Aortic Stenosis and Renal Function: A Bidirectional Mendelian Randomization Analysis.

BACKGROUND: Large observational studies have demonstrated a clear inverse association between renal function and risk of aortic stenosis (AS). Whether this represents a causal, reverse causal or correlative relationship remains unclear. We investigated this using a bidirectional 2-sample Mendelian randomization approach. METHODS AND RESULTS: We collected summary statistics for the primary analysis of chronic kidney disease (CKD) and AS from genome-wide association study meta-analyses including 480 698 and 653 867 participants, respectively. We collected further genome-wide association study summary statistics from up to 1 004 040 participants for sensitivity analyses involving estimated glomerular filtration rate (eGFR) derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. Inverse-variance weighted was the primary analysis method, with weighted-median, weighted-mode, Mendelian randomization-Egger, and Mendelian randomization-Pleiotropy Residual Sum and Outlier as sensitivity analyses. We did not find evidence of a causal relationship between genetically predicted CKD liability as the exposure and AS as the outcome (odds ratio [OR], 0.94 per unit increase in log odds of genetic liability to CKD [95% CI, 0.85-1.04], P=0.26) nor robust evidence of AS liability as the exposure and CKD as the outcome (OR, 1.04 per unit increase in log odds of genetic liability to AS [95% CI, 0.97-1.12], P=0.30). The sensitivity analyses were neutral overall, as were the analyses using eGFR derived from creatinine, eGFR derived from cystatin C, and serum urea nitrogen. All positive controls demonstrated strong significant associations. CONCLUSIONS: The present study did not find evidence of a substantial effect of genetically predicted renal impairment on risk of AS. This has important implications for research efforts that attempt to identify prevention and treatment targets for both CKD and AS.

Determinants of Mortality and Mid-Term Outcomes After Transcarotid Artery Revascularization and Transfemoral Carotid Artery Stenting.

OBJECTIVES: The potential benefit of transcarotid artery revascularization (TCAR) over transfemoral carotid artery stenting (tfCAS) has been studied in the perioperative period with lower rates of stroke and death; however, data on mid-term outcomes are limited. We aimed to evaluate 3-year outcomes after TCAR and tfCAS and determine the primary predictors of 30-day and 1-year mortality following TCAR. METHODS: Data from the Vascular Quality Initiative for patients undergoing TCAR or tfCAS from January 2016 to December 2022 were analyzed. 1:1 propensity score matching using the nearest-neighbor method was used to adjust baseline demographics and clinical characteristics. Kaplan-Meier survival analysis and Cox Proportional Hazard Regression were used to evaluate long-term outcomes. Iterative stepwise multiple logistic regression analysis and Cox Proportional Hazard Regression were used to identify predictors of 30-day and 1-year mortality, respectively, based upon preoperative, intraoperative, and postoperative factors. RESULTS: A total of 70 237 patients were included in analysis (TCAR=58.7%, tfCAS=41.3%). Transcarotid artery revascularization patients were older and had higher rates of comorbid conditions and high-risk medical and anatomic features than tfCAS patients. Propensity score matching yielded 22 322 pairs with no major differences between groups except that TCAR patients were older (71.6 years vs 70.8 years). At 3 years, TCAR was associated with a 24% reduction in hazard of death compared with tfCAS (hazard ratio [HR]=0.76, 95% confidence interval [CI]=0.71-0.82, p<0.001), for both symptomatic and asymptomatic patients. This survival advantage was established in the first 6 months (HR=0.59, 95% CI=0.53-0.62, p<0.001), with no difference in mortality risk from 6 months to 36 months (HR=0.95, 95% CI=0.86-1.05, p=0.31). Transcarotid artery revascularization was also associated with decreased hazard for 3-year stroke (HR=0.81, 95% CI=0.66-0.99, p=0.04) and stroke or death (HR=0.81, 95% CI=0.76-0.87, p<0.001) compared with tfCAS. The top predictors for 30-day and 1-year mortality were postoperative complications. The primary independent predictor was the occurrence of postoperative stroke. CONCLUSIONS: Transcarotid artery revascularization had a sustained mid-term survival advantage associated over tfCAS, with the benefit being established primarily within the first 6 months. Notably, our findings highlight the importance of postoperative stroke as the primary independent predictor for 30-day and 1-year mortal. CLINICAL IMPACT: The ongoing debate over the superiority of TCAR compared to tfCAS and CEA has been limited by a lack of comparative studies examining the impact of pre-operative symptoms on outcomes. Furthermore, data are scarce on mid-term outcomes for TCAR beyond the perioperative period. As a result, it remains uncertain whether the initial benefits of stroke and death reduction observed with TCAR over tfCAS persist beyond one year. Our study addresses these gaps in the literature, offering evidence to enable clinicians to assess the efficacy of TCAR for up to three years. Additionally, our study seeks to identify risk factors for postoperative mortality following TCAR, facilitating optimal patient stratification.

