Brainstem Anesthesia During Retrobulbar Block: An Eye-Opener Clinical Case.

The use of a retrobulbar anesthetic block for surgery of the posterior chamber is a common, effective, and safe practice, although not without risks. This clinical case aims to describe one of the most feared complications of this ophthalmic block, which demands a high degree of suspicion and agility for proper diagnosis and management. A 91-year-old female patient, physical status ASA III, presents for vitrectomy via pars plana of the left eye due to retinal detachment. Light sedoanalgesia was performed, as well as a left retrobulbar block with 5 mL of local anesthetic. Approximately two minutes after the injection of the local anesthetic, she developed a sudden clinical decline of consciousness, accompanied by bilateral photoplegic mydriasis, sinus tachycardia, and hypertension, followed by central apnea. Orotracheal intubation and connection to a ventilatory prosthesis were performed, maintaining adequate oxygenation, ventilation, and hemodynamic stability. No abnormal findings were found in complementary diagnostic methods. The condition progressively reversed, with a gradual return to the initial state of consciousness, and it was possible to successfully extubate the patient after four hours. The patient remained stable, under surveillance, and was discharged home after 48 hours with no neurological impairment or ophthalmological complications. The clinical findings are compatible with brainstem anesthesia, explained by the dispersion of the local anesthetic into the subarachnoid space, through an inadvertent puncture of the ophthalmic artery or the meninges that involve the optic nerve. Although this event is a rare complication, a low threshold of suspicion should be maintained, given the potential severity of the clinical condition. Early recognition should be followed by a systematic A-B-C-D-E approach, and the outcomes are often favorable. Careful surveillance and monitoring should accompany the performance of ophthalmic surgical procedures, and the presence of an anesthesiologist is essential for the quality of the services provided and patient safety.

Broadening the clinical spectrum of giant cell arteritis: from the classic cranial to the predominantly extracranial pattern of the disease.

INTRODUCTION: Giant cell arteritis (GCA) is a large vessel (LV) vasculitis that affects people aged 50 years and older. Classically, GCA was considered a disease that involved branches of the carotid artery. However, the advent of new imaging techniques has allowed us to reconsider the clinical spectrum of this vasculitis. AREASCOVERED: This review describes clinical differences between patients with the cranial GCA and those with a predominantly extracranial LV-GCA disease pattern. It highlights differences in the frequency of positive temporal artery biopsy depending on the predominant disease pattern and emphasizes the relevance of imaging techniques to identify patients with LV-GCA without cranial ischemic manifestations. The review shows that so far there are no well-established differences in genetic predisposition to GCA regardless of the predominant phenotype. EXPERT COMMENTARY: The large branches of the extracranial arteries are frequently affected in GCA. Imaging techniques are useful to identify the presence of 'silent' GCA in people presenting with polymyalgia rheumatica or with nonspecific manifestations. Whether these two different clinical presentations of GCA constitute a continuum in the clinical spectrum of the disease or whether they may be related but are definitely different conditions needs to be further investigated.

Enhancing HIV positivity yield in southern Mozambique: The effect of a Ministry of Health training module in targeted provider-initiated testing and counselling.

