Genomic architecture of autism from comprehensive whole-genome sequence annotation.

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

2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease" provides recommendations to guide clinicians in the treatment of patients with lower extremity peripheral artery disease across its multiple clinical presentation subsets (ie, asymptomatic, chronic symptomatic, chronic limb-threatening ischemia, and acute limb ischemia). METHODS: A comprehensive literature search was conducted from October 2020 to June 2022, encompassing studies, reviews, and other evidence conducted on human subjects that was published in English from PubMed, EMBASE, the Cochrane Library, CINHL Complete, and other selected databases relevant to this guideline. Additional relevant studies, published through May 2023 during the peer review process, were also considered by the writing committee and added to the evidence tables where appropriate. STRUCTURE: Recommendations from the "2016 AHA/ACC Guideline on the Management of Patients With Lower Extremity Peripheral Artery Disease" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing comprehensive care for patients with peripheral artery disease have been developed.

Cocoa flavanols, Nrf2 activation, and oxidative stress in peripheral artery disease: mechanistic findings in muscle based on outcomes from a randomized trial.

The pathophysiology of muscle damage in peripheral artery disease (PAD) includes increased oxidant production and impaired antioxidant defenses. Epicatechin (EPI), a naturally occurring flavanol, has antioxidant properties that may mediate the beneficial effects of natural products such as cocoa. In a phase II randomized trial, a cocoa-flavanol-rich beverage significantly improved walking performance compared with a placebo in people with PAD. In the present work, the molecular mechanisms underlying the therapeutic effect of cocoa flavanols were investigated by analyzing baseline and follow-up muscle biopsies from participants. Increases in nuclear factor erythroid 2-related factor 2 (Nrf2) target antioxidants heme oxygenase-1 (HO-1) and NAD(P)H dehydrogenase [quinone] 1 (NQO1) in the cocoa group were significantly associated with reduced accumulation of central nuclei, a myopathy indicator, in type II muscle fibers (P = 0.017 and P = 0.023, respectively). Protein levels of the mitochondrial respiratory complex III subunit, cytochrome b-c1 complex subunit 2 (UQCRC2), were significantly higher in the cocoa group than in the placebo group (P = 0.032), and increases in UQCRC2 were significantly associated with increased levels of Nrf2 target antioxidants HO-1 and NQO1 (P = 0.001 and P = 0.035, respectively). Exposure of non-PAD human myotubes to ex vivo serum from patients with PAD reduced Nrf2 phosphorylation, an indicator of activation, increased hydrogen peroxide production and oxidative stress, and reduced mitochondrial respiration. Treatment of myotubes with EPI in the presence of serum from patients with PAD increased Nrf2 phosphorylation and protected against PAD serum-induced oxidative stress and mitochondrial dysfunction. Overall, these findings suggest that cocoa flavanols may enhance antioxidant capacity in PAD via Nrf2 activation.NEW & NOTEWORTHY The current study supports the hypothesis that in people with PAD, cocoa flavanols activate Nrf2, thereby increasing antioxidant protein levels, protecting against skeletal muscle damage, and increasing mitochondrial protein abundance. These results suggest that Nrf2 activation may be an important therapeutic target for improving walking performance in people with PAD.

An Analysis of Water Used and Wasted at Operating Room (OR) Scrub Sinks and Call to Action for Reducing Water Waste.

OBJECTIVE: To model the volume of water used and wasted during wet scrubs at operating room (OR) scrub sinks and identify factors for reducing water waste. BACKGROUND: Wasteful consumption of water by US healthcare systems has not been well characterized. METHODS: This is a two-component observational study. The first was an observational study of handwashing practices and water usage at scrub sinks in the OR at a single medical center. The second component was a series of two anonymous surveys of surgeons and OR staff to assess hand scrub practices and perspectives. Data from both components were used to estimate the volume of water used and wasted annually at OR scrub sinks. RESULTS: The median total volume of water wasted at OR scrub sinks for 34,554 cases over one year is 337,595.6 L (interquartile range 139,010.0;911,210.5). This represents approximately 34.2% of the total volume of water usage associated with wet scrubs (i.e.,water used during scrubbing and wasted after the conclusion of the scrub). Other pertinent findings are that attending surgeons and OR staff perform water scrubs in 25.9% of cases; there are significant differences in scrub type preferences among OR users; the median volume of water wasted in a single wet scrub at timer-controlled sinks is 10 L; and significantly more water is wasted at timer-controlled sinks than knee-operated sinks. CONCLUSIONS: OR wet scrubs are a source of enormous water waste. We identified scrub sink characteristics and OR user beliefs and behaviors as modifiable factors for water waste reduction. We encourage all institutions and OR users to carefully examine their facility characteristics and practices to implement plans that will conserve water without compromising patient safety.

