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The mevalonate pathway produces essential lipid metabolites such as cholesterol. Although this pathway is negatively regulated by metabolic intermediates, little is known of the metabolites that positively regulate its activity. We found that the amino acid glutamine is required to activate the mevalonate pathway. Glutamine starvation inhibited cholesterol synthesis and blocked transcription of the mevalonate pathway-even in the presence of glutamine derivatives such as ammonia and α-ketoglutarate. We pinpointed this glutamine-dependent effect to a loss in the ER-to-Golgi trafficking of SCAP that licenses the activation of SREBP2, the major transcriptional regulator of cholesterol synthesis. Both enforced Golgi-to-ER retro-translocation and the expression of a nuclear SREBP2 rescued mevalonate pathway activity during glutamine starvation. In a cell model of impaired mitochondrial respiration in which glutamine uptake is enhanced, SREBP2 activation and cellular cholesterol were increased. Thus, the mevalonate pathway senses and is activated by glutamine at a previously uncharacterized step, and the modulation of glutamine synthesis may be a strategy to regulate cholesterol levels in pathophysiological conditions., (© 2024. The Author(s).)

Background: High-frequency episodic migraine (HFEM) has gained attention in the field of headache research and clinical practice. In this narrative review, we analyzed the available literature to assess the evidence that could help decide whether HFEM may represent a distinct clinical and/or biological entity within the migraine spectrum., Methods: The output of the literature search included 61 papers that were allocated to one of the following topics: (i) socio-demographic features and burden; (ii) clinical and therapeutic aspects; (iii) pathophysiology; and (iv) classification., Results: Multiple features differentiate subjects with HFEM from low-frequency episodic migraine and from chronic migraine: education, employment rates, quality of life, disability and psychiatric comorbidities load. Some evidence also suggests that HFEM bears a specific profile of activation of cortical and spinal pain-related pathways, possibly related to maladaptive plasticity., Conclusions: Subjects with HFEM bear a distinctive clinical and socio-demographic profile within the episodic migraine group, with a higher disease burden and an increased risk of transitioning to chronic migraine . Recognizing HFEM as a distinct entity is an opportunity for the better understanding of migraine and the spectrum of frequency with which it can manifest, as well as for stimulating further research and more adequate public health approaches., Competing Interests: Declaration of conflicting interestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article (past 4 years). FC: None. RDI received personal fees for participating in speaking at scientific events from Eli-Lilly, TEVA and Lundbeck. He has participated in an advisory board for Pfizer and AbbVie. MC: None. FB: None. GV received personal fees for participating in speaking at scientific events from Lundbeck. DM reports support from Abbvie for participating in advisory boards; consulting fees from LifeSciences Consultants, fees from Medscape for organizing educational programs; and personal fees from Lundbeck for lecturing at symposia. PP-R reports support for the present study from AbbVie and personal fees for consulting from AbbVie, Eli Lilly, Lundbeck, Medscape, Novartis, Pfizer and Teva. She has received personal fees for speaking from AbbVie, Dr Reddy's, Eli Lilly, Lundbeck, Medscape, Novartis and Teva, and has had grants paid to her research group from AbbVie, AGAUR, EraNet Neuron, FEDER RIS3CAT, Instituto Investigacion Carlos III, International Headache Society, Novartis and Teva. She is a member of the Scientific Advisory Board for Lilly Foundation Spain.PJG reports, over the last 36 months, grants from Celgene and Kallyope; personal fees from Aeon Biopharma, Abbvie, Amgen, eNeura, CoolTech LLC, Dr Reddys’, Eli-Lilly and Company, Epalex, Linpharma, Lundbeck, Man&Science, Novartis, Pfizer, Sanofi, Satsuma, Shiratronics and Teva Pharmaceuticals; personal fees for advice through Gerson Lehrman Group, Guidepoint, SAI Med Partners and Vector Metric; fees for educational materials from CME Outfitters; as well as publishing royalties or fees from Massachusetts Medical Society, Oxford University Press, UptoDate and Wolters Kluwer. CT reports support from Abbvie and Novartis for investigator-initiated trials; consulting fees from Abbvie, Eli Lilly, Dompé, Ipsen, Lundbeck, Pfizer, Teva and Medscape for participating in advisory boards; support from Abbvie, Eli Lilly, Dompé, Ipsen, Lundbeck, Pfizer and Teva for attending meetings; and personal fees from Abbvie, Eli Lilly, Lundbeck, Pfizer and Teva for lecturing at symposia. She is principal investigator of clinical trials sponsored by Abbvie, Biohaven, Eli Lilly, Ipsen, Lundbeck, Pfizer and Teva. She has received research grants from the European Commission, the Italian Ministry of Health and the Migraine Research Foundation.

