipocyte quantification.ConclusionsCombining fascia matrix with AAM improves angiogenesis and adipogenesis compared to AAM alone in rats. These preliminary in vitro and pilot animal studies should be further validated before definitive clinical adoption.Clinical relevance statementWhen producing an off-the-shelf adipose inducing product by adding a connective tissue fascial component (that is normally discarded) to the mix of adipose matrix, vasculogenesis is increased and, thus, adipogenesis and graft survival is improved. This is a significant advance in this line of product.

BackgroundArtificial intelligence (AI) may improve cancer detection and risk prediction during mammography screening, but radiologists' preferences regarding its characteristics and implementation are unknown.PurposeTo quantify how different attributes of AI-based cancer detection and risk prediction tools affect radiologists' intentions to use AI during screening mammography interpretation.Materials and methodsThrough qualitative interviews with radiologists, we identified five primary attributes for AI-based breast cancer detection and four for breast cancer risk prediction. We developed a discrete choice experiment based on these attributes and invited 150 US-based radiologists to participate. Each respondent made eight choices for each tool between three alternatives: two hypothetical AI-based tools versus screening without AI. We analyzed samplewide preferences using random parameters logit models and identified subgroups with latent class models.ResultsRespondents (n = 66; 44% response rate) were from six diverse practice settings across eight states. Radiologists were more interested in AI for cancer detection when sensitivity and specificity were balanced (94% sensitivity with

Introduction and Objective: Guidelines from the American Urological Association (AUA) and American College of Radiology (ACR) recommend that patients with suspected nephrolithiasis undergo low-dose CT of the kidney, ureter, and bladder (LD CT KUB) as opposed to higher dose conventional imaging. We hypothesized that even at institutions with established LD protocols, higher dose imaging is common. Materials and Methods: We identified four academic medical centers where LD CT KUB protocols were implemented to yield an effective dose (EDose) consistent with national guidelines. Fifty consecutive adult patients who underwent CT KUB specifically for the evaluation of nephrolithiasis were retrospectively reviewed at each site. Patient age, sex, body mass index (BMI), imaging location, and EDose (millisieverts [mSv]) were recorded. Results: Two hundred patients with a mean age of 54 years were identified. Forty-six patients (23%) underwent CT KUB with an EDose ≤4 mSv, accounting for 10% to 48% of each institution's cohort. One hundred sixteen patients had a BMI

ObjectiveTo assess the impact of the Urology Collaborative Online Video Didactic (COViD) lecture series series on resident knowledge as a supplement to resident education during the coronavirus disease 2019 pandemic.MethodsOne hundred thirty-nine urology residents were voluntarily recruited from 8 institutions. A 20-question test, based on 5 COViD lectures, was administered before and after watching the lectures. Pre- and posttest scores (percent correct) and score changes (posttest minus pretest score) were assessed considering demographic data and number of lectures watched. Multiple linear regression determined predictors of improved scores.ResultsOf residents recruited, 95 and 71 took the pre- and posttests. Median number of lectures watched was 3. There was an overall increase in correct scores from pretest to posttest (45% vs 57%, P < .01). Watching any lectures vs none led to higher posttest scores (60% vs 44%, P < .01) and score changes (+16% vs +1%, P < .01). There was an increase in baseline pretest scores by post-graduate year (PGY) (P < .01); however there were no significant differences in posttest or score changes by PGY. When accounting for lectures watched, PGY, and time between lecture and posttest, being a PGY6 (P = .01) and watching 3-5 lectures (P < .01) had higher overall correct posttest scores. Watching 3-5 lectures led to greater score changes (P < .001-.04). Over 65% of residents stated the COViD lectures had a large or very large impact on their education.ConclusionsCOViD lectures improved overall correct posttest scores and increased knowledge base for all resident levels. Furthermore, lectures largely impacted resident education during the coronavirus disease 2019 pandemic.

How do we think about time? Converging lesion and neuroimaging evidence indicates that orbitofrontal cortex (OFC) supports the encoding and retrieval of temporal context in long-term memory1, which may contribute to confabulation in individuals with OFC damage2. Here, we reveal that OFC damage diminishes working memory for temporal order, that is, the ability to disentangle the relative recency of events as they unfold. OFC lesions reduced working memory for temporal order but not spatial position, and individual deficits were commensurate with lesion size. Comparable effects were absent in patients with lesions restricted to lateral prefrontal cortex (PFC). Based on these findings, we propose that OFC supports understanding of the order of events. Well-documented behavioral changes in individuals with OFC damage2 may relate to impaired temporal-order understanding.

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

IntroductionRobust randomised trial data have shown that routine preoperative (pre-op) testing for cataract surgery patients is inappropriate. While guidelines have discouraged testing since 2002, cataract pre-op testing rates have remained unchanged since the 1990s. Given the challenges of reducing low-value care despite strong consensus around the evidence, innovative approaches are needed to promote high-value care. This trial evaluates the impact of an interdisciplinary electronic health record (EHR) intervention that is informed by behavioural economic theory.Methods and analysisThis pragmatic randomised trial is being conducted at UCLA Health between June 2021 and June 2022 with a 12-month follow-up period. We are randomising all UCLA Health physicians who perform pre-op visits during the study period to one of the three nudge arms or usual care. These three nudge alerts address (1) patient harm, (2) increased out-of-pocket costs for patients and (3) psychological harm to the patients related to pre-op testing. The nudges are triggered when a physician starts to order a pre-op test. We hypothesise that receipt of a nudge will be associated with reduced pre-op testing. The primary outcome will be the change in the percentage of patients undergoing pre-op testing at 12 months. Secondary outcomes will include the percentage of patients undergoing specific categories of pre-op tests (labs, EKGs, chest X-rays (CXRs)), the efficacy of each nudge, same-day surgery cancellations and cost savings.Ethics and disseminationThe study protocol was approved by the institutional review board of the University of California, Los Angeles as well as a nominated Data Safety Monitoring Board. If successful, we will have created a tool that can be disseminated rapidly to EHR vendors across the nation to reduce inappropriate testing for the most common low-risk surgical procedures in the country.Trial registration numberClinicalTrials.gov identifier: NCT04104256.