A Mechanism Underpinning the Bioenergetic Metabolism-Regulating Function of Gold Nanocatalysts.

Bioenergetic deficits are known to be significant contributors to neurodegenerative diseases. Nevertheless, identifying safe and effective means to address intracellular bioenergetic deficits remains a significant challenge. This work provides mechanistic insights into the energy metabolism-regulating function of colloidal Au nanocrystals, referred to as CNM-Au8, that are synthesized electrochemically in the absence of surface-capping organic ligands. When neurons are subjected to excitotoxic stressors or toxic peptides, treatment of neurons with CNM-Au8 results in dose-dependent neuronal survival and neurite network preservation across multiple neuronal subtypes. CNM-Au8 efficiently catalyzes the conversion of an energetic cofactor, nicotinamide adenine dinucleotide hydride (NADH), into its oxidized counterpart (NAD+ ), which promotes bioenergy production by regulating the intracellular level of adenosine triphosphate. Detailed kinetic measurements reveal that CNM-Au8-catalyzed NADH oxidation obeys Michaelis-Menten kinetics and exhibits pH-dependent kinetic profiles. Photoexcited charge carriers and photothermal effect, which result from optical excitations and decay of the plasmonic electron oscillations or the interband electronic transitions in CNM-Au8, are further harnessed as unique leverages to modulate reaction kinetics. As exemplified by this work, Au nanocrystals with deliberately tailored structures and surfactant-free clean surfaces hold great promise for developing next-generation therapeutic agents for neurodegenerative diseases.

Discordance of patient-reported outcome measures with objectively assessed walking decline in peripheral artery disease.

OBJECTIVE: Among people with peripheral artery disease (PAD), perceived change in walking difficulty over time, compared with people without PAD, is unclear. Among people reporting no change in walking difficulty over time, differences in objectively measured change in walking performance between people with and without PAD are unknown. METHODS: A total of 1289 participants were included. Eight hundred seventy-four participants with PAD (aged 71.1 ± 9.1 years) were identified from noninvasive vascular laboratories and 415 without PAD (aged 69.9 ± 7.6 years) were identified from people with normal vascular laboratory testing or general medical practices in Chicago. The Walking Impairment Questionnaire and 6-minute walk were completed at baseline and 1-year follow-up. The Walking Impairment Questionnaire assessed perceived difficulty walking due to symptoms in the calves or buttocks on a Likert scale (range, 0-4). Symptom change was determined by comparing difficulty reported at 1-year follow-up to difficulty reported at baseline. RESULTS: At 1-year follow-up, 31.9% of participants with and 20.6% of participants without PAD reported walking difficulty that was improved (P < .01), whereas 41.2% vs 55%, respectively, reported walking difficulty that was unchanged (P < .01). Among all reporting no change in walking difficulty, participants with PAD declined in 6-minute walk, whereas participants without PAD improved (-10 vs +15 meters; mean difference, -25; 95% confidence interval, -38 to -13; P < .01). CONCLUSIONS: Most people with PAD reported improvement or no change in walking difficulty from calf or buttock symptoms at one-year follow-up. Among all participants who perceived stable walking ability, those with PAD had significant greater declines in objectively measured walking performance, compared with people without PAD.

Barriers to participation in supervised exercise therapy reported by people with peripheral artery disease.

