Current Applications and Future Implications of Artificial Intelligence in Spine Surgery and Research: A Narrative Review and Commentary.

STUDY DESIGN: Narrative review. OBJECTIVES: Artificial intelligence (AI) is being increasingly applied to the domain of spine surgery. We present a review of AI in spine surgery, including its use across all stages of the perioperative process and applications for research. We also provide commentary regarding future ethical considerations of AI use and how it may affect surgeon-industry relations. METHODS: We conducted a comprehensive literature review of peer-reviewed articles that examined applications of AI during the pre-, intra-, or postoperative spine surgery process. We also discussed the relationship among AI, spine industry partners, and surgeons. RESULTS: Preoperatively, AI has been mainly applied to image analysis, patient diagnosis and stratification, decision-making. Intraoperatively, AI has been used to aid image guidance and navigation. Postoperatively, AI has been used for outcomes prediction and analysis. AI can enable curation and analysis of huge datasets that can enhance research efforts. Large amounts of data are being accrued by industry sources for use by their AI platforms, though the inner workings of these datasets or algorithms are not well known. CONCLUSIONS: AI has found numerous uses in the pre-, intra-, or postoperative spine surgery process, and the applications of AI continue to grow. The clinical applications and benefits of AI will continue to be more fully realized, but so will certain ethical considerations. Making industry-sponsored databases open source, or at least somehow available to the public, will help alleviate potential biases and obscurities between surgeons and industry and will benefit patient care.

Inpatient Use of Guideline-Directed Medical Therapy During Heart Failure Hospitalizations Among Community-Based Health Systems.

BACKGROUND: Guideline-directed medical therapy (GDMT) for heart failure with reduced ejection fraction (HFrEF) remains underused. Acute heart failure (HF) hospitalization represents a critical opportunity for rapid initiation of evidence-based medications. However, data on GDMT use at discharge are mostly derived from national quality improvement registries. OBJECTIVES: This study aimed to describe contemporary GDMT use patterns across HF hospitalizations at community-based health systems. METHODS: The authors identified HF hospitalizations from 2016 to 2022 in a U.S. database aggregating deidentified electronic health record data from more than 30 health systems. In-hospital and discharge rates of GDMT use were reported for eligible HFrEF patients. Factors associated with inpatient GDMT use and predischarge discontinuation were evaluated with the use of multivariable models. RESULTS: A total of 20,387 HF hospitalizations among 13,729 HFrEF patients were identified. Renin-angiotensin system inhibitors, beta-blockers, and mineralocorticoid receptor antagonists were administered during 70%, 86%, and 37% of eligible hospitalizations, respectively. Angiotensin receptor-neprilysin inhibitors and sodium-glucose cotransporter 2 inhibitors were used in 17% and 8% of eligible hospitalizations, respectively. Discharge GDMT rates were low. Triple/quadruple therapy was administered in 26% of hospitalizations, falling to 14% on discharge. Predischarge GDMT discontinuations were associated with inpatient hypotension, hyperkalemia, and worsening renal function, but 43%-57% had no medical contraindications. In adjusted analyses, use of 3 or more GDMT classes was associated with fewer 90-day all-cause deaths and HF readmissions compared with less comprehensive GDMT. CONCLUSIONS: Inpatient GDMT use in a national analysis of HF hospitalizations was lower than reported in quality improvement registries. High discontinuation rates emphasize an unmet need for inpatient and postdischarge strategies to optimize GDMT use.

Chemolithoautotrophic bacteria flourish at dark water-ice interfaces of an emerged Arctic cold seep.

Below their ice shells, icy moons may offer a source of chemical energy that could support microbial life in the absence of light. In the Arctic, past and present glacial retreat leads to isostatic uplift of sediments through which cold and methane-saturated groundwater travels. This fluid reaches the surface and freezes as hill-shaped icings during winter, producing dark ice-water interfaces above water ponds containing chemical energy sources. In one such system characterized by elevated methane concentrations - the Lagoon Pingo in Adventdalen, Svalbard (~10 mg/L CH4, <0.3 mg/L O2, -0.25°C, pH 7.9), we studied amplicons of the bacterial and archaeal (microbial) 16S rRNA gene and transcripts in the water pond and overlaying ice. We show that active chemolithoautotrophic sulfur-oxidizing microorganisms (Sulfurimonas, Thiomicrorhabdus) dominated a niche at the bottom of the ice in contact with the anoxic water reservoir. There, the growing ice offers surfaces interfacing with water, and hosts favorable physico-chemical conditions for sulfide oxidation. Detection of anaerobic methanotrophs further suggests that the ice led to a steady-state dark and cold methane sink under the ice throughout winter, in two steps: first methane is oxidized to carbon dioxide and sulfates concomitantly reduced to sulfides by the activity of ANME-1a and SEEP-SRB1 consortia, in a second time energy from sulfides is used by sulfur- oxidizing microorganisms to fix carbon dioxide into organic carbon. Our results underline ice- covered and dark ecosystems as a hitherto overlooked oasis of microbial life and emphasize the need to study microbial communities in icy habitats.