The primary motor cortex (M1) is essential for voluntary fine-motor control and is functionally conserved across mammals1. Here, using high-throughput transcriptomic and epigenomic profiling of more than 450,000 single nuclei in humans, marmoset monkeys and mice, we demonstrate a broadly conserved cellular makeup of this region, with similarities that mirror evolutionary distance and are consistent between the transcriptome and epigenome. The core conserved molecular identities of neuronal and non-neuronal cell types allow us to generate a cross-species consensus classification of cell types, and to infer conserved properties of cell types across species. Despite the overall conservation, however, many species-dependent specializations are apparent, including differences in cell-type proportions, gene expression, DNA methylation and chromatin state. Few cell-type marker genes are conserved across species, revealing a short list of candidate genes and regulatory mechanisms that are responsible for conserved features of homologous cell types, such as the GABAergic chandelier cells. This consensus transcriptomic classification allows us to use patch-seq (a combination of whole-cell patch-clamp recordings, RNA sequencing and morphological characterization) to identify corticospinal Betz cells from layer 5 in non-human primates and humans, and to characterize their highly specialized physiology and anatomy. These findings highlight the robust molecular underpinnings of cell-type diversity in M1 across mammals, and point to the genes and regulatory pathways responsible for the functional identity of cell types and their species-specific adaptations.

BackgroundPhysical activity and macronutrient intake, important contributors to energy balance, may be independently associated with female urinary incontinence (UI).MethodsWe evaluated the association of baseline self-reported physical activity and macronutrient intake, via food frequency questionnaire, with incident UI subtypes after 3 years among 19 741 postmenopausal women in the Women's Health Initiative Observational Study. Odds ratios (ORs) for incident urgency, stress, and mixed UI were calculated using multivariable logistic regression.ResultsWomen who reported total physical activity (metabolic equivalent task [MET]-hours/week) ≥30 versus .05 for all).ConclusionsAmong postmenopausal women, higher physical activity was associated with lower risk of incident urgency and mixed UI, but not stress UI, independent of baseline weight and weight change. Higher protein intake was associated with increased risk of urgency UI, but no associations were observed between other macronutrient and UI subtypes.

IntroductionPotentially avoidable hospitalizations are disproportionately experienced by racial and ethnic minorities and expose these groups to unnecessary iatrogenic harm (including the risk of nosocomial COVID-19) and undue financial burden. In working toward an overarching goal of eliminating racial and ethnic health disparities, it is important to understand whether and to what extent potentially avoidable hospitalizations have changed by race and ethnicity during the COVID-19 pandemic.MethodsThis single-center pre-post study included patients admitted to any UCLA Health hospital for an ambulatory care-sensitive condition between March-August 2019 (prepandemic period) and March-August 2020 (postpandemic period). Investigators measured the change in the number of potentially avoidable hospitalizations (defined per the Agency for Healthcare Research and Quality guidelines) stratified by race and ethnicity and calculated the 95% CIs for these hospitalizations using a cluster bootstrap procedure.ResultsBetween March 1, 2020 and August 31, 2020, 347 of 4,838 hospitalizations (7.2%) were potentially avoidable, compared with 557 of 6,248 (8.9%) during the same 6-month period in 2019. Potentially avoidable hospitalizations decreased by 50.3% (95% CI=41.2, 60.9) among non-Hispanic Whites but only by 8.0% (95% CI= -16.2, 39.9) among African Americans (50.3% vs 8.0%, p=0.015).ConclusionsRacial disparities in potentially avoidable hospitalizations increased during the COVID-19 pandemic at a large urban health system. Given that the prepandemic rates of potentially avoidable hospitalizations were already higher among racial and ethnic minorities, especially among African Americans, this finding should cause alarm and lead to further exploration of the complex factors contributing to these disparities.

ObjectivesSeptic cardiomyopathy develops frequently in patients with sepsis and likely increases short-term mortality. However, whether septic cardiomyopathy is associated with long-term outcomes after sepsis is unknown. We investigated whether septic patients with septic cardiomyopathy have worse long-term outcomes than septic patients without septic cardiomyopathy.DesignRetrospective cohort study.SettingAdult ICU.PatientsAdult ICU patients with sepsis.InterventionsNone.Measurements and main resultsLeft ventricular global longitudinal systolic strain was our primary measure of septic cardiomyopathy. We employed a suite of multivariable survival analyses to explore linear and nonlinear associations between left ventricular global longitudinal systolic strain and major adverse cardiovascular events, which included death, stroke, and myocardial infarction. Our primary outcome was major adverse cardiovascular event through 24 months after ICU discharge. Among 290 study patients, median left ventricular global longitudinal systolic strain was -16.8% (interquartile range, -20.4% to -12.6%), and 38.3% of patients (n = 111) experienced a major adverse cardiovascular event within 24 months after discharge. On our primary, linear analysis, there was a trend (p = 0.08) toward association between left ventricular global longitudinal systolic strain and major adverse cardiovascular event (odds ratio, 1.03; CI, < 1 to 1.07). On our nonlinear analysis, the association was highly significant (p < 0.001) with both high and low left ventricular global longitudinal systolic strain associated with major adverse cardiovascular event among patients with pre-existing cardiac disease. This association was pronounced among patients who were younger (age < 65 yr) and had Charlson Comorbidity Index greater than 5.ConclusionsAmong patients with sepsis and pre-existing cardiac disease who survived to ICU discharge, left ventricular global longitudinal systolic strain demonstrated a U-shaped association with cardiovascular outcomes through 24 months. The relationship was especially strong among younger patients with more comorbidities. These observations are likely of use to design of future trials.

