Adjunctive therapy with an oral H2S donor provides additional therapeutic benefit beyond SGLT2 inhibition in cardiometabolic heart failure with preserved ejection fraction.

BACKGROUND AND PURPOSE: Sodium glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a potent therapy for heart failure with preserved ejection fraction (HFpEF). Hydrogen sulphide (H2S), a well-studied cardioprotective agent, could be beneficial in HFpEF. SGLT2i monotherapy and combination therapy involving an SGLT2i and H2S donor in two preclinical models of cardiometabolic HFpEF was investigated. EXPERIMENTAL APPROACH: Nine-week-old C57BL/6N mice received L-NAME and a 60% high fat diet for five weeks. Mice were then randomized to either control, SGLT2i monotherapy or SGLT2i and H2S donor, SG1002, for five additional weeks. Ten-week-old ZSF1 obese rats were randomized to control, SGLT2i or SGLT2i and SG1002 for 8 weeks. SG1002 monotherapy was investigated in additional animals. Cardiac function (echocardiography and haemodynamics), exercise capacity, glucose handling and multiorgan pathology were monitored during experimental protocols. KEY RESULTS: SGLT2i treatment improved E/e' ratio and treadmill exercise in both models. Combination therapy afforded increases in cardiovascular sulphur bioavailability that coincided with improved left end-diastolic function (E/e' ratio), exercise capacity, metabolic state, cardiorenal fibrosis, and hepatic steatosis. Follow-up studies with SG1002 monotherapy revealed improvements in diastolic function, exercise capacity and multiorgan histopathology. CONCLUSIONS AND IMPLICATIONS: SGLT2i monotherapy remediated pathological complications exhibited by two well-established HFpEF models. Adjunctive H2S therapy resulted in further improvements of cardiometabolic perturbations beyond SGLT2i monotherapy. Follow-up SG1002 monotherapy studies inferred an improved phenotype with combination therapy beyond either monotherapy. These data demonstrate the differing effects of SGLT2i and H2S therapy while also revealing the superior efficacy of the combination therapy in cardiometabolic HFpEF.

Impact of progressive chronic kidney disease stage on postoperative outcomes in metabolic surgery-a propensity-matched analysis using the Metabolic and Bariatric Surgery Accreditation and Quality Improvement database.

BACKGROUND: Metabolic surgery (MS) is effective in improving renal parameters for individuals with obesity and chronic kidney disease (CKD). Despite recognized benefits, concerns linger about the perioperative safety of patients with CKD undergoing MS. This study aimed to identify the CKD stage associated with the most significant increase in postoperative complications. METHODS: The Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database (2017-2021) was used to identify patients undergoing laparoscopic gastric sleeve (SG) or Roux-en-Y gastric bypass (RYGB). Propensity matching was used to quantify the risk for adverse outcomes associated with progressive CKD stage. RESULTS: In total, 688,583 patients (483,898 without CKD and 204,685 with CKD stages I-V) were examined. Endpoints included length of stay (LOS) >5 days, infection, serious complications, major adverse cardiovascular events (MACE), and death. Both SG and RYGB exhibited a linear increase in risk of infection and death. For SG, patients who were stage IIIa/IIIb demonstrated the greatest risk for LOS >5 days (odds ratio [OR] 1.23; 95% confidence interval [CI] (1.05-1.45); P = .011), serious complications (OR 2.83; 95% CI 1.87-4.30; P < .001), and MACE (OR 2.82; 95% CI 1.81-4.37; P < .001). For RYGB, patients who were stage IIIa/IIIb the exhibited greatest risk of MACE (OR 1.67; 95% CI 1.06-2.62; P = .027). CONCLUSIONS: Although it is generally accepted that worsening CKD correlates with greater surgical risk, this analysis identified CKD stage III as a major inflection point for risk of LOS >5 days, serious complications, and MACE. These findings are useful for counseling and procedure selection and suggest a need for heightened attention to CKD stage III patients undergoing MS.

