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Functional speech by 5 years of age is widely established as increasing the probability of long-term positive outcomes across a range of domains for autistic individuals. While terms such as functional or useful speech are often used, what defines these terms is not well established. Furthermore, most research focusing on language development has emphasized the transition from little or no language to use of single words, but much less is known about the transition from single words to phrase speech, which could be equally important. The verb lexicon is foundational to the development of simple, generative phrases and has been linked to prosocial behaviors and general developmental outcomes including better social communication skills, socioemotional reciprocity, and nonverbal communication in autistic children. The current systematic review synthesized information from 20 independent samples to characterize autistic children who transitioned from single words to phrase speech. On average, 48% of the pooled sample transitioned to phrase speech during the study periods. Results were highly variable across studies. Participants under the age of 5 years were more likely to transition to phrases than participants over the age of 5. Though average standard scores were above 50, children who transitioned to phrases generally demonstrated below average adaptive and cognitive skills and moderate-high ASD symptomatology. Variable measures of cognition made it difficult to ascertain patterns in cognitive skills; nonetheless, nonverbal IQ emerged as a salient predictor of the transition to phrases across studies. More research is needed to better understand who transitions beyond single words, clinical benchmarks on the way to generative phrase speech and the factors that predict this transition. Such information can be used to inform clinical decision making and develop or improve targeted interventions based on individual communication profiles. This could make the use of phrases more likely for a greater number of autistic individuals, increasing the likelihood that these individuals communicate independently and effectively with others.

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation mediates genomic instability by inducing transcription-replication conflicts. Strikingly, CDK12-mutant organoids and patient-derived xenografts are sensitive to inhibition or degradation of the paralog kinase, CDK13. We therein establish CDK12 as a bona fide tumor suppressor, mechanistically define how CDK12 inactivation causes genomic instability, and advance a therapeutic strategy for CDK12-mutant mCRPC.

Although caregiving responsibilities and need for support persist and evolve across the life course in families with autistic youth or youth with other developmental disabilities (DDs), little is known about support during their childs adulthood years. Therefore, the present study used a mixed-methods approach to examine change and stability in formal and informal family support across the transition to adulthood. Caregivers of 126 individuals with autism or DDs completed a modified version of the Family Support Scale, including open-ended questions, at five time points from adolescence (age 16) into young adulthood (age 22). Caregivers reported that informal support from family members was the most frequently used, helpful, and valued source of support with relative stability across time. In contrast, the reported helpfulness, use, and value of formal support (e.g., professionals, schools) for caregivers declined over time. Qualitative content analyses revealed characteristics of highly valued support included support type (e.g., instrumental or emotional) and features of the support source (e.g., their understanding). There was a shift to valuing emotional support more than instrumental support over time, especially for caregivers of less able adults. Partnership and dependability emerged as highly valued features of the support source. These findings fit within a social convoy perspective and likely reflect the service cliff experienced by autistic individuals or people with DDs and their families. As social networks shrink over time and formal services are less readily available in adulthood, remaining sources of support, particularly from family members, become increasingly important.

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2. We identify an 18 base pair region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals in whom it could be determined, the de novo variants were all on the maternal allele. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologues. Using RNA sequencing, we show how 5 splice-site use is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation. Finally, we estimate that variants in this 18 base pair region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

Introduction: Capnocytophaga ochracea is found in the human oral microbiome and is a rare cause of antibiotic-resistant, opportunistic septicemia in immunocompromised hosts. The zoonotic transmission of C ochracea from canines to humans has not yet been reported in the literature. Cohabitation with people is associated with oral colonization in dogs and may be a reservoir for Capnocytophaga infections, which have a decreased susceptibility to first-line antibiotics commonly used to treat animal exposures.Case Report: This is the case of a 70-year-old male with a remote history of lymphoma status post splenectomy, in remission, who presented with stigmata of Capnocytophaga septicemia after a dog bite, which included purpura fulminans on physical examination. Initial broad-spectrum coverage with cefepime failed to slow the progression into multiorgan failure. A Capnocytophaga strain with extended resistance was suspected. Antibiotics were transitioned to meropenem, and the patient eventually made a good recovery. Blood cultures isolated C ochracea.Conclusion: Capnocytophaga infections should be suspected in patients with severe sepsis and purpura fulminans after a canine exposure. Canine pets may be a reservoir for Capnocytophaga species with increased antibiotic resistances, such as C ochracea, which trace their origins to the human oral microbiome. A thorough medical history is essential to identify risk factors such as asplenia and active immune compromise that are associated with infections from antibiotic-resistant strains and worse outcomes. For Capnocytophaga infections that fail initial therapies, cephalosporins should be avoided because of high resistance rates, and the use of carbapenems may be favored over combination beta-lactam/beta-lactamase inhibitors in select clinical scenarios.

We know that many autistic people feel lonely, but we dont know whether their loneliness changes over time. Our research study followed autistic people and people with other non-spectrum neurodevelopmental disabilities from childhood through young adulthood and asked them about their loneliness. While many people told us they felt lonely or very lonely, a sizable group also told us that they do not feel lonely. We found that people who reported feeling lonely earlier in life were likely to also report feeling lonely later in life. Overall, autistic people and people with other neurodevelopmental disabilities in our study became lonelier from adolescence to adulthood. People described multiple ways they cope with feeling lonely, such as distracting themselves or reaching out to connect with another person. People who used distraction tended to be lonelier than those who did not. Our findings tell us that there is a need for greater support of social connections for many autistic people as they become adults.

BACKGROUND: Organized physical activity programs have been shown to provide wide benefits to participants, though there are relatively few studies examining the impact of these programs for individuals with developmental disabilities. This pilot study was conducted to determine the feasibility and impact of an undergraduate-led dance intervention program for children and adolescents with developmental disabilities. We evaluated the impact of the dance program on motor ability and social skills. METHODS: The study design was a waitlist control clinical trial in which participants were randomized to active and control groups. Eligible participants included male and female children and adolescents between the ages of 4 and 17 years with neurodevelopmental disabilities. The Motor Assessment Battery for Children Checklist and the Social Responsiveness Scale were used to assess change in motor and social skills, respectively. After gathering baseline data, the active group completed 1 h of online dance classes per week for 10 weeks, while the control group entered a 10-week waiting period. All participants then returned for a follow-up visit. Pre- and post-intervention data were analyzed using linear mixed-effects modeling adjusting for age and class attendance with subject random intercept. RESULTS: We recruited and randomized 43 participants with neurodevelopmental disabilities (mean age = 8.63, SD = 2.98), of which 30 participated in dance classes. The attendance rate was 82.6% for the active group and 61.7% for the control group. The active group demonstrated a significant improvement in motor skills in an unpredictable environment, as indicated on the Motor Assessment Battery for Children Checklist (n = 21, p = 0.05). We also observed positive trends in social skills that did not reach significance. CONCLUSIONS: Our results indicate that it is feasible to develop and implement a fully digital dance intervention program for individuals with developmental disabilities. Further, we find that change in motor skills can be detected after just 10 h of low-intensity participation. However, a lack of significant change in social skills coupled with limitations in study implementation suggests further research is needed to determine the full impact of this dance program. TRIAL REGISTRATION: ClinicalTrials.gov Protocol Registration System: Protocol ID 20-001680-AM-00005, registered 17/2/2021 - Retrospectively Registered, https://clinicaltrials.gov/study/NCT04762290 .