BackgroundAlthough observational studies have shown percutaneous patent foramen ovale (PFO) closure to be a safe means of reducing the frequency and duration of migraine, randomized clinical trials have not met their primary efficacy endpoints.ObjectivesThe authors report the results of a pooled analysis of individual participant data from the 2 randomized trials using the Amplatzer PFO Occluder to assess the efficacy and safety of percutaneous device closure as a therapy for episodic migraine with or without aura.MethodsThe authors analyzed individual patient-level data from 2 randomized migraine trials (the PRIMA [Percutaneous Closure of Patent Foramen Ovale in Migraine With Aura] and PREMIUM [Prospective Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects with Migraine and PFO Using the Amplatzer PFO Occluder Compared to Medical Management] studies). Efficacy endpoints were mean reduction in monthly migraine days, responder rate (defined as ≥50% reduction in monthly migraine attacks), mean reduction in monthly migraine attacks, and percentage of patients who experienced complete cessation of migraine. The safety endpoint was major procedure- and device-related adverse events.ResultsAmong 337 subjects, 176 were randomized by blocks to device closure and 161 to medical treatment only. At 12-month follow-up, the analysis met 3 of the 4 efficacy endpoints: mean reduction of monthly migraine days (-3.1 days vs. -1.9 days; p = 0.02), mean reduction of monthly migraine attacks (-2.0 vs. -1.4; p = 0.01), and number of subjects who experienced complete cessation of migraine (14 [9%] vs. 1 [0.7%]; p

ImportanceElectronic health record (EHR) clinical decision support (CDS) tools can provide evidence-based feedback at the point of care to reduce low-value imaging. Success of these tools has been limited partly due to lack of engagement by busy clinicians.ObjectiveMeasure the impact of a time-saving quality improvement intervention to increase engagement with a CDS tool for low back pain imaging ordering.Design, setting and participantsWe conducted a quasi-experimental difference-in-differences analysis at (BLINDED), examining back pain imaging orders from 29 May 2015 to 07 January 2016. The intervention site was (BLINDED) Emergency Medicine/Urgent Care Center (n=5736) and control sites included all other (BLINDED) hospitals and clinics (n=1621). In May 2015, the Department of Health Services installed a CDS tool that triggered a survey when clinicians ordered an imaging test, generating an 'appropriateness score' based on the American College of Radiology guidelines. Clinicians often bypassed the tool, resulting in 'unscored' tests.InterventionTo increase clinician engagement with the tool and decrease the rate of unscored imaging tests, a new policy was implemented at the intervention site on 15 August 2015. If clinicians completed the CDS survey and scored an appropriateness score >3, they could forego a previously mandatory telephone call for pre-imaging utilisation review with the radiology department.Main outcomes and measuresWe used EHR data to measure pre-post-intervention differences in: (1) percentage of unscored tests and (2) percentage of tests with high appropriateness scores (>7).ResultsPercentage of unscored tests decreased from 69.4% to 10.4% at the intervention site and from 50.6% to 34.8% at the control sites (between-group difference: -23.3%, p

Surface expression of the common vertebrate sialic acid (Sia) N-acetylneuraminic acid (Neu5Ac) by commensal and pathogenic microbes appears structurally to represent "molecular mimicry" of host sialoglycans, facilitating multiple mechanisms of host immune evasion. In contrast, ketodeoxynonulosonic acid (Kdn) is a more ancestral Sia also present in prokaryotic glycoconjugates that are structurally quite distinct from vertebrate sialoglycans. We detected human antibodies against Kdn-terminated glycans, and sialoglycan microarray studies found these anti-Kdn antibodies to be directed against Kdn-sialoglycans structurally similar to those on human cell surface Neu5Ac-sialoglycans. Anti-Kdn-glycan antibodies appear during infancy in a pattern similar to those generated following incorporation of the nonhuman Sia N-glycolylneuraminic acid (Neu5Gc) onto the surface of nontypeable Haemophilus influenzae (NTHi), a human commensal and opportunistic pathogen. NTHi grown in the presence of free Kdn took up and incorporated the Sia into its lipooligosaccharide (LOS). Surface display of the Kdn within NTHi LOS blunted several virulence attributes of the pathogen, including Neu5Ac-mediated resistance to complement and whole blood killing, complement C3 deposition, IgM binding, and engagement of Siglec-9. Upper airway administration of Kdn reduced NTHi infection in human-like Cmah null (Neu5Gc-deficient) mice that express a Neu5Ac-rich sialome. We propose a mechanism for the induction of anti-Kdn antibodies in humans, suggesting that Kdn could be a natural and/or therapeutic "Trojan horse" that impairs colonization and virulence phenotypes of free Neu5Ac-assimilating human pathogens.IMPORTANCE All cells in vertebrates are coated with a dense array of glycans often capped with sugars called sialic acids. Sialic acids have many functions, including serving as a signal for recognition of "self" cells by the immune system, thereby guiding an appropriate immune response against foreign "nonself" and/or damaged cells. Several pathogenic bacteria have evolved mechanisms to cloak themselves with sialic acids and evade immune responses. Here we explore a type of sialic acid called "Kdn" (ketodeoxynonulosonic acid) that has not received much attention in the past and compare and contrast how it interacts with the immune system. Our results show potential for the use of Kdn as a natural intervention against pathogenic bacteria that take up and coat themselves with external sialic acid from the environment.

BackgroundMicrotia is an inherited condition that results in varying degrees of external ear deformities; the most extreme form is anotia. Effective surgical reconstruction techniques have been developed. However, these usually require multistage procedures and have other inherent disadvantages. Tissue engineering technologies offer new approaches in the field of external ear reconstruction. In this setting, chondrocytes are cultured in the laboratory with the aim of creating bioengineered cartilage matrices. However, cartilage engineering has many challenges, including difficulty in culturing sufficient chondrocytes. To overcome these hurdles, the authors propose a novel model of cartilage engineering that involves co-culturing chondrocytes and adipose-derived stem cells on an allograft adipose-derived extracellular matrix scaffold.MethodsAuricular chondrocytes from porcine ear were characterized. Adipose-derived stem cells were isolated and expanded from human lipoaspirate. Then, the auricular chondrocytes were cultured on the allograft adipose matrix either alone or with the adipose-derived stem cells at different ratios and examined histologically.ResultsCartilage induction was most prominent when the cells were co-cultured on the allograft adipose matrix at a ratio of 1:9 (auricular chondrocyte-to-adipose-derived stem cell ratio). Furthermore, because of the xenogeneic nature of the experiment, the authors were able to determine that the adipose-derived stem cells contributed to chondrogenesis by means of a paracrine stimulation of the chondrocytes.ConclusionsIn this situation, adipose-derived stem cells provide sufficient support to induce the formation of cartilage when the number of auricular chondrocytes available is limited. This novel model of cartilage engineering provides a setting for using the patient's own chondrocytes and adipose tissue to create a customized ear framework that could be further used for surgical reconstruction.

