Patch and matrix striatonigral neurons differentially regulate locomotion.

Striatonigral neurons, known to promote locomotion, reside in both the patch and matrix compartments of the dorsal striatum. However, their compartment-specific contributions to locomotion remain largely unexplored. Using molecular identifier Kremen1 and Calb1 , we showed in mouse models that patch and matrix striatonigral neurons exert opposite influences on locomotion. Matrix striatonigral neurons reduced their activity before the cessation of self-paced locomotion, while patch striatonigral neuronal activity increased, suggesting an inhibitory function. Indeed, optogenetic activation of patch striatonigral neurons suppressed ongoing locomotion with reduced striatal dopamine release, contrasting with the locomotion-promoting effect of matrix striatonigral neurons, which showed an initial increase in dopamine release. Furthermore, genetic deletion of the GABA-B receptor in Aldehyde dehydrogenase 1A1-positive (ALDH1A1 + ) nigrostriatal dopaminergic neurons completely abolished the locomotion-suppressing effect of patch striatonigral neurons. Our findings unravel a compartment-specific mechanism governing locomotion in the dorsal striatum, where patch striatonigral neurons suppress locomotion by inhibiting ALDH1A1 + nigrostriatal dopaminergic neurons.

BRAF Mutations in Patients with Myeloid Neoplasms: A Cancer Center Multigene Next-Generation Sequencing Analysis Experience.

BRAF mutations are rare in myeloid neoplasms and are reported to be associated with poor treatment outcomes. The purpose of our study is to characterize BRAF mutations in myeloid neoplasms using a next-generation sequencing (NGS) panel based on the experiences of a single cancer center. We conducted a retrospective review of patients with myeloid neoplasms who underwent the HopeSeq studies between January 2018 and September 2023. A total of 14 patients with myeloid neoplasms carrying BRAF mutations were included in our cohort. The clinical, pathological, and molecular features of these patients were investigated. Our study indicates that BRAF mutations are rare in myeloid neoplasms, constituting only 0.53% (14/2632) of all myeloid neoplasm cases, with the most common BRAF mutation being BRAF V600E (4/14; 28.6%). Interestingly, we observed that six out of seven patients with acute myeloid leukemia (AML) exhibited AML with monocytic differentiation, and all the patients with AML exhibited an extremely poor prognosis compared to those without BRAF mutations. TET2 (5/14; 35.7%), ASXL1 (4/14; 28.6%), and JAK2 (4/14; 28.6%) were the three most frequently co-mutated genes in these patients. Moreover, we noted concurrent KMT2A gene rearrangement with BRAF mutations in three patients with AML (3/7; 42.9%). Our study suggests that although BRAF mutations are rare in myeloid neoplasms, they play a crucial role in the pathogenesis of specific AML subtypes. Furthermore, RAS pathway alterations, including BRAF mutations, are associated with KMT2A gene rearrangement in AML. However, these findings warrant further validation in larger studies.

Feasibility study of rehabilitation for cardiac patients aided by an artificial intelligence web-based programme: a randomised controlled trial (RECAP trial)-a study protocol.

INTRODUCTION: Cardiac rehabilitation (CR) delivered by rehabilitation specialists in a healthcare setting is effective in improving functional capacity and reducing readmission rates after cardiac surgery. It is also associated with a reduction in cardiac mortality and recurrent myocardial infarction. This trial assesses the feasibility of a home-based CR programme delivered using a mobile application (app). METHODS: The Rehabilitation through Exercise prescription for Cardiac patients using an Artificial intelligence web-based Programme (RECAP) randomised controlled feasibility trial is a single-centre prospective study, in which patients will be allocated on a 1:1 ratio to a home-based CR programme delivered using a mobile app with accelerometers or standard hospital-based rehabilitation classes. The home-based CR programme will employ artificial intelligence to prescribe exercise goals to the participants on a weekly basis. The trial will recruit 70 patients in total. The primary objectives are to evaluate participant recruitment and dropout rates, assess the feasibility of randomisation, determine acceptability to participants and staff, assess the rates of potential outcome measures and determine hospital resource allocation to inform the design of a larger randomised controlled trial for clinical efficacy and health economic evaluation. Secondary objectives include evaluation of health-related quality of life and 6 minute walk distance. ETHICS AND DISSEMINATION: RECAP trial received a favourable outcome from the Berkshire research ethics committee in September 2022 (IRAS 315483).Trial results will be made available through publication in peer-reviewed journals and presented at relevant scientific meetings. TRIAL REGISTRATION NUMBER: ISRCTN97352737.