The current study investigated the utility of the Brief Observation of Social Communication Change-Phrase Speech Young Fluent (BOSCC-PSYF) as an outcome measure of treatment response by analyzing the measures psychometric properties and initial validity. The BOSCC coding scheme was applied to 345 administrations from 160 participants diagnosed with autism. Participants included individuals of any age with phrase speech, or individuals under the age of 8 years with complex sentences. All were receiving behavioral intervention throughout the study. Test-retest and inter-rater reliability were good for the Early Communication and Social Reciprocity/Language domains, and fair for the Restricted and Repetitive Behavior domain. Significant changes occurred over time in the Early Communication and Social Reciprocity/Language domains, and Core Total scores. The BOSCC-PSYF may provide a low-cost, flexible, and user-friendly outcome measure that reliably measures changes in broad social communicative behaviors in a short period of time.

Wild pigs arrived on the Bankhead Ranger District in the late 1980s and ‘90s. They proliferated and control efforts began in the early 2000s. In 2011, intensive efforts began, centered around whole sounder removal. By 2020, pigs were controlled at low densities throughout the District except for the rugged and remote Sipsey Wilderness Area. The area is 25,810 acres and surrounding environs remained off limits until a minimum resource analysis was completed, allowing for active management. The Sipsey Pig Project was born. An interagency team was formed, comprised of United States Forest Service (USFS), Alabama Department of Conservation and Natural Resources (ADCNR), and Animal and Plant Health Inspection (APHIS) Wildlife Services personnel. Crucial funding and volunteer support was provided by several local organizations including the wilderness advocacy group. The project began in 2021, when ADCNR agreed to eliminate two special hog hunts on the District. Four technicians from the three agencies began control efforts focused primarily on trapping and whole sounder removal. Other techniques were utilized including aerial gunning and Judas pig with varying levels of success. The first year concluded with approximately 50% of the wilderness receiving control efforts and a record 421 pigs removed from the District, a three-fold increase over the previous year. The next year, 2022, saw the entirety of the wilderness receive control efforts and a marked decrease in pig densities. The initial battle is won but the war remains undecided. Initial control was achieved faster than expected, yet much work remains with four years left in the project. The Sipsey Pig Project is the most aggressive action to date undertaken against wild pigs in a USFS wilderness area east of the Mississippi River. The strategic application of management techniques combined with strong partnerships can achieve wild pig control in the remote regions of our country.

Psilocybin therapy for depression has started to show promise, yet the underlying causal mechanisms are not currently known. Here, we leveraged the differential outcome in responders and non-responders to psilocybin (10 and 25 mg, 7 days apart) therapy for depression-to gain new insights into regions and networks implicated in the restoration of healthy brain dynamics. We used large-scale brain modelling to fit the spatiotemporal brain dynamics at rest in both responders and non-responders before treatment. Dynamic sensitivity analysis of systematic perturbation of these models enabled us to identify specific brain regions implicated in a transition from a depressive brain state to a healthy one. Binarizing the sample into treatment responders (>50% reduction in depressive symptoms) versus non-responders enabled us to identify a subset of regions implicated in this change. Interestingly, these regions correlate with in vivo density maps of serotonin receptors 5-hydroxytryptamine 2a and 5-hydroxytryptamine 1a, which psilocin, the active metabolite of psilocybin, has an appreciable affinity for, and where it acts as a full-to-partial agonist. Serotonergic transmission has long been associated with depression, and our findings provide causal mechanistic evidence for the role of brain regions in the recovery from depression via psilocybin.

IntroductionSocietal perceptions and lack of understanding of autism spectrum disorder can be stigmatizing for autistic individuals and their families. This may be particularly the case for individuals who meet criteria for profound autism. Despite the considerable service needs of this marginalized group, there is little data on the prevalence of profound autism, nor on the experiences of those with profound autism and their families.MethodsThe current study leveraged a mixed-methods approach to address these gaps. First, the prevalence of profound autism was examined in six samples-three from the United States and three from Western Europe. Second, inductive thematic analysis was used to code interviews from 20 caregivers of profoundly autistic adults.ResultsThe prevalence of profound autism varied widely across the six samples-from 11% to 48%. There were also notable differences between samples in prevalence by gender, race, and ethnicity. Two overarching themes were identified via inductive thematic analysis: Community Perceptions of Autism and Family Support Needs and Advocacy Challenges. Though caregivers were not directly asked about stigmatization during interviews, 85% of caregivers reported at least one instance of perceived stigma.DiscussionFuture research should continue to examine the unique needs and stigmatization experiences of profoundly autistic individuals and their families across the life course.

Introduction: Patients present to the emergency department (ED) relatively commonly with traumatic closed proximal interphalangeal joint (PIPJ) dislocations, an orthopedic emergency. There is a paucity of teaching models and training simulations for clinicians to learn either the closed dislocated dorsal or volar interphalangeal joint reduction technique. We implemented a teaching model to demonstrate the utility of a novel reduction model designed from three-dimensional (3D) printable components that are easy to connect and do not require further machining or resin models to complete.Methods: Students watched a two-minute video and a model demonstration by the authors. Learners including emergency medicine (EM) residents and physician assistant fellows assessed model fidelity, convenience, perceived competency, and observed competency.Results: Seventeen of 21 (81%) participants agreed the model mimicked dorsal and volar PIPJ dislocations. Nineteen of 21 (90%) agreed the model was easy to use, 21/21 (100%) agreed the dorsal PIPJ model and 20/21 (95%) agreed the volar PIPJ model improved their competency.Conclusion: Our 3D-printed, dorsal and volar dislocation reduction model is easy to use and affordable, and it improved perceived competency among EM learners at an academic ED.

Community college students in Los Angeles who balance work and school face an array of difficult barriers: housing insecurities, mental health hurdles, inadequate financial aid, and parenting stress, among others. These inequities were only exacerbated during the COVID-19 pandemic. Student Balancing Act: Worker and Learner Experiences in Los Angeles’ Community Colleges analyzes the experiences of Los Angeles County community college students who attend school and who work. For this analysis, the authors subsetted the data of 391 survey responses and nine interviews collected from community college workers and learners and featured in the UCLA Labor Center and Dolores Huerta Labor Institute (DHLI) report Unseen Costs: The Experiences of Workers and Learners in Los Angeles County.

BackgroundDifficult facemask ventilation is perilous in children whose tracheas are difficult to intubate. We hypothesised that certain physical characteristics and anaesthetic factors are associated with difficult mask ventilation in paediatric patients who also had difficult tracheal intubation.MethodsWe queried a multicentre registry for children who experienced "difficult" or "impossible" facemask ventilation. Patient and case factors known before mask ventilation attempt were included for consideration in this regularised multivariable regression analysis. Incidence of complications, and frequency and efficacy of rescue placement of a supraglottic airway device were also tabulated. Changes in quality of mask ventilation after injection of a neuromuscular blocking agent were assessed.ResultsThe incidence of difficult mask ventilation was 9% (483 of 5453 patients). Infants and patients having increased weight, being less than 5th percentile in weight for age, or having Treacher-Collins syndrome, glossoptosis, or limited mouth opening were more likely to have difficult mask ventilation. Anaesthetic induction using facemask and opioids was associated with decreased risk of difficult mask ventilation. The incidence of complications was significantly higher in patients with "difficult" mask ventilation than in patients without. Rescue placement of a supraglottic airway improved ventilation in 71% (96 of 135) of cases. Administration of neuromuscular blocking agents was more frequently associated with improvement or no change in quality of ventilation than with worsening.ConclusionsCertain abnormalities on physical examination should increase suspicion of possible difficult facemask ventilation. Rescue use of a supraglottic airway device in children with difficult or impossible mask ventilation should be strongly considered.