Temporal Trends and Racial Disparities in Long-Term Survival After Stroke.

BACKGROUND AND OBJECTIVES: Few studies have examined trends and disparities in long-term outcome after stroke in a representative US population. We used a population-based stroke study in the Greater Cincinnati Northern Kentucky region to examine trends and racial disparities in poststroke 5-year mortality. METHODS: All patients with acute ischemic strokes (AISs) and intracerebral hemorrhages (ICHs) among residents ≥20 years old were ascertained using ICD codes and physician-adjudicated using a consistent case definition during 5 periods: July 1993-June 1994 and calendar years 1999, 2005, 2010, and 2015. Race was obtained from the medical record; only those identified as White or Black were included. Premorbid functional status was assessed using the modified Rankin Scale, with a score of 0-1 being considered "good." Mortality was assessed with the National Death Index. Trends and racial disparities for each subtype were analyzed with logistic regression. RESULTS: We identified 8,428 AIS cases (19.3% Black, 56.3% female, median age 72) and 1,501 ICH cases (23.5% Black, 54.8% female, median age 72). Among patients with AIS, 5-year mortality improved after adjustment for age, race, and sex (53% in 1993/94 to 48.3% in 2015, overall effect of study year p = 0.009). The absolute decline in 5-year mortality in patients with AIS was larger than what would be expected in the general population (5.1% vs 2.8%). Black individuals were at a higher risk of death after AIS (odds ratio [OR] 1.23, 95% CI 1.08-1.39) even after adjustment for age and sex, and this effect was consistent across study years. When premorbid functional status and comorbidities were included in the model, the primary effect of Black race was attenuated but race interacted with sex and premorbid functional status. Among male patients with a good baseline functional status, Black race remained associated with 5-year mortality (OR 1.4, 95% CI 1.1-1.7, p = 0.002). There were no changes in 5-year mortality after ICH over time (64.4% in 1993/94 to 69.2% in 2015, overall effect of study year p = 0.32). DISCUSSION: Long-term survival improved after AIS but not after ICH. Black individuals, particularly Black male patients with good premorbid function, have a higher mortality after AIS, and this disparity did not change over time.

Synthetic extremophiles via species-specific formulations improve microbial therapeutics.

Microorganisms typically used to produce food and pharmaceuticals are now being explored as medicines and agricultural supplements. However, maintaining high viability from manufacturing until use remains an important challenge, requiring sophisticated cold chains and packaging. Here we report synthetic extremophiles of industrially relevant gram-negative bacteria (Escherichia coli Nissle 1917, Ensifer meliloti), gram-positive bacteria (Lactobacillus plantarum) and yeast (Saccharomyces boulardii). We develop a high-throughput pipeline to define species-specific materials that enable survival through drying, elevated temperatures, organic solvents and ionizing radiation. Using this pipeline, we enhance the stability of E. coli Nissle 1917 by more than four orders of magnitude over commercial formulations and demonstrate its capacity to remain viable while undergoing tableting and pharmaceutical processing. We further show, in live animals and plants, that synthetic extremophiles remain functional against enteric pathogens and as nitrogen-fixing plant supplements even after exposure to elevated temperatures. This synthetic, material-based stabilization enhances our capacity to apply microorganisms in extreme environments on Earth and potentially during exploratory space travel.

"Even Though the System Had Failed Him His Entire Life, We Were Failing Him Yet Again": How Clinical, Welfare, and Penal Medicine Interact to Drive Health Inequities and Medical Moral Injury.