In Mozambique, targeted provider-initiated HIV testing and counselling (PITC) is recommended where universal PITC is not feasible, but its effectiveness depends on healthcare providers' training. This study aimed to evaluate the effect of a Ministry of Health training module in targeted PITC on the HIV positivity yield, and identify factors associated with a positive HIV test. We conducted a single-group pre-post study between November 2018 and November 2019 in the triage and emergency departments of four healthcare facilities in Manhiça District, a resource-constrained semi-rural area. It consisted of two two-month phases split by a one-week targeted PITC training module ("observation phases"). The HIV positivity yield of targeted PITC was estimated as the proportion of HIV-positive individuals among those recommended for HIV testing by the provider. Additionally, we extracted aggregated health information system data over the four months preceding and following the observation phases to compare yield in real-world conditions ("routine phases"). Logistic regression analysis from observation phase data was conducted to identify factors associated with a positive HIV test. Among the 7,102 participants in the pre- and post-training observation phases (58.5% and 41.5% respectively), 68% were women, and 96% were recruited at triage. In the routine phases with 33,261 individuals (45.8% pre, 54.2% post), 64% were women, and 84% were seen at triage. While HIV positivity yield between pre- and post-training observation phases was similar (10.9% (269/2470) and 11.1% (207/1865), respectively), we observed an increase in yield in the post-training routine phase for women in triage, rising from 4.8% (74/1553) to 7.3% (61/831) (Yield ratio = 1.54; 95%CI: 1.11-2.14). Age (25-49 years) (OR = 2.43; 95%CI: 1.37-4.33), working in industry/mining (OR = 4.94; 95%CI: 2.17-11.23), unawareness of partner's HIV status (OR = 2.50; 95%CI: 1.91-3.27), and visiting a healer (OR = 1.74; 95%CI: 1.03-2.93) were factors associated with a positive HIV test. Including these factors in the targeted PITC algorithm could have increased new HIV diagnoses by 2.6%. In conclusion, providing refresher training and adapting the current targeted PITC algorithm through further research can help reach undiagnosed PLHIV, treat all, and ultimately eliminate HIV, especially in resource-limited rural areas.

Tubulo-interstitial inflammation increases the risk of graft loss after the recurrence of IgA nephropathy.

Background: Immunoglobulin A nephropathy (IgAN) is the most frequent recurrent disease in kidney transplant recipients and its recurrence contributes to reducing graft survival. Several variables at the time of recurrence have been associated with a higher risk of graft loss. The presence of clinical or subclinical inflammation has been associated with a higher risk of kidney graft loss, but it is not precisely known how it influences the outcome of patients with recurrent IgAN. Methods: We performed a multicentre retrospective study including kidney transplant recipients with biopsy-proven recurrence of IgAN in which Banff and Oxford classification scores were available. 'Tubulo-interstitial inflammation' (TII) was defined when 't' or 'i' were ≥2. The main endpoint was progression to chronic kidney disease (CKD) stage 5 or to death censored-graft loss (CKD5/DCGL). Results: A total of 119 kidney transplant recipients with IgAN recurrence were included and 23 of them showed TII. Median follow-up was 102.9 months and 39 (32.8%) patients reached CKD5/DCGL. TII related to a higher risk of CKD5/DCGL (3 years 18.0% vs 45.3%, log-rank 7.588, P = .006). After multivariate analysis, TII remained related to the risk of CKD5/DCGL (HR 2.344, 95% CI 1.119-4.910, P = .024) independently of other histologic and clinical variables. Conclusions: In kidney transplant recipients with IgAN recurrence, TII contributes to increasing the risk of CKD5/DCGL independently of previously well-known variables. We suggest adding TII along with the Oxford classification to the clinical variables to identify recurrent IgAN patients at increased risk of graft loss who might benefit from intensified immunosuppression or specific IgAN therapies.

Positron Emission Computed Tomography Spectrum of Large Vessel Vasculitis in a Tertiary Center: Differences in 18F-fluorodeoxyglucose Uptake between Large Vessel Vasculitis with Predominant Cranial and Extracranial Giant Cell Arteritis Phenotypes.