ObjectivePrevious studies showed that inhibiting lymphocyte costimulation reduces declining β-cell function in individuals newly diagnosed with type 1 diabetes. We tested whether abatacept would delay or prevent progression of type 1 diabetes from normal glucose tolerance (NGT) to abnormal glucose tolerance (AGT) or to diabetes and the effects of treatment on immune and metabolic responses.Research design and methodsWe conducted a phase 2, randomized, placebo-controlled, double-masked trial of abatacept in antibody-positive participants with NGT who received monthly abatacept/placebo infusions for 12 months. The end point was AGT or diabetes, assessed by oral glucose tolerance tests.ResultsA total of 101 participants received abatacept and 111 placebo. Of these, 81 (35 abatacept and 46 placebo) met the end point of AGT or type 1 diabetes diagnosis (hazard ratio 0.702; 95% CI 0.452, 1.09; P = 0.11) The C-peptide responses to oral glucose tolerance tests were higher in the abatacept arm (P < 0.03). Abatacept reduced the frequency of inducible T-cell costimulatory (ICOS)+ PD1+ T-follicular helper (Tfh) cells during treatment (P < 0.0001), increased naive CD4+ T cells, and also reduced the frequency of CD4+ regulatory T cells (Tregs) from the baseline (P = 0.0067). Twelve months after treatment, the frequency of ICOS+ Tfh, naive CD4+ T cells, and Tregs returned to baseline.ConclusionsAlthough abatacept treatment for 1 year did not significantly delay progression to glucose intolerance in at-risk individuals, it impacted immune cell subsets and preserved insulin secretion, suggesting that costimulation blockade may modify progression of type 1 diabetes.

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease. While neurons generally produce a minority of the apoE in the central nervous system, neuronal expression of apoE increases dramatically in response to stress and is sufficient to drive pathology. Currently, the molecular mechanisms of how apoE4 expression may regulate pathology are not fully understood. Here, we expand upon our previous studies measuring the impact of apoE4 on protein abundance to include the analysis of protein phosphorylation and ubiquitylation signaling in isogenic Neuro-2a cells expressing apoE3 or apoE4. ApoE4 expression resulted in a dramatic increase in vasodilator-stimulated phosphoprotein (VASP) S235 phosphorylation in a protein kinase A (PKA)-dependent manner. This phosphorylation disrupted VASP interactions with numerous actin cytoskeletal and microtubular proteins. Reduction of VASP S235 phosphorylation via PKA inhibition resulted in a significant increase in filopodia formation and neurite outgrowth in apoE4-expressing cells, exceeding levels observed in apoE3-expressing cells. Our results highlight the pronounced and diverse impact of apoE4 on multiple modes of protein regulation and identify protein targets to restore apoE4-related cytoskeletal defects.

Study designA retrospective, case-control study.ObjectiveWe aim to build a risk calculator predicting major perioperative complications after anterior cervical fusion. In addition, we aim to externally validate this calculator with an institutional cohort of patients who underwent anterior cervical discectomy and fusion (ACDF).Summary of background dataThe average age and proportion of patients with at least one comorbidity undergoing ACDF have increased in recent years. Given the increased morbidity and cost associated with perioperative complications and unplanned readmission, accurate risk stratification of patients undergoing ACDF is of great clinical utility.MethodsThis is a retrospective cohort study of adults who underwent anterior cervical fusion at any nonfederal California hospital between 2015 and 2017. The primary outcome was major perioperative complication or 30-day readmission. We built standard and ensemble machine learning models for risk prediction, assessing discrimination, and calibration. The best-performing model was validated on an external cohort comprised of consecutive adult patients who underwent ACDF at our institution between 2013 and 2020.ResultsA total of 23,184 patients were included in this study; there were 1886 cases of major complication or readmissions. The ensemble model was well calibrated and demonstrated an area under the receiver operating characteristic curve of 0.728. The variables most important for the ensemble model include male sex, medical comorbidities, history of complications, and teaching hospital status. The ensemble model was evaluated on the validation cohort (n=260) with an area under the receiver operating characteristic curve of 0.802. The ensemble algorithm was used to build a web-based risk calculator.ConclusionWe report derivation and external validation of an ensemble algorithm for prediction of major perioperative complications and 30-day readmission after anterior cervical fusion. This model has excellent discrimination and is well calibrated when tested on a contemporaneous external cohort of ACDF cases.

People with autism spectrum disorder (ASD) and non-spectrum developmental delays frequently exhibit maladaptive behaviors throughout the lifespan, which can have pervasive effects on quality of life. Maladaptive behaviors have been shown to change over time as a function of various individual-level factors (e.g., cognitive ability), yet research is primarily limited to parent-reported measures. To expand upon this work, the present study aimed to examine trajectories of teacher- and parent-reported maladaptive behaviors (i.e., hyperactivity, irritability, social withdrawal) and to test whether individual-level predictors (e.g., autism features, verbal intelligence quotient) and school-related predictors (e.g., teacher type, student-adult ratio, personal aide, school type) impact these trajectories among 165 individuals with ASD or non-spectrum delays from ages 9 to 18. Multilevel models revealed that, according to both teacher and parent report, participants showed the greatest improvement in hyperactivity, less but still notable improvement in irritability, and stable levels of social withdrawal over time. Higher verbal ability and fewer ASD features, in addition to mainstream school placement, emerged as important individual- and school-related differences associated with fewer maladaptive behaviors over time. The multi-informant perspective and longitudinal design provide novel insight into the manifestations of these maladaptive behaviors across different contexts and across time. Findings highlight the consistency of teacher- and parent-reported trajectories over time and further emphasize the importance of targeting maladaptive behaviors using a multisystem intervention approach in both school and home contexts.

Apathy is one of the most common neuropsychiatric symptoms (NPS) and is associated with poor clinical outcomes. Research that helps define the apathy phenotype is urgently needed, particularly for clinical and biomarker studies. We used latent class analysis (LCA) with two independent cohorts to understand how apathy and depression symptoms co-occur statistically. We further explored the relationship between latent class membership, demographics, and the presence of other NPS. The LCA identified a four-class solution (no symptoms, apathy, depression, and combined apathy/depression), reproducible over both cohorts, providing robust support for an apathy syndrome distinct from depression and confirming that an apathy/depression syndrome exists, supported by the model fit test with the four-class solution scores evidencing better fitting (Bayesian information criterion adjusted and entropy R 2). Using a data-driven method, we show distinct and statistically meaningful co-occurrence of apathy and depressive symptoms. There was evidence that these classes have different clinical associations, which may help inform diagnostic categories for research studies and clinical practice.HighlightsWe found four classes: no symptoms, apathy, depression and apathy/depression.Apathy conferred a higher probability for agitation.Apathy diagnostic criteria should include accompanying neuropsychiatric symptoms.

IntroductionMost people living with dementia want to remain living in their own homes, and are supported to do so by family carers and homecare workers. There are concerns that homecare is often unable to meet the needs of this client group, with limited evidence regarding effective interventions to improve it for people living with dementia. We have developed a training and support programme for homecare workers (NIDUS-Professional) to be delivered alongside support sessions for people living with dementia and their family carers (NIDUS-Family). We aim to assess (1) its acceptability among homecare workers and employing agencies, and (2) the feasibility of homecare workers, people living with dementia and their family carers completing the outcomes of intervention in a future randomised controlled trial.Methods and analysisThis is a cluster-randomised (2:1) single-blind, multisite feasibility trial. We aim to recruit 60-90 homecare workers, 30-60 clients living with dementia and their family carers through 6-9 English homecare agencies. In the intervention arm, homecare staff will be offered six group sessions on video call over three months, followed by monthly group sessions over the subsequent three-month period. Outcome measures will be collected at baseline and at six months.Ethics and disseminationThe study received ethical approval on 7 January 2020 from the Camden & King's Cross Research Ethics Committee. Study reference: 19/LO/1667. Findings will be disseminated through a peer-reviewed journal, conference presentation and blog to research and clinical audiences; we will attend forums to present findings to participating homecare agencies and their clients.Trial registration numberISRCTN15757555.