OBJECTIVE: This study identified barriers to participation in supervised exercise therapy covered by the Centers for Medicare and Medicaid Services (CMS), reported by people with lower extremity peripheral artery disease (PAD). METHODS: People with PAD participating in research studies of walking impairment due to PAD in the Chicagoland area were asked to complete a questionnaire between March 15, 2019, and July 12, 2022, assessing their experience and attitudes about supervised exercise therapy. Participants were identified using mailed postcards to people aged 50 and older in Chicagoland, from medical centers in Chicago, and using bus and train advertisements. The questionnaire was developed based on focus group feedback from people with PAD. RESULTS: Of 516 participants with PAD approached, 489 (94.8%) completed the questionnaire (mean age: 71.0 years [standard deviation: 8.7], mean ankle-brachial index: 0.71 [standard deviation: 0.25]; 204 [41.7%] women and 261 [53.4%] Black). Of the 489 participants, 416 (85.1%) reported that their physician had never prescribed or recommended supervised exercise therapy. Overall, 357 (73.2%) reported willingness to travel three times weekly to the medical center for supervised exercise participation. However, of these, 214 (59.9%) reported that they were unwilling or unable to pay the $11 per exercise session copay required for supervised exercise covered by CMS. Of 51 people with PAD who reported prior participation in supervised exercise, only 5 (9.8%) completed the 12 weeks of supervised exercise therapy covered by CMS and 29 (56.9%) completed 6 or fewer weeks. Of 131 (26.8%) unwilling to travel three times weekly to a center for supervised exercise, the most common reasons for unwillingness to participate were "too time-consuming" (55.0%), "too inconvenient" (45.8%), and "lack of interest in treadmill exercise" (28.2%). CONCLUSIONS: Approximately 2 to 4 years after CMS began covering supervised exercise for PAD, most people with PAD in this study from a large urban area had not participated in supervised exercise therapy. Of those who participated, most completed fewer than half of the sessions covered by CMS. The required CMS copayment was a common barrier to supervised exercise participation by people with PAD.

Prosthetic vascular grafts engineered to combat calcification: Progress and future directions.

Calcification in prosthetic vascular conduits is a major challenge in cardiac and vascular surgery that compromises the long-term performance of these devices. Significant research efforts have been made to understand the etiology of calcification in the cardiovascular system and to combat calcification in various cardiovascular devices. Novel biomaterial design and tissue engineering strategies have shown promise in preventing or delaying calcification in prosthetic vascular grafts. In this review, we highlight recent advancements in the development of acellular prosthetic vascular grafts with preclinical success in attenuating calcification through advanced biomaterial design. We also discuss the mechanisms of action involved in the designs that will contribute to the further understanding of cardiovascular calcification. Lastly, recent insights into the etiology of vascular calcification will guide the design of future prosthetic vascular grafts with greater potential for translational success.

Cigarette smoking and mitochondrial dysfunction in peripheral artery disease.

BACKGROUND: This study evaluated the association of smoking with mitochondrial function in gastrocnemius muscle of people with peripheral artery disease (PAD). METHODS: Participants were enrolled from Chicago, Illinois and consented to gastrocnemius biopsy. Mitochondrial oxidative capacity was measured in muscle with respirometry. Abundance of voltage-dependent anion channel (VDAC) (mitochondrial membrane abundance), peroxisome proliferator-activated receptor-γ coactivator (PGC-1α) (mitochondrial biogenesis), and electron transport chain complexes I-V were measured with Western blot. RESULTS: Fourteen of 31 people with PAD (age 72.1 years, ABI 0.64) smoked cigarettes currently. Overall, there were no significant differences in mitochondrial oxidative capacity between PAD participants who currently smoked and those not currently smoking (complex I+II-mediated oxidative phosphorylation: 86.6 vs 78.3 pmolO2/s/mg, respectively [p = 0.39]). Among participants with PAD, those who currently smoked had a higher abundance of PGC-1α (p < 0.01), VDAC (p = 0.022), complex I (p = 0.021), and complex III (p = 0.021) proteins compared to those not currently smoking. People with PAD who currently smoked had lower oxidative capacity per VDAC unit (complex I+II-mediated oxidative phosphorylation [137.4 vs 231.8 arbitrary units, p = 0.030]) compared to people with PAD not currently smoking. Among people without PAD, there were no significant differences in any mitochondrial measures between currently smoking (n = 5) and those not currently smoking (n = 63). CONCLUSIONS: Among people with PAD, cigarette smoking may stimulate mitochondrial biogenesis to compensate for reduced oxidative capacity per unit of mitochondrial membrane, resulting in no difference in overall mitochondrial oxidative capacity according to current smoking status among people with PAD. However, these results were cross-sectional and a longitudinal study is needed.