Adam, a justice-involved young man, was brought into the emergency department at the county hospital in cardiogenic shock due to a recurring episode of injection-drug-use-related infective endocarditis (IDU-IE). Adam had initiated injection opioid use in prison. He was surgically treated for the previous episodes of IDU-IE but was unable to fully recover due to limitations in care within penal medicine. This case report explores the prison as a determinant of health, interactions between clinical, welfare, and penal medicine, to produce and maintain health inequities, and structural drivers of physician moral injury through an interview with Adam and reflexive writings from emergency medicine physicians. This case demonstrates the need for three types of structural health interventions: (1) restorative justice, community-based reentry programs, and housing as welfare medicine, (2) increased harm reduction services across healthcare, especially penal medicine, and (3) equitable institutional protocols (contrary to ambiguous guidelines) to treat clinical conditions like IDU-IE that disproportionately impact structurally vulnerable patients.

BMI ≥ 70: A Multi-Center Institutional Experience of the Safety and Efficacy of Metabolic and Bariatric Surgery Intervention.

PURPOSE: With the escalating prevalence of obesity, healthcare providers are increasingly managing patients with a body mass index (BMI) exceeding 70. The aim of this study was to describe the perioperative experiences of this demographic group at two institutions. METHODS: An analysis encompassing 84 patients presenting with BMI ≥ 70 kg/m2 from two institutions was conducted. Data included patient demographics, 30-day postoperative outcomes, and weight-loss at different intervals (30 days, 6 months, 1 year). Additionally, rates of emergency department (ED) utilization, readmission, and reoperation in the first postoperative year were examined. RESULTS: Most patients were black (66.7%) and female (86.9%) with a mean age of 41.7 years. The majority underwent laparoscopic sleeve gastrectomy (SG, 88.1%). Patients exhibited a marked decrease in BMI (7.84% at 30 days, 20.13% at 6 months, and 26.83% at 1 year). Average length of stay was comparable across procedure (F(3,80) = 0.016, p = .997). While 30-day complications were minimal (0.7%), 14.4% of patients experienced ED visits within 30 days, escalating to 19.6% by six months and 25% at 1 year. Readmission and reoperation rates at 1 year were 6.45% and 4.83%, respectively. CONCLUSION: With global obesity rates rising, clinicians are being challenged to care for patients with BMI ≥ 70 kg/m2. Analysis of two institutions demonstrated low rates of 30-days complications but increased readmission rates and ED utilization in this patient population. Despite increased resource utilization, the study suggests that BMI ≥ 70 kg/m2 alone should not be a deterrent for surgery, emphasizing the need for nuanced care in this expanding demographic.

Social Determinants of Health and Health-Related Quality of Life following Pediatric Septic Shock: Secondary Analysis of the Life After Pediatric Sepsis Evaluation Dataset, 2014-2017.

OBJECTIVES: Social determinants of health (SDOH) are associated with disparities in disease severity and in-hospital outcomes among critically ill children. It is unknown whether SDOH are associated with later outcomes. We evaluated associations between SDOH measures and mortality, new functional morbidity, and health-related quality of life (HRQL) decline among children surviving septic shock. DESIGN: Secondary analysis of the Life After Pediatric Sepsis Evaluation (LAPSE) prospective cohort study was conducted between 2014 and 2017. SETTING: Twelve academic U.S. PICUs were involved in the study. PATIENTS: Children younger than 18 years with community-acquired septic shock were involved in the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We assessed associations between race, ethnicity, income, education, marital status, insurance, language, and home U.S. postal code with day 28 mortality, new functional morbidity at discharge per day 28, and HRQL decline using logistic regression. Of 389 patients, 32% (n = 98) of families had household income less than $50,000 per year. Median Pediatric Risk of Mortality (PRISM) score was 11 (interquartile range 6, 17). We found that English language and Area Deprivation Index less than 50th percentile were associated with higher PRISM scores. Mortality was 6.7% (n = 26), new functional morbidity occurred in 21.8% (n = 78) of patients, and HRQL decline by greater than 10% occurred in 31.0% of patients (n = 63). We failed to identify any association between SDOH measures and mortality, new functional morbidity, or HRQL decline. We are unable to exclude the possibility that annual household income greater than or equal to $50,000 was associated with up to 81% lesser odds of mortality and, in survivors, more than three-fold greater odds of HRQL decline by greater than 10%. CONCLUSIONS: In this secondary analysis of the 2014-2017 LAPSE dataset, we failed to identify any association between SDOH measures and in-hospital or postdischarge outcomes following pediatric septic shock. This finding may be reflective of the high illness severity and single disease (sepsis) of the cohort, with contribution of clinical factors to functional and HRQL outcomes predominating over prehospital and posthospital SDOH factors.