Are Virtual Complementary and Integrative Therapies as Effective as In-Person Therapies? Examining Patient-Reported Outcomes Among Veterans with Chronic Musculoskeletal Pain.

Background: Virtual complementary and integrative health (CIH) therapy availability increased during the COVID-19 pandemic, but little is known about effectiveness. We examined the perceived effectiveness of in-person and virtual CIH therapies for patients with chronic musculoskeletal pain who recently started using CIH therapies. Methods: The sample included Veterans (n = 1,091) with chronic musculoskeletal pain, identified in the Veterans Health Administration's electronic health record based on initiation of CIH therapy use, who responded to VA's Patient Complementary and Integrative Health Therapy Experience Survey during March, 2021, to August, 2022. Using multivariable models with self-guided virtual (apps or videos) delivery as the reference, we compared patient-reported outcomes (pain, mental health, fatigue, and general well-being) associated with any yoga, Tai Chi/Qigong, or meditation use delivered: (1) only in-person, (2) only virtually with a live provider, (3) only virtually self-guided, (4) virtually self-guided + virtually provider-guided, or (5) hybrid in-person + virtual (self-or provider-guided). Results: Under 10% of Veterans reported only in-person use; 54% used only virtual formats and 36% a hybrid of in-person and virtual. Forty-one percent reported improvement in general well-being, 40.6% in mental health, 37.1% in pain, and 22.7% in fatigue. Compared with Veterans using only self-guided virtual CIH therapies, Veterans using only in-person therapies were more likely to report improvement in fatigue (odds ratio [OR]: 1.8, confidence interval [CI]: 1.1-3.1) and general well-being (OR: 1.7, CI: 1.0-2.6). Conclusions: Many patients perceived health improvements from CIH therapies, with in-person users reporting more improvement in fatigue and well-being than those using virtual sessions and similar improvements in pain and mental health for in-person and hybrid users.

Universal screening of colorectal tumors for lynch syndrome: a survey of patient experiences and opinions.

BACKGROUND: Lynch syndrome represents the most common hereditary cause of both colorectal and endometrial cancer. It is caused by defects in mismatch repair genes, as well as EPCAM. Universal screening of colon tumors for Lynch syndrome via microsatellite instability (MSI) and/or immunohistochemistry (IHC) can identify patients and families at risk to develop further cancers and potentially impact surveillance and treatment options. The approach to implementation of universal screening, taking ethical considerations into account, is critical to its effectiveness, with patient perspectives providing valuable insight. METHODS: Patients whose colon tumors underwent universal screening at Penn State Hershey Medical Center over a period of 2.5 years were mailed a survey on universal screening in 2017. Along with the survey, they received a recruitment letter and a summary explanation of research. The survey included both multiple choice and free-response questions that covered topics including respondent knowledge of Lynch syndrome, attitudes toward universal screening and experiences with the screening protocol as implemented. RESULTS: Sixty-six of 297 possible patients (22.2%) responded to the survey, including 13 whose screening results raised concern for Lynch syndrome. 75.8% of respondents supported universal tumor screening without informed consent. 92.4% preferred receiving screening results regardless of outcome. Respondents described benefits to screening for themselves and their families. CONCLUSIONS: While broadly supporting universal tumor screening without informed consent, respondents also wanted more information shared about the screening policy, as well as their results. These patient preferences should be one of many factors considered when implementing universal screening and can also inform practices regarding both tumor profiling and universal genetic testing, which is becoming more prevalent.

Global alpha power fluctuations in a self-caught mind-wandering paradigm are independent of arousal.