COVID-19 Infection Rates in Vaccinated and Unvaccinated Inmates: A Retrospective Cohort Study.

Background In 2023, breakthrough COVID-19 infections among vaccinated individuals and reinfections in previously infected people have become common. Additionally, infections are due to Omicron subvariants of the virus that behave differently from those at the onset of the pandemic. Understanding how vaccination and natural immunity influence COVID-19 infection rates is crucial, especially in high-density congregate settings such as prisons, to inform public health strategies. Methods We analyzed COVID-19 surveillance data from January to July 2023 across 33 California state prisons, primarily a male population of 96,201 individuals. We computed the incidence rate of new COVID-19 infections among COVID-bivalent-vaccinated and entirely unvaccinated groups (those not having received either the bivalent or monovalent vaccine). Results Our results indicate that the infection rates in the bivalent-vaccinated and entirely unvaccinated groups are 3.24% (95% confidence interval (CI): 3.06-3.42%) and 2.72% (CI: 2.50-2.94%), respectively, with an absolute risk difference of only 0.52%. When the data were filtered for those aged 50 and above, the infection rates were 4.07% (CI: 3.77-4.37%) and 3.1% (CI: 2.46-3.74%), respectively, revealing a mere 0.97% absolute risk difference. Among those aged 65 and above, the infection rates were 6.45% (CI: 5.74-7.16%) and 4.5% (CI: 2.57-6.43%), respectively, with an absolute risk difference of 1.95%. Conclusion We note low infection rates in both the vaccinated and unvaccinated groups, with a small absolute difference between the two across age groups. A combination of monovalent and bivalent vaccines and natural infections likely contributed to immunity and a lower level of infection rates compared to the height of the pandemic. It is possible that a degree of 'herd immunity' has been achieved. Yet, using p<0.05 as the threshold for statistical significance, the bivalent-vaccinated group had a slightly but statistically significantly higher infection rate than the unvaccinated group in the statewide category and the age ≥50 years category. However, in the older age category (≥65 years), there was no significant difference in infection rates between the two groups. This suggests that while the bivalent vaccine might offer protection against severe outcomes, it may not significantly reduce the risk of infections entirely. Further research is needed to understand the reasons behind these findings and to consider other factors, such as underlying health conditions. This study underscores the importance of developing vaccines that target residual COVID-19 infections, especially in regard to evolving COVID-19 variants.

Gastrointestinal symptoms in 609 Japanese patients with COVID-19: a single-center retrospective study.

BACKGROUND: GI symptoms are common in acute COVID-19 patients. This study aimed to characterize the GI symptoms occurring in Japanese COVID-19 patients. METHODS: This retrospective single-center cohort study included 751 hospitalized acute COVID-19 patients. The primary outcomes were the frequency and severity of GI symptoms. The secondary outcomes included the association between COVID-19 severity and GI symptoms and the timing of GI symptom onset. RESULTS: After exclusion, the data of 609 patients were analyzed. The median age was 62 years, and 55% were male. The median time from initial symptom onset to admission was five days. On admission, 92% of the patients had fever, 35.1% had fatigue, 75% had respiratory symptoms, and 75% had pneumonia. The sample included patients with mild (19%), moderate (59%), and severe COVID-19 (22%). A total of 218 patients (36%) had GI symptoms, of which 93% were classified as grade 1/2; 170 patients had both respiratory and GI symptoms. Diarrhea was the most frequent GI symptom, occurring in 170 patients, followed by anorexia in 73 patients and nausea/vomiting in 36 patients, and abdominal pain in 8 patients. There was no significant relationship between COVID-19 severity and GI symptoms. Among COVID-19 patients with both GI and respiratory symptoms, 48% had respiratory symptoms preceding GI symptoms, 25% had GI symptoms preceding respiratory symptoms and 27% had a simultaneous onset of respiratory and GI symptoms. CONCLUSION: Thirty-six percent of the Japanese COVID-19 patients had GI symptoms; diarrhea was the most frequent GI symptom but did not predict severe COVID-19.