ADP-ribosylation, a modification of proteins, nucleic acids, and metabolites, confers broad functions, including roles in stress responses elicited, for example, by DNA damage and viral infection and is involved in intra- and extracellular signaling, chromatin and transcriptional regulation, protein biosynthesis, and cell death. ADP-ribosylation is catalyzed by ADP-ribosyltransferases (ARTs), which transfer ADP-ribose from NAD+ onto substrates. The modification, which occurs as mono- or poly-ADP-ribosylation, is reversible due to the action of different ADP-ribosylhydrolases. Importantly, inhibitors of ARTs are approved or are being developed for clinical use. Moreover, ADP-ribosylhydrolases are being assessed as therapeutic targets, foremost as antiviral drugs and for oncological indications. Due to the development of novel reagents and major technological advances that allow the study of ADP-ribosylation in unprecedented detail, an increasing number of cellular processes and pathways are being identified that are regulated by ADP-ribosylation. In addition, characterization of biochemical and structural aspects of the ARTs and their catalytic activities have expanded our understanding of this protein family. This increased knowledge requires that a common nomenclature be used to describe the relevant enzymes. Therefore, in this viewpoint, we propose an updated and broadly supported nomenclature for mammalian ARTs that will facilitate future discussions when addressing the biochemistry and biology of ADP-ribosylation. This is combined with a brief description of the main functions of mammalian ARTs to illustrate the increasing diversity of mono- and poly-ADP-ribose mediated cellular processes.

Fully understanding autism spectrum disorder (ASD) genetics requires whole-genome sequencing (WGS). We present the latest release of the Autism Speaks MSSNG resource, which includes WGS data from 5,100 individuals with ASD and 6,212 non-ASD parents and siblings (total n = 11,312). Examining a wide variety of genetic variants in MSSNG and the Simons Simplex Collection (SSC; n = 9,205), we identified ASD-associated rare variants in 718/5,100 individuals with ASD from MSSNG (14.1%) and 350/2,419 from SSC (14.5%). Considering genomic architecture, 52% were nuclear sequence-level variants, 46% were nuclear structural variants (including copy-number variants, inversions, large insertions, uniparental isodisomies, and tandem repeat expansions), and 2% were mitochondrial variants. Our study provides a guidebook for exploring genotype-phenotype correlations in families who carry ASD-associated rare variants and serves as an entry point to the expanded studies required to dissect the etiology in the ∼85% of the ASD population that remain idiopathic.

Predicting the survival outcomes of patients with colorectal cancer (CRC) remains challenging. We investigated the prognostic significance of the transcriptome and tumour-infiltrating lymphocyte T-cell receptor (TIL/Tc-TCR) repertoire and analysed TIL/Tc-TCR sequences of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) CRC cohorts. Using a multivariate Cox regression, we tested whether TIL/Tc-TCR repertoire, patient and tumour characteristics (stage, sidedness, total non-synonymous mutations, microsatellite instability (MSI) and transcriptional signatures) correlated with patient overall survival (OS) and designed a prognostic nomogram. A multivariate analysis (C-index = 0.75) showed that only patient age, disease stage, TIL/Tc degree of infiltration and clonality were independent prognostic factors for OS. The cut-offs for patients’ allocation to TIL/Tc abundance subgroups were determined using a strategy of maximally selected rank statistics with the OptimalCutpoints R package. These were “high”, “low” and “very high” (90 th percentile) TIL/Tc infiltration-stratified OS (median not reached, 67 and 44.3 months; p < 0.001); the results were validated in the CPTAC cohort. TIL/Tc clonality was prognostic (median OS in “high” vs. “low” clonality not reached and 67.3 months; p = 0.041) and independent of TIL/Tc infiltration. Whilst tumour sidedness was not prognostic, the “very highly” infiltrated tumours were prevalent among right-sided CRCs (p = 0.039) and showed distinct immunological features, with lower Th1 signature (p = 0.004), higher PD-L1 expression (p < 0.001) and likely enrichment in highly suppressory IL1R1+ Tregs (FoxP3 and IL1R1 overexpression, p < 0.001). TIL/Tc abundance and clonality are independent prognosticators in CRC and, combined with clinical variables, refine risk stratification. We identified a subset of CRCs with “very high” TIL/Tc infiltration, poor prognosis and distinct genetic and immunologic features, which may benefit from alternative therapeutic approaches. These results need validation in prospective patient cohorts.

BackgroundC5 palsy is a common postoperative complication after cervical fusion and is associated with increased health care costs and diminished quality of life. Accurate prediction of C5 palsy may allow for appropriate preoperative counseling and risk stratification. We primarily aim to develop an algorithm for the prediction of C5 palsy after instrumented cervical fusion and identify novel features for risk prediction. Additionally, we aim to build a risk calculator to provide the risk of C5 palsy.MethodsWe identified adult patients who underwent instrumented cervical fusion at a tertiary care medical center between 2013 and 2020. The primary outcome was postoperative C5 palsy. We developed ensemble machine learning, standard machine learning, and logistic regression models predicting the risk of C5 palsy-assessing discrimination and calibration. Additionally, a web-based risk calculator was built with the best-performing model.ResultsA total of 1024 patients were included, with 52 cases of C5 palsy. The ensemble model was well-calibrated and demonstrated excellent discrimination with an area under the receiver-operating characteristic curve of 0.773. The following features were the most important for ensemble model performance: diabetes mellitus, bipolar disorder, C5 or C4 level, surgical approach, preoperative non-motor neurologic symptoms, degenerative disease, number of fused levels, and age.ConclusionsWe report a risk calculator that generates patient-specific C5 palsy risk after instrumented cervical fusion. Individualized risk prediction for patients may facilitate improved preoperative patient counseling and risk stratification as well as potential intraoperative mitigating measures. This tool may also aid in addressing potentially modifiable risk factors such as diabetes and obesity.

Siblings play an important role in the behavioral trajectories of individuals with autism spectrum disorder (ASD). While having siblings has been associated with positive outcomes in ASD, including stronger adaptive functioning, social and non-verbal communication, and theory of mind, little is known about the impact of siblings on more negative outcomes, such as maladaptive behaviors. To address this gap, the present longitudinal study tested sibling predictors of trajectories of maladaptive behaviors (e.g., teacher- and parent-reported hyperactivity, irritability, and social withdrawal) from childhood through early adulthood among individuals with ASD and non-spectrum delays. Multilevel models revealed that, while the mere presence of a sibling did not impact maladaptive behavior trajectories apart from teacher-reported hyperactivity, the diagnostic profile of the sibling (e.g., emotional/behavioral disorder, ASD, medical condition) emerged as an important predictor. Specifically, although findings varied across teacher and parent reports, more hyperactivity and irritability across time was identified when the sibling had diagnoses of an emotional/behavioral disorder, ASD, and/or a medical condition. Overall, this study provides novel insight into the broader family-level factors that influence the presentation of maladaptive behaviors across time and across contexts.

