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Inborn errors of immunity (IEI) presenting with immunodeficiency and autoimmunity can illuminate pathways essential for immunocompetence and self-tolerance. We recently characterized a new IEI named MAGIS (“Midline malformations of the brain, Anterior pituitary gland dysfunction, Growth retardation, Immunodysregulation/Immunodeficiency, and Skeletal defects”) caused by heterozygous germline-activating mutations in GNAI2 (encoding the heterotrimeric G protein, Gαi2). This disorder demonstrates the central role of Gαi2 regulation of chemotaxis in humans and a novel pathway by which G proteins regulate T cell activation. Here, we review the clinical features, current genetic and biochemical understanding, and future therapeutic considerations for this new syndromic immune dysregulation disorder.

AimsThere are no standardized histologic criteria for diagnosing serrated epithelial change (SEC) in inflammatory bowel disease (IBD), but two commonly used definitions are currently in use. The first definition (DEF1) is a simpler definition but requires endoscopic correlation. It encompasses all endoscopically invisible or non‐targeted serrated lesions without morphologic evidence of dysplasia that do not meet the diagnostic criteria of sessile serrated lesion (SSL) or traditional serrated adenoma (TSA). In contrast, the second definition (DEF2) incorporates more complex morphologic criteria (i.e., disorganized crypt architecture with some crypts no longer perpendicular or extending down to the muscularis mucosae, irregular serration spanning the entire thickness of the mucosa, and goblet cell‐rich epithelium), but does not necessitate endoscopic correlation. The reproducibility of SEC diagnoses using these definitions among gastrointestinal (GI) pathologists has not yet been evaluated.Methods and resultsSeven GI pathologists independently evaluated 38 GI cases, including 21 digitally scanned biopsy slides and 17 previously published images, demonstrating various types of serrated changes and their morphologic mimics. The diagnostic categories included: (1) SEC, (2) hyperplastic polyp (HP), (3) SSL, (4) TSA, (5) hypermucinous dysplasia (HMD), and (6) no serrated change or dysplasia (NSD). All cases were selected by a single pathologist (WTC) who did not participate in the interobserver study. The pathologists initially assessed each case as if it were endoscopically normal and provided a diagnosis using DEF1. Next, they re‐evaluated each case, this time considering it as a nodular or polypoid lesion, and again made a diagnosis using DEF1. The same process was then repeated for each case but using DEF2. A total of 532 diagnoses were made for each definition (7 pathologists × 38 cases × 2 endoscopic appearances). Fleiss' kappa statistics were used to assess the level of agreement among the seven pathologists. The total number of SEC diagnoses using DEF1 (n = 110 of 532) was more than twice that of DEF2 (n = 50 of 532). Also, the number of SEC diagnoses per pathologist was higher using DEF1 (mean: 16, range: 12–18) compared to DEF2 (mean: 7, range: 0–14). Furthermore, the instances where four or more pathologists agreed on the diagnosis of SEC were more frequent with DEF1 (16 of 38 cases) than with DEF2 (1 of 38 cases). The overall agreement in diagnosing SEC (vs. no SEC) using DEF1 was substantial (k = 0.69, P < 0.001), whereas the agreement using DEF2 was only slight (k = 0.18, P < 0.001). Among potential SEC mimics, there was substantial agreement in diagnosing HP (k = 0.69 using DEF1), SSL (k = 0.68), TSA (k = 1.00), HMD (k = 0.79), and NSD (k = 0.61) (P < 0.001).ConclusionsThe diagnosis of SEC using DEF1 is significantly more reproducible than using DEF2. Utilizing DEF1 is also less likely to miss potentially important cases of SEC. Therefore, DEF1 could be adopted to separate SEC from other serrated lesions and morphologic mimics in IBD.

Abstract Dementia with Lewy bodies (DLB), a progressive neurodegenerative disease with heterogeneous clinical presentations, greatly impacts patients, caregivers, and society. Despite its frequency, diagnosing and treating DLB remains challenging. Advances in in vivo biomarker assays reflecting underlying pathology are improving disease identification, diagnostic accuracy, and therapeutic development for biologically targeted, disease‐modifying agents. Consequently, definitions of Alzheimer's disease and Parkinson's disease (PD) have shifted to focus on pathological changes occurring before clinical features, with proposed frameworks for detecting pathological amyloid and tau, neurodegeneration, and other markers (National Institute on Aging‐Alzheimer's Association) and alpha‐synucleinopathy and dopaminergic degeneration (Neuronal α‐synuclein Disease Integrated Staging System, SynNeurGe). The biological frameworks, particularly those related to alpha‐synuclein (α‐synuclein), have sparked debate about unifying DLB and PD under a single pathobiologic disease. This paper discusses the implications of these biological frameworks for the DLB community, addressing topics regarding multiple pathologies and neurochemical systems, clinical heterogeneity, and functional impairment, and exploring the potential impact on clinical trials and care. Highlights DLB is a progressive neurodegenerative disease with varied clinical presentations. Diagnosing and treating DLB remains challenging despite its frequency. Biological frameworks are reshaping Alzheimer's and Parkinson's definitions. In vivo biomarkers are improving DLB identification and diagnostic accuracy. Debate exists regarding unifying DLB and Parkinson's under one pathobiology.