Prediction of Weight Loss to Decrease the Risk for Type 2 Diabetes Using Multidimensional Data in Filipino Americans: Secondary Analysis.

BACKGROUND: Type 2 diabetes (T2D) has an immense disease burden, affecting millions of people worldwide and costing billions of dollars in treatment. As T2D is a multifactorial disease with both genetic and nongenetic influences, accurate risk assessments for patients are difficult to perform. Machine learning has served as a useful tool in T2D risk prediction, as it can analyze and detect patterns in large and complex data sets like that of RNA sequencing. However, before machine learning can be implemented, feature selection is a necessary step to reduce the dimensionality in high-dimensional data and optimize modeling results. Different combinations of feature selection methods and machine learning models have been used in studies reporting disease predictions and classifications with high accuracy. OBJECTIVE: The purpose of this study was to assess the use of feature selection and classification approaches that integrate different data types to predict weight loss for the prevention of T2D. METHODS: The data of 56 participants (ie, demographic and clinical factors, dietary scores, step counts, and transcriptomics) were obtained from a previously completed randomized clinical trial adaptation of the Diabetes Prevention Program study. Feature selection methods were used to select for subsets of transcripts to be used in the selected classification approaches: support vector machine, logistic regression, decision trees, random forest, and extremely randomized decision trees (extra-trees). Data types were included in different classification approaches in an additive manner to assess model performance for the prediction of weight loss. RESULTS: Average waist and hip circumference were found to be different between those who exhibited weight loss and those who did not exhibit weight loss (P=.02 and P=.04, respectively). The incorporation of dietary and step count data did not improve modeling performance compared to classifiers that included only demographic and clinical data. Optimal subsets of transcripts identified through feature selection yielded higher prediction accuracy than when all available transcripts were included. After comparison of different feature selection methods and classifiers, DESeq2 as a feature selection method and an extra-trees classifier with and without ensemble learning provided the most optimal results, as defined by differences in training and testing accuracy, cross-validated area under the curve, and other factors. We identified 5 genes in two or more of the feature selection subsets (ie, CDP-diacylglycerol-inositol 3-phosphatidyltransferase [CDIPT], mannose receptor C type 2 [MRC2], PAT1 homolog 2 [PATL2], regulatory factor X-associated ankyrin containing protein [RFXANK], and small ubiquitin like modifier 3 [SUMO3]). CONCLUSIONS: Our results suggest that the inclusion of transcriptomic data in classification approaches for prediction has the potential to improve weight loss prediction models. Identification of which individuals are likely to respond to interventions for weight loss may help to prevent incident T2D. Out of the 5 genes identified as optimal predictors, 3 (ie, CDIPT, MRC2, and SUMO3) have been previously shown to be associated with T2D or obesity. TRIAL REGISTRATION: ClinicalTrials.gov NCT02278939; https://clinicaltrials.gov/ct2/show/NCT02278939.

Prediction Performance of Feature Selectors and Classifiers on Highly Dimensional Transcriptomic Data for Prediction of Weight Loss in Filipino Americans at Risk for Type 2 Diabetes.

Background: Accurate prediction of risk for chronic diseases like type 2 diabetes (T2D) is challenging due to the complex underlying etiology. Integration of more complex data types from sensors and leveraging technologies for collection of -omics datasets may provide greater insights into the specific risk profile for complex diseases.Methods: We performed a literature review to identify feature selection methods and machine learning models for prediction of weight loss in a previously completed clinical trial (NCT02278939) of a behavioral intervention for weight loss in Filipinos at risk for T2D. Features included demographic and clinical characteristics, dietary factors, physical activity, and transcriptomics.Results: We identified four feature selection methods: Correlation-based Feature Subset Selection (CfsSubsetEval) with BestFirst, Kolmogorov-Smirnov (KS) test with correlation featureselection (CFS), DESeq2, and max-relevance-min-relevance (MRMR) with linear forward search and mutual information (MI) and four machine learning algorithms: support vector machine, decision tree, random forest, and extra trees that are applicable to prediction of weight loss using the specified feature types.Conclusion: More accurate prediction of risk for T2D and other complex conditions may be possible by leveraging complex data types from sensors and -omics datasets. Emerging methods for feature selection and machine learning algorithms make this type of modeling feasible.