Backgroundfalls and fall-related injuries are common in older adults, have negative effects on functional independence and quality of life and are associated with increased morbidity, mortality and health related costs. Current guidelines are inconsistent, with no up-to-date, globally applicable ones present.Objectivesto create a set of evidence- and expert consensus-based falls prevention and management recommendations applicable to older adults for use by healthcare and other professionals that consider: (i) a person-centred approach that includes the perspectives of older adults with lived experience, caregivers and other stakeholders; (ii) gaps in previous guidelines; (iii) recent developments in e-health and (iv) implementation across locations with limited access to resources such as low- and middle-income countries.Methodsa steering committee and a worldwide multidisciplinary group of experts and stakeholders, including older adults, were assembled. Geriatrics and gerontological societies were represented. Using a modified Delphi process, recommendations from 11 topic-specific working groups (WGs), 10 ad-hoc WGs and a WG dealing with the perspectives of older adults were reviewed and refined. The final recommendations were determined by voting.Recommendationsall older adults should be advised on falls prevention and physical activity. Opportunistic case finding for falls risk is recommended for community-dwelling older adults. Those considered at high risk should be offered a comprehensive multifactorial falls risk assessment with a view to co-design and implement personalised multidomain interventions. Other recommendations cover details of assessment and intervention components and combinations, and recommendations for specific settings and populations.Conclusionsthe core set of recommendations provided will require flexible implementation strategies that consider both local context and resources.

BackgroundLumbar fusion (LF) is commonly performed to manage lumbar degenerative disc disease (LDDD) that has failed conservative measures. However, lumbar disc replacement (LDR) procedures are increasingly prevalent and designed to preserve motion in carefully selected patients.MethodsA retrospective cohort study was performed using the National Inpatient Sample (NIS), queried from 2010 to 2019 to identify patients undergoing single and double-level LF or LDR with a diagnosis of LDDD using International Classification of Diseases (ICD) 9th (ICD-9) and 10th (ICD-10) revision diagnostic and procedure codes. Propensity score matching (PSM) with a ratio of 2:1 was performed. All cost estimates reflect reported hospital costs adjusted to December 2019 United States Dollars.ResultsA total of 1,129,121 LF cases (99.3%) and 8,049 LDR cases (0.7%) were identified, with 364,637 (32.3%) and 712 (8.8%) comprising two-level surgeries, respectively. 1,712 LDRs were performed in 2010 (1.27% of all), decreasing to 565 in 2013 (0.52%), and increased slightly to 870 in 2019 (0.74%). LDR patients were significantly more likely to be younger (mean age 41.2 vs. 57.1, P

Quantifying behavioral synchrony can inform clinical diagnosis, long-term monitoring, and individualised interventions in neuro-developmental disorders characterized by deficit in communication and social interaction, such as autism spectrum disorder. In this work, three different objective measures of interpersonal synchrony are evaluated across vocal and linguistic communication modalities. For vocal prosodic and spectral features, dynamic time warping distance and squared cosine distance of (feature-wise) complexity are used, and for lexical features, word mover's distance is applied to capture behavioral synchrony. It is shown that these interpersonal vocal and linguistic synchrony measures capture complementary information that helps in characterizing overall behavioral patterns.

PurposePosterior cervical fusion is associated with increased rates of complications and readmission when compared to anterior fusion. Machine learning (ML) models for risk stratification of patients undergoing posterior cervical fusion remain limited. We aim to develop a novel ensemble ML algorithm for prediction of major perioperative complications and readmission after posterior cervical fusion and identify factors important to model performance.MethodsThis is a retrospective cohort study of adults who underwent posterior cervical fusion at non-federal California hospitals between 2015 and 2017. The primary outcome was readmission or major complication. We developed an ensemble model predicting complication risk using an automated ML framework. We compared performance with standard ML models and logistic regression (LR), ranking contribution of included variables to model performance.ResultsOf the included 6822 patients, 18.8% suffered a major complication or readmission. The ensemble model demonstrated slightly superior predictive performance compared to LR and standard ML models. The most important features to performance include sex, malignancy, pneumonia, stroke, and teaching hospital status. Seven of the ten most important features for the ensemble model were markedly less important for LR.ConclusionWe report an ensemble ML model for prediction of major complications and readmission after posterior cervical fusion with a modest risk prediction advantage compared to LR and benchmark ML models. Notably, the features most important to the ensemble are markedly different from those for LR, suggesting that advanced ML methods may identify novel prognostic factors for adverse outcomes after posterior cervical fusion.

[This corrects the article DOI: 10.3389/fpsyg.2022.927847.].

BackgroundCervical radiculopathy is a relatively common problem that often affects individuals in their 5th decade. Most cases resolve with conservative treatment, but when unsuccessful, many opt for surgical intervention. Anterior cervical discectomy and fusion is currently considered the gold standard for the surgical management of cervical radiculopathy. One promising alternative, the DTRAX facet system is minimally invasive and may significantly reduce or eliminate cervical radicular symptoms. This case series and literature review looks to investigate the safety and efficacy of the DTRAX facet system in treating cervical radiculopathy.MethodsThis retrospective analysis was performed by chart review of patients who underwent posterior cervical fusion and received the DTRAX spinal implant at University of California, Los Angeles within the last 8 years. Patient charts were located using the surgical cases report function of Epic electronic medical record, and patients were included in the study if they received a DTRAX implant during the stated time period. Data were compiled and analyzed using Microsoft Excel.ResultsA total of 14 patient charts were reviewed. Of the 14, there were no immediate postoperative complications. One international patient was subsequently lost to follow-up, and of the remaining 13, mean follow-up duration was 273 days, with a range of 15-660 days. All but one reported improvement of symptoms postoperatively, there were no device failures, and no reoperations were required. There were similar outcomes in patients who received single versus multilevel operations.ConclusionThe findings of this retrospective study of 14 patients who received the DTRAX facet system over the last 8 years support the conclusions of previous studies that DTRAX is safe and effective. In addition, this is the first study to look for differences in outcomes between single and multi-level DTRAX operations, of which there were none. Further investigation with larger cohorts should be conducted as DTRAX becomes more widely adopted in order to verify its safety and efficacy in various clinical scenarios.

Increasing numbers of children with known genetic conditions and/or intellectual disability are referred for evaluation of autism spectrum disorder (ASD), highlighting the need to refine autism symptom measures to facilitate differential diagnoses in children with cognitive and language impairments. Previous studies have reported decreased specificity of ASD screening and diagnostic measures in children with intellectual disability. However, little is known about how cognitive and language abilities impact the measurement of specific ASD symptoms in this group. We aggregated a large sample of young children (N = 1196; aged 31-119 months) to examine measurement invariance of ASD symptoms among minimally verbal children within the context of the Autism Diagnostic Observation Schedule (ADOS) Module 1. Using confirmatory factor analysis (CFA) and moderated non-linear factor analysis (MNLFA), we examined how discrete behaviors were differentially associated with the latent symptom domains of social communication impairments (SCI) and restricted and repetitive behaviors (RRB) across spoken language levels and non-verbal mental age groupings. While the two-factor structure of SCI and RRB held consistently across language and cognitive levels, only partial invariance was observed for both ASD symptom domains of SCI and RRB. Specifically, four out of the 15 SCI items and one out of the three RRB items examined showed differential item functioning between children with "Few to No Words" and those with "Some Words"; and one SCI item and one RRB item showed differential item functioning across non-verbal mental age groups. Moreover, even after adjusting for the differential item functioning to reduce measurement bias across groups, there were still differences in ASD symptom domain scores across spoken language levels. These findings further underscore the influence of spoken language level on measurement of ASD symptoms and the importance of measuring ASD symptoms within refined spoken language levels, even among those with minimal verbal abilities.