Background/objectivesMedication discrepancies and adverse drug events are common following hospital discharge. This study evaluates whether a collaboration between community-based health coaches and primary care-based pharmacists was associated with a reduction in inpatient utilization following hospitalization.DesignRetrospective cohort study using propensity score matching.SettingUrban academic medical center and surrounding community.ParticipantsIntervention patients (n = 494) were adults aged 65 and older admitted to the University of California, Los Angeles (UCLA) Ronald Reagan Medical Center during the study period and who met study inclusion criteria. A matched-control group was composed of patients with similar demographic and clinical characteristics who were admitted to the study site during the study period but who received usual care (n = 2,470). A greedy algorithm approach was used to conduct the propensity score match.InterventionFollowing acute hospitalization, a health coach conducted a home visit and transmitted all medication-related information to a pharmacist based in a primary care practice. The pharmacist compared this information with the patient's electronic medical record medication list and consulted with the patient's primary care provider to optimize medication management.MeasurementsThirty-day readmissions (primary outcome), 60- and 90-day readmissions, and 30-day emergency department (ED) visits (secondary outcomes) to UCLA Health.ResultsAmong 494 patients who received the intervention, 307 (62.1%) were female with a mean age of 83.0 years (interquartile range [IQR] = 76-90 years). Among 2,470 matched-control patients, 1,541 (62.4%) were female with a mean age of 82.7 years (IQR = 74.9-89.5 years). For the propensity score match, standardized mean differences were below .1 for 23 of 25 variables, indicating good balance. Patients who received this intervention had a significantly lower predicted probability of being readmitted within 30 days compared with matched-control patients (10.6%; 95% confidence interval [CI] = 7.9-13.2) vs 21.4%; 95% CI = 19.8-23.0; P value < .001).ConclusionA home visit conducted by a health coach combined with a medication review by a primary care-based pharmacist may prevent subsequent inpatient utilization.

BackgroundWith the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.MethodsWe tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.ResultsWe report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.ConclusionsOverall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.

ObjectiveTo capture the perspective of prospective urology applicants experiencing unique challenges in the context of COVID-19.MethodsA voluntary, anonymous survey was distributed online, assessing the impact of COVID-19 on a large sample of US medical students planning to apply to urology residencies. Themes of (1) specialty discernment, (2) alterations to medical education, and (3) the residency application process were explored.ResultsA total of 238 medical students, 87% third and fourth years, responded to the survey. While 85% indicated that the pandemic had not deterred their specialty choice, they noted substantial impacts on education, including 82% reporting decreased exposure to urology. Nearly half of students reported changes to required rotations and 35% reported changes to urology-specific rotations at their home institutions. Students shared concerns about suspending in-person experiences, including the impact on letters of recommendation (68% "very concerned) and program choice (73% "very concerned"). Looking to the possibility of virtual interactions, students identified the importance of small group and one-on-one communication with residents (83% "very important") and opportunities to learn about hospital facilities (72% "very important").ConclusionDespite the impacts of COVID-19 on medical education, prospective urology applicants appear to remain confident in their specialty choice. Students' biggest concerns involve disruption of away rotations, including impacts on obtaining letters of recommendation and choosing a residency program.

Artificial intelligence (AI) is transforming healthcare delivery. The digital revolution in medicine and healthcare information is prompting a staggering growth of data intertwined with elements from many digital sources such as genomics, medical imaging and electronic health records. Such massive growth has sparked the development of an increasing number of AI-based applications that can be deployed in clinical practice. Pulmonary specialists who are familiar with the principles of AI and its applications will be empowered and prepared to seize future practice and research opportunities. The goal of this review is to provide pulmonary specialists and other readers with information pertinent to the use of AI in pulmonary medicine. First, we describe the concept of AI and some of the requisites of machine learning and deep learning. Next, we review some of the literature relevant to the use of computer vision in medical imaging, predictive modelling with machine learning, and the use of AI for battling the novel severe acute respiratory syndrome-coronavirus-2 pandemic. We close our review with a discussion of limitations and challenges pertaining to the further incorporation of AI into clinical pulmonary practice.

De novo assembly of a human genome using nanopore long-read sequences has been reported, but it used more than 150,000 CPU hours and weeks of wall-clock time. To enable rapid human genome assembly, we present Shasta, a de novo long-read assembler, and polishing algorithms named MarginPolish and HELEN. Using a single PromethION nanopore sequencer and our toolkit, we assembled 11 highly contiguous human genomes de novo in 9 d. We achieved roughly 63× coverage, 42-kb read N50 values and 6.5× coverage in reads >100 kb using three flow cells per sample. Shasta produced a complete haploid human genome assembly in under 6 h on a single commercial compute node. MarginPolish and HELEN polished haploid assemblies to more than 99.9% identity (Phred quality score QV = 30) with nanopore reads alone. Addition of proximity-ligation sequencing enabled near chromosome-level scaffolds for all 11 genomes. We compare our assembly performance to existing methods for diploid, haploid and trio-binned human samples and report superior accuracy and speed.

Inversions play an important role in disease and evolution but are difficult to characterize because their breakpoints map to large repeats. We increased by sixfold the number (n = 1,069) of previously reported great ape inversions by using single-cell DNA template strand and long-read sequencing. We find that the X chromosome is most enriched (2.5-fold) for inversions, on the basis of its size and duplication content. There is an excess of differentially expressed primate genes near the breakpoints of large (>100 kilobases (kb)) inversions but not smaller events. We show that when great ape lineage-specific duplications emerge, they preferentially (approximately 75%) occur in an inverted orientation compared to that at their ancestral locus. We construct megabase-pair scale haplotypes for individual chromosomes and identify 23 genomic regions that have recurrently toggled between a direct and an inverted state over 15 million years. The direct orientation is most frequently the derived state for human polymorphisms that predispose to recurrent copy number variants associated with neurodevelopmental disease.