Stratification Based on Risk Factors at Diagnosis Could Predict Progression in Patients with Pancreatic Cysts.

BACKGROUND: Predicting the risk of malignant transformation in pancreatic cyst patients is challenging. AIM: We retrospectively investigated the risk factors for malignant transformation in pancreatic cyst patients. METHODS: Patients with pancreatic cysts diagnosed using imaging tests were followed from November 2008 to December 2021. A significant change was defined as the additional development of high-risk stigmata (HRS), worrisome features (WFs), or pancreatic cancer during monitoring. RESULTS: In total, 479 patients were analyzed, with a median observation period of 50 months. Forty-four patients (9.2%) showed significant changes, and eight (1.7%) developed pancreatic cancer. The univariate analysis showed that the cyst diameter at diagnosis (≥ 14 mm), main pancreatic duct (MPD) diameter at diagnosis (≥ 3 mm), presence of multilocular cysts, and an inconsistent MPD caliber were significant predictive factors for a significant change. One point was assigned for each significant factor. We grouped the patients into three groups: the low-risk group (total score 0), medium-risk group (score 1-2), and high-risk group (score 3-4). The high-risk group had a higher risk of a significant change than the medium- and low-risk groups (age-adjusted HRs for the medium-risk and high-risk groups were 3.0 and 5.2 compared with the low-risk group). CONCLUSION: Stratification based on risk factors may help predict the development of significant changes in pancreatic cyst patients.

Preventing cardiotoxicity in patients with breast cancer and lymphoma: protocol for a multicentre randomised controlled trial (PROACT).

INTRODUCTION: Anthracyclines are included in chemotherapy regimens to treat several different types of cancer and are extremely effective. However, it is recognised that a significant side effect is cardiotoxicity; anthracyclines can cause irreversible damage to cardiac cells and ultimately impaired cardiac function and heart failure, which may only be evident years after exposure. The PROACT trial will establish the effectiveness of the ACE inhibitor enalapril maleate (enalapril) in preventing cardiotoxicity in patients with breast cancer and non-Hodgkin's lymphoma (NHL) receiving anthracycline-based chemotherapy. METHODS AND ANALYSIS: PROACT is a prospective, randomised, open-label, blinded end-point, superiority trial which will recruit adult patients being treated for breast cancer and NHL at NHS hospitals throughout England. The trial aims to recruit 106 participants, who will be randomised to standard care (high-dose anthracycline-based chemotherapy) plus enalapril (intervention) or standard care alone (control). Patients randomised to the intervention arm will receive enalapril (starting at 2.5 mg two times per day and titrating up to a maximum dose of 10 mg two times per day), commencing treatment at least 2 days prior to starting chemotherapy and finishing 3 weeks after their last anthracycline dose. The primary outcome is the presence or absence of cardiac troponin T release at any time during anthracycline treatment, and 1 month after the last dose of anthracycline. Secondary outcomes will focus on cardiac function measured using echocardiogram assessment, adherence to enalapril and side effects. ETHICS AND DISSEMINATION: A favourable opinion was given following research ethics committee review by West Midlands-Edgbaston REC, Ref: 17/WM/0248. Trial findings will be disseminated through engagement with patients, the oncology and cardiology communities, NHS management and commissioning groups and through peer-reviewed publication. TRIAL REGISTRATION NUMBER: NCT03265574.

Impact of anticoagulants on the clinical outcomes of colonic diverticular bleeding comparing warfarin and direct oral anticoagulants.