Young adults with autism spectrum disorder (ASD) experience limited social connectedness, difficulty living independently, and other poor outcomes at high rates. Vocational activities, including employment and postsecondary education, are associated with increased positive outcomes and subjective well-being in typical adults. This study identified vocational activity trajectory groups in adults with ASD, examined change in these trajectories from ages 18 to 28, and compared levels of parent- and self-report subjective well-being across trajectory groups. One hundred fifty-one adults with ASD were drawn from an ongoing longitudinal study. Data on psychosocial outcomes and vocational activities were compiled from parent-report demographic forms. Vocational activities were scored using the vocational index (VDI). There was no significant effect of age on the slope of vocational trajectories (p = 0.787). Participants in the Independent Activities group had significantly higher parent-report happiness factor scores than participants in the No Activities group (F [3, 107] = 3.56, p = 0.017) and significantly higher self-report happiness factor scores than participants in the Volunteer Activities group (F [2, 35] = 6.46, p = 0.004). The Independent Activities group was also significantly more likely to have at least one social contact (X2 [3, 118] = 10.54, p = 0.014), however, there was no difference in trajectories groups in the likelihood of living independently (X2 [3, 120] = 1.71, p = 0.634). The results of this study indicate vocational activities in young adults with ASD are stable across time. In the current sample, participation in independent vocational activities was associated with increased levels of subjective well-being.

BackgroundMost people living with dementia want to remain living in their own homes and are supported to do so by family carers. No interventions have consistently demonstrated improvements to people with dementia's life quality, functioning, or other indices of living as well as possible with dementia. We have co-produced, with health and social care professionals and family carers of people with dementia, a new intervention (NIDUS-family). To our knowledge, NIDUS-family is the first manualised intervention that can be tailored to personal goals of people living with dementia and their families and is delivered by facilitators without clinical training. The intervention utilizes components of behavioural management, carer support, psychoeducation, communication and coping skills training, enablement, and environmental adaptations, with modules selected to address dyads' selected goals. We will evaluate the effect of NIDUS-family and usual care on goal attainment, as measured by Goal Attainment Scaling (GAS) rated by family carers, compared to usual care alone at 12-month follow-up. We will also determine whether NIDUS-family and usual care is more cost-effective than usual care alone over 12 months.MethodsA randomised, two-arm, single-masked, multi-site clinical trial involving 297 people living with dementia-family carer dyads. Dyads will be randomised 2:1 to receive the NIDUS-family intervention with usual care (n = 199) or usual care alone (n = 98). The intervention group will be offered, over 1 year, via 6-8 video call or telephone sessions (or face to face if COVID-19 restrictions allow in the recruitment period) in the initial 6 months, followed by telephone follow-ups every 1-2 months to support implementation, with a trained facilitator.DiscussionIncreasing the time lived at home by people living with dementia is likely to benefit lives now and in the future. Our intervention, which we adapted to include remote delivery prior to trial commencement due to the COVID-19 pandemic, aims to address barriers to living as well and as independently as possible that distress people living with dementia, exacerbate family carer(s) stress, negatively affect relationships, lead to safety risks, and frequently precipitate avoidable moves to a care home.Trial registrationInternational Standard Randomised Controlled Trials Number ISRCTN11425138 . Registered on 7 October 2019.

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual β cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual β cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

In support of the U.S. DOE SubTER Crosscut initiative, we established a field test facility in a deep mine and designed and carried outin situ hydraulic fracturing experiments relevant to enhanced geothermal systems (EGS) in crystalline rock to characterize the stressfield, understand the effects of rock fabric on fracturing, and gain experience in monitoring using geophysical methods. The project alsoincluded pre- and post-fracturing simulation and analysis, and laboratory measurements and experiments. The kISMET (permeability(k) and Induced Seismicity Management for Energy Technologies) site was established in the West Access Drift of the SanfordUnderground Research Facility (SURF) 4757 ft (1450 m) below ground (on the 4850 ft level (4850L)) in phyllite of the PrecambrianPoorman Formation. We drilled and continuously cored five near-vertical boreholes in a line on 3 m (10 ft) spacing, deviating the twooutermost boreholes slightly to create a five-spot pattern around the test borehole centered in the test volume 40 m below the drift invert(floor) at a total depth of ~1490 m (4890 ft). Laboratory measurements of core from the center test borehole showed P-wave velocityheterogeneity along each core indicating strong, fine-scale (~1 cm or smaller) changes in the mechanical properties of the rock. Fieldmeasurements of the stress field by hydraulic fracturing showed that the minimum horizontal stress at the kISMET site averages 21.7MPa (3146 psi) trending approximately N-S (356 degrees azimuth) and plunging slightly NNW at 12°. The vertical and horizontalmaximum stresses are similar in magnitude at 42-44 MPa (6090-6380 psi) for the depths of testing, which averaged approximately 1530m (5030 ft). Hydraulic fractures were remarkably uniform suggesting core-scale and larger rock fabric did not play a role in controllingfracture orientation. Analytical solutions suggest that the fracture radius of the large fracture (stimulation test) was more than 6 m (20ft), depending on the unknown amount of leak-off.

Introduction: Pericardiocentesis is a high-risk/low-frequency procedure important to emergency medicine (EM). However, due to case rarity it is not often performed on a patient during residency training. Because the coronavirus disease 2019 pandemic limited cadaver-based practice, we developed a novel, low-cost, low-fidelity pericardiocentesis model using three dimensional-printing technology to provide advances on prior home-made models.  Methods: Residents watched a 20-minute video about performing a pericardiocentesis and practiced both a blind and ultrasound-guided technique. We assessed model fidelity, convenience, and perceived provider competence via post-workshop questionnaire.  Results: A total of 24/26 (93%) individuals practicing on the ultrasound-guided model and 22/24 (92%) on the blind approach model agreed or strongly agreed that the models reasonably mimicked a pericardial effusion.  Conclusion: Our low-cost, low-fidelity model is durable, mimics the clinical case, and is easy to use. It also addresses known limitations from prior low-fidelity models.

There is a critical need for accurate screening tools for autism spectrum disorder in very young children so families can access tailored intervention services as early as possible. However, there are few screeners designed for children 18-24 months. Developing screeners that pick up on the signs of autism spectrum disorder in very young children has proved even more challenging. In this study, we examined a new autism-specific parent-report screening tool, the Early Screening for Autism and Communication Disorders for children between 12 and 36 months of age. Field-testing was done in five sites with 471 children screened for communication delays in primary care or referred for familial risk or concern for autism spectrum disorder. The Early Screening for Autism and Communication Disorders was tested in three age groups: 12-17, 18-23, and 24-36 months. A best-estimate diagnosis of autism spectrum disorder, developmental delay, or typical development was made. Analyses examined all 46 items and identified 30 items that best discriminated autism spectrum disorder from the non-spectrum groups. Cutoffs were established for each age group with good sensitivity and specificity. Results provide preliminary support for the accuracy of the Early Screening for Autism and Communication Disorders as an autism-specific screener in children 12-36 months with elevated risk of communication delay or autism spectrum disorder.

