Eat, Sleep, Console Approach or Usual Care for Neonatal Opioid Withdrawal.

BACKGROUND: Although clinicians have traditionally used the Finnegan Neonatal Abstinence Scoring Tool to assess the severity of neonatal opioid withdrawal, a newer function-based approach - the Eat, Sleep, Console care approach - is increasing in use. Whether the new approach can safely reduce the time until infants are medically ready for discharge when it is applied broadly across diverse sites is unknown. METHODS: In this cluster-randomized, controlled trial at 26 U.S. hospitals, we enrolled infants with neonatal opioid withdrawal syndrome who had been born at 36 weeks' gestation or more. At a randomly assigned time, hospitals transitioned from usual care that used the Finnegan tool to the Eat, Sleep, Console approach. During a 3-month transition period, staff members at each hospital were trained to use the new approach. The primary outcome was the time from birth until medical readiness for discharge as defined by the trial. Composite safety outcomes that were assessed during the first 3 months of postnatal age included in-hospital safety, unscheduled health care visits, and nonaccidental trauma or death. RESULTS: A total of 1305 infants were enrolled. In an intention-to-treat analysis that included 837 infants who met the trial definition for medical readiness for discharge, the number of days from birth until readiness for hospital discharge was 8.2 in the Eat, Sleep, Console group and 14.9 in the usual-care group (adjusted mean difference, 6.7 days; 95% confidence interval [CI], 4.7 to 8.8), for a rate ratio of 0.55 (95% CI, 0.46 to 0.65; P<0.001). The incidence of adverse outcomes was similar in the two groups. CONCLUSIONS: As compared with usual care, use of the Eat, Sleep, Console care approach significantly decreased the number of days until infants with neonatal opioid withdrawal syndrome were medically ready for discharge, without increasing specified adverse outcomes. (Funded by the Helping End Addiction Long-term (HEAL) Initiative of the National Institutes of Health; ESC-NOW ClinicalTrials.gov number, NCT04057820.).

The Influence of Mediators on the Relationship Between Antenatal Opioid Agonist Exposure and the Severity of Neonatal Opioid Withdrawal Syndrome.

OBJECTIVES: (1) To evaluate the direct (un-mediated) and indirect (mediated) relationship between antenatal exposure to opioid agonist medication as treatment for opioid use disorder (MOUD) and the severity of neonatal opioid withdrawal syndrome (NOWS), and (2) to understand the degree to which mediating factors influence the direct relationship between MOUD exposure and NOWS severity. METHODS: This cross-sectional study includes data abstracted from the medical records of 1294 opioid-exposed infants (859 MOUD exposed and 435 non-MOUD exposed) born at or admitted to one of 30 US hospitals from July 1, 2016, to June 30, 2017. Regression models and mediation analyses were used to evaluate the relationship between MOUD exposure and NOWS severity (i.e., infant pharmacologic treatment and length of newborn hospital stay (LOS)) to identify potential mediators of this relationship in analyses adjusted for confounding factors. RESULTS: A direct (un-mediated) association was found between antenatal exposure to MOUD and both pharmacologic treatment for NOWS (aOR 2.34; 95%CI 1.74, 3.14) and an increase in LOS (1.73 days; 95%CI 0.49, 2.98). Delivery of adequate prenatal care and a reduction in polysubstance exposure were mediators of the relationship between MOUD and NOWS severity and as thus, were indirectly associated with a decrease in both pharmacologic treatment for NOWS and LOS. CONCLUSIONS FOR PRACTICE: MOUD exposure is directly associated with NOWS severity. Prenatal care and polysubstance exposure are potential mediators in this relationship. These mediating factors may be targeted to reduce the severity of NOWS while maintaining the important benefits of MOUD during pregnancy.

First-in-human experience with occlusion of the superior vena cava to reduce cardiac filling pressures in congestive heart failure.