Recently, direct oral anticoagulants (DOACs) have been widely used as antithrombotic agents to replace warfarin, but their clinical impact in patients with gastrointestinal bleeding is unclear. We compared the effects of warfarin and DOACs on the outcomes of patients with colonic diverticular bleeding. The patients were divided into warfarin and DOAC groups. We compared the clinical outcomes and the effect of the DOAC dosing and examined any readmissions due to colonic diverticular bleeding within 1 year. A total of 95 events (warfarin group: n = 43 and DOAC group: n = 52) were included. Compared with the warfarin group, the DOAC group was significantly older, had a lower rate of concomitant antiplatelet agents, and a shorter hospital stay, but no significant differences were found in the other clinical outcomes. Thirty-seven patients (71.2%) in the DOAC group had appropriate dosing, whereas 15 patients (28.9%) had an inappropriate dose. The patients with overdose or contraindications had significantly lower minimum hemoglobin levels. In the univariate analysis, prior hospitalization for colonic diverticular bleeding was a significant predictor of readmission. Compared with warfarin, patients with colonic diverticular bleeding treated with DOACs were older and had shorter hospital stays, and the inappropriate use of DOACs may worsen outcomes.

Deficiency in endocannabinoid synthase DAGLB contributes to early onset Parkinsonism and murine nigral dopaminergic neuron dysfunction.

Endocannabinoid (eCB), 2-arachidonoyl-glycerol (2-AG), the most abundant eCB in the brain, regulates diverse neural functions. Here we linked multiple homozygous loss-of-function mutations in 2-AG synthase diacylglycerol lipase ß (DAGLB) to an early onset autosomal recessive Parkinsonism. DAGLB is the main 2-AG synthase in human and mouse substantia nigra (SN) dopaminergic neurons (DANs). In mice, the SN 2-AG levels were markedly correlated with motor performance during locomotor skill acquisition. Genetic knockdown of Daglb in nigral DANs substantially reduced SN 2-AG levels and impaired locomotor skill learning, particularly the across-session learning. Conversely, pharmacological inhibition of 2-AG degradation increased nigral 2-AG levels, DAN activity and dopamine release and rescued the locomotor skill learning deficits. Together, we demonstrate that DAGLB-deficiency contributes to the pathogenesis of Parkinsonism, reveal the importance of DAGLB-mediated 2-AG biosynthesis in nigral DANs in regulating neuronal activity and dopamine release, and suggest potential benefits of 2-AG augmentation in alleviating Parkinsonism.

Systematic review of transcriptome and microRNAome associations with gestational diabetes mellitus.

Purpose: Gestational diabetes (GDM) is associated with increased risk for preterm birth and related complications for both the pregnant person and newborn. Changes in gene expression have the potential to characterize complex interactions between genetic and behavioral/environmental risk factors for GDM. Our goal was to summarize the state of the science about changes in gene expression and GDM. Design: The systematic review was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Methods: PubMed articles about humans, in English, from any date were included if they described mRNA transcriptome or microRNA findings from blood samples in adults with GDM compared with adults without GDM. Results: Sixteen articles were found representing 1355 adults (n=674 with GDM, n=681 controls) from 12 countries. Three studies reported transcriptome results and thirteen reported microRNA findings. Identified pathways described various aspects of diabetes pathogenesis, including glucose and insulin signaling, regulation, and transport; natural killer cell mediated cytotoxicity; and fatty acid biosynthesis and metabolism. Studies described 135 unique miRNAs that were associated with GDM, of which eight (miR-16-5p, miR-17-5p, miR-20a-5p, miR-29a-3p, miR-195-5p, miR-222-3p, miR-210-3p, and miR-342-3p) were described in 2 or more studies. Findings suggest that miRNA levels vary based on the time in pregnancy when GDM develops, the time point at which they were measured, sex assigned at birth of the offspring, and both the pre-pregnancy and gestational body mass index of the pregnant person. Conclusions: The mRNA, miRNA, gene targets, and pathways identified in this review contribute to our understanding of GDM pathogenesis; however, further research is warranted to validate previous findings. In particular, longitudinal repeated-measures designs are needed that control for participant characteristics (e.g., weight), use standardized data collection methods and analysis tools, and are sufficiently powered to detect differences between subgroups. Findings may be used to improve early diagnosis, prevention, medication choice and/or clinical treatment of patients with GDM.

