ABSTRACT
Environmental exposures such as cadmium might be contributing to the increasing incidence of pancreatic cancer. Few prospective studies have examined the association between trace elements and pancreatic ductal adenocarcinoma (PDAC). We conducted a nested case-control study in participants aged 55-74 years at baseline from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to examine the association between 12 trace elements measured in predignostic whole blood and PDAC. From May 1998 through December 2014, 318 incident PDAC cases were identified during follow-up to 16.7 years. Two controls (n = 636) alive when each case was diagnosed were selected and matched by age (+ 5 years), sex, calendar date of blood draw (2-month blocks), and race and ethnic group. We used multivariable adjusted conditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Cadmium and molybdenum were associated with PDAC [highest compared to lowest quintile: cadmium OR=1.81; 95% CI: 01.12, 2.95; P-trend = 0.03; molybdenum OR=0.50; 95% CI: 0.32, 0.80; P-trend = 0.02]. The inverse molybdenum association was only observed among ever smokers (OR=0.31, 95% CI: 0.17, 0.58, P-trend= 0.003, P-interaction=0.03) with no association in never smokers. Lead, arsenic, and other trace elements were not associated with PDAC. Our results support that increasing prediagnostic whole blood cadmium increases while molybdenum reduces PDAC risk.
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Atypical acute promyelocytic leukemia (aAPL) presents a complex landscape of retinoic acid receptor (RAR) fusion genes beyond the well-known PML::RARA fusion. Among these, 31 individually rare RARA and RARG fusion genes have been documented, often reported in the canonical X::RAR bipartite fusion form. Intriguingly, some artificially mimicked bipartite X::RAR fusions respond well to all-trans retinoic acid (ATRA) in vitro, contrasting with the ATRA resistance observed in patients. To unravel the underlying mechanisms, we conducted a comprehensive molecular investigation into the fusion transcripts in 27 RARA fusion gene-positive aAPL (RARA-aAPL) and 21 RARG-aAPL cases. Our analysis revealed an unexpected novel form of X::RAR::X or X::RAR::Y-type tripartite fusions in certain RARA- and all RARG-aAPL cases, with shared features and notable differences between these two disease subgroups. In RARA-aAPL cases, the occurrence of RARA 3' splices was associated with their 5' fusion partner genes, mapping across the coding region of helix 11_12 (H11_12) within the ligand-binding domain (LBD), resulting in LBD-H12 or H11_12 truncation. In RARG-aAPL cases, RARG 3' splices were consistently localized to the terminus of exon 9, leading to LBD-H11_12 truncation. Significant differences were also observed between RARA and RARG 5' splice patterns. Our analysis also revealed extensive involvement of transposable elements in constructing RARA and RARG 3' fusions, suggesting transposition mechanisms for fusion gene ontogeny. Both protein structural analysis and experimental results highlighted the pivotal role of LBD-H11_12/H12 truncation in driving ATRA unresponsiveness and leukemogenesis in tripartite fusion-positive aAPL, through a protein allosteric dysfunction mechanism.