ObjectiveSignificant interscorer variability is found in manual scoring of arousals in polysomnographic recordings (PSGs). We propose a fully automatic method, the Multimodal Arousal Detector (MAD), for detecting arousals.MethodsA deep neural network was trained on 2,889 PSGs to detect cortical arousals and wakefulness in 1-second intervals. Furthermore, the relationship between MAD-predicted labels on PSGs and next day mean sleep latency (MSL) on a multiple sleep latency test (MSLT), a reflection of daytime sleepiness, was analyzed in 1447 MSLT instances in 873 subjects.ResultsIn a dataset of 1,026 PSGs, the MAD achieved an F1 score of 0.76 for arousal detection, while wakefulness was predicted with an accuracy of 0.95. In 60 PSGs scored by nine expert technicians, the MAD performed comparable to four and significantly outperformed five expert technicians for arousal detection. After controlling for known covariates, a doubling of the arousal index was associated with an average decrease in MSL of 40 seconds (p = 0.0075).ConclusionsThe MAD performed better or comparable to human expert scorers. The MAD-predicted arousals were shown to be significant predictors of MSL.SignificanceThis study validates a fully automatic method for scoring arousals in PSGs.

We analyzed genetic data of 47,429 multiple sclerosis (MS) and 68,374 control subjects and established a reference map of the genetic architecture of MS that includes 200 autosomal susceptibility variants outside the major histocompatibility complex (MHC), one chromosome X variant, and 32 variants within the extended MHC. We used an ensemble of methods to prioritize 551 putative susceptibility genes that implicate multiple innate and adaptive pathways distributed across the cellular components of the immune system. Using expression profiles from purified human microglia, we observed enrichment for MS genes in these brain-resident immune cells, suggesting that these may have a role in targeting an autoimmune process to the central nervous system, although MS is most likely initially triggered by perturbation of peripheral immune responses.

Purpose: Kidney stone patients routinely have CT scans during diagnostic work-up before being referred to a tertiary center. How often these patients exceed the recommended dose limits for occupational radiation exposure of >100 mSv for 5 years and >50 mSv in a single year from CT alone remains unknown. This study aimed to quantify radiation doses from CTs received by stone patients before their evaluation at a tertiary care stone clinic. Methods: From November 2015 to March 2017, consecutive new patients enrolled into the Registry for Stones of the Kidney and Ureter (ReSKU™) had the dose-length product of every available CT abdomen/pelvis within 5 years of their initial visit recorded, allowing for an effective dose (EDose) calculation. Multivariate logistic regression analysis identified factors associated with exceeding recommended dose limits. Models were created to test radiation reducing effects of low-dose and phase-reduction CT protocols. Results: Of 343 noncontrast CTs performed, only 29 (8%) were low-dose CTs (calculated EDose 20 mSv and >50 mSv/year, respectively. Increased body mass index, number of scans, and multiphase scans were associated with exceeding exposure thresholds (p 50%. Conclusions: Stone patients referred to a tertiary stone center may receive excessive radiation from CT scans alone. Unnecessary phases and underutilization of low-dose CT protocols continue to take place. Enacting new approaches to CT protocols may spare stone patients from exceeding recommended dose limits.

It has been proposed that one of the mechanisms of taxane-site ligand-mediated tubulin activation is modulation of the structure of a switch element (the M-loop) from a disordered form in dimeric tubulin to a folded helical structure in microtubules. Here, we used covalent taxane-site ligands, including cyclostreptin, to gain further insight into this mechanism. The crystal structure of cyclostreptin-bound tubulin reveals covalent binding to βHis229, but no stabilization of the M-loop. The capacity of cyclostreptin to induce microtubule assembly compared to other covalent taxane-site agents demonstrates that the induction of tubulin assembly is not strictly dependent on M-loop stabilization. We further demonstrate that most covalent taxane-site ligands are able to partially overcome drug resistance mediated by βIII-tubulin (βIII) overexpression in HeLa cells, and compare their activities to pironetin, an interfacial covalent inhibitor of tubulin assembly that displays invariant growth inhibition in these cells. Our findings suggest a relationship between a diminished interaction of taxane-site ligands with βIII-tubulin and βIII tubulin-mediated drug resistance. This supports the idea that overexpression of βIII increases microtubule dynamicity by counteracting the enhanced microtubule stability promoted by covalent taxane-site binding ligands.

Glioblastoma (GBM) remains uniformly lethal, and despite a large accumulation of immune cells in the microenvironment, there is limited antitumor immune response. To overcome these challenges, a comprehensive understanding of GBM systemic immune response during disease progression is required. Here, we integrated multiparameter flow cytometry and mass cytometry TOF (CyTOF) analysis of patient blood to determine changes in the immune system among tumor types and over disease progression. Utilizing flow cytometry analysis in a cohort of 259 patients ranging from benign to malignant primary and metastatic brain tumors, we found that GBM patients had a significant elevation in myeloid-derived suppressor cells (MDSCs) in peripheral blood but not immunosuppressive Tregs. In GBM patient tissue, we found that increased MDSC levels in recurrent GBM portended poor prognosis. CyTOF analysis of peripheral blood from newly diagnosed GBM patients revealed that reduced MDSCs over time were accompanied by a concomitant increase in DCs. GBM patients with extended survival also had reduced MDSCs, similar to the levels of low-grade glioma (LGG) patients. Our findings provide a rationale for developing strategies to target MDSCs, which are elevated in GBM patients and predict poor prognosis.