Liposomal Bupivacaine vs Ropivacaine for Adductor Canal Blocks in Total Knee Arthroplasty: A Prospective Randomized Trial.

BACKGROUND: The purpose of this study is to determine the benefit of the analgesic liposomal bupivacaine compared to ropivacaine, by assessing pain and joint stiffness, and total oral opioid consumption by milligram morphine equivalent (MME) after total knee arthroplasty. METHODS: Patients were randomized to receive either the study drug (liposomal bupivacaine admixed with bupivacaine) or the control drug (ropivacaine) in an adductor canal block. Only the anesthesiologist performing the block was aware of which arm of the study the patient was randomized to. MME, pain, Knee injury and Osteoarthritis Outcome Score Joint Replacement, and overall benefit of analgesia scores were recorded 24, 48, and 72 hours post-surgery either face-to-face or via telephone depending on patient discharge status. RESULTS: One hundred patients were enrolled into the study and analyzed: 54 in the control group and 46 in the experimental group. Primary outcomes measured were pain as a numerical rating scale, MME, and length of stay in hours. Secondary outcomes were joint pain and stiffness recorded as Knee injury and Osteoarthritis Outcome Score Joint Replacement outcome and overall benefit of analgesia score. No statistically significant between-group differences were observed for any measured outcome. CONCLUSION: We did not find any supporting evidence that liposomal bupivacaine yields increased pain relief following total knee arthroplasty compared to the control drug, ropivacaine.

The Effect of Lockdown Period during the COVID-19 Pandemic on Air Quality in Sydney Region, Australia.

In early 2020 from April to early June, the metropolitan area of Sydney as well as the rest of New South Wales (NSW, Australia) experienced a period of lockdown to prevent the spread of COVID-19 virus in the community. The effect of reducing anthropogenic activities including transportation had an impact on the urban environment in terms of air quality which is shown to have improved for a number of pollutants, such as Nitrogen Dioxides (NO2) and Carbon Monoxide (CO), based on monitoring data on the ground and from a satellite. In addition to primary pollutants CO and NOx emitted from mobile sources, PM2.5 (primary and secondary) and secondary Ozone (O3) during the lockdown period will also be analyzed using both statistical methods on air quality data and the modelling method with emission and meteorological data input to an air quality model. By estimating the decrease in traffic volume in the Sydney region, the corresponding decrease in emission input to the Weather Research and Forecasting-Community Multiscale Air Quality Modelling System (WRF-CMAQ) air quality model is then used to estimate the effect of lockdown on the air quality especially CO, NO2, O3, and PM2.5 in the Greater Metropolitan Region (GMR) of Sydney. The results from both statistical and modelling methods show that NO2, CO, and PM2.5 levels decreased during the lockdown, but O3 instead increased. However, the change in the concentration levels are small considering the large reduction of ~30% in traffic volume.

The Summer 2019-2020 Wildfires in East Coast Australia and Their Impacts on Air Quality and Health in New South Wales, Australia.

The 2019-2020 summer wildfire event on the east coast of Australia was a series of major wildfires occurring from November 2019 to end of January 2020 across the states of Queensland, New South Wales (NSW), Victoria and South Australia. The wildfires were unprecedent in scope and the extensive character of the wildfires caused smoke pollutants to be transported not only to New Zealand, but also across the Pacific Ocean to South America. At the peak of the wildfires, smoke plumes were injected into the stratosphere at a height of up to 25 km and hence transported across the globe. The meteorological and air quality Weather Research and Forecasting with Chemistry (WRF-Chem) model is used together with the air quality monitoring data collected during the bushfire period and remote sensing data from the Moderate Resolution Imaging Spectroradiometer (MODIS) and Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation (CALIPSO) satellites to determine the extent of the wildfires, the pollutant transport and their impacts on air quality and health of the exposed population in NSW. The results showed that the WRF-Chem model using Fire Emission Inventory (FINN) from National Center for Atmospheric Research (NCAR) to simulate the dispersion and transport of pollutants from wildfires predicted the daily concentration of PM2.5 having the correlation (R2) and index of agreement (IOA) from 0.6 to 0.75 and 0.61 to 0.86, respectively, when compared with the ground-based data. The impact on health endpoints such as mortality and respiratory and cardiovascular diseases hospitalizations across the modelling domain was then estimated. The estimated health impact on each of the Australian Bureau of Statistics (ABS) census districts (SA4) of New South Wales was calculated based on epidemiological assumptions of the impact function and incidence rate data from the 2016 ABS and NSW Department of Health statistical health records. Summing up all SA4 census district results over NSW, we estimated that there were 247 (CI: 89, 409) premature deaths, 437 (CI: 81, 984) cardiovascular diseases hospitalizations and 1535 (CI: 493, 2087) respiratory diseases hospitalizations in NSW over the period from 1 November 2019 to 8 January 2020. The results are comparable with a previous study based only on observation data, but the results in this study provide much more spatially and temporally detailed data with regard to the health impact from the summer 2019-2020 wildfires.