Bridge centrality network structure of negative symptoms in people with schizophrenia.

Negative symptoms are complex psychopathology. Although evidence generally supported the NIMH five consensus domains, research seldom examined measurement invariance of this model, and domain-specific correspondence across multiple scales. This study aimed to examine the interrelationship between negative symptom domains captured by different rating scales, and to examine the domain-specific correspondence across multiple scales. We administered the Brief Negative Symptom Scale (BNSS), the Self-evaluation of Negative Symptoms (SNS), and the Scale for Assessment of Negative Symptoms (SANS) to 204 individuals with schizophrenia. We used network analysis to examine the interrelationship between negative symptom domains. Besides regularized partial correlation network, we estimated bridge centrality indices to investigate domain-specific correspondence, while taking each scale as an independent community. The regularized partial correlation network showed that the SNS nodes clustered together, whereas the SANS and the BNSS nodes intermingled together. The SANS attention domain lied at the periphery of the network according to the Fruchterman-Reingold algorithm. The SANS anhedonia-asociality (strength = 1.48; EI = 1.48) and the SANS affective flattening (strength = 1.06; EI = 1.06) had the highest node strength and EI. Moreover, the five nodes of the BNSS bridged the nodes of the SANS and the SNS. BNSS blunted affect (strength = 0.76; EI = 0.76) and SANS anhedonia-asociality (strength = 0.76; EI = 0.74) showed the highest bridge strength and bridge EI. The BNSS captures negative symptoms and bridges the symptom domains measured by the SANS and the SNS. The three scales showed domain-specific correspondence.

Evidence of brain target engagement in Parkinson's disease and multiple sclerosis by the investigational nanomedicine, CNM-Au8, in the REPAIR phase 2 clinical trials.

BACKGROUND: Impaired brain energy metabolism has been observed in many neurodegenerative diseases, including Parkinson's disease (PD) and multiple sclerosis (MS). In both diseases, mitochondrial dysfunction and energetic impairment can lead to neuronal dysfunction and death. CNM-Au8® is a suspension of faceted, clean-surfaced gold nanocrystals that catalytically improves energetic metabolism in CNS cells, supporting neuroprotection and remyelination as demonstrated in multiple independent preclinical models. The objective of the Phase 2 REPAIR-MS and REPAIR-PD clinical trials was to investigate the effects of CNM-Au8, administered orally once daily for twelve or more weeks, on brain phosphorous-containing energy metabolite levels in participants with diagnoses of relapsing MS or idiopathic PD, respectively. RESULTS: Brain metabolites were measured using 7-Tesla 31P-MRS in two disease cohorts, 11 participants with stable relapsing MS and 13 participants with PD (n = 24 evaluable post-baseline scans). Compared to pre-treatment baseline, the mean NAD+/NADH ratio in the brain, a measure of energetic capacity, was significantly increased by 10.4% after 12 + weeks of treatment with CNM-Au8 (0.584 units, SD: 1.3; p = 0.037, paired t-test) in prespecified analyses of the combined treatment cohorts. Each disease cohort concordantly demonstrated increases in the NAD+/NADH ratio but did not reach significance individually (p = 0.11 and p = 0.14, PD and MS cohorts, respectively). Significant treatment effects were also observed for secondary and exploratory imaging outcomes, including ß-ATP and phosphorylation potential across both cohorts. CONCLUSIONS: Our results demonstrate brain target engagement of CNM-Au8 as a direct modulator of brain energy metabolism, and support the further investigation of CNM-Au8 as a potential disease modifying drug for PD and MS.

Identifying gaps in disease knowledge among patients with peripheral artery disease.