BACKGROUND: Acutely decompensated heart failure remains a major clinical problem. Volume overload promotes cardiac and renal dysfunction and is associated with increased morbidity and mortality in heart failure. We hypothesized that transient occlusion of the superior vena cava (SVC) will reduce cardiac filling pressures without reducing cardiac output or systemic blood pressure. The objective of this proof of concept study was to provide initial evidence of safety and feasibility of transient SVC occlusion in patients with acutely decompensated heart failure and reduced ejection fraction. METHODS AND RESULTS: In eight patients with systolic heart failure, SVC occlusion was performed using a commercially available occlusion balloon. Five minutes of SVC occlusion reduced biventricular filling pressures without decreasing systemic blood pressure or total cardiac output. In three of the eight patients, a second 10-minutes occlusion had similar hemodynamic effects. SVC occlusion was well-tolerated without development of new symptoms, new neurologic deficits, or any adverse events including stroke, heart attack, or reported SVC injury or thrombosis at 7 days of follow up. CONCLUSION: We report the first clinical experience with transient SVC occlusion as a potentially new therapeutic approach to rapidly reduce cardiac filling pressures in heart failure. No prohibitive safety signal was identified and further testing to establish the clinical utility of transient SVC occlusion for acute decompensated heart failure is justified.

Clinical Associations of Early Dysnatremias in Critically Ill Neonates and Infants Undergoing Cardiac Surgery.

Dysnatremias (DN) are common electrolyte disturbances in cardiac critical illness and are known risk factors for adverse outcomes in certain populations. Little information exists on DN in children with cardiac disease admitted to the cardiac intensive care unit (CICU) after undergoing cardiac surgery, either corrective or palliative. The aim was to determine the incidence and adverse outcomes associated with DN in neonates and infants undergoing cardiac surgery. Retrospective cohort and single center study performed at Children's Hospital Colorado from May 2013 to May 2014, in children under 1 year old admitted to the CICU after undergoing surgery for congenital or acquired cardiac disease. 183 subjects were analyzed. EXCLUSIONS: subjects that demonstrated DN before surgery. Serum sodium levels were recorded for the first 72 h post-operatively. DN was present in 54% of the subjects (98/183): hypernatremia in 60 (33%), hyponatremia in 38 (21%). Multivariate analysis revealed that mild hypernatremia (146-150 mmol/dl) and moderate hypernatremia (151-155 mmol/dl) were associated with longer hospital length of stay (LOS, p < 0.05) and ventilation times (p < 0.05). No association was shown between mild/moderate hyponatremia (125-134 mmol/dl) with either outcome. Hours to DN were significantly lower in hypernatremic (median = 5.8 h) than hyponatremic (median = 43.8 h) patients (p < 0.001). Children younger than 30 days presented DN at an earlier stage than those 31 days-1 year old (median +2.2 vs. 17.3 h). No associations present between DN and the class of diuretic (loop vs. thiazide) administered, or the route of administration (intravenous bolus vs. constant infusion). Total median sodium bicarbonate administration was associated with hypernatremia, as was exposure to vasopressin within the first 72 h post-operatively. Dysnatremias are common in the early post-operative period in neonates and infants undergoing cardiac surgery. Mild to moderate hypernatremia, but not hyponatremia, is associated with longer LOS and longer ventilation time in infants undergoing cardiovascular surgery. Hypernatremia is also associated with younger infants, a higher surgical complexity, administration of bicarbonate and exposure to vasopressin. Diuretic type or interval timing of intravenous delivery did not demonstrate any effect. Prospective studies are needed in this population, in order to determine how DN, particularly hypernatremia, contributes to adverse outcomes, whether this association is independent of illness severity, and what may be safe treatments and interventions for these disorders.

Assessment of Staffing, Services, and Partnerships of Local Health Departments - United States, 2015.

Beginning in 2008, the National Association of County and City Health Officials (NACCHO) periodically surveyed local health departments (LHDs) to assess the impact of the economic recession on jobs and budgets (1). In 2014, the survey was expanded to assess a wider range of factors affecting programs, services, and infrastructure in LHDs and renamed the Forces of Change survey (2). The survey was administered in to January-February 2015 to 948 LHDs across the United States to assess budget changes, job losses, changes in services, and collaboration with health care partners; 690 (73%) LHDs responded. Findings indicated a change in LHD infrastructure: compared with the previous fiscal year.* Overall, LHDs reported 3,400 jobs lost; 25% of LHDs reported budget decreases; 36% reported a reduction in at least one service area; and 35% reported serving fewer patients in clinics. In addition, up to 24% of LHDs reported expanding population-based prevention services, and LHDs reported exploring new collaborations with nonprofit hospitals and primary care providers (PCPs).