ABSTRACT
Importance: While most patients with acute pancreatitis (AP) fulfill diagnostic criteria with characteristic abdominal pain and serum lipase levels of at least 3 times the upper limit of normal (reference range) at presentation, early imaging is often used for confirmation. A prior prediction model and corresponding point-based score were developed using nonimaging parameters to diagnose AP in patients presenting to the emergency department (ED). Objective: To evaluate the performance of the prediction model to diagnose AP in a prospective patient cohort. Design, Setting, and Participants: This prospective diagnostic study included consecutive adult patients presenting to the ED between January 1, 2020, and March 9, 2021, at 2 large academic medical centers in the northeastern US with serum lipase levels at least 3 times the upper limit of normal. Patients transferred from outside institutions or with malignant disease and established intra-abdominal metastases, acute trauma, or altered mentation were excluded. Data were analyzed from October 15 to October 23, 2023. Exposures: Participants were assigned scores for initial serum lipase level, number of prior AP episodes, prior cholelithiasis, abdominal surgery within 2 months, presence of epigastric pain, pain of worsening severity, duration from pain onset to presentation, and pain level at ED presentation. Main Outcome and Measures: A final diagnosis of AP, established by expert review of hospitalization records. Results: Prospective scores in 349 participants (mean [SD] age, 53.0 [18.8] years; 184 women [52.7%]; 66 Black [18.9%]; 199 White [57.0%]) demonstrated an area under the receiver operating characteristics curve of 0.91. A score of at least 6 points achieved highest accuracy (F score, 82.0), corresponding to a sensitivity of 81.5%, specificity of 85.9%, positive predictive value of 82.6%, and negative predictive value of 85.1% for AP diagnosis. Early computed tomography or magnetic resonance imaging was performed more often in participants predicted to have AP (116 of 155 [74.8%] with a score ≥6 vs 111 of 194 [57.2%] with a score <6; P < .001). Early imaging revealed an alternative diagnosis in 8 of 116 participants (6.9%) with scores of at least 6 points, 1 of 93 (1.1%) with scores of at least 7 points, and 1 of 73 (1.4%) with scores of at least 8 points. Conclusions and Relevance: In this multicenter diagnostic study, the prediction model demonstrated excellent AP diagnostic accuracy. Its application may be used to avoid unnecessary confirmatory imaging.
Subject(s)
Lipase , Pancreatitis , Humans , Pancreatitis/diagnosis , Pancreatitis/blood , Female , Male , Prospective Studies , Middle Aged , Adult , Lipase/blood , Emergency Service, Hospital , Aged , Predictive Value of Tests , Acute Disease , Abdominal Pain/etiologyABSTRACT
BACKGROUND: The American Society for Metabolic and Bariatric Surgery (ASMBS) textbook serves as a comprehensive resource for bariatric surgery, covering recent advancements and clinical questions. Testing artificial intelligence (AI) engines using this authoritative source ensures accurate and up-to-date information and provides insight in its potential implications for surgical education and training. OBJECTIVES: To determine the quality and to compare different large language models' (LLMs) ability to respond to textbook questions relating to bariatric surgery. SETTING: Remote. METHODS: Prompts to be entered into the LLMs were multiple-choice questions found in "The ASMBS Textbook of Bariatric Surgery, second Edition. The prompts were queried into 3 LLMs: OpenAI's ChatGPT-4, Microsoft's Bing, and Google's Bard. The generated responses were assessed based on overall accuracy, the number of correct answers according to subject matter, and the number of correct answers based on question type. Statistical analysis was performed to determine the number of responses per LLMs per category that were correct. RESULTS: Two hundred questions were used to query the AI models. There was an overall significant difference in the accuracy of answers, with an accuracy of 83.0% for ChatGPT-4, followed by Bard (76.0%) and Bing (65.0%). Subgroup analysis revealed a significant difference between the models' performance in question categories, with ChatGPT-4's demonstrating the highest proportion of correct answers in questions related to treatment and surgical procedures (83.1%) and complications (91.7%). There was also a significant difference between the performance in different question types, with ChatGPT-4 showing superior performance in inclusionary questions. Bard and Bing were unable to answer certain questions whereas ChatGPT-4 left no questions unanswered. CONCLUSIONS: LLMs, particularly ChatGPT-4, demonstrated promising accuracy when answering clinical questions related to bariatric surgery. Continued AI advancements and research is required to elucidate the potential applications of LLMs in training and education.