BackgroundDelayed walking is common in intellectual disability (ID) but may be less common when ID occurs with autism spectrum disorder (ASD). Previous studies examining this were limited by reliance on clinical samples and exclusion of children with severe motor deficits.ObjectiveTo examine in a population-based sample if age of walking is differentially related to intellectual ability in children with ASD versus other neurodevelopmental disorders (NDD).MethodsParticipants were from the nested Autism Birth Cohort Study of the Norwegian Mother, Father and Child Cohort Study (MoBa). Cox proportional hazards regression assessed if diagnosis (ASD n = 212 vs. NDD n = 354), continuous nonverbal IQ, and their interaction, were associated with continuous age of walking.ResultsThe relationship between nonverbal IQ and age of walking was stronger for NDD than for ASD (Group × nonverbal IQ interaction, χ2  = 13.93, p = .0002). This interaction was characterized by a 21% decrease in the likelihood of walking onset at any given time during the observation period per 10-point decrease in nonverbal IQ (hazard ratio = 0.79, 95% CI: 0.78-0.85) in the NDD group compared to 8% (hazard ratio = 0.92, 95% CI: 0.86-0.98) in the ASD group.ConclusionsThe finding that age of walking is less strongly related to low intellectual ability in children with ASD than in children without other NDDs supports the hypothesis that ID in ASD may result from heterogeneous developmental pathways. Late walking may be a useful stratification variable in etiological research focused on ASD and other NDDs.

BackgroundGiven the significant cost and morbidity of patients undergoing lumbar fusion, accurate preoperative risk-stratification would be of great utility. We aim to develop a machine learning model for prediction of major complications and readmission after lumbar fusion. We also aim to identify the factors most important to performance of each tested model.MethodsWe identified 38,788 adult patients who underwent lumbar fusion at any California hospital between 2015 and 2017. The primary outcome was major perioperative complication or readmission within 30 days. We build logistic regression and advanced machine learning models: XGBoost, AdaBoost, Gradient Boosting, and Random Forest. Discrimination and calibration were assessed using area under the receiver operating characteristic curve and Brier score, respectively.ResultsThere were 4470 major complications (11.5%). The XGBoost algorithm demonstrates the highest discrimination of the machine learning models, outperforming regression. The variables most important to XGBoost performance include angina pectoris, metastatic cancer, teaching hospital status, history of concussion, comorbidity burden, and workers' compensation insurance. Teaching hospital status and concussion history were not found to be important for regression.ConclusionsWe report a machine learning algorithm for prediction of major complications and readmission after lumbar fusion that outperforms logistic regression. Notably, the predictors most important for XGBoost differed from those for regression. The superior performance of XGBoost may be due to the ability of advanced machine learning methods to capture relationships between variables that regression is unable to detect. This tool may identify and address potentially modifiable risk factors, helping risk-stratify patients and decrease complication rates.

ObjectiveDaily living skills (DLS) are a predictor of positive outcomes in youths with autism spectrum disorder (ASD), yet little is known about trajectories of DLS in adults with ASD. This study investigated the impact of high school exit on participants' trajectories of daily living skills age equivalent (DLS-AE) scores from ages 2 to 26 and the relationship between DLS-AE trajectories and employment and education outcomes.MethodParticipants were 98 adults with ASD drawn from an ongoing longitudinal study. The Vineland Adaptive Behavior Scales were administered 8 times from ages 2 to 26. Employment and education data were compiled from parent report demographic forms.ResultsDLS-AE trajectories modestly increased with age before exiting school, at which point DLS-AE trajectories plateaued, then declined. A significant (p < .01) decrease occurred in the slope of DLS-AE trajectories following school exit. High DLS-AE scores predicted participation in postsecondary education (χ25 [n = 73] = 27.83, p < .001). Autism symptom severity predicted participation in employment (χ25 [n = 58] = 27.54, p < .001).ConclusionThese findings provide evidence that DLS decline in adults with ASD, specifically after school exit, and highlight the importance of DLS in normative adult outcomes. Future work should examine the trajectories of DLS in middle and later adulthood and consider intervention targets for bolstering DLS following school exit.

ObjectiveSocial communication deficits associated with autism spectrum disorder (ASD) are commonly represented as a single behavioral domain. However, increased precision of measurement of social communication is needed to promote more nuanced phenotyping, both within the autism spectrum and across diagnostic boundaries.MethodA large sample (N = 1,470) of 4- to 10-year-old children was aggregated from across 4 data sources, and then randomly split into testing and validation samples. A total of 57 selected social communication items from 3 widely used autism symptom measures (the Autism Diagnostic Observation Scale [ADOS], Autism Diagnostic Interview-Revised [ADI-R], and Social Responsiveness Scale [SRS]) were analyzed in the multi-trait/multi-method factor analysis framework. The selected model was then confirmed with the validation sample.ResultsThe 4-substantive factor model, with 3 orthogonal method factors, was selected using the testing sample based on fit indices and then confirmed with the validation sample. Two of the factors, "Basic Social Communication Skills" and "Interaction Quality," were similar to those identified in a previous analysis of the ADOS, Module 3. Two additional factors, "Peer Interaction and Modification of Behavior" and "Social Initiation and Affiliation," also emerged. Factor scores showed nominal correlations with age and verbal IQ.ConclusionIdentification of subdimensions could inform the creation of better conceptual models of social communication impairments, including mapping of how the cascading effects of social communication deficits unfold in ASD versus other disorders. Especially if extended to include both older and younger age cohorts and individuals with more varying developmental levels, these efforts could inform phenotype-based exploration for biological and genetic mechanisms by pinpointing specific mechanisms that contribute to various types of social communication deficits.

Machine learning (ML) models have demonstrated the power of utilizing clinical instruments to provide tools for domain experts in gaining additional insights toward complex clinical diagnoses. In this context these tools desire two additional properties: interpretability, being able to audit and understand the decision function, and robustness, being able to assign the correct label in spite of missing or noisy inputs. This work formulates diagnostic classification as a decision-making process and utilizes Q-learning to build classifiers that meet the aforementioned desired criteria. As an exemplary task, we simulate the process of differentiating Autism Spectrum Disorder from Attention Deficit-Hyperactivity Disorder in verbal school aged children. This application highlights how reinforcement learning frameworks can be utilized to train more robust classifiers by jointly learning to maximize diagnostic accuracy while minimizing the amount of information required.

The performance of most speaker diarization systems with x-vector embeddings is both vulnerable to noisy environments and lacks domain robustness. Earlier work on speaker diarization using generative adversarial network (GAN) with an encoder network (ClusterGAN) to project input x-vectors into a latent space has shown promising performance on meeting data. In this paper, we extend the ClusterGAN network to improve diarization robustness and enable rapid generalization across various challenging domains. To this end, we fetch the pre-trained encoder from the ClusterGAN and fine tune it by using prototypical loss (meta-ClusterGAN or MCGAN) under the meta-learning paradigm. Experiments are conducted on CALLHOME telephonic conversations, AMI meeting data, DIHARD-II (dev set) which includes challenging multi-domain corpus, and two child-clinician interaction corpora (ADOS, BOSCC) related to the autism spectrum disorder domain. Extensive analyses of the experimental data are done to investigate the effectiveness of the proposed ClusterGAN and MCGAN embeddings over x-vectors. The results show that the proposed embeddings with normalized maximum eigengap spectral clustering (NME-SC) back-end consistently outperform the Kaldi state-of-the-art x-vector diarization system. Finally, we employ embedding fusion with x-vectors to provide further improvement in diarization performance. We achieve a relative diarization error rate (DER) improvement of 6.67% to 53.93% on the aforementioned datasets using the proposed fused embeddings over x-vectors. Besides, the MCGAN embeddings provide better performance in the number of speakers estimation and short speech segment diarization compared to x-vectors and ClusterGAN on telephonic conversations.