(1) Objective:To assess the spectrum of PET-CT-related large vessel vasculitis (LVV) in a Spanish tertiary center and to determine whether FDG uptake by PET-CT differs between giant cell arteritis (GCA) with predominant cranial or extracranial phenotypes. (2) Methods: The spectrum of patients diagnosed with LVV by PET-CT in a tertiary referral hospital that cares for 450,000 people over a period of two years was reviewed. Moreover, differences in FDG uptake between LVV-GCA with predominantly cranial and extracranial phenotype were analyzed. (3) Results: Eighty patients were diagnosed with LVV by PET-CT. Most were due to systemic vasculitis (n = 64; 80%), especially GCA (n = 54; 67.5%). Other conditions included the presence of rheumatic diseases (n = 4; 3.2%), tumors (n = 9; 7.2%) and infections (n = 3; 2.4%). LVV-GCA patients with predominant extracranial GCA phenotype were younger (mean ± SD: 68.07 ± 9.91 vs. 75.46 ± 7.64 years; p = 0.017) and had a longer delay to the diagnosis (median [interquartile range] 12 [4-18] vs. 4 [3-8]; p = 0.006), but had polymyalgia rheumatica symptoms more frequently than those with predominantly cranial GCA phenotype (46.3% vs. 15.4%, p = 0.057). When FDG uptake was compared according to the two different disease patterns, no statistically significant differences were observed. However, patients with extracranial LVV-GCA showed a non-significantly higher frequency of vasculitic involvement of lower-extremity arteries. (4) Conclusions: Regardless of the predominant phenotype, LVV identified by PET-CT is more commonly due to GCA in the Spanish population. In these GCA patients, younger age, PMR, and a higher frequency of lower-extremity artery vasculitis suggest the presence of LVV.

A Simple, Safe, and Effective Method for Preparing Autologous Bio-Based Fibrin Glue for Ophthalmic Use.

This study proposes a method to prepare autologous bio-based fibrin glue (FG) for use in ophthalmic surgery. FGs containing three fibrinogen concentrations and a thrombin concentrate were prepared using human blood from five donors (FG1: physiological fibrinogen concentration; FG2 and FG3: concentrated fibrinogen). The adhesion strength was tested, and the clinical safety and efficacy were studied in rabbit eyes in conjunctival surgery. A commercial FG was used as a control. From each donor, 2 mL of FG was prepared, containing 1 mL of 3.49 ± 0.78 (FG1), 17.74 ± 4.66 (FG2), or 47.46 ± 9.36 mg/mL (FG3) of fibrinogen and 1 mL of 2248.12 ± 604.20 UI/mL of thrombin. The average adhesion strength increased with the fibrinogen concentration, from 1.49 ± 0.39 kPa (FG1) to 3.14 ± 1.09 kPa (FG3). FG1 showed poor results when used for autograft adhesion. In contrast, the conjunctival autografts were successfully grafted using FG2 and FG3, revealing equivalent adhesion properties compared with commercial FG, but with less inflammation. In conclusion, FGs could be prepared on demand within minutes from small volumes of human blood, using a method that results in FGs which exhibit good adhesion capacity and are also safe and effective in a preclinical study.

Translation of a tissue epigenetic signature to circulating free DNA suggests BCAT1 as a potential noninvasive diagnostic biomarker for lung cancer.

Lung cancer patients are diagnosed at late stages when curative treatments are no longer possible; thus, molecular biomarkers for noninvasive detection are urgently needed. In this sense, we previously identified and validated an epigenetic 4-gene signature that yielded a high diagnostic performance in tissue and invasive pulmonary fluids. We analyzed DNA methylation levels using the ultrasensitive digital droplet PCR in noninvasive samples in a cohort of 83 patients. We demonstrated that BCAT1 is the candidate that achieves high diagnostic efficacy in circulating DNA derived from plasma (area under the curve: 0.85). Impact of potentially confounding variables was also explored.

Cardio-renal benefits of sacubitril/valsartan in patients with advanced chronic kidney disease: experience in daily clinical practice.