The association of pain impact and sleep disruption with opioid withdrawal during opioid-use disorder treatment.

AIMS: Persons with opioid-use disorder (OUD) often experience opioid withdrawal and opioid craving, which can drive continued opioid use and treatment discontinuation. In addition, hyperalgesia is common among persons with OUD, yet few studies have examined the role of pain impact during OUD treatment. The purpose of the present study was to test whether opioid withdrawal and craving were elevated in the context of greater pain impact (i.e. greater pain intensity and interference), and whether these associations changed throughout treatment. METHODS: Participants in residential OUD treatment (n = 24) wore wrist actigraphy to measure sleep and completed daily measures of pain impact, opioid withdrawal and opioid craving for up to 28 days. Mixed effects models were used to examine whether daily elevations in pain impact and sleep continuity were associated with withdrawal severity and opioid craving. RESULTS: Elevations in withdrawal, but not craving, occurred on days when individuals reported higher scores on the pain impact scale. Associations between pain impact and withdrawal were present throughout treatment, but stronger during early treatment. In contrast, both withdrawal and opioid craving were elevated following nights of greater wake after sleep onset and awakenings, but these findings were often more pronounced in early treatment. CONCLUSIONS: Pain impact and sleep disturbance are 2 factors associated with opioid withdrawal and opioid craving. Novel pharmacotherapies and scalable adjunctive interventions targeting sleep and pain impact should be tested in future work to improve OUD treatment outcomes.

Training Medical Student Counselors for the Rochester Model, a Hospital Tobacco Treatment Program.

Purpose: Providing effective tobacco dependence treatments to hospitalized patients remains a challenge. Prior to 2021, the Rochester Model program used staff nurses for both bedside and post-discharge counseling necessary to maintain abstinence. When nurse shortages and elevated job stress occurred during the COVID Pandemic, we proposed that medical students learn to counsel patients at the bedside and after discharge. Patients and Methods: Due to COVID restrictions, first- and second-year medical students trained using remote Zoom sessions. The total training time was 2.5 hr without role-play or additional evaluations. A survey measured the students' satisfaction, confidence, and counseling barriers. A smoking patient on a participating hospital unit can enroll in the program. Students delivered bedside counseling, then provided follow-up treatment and outcome calls along with New York State Quitline counselors. Results: The survey demonstrated that 89% of the students were satisfied with the training. The bedside counseling confidence was greater than the phone counseling confidence. All students felt the program experience has value to them as future physicians. 124 smoking patients enrolled, and outcomes followed out to 6 months. The 7-day point prevalence quit rates using the as-treated (patients contacted) analysis were 57% at 4 weeks, 48% at 3 months, and 43% at 6 months. The 7-day point prevalence quit rates using the intent-to-treat (all patients) analysis were 31% at 4 weeks, 16% at 3 months and 14% at 6 months. Conclusion: Medical students given minimal training are effective tobacco cessation counselors at no cost to the hospital system. The Rochester Model program using student counseling benefits patients, the students, and the health-care system.

Neck radiation is not associated with increased risk of perioperative adverse events after transcarotid artery revascularization or transfemoral carotid artery stenting.