Structure and repair of replication-coupled DNA breaks.

Using CRISPR/Cas9 nicking enzymes, we examine the interaction between the replication machinery and single strand breaks, one of the most common forms of endogenous DNA damage. We show that replication fork collapse at leading strand nicks generates resected single-ended double-strand breaks (seDSBs) that are repaired by homologous recombination (HR). If these seDSBs are not promptly repaired, arrival of adjacent forks creates double ended DSBs (deDSBs), which could drive genomic scarring in HR-deficient cancers. deDSBs can also be generated directly when the replication fork bypasses lagging strand nicks. Unlike deDSBs produced independently of replication, end-resection at nick-induced se/deDSBs is BRCA1-independent. Nevertheless, BRCA1 antagonizes 53BP1 suppression of RAD51 filament formation. These results highlight unique mechanisms that maintain replication fork stability.

Projections of Endovascular Therapy-Eligible Patients With Stroke for the US Population.

BACKGROUND: As stroke endovascular thrombectomy (EVT) treatment indications expand, understanding population-based EVT eligibility becomes critical for resource planning. We aimed to project current and future population-based EVT eligibility in the United States. METHODS: We conducted a post hoc analysis of the physician-adjudicated GCNKSS (Greater Cincinnati Northern Kentucky Stroke Study; 2015 epoch), a population-based, cross sectional, observational study of stroke incidence, treatment, and outcomes across a 5-county region. All hospitalized patients ≥18 years of age with acute ischemic stroke were ascertained using the International Classification of Diseases, Ninth Revision codes 430-436 and Tenth Revision codes I60-I67 and G45-G46 and extrapolated to the US adult census 2020. We determined the rate of EVT eligibility within the GCNKSS population using time from last known well to presentation (0-5 versus 5-23 hours), presenting National Institutes of Health Stroke Scale, and prestroke modified Rankin Scale. Both conservative and liberal estimates of prevalence of large vessel occlusion and large core were then applied based on literature review (unavailable within the 2015 GCNKSS). This eligibility was then extrapolated to the 2020 US population. RESULTS: Of the 1 057 183 adults within GCNKSS in 2015, 2741 had an ischemic stroke and 2176 had data available for analysis. We calculated that 8659 to 17 219 patients (conservative to liberal) meet the current guideline-recommended EVT criteria (nonlarge core, no prestroke disability, and National Institutes of Health Stroke Scale score ≥6) in the United States. Estimates (conservative to liberal) for expanded EVT eligibility subpopulations include (1) 5316 to 10 635 by large core; (2) 10 635 to 21 270 by mild presenting deficits with low National Institutes of Health Stroke Scale score; (3) 13 572 to 27 089 by higher prestroke disability; and (4) 7039 to 14 180 by >1 criteria. These expanded eligibility subpopulations amount to 36 562 to 73 174 patients. CONCLUSIONS: An estimated 8659 to 17 219 adult patients in the United States met strict EVT eligibility criteria in 2020. A 4-fold increase in population-based EVT eligibility can be anticipated with incremental adoption of recent or future positive trials. US stroke systems need to be rapidly optimized to handle all EVT-eligible patients with stroke.

Impact of Poverty on Stroke Recurrence: A Population-Based Study.