Mind-wandering is characterised as the emergence of thought and emotions which shift attention away from a primary task. It is thought to consume up to 50 % of our waking lives and has several negative implications. Breath-counting is one task that has been utilised in conjunction with electroencephalography (EEG) to examine the brain states associated with mind-wandering. Research has consistently found reductions in alpha oscillations during periods of mind-wandering relative to breath-focus. It is possible that such fluctuations reflect an arousal mechanism warranting further investigation. Thirty-seven participants completed a 15 min breath-counting task, with simultaneous recording of EEG and skin conductance level (SCL). During this task participants were required to self-identify periods of mind-wandering via button-press. Event-related spectral perturbation (ERSP) analysis was used to quantify changes in global alpha power (8-13 Hz) relative to the button press. The -8 to -4 s period prior to button-press was assessed as mind-wandering, and the 4 to 8 s period following the button-press as breath-focus. Relative to breath-focus, mind-wandering was associated with a significant decrease in global alpha power and significant increase in SCL, consistent with perceptual decoupling theory. However, changes in global alpha power and SCL did not correlate. These results suggest arousal is not the primary mechanism underlying alpha changes observed during breath-counting, thus additional processes should be considered.

Patient Perspectives on Evolving Diverticulitis Treatment: An Assessment of Patient Willingness to Enroll in a Randomized Controlled Trial.

Objective: The objective of the study was to assess patients' attitudes regarding participation in a randomized trial of antibiotics versus placebo for acute diverticulitis. Background: Despite evidence that antibiotics may not be necessary to treat acute uncomplicated diverticulitis, they remain the mainstay of treatment in the United States. A randomized trial in the United States evaluating antibiotic effectiveness could accelerate the implementation of antibiotic-free treatment, but providers maintain concerns that patients may be unwilling to participate. Methods: This mixed-methods study conducted semi-structured interviews of patients presenting to a quaternary care emergency department with acute diverticulitis and a web-based survey of a larger cohort. The interviews assessed patients' experiences with diverticulitis and perceptions of participation in a trial comparing antibiotics versus placebo. The survey quantified patients' willingness to participate in such a study and the relative importance of factors influencing the process. Results: Thirteen patients completed an interview. Reasons to participate included a desire to help others or contribute to scientific knowledge. Doubts about the efficacy of observation as a treatment method were the main barrier to participation. In a survey of 218 subjects, 62% of respondents reported willingness to participate in a randomized clinical trial. "What my doctor thinks," followed by "What I have experienced in the past" were the most important decision-making factors. Conclusion: Patients with acute uncomplicated diverticulitis maintain complex and varying perceptions of antibiotic use. Most surveyed patients would be willing to participate in a trial of antibiotics versus placebo. Our findings support the trial's feasibility and may facilitate an informed approach to recruitment and consent.

Multiancestry transferability of a polygenic risk score for diverticulitis.

OBJECTIVE: Polygenic risk scores (PRS) for diverticular disease must be evaluated in diverse cohorts. We sought to explore shared genetic predisposition across the phenome and to assess risk stratification in individuals genetically similar to European, African and Admixed-American reference samples. METHODS: A 44-variant PRS was applied to the All of Us Research Program. Phenome-wide association studies (PheWAS) identified conditions linked with heightened genetic susceptibility to diverticular disease. To evaluate the PRS in risk stratification, logistic regression models for symptomatic and for severe diverticulitis were compared with base models with covariates of age, sex, body mass index, smoking and principal components. Performance was assessed using area under the receiver operating characteristic curves (AUROC) and Nagelkerke's R2. RESULTS: The cohort comprised 181 719 individuals for PheWAS and 50 037 for risk modelling. PheWAS identified associations with diverticular disease, connective tissue disease and hernias. Across ancestry groups, one SD PRS increase was consistently associated with greater odds of severe (range of ORs (95% CI) 1.60 (1.27 to 2.02) to 1.86 (1.42 to 2.42)) and of symptomatic diverticulitis ((95% CI) 1.27 (1.10 to 1.46) to 1.66 (1.55 to 1.79)) relative to controls. European models achieved the highest AUROC and Nagelkerke's R2 (AUROC (95% CI) 0.78 (0.75 to 0.81); R2 0.25). The PRS provided a maximum R2 increase of 0.034 and modest AUROC improvement. CONCLUSION: Associations between a diverticular disease PRS and severe presentations persisted in diverse cohorts when controlling for known risk factors. Relative improvements in model performance were observed, but absolute change magnitudes were modest.