OBJECTIVE: It is unclear whether patients with prior neck radiation therapy (RT) are at high risk for carotid artery stenting (CAS). We aimed to delineate 30-day perioperative and 3-year long-term outcomes in patients treated for radiation-induced stenotic lesions by the transfemoral carotid artery stenting (TFCAS) or transcarotid artery revascularization (TCAR) approach to determine comparative risk and to ascertain the optimal intervention in this cohort. METHODS: Data were extracted from the Vascular Quality Initiative CAS registry for patients with prior neck radiation who had undergone either TCAR or TFCAS. The Student t-test and the χ2 test were used to compare baseline patient characteristics. Multivariable logistic regression and Cox Hazard Proportional analysis were used to compare perioperative and long-term differences between patients with and without prior neck radiation following TCAR and TFCAS. Kaplan-Meier estimator was used to determine the incidence of 3-year adverse events. RESULTS: A total of 72,656 patients (TCAR, 40,879; TFCAS, 31,777) were included in the analysis. Of these, 4151 patients had a history of neck radiation. Patients with a history of neck radiation were more likely to be younger, white, and have fewer comorbidities than patients with no neck radiation history. After adjustment for confounding factors, there was no difference in relative risk of 30-day perioperative stroke (P = .11), death (P = .36), or myocardial infarction (MI) (P = .61) between TCAR patients with or without a history of neck radiation. The odds of stroke/death (P = .10) and stroke/death/MI (P = .07) were also not statistically significant. In patients with prior neck radiation, TCAR had lower odds for in-hospital stroke/death/MI (odds ratio, 0.59; 95% confidence interval [CI], 0.35-0.99; P = .05) and access site complications than TFCAS. At year 3, patients with prior neck radiation had an increased hazard for mortality after TCAR (hazard ratio [HR], 1.24; 95% CI, 1.02-1.51; P = .04) and TFCAS (HR, 1.33; 95% CI, 1.12-1.58; P = .001). Patients with prior neck radiation also experienced an increased hazard for reintervention after TCAR (HR, 2.16; 95% CI, 1.45-3.20; P < .001) and TFCAS (HR, 1.67; 95% CI, 1.02-2.73; P<.001). CONCLUSIONS: Patients with prior neck radiation had a similar relative risk of 30-day perioperative adverse events as patients with no neck radiation after adjustment for baseline demographics and disease characteristics. In these patients, TCAR was associated with reduced odds of perioperative stroke/death/MI as compared with TFCAS. However, patients with prior neck radiation were at increased risk for 3-year mortality and reintervention.

Population heterogeneity in the fractional master equation, ensemble self-reinforcement, and strong memory effects.

We formulate a fractional master equation in continuous time with random transition probabilities across the population of random walkers such that the effective underlying random walk exhibits ensemble self-reinforcement. The population heterogeneity generates a random walk with conditional transition probabilities that increase with the number of steps taken previously (self-reinforcement). Through this, we establish the connection between random walks with a heterogeneous ensemble and those with strong memory where the transition probability depends on the entire history of steps. We find the ensemble-averaged solution of the fractional master equation through subordination involving the fractional Poisson process counting the number of steps at a given time and the underlying discrete random walk with self-reinforcement. We also find the exact solution for the variance which exhibits superdiffusion even as the fractional exponent tends to 1.

The effect of immunomodulatory drugs on aortic stenosis: a Mendelian randomisation analysis.

There are currently no approved pharmacological treatment options for aortic stenosis (AS), and there are limited identified drug targets for this chronic condition. It remains unclear whether inflammation plays a role in AS pathogenesis and whether immunomodulation could become a therapeutic target. We evaluated the potentially causal association between inflammation and AS by investigating the genetically proxied effects of tocilizumab (IL6 receptor, IL6R, inhibitor), canakinumab (IL1ß inhibitor) and colchicine (ß-tubulin inhibitor) through a Mendelian randomisation (MR) approach. Genetic proxies for these drugs were identified as single nucleotide polymorphisms (SNPs) in the gene, enhancer or promoter regions of IL6R, IL1ß or ß-tubulin gene isoforms, respectively, that were significantly associated with serum C-reactive protein (CRP) in a large European genome-wide association study (GWAS; 575,531 participants). These were paired with summary statistics from a large GWAS of AS in European patients (653,867 participants) to then perform primary inverse-variance weighted random effect and sensitivity MR analyses for each exposure. This analysis showed that genetically proxied tocilizumab was associated with reduced risk of AS (OR 0.56, 95% CI 0.45-0.70 per unit decrease in genetically predicted log-transformed CRP). Genetically proxied canakinumab was not associated with risk of AS (OR 0.80, 95% CI 0.51-1.26), and only one suitable SNP was identified to proxy the effect of colchicine (OR 34.37, 95% CI 1.99-592.89). The finding that genetically proxied tocilizumab was associated with reduced risk of AS is concordant with an inflammatory hypothesis of AS pathogenesis. Inhibition of IL6R may be a promising therapeutic target for AS management.

Impairment of Endothelial Function by Aerosol From Marijuana Leaf Vaporizers.