BACKGROUND AND OBJECTIVES: Poverty is associated with greater stroke incidence. The relationship between poverty and stroke recurrence is less clear. METHODS: In this population-based study, incident strokes within the Greater Cincinnati/Northern Kentucky region were ascertained during the 2015 study period and followed up for recurrence until December 31, 2018. The primary exposure was neighborhood socioeconomic status (nSES), defined by the percentage of households below the federal poverty line in each census tract in 4 categories (≤5%, >5%-10%, >10%-25%, >25%). Poisson regression models provided recurrence rate estimates per 100,000 residents using population data from the 2015 5-year American Community Survey, adjusting for age, sex, and race. In a secondary analysis, Cox models allowed for the inclusion of vascular risk factors in the assessment of recurrence risk by nSES among those with incident stroke. RESULTS: Of 2,125 patients with incident stroke, 245 had a recurrent stroke during the study period. Poorer nSES was associated with increased stroke recurrence, with rates of 12.5, 17.5, 25.4, and 29.9 per 100,000 in census tracts with ≤5%, >5%-10%, >10%-25%, and >25% below the poverty line, respectively (p < 0.01). The relative risk (95% CI) for recurrent stroke among Black vs White individuals was 2.54 (1.91-3.37) before adjusting for nSES, and 2.00 (1.47-2.74) after adjusting for nSES, a 35.1% decrease. In the secondary analysis, poorer nSES (HR 1.74, 95% CI 1.10-2.76 for lowest vs highest category) and Black race (HR 1.31, 95% CI 1.01-1.70) were both independently associated with recurrence risk, though neither retained significance after full adjustment. Age, diabetes, and left ventricular hypertrophy were associated with increased recurrence risk in fully adjusted models. DISCUSSION: Residents of poorer neighborhoods had a dose-dependent increase in stroke recurrence risk, and neighborhood poverty accounted for approximately one-third of the excess risk among Black individuals. These results highlight the importance of poverty, race, and the intersection of the 2 as potent drivers of stroke recurrence.

Prediction of Recurrent Lateral Ankle Sprain and Ankle Pain Using Applied Care Strategies and Patient-Reported Outcomes.

CONTEXT: Lateral ankle sprain (LAS) patients often have deficient patient-reported outcomes (PROs) at return-to-activity (RTA), potentially increasing risk for recurrent LAS and ankle pain. Additionally, applied care strategies are known to correct impairments, but their ability to mitigate risk for long-term consequences remains unknown. OBJECTIVE: To determine if applied care strategies and PRO scores at RTA and 6-months post-RTA predict recurrent LAS and ankle pain 12 months after an acute LAS. DESIGN: Prospective cohort study. SETTING: Online survey. PATIENTS OR OTHER PARTICIPANTS: We enrolled 63 individuals within one week of sustaining an acute LAS. MAIN OUTCOME MEASURES: Participants completed online surveys about their health history and recent LAS. At RTA and 6 months post-RTA, participants completed online surveys regarding demographics, applied care strategies, and patient reported outcomes (PROs): Foot and Ankle Disability Index, Identification of Functional Ankle Instability, Godin Leisure-Time Exercise Questionnaire, Short Form-8. At 12 months post-RTA, we asked participants if they sustained recurrent LAS. Chi-squares determined if recurrent LAS and ankle pain at 12-months were related to applied care strategies or ankle pain at RTA. Independent t-tests compared demographics and PROs at RTA and 6-months between participants with and without a recurrent LAS or ankle pain at 12-months. Logistic regression and area under the receiver operating characteristic (AUROC) analyses determined if demographics, applied care strategies, ankle pain at RTA, and PRO scores at RTA and 6-months predicted recurrent LAS and ankle pain at 12-months. RESULTS: Participants with a recurrent LAS had a lower walking boot use (P=0.05) and were taller than those without (P=0.03). Increased height and lack of walking boot use were predictive of recurrent LAS (P<0.01, R2=0.33, AUROC=0.81[0.68, 0.95]). CONCLUSIONS: LAS patients who are taller and do not use a walking boot might have greater risk for a recurrent LAS withing 12 months of RTA.