Abstract Background Indigenous populations worldwide experience unjust inequities in surgical outcomes. In Aotearoa New Zealand, Indigenous Māori experience poorer health outcomes, including higher rates of postoperative mortality. The aim of this study was to quantify ethnic disparities in ‘failure to rescue’ (FTR), complications, and mortality following gastrointestinal cancer surgery and to analyse trends over time. Methods A retrospective national population-based cohort study of patients undergoing resection for gastrointestinal and hepatopancreatobiliary cancers from 2005 to 2020 was conducted. Self-reported ethnicity data were collected at the time of surgery. The primary outcome was FTR, defined as mortality following a complication within 90 days of surgery. Results In total, 31 185 patients were included; 2479 (7.9%) were Māori, 46.5% were female, and the median age was 71 (interquartile range 62–78) years. Māori patients were younger and had higher levels of socio-economic deprivation and co-morbidity. Māori had higher age-standardized rates of mortality (5.9% versus 3.2%), complications (52.9% versus 42.4%), and FTR (10.8% versus 7.2%), compared with European/Other. Multivariable regression demonstrated higher odds of mortality (adjusted OR (aOR) 1.45 (95% c.i. 1.15–1.82)), complications (aOR 1.30 (95% c.i. 1.17–1.45)), and FTR (aOR 1.29 (95% c.i. 1.01–1.62)) for Māori. Analysis over time showed a significant improvement in risk-adjusted rates of mortality (6.2% in 2005–2008 versus 3.4% in 2017–2020) and FTR (7.3% in 2005–2008 versus 4.0% in 2017–2020) for European/Other, but no change for Māori (rates of mortality were 6.6% in 2005–2008 versus 5.4% in 2017–2020 and rates of FTR were 7.8% in 2005–2008 versus 6.3% in 2017–2020). Conclusion Widening inequities in FTR have worsened disparities in postoperative mortality for Māori patients. ‘Complication rescue’ is a target to reduce inequities and improve perioperative care for Māori patients.

Background and importance Rapid sequence intubation in emergency settings may involve opioid pretreatment to blunt hemodynamic responses during laryngoscopy and intubation; however, opioids may lead to postintubation hypotension, increasing morbidity and mortality. Global clinical practice varies significantly, reflecting uncertainty about opioids’ benefits and risks. Objective Our goal was to evaluate the association between opioid pretreatment and hemodynamic instability, focusing on postintubation hypotension in adult patients undergoing emergency intubation. Design, settings, and participants We performed a systematic review of randomized controlled trials and observational studies comparing opioid administration vs. no opioids before adult emergency intubations. Searches included Cochrane, Embase, Medline, Scopus, and Web of Science databases until November 2024. Elective intubations were excluded. Eight (6708 patients) studies met criteria. Outcomes measure and analysis The primary outcome was postintubation hypotension, variably defined across studies. Secondary outcomes included hypoxemia, first-attempt success, cardiac arrest, and vasopressor use. Independent reviewers conducted data extraction, risk-of-bias assessments, and certainty evaluation. Results were qualitatively synthesized. Main results Among 6708 (2757 opioids and 3951 controls) patients, postintubation hypotension incidence varied widely (risk differences: −12.5% favoring opioids to +13.2% favoring controls). The single low-risk randomized study reported opioids increased hypotension (risk difference: 13%, odds ratio: 2.15, 95% confidence interval: 1.22–3.78). Observational studies yielded inconsistent results. Secondary outcomes showed no consistent differences. Evidence certainty was very low because of risk of bias, inconsistency, and imprecision. Conclusions Current evidence regarding opioid pretreatment effect on postintubation hypotension risk during emergency intubation is limited and conflicting.