Alpha transcranial alternating current stimulation as add-on to neglect training: a randomized trial.

Visuospatial neglect is a common and debilitating condition following unilateral stroke, significantly impacting cognitive functioning and daily life. There is an urgent need for effective treatments that can provide clinically relevant and sustained benefits. In addition to traditional stroke treatment, non-invasive brain stimulation, such as transcranial alternating current stimulation, shows promise as a complementary approach to enhance stroke recovery. In the current study, we aimed to evaluate the additive effects of multi-session transcranial alternating current stimulation at alpha frequency when combined with visual scanning training in chronic stroke patients with visuospatial neglect. In this double-blind randomized controlled trial, we compared the effects of active transcranial alternating current stimulation at alpha frequency to sham (placebo) transcranial alternating current stimulation, both combined with visual scanning training. Both groups received eighteen 40-minute training sessions over a 6-week period. A total of 22 chronic visuospatial neglect patients participated in the study (active group n = 12, sham group n = 10). The median age was 61.0 years, with a median time since stroke of 36.1 months. We assessed the patients at six time-points: at baseline, after the first, ninth and eighteenth training sessions, as well as 1 week and 3 months following the completion of the combined neuromodulation intervention. The primary outcome measure was the change in performance on a visual search task, specifically the star cancellation task. Secondary outcomes included performance on a visual detection task, two line bisection tasks and three tasks evaluating visuospatial neglect in daily living. We found significantly improved visual search (primary outcome) and visual detection performance in the neglected side in the active transcranial alternating current stimulation group, compared to the sham transcranial alternating current stimulation group. We did not observe stimulation effects on line bisection performance nor in daily living. Time effects were observed on all but one outcome measures. Multi-session transcranial alternating current stimulation combined with visual scanning training may be a more effective treatment for chronic visuospatial neglect than visual scanning training alone. These findings provide valuable insights into novel strategies for stroke recovery, even long after the injury, with the aim of enhancing cognitive rehabilitation outcomes and improving the overall quality of life for individuals affected by this condition. Trial registration: ClinicalTrials.gov; registration number: NCT05466487; https://clinicaltrials.gov/ct2/show/NCT05466487.

Wastewater Surveillance for Influenza A Virus and H5 Subtype Concurrent with the Highly Pathogenic Avian Influenza A(H5N1) Virus Outbreak in Cattle and Poultry and Associated Human Cases - United States, May 12-July 13, 2024.

As part of the response to the highly pathogenic avian influenza A(H5N1) virus outbreak in U.S. cattle and poultry and the associated human cases, CDC and partners are monitoring influenza A virus levels and detection of the H5 subtype in wastewater. Among 48 states and the District of Columbia that performed influenza A testing of wastewater during May 12-July 13, 2024, a weekly average of 309 sites in 38 states had sufficient data for analysis, and 11 sites in four states reported high levels of influenza A virus. H5 subtype testing was conducted at 203 sites in 41 states, with H5 detections at 24 sites in nine states. For each detection or high level, CDC and state and local health departments evaluated data from other influenza surveillance systems and partnered with wastewater utilities and agriculture departments to investigate potential sources. Among the four states with high influenza A virus levels detected in wastewater, three states had corresponding evidence of human influenza activity from other influenza surveillance systems. Among the 24 sites with H5 detections, 15 identified animal sources within the sewershed or adjacent county, including eight milk-processing inputs. Data from these early investigations can help health officials optimize the use of wastewater surveillance during the upcoming respiratory illness season.

Systematic review with meta-analysis of the effectiveness of subcutaneous biologics versus intravenous biologics in inflammatory bowel diseases.