Tandem lesions associate with angiographic progression of coronary artery stenoses.

Background: Although the clinical factors associated with progression of coronary artery disease have been well studied, the angiographic predictors are less defined. Objectives: Our objective was to study the clinical and angiographic factors that associate with progression of coronary artery stenoses. Methods: We conducted a retrospective analysis of consecutive patients undergoing multiple, clinically indicated invasive coronary angiograms with an interval greater than 6 months, between January 2013 and December 2016. Lesion segments were analysed using Quantitative Coronary Angiography (QCA) if a stenosis ≥ 20 % was identified on either angiogram. Stenosis progression was defined as an increase ≥ 10 % in stenosis severity, with progressor groups analysed on both patient and lesion levels. Mixed-effects regression analyses were performed to evaluate factors associated with progression of individual stenoses. Results: 199 patients were included with 881 lesions analysed. 108 (54.3 %) patients and 186 (21.1 %) stenoses were classified as progressors. The median age was 65 years (IQR 56-73) and the median interval between angiograms was 2.1 years (IQR 1.2-3.0). On a patient level, age, number of lesions and presence of multivessel disease at baseline were each associated with progressor status. On a lesion level, presence of a stenosis downstream (OR 3.07, 95 % CI 2.04-4.63, p < 0.001) and circumflex artery stenosis location (OR 1.81, 95 % CI 1.21-2.7, p = 0.004) were associated with progressor status. Other lesion characteristics did not significantly impact progressor status or change in stenosis severity. Conclusion: Coronary lesions which have a downstream stenosis may be at increased risk of stenosis progression. Further research into the mechanistic basis of this finding is required, along with its implications for plaque vulnerability and clinical outcomes.

Amelioration of Anxiety Associated with Opioid Withdrawal by Activation of Spinal Mechanoreceptors Via Novel Heterodyned Whole Body Vibration.

Objectives: Opioid use disorder (OUD)-associated overdose deaths have reached epidemic proportions worldwide. An important driving force for relapse is anxiety associated with opioid withdrawal. We hypothesized that our new technology, termed heterodyned whole-body vibration (HWBV) would ameliorate anxiety associated with OUD. Methods: Using a randomized, placebo (sham)-controlled, double-blind study design in an NIH-sponsored Phase 1 trial, we evaluated 60 male and 26 female participants diagnosed with OUD and undergoing treatment at pain and rehabilitation clinics. We utilized the Hamilton Anxiety Scale (HAM-A) and a daily visual analog scale anxiety rating (1-10) to evaluate anxiety. Subjects were treated for 10 min 5X/week for 4 weeks with either sham vibration (no interferential beat or harmonics) or HWBV (beats and harmonics). The participants also completed a neuropsychological test battery at intake and discharge. Results: In OUD subjects with moderate anxiety, there was a significant improvement in daily anxiety scores in the HWBV group compared to the sham treatment group (p=3.41 × 10-7). HAM-A scores in OUD participants at intake showed moderate levels of anxiety in OUD participants (HWBV group: 15.9 ± 1.6; Sham group: 17.8 ± 1.6) and progressively improved in both groups at discharge, but improvement was greater in the HWBV group (p=1.37 × 10-3). Furthermore, three indices of neuropsychological testing (mental rotations, spatial planning, and response inhibition) were significantly improved by HWBV treatment. Conclusions: These findings support HWBV as a novel, non-invasive, non-pharmacological treatment for anxiety associated with OUD.

Measuring perceived utility of genomic sequencing: Development and validation of the GENEtic Utility (GENE-U) scale for pediatric diagnostic testing.

