Hepatic NADH reductive stress underlies common variation in metabolic traits.

The cellular NADH/NAD+ ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD+ ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD+ ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance2, insulin resistance3 and mitochondrial disease4, and are associated with a common genetic variant in GCKR5, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD+ ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of 'causal metabolism'.

An insulin-regulated arrestin domain protein controls hepatic glucagon action.

Glucagon signaling is essential for maintaining normoglycemia in mammals. The arrestin fold superfamily of proteins controls the trafficking, turnover, and signaling of transmembrane receptors as well as other intracellular signaling functions. Further investigation is needed to understand the in vivo functions of the arrestin domain-containing 4 (ARRDC4) protein family member and whether it is involved in mammalian glucose metabolism. Here, we show that mice with a global deletion of the ARRDC4 protein have impaired glucagon responses and gluconeogenesis at a systemic and molecular level. Mice lacking ARRDC4 exhibited lower glucose levels after fasting and could not suppress gluconeogenesis at the refed state. We also show that ARRDC4 coimmunoprecipitates with the glucagon receptor, and ARRDC4 expression is suppressed by insulin. These results define ARRDC4 as a critical regulator of glucagon signaling and glucose homeostasis and reveal a novel intersection of insulin and glucagon pathways in the liver.

New approach to testing treatments for osteoarthritis: FastOA.

Animal models of post traumatic osteoarthritis have shown many promising treatments for disease, but human trials have mostly failed to identify effective treatments. This viewpoint suggests that the frequent failure of drug and treatment development in osteoarthritis is due, in part, to the advanced stage of disease of patients in trials and suggests that mirroring the animal model approach might be more successful. It suggests a path forward by enriching trial enrollees with those likely to develop post traumatic OA quickly.

Hepatobiliary infection after transjugular intrahepatic portosystemic shunt creation in patients with prior biliary intervention: A multi-institution retrospective study.

PURPOSE: To estimate the risk of hepatobiliary infection, including endoTIPSitis, liver abscesses, and cholangitis, after transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with prior biliary intervention. MATERIALS AND METHODS: This multi-institution, retrospective study identified 76 patients (n=48 males; mean age 54.9; mean model for end stage liver disease score=13.2; n=45 for ascites and n=23 for varices; n=31 with prior liver transplantation) among 2,130 undergoing TIPS (3.6%) who had prior biliary intervention (n=19 bilioenteric anastomoses, n=35 sphincterotomies, n=28 internal plastic stents, n=4 internal metal stents, and n=6 percutaneous biliary drains). The baseline risk of post-TIPS hepatobiliary infection was estimated from a control group of 1,202 TIPS procedures in patients without prior biliary intervention. RESULTS: Eleven of 76 patients (14.5%) developed hepatobiliary infection after TIPS, including 7 with endoTIPSitis, 4 with hepatic abscesses, and 2 with cholangitis. The 30-day risk of infection was 10.9% (95% CI=3.5-17.8%), significantly higher than the 0.4% risk (95% CI=0.1-0.8%) observed in patients without prior biliary intervention (hazard ratio (HR)=25.56, 95% CI=8.36-78.13, p<0.001). All types of biliary intervention were associated with increased risk of infection, with bilioenteric anastomoses conferring the highest risk. Paradoxically, among patients with prior biliary intervention, use of post-procedural antibiotic prophylaxis was associated with an increased infection risk (HR=19.85; 95% CI=2.44-161.50; p=0.005). Microbial culture data showed high rates of Enterococcus, Klebsiella, and Candida species. CONCLUSIONS: Prior biliary intervention was associated with a 10.9% risk of hepatobiliary infection, including endoTIPSitis, liver abscess, and cholangitis, within 30 days after TIPS creation.

Fluid intake behavior in women with refractory overactive bladder undergoing third line therapy.