OBJECTIVE: An individual's understanding of disease risk factors and outcomes is important for the ability to make healthy lifestyle choices and decisions about disease treatment. Peripheral artery disease (PAD) is a condition with increasing global prevalence and high risk of adverse patient outcomes. This study seeks to understand the adequacy of disease understanding in patients with PAD. METHODS: This was an observational study of patients with PAD recruited from vascular surgery outpatient clinic and PAD clinical studies at a single academic medical center over an 8-month period. A 44-item paper survey assessed demographic and socioeconomic information, knowledge of personal medical history, PAD risk factors, consequences of PAD, and health education preferences. Patients with documented presence of PAD were offered the survey. Patients unable to complete the survey or provide informed consent were not considered eligible. Disease "awareness" was defined as correct acknowledgement of the presence or absence of a disease, including PAD, in the personal medical history. "PAD knowledge score" was the percentage of correct responses to questions on general PAD risk factors and consequences. Of 126 eligible patients, 109 participated. Bivariate analysis was used to study factors associated with awareness of PAD diagnosis. Factors associated with the PAD knowledge score were studied using the Pearson correlation coefficient, two-sample t test, or one-way analysis of variance. P value < .05 was considered statistically significant. RESULTS: The mean participant age was 69.4 ± 11.0 years, and 39.4% (n = 43) were female. Most participants (78.9%; n = 86) had critical limb-threatening ischemia. Only 65.4% (n = 70) of participants were aware of a diagnosis of PAD, which was less than their awareness of related comorbidities. Factors positively associated with PAD diagnosis awareness were female sex (81.4% vs 54.7%; P = .004) and history of percutaneous leg revascularization (78.6% vs 47.9%; P = .001). Among 17 patients who had undergone major leg amputation, 35% (n = 6) were unaware of a diagnosis of PAD. PAD knowledge scores correlated positively with an awareness of PAD diagnosis (59.1% vs 48.7%; P = .02) and negatively with a history of hypertension (53.4% vs 68.1%; P = .001). Most participants (86.5%; n = 90) expressed a desire to be further educated on PAD. The most popular education topics were dietary recommendations, causes, and treatment for PAD. CONCLUSIONS: Patients with PAD have deficits in their awareness of this diagnosis and general knowledge about PAD. Future research priorities should further define these deficits and their causes in order to inform new strategies that foster information-seeking behavior and effective educational programs for PAD.

Combined chemotherapy and endoscopic ultrasound-guided intratumoral 32P implantation for locally advanced pancreatic adenocarcinoma: a pilot study.

BACKGROUND: This study evaluated clinical outcomes of combined chemotherapy and endoscopic ultrasound (EUS)-guided intratumoral radioactive phosphorus-32 (32P) implantation in locally advanced pancreatic adenocarcinoma (LAPC). METHODS: Consecutive patients with newly diagnosed LAPC were recruited over 20 months. Baseline computed tomography and 18F-2-fluoro-2-deoxy-D-glucose (18FDG) positron emission tomography-computed tomography were performed and repeated after 12 weeks to assess treatment response. Following two cycles of conventional chemotherapy, patients underwent EUS-guided 32P implantation followed by six chemotherapy cycles. RESULTS: 12 patients with LAPC (median age 69 years [interquartile range 61.5-73.3]; 8 male) completed treatment. Technical success was 100 % with no procedural complications. At 12 weeks, median reduction in tumor volume was 8.2 cm3 (95 % confidence interval 4.95-10.85; P = 0.003), with minimal or no 18FDG uptake in nine patients (75 %). Tumor downstaging was achieved in six patients (50 %), leading to successful resection in five (42 %), including four R0 resections (80 %). CONCLUSIONS: EUS-guided 32P implantation was feasible, well tolerated, and resulted in a 42 % surgical resection rate. Further evaluation in a larger randomized multicenter trial is warranted.

Differences in goals of care discussion outcomes among healthcare professionals: an observational cross-sectional study.