Recruitment for longitudinal, randomised pregnancy trials initiated preconception: lessons from the effects of aspirin in gestation and reproduction trial.

BACKGROUND: Recruitment into large, preconception randomised clinical trials (RCT) is challenging. We describe clinic and community-based preconception recruitment strategies for the Effects of Aspirin in Gestation and Reproduction (EAGeR) trial and highlight approaches that were and were not successful. This longitudinal RCT was conducted at four major sites in the US. Eligible women had one to two prior pregnancy losses and were actively trying to become pregnant. METHODS: Provider/clinic and community-based outreach strategies were utilised, and the recruitment rate and costs of methods were assessed. RESULTS: A screening questionnaire was completed by 5485 women; 42.4% (n = 2323) screened were initially eligible, of whom 50.7% (n = 1228) were randomised. Provider/clinic-based recruitment yielded the highest number eligible of those screened (30.1%) and also the most randomised participants overall (40.3%). The next highest yield came from direct mail and brochures/flyers at 13.1% and 12.5% of women randomised, respectively. However, direct mailings cost $720 per participant randomised. Other than word of mouth, provider/clinic-based recruitment was the most cost effective method, costing an average of $60 per randomised participant. Web-based recruitment yielded 4.7% of participants at a cost of $278 per randomised participant. CONCLUSIONS: Provider and clinic-based recruitment was the most effective and cost-efficient method of recruitment in a preconception intervention study of reproduction among women.

Reductions of budgets, staffing, and programs among local health departments: results from NACCHO's economic surveillance surveys, 2009-2013.

OBJECTIVES: To provide an overview of budget cuts, job losses, and program reductions among local health departments (LHDs) and to examine the association between LHD infrastructure characteristics and the likelihood of budget cuts. DESIGN: Data from 4 waves of the economic surveillance survey (July-August 2009, September-November 2010, January-February 2012, and January-March 2013) conducted by the National Association of County & City Health Officials were analyzed to assess cuts to budgets, jobs, and programs since 2009. Data from the 2013 National Profile of Local Health Departments survey were used to assess the infrastructural characteristics associated with budget cuts. RESULTS: When asked in early 2013, more than a quarter of LHDs (26.9%) reported a reduced budget, continuing the trend of a substantial proportion of LHDs experiencing financial hardship in recent years. The percentages of LHDs that made cuts to programmatic areas fluctuated from year to year but have never been lower than 40%. Maternal and child health services were among areas most often cut during all 4 time points of the survey. Governance type, total expenditures, and percentage of revenues from local sources were significantly associated with LHD budget cuts. CONCLUSIONS: Cuts in LHD budgets, staff, and activities have been widespread for a period that lasted long after the official end of the Great Recession. There is a great need for substantive and consistent funding to ensure the retention of the workforce and the delivery of essential public health services.

Perception of Workforce Skills Needed Among Public Health Professionals in Local Health Departments: Staff Versus Top Executives.

OBJECTIVES: To examine how top executives and staff from local health departments (LHDs) perceive the importance of various types of workforce skills, and to assess the differences in the perception of the importance of these workforce skills between these 2 groups and among LHDs serving different-sized jurisdictions. DESIGN: Data for this study were drawn from the 2014 Public Health Workforce Interests and Needs Survey (PH WINS) and the 2015 Forces of Change survey. While PH WINS collected data from LHD staff, the Forces of Change survey was administered to LHD top executives. Ratings of perceived importance of workforce skills from LHD staff and top executives were compared. RESULTS: Overall, LHD workers at all levels believe that core competencies are important for their jobs. The perceived importance of these skills differed somewhat across supervisory level (nonsupervisory staff vs supervisory staff vs top executives). Communication was rated as one of the most important skills by all groups. For top executives, ensuring that programs are managed within budget constraints was the most important skill for their employees. However, this skill was rated much lower among staff. Policy development skills were rated to be of lowest importance by LHD leaders and staff. CONCLUSIONS: LHD leaders and staff agree on the relative importance of some competencies, although they also show some clear differences in the relative importance that they place on other competencies. It is essential to strengthen the communication between public health leaders and staff regarding the importance of workforce skills. More investigation is needed to assess whether and how gaps in staff competencies are addressed in the workforce development strategies.