INTRODUCTION AND OBJECTIVES: Fluid intake has been shown to be related to urinary symptoms, but no studies to date have investigated the effect of fluid intake on urinary symptoms in women with refractory overactive bladder (OAB). As this group of women are considered to have a possible unique pathophysiologic mechanism of OAB, we investigated the relationship between fluid intake, fluid intake behavior, and urinary symptoms in women with refractory OAB. METHODS: A prospective cross-sectional study of women with refractory OAB was conducted by assessing the relationship between fluid intake and lower urinary tract symptoms (LUTS) in women undergoing third line OAB therapies. Fluid intake and behavior were measured by the questionnaire based voiding diary and urinary symptoms were measured by the International Consultation on Incontinence Questionnaire for Female Lower Urinary Tract Symptoms (ICIQ-FLUTS). The relationship between fluid intake and symptom severity was assessed using Spearman's rank correlation and χ2  tests. RESULTS: Of the 126 individuals undergoing third line therapy for OAB, 60 (48%) underwent intradetrusor onabotulinumtoxinA injection (BTX) injection, 42 (33%) peripheral tibial nerve stimulation, and 24 (19%) sacral neuromodulation. The mean total daily fluid intake was 2567.0 ± SD 1292.4 mL and did not differ significantly across treatment groups. Total fluid intake was weakly correlated with worse filling-type LUTS (r = 0.241, p = 0.007), and there was no relationship between LUTS and caffeinated fluid intake. Half (52%) of the subjects reported current fluid restricting behavior to control urinary symptoms, but this behavior was not correlated with LUTS severity (all p > 0.05). Patients that currently use tobacco have greater LUTS (current = 25.8 ± SD 9.5, former = 14.8 ± SD 6.1, never = 15.0 ± SD 6.1; p < 0.001). BMI was also positively correlated with worse incontinence symptoms (r = 0.351, p < 0.001). CONCLUSIONS: Fluid intake along with other lifestyle factors, including tobacco use and weight, are minimally related to the symptomatology seen in women with refractory OAB. Further studies are needed to assess if behaviors change during treatment with third line therapies, and if these behavioral changes may affect treatment response.

Shifts in patient preference of third-line overactive bladder therapy after introduction of the implantable tibial nerve stimulator.