BACKGROUND: Marijuana leaf vaporizers, which heat plant material and sublimate Δ-9-tetrahydrocannabinol without combustion, are popular alternatives to smoking cannabis that are generally perceived to be less harmful. We have shown that smoke from tobacco and marijuana, as well as aerosol from e-cigarettes and heated tobacco products, impair vascular endothelial function in rats measured as arterial flow-mediated dilation (FMD). METHODS AND RESULTS: We exposed 8 rats per group to aerosol generated by 2 vaporizer systems (Volcano and handheld Yocan) using marijuana with varying Δ-9-tetrahydrocannabinol levels, in a single pulsatile exposure session of 2 s/min over 5 minutes, and measured changes in FMD. To model secondhand exposure, we exposed rats for 1 minute to diluted aerosol approximating release of uninhaled Volcano aerosol into typical residential rooms. Exposure to aerosol from marijuana with and without cannabinoids impaired FMD by ≈50%. FMD was similarly impaired by aerosols from Yocan (237 °C), and from Volcano at both its standard temperature (185 °C) and the minimum sublimation temperature of Δ-9-tetrahydrocannabinol (157 °C), although the low-temperature aerosol condition did not effectively deliver Δ-9-tetrahydrocannabinol to the circulation. Modeled secondhand exposure based on diluted Volcano aerosol also impaired FMD. FMD was not affected in rats exposed to clean air or water vapor passed through the Volcano system. CONCLUSIONS: Acute direct exposure and modeled secondhand exposure to marijuana leaf vaporizer aerosol, regardless of cannabinoid concentration or aerosol generation temperature, impair endothelial function in rats comparably to marijuana smoke. Our findings indicate that use of leaf vaporizers is unlikely to reduce the vascular risk burden of smoking marijuana.

Dual Role of Caspase 8 in Adipocyte Apoptosis and Metabolic Inflammation.

Caspases are cysteine-aspartic proteases that were initially discovered to play a role in apoptosis. However, caspase 8, in particular, also has additional nonapoptotic roles, such as in inflammation. Adipocyte cell death and inflammation are hypothesized to be initiating pathogenic factors in type 2 diabetes. Here, we examined the pleiotropic role of caspase 8 in adipocytes and obesity-associated insulin resistance. Caspase 8 expression was increased in adipocytes from mice and humans with obesity and insulin resistance. Treatment of 3T3-L1 adipocytes with caspase 8 inhibitor Z-IETD-FMK decreased both death receptor-mediated signaling and targets of nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling. We generated novel adipose tissue and adipocyte-specific caspase 8 knockout mice (aP2Casp8-/- and adipoqCasp8-/-). Both males and females had improved glucose tolerance in the setting of high-fat diet (HFD) feeding. Knockout mice also gained less weight on HFD, with decreased adiposity, adipocyte size, and hepatic steatosis. These mice had decreased adipose tissue inflammation and decreased activation of canonical and noncanonical NF-κB signaling. Furthermore, they demonstrated increased energy expenditure, core body temperature, and UCP1 expression. Adipocyte-specific activation of Ikbkb or housing mice at thermoneutrality attenuated improvements in glucose tolerance. These data demonstrate an important role for caspase 8 in mediating adipocyte cell death and inflammation to regulate glucose and energy homeostasis. ARTICLE HIGHLIGHTS: Caspase 8 is increased in adipocytes from mice and humans with obesity and insulin resistance. Knockdown of caspase 8 in adipocytes protects mice from glucose intolerance and weight gain on a high-fat diet. Knockdown of caspase 8 decreases Fas signaling, as well as canonical and noncanonical nuclear factor κ-light-chain-enhancer of activated B (NF-κB) signaling in adipose tissue. Improved glucose tolerance occurs via reduced activation of NF-κB signaling and via induction of UCP1 in adipocytes.

Porcine Astrocytes and Their Relevance for Translational Neurotrauma Research.

Astrocytes are essential to virtually all brain processes, from ion homeostasis to neurovascular coupling to metabolism, and even play an active role in signaling and plasticity. Astrocytic dysfunction can be devastating to neighboring neurons made inherently vulnerable by their polarized, excitable membranes. Therefore, correcting astrocyte dysfunction is an attractive therapeutic target to enhance neuroprotection and recovery following acquired brain injury. However, the translation of such therapeutic strategies is hindered by a knowledge base dependent almost entirely on rodent data. To facilitate additional astrocytic research in the translatable pig model, we present a review of astrocyte findings from pig studies of health and disease. We hope that this review can serve as a road map for intrepid pig researchers interested in studying astrocyte biology.