BACKGROUND: Goals of care discussions ensure patients receive the care that they want. Recent studies have recognized the opportunity for allied health professionals, such as nurses, in facilitating goals of care discussions. However, the outcomes of such interventions are not well studied. AIM: To compare the outcomes of goals of care discussions led by physicians and nurses. DESIGN: This is a retrospective cohort study of patients admitted to an Internal Medicine unit from January 2018 to August 2019. A comprehensive chart review was performed on a random sample of patients. Patient's decision to accept or refuse cardiopulmonary resuscitation was recorded and analyzed. Analysis was stratified by patients' comorbidity burden and illness severity. SETTING/PARTICIPANTS: The study took place at a tertiary care center and included 200 patients. Patients aged ⩾ 18 were included. Patients who have had pre-existing goals of care documentation were excluded. RESULTS: About 52% of the goals of care discussions were completed by nurses and 48% by physicians. Patients were more likely to accept cardiopulmonary resuscitation in nurse-led discussions compared to physician-led ones (80.8% vs 61.4%, p = 0.003). Multiple regression showed that patients with higher comorbidity burden (OR 0.71, 95% CI: 0.62-0.82), more severe illness (OR 0.89, 95% CI 0.88-0.99), and physician-led goals of care discussions (OR 0.30, 95% CI: 0.15-0.62) were less likely to accept cardiopulmonary resuscitation. CONCLUSIONS: There was a significant difference between the outcomes of goals of care discussions led by nurses and physicians. Patients were more likely to accept aggressive resuscitative measures in nurse-led goals of care discussions. Further research efforts are needed to identify the factors contributing to this discrepancy, and to devise ways of improving goals of care discussion delivery.

OTUD7A Regulates Neurodevelopmental Phenotypes in the 15q13.3 Microdeletion Syndrome.

Copy-number variations (CNVs) are strong risk factors for neurodevelopmental and psychiatric disorders. The 15q13.3 microdeletion syndrome region contains up to ten genes and is associated with numerous conditions, including autism spectrum disorder (ASD), epilepsy, schizophrenia, and intellectual disability; however, the mechanisms underlying the pathogenesis of 15q13.3 microdeletion syndrome remain unknown. We combined whole-genome sequencing, human brain gene expression (proteome and transcriptome), and a mouse model with a syntenic heterozygous deletion (Df(h15q13)/+ mice) and determined that the microdeletion results in abnormal development of cortical dendritic spines and dendrite outgrowth. Analysis of large-scale genomic, transcriptomic, and proteomic data identified OTUD7A as a critical gene for brain function. OTUD7A was found to localize to dendritic and spine compartments in cortical neurons, and its reduced levels in Df(h15q13)/+ cortical neurons contributed to the dendritic spine and dendrite outgrowth deficits. Our results reveal OTUD7A as a major regulatory gene for 15q13.3 microdeletion syndrome phenotypes that contribute to the disease mechanism through abnormal cortical neuron morphological development.

Limb ischemia and bleeding in patients requiring venoarterial extracorporeal membrane oxygenation.

OBJECTIVE: Acute limb ischemia (ALI) and cannulation site bleeding are frequent complications of venoarterial (VA) extracorporeal membrane oxygenation (ECMO) and are associated with worse outcomes. The goals of this study were to assess our rates of ECMO-related ALI and bleeding and to evaluate the efficacy of strategies to prevent them, such as distal perfusion cannula (DPC) and ultrasound-guided cannulation. METHODS: This is a single-center retrospective cohort study of adult patients placed on peripheral VA-ECMO at a tertiary medical center between 2014 and 2018. ALI was defined as new ischemia of the extremity ipsilateral to arterial cannulation. Significant cannulation site bleeding was defined as excessive bleeding requiring intervention (eg, transfusion or reoperation). Univariate analyses were used to identify factors associated with ALI, bleeding, and in-hospital mortality. RESULTS: During the study period, 105 patients were placed on peripheral VA-ECMO (61.3% female; mean age, 54.9 ± 14.8 years). Nearly half (46.6%) had ECMO implantation in an extracorporeal cardiopulmonary resuscitation setting and 37 (44.0%) had a DPC. Average duration of support was 5.6 ± 5.0 days. Overall in-hospital mortality and death on ECMO support were 65.1% and 50%, respectively. ALI occurred in 21 (20%) and cannulation-related bleeding occurred in 24 (22.9%) patients who were treated with a total of 27 procedures, including thromboembolectomy (22.2%), vascular repair (18.5%), and fasciotomy (25.9%). On univariate analysis, cannulation in the operating room (odds ratio [OR], 0.25; 95% confidence interval [CI], 0.08-0.77; P = .02) was associated with decreased risk of ALI, whereas cannulation in the operating room (OR, 2.65; 95% CI, 1.09-6.45; P = .03) and cutdown approach (OR, 4.96; 95% CI, 2.32-10.61; P < .0001) were associated with increased risk of bleeding. Ultrasound-guided placement was associated with decreased risk of bleeding (OR, 0.81; 95% CI, 0.04-0.84; P = .03). DPC was not associated with either ALI (P = .47) or bleeding (P = .06). ALI (OR, 2.68; 95% CI 1.03-6.98; P = .04), age (OR, 1.94; 95% CI, 1.03-3.69; P = .04), and worse baseline heart failure (OR, 2.01; 95% CI, 1.02-3.97; P = .04) were associated with greater risk of in-hospital mortality. Ultrasound-guided cannulation (OR, 0.41; 95% CI, 0.20-0.87; P = .02) was associated with decreased risk of in-hospital mortality. CONCLUSIONS: ALI and significant bleeding are common occurrences after peripheral VA-ECMO cannulation. Whereas DPC placement did not significantly decrease risk of ALI, ultrasound-guided cannulation decreased the risk of bleeding. Cannulation in the operating room is associated with decreased risk of ALI at the expense of increased risk of bleeding. ALI, older age (≥65 years), and worse heart failure increased risk of in-hospital mortality.