INTRODUCTION: Third-line therapies for overactive bladder (OAB) that are currently recommended include intravesical Onabotulinumtoxin-A injections (BTX-A), percutaneous tibial nerve stimulation (PTNS), and sacral neuromodulation (SNM). The implantable tibial nerve stimulator (ITNS) is a novel therapy that is now available to patients with OAB. OBJECTIVE: The objective of this study was to analyze shifts in patient preference of third-line therapies for OAB after introducing ITNS as an option among the previously established therapies for non-neurogenic OAB. METHODS: A survey was designed and distributed via SurveyMonkey to the platform's audience of U.S. adults of age 18 and older. Screening questions were asked to include only subjects who reported symptoms of OAB. Descriptions of current AUA/SUFU guideline-approved third-line therapies (BTX-A, PTNS, and SNM) were provided, and participants were asked to rank these therapies in order of preference (stage A). Subsequently, ITNS was introduced with a description, and participants were then asked to rank their preferences amongst current guideline-approved therapies and ITNS (stage B). Absolute and relative changes in therapy preferences between stage A and stage B were calculated. Associations between ultimate therapy choice in stage B and participant characteristics were analyzed. RESULTS: A total of 485 participants completed the survey (62.5% female). The mean age was 49.1 ± 36.5 years (SD). The most common OAB symptoms reported were urgency urinary incontinence (UUI) (73.0%) and urinary urgency (68.0%). 29.2% of patients had tried medication for OAB in the past, and 8.0%-10.3% of patients were previously treated with a third-line therapy for OAB. In stage A, participants ranked their first choice of third-line therapy as follows: 28% BTX-A, 27% PTNS, and 13.8% SNM. 26.6% of participants chose no therapy, and 4.5% chose all three equally. In stage B, participants ranked their first choice as follows: 27.6% BTX-A, 19.2% PTNS, 7.8% SNM, and 19.2% ITNS. 21.9% of participants chose no therapy and 4.3% chose all four equally as their first choice. There were both absolute and relative declines in proportions of patients interested in BTX-A, SNM, and PTNS as their first choice of third-line therapy with the introduction of ITNS. Patients originally interested in PTNS in stage A had the greatest absolute change after the introduction of ITNS with 7.8% of participants opting for ITNS in stage B. Those interested in SNM in stage A had the largest relative change in interest, with 43.5% of those originally interested in SNM opting for ITNS in stage B. Finally, with the introduction of ITNS, the number of participants initially not interested in any third-line therapy declined by an absolute change of 4.7% and relative change of 17.6%. Participants experiencing concurrent stress urinary incontinence (SUI) symptoms were more likely to choose a current guideline-approved third-line therapy than ITNS or no therapy at all (p = 0.047). Those who had prior experience with third-line therapies were more likely to choose a third-line therapy other than ITNS as their ultimate choice of therapy in stage B. Of those who had chosen a guideline-approved third-line therapy in stage B (not ITNS), 13.6% had prior experience with BTX-A, 14.7% with PTNS, and 32 (11.2%) with SNM (p < 0.001, p < 0.001, p = 0.009, respectively). CONCLUSION: From our study, it appears that ITNS may attract a subset of patients who would not have otherwise pursued current guideline-approved third-line therapies for OAB. When patients are provided with descriptions of third-line OAB therapies including ITNS as an option, ITNS appears to compete with SNM and PTNS. It is possible that ITNS will provide patients with a different phenotype of neuromodulation therapy that can appeal to a niche OAB population. Given that ITNS devices have been introduced relatively recently to the market, their application will largely depend on cost and payer coverage, provider bias, and patient comorbidities. Further study is needed to understand how these factors interact with and influence patient preference of advanced OAB therapy to understand which patients will most benefit from this treatment modality.

Breaking reflection symmetry: evolving long dynamical cycles in Boolean systems.

In interacting dynamical systems, specific local interaction rules for system components give rise to diverse and complex global dynamics. Long dynamical cycles are a key feature of many natural interacting systems, especially in biology. Examples of dynamical cycles range from circadian rhythms regulating sleep to cell cycles regulating reproductive behavior. Despite the crucial role of cycles in nature, the properties of network structure that give rise to cycles still need to be better understood. Here, we use a Boolean interaction network model to study the relationships between network structure and cyclic dynamics. We identify particular structural motifs that support cycles, and other motifs that suppress them. More generally, we show that the presence of dynamical reflection symmetry in the interaction network enhances cyclic behavior. In simulating an artificial evolutionary process, we find that motifs that break reflection symmetry are discarded. We further show that dynamical reflection symmetries are over-represented in Boolean models of natural biological systems. Altogether, our results demonstrate a link between symmetry and functionality for interacting dynamical systems, and they provide evidence for symmetry's causal role in evolving dynamical functionality.

Paradoxical activation of transcription factor SREBP1c and de novo lipogenesis by hepatocyte-selective ATP-citrate lyase depletion in obese mice.