Intramedullary Spinal Cord Tumors: Whole-Genome Sequencing to Assist Management and Prognosis.

Intramedullary spinal cord tumors (IMSCTs) harbor unique genetic mutations which may play a role in prognostication and management. To this end, we present the largest cohort of IMSCTs with genetic characterization in the literature from our multi-site institutional registry. A total of 93 IMSCT patient records were reviewed from the years 1999 to 2020. Out of these, 61 complied with all inclusion criteria, 14 of these patients had undergone genetic studies with 8 undergoing whole-genomic sequencing. Univariate analyses were used to assess any factors associated with progression-free survival (PFS) using the Cox proportional hazards model. Firth's penalized likelihood approach was used to account for the low event rates. Fisher's exact test was performed to compare whole-genome analyses and specific gene mutations with progression. PFS (months) was given as a hazard ratio. Only the absence of copy neutral loss of heterozygosity (LOH) was shown to be significant (0.05, p = 0.008). Additionally, higher risk of recurrence/progression was associated with LOH (p = 0.0179). Our results suggest LOH as a genetic predictor of shorter progression-free survival, particularly within ependymoma and glioblastoma tumor types. Further genomic research with larger multi-institutional datasets should focus on these mutations as possible prognostic factors.

Radiomic analysis of patient and inter-organ heterogeneity in response to immunotherapies and BRAF targeted therapy in metastatic melanoma.

Background: Variability in treatment response may be attributable to organ-level heterogeneity in tumor lesions. Radiomic analysis of medical images can elucidate non-invasive biomarkers of clinical outcome. Organ-specific radiomic comparison across immunotherapies and targeted therapies has not been previously reported. Methods: We queried UPMC Hillman Cancer Center registry for patients with metastatic melanoma (MEL) treated with immune checkpoint inhibitors (ICI) (anti-PD1/CTLA4 [ipilimumab+nivolumab; I+N] or anti-PD1 monotherapy) or BRAF targeted therapy. Best overall response was measured using RECIST v1.1. Lesions were segmented into discrete volume-of-interest with 400 radiomics features extracted. Overall and organ-specific machine-learning models were constructed to predict disease control (DC) versus progressive disease (PD) using XGBoost. Results: 291 MEL patients were identified, including 242 ICI (91 I+N, 151 PD1) and 49 BRAF. 667 metastases were analyzed, including 541 ICI (236 I+N, 305 PD1) and 126 BRAF. Across cohorts, baseline demographics included 39-47% female, 24-29% M1C, 24-46% M1D, and 61-80% with elevated LDH. Among patients experiencing DC, the organs with the greatest reduction were liver (-88%±12%, I+N; mean±S.E.M.) and lung (-72%±8%, I+N). For patients with multiple same-organ target lesions, the highest inter-lesion heterogeneity was observed in brain among patients who received ICI while no intra-organ heterogeneity was observed in BRAF. 267 patients were kept for radiomic modeling, including 221 ICI (86 I+N, 135 PD1) and 46 BRAF. Models consisting of optimized radiomic signatures classified DC/PD across I+N (AUC=0.85) and PD1 (0.71) and within individual organ sites (AUC=0.72∼0.94). Integration of clinical variables improved the models' performance. Comparison of models between treatments and across organ sites suggested mostly non-overlapping DC or PD features. Skewness, kurtosis, and informational measure of correlation (IMC) were among the radiomic features shared between overall response models. Kurtosis and IMC were also utilized by multiple organ-site models. Conclusions: Differential organ-specific response was observed across BRAF and ICI with within organ heterogeneity observed for ICI but not for BRAF. Radiomic features of organ-specific response demonstrated little overlap. Integrating clinical factors with radiomics improves the prediction of disease course outcome and prediction of tumor heterogeneity.

Influence of Eat, Sleep, and Console on Infants Pharmacologically Treated for Opioid Withdrawal: A Post Hoc Subgroup Analysis of the ESC-NOW Randomized Clinical Trial.