AimsThere is a lack of published literature on the diagnostic reproducibility of oesophageal squamous dysplasia using a two‐tiered grading system.Methods and resultsWe identified 75 oesophageal biopsies, which were reviewed by 10 international pathologists twice (1500 total observations) with a > 4‐week washout period. Between rounds, a consensus meeting refining diagnostic criteria was held and an atlas was created to provide illustrations. Overall agreement was fair with kappa of 0.35 and 0.32 in round 1 and 2, respectively. Agreement was moderate to fair for negative for dysplasia (ND) (round 1 = 0.41 and round 2 = 0.34) and poor for indefinite for dysplasia (IND) and low‐grade dysplasia (LGD) (kappa <0.2). Agreement for high‐grade dysplasia (HGD) was good in both rounds (round 1 = 0.64; round 2 = 0.61). In round 1, majority diagnosis (MDx, ≥6 of 10 raters agreeing) was seen in 51 (68%) cases with the majority classified as ND (N = 27) or HGD (N = 18). MDx was rarely achieved for LGD (N = 6). In round 2, MDx was seen in 49 (65%) cases (20 ND, 1 IND, 11 LGD and 17 HGD). Of the 40 cases with MDx for both rounds, 39 were concordant (15 HGD, 6 LGD and 18 ND).ConclusionsOverall agreement among pathologists in diagnosing squamous lesions is fair; however, HGD had good agreement. This study fills an important gap in our knowledge of the inter‐rater variability in the diagnosis of oesophageal squamous dysplasia.

Abstract Introduction As the field of sexual medicine continues to grow, there has been increasing attention on methodological integrity and rigor of sexual medicine research, including an emphasis on guidelines for quantitative research design and standards for assessing clinical trial outcomes. However, qualitative research (QR) methodology has garnered relatively scant attention in comparison. Objectives To clarify the value of QR and provide recommendations for improving implementation of QR methods in sexual medicine research. Methods A PubMed review was conducted. Expert opinion was based on a process of literature review and expert consensus. Results An essential goal of QR is to describe and explain unknown or insufficiently understood phenomena through detailed investigation of subjective human experience. Results from QR allow for generating hypotheses that may then be tested. More recently, mixed-methods research, ie, research integrating both qualitative and quantitative methods, is being increasingly used across domains of biomedical and health science research. While there remain differences of opinion regarding use of qualitative methodology in sexual medicine, best-practice models of QR underscore the principle of trustworthiness and include ethics and transparency in protocols for data collection and analysis. It is recommended that established QR frameworks for developing a research question are utilized and that consolidated criteria for reporting research results are employed. Furthermore, authors and reviewers need training in both QR methods and qualitative reporting frameworks to be able to adequately report and review this type of research. Specific areas in sexual medicine that would ideally benefit from QR methods are suggested. Conclusion As the field of sexual medicine continues to expand, qualitative methodologies including mixed-methods research, offer significant value for understanding domains of inquiry that have not been thoroughly investigated. To achieve these targets, training of authors and reviewers on QR is needed.