Hepatic steatosis associated with high-fat diet, obesity, and type 2 diabetes is thought to be the major driver of severe liver inflammation, fibrosis, and cirrhosis. Cytosolic acetyl CoA (AcCoA), a central metabolite and substrate for de novo lipogenesis (DNL), is produced from citrate by ATP-citrate lyase (ACLY) and from acetate through AcCoA synthase short chain family member 2 (ACSS2). However, the relative contributions of these two enzymes to hepatic AcCoA pools and DNL rates in response to high-fat feeding are unknown. We report here that hepatocyte-selective depletion of either ACSS2 or ACLY caused similar 50% decreases in liver AcCoA levels in obese mice, showing that both pathways contribute to the generation of this DNL substrate. Unexpectedly however, the hepatocyte ACLY depletion in obese mice paradoxically increased total DNL flux measured by D2O incorporation into palmitate, whereas in contrast, ACSS2 depletion had no effect. The increase in liver DNL upon ACLY depletion was associated with increased expression of nuclear sterol regulatory element-binding protein 1c and of its target DNL enzymes. This upregulated DNL enzyme expression explains the increased rate of palmitate synthesis in ACLY-depleted livers. Furthermore, this increased flux through DNL may also contribute to the observed depletion of AcCoA levels because of its increased conversion to malonyl CoA and palmitate. Together, these data indicate that in fat diet-fed obese mice, hepatic DNL is not limited by its immediate substrates AcCoA or malonyl CoA but rather by activities of DNL enzymes.

The Role of Compassionate Care in Medicine: Toward Improving Patients' Quality of Care and Satisfaction.

INTRODUCTION: Despite its description as a cornerstone of a healthcare provider's professional identity, the impact of compassionate care on various aspects of medicine has been poorly defined. In this review, we aimed to elucidate the role of compassionate care in various aspects of medicine and healthcare delivery. METHODS: Four databases were searched using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses protocol for a literature review regarding compassionate care and its intersection with medical education, patient-provider communication, patient care, and clinical outcomes, patient and provider characteristics, telemedicine and artificial intelligence, caregiver compassion fatigue, and cost of care. RESULTS: Twenty-two articles met the inclusion criteria. Analysis revealed that clinical outcomes are correlated with the degree of patients' perception of empathy and compassion from their providers. Along with enhanced patient outcomes, compassionate care was shown to reduce the costs of care, compassion fatigue and burnout, and the number of malpractice claims. However, compassion can be perceived differently among patients of various cultural and ethnic backgrounds. Compassion training sessions can be implemented among residents in surgical and nonsurgical medical specialties to improve perceived compassion. Furthermore, the use of telehealth modalities may positively or negatively impact compassionate care, requiring further exploration. CONCLUSIONS: Compassionate care plays a crucial role in improving patient care and clinical outcomes while reducing caregiver burnout and the risk of malpractice litigation. However, a lack of compassion training and caregiver compassion fatigue may detract from the delivery of effective compassionate care.

CAB versus ABC approach for resuscitation of patients following traumatic injury: Toward improving patient safety and survival.

INTRODUCTION: Though a circulation-airway-breathing (CAB) resuscitation sequence is now widely accepted in administering CPR over the airway-breathing-circulation (ABC) sequence following cardiac arrest, current evidence and guidelines vary considerably for complex polytraumas, with some prioritizing management of the airway and others advocating for initial treatment of hemorrhage. This review aims to evaluate existing literature comparing ABC and CAB resuscitation sequences in adult trauma patients in-hospital to direct future research and guide evidence-based recommendations for management. METHODS: A literature search was conducted on PubMed, Embase, and Google Scholar until September 29, 2022. Articles were assessed for comparison between CAB and ABC resuscitation sequences, adult trauma patients, in-hospital treatment, patient volume status, and clinical outcomes. RESULTS: Four studies met the inclusion criteria. Two studies compared the CAB and ABC sequences specifically in hypotensive trauma patients, one study evaluated the sequences in trauma patients with hypovolemic shock, and one study in patients with all types of shock. Hypotensive trauma patients who underwent rapid sequence intubation before blood transfusion had a significantly higher mortality rate than those who had blood transfusion initiated first (50 vs 78% P < 0.05) and a significant drop in blood pressure. Patients who subsequently experienced post-intubation hypotension (PIH) had increased mortality over those without PIH. overall mortality was higher in patients that developed PIH (mortality, n (%): PIH = 250/753 (33.2%) vs 253/1291 (19.6%), p < 0.001). CONCLUSION: This study found that hypotensive trauma patients, especially those with active hemorrhage, may benefit more from a CAB approach to resuscitation, as early intubation may increase mortality secondary to PIH. However, patients with critical hypoxia or airway injury may still benefit more from the ABC sequence and prioritization of the airway. Future prospective studies are needed to understand the benefits of CAB with trauma patients and identify which patient subgroups are most affected by prioritizing circulation before airway management.

Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.

Insulin action in the liver is critical for glucose homeostasis through regulation of glycogen synthesis and glucose output. Arrestin domain-containing 3 (Arrdc3) is a member of the α-arrestin family previously linked to human obesity. Here, we show that Arrdc3 is differentially regulated by insulin in vivo in mice undergoing euglycemic-hyperinsulinemic clamps, being highly up-regulated in liver and down-regulated in muscle and fat. Mice with liver-specific knockout (KO) of the insulin receptor (IR) have a 50% reduction in Arrdc3 messenger RNA, while, conversely, mice with liver-specific KO of Arrdc3 (L-Arrdc3 KO) have increased IR protein in plasma membrane. This leads to increased hepatic insulin sensitivity with increased phosphorylation of FOXO1, reduced expression of PEPCK, and increased glucokinase expression resulting in reduced hepatic glucose production and increased hepatic glycogen accumulation. These effects are due to interaction of ARRDC3 with IR resulting in phosphorylation of ARRDC3 on a conserved tyrosine (Y382) in the carboxyl-terminal domain. Thus, Arrdc3 is an insulin target gene, and ARRDC3 protein directly interacts with IR to serve as a feedback regulator of insulin action in control of liver metabolism.

Opioid Use in Pediatric Patients After Common Orthopaedic Surgeries.

BACKGROUND: The use and misuse of opioid medications is an epidemic and public health emergency. There are currently no standard guidelines for treating perioperative pain in the pediatric population. The purpose of this study is to describe opioid use among pediatric patients after common orthopaedic surgeries. METHODS: Patients between 5 and 20 years of age undergoing one of 7 common orthopaedic surgeries between the years 2018 to 2020 were prospectively studied. Patients and their families completed a medication logbook to track all doses of pain medication and associated pain scores. RESULTS: Three hundred forty-two patients completed the study, including 174 females and 168 males with a mean age of 14.0 years (range, 5 to 20 y). A total of 4351 tablets or liquid doses of the narcotic medication, 44% of the total prescribed, were consumed. Of the prescribed medication,56% remained unused. Nonsteroidal anti-inflammatory drug use was identified to be the only independent predictor of less narcotic use, with a mean of 5.1 tablets ( P = 0.003) and 1.7 days ( P < 0.01) less opioid consumed among these patients. Thirty-two (9.4%) patients consumed 100% of their prescriptions. Nonmedicinal methods of pain control, most commonly ice, were used by 77% of patients, and this was highly variable between procedures. Physicians were cited as a source of medication information by only 50% of patients, with high variability between procedures. CONCLUSIONS: Opioid medication use in children and adolescents after orthopaedic surgery is significantly less than the number of tablets prescribed, with 56% of the medication prescribed remaining unused in the postoperative period. Duration of narcotic use was longer than anticipated with a wide SD (4.7 d +/-3 d).We recommend orthopaedic surgeons responsibly prescribe pain medications using evidence-based data or the results of their own experience monitoring medication consumption. In addition, and important in the setting of the "opioid epidemic," physicians must counsel patients and families on postoperative pain expectations and appropriate medication use. LEVEL OF EVIDENCE: Level IV, prospective case series.

Treatment of an aberrant inferior temporal artery aneurysm arising off the proximal cavernous segment of the internal carotid artery.

We report the clinical details, imaging findings, and management of a 41-year-old female who presented with 6th cranial nerve palsy from a right proximal cavernous segment internal carotid artery aneurysm arising distal to the branch point of an aberrant inferior temporal artery. Although rare, aberrant branches arising off the proximal ICA may supply the cerebral cortex. Careful evaluation prior to surgical intervention in this setting may reduce the incidence of ischemic complications.