Lipids, Blood Pressure, and Diabetes Mellitus on Risk of Cardiovascular Diseases in East Asians: A Mendelian Randomization Study.

Elevated blood pressure, dyslipidemia, and impaired glycemic control are well-established cardiovascular risk factors in Europeans, but there are comparatively few studies focused on East Asian populations. This study evaluated the potential causal relations between traditional cardiovascular risk factors and disease risk in East Asians through a 2-sample Mendelian randomization approach. We collected summary statistics for blood pressure parameters, lipid subsets, and type 2 diabetes mellitus liability from large genome-wide association study meta-analyses conducted in East Asians and Europeans. These were paired with summary statistics for ischemic heart disease (IHD), ischemic stroke (IS), peripheral vascular disease, heart failure (HF) and atrial fibrillation (AF). We performed univariable Mendelian randomization analyses for each exposure-outcome pair, followed by multivariable analyses for the available lipid subsets. The genetically predicted risk factors associated with IHD and AF were similar between East Asians and Europeans. However, in East Asians only genetically predicted elevated blood pressure was significantly associated with IS (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001) and HF (odds ratio 1.05, 95% confidence interval 1.04 to 1.06, p <0.0001), whereas nearly all genetically predicted risk factors were significantly associated with IS and HF in Europeans. In conclusion, this study provides supportive evidence for similar causal relations between traditional cardiovascular risk factors and IHD and AF in both East Asian and European ancestry populations. However, the identified risk factors for IS and HF differed between East Asians and Europeans, potentially highlighting distinct disease etiologies between these populations.

Inhibition of galectin-3 post-infarction impedes progressive fibrosis by regulating inflammatory profibrotic cascades.

AIMS: Acute myocardial infarction (MI) causes inflammation, collagen deposition, and reparative fibrosis in response to myocyte death and, subsequently, a pathological myocardial remodelling process characterized by excessive interstitial fibrosis, driving heart failure (HF). Nonetheless, how or when to limit excessive fibrosis for therapeutic purposes remains uncertain. Galectin-3, a major mediator of organ fibrosis, promotes cardiac fibrosis and remodelling. We performed a preclinical assessment of a protein inhibitor of galectin-3 (its C-terminal domain, Gal-3C) to limit excessive fibrosis resulting from MI and prevent ventricular enlargement and HF. METHODS AND RESULTS: Gal-3C was produced by enzymatic cleavage of full-length galectin-3 or by direct expression of the truncated form in Escherichia coli. Gal-3C was intravenously administered for 7 days in acute MI models of young and aged rats, starting either pre-MI or 4 days post-MI. Echocardiography, haemodynamics, histology, and molecular and cellular analyses were performed to assess post-MI cardiac functionality and pathological fibrotic progression. Gal-3C profoundly benefitted left ventricular ejection fraction, end-systolic and end-diastolic volumes, haemodynamic parameters, infarct scar size, and interstitial fibrosis, with better therapeutic efficacy than losartan and spironolactone monotherapies over the 56-day study. Gal-3C therapy in post-MI aged rats substantially improved pump function and attenuated ventricular dilation, preventing progressive HF. Gal-3C in vitro treatment of M2-polarized macrophage-like cells reduced their M2-phenotypic expression of arginase-1 and interleukin-10. Gal-3C inhibited M2 polarization of cardiac macrophages during reparative response post-MI. Gal-3C impeded progressive fibrosis post-MI by down-regulating galectin-3-mediated profibrotic signalling cascades including a reduction in endogenous arginase-1 and inducible nitric oxide synthase (iNOS). CONCLUSION: Gal-3C treatment improved long-term cardiac function post-MI by reduction in the wound-healing response, and inhibition of inflammatory fibrogenic signalling to avert an augmentation of fibrosis in the periinfarct region. Thus, Gal-3C treatment prevented the infarcted heart from extensive fibrosis that accelerates the development of HF, providing a potential targeted therapy.

Interdisciplinary Inquiry via PanelGPT: Application to Explore Chatbot Application in Sports Rehabilitation.