Subject(s)
Artificial Intelligence , Bariatric Surgery , Bariatric Surgery/education , Humans , Textbooks as Topic , United States , Societies, Medical , Clinical CompetenceABSTRACT
BACKGROUND: The formulation of clinical recommendations pertaining to bariatric surgery is essential in guiding healthcare professionals. However, the extensive and continuously evolving body of literature in bariatric surgery presents considerable challenge for staying abreast of latest developments and efficient information acquisition. Artificial intelligence (AI) has the potential to streamline access to the salient points of clinical recommendations in bariatric surgery. OBJECTIVES: The study aims to appraise the quality and readability of AI-chat-generated answers to frequently asked clinical inquiries in the field of bariatric and metabolic surgery. SETTING: Remote. METHODS: Question prompts inputted into AI large language models (LLMs) and were created based on pre-existing clinical practice guidelines regarding bariatric and metabolic surgery. The prompts were queried into 3 LLMs: OpenAI ChatGPT-4, Microsoft Bing, and Google Bard. The responses from each LLM were entered into a spreadsheet for randomized and blinded duplicate review. Accredited bariatric surgeons in North America independently assessed appropriateness of each recommendation using a 5-point Likert scale. Scores of 4 and 5 were deemed appropriate, while scores of 1-3 indicated lack of appropriateness. A Flesch Reading Ease (FRE) score was calculated to assess the readability of responses generated by each LLMs. RESULTS: There was a significant difference between the 3 LLMs in their 5-point Likert scores, with mean values of 4.46 (SD .82), 3.89 (.80), and 3.11 (.72) for ChatGPT-4, Bard, and Bing (P < .001). There was a significant difference between the 3 LLMs in the proportion of appropriate answers, with ChatGPT-4 at 85.7%, Bard at 74.3%, and Bing at 25.7% (P < .001). The mean FRE scores for ChatGPT-4, Bard, and Bing, were 21.68 (SD 2.78), 42.89 (4.03), and 14.64 (5.09), respectively, with higher scores representing easier readability. CONCLUSIONS: LLM-based AI chat models can effectively generate appropriate responses to clinical questions related to bariatric surgery, though the performance of different models can vary greatly. Therefore, caution should be taken when interpreting clinical information provided by LLMs, and clinician oversight is necessary to ensure accuracy. Future investigation is warranted to explore how LLMs might enhance healthcare provision and clinical decision-making in bariatric surgery.
Subject(s)
Artificial Intelligence , Bariatric Surgery , Bariatric Surgery/standards , Humans , Obesity, Morbid/surgery , Practice Guidelines as Topic , ComprehensionABSTRACT
Cone-beam Computed Tomography (CBCT) is widely used in dental imaging, small animal imaging, radiotherapy, and non-destructive industrial inspection. The quality of CBCT images depends on the precise knowledge of the CBCT system's alignment. We introduce a distinct procedure, "precision alignment loop (PAL)", to calibrate any CBCT system with a circular trajectory. We describe the calibration procedure by using a line-beads phantom, and how PAL determines the misalignments from a CBCT system. PAL also yields the uncertainties in the simulated calibration to give an estimate of the errors in the misalignments. From the analytical simulations, PAL can precisely obtain the source-to-rotation axis distance (SRD), and the geometric center G, "the point in z-axis meets the detector", where the z-axis is coincident with the line from the X-ray source that intersects the axis of the rotation (AOR) orthogonally. The uncertainties of three misalignment angles of the detector are within ±0.05°, which is close to ±0.04° for the results of Yang et al. [18], but our method is easy and simple to implement. Our distinct procedure, on the other hand, yields the calibration of a micro-CT system and an example of reconstructed images, showing our calibration method for the CBCT system to be simple, precise, and accurate.
ABSTRACT
Reliance on animal foods must be reduced to improve planetary and human well-being. This research studied plant-based cheese alternatives (PBCA) relative to dairy cheese in a consumer taste test with 157 consumers in New Zealand. A case study approach used cream cheese (commercially available) as the focal product category (2 PBCA, 2 dairy) and implemented a multi-response paradigm (hedonic, sensory, emotional, conceptual, situational). "Beyond liking" insights were established, including drivers of liking (sensory, non-sensory) and sensory drivers of non-sensory product associations. Two consumer segments were identified, of which the largest (n = 111) liked PBCA and dairy samples equally (6.5-6.7 of 9). In this PBCA Likers cluster, the key sensory drivers of liking were 'creamy/smooth mouthfeel', 'dissolves quickly in mouth', and 'sweet', while a significant penalty was associated with 'mild/bland flavour'. The non-sensory data contributed additional consumer insights, including the four samples being perceived as differently appropriate for 9 of 12 use situations, with PBCA being regarded as less appropriate. In the limited confines of this case on cream cheese, the findings show that PBCA need not be inferior to their dairy counterparts despite a general narrative to the contrary. Of note, the results were obtained among participants who were open to eating a more PB diet but were not vegetarian or vegan.