Comparison of colonoscopy after colonic diverticulitis and positive fecal immunochemical tests for the detection of colorectal neoplasia.

Background and study aims The relationship between acute colonic diverticulitis and colorectal cancer (CRC) is unclear, but colonoscopy is recommended to exclude malignancy. We compared the detection rates for colorectal neoplasia in patients with colonic diverticulitis and asymptomatic patients who had positive fecal immunochemical tests (FITs). Patients and methods In total, 282 patients with acute colonic diverticulitis were hospitalized in our hospital from February 2011 to December 2019. Of them, 143 patients with diverticulitis and 1819 with positive FITs patients during the same period underwent colonoscopy without a prior colonoscopy within 5 years. We retrospectively compared these patients in terms of the invasive CRC rate, advanced neoplasia detection rate (ANDR), adenoma detection rate (ADR), and polyp detection rate (PDR). Results Compared to the diverticulitis group, the FIT-positive group had a significantly higher CRC rate (0 vs 2.7 %, P  = 0.0061), ANDR (5.6 vs. 14.0 %, P  = 0.0017), ADR (19.6 vs. 53.2 %, P  < .0001), and PDR (44.1 vs. 91.0 %, P  < .0001). Using 1:1 propensity score matching based on age and sex, we obtained 276 matched patients in both groups. After matching, no difference was found in the CRC rate (0 vs 0.7 %) or ANDR (5.8 vs 7.3 %) between groups, but the ADR and PDR were significantly higher in the FIT-positive group (20.3 vs 43.5 %, P  < .0001; 45.7 % vs 86.2 %, P  < .0001). Conclusion Patients with acute diverticulitis had lower ADRs and PDRs than patients with positive FITs.

Radiation exposure dose of fluoroscopy-guided gastrointestinal procedures: A single-center retrospective study.

Background and study aims Fluoroscopy-guided gastrointestinal procedures (FGPs) are increasingly common. However, the radiation exposure (RE) to patients undergoing FGPs is still unclear. We examined the actual RE of FGPs. Patients and methods This retrospective, single-center cohort study included consecutive FGPs, including endoscopic retrograde cholangiopancreatography (ERCP), interventional endoscopic ultrasound (EUS), enteral stenting, balloon-assisted enteroscopy, tube placement, endoscopic injection sclerotherapy (EIS), esophageal balloon dilatation and repositioning for sigmoid volvulus, from September 2012 to June 2019. We measured the air kerma (AK, mGy), dose area product (DAP, Gycm 2 ), and fluoroscopy time (FT, min) for each procedure. Results In total, 3831 patients were enrolled. Overall, 2778 ERCPs were performed. The median AK, DAP, and FT were as follows: ERCP: 109 mGy, 13.3 Gycm 2 and 10.0 min; self-expandable enteral stenting (SEMS): 62 mGy, 12.4 Gycm 2 and 10.4 min; tube placement: 40 mGy, 13.8 Gycm 2 and 11.1 min; balloon-assisted enteroscopy: 43 mGy, 22.4 Gycm 2 and 18.2 min; EUS cyst drainage (EUS-CD): 96 mGy, 18.3 Gycm 2 and 10.4 min; EIS: 36 mGy, 8.1 Gycm 2 and 4.4 min; esophageal balloon dilatation: 9 mGy, 2.2 Gycm 2 and 1.8 min; and repositioning for sigmoid volvulus: 7 mGy, 4.7 Gycm 2 and 1.6 min. Conclusion This large series reporting actual RE doses of various FGPs could serve as a reference for future prospective studies.