Interrelationships between Cellular Density, Mosaic Patterning, and Dendritic Coverage of VGluT3 Amacrine Cells.

Amacrine cells of the retina are conspicuously variable in their morphologies, their population demographics, and their ensuing functions. Vesicular glutamate transporter 3 (VGluT3) amacrine cells are a recently characterized type of amacrine cell exhibiting local dendritic autonomy. The present analysis has examined three features of this VGluT3 population, including their density, local distribution, and dendritic spread, to discern the extent to which these are interrelated, using male and female mice. We first demonstrate that Bax-mediated cell death transforms the mosaic of VGluT3 cells from a random distribution into a regular mosaic. We subsequently examine the relationship between cell density and mosaic regularity across recombinant inbred strains of mice, finding that, although both traits vary across the strains, they exhibit minimal covariation. Other genetic determinants must therefore contribute independently to final cell number and to mosaic order. Using a conditional KO approach, we further demonstrate that Bax acts via the bipolar cell population, rather than cell-intrinsically, to control VGluT3 cell number. Finally, we consider the relationship between the dendritic arbors of single VGluT3 cells and the distribution of their homotypic neighbors. Dendritic field area was found to be independent of Voronoi domain area, while dendritic coverage of single cells was not conserved, simply increasing with the size of the dendritic field. Bax-KO retinas exhibited a threefold increase in dendritic coverage. Each cell, however, contributed less dendrites at each depth within the plexus, intermingling their processes with those of neighboring cells to approximate a constant volumetric density, yielding a uniformity in process coverage across the population.SIGNIFICANCE STATEMENT Different types of retinal neuron spread their processes across the surface of the retina to achieve a degree of dendritic coverage that is characteristic of each type. Many of these types achieve a constant coverage by varying their dendritic field area inversely with the local density of like-type neighbors. Here we report a population of retinal amacrine cells that do not develop dendritic arbors in relation to the spatial positioning of such homotypic neighbors; rather, this cell type modulates the extent of its dendritic branching when faced with a variable number of overlapping dendritic fields to approximate a uniformity in dendritic density across the retina.

Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model.

Skeletal muscle is responsible for the majority of glucose disposal following meals, and this is achieved by insulin-mediated trafficking of glucose transporter type 4 (GLUT4) to the cell membrane. The eight-protein exocyst trafficking complex facilitates targeted docking of membrane-bound vesicles, a process underlying the regulated delivery of fuel transporters. We previously demonstrated the role of exocyst subunit EXOC5 in insulin-stimulated GLUT4 exocytosis and glucose uptake in cultured rat skeletal myoblasts. However, the in vivo role of EXOC5 in skeletal muscle remains unclear. Using mice with inducible, skeletal-muscle-specific knockout of exocyst subunit EXOC5 (Exoc5-SMKO), we examined how muscle-specific disruption of the exocyst would affect glucose homeostasis in vivo. We found that both male and female Exoc5-SMKO mice displayed elevated fasting glucose levels. Additionally, male Exoc5-SMKO mice had impaired glucose tolerance and lower serum insulin levels. Using indirect calorimetry, we observed that male Exoc5-SMKO mice have a reduced respiratory exchange ratio during the light period and lower energy expenditure. Using the hyperinsulinemic-euglycemic clamp method, we further showed that insulin-stimulated skeletal muscle glucose uptake is reduced in Exoc5-SMKO males compared with wild-type controls. Overall, our findings indicate that EXOC5 and the exocyst are necessary for insulin-stimulated glucose uptake in skeletal muscle and regulate glucose homeostasis in vivo.

Rho/ROCK mechanosensor in adipocyte stiffness and traction force generation.