ABSTRACT
Two recent guidelines, the 5th edition of the World Health Organization Classification of Haematolymphoid Tumours (WHO-HAEM5) and the International Consensus Classification (ICC), were published to refine the diagnostic criteria of acute myeloid leukemia (AML). They both consider genomic features more extensively and expand molecularly defined AML subtypes. In this study, we compared the classifications of 1135 AML cases under both criteria. According to WHO-HAEM5 and ICC, the integration of whole transcriptome sequencing, targeted gene mutation screening, and conventional cytogenetic analysis identified defining genetic abnormalities in 89% and 90% of AML patients, respectively. The classifications displayed discrepancies in 16% of AML cases after being classified using the two guidelines, respectively. Both new criteria significantly reduce the number of cases defined by morphology and differentiation. However, their clinical implementation heavily relies on comprehensive and sophisticated genomic analysis, including genome and transcriptome levels, alongside the assessment of pathogenetic somatic and germline variations. Discrepancies between WHO-HAEM5 and ICC, such as the assignment of RUNX1 mutations, the rationality of designating AML with mutated TP53 as a unique entity, and the scope of rare genetic fusions, along with the priority of concurrent AML-defining genetic abnormalities, are still pending questions requiring further research for more elucidated insights.
Subject(s)
Leukemia, Myeloid, Acute , Humans , Consensus , Mutation , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Genomics , World Health OrganizationABSTRACT
This study developed a prototype for a rotational cone-beam x-ray luminescence computed tomography (CB-XLCT) system, considering its potential application in pre-clinical theranostic imaging. A geometric calibration method applicable to both imaging chains (XL and CT) was also developed to enhance image quality. The results of systematic performance evaluations were presented to assess the feasibility of commercializing XLCT technology. Monte Carlo GATE simulation was performed to determine the optimal imaging conditions for nanophosphor particles (NPs) irradiated by 70 kV x-rays. We acquired a low-dose transmission x-ray tube and designed a prone positioning platform and a rotating gantry, using mice as targets from commercial small animalµ-CT systems. We then employed the image cross-correlation (ICC) automatic geometric calibration method to calibrate XL and CT images. The performance of the system was evaluated through a series of phantom experiments with a linearity of 0.99, and the contrast-to-noise ratio (CNR) between hydroxyl-apatite (HA) and based epoxy resin is 19.5. The XL images of the CB-XLCT prototype achieved a Dice similarity coefficient (DICE) of 0.149 for a distance of 1 mm between the two light sources. Finally, the final XLCT imaging results were demonstrated using the Letter phantoms with NPs. In summary, the CB-XLCT prototype developed in this study showed the potential to achieve high-quality imaging with acceptable radiation doses for small animals. The performance of CT images was comparable to current commercial machines, while the XL images exhibited promising results in phantom imaging, but further efforts are needed for biomedical applications.
Subject(s)
Image Processing, Computer-Assisted , Luminescence , Animals , Mice , X-Rays , Image Processing, Computer-Assisted/methods , Algorithms , Tomography, X-Ray Computed/methods , Cone-Beam Computed Tomography/methods , Phantoms, ImagingABSTRACT
OBJECTIVES: The 2018 American Gastroenterological Association (AGA) guidelines strongly recommended early oral feeding as tolerated in patients with acute pancreatitis (AP). We compare early oral feeding rates in AP patients hospitalized in the periods before (2013-2016, Period A) and after (2019-2020, Period B) publication of the AGA guidelines, hypothesizing increased adherence in Period B. METHODS: We performed a retrospective cohort study of AP patients presenting to the emergency department during each period. Early oral feeding was defined as diet initiation within the first 48 hours of presentation. RESULTS: The cohort included 276 AP cases in period A and 104 in period B. A higher percentage of patients were offered early oral feeding during period B as compared to period A (70.2% vs. 43.5%). Similarly, more patients in period B were started on solid diet as compared to period A (34.6% vs. 20.3%). On multivariable regression analysis, the independent predictors of delayed oral feeding included early opioid analgesics use (OR 0.37), presence of pancreatic necrosis (OR 0.14), and organ failure (OR 0.33). CONCLUSIONS: More AP patients were initiated on early oral feeding in the period following the publication of the AGA guidelines. Opioid analgesics use, pancreatic necrosis, and organ failure were associated with delayed oral feeding.