INTRODUCTION: The increased likelihood of adverse cardiovascular events (CVE) shortly after awakening has been partially attributed to low nitric oxide (NO) production in the early morning. Thus, increasing early morning NO levels to improve vascular function could reduce adverse CVE incidence, especially among older adults as total NO production declines with aging. The increased adverse CVE among post-menopausal women (PMW) are likely due to a steeper decline in their vascular function. As inorganic nitrate increases circulating NO levels for up to 12hrs, our primary hypothesis was to determine if nocturnal inorganic nitrate supplementation improves early morning vascular function relative to a placebo in eight generally healthy adults (6F, 37±5yrs, 26.9±1.8kg/m 2 ). Our secondary hypothesis was that PMW (n=3, 27.1±4.3kg/m 2 ), identified by their age (71±2yrs) and follicle-stimulating hormone levels (72.3±8.0mIU/mL), would show greater improvements in their vascular function compared to younger participants (n=5, 3F, 28±2yrs, 26.8±2.0kg/m 2 ). METHODS: Written informed consent was obtained from all participants before data collection. Participants completed three overnight study visits: Visit 1 was for acclimation with vascular function assessments occurring during Visits 2 and 3. During the latter visits, participants consumed beetroot juice with (6.45mmol) or devoid of (0mmol) inorganic nitrate at 2200 in randomized, cross-over fashion followed by vascular function assessments post-awakening (0630-0800) while participants were supine. Vascular assessments consisted of brachial blood pressure, aortic augmentation index (AIx), carotid-femoral pulse wave velocity (cfPWV), and endothelial function (FMD). Data were compared using a paired-samples t-test (α<0.05). RESULTS: Systolic (125±4 vs. 126±6mmHg, p=0.35) and diastolic (71±2 vs. 72±2mmHg, p=0.32) blood pressure were similar the morning after nitrate and placebo. Additionally, AIx (31±5 vs. 33±6%, p=0.29) and FMD (n=7, 8.8±2.0 vs. 7.6±1.7%, p=0.25) were not different the morning after nitrate and placebo consumption. However, cfPWV was lower the morning following nitrate consumption relative to the placebo (6.3±0.5 vs. 6.9±0.6m/s, p=0.01). A sub-group analysis of PMW showed that both systolic (132±6 vs. 139±9mmHg, p=0.18) and diastolic (70±3 vs. 75±2mmHg, p=0.09) blood pressure tended to be lower following nitrate relative to the placebo whereas AIx (46±1 vs. 50±5%, p=0.31) and FMD (n=2, 8.5±2.7 vs. 6.9±1.6%, p=0.78) did not differ; however, cfPWV was lower the morning after nitrate consumption (7.4±0.9 vs. 8.4±1.1m/s, p=0.02) in PMW but not in the younger participants (5.6±0.4 vs. 6.0±0.3m/s, p=0.23). CONCLUSION: Acute nocturnal inorganic nitrate supplementation lowers aortic stiffness in the early morning, especially among PMW. Although the differences in systolic (7mmHg) and diastolic blood pressure (5mmHg) were not statistically significant, they remain clinically meaningful due to their magnitude. This may suggest a role for nocturnal nitrate supplementation in reducing early-morning adverse CVE among PMW. AHA 24POST1241616 (IMG), NIH K12 AR084222 (JMB), Sleep Research Society 038-JP-23 (JMB), and a grant from Sleep Number Corporation to Mayo Clinic for studies in Aging. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Tandem exposure to cannabinoids and nicotine during pregnancy poses significant risks to fetal development and health including low birth weight, preterm birth, and perinatal death. However, the effect of co-exposure with the most prominent cannabinoids found in Cannabis sativa (Trans-Δ-9- tetrahydrocannabinol (THC) and cannabidiol (CBD)) alongside nicotine on fetal lung development is not well understood. This study aims to investigate the combinatorial impact of CBD, THC, and nicotine, on human lung development through investigating cellular senescence and the potential role of senolytics in alleviating these effects. Human fetal lung explants from 10 to 16 weeks gestation were cultured on air-liquid interface and treated with various concentrations of nicotine (1µM), CBD, and THC (5µM, or 2.5µM each when used in combination), for 72 hours. To assess the effect of senolytics, the explants were also treated for 48 hours with a combination of CBD, THC, and nicotine. Subsequently, senolytics, Dasatinib (D, 250nM) and Quercetin (Q, 375nM), were added or not for an additional 24 hours. After the 72-hour treatment, explants were collected and either fixed for immunofluorescence staining (IF) analyses or used for RNA extraction and quantitative reverse transcription PCR (qRT-PCR). Additionally, the supernatants were used to evaluate the expression of the senescence-associated secretory phenotype (SASP), conducted by Eve Technologies Corporation-Canada. This study used Luminex xMAP technology for multiplexed quantification of 96 Human cytokines, chemokines, and growth factors. Our results demonstrated that co-exposure to CBD, THC, and nicotine increases the expression of the senescence markers CDKN1A (0.1163±0.02384, p=0.0094, n=8) and CDKN2A (0.005793±0.002157, p=0.0516, n=8) encoding P21 and P16 respectively. Moreover, the IF staining showed increased expression of the DNA damage marker γH2A.X following treatment with CBD+THC+nicotine (7.375±2.154% vs 2.245±0.8329%, p=0.0604, n=6). Furthermore, the lung explants treated with cannabinoids and nicotine released cytokines and chemokines involved in immune responses and inflammation among others IL-6, IL-8, M-CSF, MCP-3, MIP-1β, TNFα, MIP-3β, and TSLP (p<0.05). The addition of D+Q reduced SASP secretion and showed a decreasing trend in expression of the senescence genes CDKN1A and CDKN2A compared to the triple treatment. Taken together, our results showed that the combinatorial exposure to CBD, THC, and nicotine increases senescence, DNA damage, and the senescence-associated secretory phenotypes (SASP) secretion. The use of senolytics (D+Q) may prove to be a promising therapeutic option, alleviating several of the negative effects induced by the different substances. RO1HL171915-01A1 RO!HL155104 RO1HL158532-03 ROIHL160570 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.