BACKGROUND: Biologic therapies are commonly used for inflammatory bowel disease (IBD) patients. Multiple biologic medicines can now be given both intravenously and subcutaneously. The different administration routes present provide different advantages regarding dose escalation, healthcare resource utilisation, pharmacokinetics, convenience and safety. Comparator effectiveness studies between intravenous and subcutaneous administration are lacking. AIM: Our primary outcome was to compare the effectiveness between intravenous and subcutaneous biologics in rates of clinical remission. METHODS: We performed a systematic review and meta-analysis to include all relevant articles from MEDLINE (Ovid), EMBASE, PubMed and Cochrane Central Register of Controlled Trials from 1 January 2003 to 28 January 2024. Studies that compared intravenous and subcutaneous administration of the same biologic therapy in IBD patients and reported effectiveness outcomes were included. This study was registered on PROSPERO (CRD42023442675). RESULTS: Twenty studies met the inclusion criteria for the systematic review. Nine vedolizumab cohort studies were meta-analysed for clinical remission and no difference was found in clinical remission rates between intravenous and subcutaneous administration (relative risk = 0.99; 95% confidence interval: 0.88, 1.11). Six infliximab cohort studies were meta-analysed for clinical remission and no difference was found in clinical remission rates between intravenous and subcutaneous administration (relative risk = 0.91; 95% confidence interval: 0.77, 1.08). CONCLUSIONS: Our findings in the first meta-analysis comparing the effectiveness of intravenous and subcutaneous biologic therapies in IBD suggest there is no difference in the effectiveness between these two administration routes. However, further high-quality studies, particularly head-to-head studies are needed to confirm this finding.

Equity in Heart Failure Care: A Get With the Guidelines Analysis of Between- and Within-Hospital Differences in Care by Sex, Race, Ethnicity, and Insurance.

BACKGROUND: Disparities in guideline-based quality measures likely contribute to differences in heart failure (HF) outcomes. We evaluated between- and within-hospital differences in the quality of care across sex, race, ethnicity, and insurance for patients hospitalized for HF. METHODS: This retrospective analysis included patients hospitalized for HF across 596 hospitals in the Get With the Guidelines-HF registry between 2016 and 2021. We evaluated performance across 7 measures stratified by patient sex, race, ethnicity, and insurance. We evaluated differences in performance with and without adjustment for the treating hospital. We also measured variation in hospital-specific disparities. RESULTS: Among 685 227 patients, the median patient age was 72 (interquartile range, 61-82) and 47.2% were women. Measure performance was significantly lower (worse) for women compared with men for all 7 measures before adjustment. For 4 of 7 measures, there were no significant sex-related differences after patient-level adjustment. For 20 of 25 other comparisons, racial and ethnic minorities and Medicaid/uninsured patients had similar or higher (better) adjusted measure performance compared with White and Medicare/privately insured patients, respectively. Angiotensin receptor neprilysin inhibitor measure performance was significantly lower for Asian, Hispanic, and Medicaid/uninsured patients, and cardiac resynchronization therapy implant/prescription was lower among women and Black patients after hospital adjustment, indicating within-hospital differences. There was hospital-level variation in these differences. For cardiac resynchronization therapy implantation/prescription, 278 hospitals (46.6%) had ≥2% lower implant/prescription for Black versus White patients compared with 109 hospitals (18.3%) with the same or higher cardiac resynchronization therapy implantation/prescription for Black patients. CONCLUSIONS: HF quality measure performance was equitable for most measures. There were within-hospital differences in angiotensin receptor neprilysin inhibitor and cardiac resynchronization therapy implant/prescription for historically marginalized groups. The magnitude of hospital-specific disparities varied across hospitals.

Anti-DEFA5 Monoclonal Antibody Clones 1A8 and 4F5 Immunoreactive Bioassay for Diagnosing Inflammatory Bowel Disease.

Background: Robust evidence suggests that the aberrant expression of α defensin 5 protein (DEFA5) in colon inflammatory bowel diseases (IBDs) underlies the distinct pathogenesis of Crohn's colitis, can be exploited as a reliable diagnostic biomarker to differential diagnosis of Crohn's colitis (CC) from Ulcerative colitis (UC) in otherwise indeterminate colitis (IC). We evaluated the specificity of the commercially available anti-DEFA5 antibodies and showed further validation of their appropriateness for a given application is required. Methods: We established two mouse monoclonal DEFA5 antibody clones 1A8 and 4F5 by immunizing the mice with purified recombinant protein and validated the specificity, selectivity and cross reactivity in recognizing the endogenous and recombinant DEFA5 protein, especially for Immunohistochemistry, Western blot, Immunoprecipitation, or enzyme-linked immunosorbent assay. Results: Clones 1A8 and 4F5 recognized effectively the endogenous DEFA5 in active human diverticulitis (DV), UC, CC or IC disease samples, including transiently transfected HEK293T cells expressing DEFA5 with high degree of specificity and minimal non-confounding cross reactivity. Conclusions: 1A8 and 4F5 clones are worth studying in larger IBD cohorts to fully address whether DEFA5 expression may be used as a diagnostic biomarker to discrimination of the diagnosis of UC from CC or IC into authentic CC or UC or a colitis with different pathological characteristics.