Subject(s)
Pancreatitis, Acute Necrotizing , Humans , Retrospective Studies , Analgesics, Opioid , Acute DiseaseABSTRACT
Here, we present Brain Registration and Evaluation for Zebrafish (BREEZE)-mapping, a user-friendly pipeline for the registration and analysis of whole-brain images in larval zebrafish. We describe steps for pre-processing, registration, quantification, and visualization of whole-brain phenotypes in zebrafish mutants of genes associated with neurodevelopmental and neuropsychiatric disorders. By utilizing BioImage Suite Web, an open-source software package originally developed for processing human brain imaging data, we provide a highly accessible whole-brain mapping protocol developed for users with general computational proficiency. For complete details on the use and execution of this protocol, please refer to Weinschutz Mendes et al. (2023).1.
Subject(s)
Brain , Zebrafish , Humans , Animals , Brain/diagnostic imaging , Brain Mapping , Larva , PhenotypeABSTRACT
While the use of chimeric antigen receptor-T (CAR-T) therapy for T-cell malignancies is in the early stage of clinical trials, it exhibits substantial potential to offer long-term remission for patients with refractory/relapsed (R/R) T-cell malignancies. In our phase I/II clinical trials, 65 pediatric and adult patients with R/R T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma (T-ALL/LBL) were enrolled (NCT04572308 and NCT04916860). Of these, 60 participants (T-ALL 35, T-LBL 25) received a single dose of naturally selected anti-CD7 CAR (NS7CAR) T cells at three levels: a low dose (5 × 105 /kg), a medium dose (1 to 1.5 × 106 /kg), and a high dose (2 × 106 /kg). On day 28, 94.4% of patients achieved deep complete remission (CR) in bone marrow. Among the 32 patients with extramedullary disease, 78.1% showed response, with 56.3% in CR and 21.9% in partial remission. The 2-year overall survival and progression-free survival (PFS) were 63.5% (95% CI 47.7-79.4) and 53.7% (95% CI, 38.9-68.6), with no difference between pediatric and adult patients. PFS was significantly higher among the 37 CR patients who proceeded with consolidation transplant than the 10 patients who did not with 1-year PFS 67.2% (95% CI 51.9-82.4) versus 15.0% (95% CI 0-40.2), p < .0001. Of the 10 CR patients without transplants, eight relapsed, while two sustained CR on day 128, and day 180, respectively. Cytokine release syndrome occurred in 91.7% of patients (grade 1/2 in 80.0%, grade 3/4 in 11.7%) and 5% of patients had neurotoxicity. NS7CAR-T therapy is effective in treating R/R T-ALL/LBL patients with promising PFS while maintaining a manageable safety profile.
Subject(s)
Lymphoma, T-Cell, Peripheral , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma , Receptors, Chimeric Antigen , Adult , Humans , Child , Receptors, Chimeric Antigen/therapeutic use , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Immunotherapy, Adoptive/adverse effects , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , T-Lymphocytes , Lymphoma, T-Cell, Peripheral/drug therapy , Recurrence , Cell- and Tissue-Based Therapy , Antigens, CD19ABSTRACT
Coronary vasospasm is a relatively well-documented cause for ischemia and myocardial infarction in patients with nonobstructive coronary artery disease. Patients with coexisting eosinophilia present with severe manifestations and are often refractory to traditional therapies. There are few reported cases in the literature. We describe 3 cases occurring within 10 months. (Level of Difficulty: Intermediate.).