Maintenance of flexible ureteroscopes can involve high costs and administrative burden. Instrument fragility necessitates eventual repair, rendering scopes inaccessible during refurbishment. We conducted a multi-institutional prospective cohort study to identify perioperative factors influencing flexible ureteroscope durability. Patients undergoing flexible ureteroscopy (URS) at six United States endourology centers were enrolled between August 2014 and June 2015. Surgeon self-reported concern and satisfaction with scope performance as well as upward and downward angles of deflection for each scope tip were measured before and after each procedure. The need for scope repair was determined by the operating surgeon at the time of the procedure and recorded. 424 URS cases using 74 flexible ureteroscopes were identified. Scope repair was required in 28 cases (6.6%) involving 26 scopes (35.1%). Upon univariate analysis, shorter patient height, absence of guidewire use, presence of a ureteral access sheath (UAS), longer procedure time, larger stone size, lithotrite type, surgeon training level, and self-reported concern were associated with scope repair. Upon multivariate analysis, UAS use (OR = 2.53, p = 0.005) and degree loss of scope upward flexion during a case (OR = 1.02, p = 0.03) increased the odds of a scope needing repair while the use of safety guidewire decreased the odds of a scope repair (OR = 0.50, p = 0.045). Lithotrite use and surgeon concern were associated with degree loss of scope upward flexion. The use of a UAS, absence of a safety guidewire, and the loss of upward ureteroscope flexion should be considered when evaluating means of optimizing reusable ureteroscope durability.

Sex risk behaviors and substance use are intertwined. Many men continue to engage in high-risk sexual behaviors even when enrolled in substance use disorder (SUD) treatment. We hypothesized that changes in sex risk behaviors would coincide with changes in drug/alcohol use severity among men in SUD treatment. During an HIV risk-reduction trial, men in methadone maintenance and outpatient drug-free treatment (N = 359) completed assessments at baseline and six months after. We assessed changes in sex risk and substance use severity, using the Addiction Severity Index-Lite (ASI-Lite), controlling for treatment condition. In multinomial logistic regressions, decreased alcohol severity was significantly associated with decreases in reported sex partners, and increased alcohol severity was significantly associated with increases in reported sex partners. Increasing drug use severity was significantly associated with maintaining and initiating sex with a high-risk partner, while decreasing alcohol use severity was significantly associated with discontinuing sex under the influence. However, changes in drug/alcohol use severity were not associated with changes in unprotected sex. Substance use reductions may decrease HIV risk behaviors among male substance users. Our findings highlight the importance of integrating interventions in SUD treatment settings that address the intersection of sex risk behaviors and substance use.

Addiction treatment can improve its impact by providing evidence-based care for the variety of problems that accompany substance use disorders. We conducted a retrospective evaluation of a new treatment program in California that aimed at providing multifaceted services through affiliated licensed and certified outpatient providers. The process evaluation used a logic model, focusing on program inputs, activities, and outputs, to understand the services received by the initial 18 clients who entered treatment. Outcomes for these patients were not assessed. Results indicated that clients received a variety of services: On average clients contracted for 118 treatment sessions and received 143 sessions. Among the many types of services provided, the most frequently received were integrative healthcare (averaging 42 sessions), group therapy (32 sessions), and individual therapy (32 sessions). This logic-model process evaluation indicated that a range of services were provided. The comprehensive approach may have promise for extending addiction treatment beyond its usual boundaries.

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

ObjectiveTo evaluate participants' perceptions about frequent use and reasons for substance use (SU) in the qualitative interview study, an add-on to the multimodal treatment study of ADHD (MTA).MethodUsing the longitudinal MTA database, 39 ADHD cases and 19 peers with Persistent SU, and 86 ADHD cases and 39 peers without Persistent SU were identified and recruited. In adulthood, an open-ended interview was administered, and SU excerpts were indexed and classified to create subtopics (frequent use and reasons for use of alcohol, marijuana, and other drugs).ResultsFor marijuana, the Persistent compared with Nonpersistent SU group had a significantly higher percentage of participants describing frequent use and giving reasons for use, and the ADHD group compared with the group of peers had a significantly higher percentage giving "stability" as a reason for use.ConclusionMotivations for persistent marijuana use may differ for adults with and without a history of ADHD.

ObjectiveQualitative interviews with 183 young adults (YA) in the follow-up of the Multimodal Treatment Study of Children With and Without ADHD (MTA) provide rich information on beliefs and expectations regarding ADHD, life's turning points, medication use, and substance use (SU).MethodParticipants from four MTA sites were sampled to include those with persistent and atypically high SU, and a local normative comparison group (LNCG). Respondents were encouraged to "tell their story" about their lives, using a semistructured conversational interview format.ResultsInterviews were reliably coded for interview topics. ADHD youth more often desisted from SU because of seeing others going down wrong paths due to SU. Narratives revealed very diverse accounts and explanations for SU-ADHD influences.ConclusionQualitative methods captured the perspectives of YAs regarding using substances. This information is essential for improving resilience models in drug prevention and treatment programs and for treatment development for this at-risk population.

Genetic studies of human evolution require high-quality contiguous ape genome assemblies that are not guided by the human reference. We coupled long-read sequence assembly and full-length complementary DNA sequencing with a multiplatform scaffolding approach to produce ab initio chimpanzee and orangutan genome assemblies. By comparing these with two long-read de novo human genome assemblies and a gorilla genome assembly, we characterized lineage-specific and shared great ape genetic variation ranging from single- to mega-base pair-sized variants. We identified ~17,000 fixed human-specific structural variants identifying genic and putative regulatory changes that have emerged in humans since divergence from nonhuman apes. Interestingly, these variants are enriched near genes that are down-regulated in human compared to chimpanzee cerebral organoids, particularly in cells analogous to radial glial neural progenitors.

BackgroundAmyloid deposition is a potential contributor to postoperative cognitive dysfunction. The authors hypothesized that 6-week global cortical amyloid burden, determined by F-florbetapir positron emission tomography, would be greater in those patients manifesting cognitive dysfunction at 6 weeks postoperatively.MethodsAmyloid deposition was evaluated in cardiac surgical patients at 6 weeks (n = 40) and 1 yr (n = 12); neurocognitive function was assessed at baseline (n = 40), 6 weeks (n = 37), 1 yr (n = 13), and 3 yr (n = 9). The association of 6-week amyloid deposition with cognitive dysfunction was assessed by multivariable regression, accounting for age, years of education, and baseline cognition. Differences between the surgical cohort with cognitive deficit and the Alzheimer's Disease Neuroimaging Initiative cohorts (normal and early/late mild cognitive impairment) was assessed, adjusting for age, education, and apolipoprotein E4 genotype.ResultsThe authors found that 6-week abnormal global cortical amyloid deposition was not associated with cognitive dysfunction (13 of 37, 35%) at 6 weeks postoperatively (median standard uptake value ratio [interquartile range]: cognitive dysfunction 0.92 [0.89 to 1.07] vs. 0.98 [0.93 to 1.05]; P = 0.455). In post hoc analyses, global cortical amyloid was also not associated with cognitive dysfunction at 1 or 3 yr postoperatively. Amyloid deposition at 6 weeks in the surgical cohort was not different from that in normal Alzheimer's Disease Neuroimaging Initiative subjects, but increased over 1 yr in many areas at a rate greater than in controls.ConclusionsIn this study, postoperative cognitive dysfunction was not associated with 6-week cortical amyloid deposition. The relationship between cognitive dysfunction and regional amyloid burden and the rate of postoperative amyloid deposition merit further investigation.