Age-Related Differences in Prestimulus EEG Affect ERPs and Behaviour in the Equiprobable Go/NoGo Task.

Detailed studies of the equiprobable auditory Go/NoGo task have allowed for the development of a sequential-processing model of the perceptual and cognitive processes involved. These processes are reflected in various components differentiating the Go and NoGo event-related potentials (ERPs). It has long been established that electroencephalography (EEG) changes through normal lifespan development. It is also known that ERPs and behaviour in the equiprobable auditory Go/NoGo task change from children to young adults, and again in older adults. Here, we provide a novel examination of links between in-task prestimulus EEG, poststimulus ERPs, and behaviour in three gender-matched groups: children (8-12 years), young adults (18-24 years), and older adults (59-74 years). We used a frequency Principal Component Analysis (f-PCA) to estimate prestimulus EEG components and a temporal Principal Component Analysis (t-PCA) to separately estimate poststimulus ERP Go and NoGo components in each age group to avoid misallocation of variance. The links between EEG components, ERP components, and behavioural measures differed markedly between the groups. The young adults performed best and accomplished this with the simplest EEG-ERP-behaviour brain dynamics pattern. The children performed worst, and this was reflected in the most complex brain dynamics pattern. The older adults showed some reduction in performance, reflected in an EEG-ERP-behaviour pattern with intermediate complexity between those of the children and young adults. These novel brain dynamics patterns hold promise for future developmental research.

Thrombolysis and Surgical Decompression for Venous Thoracic Outlet Syndrome.

INTRODUCTION: Treatment for venous thoracic outlet syndrome (vTOS) includes thrombolysis followed by decompressive rib resection. Given the rarity of the disease, the goal of this study was to describe current practices in treatment of vTOS. METHODS: All patients with diagnoses of subclavian vTOS who underwent rib resection in the 2018-2020 Nationwide Readmissions Database were included in this study. Patients were grouped based on number of days between thrombolysis and by number of hospitalizations: thrombolysis followed by surgery in the same hospitalization was considered "simultaneous" and in separate hospitalizations was "staged." RESULTS: Five hundred ninety patients met the inclusion criteria. The average age was 34.1 ± 13.3 y, and 42.9% (253 of 590) were female. Among the patients receiving thrombolysis and decompressive rib resection, 46.8% (164 of 350) patients had <14 d between interventions, 19.1% (67 of 350) patients had 14-30 d between interventions, and 34.0% (119 of 350) had >30 d between interventions. There were no significant differences in postoperative bleeding between patients with <14 d, 14-30 d, and >30 d between thrombolysis and surgery. In terms of number of hospital visits, 19.0% (112 of 590) had "simultaneous" thrombolysis and surgery and 40.5% (239 of 590) had thrombolysis and surgery in a "staged" approach. Forty point five percent (239 of 590) of patients received only surgical decompression without thrombolysis. CONCLUSIONS: Thrombolysis followed by first rib resection for vTOS can be performed during the same hospital admission without an associated risk of bleeding complications.

Oral Everolimus Following Dilation in Idiopathic Subglottic Stenosis: A Phase 1 Nonrandomized Clinical Trial.