ABSTRACT
Affinity-based biosensing can enable point-of-care diagnostics and continuous health monitoring, which commonly follows bottom-up approaches and is inherently constrained by bioprobes' intrinsic properties, batch-to-batch consistency, and stability in biofluids. We present a biomimetic top-down platform to circumvent such difficulties by combining a "dual-monolayer" biorecognition construct with graphene-based field-effect-transistor arrays. The construct adopts redesigned water-soluble membrane receptors as specific sensing units, positioned by two-dimensional crystalline S-layer proteins as dense antifouling linkers guiding their orientations. Hundreds of transistors provide statistical significance from transduced signals. System feasibility was demonstrated with rSbpA-ZZ/CXCR4QTY-Fc combination. Nature-like specific interactions were achieved toward CXCL12 ligand and HIV coat glycoprotein in physiologically relevant concentrations, without notable sensitivity loss in 100% human serum. The construct is regeneratable by acidic buffer, allowing device reuse and functional tuning. The modular and generalizable architecture behaves similarly to natural systems but gives electrical outputs, which enables fabrication of multiplex sensors with tailored receptor panels for designated diagnostic purposes.
Subject(s)
Biosensing Techniques , Graphite , Humans , Graphite/chemistry , Biomimetics , Electricity , Biosensing Techniques/methods , Transistors, ElectronicABSTRACT
INTRODUCTION: The prevalence of frailty among patients with chronic pancreatitis (CP) and its impact on clinical outcomes is unclear. We report the impact of frailty on mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the United States. METHODS: We extracted data on patients hospitalized with a primary or secondary diagnosis of CP from the Nationwide Readmissions Database 2019. We applied a previously validated hospital frailty risk scoring system to classify CP patients into frail and non-frail on index hospitalization and compared the characteristics of frail and non-frail patients. We studied the impact of frailty on mortality, readmission, and healthcare utilization. RESULTS: Of 56,072 patients with CP, 40.78% of patients were classified as frail. Frail patients experienced a higher rate of unplanned and preventable hospitalizations. Almost two-thirds of frail patients were younger than 65, and one-third had no or only single comorbidity. On multivariate analysis, frailty was independently associated with two times higher mortality risk (adjusted hazard ratio [aHR], 2.05; 95% CI 1.7-2.5). Frailty was also associated with a higher risk of all-cause readmission with an aHR of 1.07; (95% CI 1.03-1.1). Frail patients experienced a longer length of stay, higher hospitalization costs, and hospitalization charges. Infectious causes were the most common cause of readmission among frail patients compared to acute pancreatitis among non-frail patients. CONCLUSIONS: Frailty is independently associated with higher mortality, readmission rates, and healthcare utilization among patients with chronic pancreatitis in the US.
Subject(s)
Frailty , Pancreatitis, Chronic , Humans , United States/epidemiology , Frailty/diagnosis , Frailty/epidemiology , Acute Disease , Risk Factors , Hospitals , Pancreatitis, Chronic/therapy , Length of Stay , Patient Readmission , Retrospective StudiesABSTRACT
Plant-based (PB) yoghurts is a rapidly expanding food category with the potential to reduce many of the negative environmental impacts associated with the farming of dairy cattle and related greenhouse gas emissions. Within the context of growing consumer demand for PB products, this research aimed to identify the main drivers of consumer acceptance of PB yoghurts through data drawn from a consumer study of 113 adult New Zealand participants who tasted a representative range of commercially available vanilla-flavoured PB yoghurts, and provided sample evaluations using a multi-variable measurement approach comprised of liking ratings, emotional responses, sensory characterisations, and holistic / conceptual perceptions. The primary finding of this study was that the overall acceptability of currently available PB yoghurts is low, leading to poor attitudes and low willingness to consume PB yoghurts. The examined products were characterised by the presence of several sensory attributes that negatively impacted consumer liking, either because they were unexpected or because their intensity level was too high. Among the main sensory issues identified were perceived sourness (acidity), lumpy appearance and non-white colour. In contrast, vanilla flavour and a creamy/smooth texture were identified as the main drivers of liking. The multi-response approach used in this study enabled a comprehensive characterisation of the products. One of the key insights gained was that negative emotional activation, caused by the presence of unexpected sensory attributes in the samples, was the main driver of product rejection. This was likely due to the disparity between consumers' sensory expectations, formed primarily based on their experience with dairy yoghurts, and the actual experience upon tasting the PB yoghurts. Overall, the findings indicate that the sensory properties of currently available PB yoghurts are a significant barrier to their adoption by most consumers and that addressing these sensory deficiencies is essential to achieving mainstream market acceptance of these products.