BackgroundConcerns have been raised that scores on standard measures of autism spectrum disorder (ASD) symptoms may differ as a function of sex. However, these findings are hindered by small female samples studied thus far. The current study evaluated if, after accounting for age, IQ, and language level, sex affects ASD severity estimates from diagnostic measures among children with ASD.MethodsData were obtained from eight sources comprising 27 sites. Linear mixed-effects models, including a random effect for site, were fit for 10 outcomes (Autism Diagnostic Observation Schedule [ADOS] domain-level calibrated severity scores, Autism Diagnostic Interview-Revised [ADI-R] raw scores by age-based algorithm, and raw scores from the two indices on the Social Responsiveness Scale [SRS]). Sex was added to the models after controlling for age, NVIQ, and an indicator for language level.ResultsSex significantly improved model fit for half of the outcomes, but least square mean differences were generally negligible (effect sizes [ES]

BackgroundAnterior lumbar interbody fusion (ALIF) is commonly utilized in lumbar degenerative pathologies. Standalone ALIF (ST-ALIF) systems were developed to avoid added morbidity, surgical time, and cost of anterior and posterior fusion (APF). Controversy exists in the literature about which of these two techniques yields superior clinical and radiographic outcomes, and few studies have directly compared them. This study seeks to compare ST-ALIF and APF in terms of sagittal correction and surgical complications.MethodsNinty-two consecutive ALIF cases performed from 2013-2018 were retrospectively reviewed and separated into 2 groups. Radiographic measurements were performed on pre- and post-operative radiographs, including segmental lordosis (SL), lumbar lordosis (LL), and pelvic incidence-lumbar lordosis mismatch (PI-LL). Surgical complications were determined. Statistical analysis was performed using chi-square test of homogeneity, Fisher's exact test, and independent sample t-test. Comparisons between groups were deemed statistically significant at the P

BackgroundExisting diagnostic methods for the parasitic gastrointestinal nematode, Haemonchus contortus, are time consuming and require specialised expertise, limiting their utility in the field. A practical, on-farm diagnostic tool could facilitate timely treatment decisions, thereby preventing losses in production and flock welfare. We previously demonstrated the ability of visible-near-infrared (Vis-NIR) spectroscopy to detect and quantify blood in sheep faeces with high accuracy. Here we report our investigation of whether variation in sheep type and environment affect the prediction accuracy of Vis-NIR spectroscopy in quantifying blood in faeces.MethodsVisible-NIR spectra were obtained from worm-free sheep faeces collected from different environments and sheep types in South Australia (SA) and New South Wales, Australia and spiked with various sheep blood concentrations. Spectra were analysed using principal component analysis (PCA), and calibration models were built around the haemoglobin (Hb) wavelength region (387-609 nm) using partial least squares regression. Models were used to predict Hb concentrations in spiked faeces from SA and naturally infected sheep faeces from Queensland (QLD). Samples from QLD were quantified using Hemastix® test strip and FAMACHA© diagnostic test scores.ResultsPrincipal component analysis showed that location, class of sheep and pooled versus individual samples were factors affecting the Hb predictions. The models successfully differentiated 'healthy' SA samples from those requiring anthelmintic treatment with moderate to good prediction accuracy (sensitivity 57-94%, specificity 44-79%). The models were not predictive for blood in the naturally infected QLD samples, which may be due in part to variability of faecal background and blood chemistry between samples, or the difference in validation methods used for blood quantification. PCA of the QLD samples, however, identified a difference between samples containing high and low quantities of blood.ConclusionThis study demonstrates the potential of Vis-NIR spectroscopy for estimating blood concentration in faeces from various types of sheep and environmental backgrounds. However, the calibration models developed here did not capture sufficient environmental variation to accurately predict Hb in faeces collected from environments different to those used in the calibration model. Consequently, it will be necessary to establish models that incorporate samples that are more representative of areas where H. contortus is endemic.

BackgroundExisting diagnostic methods for the parasitic gastrointestinal nematode, Haemonchus contortus, are time consuming and require specialised expertise, limiting their utility in the field. A practical, on-farm diagnostic tool could facilitate timely treatment decisions, thereby preventing losses in production and flock welfare. We previously demonstrated the ability of visible-near-infrared (Vis-NIR) spectroscopy to detect and quantify blood in sheep faeces with high accuracy. Here we report our investigation of whether variation in sheep type and environment affect the prediction accuracy of Vis-NIR spectroscopy in quantifying blood in faeces.MethodsVisible-NIR spectra were obtained from worm-free sheep faeces collected from different environments and sheep types in South Australia (SA) and New South Wales, Australia and spiked with various sheep blood concentrations. Spectra were analysed using principal component analysis (PCA), and calibration models were built around the haemoglobin (Hb) wavelength region (387-609 nm) using partial least squares regression. Models were used to predict Hb concentrations in spiked faeces from SA and naturally infected sheep faeces from Queensland (QLD). Samples from QLD were quantified using Hemastix® test strip and FAMACHA© diagnostic test scores.ResultsPrincipal component analysis showed that location, class of sheep and pooled versus individual samples were factors affecting the Hb predictions. The models successfully differentiated 'healthy' SA samples from those requiring anthelmintic treatment with moderate to good prediction accuracy (sensitivity 57-94%, specificity 44-79%). The models were not predictive for blood in the naturally infected QLD samples, which may be due in part to variability of faecal background and blood chemistry between samples, or the difference in validation methods used for blood quantification. PCA of the QLD samples, however, identified a difference between samples containing high and low quantities of blood.ConclusionThis study demonstrates the potential of Vis-NIR spectroscopy for estimating blood concentration in faeces from various types of sheep and environmental backgrounds. However, the calibration models developed here did not capture sufficient environmental variation to accurately predict Hb in faeces collected from environments different to those used in the calibration model. Consequently, it will be necessary to establish models that incorporate samples that are more representative of areas where H. contortus is endemic.

Because of the COVID-19 pandemic, colleges have rapidly transitioned from in-person classes to remote learning, dramatically changing the way students receive instruction. At the same time, students who work are also facing unemployment or reduced hours. Most of those who were not laid off are working in frontline positions in essential services. Compounding those challenges are government policies that prohibit many college students and certain low-wage workers from accessing economic relief benefits. Based on 138 surveys and 25 interviews collected from Los Angeles public colleges and universities, this study builds on existing knowledge concerning the experiences of workers and learners by documenting how their academic, employment, and life experiences have changed since the onset of the global health crisis.

Expressive language impairment is one of the most frequently associated clinical features of 16p11.2 copy number variations (CNV). However, our understanding of the language profiles of individuals with 16p11.2 CNVs is still limited. This study builds upon previous work in the Simons Variation in Individuals Project (VIP, now known as Simons Searchlight), to characterize language abilities in 16p11.2 deletion and duplication carriers using comprehensive assessments. Participants included 110 clinically ascertained children and family members (i.e., siblings and cousins) with 16p11.2 BP4-BP5 deletion and 58 with 16p11.2 BP4-BP5 duplication between the ages of 2-23 years, most of whom were verbal. Regression analyses were performed to quantify variation in language abilities in the presence of the 16p11.2 deletion and duplication, both with and without autism spectrum disorder (ASD) and cognitive deficit. Difficulties in pragmatic skills were equally prevalent in verbal individuals in both deletion and duplication groups. NVIQ had moderate quantifiable effects on language scores in syntax and semantics/pragmatics (a decrease of less than 1 SD) for both groups. Overall, language impairments persisted even after controlling for ASD diagnosis and cognitive deficit. Language impairment is one of the core clinical features of individuals with 16p11.2 CNVs even in the absence of ASD and cognitive deficit. Results highlight the need for more comprehensive and rigorous assessment of language impairments to maximize outcomes in carriers of 16p11.2 CNVs.