Importance: Current medical therapies in idiopathic subglottic stenosis (iSGS) are insufficient in preventing the development and progression of scar tissue. An inhibitor of mammalian target of rapamycin, everolimus is an immunosuppressive medication shown to be effective in reducing fibrosis across a variety of fibroproliferative disorders, including preclinical models of iSGS. Objective: To evaluate the effect of oral everolimus on postoperative recurrence of stenosis in iSGS. Design, Setting, and Participants: This open-label, single-arm, phase 1, nonrandomized clinical trial analyzed 7 perimenopausal participants diagnosed with iSGS and followed-up at a tertiary care academic center for 6 months after dilation surgery. The trial was conducted from November 1, 2022, through May 15, 2024. Intervention: Participants took a 1.5-mg daily oral dose of everolimus for 42 days after surgery. Main outcomes and measures: The primary outcome measure was safety as determined by adverse events. Secondary outcome measures included change in peak expiratory flow from baseline through 180 days after surgery; change in the luminal area, measured by computed tomographic (CT) scan, from the 14th and the 180th day; and changes in quality-of-life scores. Results: Of the 8 perimenopausal participants, 7 (median age, 50 years [IQR, 45.0-52.5 years]) completed the study. Compared with baseline at all time points, there was an increase in peak expiratory flow. The median difference in liters per minute was 125 (95% CI, 90-270) on day 7 after surgery; 150 (95% CI, 110-290) on day 14; 138 (95% CI, 116-280) on day 28; 160 (95% CI, 100-270) on day 42; 155 (95% CI, 110-270) on day 60; 140 (95% CI, 100-270) on day 90; and 100 (95% CI, 20-240) on day 180. A decrease in the CT luminal area was observed from the day-14 measure to the day-180 measure (median stenosis, 7.2%; IQR, 1.9%-15.4%). During the trial, 1 participant (14.3%) each developed oral ulcers, a urinary tract infection, and a skin infection. Conclusions and Relevance: In this interventional nonrandomized clinical trial of iSGS, adjuvant everolimus was well-tolerated with minor adverse events. Participants sustained postdilation peak expiratory flow for 13 weeks. These results support proceeding to a phase 2 trial to study drug efficacy and a more detailed investigation of adverse effects. Trial Registration: ClinicalTrials.gov Identifier: NCT05153668.

Biochemical and Epigenetic Regulation of Glutamate Metabolism in Maize (Zea mays L.) Leaves under Salt Stress.

The effect of salt stress (150 mM NaCl) on the expression of genes, methylation of their promoters, and enzymatic activity of glutamate dehydrogenase (GDH), glutamate decarboxylase (GAD), and the 2-oxoglutarate (2-OG)-dehydrogenase (2-OGDH) complex was studied in maize (Zea mays L.). GDH activity increased continuously under salt stress, being 3-fold higher after 24 h. This was accompanied by the appearance of a second isoform with lower electrophoretic mobility. The expression of the Gdh1 gene strongly increased after 6-12 h of incubation, which corresponded to the demethylation of its promoter, while Gdh2 gene expression slightly increased after 2-6 h and then decreased. GAD activity gradually increased in the first 12 h, and then returned to the control level. This corresponded to the increase of Gad expression and its demethylation. Salt stress led to a 2-fold increase in the activity of 2-OGDH during the first 6 h of NaCl treatment, then the activity returned to the control level. Expression of the genes Ogdh1 and Ogdh3 peaked after 1-2 h of incubation. After 6-8 h with NaCl, the expression of these genes declined below the control levels, which correlated with the higher methylation of their promoters. We conclude that salt stress causes a redirection of the 2-OG flux to the γ-aminobutyric acid shunt via its amination to glutamate, by altering the expression of the Gdh1 and Gdh2 genes, which likely promotes the assembly of the native GDH molecule having a different subunit composition and greater affinity for 2-OG.

Longitudinal Multi-omic Immune Profiling Reveals Age-Related Immune Cell Dynamics in Healthy Adults.

The generation and maintenance of protective immunity is a dynamic interplay between host and environment that is impacted by age. Understanding fundamental changes in the healthy immune system that occur over a lifespan is critical in developing interventions for age-related susceptibility to infections and diseases. Here, we use multi-omic profiling (scRNA-seq, proteomics, flow cytometry) to examined human peripheral immunity in over 300 healthy adults, with 96 young and older adults followed over two years with yearly vaccination. The resulting resource includes scRNA-seq datasets of >16 million PBMCs, interrogating 71 immune cell subsets from our new Immune Health Atlas. This study allows unique insights into the composition and transcriptional state of immune cells at homeostasis, with vaccine perturbation, and across age. We find that T cells specifically accumulate age-related transcriptional changes more than other immune cells, independent from inflammation and chronic perturbation. Moreover, impaired memory B cell responses to vaccination are linked to a Th2-like state shift in older adults' memory CD4 T cells, revealing possible mechanisms of immune dysregulation during healthy human aging. This extensive resource is provided with a suite of exploration tools at https://apps.allenimmunology.org/aifi/insights/dynamics-imm-health-age/ to enhance data accessibility and further the understanding of immune health across age.