Subject(s)
Taste , Yogurt , Animals , Cattle , Taste Perception , Food , EmotionsABSTRACT
Advancing from gene discovery in autism spectrum disorders (ASDs) to the identification of biologically relevant mechanisms remains a central challenge. Here, we perform parallel in vivo functional analysis of 10 ASD genes at the behavioral, structural, and circuit levels in zebrafish mutants, revealing both unique and overlapping effects of gene loss of function. Whole-brain mapping identifies the forebrain and cerebellum as the most significant contributors to brain size differences, while regions involved in sensory-motor control, particularly dopaminergic regions, are associated with altered baseline brain activity. Finally, we show a global increase in microglia resulting from ASD gene loss of function in select mutants, implicating neuroimmune dysfunction as a key pathway relevant to ASD biology.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Animals , Autistic Disorder/genetics , Zebrafish/genetics , Brain , Autism Spectrum Disorder/genetics , Brain MappingABSTRACT
Importance: Higher physical activity levels are associated with lower risks of cancer, cardiovascular disease, and diabetes, but associations with many common and less severe health conditions are not known. These conditions impose large health care burdens and reduce quality of life. Objectives: To investigate the association between accelerometer-measured physical activity and the subsequent risk of hospitalization for 25 common reasons for hospitalization and to estimate the proportion of these hospitalizations that might have been prevented if participants had higher levels of physical activity. Design, Setting, and Participants: This prospective cohort study used data from a subset of 81 717 UK Biobank participants aged 42 to 78 years. Participants wore an accelerometer for 1 week (between June 1, 2013, and December 23, 2015) and were followed up over a median (IQR) of 6.8 (6.2-7.3) years; follow-up for the current study ended in 2021 (exact date varied by location). Exposures: Mean total and intensity-specific accelerometer-measured physical activity. Main Outcomes and Measures: Hospitalization for the most common health conditions. Cox proportional hazards regression analysis was used to estimate hazard ratios (HRs) and 95% CIs for mean accelerometer-measured physical activity (per 1-SD increment) and risks of hospitalization for 25 conditions. Population-attributable risks were used to estimate the proportion of hospitalizations for each condition that might be prevented if participants increased their moderate to vigorous physical activity (MVPA) by 20 minutes per day. Results: Among 81 717 participants, the mean (SD) age at accelerometer assessment was 61.5 (7.9) years; 56.4% were female, and 97.0% self-identified as White. Higher levels of accelerometer-measured physical activity were associated with lower risks of hospitalization for 9 conditions: gallbladder disease (HR per 1 SD, 0.74; 95% CI, 0.69-0.79), urinary tract infections (HR per 1 SD, 0.76; 95% CI, 0.69-0.84), diabetes (HR per 1 SD, 0.79; 95% CI, 0.74-0.84), venous thromboembolism (HR per 1 SD, 0.82; 95% CI, 0.75-0.90), pneumonia (HR per 1 SD, 0.83; 95% CI, 0.77-0.89), ischemic stroke (HR per 1 SD, 0.85; 95% CI, 0.76-0.95), iron deficiency anemia (HR per 1 SD, 0.91; 95% CI, 0.84-0.98), diverticular disease (HR per 1 SD, 0.94; 95% CI, 0.90-0.99), and colon polyps (HR per 1 SD, 0.96; 95% CI, 0.94-0.99). Positive associations were observed between overall physical activity and carpal tunnel syndrome (HR per 1 SD, 1.28; 95% CI, 1.18-1.40), osteoarthritis (HR per 1 SD, 1.15; 95% CI, 1.10-1.19), and inguinal hernia (HR per 1 SD, 1.13; 95% CI, 1.07-1.19), which were primarily induced by light physical activity. Increasing MVPA by 20 minutes per day was associated with reductions in hospitalization ranging from 3.8% (95% CI, 1.8%-5.7%) for colon polyps to 23.0% (95% CI, 17.1%-28.9%) for diabetes. Conclusions and Relevance: In this cohort study of UK Biobank participants, those with higher physical activity levels had lower risks of hospitalization across a broad range of health conditions. These findings suggest that aiming to increase MVPA by 20 minutes per day may be a useful nonpharmaceutical intervention to reduce health care burdens and improve quality of life.