It is increasingly recognized that interaction of adipose cells with extracellular mechanophysical milieus may play a role in regulating adipogenesis and differentiated adipocyte function and such interaction can be mediated by the mechanics of adipose cells. We measured the stiffness and traction force of adipose cells and examined the role of Rho/ROCK, the upstream effector of actin cytoskeletal contractility, in affecting these mechanical properties. Cellular Young's modulus obtained from atomic force microscopy (AFM) was significantly reduced by ROCK inhibitor (Y-27632) but elevated by Rho activator (CN01), for both preadipocytes and differentiated adipocytes. Immunofluorescent imaging suggested this could be attributed to the changes in Rho/ROCK-induced stressed actin filament formation. AFM also confirmed that differentiated adipocytes had higher stiffness than preadipocytes. On the other hand, traction force microscopy (TFM) revealed differentiated adipocytes exerted lower traction forces than preadipocytes. Traction forces of both preadipocytes and adipocytes were decreased by ROCK inhibition, but not significantly altered by Rho activation. Notably, an increasing trend of traction force with respect to cell spreading area was detected, and this trend was substantially amplified by Rho activation. Such traction force-cell area correlation was an order-of-magnitude smaller for differentiated adipocytes relative to preadipocytes, potentially due to disrupted force transmission through cytoskeleton-focal adhesion linkage by lipid droplets. Our work provides new data evidencing the Rho/ROCK control in adipose cell mechanics, laying the groundwork for adipocyte mechanotransduction studies on adipogenesis and adipose tissue remodeling.

Initial experience using the Axonics sacral neuromodulation system in patients with multiple sclerosis.

INTRODUCTION: Sacral neuromodulation (SNM) is third-line therapy approved for urge urinary incontinence (UUI) and urgency, and nonobstructive urinary retention. Multiple sclerosis (MS) patients often suffer from neurogenic lower urinary tract dysfunction (NLUTD). The utility of SNM in the MS population is limited by magnetic resonance imaging (MRI) incompatibility as routine MRIs to evaluate for disease progression are required. The Axonics System is the first Food and Drug Administration-approved SNM device that is 1.5/3 T full-body MRI-conditionally safe. This study seeks to investigate the symptomatic improvement in MS patients after implantation of the Axonics System. METHODS: All MS patients who elected for Axonics SNM from December 2019 to January 2021 were included. Demographics and scores were queried for urogenital distress inventory (UDI-6), incontinence impact questionnaire (IIQ-7), and global response assessment (GRA). RESULTS: Fifteen MS patients with UUI were included. The time to follow-up averaged 121 days. On UDI-6, 12 patients reported improvement, 1 worsening, and 2 no change. Average UDI-6 scores before and after implantation were 56.6 and 25.2 (p < 0.0001). Improvements were significant for all questions under stress urinary incontinence, UUI, and voiding difficulty subcategories. On IIQ-7, 14 patients reported improvement and 1 reported worsening. Average IIQ-7 scores before and after implantation were 59.0 and 22.2 (p < 0.001). Improvements were significant for travel, social, and emotional subcategories, but not for physical activity. The average GRA score was 6 ("moderately improved"). CONCLUSION: The majority of MS patients reported significant initial improvement in UUI and associated quality of life measures on validated questionnaires after implantation of the Axonics System. Future studies are needed to determine the long-term outcomes and durability of this MRI full-body conditionally-safe system.

An analysis of factors that influence patient preference of third-line therapy for overactive bladder.