Importance: The function-based eat, sleep, console (ESC) care approach substantially reduces the proportion of infants who receive pharmacologic treatment for neonatal opioid withdrawal syndrome (NOWS). This reduction has led to concerns for increased postnatal opioid exposure in infants who receive pharmacologic treatment. However, the effect of the ESC care approach on hospital outcomes for infants pharmacologically treated for NOWS is currently unknown. Objective: To evaluate differences in opioid exposure and total length of hospital stay (LOS) for pharmacologically treated infants managed with the ESC care approach vs usual care with the Finnegan tool. Design, Setting, and Participants: This post hoc subgroup analysis involved infants pharmacologically treated in ESC-NOW, a stepped-wedge cluster randomized clinical trial conducted at 26 US hospitals. Hospitals maintained pretrial practices for pharmacologic treatment, including opioid type, scheduled opioid dosing, and use of adjuvant medications. Infants were born at 36 weeks' gestation or later, had evidence of antenatal opioid exposure, and received opioid treatment for NOWS between September 2020 and March 2022. Data were analyzed from November 2022 to January 2024. Exposure: Opioid treatment for NOWS and the ESC care approach. Main Outcomes and Measures: For each outcome (total opioid exposure, peak opioid dose, time from birth to initiation of first opioid dose, length of opioid treatment, and LOS), we used generalized linear mixed models to adjust for the stepped-wedge design and maternal and infant characteristics. Results: In the ESC-NOW trial, 463 of 1305 infants were pharmacologically treated (143/603 [23.7%] in the ESC care approach group and 320/702 [45.6%] in the usual care group). Mean total opioid exposure was lower in the ESC care approach group with an absolute difference of 4.1 morphine milligram equivalents per kilogram (MME/kg) (95% CI, 1.3-7.0) when compared with usual care (4.8 MME/kg vs 8.9 MME/kg, respectively; P = .001). Mean time from birth to initiation of pharmacologic treatment was 22.4 hours (95% CI, 7.1-37.7) longer with the ESC care approach vs usual care (75.4 vs 53.0 hours, respectively; P = .002). No significant difference in mean peak opioid dose was observed between groups (ESC care approach, 0.147 MME/kg, vs usual care, 0.126 MME/kg). The mean length of treatment was 6.3 days shorter (95% CI, 3.0-9.6) in the ESC care approach group vs usual care group (11.8 vs 18.1 days, respectively; P < .001), and mean LOS was 6.2 days shorter (95% CI, 3.0-9.4) with the ESC care approach than with usual care (16.7 vs 22.9 days, respectively; P < .001). Conclusion and Relevance: When compared with usual care, the ESC care approach was associated with less opioid exposure and shorter LOS for infants pharmacologically treated for NOWS. The ESC care approach was not associated with a higher peak opioid dose, although pharmacologic treatment was typically initiated later. Trial Registration: ClinicalTrials.gov Identifier: NCT04057820.

Management and Long-Term Outcomes of Patients With Infectious Intracranial Aneurysms.

BACKGROUND: Infectious intracranial aneurysms (IIAs) are rare complications of infective endocarditis (IE). Data on management and long-term outcomes remain limited. OBJECTIVE: To retrospectively study long-term outcomes of IIAs in patients treated medically or surgically. METHODS: Adult cases of IE and/or IIAs admitted to Emory or Grady Healthcare Systems between May 2015 and May 2020 were reviewed for demographic, clinical, and radiographic variables for up to 2 years. Primary outcome measure was 2-year survival. RESULTS: Among 1714 cases of IE, intracerebral hemorrhage occurred in 322 patients and IIAs in 17 patients. The presence of IIAs in IE was associated with higher odds of disposition to hospice/death (odds ratio = 6.9). Including non-IE patients, 24 patients had 38 IIAs mainly involving the distal middle cerebral artery and 16 were ruptured on admission. IIAs were predominantly treated with antibiotics as the primary approach. Open microsurgery was the primary approach for 5 aneurysms and was used as salvage in 7 IIAs. Endovascular management was the primary approach for 2 IIAs and used as salvage for 5 IIAs with antibiotic failure. Medical management had high rate of treatment failure (15/31) which predominantly occurred within 2 weeks of onset. The 2-year survival in this cohort was 70% (17/24). CONCLUSION: IIAs are rare complications of IE with a poor prognosis. Patients treated with antibiotics have higher risk of treatment failure requiring salvage surgical or endovascular intervention. Medical treatment failure occurred mostly within 2 weeks of onset and had a negative prognostic value emphasizing the need for close follow-up and early surgical or endovascular management.