Background: ChatGPT showcases exceptional conversational capabilities and extensive cross-disciplinary knowledge. In addition, it possesses the ability to perform multiple roles within a single chat session. This unique multi-role-playing feature positions ChatGPT as a promising tool to explore interdisciplinary subjects. Objective: The study intended to guide ChatGPT for interdisciplinary exploration through simulated panel discussions. As a proof-of-concept, we employed this method to evaluate the advantages and challenges of using chatbots in sports rehabilitation. Methods: We proposed a model termed PanelGPT to explore ChatGPTs' knowledge graph on interdisciplinary topics through simulated panel discussions. Applied to "chatbots in sports rehabilitation", ChatGPT role-played both the moderator and panelists, which included a physiotherapist, psychologist, nutritionist, AI expert, and an athlete. We act as the audience posed questions to the panel, with ChatGPT acting as both the panelists for responses and the moderator for hosting the discussion. We performed the simulation using the ChatGPT-4 model and evaluated the responses with existing literature and human expertise. Results: Each simulation mimicked a real-life panel discussion: The moderator introduced the panel and posed opening/closing questions, to which all panelists responded. The experts engaged with each other to address inquiries from the audience, primarily from their respective fields of expertise. By tackling questions related to education, physiotherapy, physiology, nutrition, and ethical consideration, the discussion highlighted benefits such as 24/7 support, personalized advice, automated tracking, and reminders. It also emphasized the importance of user education and identified challenges such as limited interaction modes, inaccuracies in emotion-related advice, assurance on data privacy and security, transparency in data handling, and fairness in model training. The panelists reached a consensus that chatbots are designed to assist, not replace, human healthcare professionals in the rehabilitation process. Conclusions: Compared to a typical conversation with ChatGPT, the multi-perspective approach of PanelGPT facilitates a comprehensive understanding of an interdisciplinary topic by integrating insights from experts with complementary knowledge. Beyond addressing the exemplified topic of chatbots in sports rehabilitation, the model can be adapted to tackle a wide array of interdisciplinary topics within educational, research, and healthcare settings.

Whole-brain annotation and multi-connectome cell typing quantifies circuit stereotypy in Drosophila.

The fruit fly Drosophila melanogaster combines surprisingly sophisticated behaviour with a highly tractable nervous system. A large part of the fly's success as a model organism in modern neuroscience stems from the concentration of collaboratively generated molecular genetic and digital resources. As presented in our FlyWire companion paper 1 , this now includes the first full brain connectome of an adult animal. Here we report the systematic and hierarchical annotation of this ~130,000-neuron connectome including neuronal classes, cell types and developmental units (hemilineages). This enables any researcher to navigate this huge dataset and find systems and neurons of interest, linked to the literature through the Virtual Fly Brain database 2 . Crucially, this resource includes 4,552 cell types. 3,094 are rigorous consensus validations of cell types previously proposed in the hemibrain connectome 3 . In addition, we propose 1,458 new cell types, arising mostly from the fact that the FlyWire connectome spans the whole brain, whereas the hemibrain derives from a subvolume. Comparison of FlyWire and the hemibrain showed that cell type counts and strong connections were largely stable, but connection weights were surprisingly variable within and across animals. Further analysis defined simple heuristics for connectome interpretation: connections stronger than 10 unitary synapses or providing >1% of the input to a target cell are highly conserved. Some cell types showed increased variability across connectomes: the most common cell type in the mushroom body, required for learning and memory, is almost twice as numerous in FlyWire as the hemibrain. We find evidence for functional homeostasis through adjustments of the absolute amount of excitatory input while maintaining the excitation-inhibition ratio. Finally, and surprisingly, about one third of the cell types proposed in the hemibrain connectome could not yet be reliably identified in the FlyWire connectome. We therefore suggest that cell types should be defined to be robust to inter-individual variation, namely as groups of cells that are quantitatively more similar to cells in a different brain than to any other cell in the same brain. Joint analysis of the FlyWire and hemibrain connectomes demonstrates the viability and utility of this new definition. Our work defines a consensus cell type atlas for the fly brain and provides both an intellectual framework and open source toolchain for brain-scale comparative connectomics.

Mesenchymal Stem Cells Delivered Locally to Ischemia-Reperfused Kidneys via Injectable Hyaluronic Acid Hydrogels Decrease Extracellular Matrix Remodeling 1 Month after Injury in Male Mice.