Targeted Inhibition of Gut Microbial Trimethylamine N-Oxide Production Reduces Renal Tubulointerstitial Fibrosis and Functional Impairment in a Murine Model of Chronic Kidney Disease.

OBJECTIVE: Gut microbial metabolism of dietary choline, a nutrient abundant in a Western diet, produces trimethylamine (TMA) and the atherothrombosis- and fibrosis-promoting metabolite TMA-N-oxide (TMAO). Recent clinical and animal studies reveal that elevated TMAO levels are associated with heightened risks for both cardiovascular disease and incident chronic kidney disease development. Despite this, studies focusing on therapeutically targeting gut microbiota-dependent TMAO production and its impact on preserving renal function are limited. Approach and Results: Herein we examined the impact of pharmacological inhibition of choline diet-induced gut microbiota-dependent production of TMA, and consequently TMAO, on renal tubulointerstitial fibrosis and functional impairment in a model of chronic kidney disease. Initial studies with a gut microbial choline TMA-lyase mechanism-based inhibitor, iodomethylcholine, confirmed both marked suppression of TMA generation, and consequently TMAO levels, and selective targeting of the gut microbial compartment (ie, both accumulation of the drug in intestinal microbes and limited systemic exposure in the host). Dietary supplementation of either choline or TMAO significantly augmented multiple indices of renal functional impairment and fibrosis associated with chronic subcutaneous infusion of isoproterenol. However, the presence of the gut microbiota-targeting inhibitor iodomethylcholine blocked choline diet-induced elevation in TMAO, and both significantly improved decline in renal function, and significantly attenuated multiple indices of tubulointerstitial fibrosis. Iodomethylcholine treatment also reversed many choline diet-induced changes in cecal microbial community composition associated with TMAO and renal functional impairment. CONCLUSIONS: Selective targeting of gut microbiota-dependent TMAO generation may prevent adverse renal structural and functional alterations in subjects at risk for chronic kidney disease.

The benefits of emotionally salient cues on event-based prospective memory in bipolar patients and schizophrenia patients.

Prospective memory (PM) refers to the ability to remember to carry out a delayed intention in the future. Evidence suggests that emotionally salient cues can enhance PM functions in healthy population, but whether the benefit exists in schizophrenia and bipolar patients remains unclear. This study aimed to examine and compare the potential enhancement effect of emotional PM cues in schizophrenia patients and bipolar patients. Twenty-eight clinically stable schizophrenia participants, 26 euthymic bipolar participants and 29 controls completed a computerized PM task involving PM cues with different types of valences (i.e., positive, neutral and negative). All the three groups showed better PM performance when negative PM cues were presented compared with positive and neutral PM cues. The sizes of the enhancement effects of negative PM cues were large (all Cohen's d ≥ 1.00) and comparable across three groups. Our findings suggested that patients with schizophrenia and bipolar disorders could benefit from negative PM cues to an extent similar to healthy individuals, thus extended the notion of psychosis continuum to the important area of emotion-cognition interaction.