Hypertrophic cardiomyopathy (HCM) stems from mutations in sarcomeric proteins that elicit distinct biophysical sequelae, which in turn may yield radically different intracellular signaling and molecular pathologic profiles. These signaling events remain largely unaddressed by clinical trials that have selected patients based on clinical HCM diagnosis, irrespective of genotype. In this study, we determined how two mouse models of HCM differ, with respect to cellular/mitochondrial function and molecular biosignatures, at an early stage of disease. We show that hearts from young R92W-TnT and R403Q-αMyHC mutation-bearing mice differ in their transcriptome, miRNome, intracellular redox environment, mitochondrial antioxidant defense mechanisms, and susceptibility to mitochondrial permeability transition pore opening. Pathway analysis of mRNA-sequencing data and microRNA profiles indicate that R92W-TnT mutants exhibit a biosignature consistent with activation of profibrotic TGF-β signaling. Our results suggest that the oxidative environment and mitochondrial impairment in young R92W-TnT mice promote activation of TGF-β signaling that foreshadows a pernicious phenotype in young individuals. Of the two mutations, R92W-TnT is more likely to benefit from anti-TGF-β signaling effects conferred by angiotensin receptor blockers and may be responsive to mitochondrial antioxidant strategies in the early stage of disease. Molecular and functional profiling may therefore serve as aids to guide precision therapy for HCM.

Hypertrophic cardiomyopathy (HCM) is a common inherited cardiac disease characterized by varying degrees of left ventricular outflow tract obstruction. In a large cohort, we compare the outcomes among 3 different hemodynamic groups. We prospectively enrolled patients fulfilling standard diagnostic criteria for HCM from January 2005 to June 2015. Detailed phenotypic characterization, including peak left ventricular outflow tract pressure gradients at rest and after provocation, was measured by echocardiography. The primary outcome was a composite cardiovascular end point, which included new-onset atrial fibrillation, new sustained ventricular tachycardia/ventricular fibrillation, new or worsening heart failure, and death. The mean follow-up was 3.4±2.8 years. Among the 705 patients with HCM (mean age, 52±15 years; 62% men), 230 with obstructive HCM were older and had a higher body mass index and New York Heart Association class. The 214 patients with nonobstructive HCM were more likely to have a history of sustained ventricular tachycardia/ventricular fibrillation and implantable cardioverter defibrillator implantation. During follow-up, 121 patients experienced a composite cardiovascular end point. Atrial fibrillation occurred most frequently in the obstructive group. Patients with nonobstructive HCM had more frequent sustained ventricular tachycardia/ventricular fibrillation events. In multivariate analysis, obstructive (hazard ratio, 2.80; 95% confidence interval, 1.64-4.80) and nonobstructive (hazard ratio, 1.94; 95% confidence interval, 1.09-3.45) HCM were associated with more adverse events compared with labile HCM. Nonobstructive HCM carries notable morbidity, including a higher arrhythmic risk than the other HCM groups. Patients with labile HCM have a relatively benign clinical course. Our data suggest detailed sudden cardiac death risk stratification in nonobstructive HCM and monitoring with less aggressive management in labile HCM.

Alzheimer's disease (AD) is a leading cause of mortality among the elderly. We performed a whole-genome sequencing study of AD in the Chinese population. In addition to the variants identified in or around the APOE locus (sentinel variant rs73052335, P = 1.44 × 10-14), two common variants, GCH1 (rs72713460, P = 4.36 × 10-5) and KCNJ15 (rs928771, P = 3.60 × 10-6), were identified and further verified for their possible risk effects for AD in three small non-Asian AD cohorts. Genotype-phenotype analysis showed that KCNJ15 variant rs928771 affects the onset age of AD, with earlier disease onset in minor allele carriers. In addition, altered expression level of the KCNJ15 transcript can be observed in the blood of AD subjects. Moreover, the risk variants of GCH1 and KCNJ15 are associated with changes in their transcript levels in specific tissues, as well as changes of plasma biomarkers levels in AD subjects. Importantly, network analysis of hippocampus and blood transcriptome datasets suggests that the risk variants in the APOE, GCH1, and KCNJ15 loci might exert their functions through their regulatory effects on immune-related pathways. Taking these data together, we identified common variants of GCH1 and KCNJ15 in the Chinese population that contribute to AD risk. These variants may exert their functional effects through the immune system.

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

A multi-center imaging trial by the American College of Radiology Imaging Network (ACRIN) "A Multicenter, phase II assessment of tumor hypoxia in glioblastoma using 18F Fluoromisonidazole (FMISO) with PET and MRI (ACRIN 6684)", was conducted to assess hypoxia in patients with glioblastoma (GBM). The aims of this study were to support the role of proton magnetic resonance spectroscopic imaging (1H MRSI) as a prognostic marker for brain tumor patients in multi-center clinical trials. Seventeen participants from four sites had analyzable 3D MRSI datasets acquired on Philips, GE or Siemens scanners at either 1.5T or 3T. MRSI data were analyzed using LCModel to quantify metabolites N-acetylaspartate (NAA), creatine (Cr), choline (Cho), and lactate (Lac). Receiver operating characteristic curves for NAA/Cho, Cho/Cr, lactate/Cr, and lactate/NAA were constructed for overall survival at 1-year (OS-1) and 6-month progression free survival (PFS-6). The OS-1 for the 17 evaluable patients was 59% (10/17). Receiver operating characteristic analyses found the NAA/Cho in tumor (AUC = 0.83, 95% CI: 0.61 to 1.00) and in peritumoral regions (AUC = 0.95, 95% CI 0.85 to 1.00) were predictive for survival at 1 year. PFS-6 was 65% (11/17). Neither NAA/Cho nor Cho/Cr was effective in predicting 6-month progression free survival. Lac/Cr in tumor was a significant negative predictor of PFS-6, indicating that higher lactate/Cr levels are associated with poorer outcome. (AUC = 0.79, 95% CI: 0.54 to 1.00). In conclusion, despite the small sample size in the setting of a multi-center trial comprising different vendors, field strengths, and varying levels of expertise at data acquisition, MRS markers NAA/Cho, Lac/Cr and Lac/NAA predicted overall survival at 1 year and 6-month progression free survival. This study validates that MRSI may be useful in evaluating the prognosis in glioblastoma and should be considered for incorporating into multi-center clinical trials.