BACKGROUND: The association between cardiac complications, such as heart failure (HF), and chronic kidney disease (CKD) is well known. In this study, we examined the effectiveness and safety of treatment with neprilysin inhibition in patients with advanced chronic kidney disease (stage 3b-4). METHODS: This single-centre, longitudinal, retrospective study of 31 months duration involved consecutive patients with CKD and HF with a reduced ejection fraction (HFrEF) who started treatment with sacubitril/valsartan. Glomerular filtration rate (GFR), cardiovascular risk factors, proteinuria, potassium, echocardiographic parameters and admissions for heart failure were analysed. RESULTS: The study comprised 25 patients with a median age of 73.2 ± 5.9 years. The most frequent aetiology of heart failure was ischemic heart disease. The median GFR was 29.4 ± 8.3 ml/min/1.73 m2 and the left ventricular ejection fraction (LVEF) 36.4 ± 8.9%. The GFR improved after initiating the treatment (F = 3.396, p = 0.019), as did the LVEF at one year of follow-up (p = 0.018). The number of visits to the emergency department for heart failure was also reduced. No patients needed to start renal replacement therapy. CONCLUSIONS: This study shows that sacubitril/valsartan may play a beneficial role in patients who have advanced CKD and HFrEF, with a satisfactory safety profile.

Analysis of Septin 9 Gene Hypermethylation as Follow-Up Biomarker of Colorectal Cancer Patients after Curative Surgery.

BACKGROUND: The Septin 9 test analyzes the methylation status of the SEPT9 gene, which appears to be hypermethylated in patients with colorectal cancer (CRC). This has been validated as a colorectal cancer screening test. Due to the high sensitivity and specificity found, the justification was to use it as a biomarker tool for monitoring minimal residual disease after radical surgery and recurrence. METHODS: A prospective study was carried out at the Fundación Jiménez Díaz University Hospital extracting peripheral blood from 28 patients and 4 healthy donors. Free circulating DNA was obtained and subsequently a PCR reaction to quantify the number of methylated genes. Samples were obtained preoperatively and postoperatively at five to seven days, one and three months after surgery. RESULTS: A total of 32 preoperative samples were analyzed. The sensitivity of the test to detect CRC was 55.6% and specificity was 100%. There were 22 postsurgical samples obtained at 5-7 days after surgery, the sensitivity to detect tumor recurrences was 100% and specificity was 75%. There were 21 samples analyzed 1 month after surgery exhibiting a sensitivity and specificity of 100% and 94.7%, respectively. At 3 months, 31 postsurgical samples were analyzed and the sensitivity and specificity were 66.7% and 80%. CONCLUSIONS: Detection of methylation of Septin 9 gene in circulating plasma DNA, obtained from a peripheral blood sample, may be a useful, non-invasive and effective method for detecting minimal residual disease and could therefore predict CRC tumor recurrences. The optimal time in our series to obtain the best prediction results based on Septin 9 methylation levels was one month after surgery. Despite these considerable findings, a study with more patients is necessary to obtain more robust conclusions.

How to strengthen the management of acute diverticulitis: the utility of the WSES classification-a prospective single-center observational study.

PURPOSE: This study aimed to validate the World Society for Emergent Surgery (WSES) scale for the management of acute left-sided colonic diverticulitis (ALCD). METHODS: An observational study based on a prospective database of patients with ultrasound (US) and computerized tomography (CT) confirmed ALCD was conducted at our center from April 2018 to May 2019. The primary outcome was the success rate of outpatient management. Secondary outcomes were the association between different WSES stages, clinical and analytical parameters, treatments modalities, and outcomes, and the accuracy of US for management decisions. RESULTS: A total of 230 patients were included. Outpatient management was successful in 51/53 (96.23%) cases with ALCD stage 0 and 62/72 (86.11%) patients with stage 1A. There were no differences in age (p = 0.076) or the presence of pericolic air bubbles (p = 0.06) between patients who underwent admission or outpatient management. Clinical and analytical data, treatment decisions, and outcomes showed statistically significant differences between WSES stages. In 7/12 patients with stage 2A, percutaneous drainage or emergency surgery was required. All cases with stage 2B (distant air) underwent conservative management without the need for emergency or elective surgery. The accuracy of US WSES stages for management decisions, when compared with CT, was 96.96%. CONCLUSION: The WSES classification for ALCD seemed to be valid helping clinicians in the decision-making process to select between admission or outpatient management. Differences in clinical and analytical data, elected treatments, and outcomes were found between WSES stages. The US WSES stages showed high accuracy for management decisions.