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma.

Acral melanoma (AM) has distinct characteristics as compared with cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICIs). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3+CD8+PD1+ intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low versus high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared with responders across cancers, including AM, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

Identification of tumor-intrinsic drivers of immune exclusion in acral melanoma.

Background: Acral melanoma (AM) has distinct characteristics as compared to cutaneous melanoma and exhibits poor response to immune checkpoint inhibitors (ICI). Tumor-intrinsic mechanisms of immune exclusion have been identified in many cancers but less studied in AM. Methods: We characterized clinically annotated tumors from patients diagnosed with AM at our institution in correlation with ICI response using whole transcriptome RNAseq, whole exome sequencing, CD8 immunohistochemistry, and multispectral immunofluorescence imaging. A defined interferon-γ-associated T cell-inflamed gene signature was used to categorize tumors into non-T cell-inflamed and T cell-inflamed phenotypes. In combination with AM tumors from two published studies, we systematically assessed the immune landscape of AM and detected differential gene expression and pathway activation in a non-T cell-inflamed tumor microenvironment (TME). Two single-cell(sc) RNAseq AM cohorts and 11 bulk RNAseq cohorts of various tumor types were used for independent validation on pathways associated with lack of ICI response. In total, 892 specimens were included in this study. Results: 72.5% of AM tumors showed low expression of the T cell-inflamed gene signature, with 23.9% of total tumors categorized as the non-T cell-inflamed phenotype. Patients of low CD3 + CD8 + PD1 + intratumoral T cell density showed poor prognosis. We identified 11 oncogenic pathways significantly upregulated in non-T cell-inflamed relative to T cell-inflamed TME shared across all three acral cohorts (MYC, HGF, MITF, VEGF, EGFR, SP1, ERBB2, TFEB, SREBF1, SOX2, and CCND1). scRNAseq analysis revealed that tumor cell-expressing pathway scores were significantly higher in low vs high T cell-infiltrated AM tumors. We further demonstrated that the 11 pathways were enriched in ICI non-responders compared to responders across cancers, including acral melanoma, cutaneous melanoma, triple-negative breast cancer, and non-small cell lung cancer. Pathway activation was associated with low expression of interferon stimulated genes, suggesting suppression of antigen presentation. Across the 11 pathways, fatty acid synthase and CXCL8 were unifying downstream target molecules suggesting potential nodes for therapeutic intervention. Conclusions: A unique set of pathways is associated with immune exclusion and ICI resistance in AM. These data may inform immunotherapy combinations for immediate clinical translation.

Dietary restriction of isoleucine increases healthspan and lifespan of genetically heterogeneous mice.

Low-protein diets promote health and longevity in diverse species. Restriction of the branched-chain amino acids (BCAAs) leucine, isoleucine, and valine recapitulates many of these benefits in young C57BL/6J mice. Restriction of dietary isoleucine (IleR) is sufficient to promote metabolic health and is required for many benefits of a low-protein diet in C57BL/6J males. Here, we test the hypothesis that IleR will promote healthy aging in genetically heterogeneous adult UM-HET3 mice. We find that IleR improves metabolic health in young and old HET3 mice, promoting leanness and glycemic control in both sexes, and reprograms hepatic metabolism in a sex-specific manner. IleR reduces frailty and extends the lifespan of male and female mice, but to a greater degree in males. Our results demonstrate that IleR increases healthspan and longevity in genetically diverse mice and suggests that IleR, or pharmaceuticals that mimic this effect, may have potential as a geroprotective intervention.

Tumor cell p38 inhibition to overcome immunotherapy resistance.