PURPOSE: Measuring the effects of genomic sequencing (GS) on patients and families is critical for translational research. We aimed to develop and validate an instrument to assess parents' perceived utility of pediatric diagnostic GS. METHODS: Informed by a 5-domain conceptual model, the study comprised 5 steps: (1) item writing, (2) cognitive testing, (3) pilot testing and item reduction, (4) psychometric testing, and (5) evaluation of construct validity. Parents of pediatric patients who had received results of clinically indicated GS participated in structured cognitive interviews and 2 rounds of surveys. After eliminating items based on theory and quantitative performance, we conducted an exploratory factor analysis and calculated Pearson correlations with related instruments. RESULTS: We derived the 21-item Pediatric Diagnostic version of the GENEtic Utility (GENE-U) scale, which has a 2-factor structure that includes an Informational Utility subscale (16 items, α = 0.91) and an Emotional Utility subscale (5 items, α = 0.71). Scores can be summed to calculate a Total scale score (α = 0.87). The Informational Utility subscale was strongly associated with empowerment and personal utility of GS, and the Emotional Utility subscale was moderately associated with psychosocial impact and depression and anxiety. CONCLUSION: The pediatric diagnostic GENE-U scale demonstrated good psychometric performance in this initial evaluation and could be a useful tool for translational genomics researchers, warranting additional validation.

Development and validation of a point-of-care clinical risk score to predict surgical site complication-associated readmissions following open spine surgery.

Background: Surgical site complications (SSCs) contribute to increased healthcare costs. Predictive analytics can aid in identifying high-risk patients and implementing optimization strategies. This study aimed to develop and validate a risk-assessment score for SSC-associated readmissions (SSC-ARs) in patients undergoing open spine surgery. Methods: The Premier Healthcare Database (PHD) of adult patients (n=157,664; 3,182 SSC-ARs) between January 2019 and September 2020 was used for retrospective data analysis to create an SSC risk score using mixed effects logistic regression modeling. Full and reduced models were developed using patient-, facility-, or procedure-related predictors. The full model used 37 predictors and the reduced used 19. Results: The reduced model exhibited fair discriminatory capability (C-statistic =74.12%) and demonstrated better model fit [Pearson chi-square/degrees of freedom (DF) =0.93] compared to the full model (C-statistic =74.56%; Pearson chi-square/DF =0.92). The risk scoring system, based on the reduced model, comprised the following factors: female (1 point), blood disorder [2], congestive heart failure [2], dementia [3], chronic pulmonary disease [2], rheumatic disease [3], hypertension [2], obesity [2], severe comorbidity [2], nicotine dependence [1], liver disease [2], paraplegia and hemiplegia [3], peripheral vascular disease [2], renal disease [2], cancer [1], diabetes [2], revision surgery [2], operative hours ≥5 [4], emergency/urgent surgery [2]. A final risk score (sum of the points for each surgery; range, 0-40) was validated using a 1,000-surgery random hold-out sample (C-statistic =85.16%). Conclusions: The resulting SSC-AR risk score, composed of readily obtainable clinical information, could serve as a robust predictive tool for unplanned readmissions related to wound complications in the preoperative setting of open spine surgery.

Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors.

Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.

The tumor microenvironment of benign and malignant salivary gland tumors.

BACKGROUND: Treatment of salivary gland tumors (SGTs) remains challenging. Little is known about the immune landscape of SGTs. We aimed to characterize the tumor microenvironment in benign and malignant SGTs. METHODS: Eleven benign and nine malignant tumors were collected from patients undergoing curative intent surgery. Specimens were analyzed using mass cytometry by time-of-flight. Immune cell populations were manually gated, and T cells were clustered using the FlowSOM algorithm. Population frequencies were compared between high-grade and low-grade malignancies, corrected for multiple hypothesis testing. RESULTS: There were trends towards increased CD4+ and CD8+ T cells among malignant tumors. High-grade malignancies exhibited trends towards higher frequencies of CD8+ PD-1+ CD39+ CD103+ exhausted T cells, CD4+ FoxP3+ TCF-1+ CD127- Tregs, and CD69+ CD25- CD4+ T cells compared to low-grade malignancies. CONCLUSION: SGTs exhibit significant immunologic diversity. High-grade malignancies tended to have greater infiltration of exhausted CD8+ T cells and Tregs, which may guide future studies for immunotherapy strategies.

synNotch-programmed iPSC-derived NK cells usurp TIGIT and CD73 activities for glioblastoma therapy.