When the Donor Surprises You: A Case Report.

The possibility of transplanting a graft from a cadaveric donor with unknown membranous nephropathy (MN) has been described in the literature. We present the case of 2 patients who received their first kidney transplant (KT) from a 27-year-old male donor with no relevant medical history. The first recipient was a 50-year-old man with stage 5 chronic kidney disease secondary to diabetic kidney disease. Two biopsies were performed; the first was performed on day +9 because of impaired renal function coinciding with high levels of tacrolimus, and vacuolization of the arteriolar walls was observed with no other findings; the second was performed on day +13 because of creatinine stagnation, and methenamine silver staining showed multiple cavities and isolated spikes. Immunofluorescence revealed contiguous granular positivity in capillary walls for IgG and C4d, and immunohistochemistry showed contiguous parietal positivity for IgG4, compatible with donor membranous glomerulopathy. Anti-phospholipase-2 receptor (PLA2R) antibodies were negative. The second-year biopsy showed persistence of stage 1 MN, without proteinuria. The second recipient was a 38-year-old man with hypertension and unknown stage 5 chronic kidney disease who experienced immediate kidney function post-KT. In the protocol kidney biopsy 3 months post-KT, data consistent with stage 1 membranous glomerulopathy were also observed. Anti-PLA2R antibodies were negative, and proteinuria did not increase. The second-year protocol biopsy showed no MN data.

Decrease in CD14++CD16+ Monocytes in Low-Immunological-Risk Kidney Transplant Patients with Subclinical Borderline Inflammation.

We determined the association between CD14++CD16+ monocytes and subclinical infiltrates that do not reach the histological threshold for rejection (≥Banff IA). We studied low-immunological-risk kidney-transplant recipients in a clinical trial (NCT02284464; EudraCT 2012-003298-24) whose protocol biopsy in the third month showed no significant changes or borderline lesions (BL). Flow cytometry was used to analyze the percentage of CD14++CD16+ monocytes in peripheral blood (PB) and blood from a fine-needle-aspiration biopsy (FNAB). A protocol biopsy was performed in 81 low-immunological-risk patients, of whom 15 were excluded (BK polyomavirus and rejection). The 28 (42.4%) with borderline lesions had significantly low levels of CD14++CD16+ in PB compared to patients with normal biopsies (7.9 ± 5.4 vs. 13.0 ± 12.8; p = 0.047). Patients without significant changes had similar percentages of CD14++CD16+ monocytes in the graft blood (GB) and FNAB blood. The percentage of these monocytes in the patients with an interstitial infiltrate, however, increased significantly in the FNAB blood compared to the GB: 16.9 ± 16.6 vs. 7.9 ± 5.4; p = 0.006. A difference of 50% in CD14++CD16+ in the GB versus the PB was a significant risk factor (p = 0.002) for BL, increasing the risk seven times. A decrease in CD14++CD16+ in the PB could be associated with the recruitment of these cells to the graft tissue in cases of subclinical BL inflammatory infiltrates below the threshold for rejection.

[Active surveillance for patients with localized prostate cáncer. Adherence and protocol drop analysis.] / La vigilancia activa en pacientes con cáncer de próstata localizado. Análisis de adherencia y salida del protocolo.