OBJECTIVE: Patients with overactive bladder (OAB) refractory to first- and second-line therapy may pursue third-line therapies, including intradetrusor onabotulinum toxin-A (BTX), peripheral tibial nerve stimulation (PTNS), and sacral neuromodulation (SNM). The factors that influence patient preference for each treatment modality have not yet been explored. This study sought to investigate the specific parameters that patients consider in choosing a third-line therapy for OAB. METHODS: Patients refractory to first- and second-line therapies for OAB were identified in our outpatient clinic and asked to watch an educational video providing information on the risks and benefits of each third-line treatment option. They were then given a questionnaire to rank their preference of therapy and select reasons for why they found each therapy favorable and unfavorable. Patients under age 18 years, non-English speakers, those with a developmental disability, and those with a diagnosis of neurogenic bladder were excluded. RESULTS: Of the 98 patients included in the study, 40 participants (40.8%) chose intradetrusor BTX injections, 34 (34.7%) chose PTNS, and 16 (16.3%) chose SNM as their first choice. Seven patients (7.1%) chose none of the offered therapies, and one patient (1.0%) chose all three therapies with equal preference. BTX was found most attractive for its long efficacy (47%); its least attractive feature was the potential need for self-catheterization due to urinary retention (54%). PTNS was found most attractive for being a nonsurgical option (32%) and having no reported significant complications (39%); its least attractive feature was need for frequent office visits (61%). SNM was found most attractive for its potential for long-term relief without frequent office visits (53%); its least attractive feature was need for an implanted device (33%). Patients opting for SNM had higher scores on Urinary Distress Inventory-6 and Incontinence Impact Questionnaire-7 questionnaires when compared to patients opting for BTX injections or PTNS (p < 0.05). 47.4% of patients eventually pursued a third-line therapy. Of those, there was a 67.6% concordance rate between the therapy patients ranked first and the therapy they eventually underwent. CONCLUSIONS: Patients with more severe OAB symptoms opt for more invasive and less time-consuming therapy with the potential for long-term relief, namely SNM. Despite thorough counseling, many patients do not progress to advanced OAB therapies. Understanding factors that influence patients' affinity toward a specific type of treatment can aid with individualized counseling on third-line OAB therapies.

GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.

Accumulating evidence suggests that subcutaneous and visceral adipose tissues are differentially associated with metabolic disorders. In obesity, subcutaneous adipose tissue is beneficial for metabolic homeostasis because of repressed inflammation. However, the underlying mechanism remains unclear. Here, we demonstrate that γ-aminobutyric acid (GABA) sensitivity is crucial in determining fat depot-selective adipose tissue macrophage (ATM) infiltration in obesity. In diet-induced obesity, GABA reduced monocyte migration in subcutaneous inguinal adipose tissue (IAT), but not in visceral epididymal adipose tissue (EAT). Pharmacological modulation of the GABAB receptor affected the levels of ATM infiltration and adipose tissue inflammation in IAT, but not in EAT, and GABA administration ameliorated systemic insulin resistance and enhanced insulin-dependent glucose uptake in IAT, accompanied by lower inflammatory responses. Intriguingly, compared with adipose-derived stem cells (ADSCs) from EAT, IAT-ADSCs played key roles in mediating GABA responses that repressed ATM infiltration in high-fat diet-fed mice. These data suggest that selective GABA responses in IAT contribute to fat depot-selective suppression of inflammatory responses and protection from insulin resistance in obesity.

Learning continuous chaotic attractors with a reservoir computer.

Neural systems are well known for their ability to learn and store information as memories. Even more impressive is their ability to abstract these memories to create complex internal representations, enabling advanced functions such as the spatial manipulation of mental representations. While recurrent neural networks (RNNs) are capable of representing complex information, the exact mechanisms of how dynamical neural systems perform abstraction are still not well-understood, thereby hindering the development of more advanced functions. Here, we train a 1000-neuron RNN-a reservoir computer (RC)-to abstract a continuous dynamical attractor memory from isolated examples of dynamical attractor memories. Furthermore, we explain the abstraction mechanism with a new theory. By training the RC on isolated and shifted examples of either stable limit cycles or chaotic Lorenz attractors, the RC learns a continuum of attractors as quantified by an extra Lyapunov exponent equal to zero. We propose a theoretical mechanism of this abstraction by combining ideas from differentiable generalized synchronization and feedback dynamics. Our results quantify abstraction in simple neural systems, enabling us to design artificial RNNs for abstraction and leading us toward a neural basis of abstraction.