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

OBJECTIVE:To compare the measured stone burden recorded between urologists and radiologists, and examine how these differences could potentially impact stone management. As current urologic stone surgery guideline recommendations are based on stone size, accurate stone measurements are crucial to direct appropriate treatment. This study investigated the discrepant interpretation that often exists between urologic surgeons and radiologists' estimation of patient urinary stone burden. MATERIALS AND METHODS:From November 2015 through August 2016, new patients prospectively enrolled into the Registry for Stones of the Kidney and Ureter (ReSKU) were included if they had computed tomography images available and an accompanying official radiologic report at the time of their urologist provider visit. Stone number and aggregate stone size were compared between the urologic interpretation and the corresponding radiologic reports. RESULTS:Of 219 patients who met the inclusion criteria, concordance between urologic and radiologic assessment of aggregate stone size was higher for single stone sizing (63%) compared with multiple stones (32%). Statistical significance was found in comparing the mean difference in aggregate stone size for single and multiple stones (P

BackgroundMigraine is a prevalent and disabling disorder. Patent foramen ovale (PFO) has been associated with migraine, but its role in the disorder remains poorly understood.ObjectivesThis study examined the efficacy of percutaneous PFO closure as a therapy for migraine with or without aura.MethodsThe PREMIUM (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management) was a double-blind study investigating migraine characteristics over 1 year in subjects randomized to medical therapy with a sham procedure (right heart catheterization) versus medical therapy and PFO closure with the Amplatzer PFO Occluder device (St. Jude Medical, St. Paul, Minnesota). Subjects had 6 to 14 days of migraine per month, had failed at least 3 migraine preventive medications, and had significant right-to-left shunt defined by transcranial Doppler. Primary endpoints were responder rate defined as 50% reduction in migraine attacks and adverse events. Secondary endpoints included reduction in migraine days and efficacy in patients with versus without aura.ResultsOf 1,653 subjects consented, 230 were enrolled. There was no difference in responder rate in the PFO closure (45 of 117) versus control (33 of 103) groups. One serious adverse event (transient atrial fibrillation) occurred in 205 subjects who underwent PFO closure. Subjects in the PFO closure group had a significantly greater reduction in headache days (-3.4 vs. -2.0 days/month, p = 0.025). Complete migraine remission for 1 year occurred in 10 patients (8.5%) in the treatment group versus 1 (1%) in the control group (p = 0.01).ConclusionsPFO closure did not meet the primary endpoint of reduction in responder rate in patients with frequent migraine. (Prospective, Randomized Investigation to Evaluate Incidence of Headache Reduction in Subjects With Migraine and PFO Using the AMPLATZER PFO Occluder to Medical Management [PREMIUM]; NCT00355056).

Most differentiated cells convert glucose to pyruvate in the cytosol through glycolysis, followed by pyruvate oxidation in the mitochondria. These processes are linked by the mitochondrial pyruvate carrier (MPC), which is required for efficient mitochondrial pyruvate uptake. In contrast, proliferative cells, including many cancer and stem cells, perform glycolysis robustly but limit fractional mitochondrial pyruvate oxidation. We sought to understand the role this transition from glycolysis to pyruvate oxidation plays in stem cell maintenance and differentiation. Loss of the MPC in Lgr5-EGFP-positive stem cells, or treatment of intestinal organoids with an MPC inhibitor, increases proliferation and expands the stem cell compartment. Similarly, genetic deletion of the MPC in Drosophila intestinal stem cells also increases proliferation, whereas MPC overexpression suppresses stem cell proliferation. These data demonstrate that limiting mitochondrial pyruvate metabolism is necessary and sufficient to maintain the proliferation of intestinal stem cells.

Contempt is a powerful emotion. Marriages fail (Gottman, 1994), coworkers are shamed (Melwani & Barsade, 2011), terrorism is tended toward (Tausch et al., 2011). Despite its importance, contempt has not been investigated at the level of personality. The present research examines how our contemptuous reactions can be conceptualized and measured as a stable individual-difference variable with a range of theoretically predicted correlates. First, we introduce a measure of dispositional contempt, the tendency to look down on, distance, and derogate others who violate our standards. We then unpack the dynamics of dispositional contempt. Across 6 studies using self-report and emotion elicitation in student and MTurk samples (Ns = 165 to 1,368), we examined its (a) nomological network, (b) personality and behavioral correlates, and (c) implications for relationship functioning. Dispositional contempt was distinguished from tendencies toward related emotions and was most associated with dispositional envy, anger, and hubristic pride. Somewhat paradoxically, dispositional contempt was related to being cold and "superior," with associations found with narcissism, other-oriented perfectionism, and various antisocial tendencies (e.g., Disagreeableness, Machiavellianism, racism), but it was also related to being self-deprecating and emotionally fragile, with associations found with low self-esteem, insecure attachment, and feeling that others impose perfectionistic standards on oneself. Dispositional contempt predicted contemptuous reactions to eliciting film clips, particularly when targets showed low competence/power. Finally, perceiving one's romantic partner as dispositionally contemptuous was associated with lower commitment and satisfaction. Taken together, results give a first look at the contemptuous person and provide a new organizing framework for understanding contempt. (PsycINFO Database Record