Correction to: Parkinson's disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging.

The original article had mistakenly inverted co-author, Wang Zheng's name. This has since been corrected.

Parkinson's disease-related Leucine-rich repeat kinase 2 modulates nuclear morphology and genomic stability in striatal projection neurons during aging.

BACKGROUND: Multiple missense mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with familial forms of late onset Parkinson's disease (PD), the most common age-related movement disorder. The dysfunction of dopamine transmission contributes to PD-related motor symptoms. Interestingly, LRRK2 is more abundant in the dopaminoceptive striatal spiny projection neurons (SPNs) compared to the dopamine-producing nigrostriatal dopaminergic neurons. Aging is the most important risk factor for PD and other neurodegenerative diseases. However, whether LRRK2 modulates the aging of SPNs remains to be determined. METHODS: We conducted RNA-sequencing (RNA-seq) analyses of striatal tissues isolated from Lrrk2 knockout (Lrrk2-/-) and control (Lrrk2+/+) mice at 2 and 12 months of age. We examined SPN nuclear DNA damage and epigenetic modifications; SPN nuclear, cell body and dendritic morphology; and the locomotion and motor skill learning of Lrrk2+/+ and Lrrk2-/- mice from 2 to 24 months of age. Considering the strength of cell cultures for future mechanistic studies, we also performed preliminary studies in primary cultured SPNs derived from the Lrrk2+/+ and Lrrk2-/- mice as well as the PD-related Lrrk2 G2019S and R1441C mutant mice. RESULTS: Lrrk2-deficiency accelerated nuclear hypertrophy and induced dendritic atrophy, soma hypertrophy and nuclear invagination in SPNs during aging. Additionally, increased nuclear DNA damage and abnormal histone methylations were also observed in aged Lrrk2-/- striatal neurons, together with alterations of molecular pathways involved in regulating neuronal excitability, genome stability and protein homeostasis. Furthermore, both the PD-related Lrrk2 G2019S mutant and LRRK2 kinase inhibitors caused nuclear hypertrophy, while the Lrrk2 R1441C mutant and γ-Aminobutyric acid type A receptor (GABA-AR) inhibitors promoted nuclear invagination in the cultured SPNs. On the other hand, inhibition of neuron excitability prevented the formation of nuclear invagination in the cultured Lrrk2-/- and R1441C SPNs. CONCLUSIONS: Our findings support an important physiological function of LRRK2 in maintaining nuclear structure integrity and genomic stability during the normal aging process, suggesting that PD-related LRRK2 mutations may cause the deterioration of neuronal structures through accelerating the aging process.

Distinct Connectivity and Functionality of Aldehyde Dehydrogenase 1a1-Positive Nigrostriatal Dopaminergic Neurons in Motor Learning.

Parkinson's disease causes the most profound loss of the aldehyde dehydrogenase 1A1-positive (ALDH1A1+) nigrostriatal dopaminergic neuron (nDAN) subpopulation. The connectivity and functionality of ALDH1A1+ nDANs, however, remain poorly understood. Here, we show in rodent brains that ALDH1A1+ nDANs project predominantly to the rostral dorsal striatum, from which they also receive most monosynaptic inputs, indicating extensive reciprocal innervations with the striatal spiny projection neurons (SPNs). Functionally, genetic ablation of ALDH1A1+ nDANs causes severe impairments in motor skill learning, along with a reduction in high-speed walking. While dopamine replacement therapy accelerated walking speed, it failed to improve motor skill learning in ALDH1A1+ nDAN-ablated mice. Altogether, our study provides a comprehensive whole-brain connectivity map and reveals a key physiological function of ALDH1A1+ nDANs in motor skill acquisition, suggesting the motor learning processes require ALDH1A1+ nDANs to integrate diverse presynaptic inputs and supply dopamine with dynamic precision.