Severe heterogeneity within glioblastoma has spurred the notion that disrupting the interplay between multiple elements on immunosuppression is at the core of meaningful anti-tumor responses. T cell immunoreceptor with Ig and ITIM domains (TIGIT) and its glioblastoma-associated antigen, CD155, form a highly immunosuppressive axis in glioblastoma and other solid tumors, yet targeting of TIGIT, a functionally heterogeneous receptor on tumor-infiltrating immune cells, has largely been ineffective as monotherapy, suggesting that disruption of its inhibitory network might be necessary for measurable responses. It is within this context that we show that the usurpation of the TIGIT - CD155 axis via engineered synNotch-mediated activation of induced pluripotent stem cell-derived natural killer (NK) cells promotes transcription factor-mediated activation of a downstream signaling cascade that results in the controlled, localized blockade of CD73 to disrupt purinergic activity otherwise resulting in the production and accumulation of immunosuppressive extracellular adenosine. Such "decoy" receptor engages CD155 binding to TIGIT, but tilts inhibitory TIGIT/CD155 interactions toward activation via downstream synNotch signaling. Usurping activities of TIGIT and CD73 promotes the function of adoptively transferred NK cells into intracranial patient-derived models of glioblastoma and enhances their natural cytolytic functions against this tumor to result in complete tumor eradication. In addition, targeting both receptors, in turn, reprograms the glioblastoma microenvironment via the recruitment of T cells and the downregulation of M2 macrophages. This study demonstrates that TIGIT/CD155 and CD73 are targetable receptor partners in glioblastoma. Our data show that synNotch-engineered pluripotent stem cell-derived NK cells are not only effective mediators of anti-glioblastoma responses within the setting of CD73 and TIGIT/CD155 co-targeting, but represent a powerful allogeneic treatment option for this tumor.

Precise and Rapid Whole-Head Segmentation from Magnetic Resonance Images of Older Adults using Deep Learning.

Whole-head segmentation from Magnetic Resonance Images (MRI) establishes the foundation for individualized computational models using finite element method (FEM). This foundation paves the path for computer-aided solutions in fields, particularly in non-invasive brain stimulation. Most current automatic head segmentation tools are developed using healthy young adults. Thus, they may neglect the older population that is more prone to age-related structural decline such as brain atrophy. In this work, we present a new deep learning method called GRACE, which stands for General, Rapid, And Comprehensive whole-hEad tissue segmentation. GRACE is trained and validated on a novel dataset that consists of 177 manually corrected MR-derived reference segmentations that have undergone meticulous manual review. Each T1-weighted MRI volume is segmented into 11 tissue types, including white matter, grey matter, eyes, cerebrospinal fluid, air, blood vessel, cancellous bone, cortical bone, skin, fat, and muscle. To the best of our knowledge, this work contains the largest manually corrected dataset to date in terms of number of MRIs and segmented tissues. GRACE outperforms five freely available software tools and a traditional 3D U-Net on a five-tissue segmentation task. On this task, GRACE achieves an average Hausdorff Distance of 0.21, which exceeds the runner-up at an average Hausdorff Distance of 0.36. GRACE can segment a whole-head MRI in about 3 seconds, while the fastest software tool takes about 3 minutes. In summary, GRACE segments a spectrum of tissue types from older adults T1-MRI scans at favorable accuracy and speed. The trained GRACE model is optimized on older adult heads to enable high-precision modeling in age-related brain disorders. To support open science, the GRACE code and trained weights are made available online and open to the research community at https://github.com/lab-smile/GRACE.