OBJECTIVE: VA is currently considered the treatment of choice for patients with low and very low risk prostate cancer. We analyzed the evolution of this treatment strategy in our series and adherence to the protocol. MATERIAL AND METHODS: Ambispective study of patients in VA in our center between 2014- 2019. 237 meet inclusion criteria, of which 142 (60%) have a minimum of 12 months of follow- up. Mean age: 68.5 (4678), median PSA 6.37 ng / ml (1-33). 229 (96.6%) are ISUP 1 and 8 (3.4%) ISUP 2. Objectives are proposed to assess our adherence to the protocol. Descriptive statistics are used to communicate the results. RESULTS: According to the classification by risk groups of the NCCN, 145 (61.2%), 49 (20.7%) and 42 (17.7%) were very low risk, low risk and favorable intermediate risk patients, respectively. The median of follow-up is 14 months (0-66). Of the patients with a minimum follow-up of 12 months, 107 (75.4%) were re-biopsied. 80 (33.8%) leave the protocol in these 5 years, 31.3% (25) by their own decision, 55% (44) due to medical criteria, and 11.3% (9) go to WW. After 5 years of follow-up, 99.2% of patients are still alive, 0.8% died of specific non-cancer causes. Of the objectives to assess adherence, 8 are achieved, 1 partially and 1 is not evaluable. CONCLUSIONS: VA in our center is already the treatment of choice for very low-risk patients, with a constant increase from year to year. Adherence to the protocol has been favorable during the period of time studied.

OBJETIVO: La VA se ha convertido en uno de los tratamientos de elección del CP localizado de bajo y muy bajo riesgo. Analizamos la evolución de esta estrategia de tratamiento en nuestra serie, así como la adherencia al protocolo.MATERIAL Y MÉTODOS: Estudio ambispectivo de los pacientes incluidos en VA en nuestro centro entre los años 2014-2019. 237 pacientes cumplen los criterios de inclusión en VA, de los cuales 142 (60%) tienen un seguimiento mínimo de 12 meses. Edad media: 68,5(46-78), mediana PSA 6,37 ng/ml (1-33). 229 pacientes (96,6%) son ISUP 1 y 8 (3,4%) ISUP 2. Se proponen unos objetivos para valorar nuestra adherencia al protocolo. Se utiliza estadística descriptiva y contraste de hipótesis para comunicar los resultados.RESULTADOS Y DISCUSIÓN: Atendiendo a la clasificación por grupos de riesgo de la NCCN, 145 (61,2%), 49 (20,7%) y 42 (17,7%) eran pacientes muy bajo riesgo, bajo riesgo y riesgo intermedio favorable respectivamente. El tiempo (mediana) de permanencia en el programa es de 14 meses (0-66). De los pacientes con un seguimiento mínimo de 12 meses, 107 (75,4%) son re ­ biopsiados. 80 pacientes (33,8%) salen del protocolo en estos 5 años, 31,3% (25) por decisión propia, 55% (44) por criterios médicos, y 11,3% (9) pasan a WW. Tras 5 años de seguimiento, el 99,2% de los pacientes continúan vivos, el 0,8% falleció por causas no cáncer específicas. De los objetivos para evaluar la adherencia, 8 de ellos se alcanzan, 1 parcialmente y 1 no es evaluable. CONCLUSIONES: La VA en nuestro centro constituye actualmente el tratamiento de elección para los pacientes con muy bajo riesgo. La adherencia al protocolo ha sido favorable durante el periodo de tiempo estudiado.

Ultrasound can differentiate complicated and noncomplicated acute colonic diverticulitis: a prospective comparative study with computed tomography.

OBJECTIVE: To prospectively assess the diagnostic value of intestinal ultrasound (US) compared to computerized tomography (CT) in differentiating uncomplicated and complicated acute colonic diverticulitis (ACD). MATERIALS AND METHODS: During a period of 14 months patients referred to the department of Radiology with clinical suspicion of ACD underwent an US examination. All confirmed US ACD diagnosis were included and subsequently underwent an emergency abdominal CT, used as gold standard. The WSES (World Society for Emergent Surgery) classification of diverticulitis was used. Diverticulitis was prospectively classified as either uncomplicated or complicated. Sensitivity, specificity, positive predictive value, and negative predictive values of US were evaluated. Before CT scan, the radiologist indicated whether they would have required or not a complementary CT scan, based on US findings. RESULTS: Of the 240 patients included in our study, 71 (29.6%) were Stage 0, 127 (53%) Stage 1A, and 42 (17.5%) were moderate-severe ACD (stages 1B, 2A, 2B, 3 and 4). The sensitivity of US for diagnosing complicated ACD was 84% and specificity of 95.8%. Most patients (24 of 27) misclassified by US as uncomplicated diverticulitis were classified on CT as stage 1A. From the 148 cases in which the radiologist considered CT unnecessary, only 3 of these revealed signs of complicated ACD on CT; none of them required emergency surgery. CONCLUSION: US is an effective technique to differentiate complicated from uncomplicated ACD. Our results suggest that US, may be a valuable alternative to CT for the initial radiologic evaluation in patients with clinical suspicion of ACD.