The translation of stem cell therapies has been hindered by low cell survival and retention rates. Injectable hydrogels enable the site-specific delivery of therapeutic cargo, including cells, to overcome these challenges. We hypothesized that delivery of mesenchymal stem cells (MSC) via shear-thinning and injectable hyaluronic acid (HA) hydrogels would mitigate renal damage following ischemia-reperfusion acute kidney injury. Acute kidney injury (AKI) was induced in mice by bilateral or unilateral ischemia-reperfusion kidney injury. Three days later, mice were treated with MSCs either suspended in media injected intravenously via the tail vein, or injected under the capsule of the left kidney, or MSCs suspended in HA injected under the capsule of the left kidney. Serial measurements of serum and urine biomarkers of renal function and injury, as well as transcutaneous glomerular filtration rate (tGFR) were performed. In vivo optical imaging showed that MSCs localized to both kidneys in a sustained manner after bilateral ischemia and remained within the ipsilateral treated kidney after unilateral ischemic AKI. One month after injury, MSC/HA treatment significantly reduced urinary NGAL compared to controls; it did not significantly reduce markers of fibrosis compared to untreated controls. An analysis of kidney proteomes revealed decreased extracellular matrix remodeling and high overlap with sham proteomes in MSC/HA-treated animals. Hydrogel-assisted MSC delivery shows promise as a therapeutic treatment following acute kidney injury.

Population heterogeneity in the fractional master equation, ensemble self-reinforcement, and strong memory effects.

We formulate a fractional master equation in continuous time with random transition probabilities across the population of random walkers such that the effective underlying random walk exhibits ensemble self-reinforcement. The population heterogeneity generates a random walk with conditional transition probabilities that increase with the number of steps taken previously (self-reinforcement). Through this, we establish the connection between random walks with a heterogeneous ensemble and those with strong memory where the transition probability depends on the entire history of steps. We find the ensemble-averaged solution of the fractional master equation through subordination involving the fractional Poisson process counting the number of steps at a given time and the underlying discrete random walk with self-reinforcement. We also find the exact solution for the variance which exhibits superdiffusion even as the fractional exponent tends to 1.

Extended Lymph Node Sampling During Surgery for Pediatric Renal Tumors Concerning for Malignancy Does Not Increase Postoperative Complication Rates.

PURPOSE: Although Children's Oncology Group renal tumor protocols mandate lymph node sampling during extirpative surgery for pediatric renal tumors, lymph node sampling is often omitted or low yield. Concerns over morbidity associated with extended lymph node sampling have led to hesitancy in adopting a formal lymph node sampling template. We hypothesized that complications in children undergoing lymph node sampling for renal tumors would be rare, and not associated with the number of lymph nodes sampled. MATERIALS AND METHODS: A single-institution, retrospective review of patients aged 0-18 years undergoing extirpative renal surgery with lymph node sampling for a suspected malignancy between 2005 and 2019 was performed. Patients with 0 or an unknown number of lymph nodes sampled or <150 days of follow-up were excluded. A "clinically significant" complication was defined as any Clavien complication ≥III, small-bowel obstruction, chylous ascites, organ injury, or wound infection. The number of lymph nodes sampled and its influence on the odds of experiencing a clinically significant complication was examined. RESULTS: A total of 144 patients met inclusion criteria. Median patient age was 38 months. Twenty-one patients (15%) had a clinically significant complication, the most common of which was ileus/small-bowel obstruction (n=16). In a multivariable analysis, increased lymph node yield was not found to influence the odds of experiencing a clinically significant complication (P = .6). CONCLUSIONS: In this cohort, there was no statistically significant difference in clinically significant complications in patients who underwent more extensive lymph node sampling during surgery for a suspected malignant pediatric renal tumor. Future studies on protocol adherence, staging accuracy, and survival trends using a lymph node sampling template in these patients should be performed.

Forecasting GDP with many predictors in a small open economy: forecast or information pooling?

This study compares two distinct approaches, pooling forecasts from single indicator MIDAS models versus pooling information from indicators into factor MIDAS models, for short-term Singapore GDP growth forecasting with a large ragged-edge mixed frequency dataset. We consider various popular weighting schemes in the literature when conducting forecast pooling. As for factor extraction, both the conventional dynamic factor model and the three-pass regression filter approach are considered. We investigate the relative predictive performance of all methods in a pseudo-out-of-sample forecasting exercise from 2007Q4 to 2020Q3. In the stable growth non-crisis period, no substantial difference in predictive performance is found across forecast models. In comparison, we find information pooling tends to dominate both the quarterly autoregressive benchmark model and the forecast pooling strategy particularly during the Global Financial Crisis. Supplementary Information: The online version contains supplementary material available at 10.1007/s00181-022-02356-9.