Ankle-brachial index to monitor limb perfusion in patients with femoral venoarterial extracorporeal membrane oxygenation.

BACKGROUND: Limb ischemia is a major complication of femoral venoarterial extracorporeal membrane oxygenation (VA-ECMO). Use of ankle-brachial index (ABI) to monitor limb perfusion in VA-ECMO has not been described. We report our experience monitoring femoral VA-ECMO patients with serial ABI and the relationships between ABI and near infrared spectroscopy (NIRS). METHODS: This is a retrospective single-center review of consecutive adult patients placed on femoral VA-ECMO between January 2019 and October 2019. Data were collected on patients with paired ABI and NIRS values. Relationships between NIRS and ABI of the cannulated (E-NIRS and E-ABI) and non-cannulated legs (N-NIRS and N-ABI) along with the difference between legs (d-NIRS and d-ABI) were determined using Pearson correlation. RESULTS: Overall, 22 patients (mean age 56.5 ± 14.0 years, 72.7% male) were assessed with 295 E-ABI and E-NIRS measurements, and 273 N-ABI and N-NIRS measurements. Mean duration of ECMO support was 129.8 ± 78.3 h. ECMO-mortality was 13.6% and in-hospital mortality was 45.5%. N-ABI and N-NIRS were significantly higher than their ECMO counterparts (ABI mean difference 0.16, 95% confidence interval [CI]: 0.13-0.19, p < .0001; NIRS mean difference 2.51, 95% CI: 1.48-3.54, p < .0001). There was no correlation between E-ABI versus E-NIRS (r = .032, p = .59), N-ABI versus N-NIRS (r = .097, p = .11), or d-NIRS versus d-ABI (r = .11, p = .069). CONCLUSION: ABI is a quantitative metric that may be used to monitor limb perfusion and supplement clinical exams to identify limb ischemia in femorally cannulated VA-ECMO patients. More studies are needed to characterize the significance of ABI in femoral VA-ECMO and its value in identifying limb ischemia in this patient population.

Microbiota composition modulates inflammation and neointimal hyperplasia after arterial angioplasty.

BACKGROUND: Neointimal hyperplasia is a major contributor to restenosis after arterial interventions, but the genetic and environmental mechanisms underlying the variable propensity for neointimal hyperplasia between individuals, including the role of commensal microbiota, are not well understood. We sought to characterize how shifting the microbiome using cage sharing and bedding mixing between rats with differing restenosis phenotypes after carotid artery balloon angioplasty could alter arterial remodeling. METHODS: We co-housed and mixed bedding between genetically distinct rats (Lewis [LE] and Sprague-Dawley [SD]) that harbor different commensal microbes and that are known to have different neointimal hyperplasia responses to carotid artery balloon angioplasty. Sequencing of the 16S ribosomal RNA gene was used to monitor changes in the gut microbiome. RESULTS: There were significant differences in neointimal hyperplasia between non-co-housed LE and SD rats 14 days after carotid artery angioplasty (mean intima + media [I + M] area, 0.117 ± 0.014 mm2 LE vs 0.275 ± 0.021 mm2 SD; P < .001) that were diminished by co-housing. Co-housing also altered local adventitial Ki67 immunoreactivity, local accumulation of leukocytes and macrophages (total and M2), and interleukin 17A concentration 3 days after surgery in each strain. Non-co-housed SD and LE rats had microbiomes distinguished by both weighted (P = .012) and unweighted (P < .001) UniFrac beta diversity distances, although without significant differences in alpha diversity. The difference in unweighted beta diversity between the fecal microbiota of SD and LE rats was significantly reduced by co-housing. Operational taxonomic units that significantly correlated with average I + M area include Parabacteroides distasonis, Desulfovibrio, Methanosphaera, Peptococcus, and Prevotella. Finally, serum concentrations of microbe-derived metabolites hydroxyanthranilic acid and kynurenine/tryptophan ratio were significantly associated with I + M area in both rat strains independent of co-housing. CONCLUSIONS: We describe a novel mechanism for how microbiome manipulations affect arterial remodeling and the inflammatory response after arterial injury. A greater understanding of the host inflammatory-microbe axis could uncover novel therapeutic targets for the prevention and treatment of restenosis.