Analyses of PD-L1 and Inflammatory Gene Expression Association with Efficacy of Nivolumab ± Ipilimumab in Gastric Cancer/Gastroesophageal Junction Cancer.

PURPOSE: In advanced gastric cancer/gastroesophageal junction cancer (GC/GEJC), there is a need to identify biomarkers of response to therapies, such as immune checkpoint inhibitors. PATIENTS AND METHODS: In post hoc exploratory analyses from CheckMate 032 (GC/GEJC cohort), we evaluated associations between nivolumab ± ipilimumab (NIVO ± IPI) efficacy and programmed death ligand 1 (PD-L1) expression, defined by tumor cells (% TC) or combined positive score (CPS; sum of PD-L1-staining TCs + immune cells, divided by total viable TCs, × 100) using the Dako PD-L1 IHC 28-8 pharmDx assay, or inflammatory gene expression. RESULTS: There was a trend toward increased efficacy (objective response and overall survival) when PD-L1 expression was determined by CPS compared with % TC at higher cutoffs of ≥5 and ≥10 in the pooled analysis of all treatment regimens. In this analysis, 19% and 26% of patients with PD-L1-positive tumors at a CPS cutoff of ≥5 and ≥10, respectively, had an objective response compared with 8% and 9% of patients at the equivalent % TC cutoffs. Longer survival was demonstrated in patients with PD-L1-positive (defined by CPS cutoffs of ≥5 and ≥10) versus PD-L1-negative status. Similar results were observed in the NIVO 1 mg/kg + IPI 3 mg/kg subgroup. Multiple inflammatory gene signatures/transcripts, including a signature consisting of four genes (CD274, CD8A, LAG3, and STAT1), showed associations with response to NIVO ± IPI. CONCLUSIONS: This study suggests a greater association of PD-L1 expression by CPS with NIVO ± IPI efficacy compared with % TC PD-L1 expression in patients with GC/GEJC. Inflammatory signatures were also associated with NIVO ± IPI response, warranting further investigation.See related commentary by Moutafi and Rimm, p. 3812.

Cellular stress signaling activates type-I IFN response through FOXO3-regulated lamin posttranslational modification.

Neural stem/progenitor cells (NSPCs) persist over the lifespan while encountering constant challenges from age or injury related brain environmental changes like elevated oxidative stress. But how oxidative stress regulates NSPC and its neurogenic differentiation is less clear. Here we report that acutely elevated cellular oxidative stress in NSPCs modulates neurogenic differentiation through induction of Forkhead box protein O3 (FOXO3)-mediated cGAS/STING and type I interferon (IFN-I) responses. We show that oxidative stress activates FOXO3 and its transcriptional target glycine-N-methyltransferase (GNMT) whose upregulation triggers depletion of s-adenosylmethionine (SAM), a key co-substrate involved in methyl group transfer reactions. Mechanistically, we demonstrate that reduced intracellular SAM availability disrupts carboxymethylation and maturation of nuclear lamin, which induce cytosolic release of chromatin fragments and subsequent activation of the cGAS/STING-IFN-I cascade to suppress neurogenic differentiation. Together, our findings suggest the FOXO3-GNMT/SAM-lamin-cGAS/STING-IFN-I signaling cascade as a critical stress response program that regulates long-term regenerative potential.