Patients with tumors that do not respond to immune-checkpoint inhibition often harbor a non-T cell-inflamed tumor microenvironment, characterized by the absence of IFN-γ-associated CD8+ T cell and dendritic cell activation. Understanding the molecular mechanisms underlying immune exclusion in non-responding patients may enable the development of novel combination therapies. p38 MAPK is a known regulator of dendritic and myeloid cells however a tumor-intrinsic immunomodulatory role has not been previously described. Here we identify tumor cell p38 signaling as a therapeutic target to potentiate anti-tumor immunity and overcome resistance to immune-checkpoint inhibitors (ICI). Molecular analysis of tumor tissues from patients with human papillomavirus-negative head and neck squamous carcinoma reveals a p38-centered network enriched in non-T cell-inflamed tumors. Pan-cancer single-cell RNA analysis suggests that p38 activation may be an immune-exclusion mechanism across multiple tumor types. P38 knockdown in cancer cell lines increases T cell migration, and p38 inhibition plus ICI in preclinical models shows greater efficacy compared to monotherapies. In a clinical trial of patients refractory to PD1/L1 therapy, pexmetinib, a p38 inhibitor, plus nivolumab demonstrated deep and durable clinical responses. Targeting of p38 with anti-PD1 has the potential to induce the T cell-inflamed phenotype and overcome immunotherapy resistance.

Revascularization Is Associated With a Reduced Stroke Risk in Patients With Sickle Cell-Associated Moyamoya Syndrome.

BACKGROUND: Moyamoya syndrome refers to a progressive stenosis of the internal carotid arteries and can be associated with sickle cell disease. These codiagnoses result in severe risk for stroke, even in patients on optimal medical management. Surgical revascularization has been shown to be safe in small case series. OBJECTIVE: To evaluate the efficacy of revascularization with direct comparison to a medically managed control group within a single institution. METHODS: A retrospective cohort study of medically managed vs surgically revascularized patients with moyamoya syndrome and sickle cell disease was conducted. Demographic data and outcomes including the number of prediagnosis, postdiagnosis, and postrevascularization strokes were collected. Risk factors for stroke were identified using a binary logistic regression model, and stroke rates and mortality between groups were compared. RESULTS: Of the 29 identified patients, 66% were medically managed and 34% underwent surgical revascularization (50% direct and 50% indirect). Calculated stroke rates were 1 per 5.37 (medical management), 1 per 3.43 (presurgical revascularization), and 1 per 23.14 patient-years (postsurgical revascularization). There was 1 surgical complication with no associated permanent deficits. No risk factors for stroke after time of diagnosis were found to be significant. CONCLUSION: The results of this study demonstrate that revascularization is associated with a significant reduction in stroke risk, both relative to prerevascularization rates and compared with medical management. According to these findings, surgical revascularization offers a safe and durable preventative therapy for stroke and should be pursued aggressively in this patient population.

Keyhole Supraorbital-Eyebrow Approach for Resection of an Olfactory Groove Meningioma with Intraoperative Endoscopic Assistance.

The authors present the case of a 52-year-old male with a history of new-onset seizures who presented in status epilepticus. Computed tomography and magnetic resonance imaging demonstrated an olfactory groove mass. A keyhole supraorbital-eyebrow approach assisted with a microinspection tool was performed for tumor resection.1-5 A Simpson grade 2 tumor resection was achieved, and histopathology revealed a World Health Organization grade I olfactory groove meningioma. Postoperative and follow-up course has been unremarkable, with early postoperative imaging demonstrating no residual tumoral mass. The operative video highlights the advantages of using the microinspection tool for the visualization of deep lesions.

Weight Pulling: A Novel Mouse Model of Human Progressive Resistance Exercise.

This study describes a mouse model of progressive resistance exercise that utilizes a full-body/multi-joint exercise (weight pulling) along with a training protocol that mimics a traditional human paradigm (three training sessions per week, ~8-12 repetitions per set, 2 min of rest between sets, approximately two maximal-intensity sets per session, last set taken to failure, and a progressive increase in loading that is based on the individual's performance). We demonstrate that weight pulling can induce an increase in the mass of numerous muscles throughout the body. The relative increase in muscle mass is similar to what has been observed in human studies, and is associated with the same type of long-term adaptations that occur in humans (e.g., fiber hypertrophy, myonuclear accretion, and, in some instances, a fast-to-slow transition in Type II fiber composition). Moreover, we demonstrate that weight pulling can induce the same type of acute responses that are thought to drive these long-term adaptations (e.g., the activation of signaling through mTORC1 and the induction of protein synthesis at 1 h post-exercise). Collectively, the results of this study indicate that weight pulling can serve as a highly translatable mouse model of progressive resistance exercise.