Background : Stroke-induced immunosuppression (SII) represents a negative rehabilitative prognostic factor associated with poor motor performance at discharge from a neurorehabilitation unit (NRB). This study aims to evaluate the association between SII and gait impairment at NRB admission. Methods : Forty-six stroke patients (65.4 ± 15.8 years, 28 males) and 42 healthy subjects (HS), matched for age, sex, and gait speed, underwent gait analysis using an inertial measurement unit at the lumbar level. Stroke patients were divided into two groups: (i) the SII group was defined using a neutrophil-to-lymphocyte ratio ≥ 5, and (ii) the immunocompetent (IC) group. Harmonic ratio (HR) and short-term largest Lyapunov's exponent (sLLE) were calculated as measures of gait symmetry and stability, respectively. Results : Out of 46 patients, 14 (30.4%) had SII. HR was higher in HS when compared to SII and IC groups ( p < 0.01). HR values were lower in SII when compared to IC subjects ( p < 0.01). sLLE was lower in HS when compared to SII and IC groups in the vertical and medio-lateral planes ( p ≤ 0.01 for all comparisons). sLLE in the medio-lateral plane was higher in SII when compared to IC subjects ( p = 0.04). Conclusions : SII individuals are characterized by a pronounced asymmetric gait and a more impaired dynamic gait stability. Our findings underline the importance of devising tailored rehabilitation programs in patients with SII. Further studies are needed to assess the long-term outcomes and the role of other clinical features on gait pattern.

The development of multiple-choice questions (MCQs) for undergraduate medical education study purposes is resource intensive. Commercially available question banks are typically expensive, only available in English, and may not be aligned with medical school learning objectives. Here, we introduce The Ottawa Question Bank : a student-led, bilingual study resource curated to a Canadian undergraduate medicine curriculum (www.theottawaquestionbank.ca). In total, 205 medical students wrote and edited 4438 original MCQs linked to objectives from the University of Ottawa undergraduate medical education curriculum. The project has received positive feedback from both developers and users. Our experience suggests that involving medical students in MCQ development is feasible and can result in the rapid creation of a low-cost, high-quality study resource curated to a program's learning objectives. The platform outlined here can be used as a model for other medical schools and professional degree programs to develop their own question banks, including pharmacy, dentistry, nursing, and physiotherapy. Interested programs are encouraged to contact our team for collaborative opportunities., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 Corrado, McNeely, Lefebvre, Raichura, Bogie, Wood; licensee Synergies Partners.)

Background: miR-155 is involved in the generation and maintenance of inflammation and pain, endothelial function and immune system homeostasis, all functions that are relevant for migraine. The present study aims to assess the levels of miR-155 in migraine subtypes (episodic and chronic) in comparison to age- and sex-matched healthy controls., Methods: This is a cross-sectional, controlled, study involving three study groups: I) episodic migraine (n = 52, EM), II) chronic migraine with medication overuse (n = 44, CM-MO), and III) healthy controls (n = 32, HCs). We assessed the interictal gene expression levels of miR-155, IL-1β, TNF-α, and IL-10 in peripheral blood monocytes using rtPCR. The monocytic differentiation toward the M1 (pro-inflammatory) or M2 (anti-inflammatory) phenotypes was assessed in circulating monocytes with flow cytometry analysis and cell sorting., Results: miR-155 gene expression was higher in CM-MO group (2.68 ± 2.47 Relative Quantification - RQ) when compared to EM group (1.46 ± 0.85 RQ, p = 0.006) and HCs (0.44 ± 0.18 RQ, p = 0.001). In addition, miR-155 gene expression was higher in EM group when compared to HCs (p = 0.001). A multivariate analysis confirmed the difference between EM and CM-MO groups after correction for age, sex, smoking habit, preventive treatment, aura, presence of psychiatric or other pain conditions. We found higher gene expression of IL-1β, TNF-α, and lower gene expression of IL-10 in migraine participants when compared to HCs (p = 0.001 for all comparisons). TNF-α and IL-10 genes alterations were more prominent in CM-MO when compared to EM participants (p = 0.001). miR-155 positively correlated with IL-1β (p = 0.001) and TNF-α (p = 0.001) expression levels. Finally, in people with CM-MO, we described an up-regulated percentage of events in both M1 and M2 monocytic profiles., Conclusions: Our study shows for the first time a specific profile of activation of miR-155 gene expression levels in monocytes of selected migraine subpopulations, more pronounced in subjects with CM-MO. Interestingly, mir-155 expression correlated with markers of activation of the inflammatory and immune systems. The CM-MO subpopulation showed a peculiar increase of both pro-inflammatory and anti-inflammatory monocytes which worths further investigation., Trial Registration: www., Clinicaltrials: gov . (NCT05891808)., (© 2024. The Author(s).)

Functional and phenotypic heterogeneity of dendritic cells (DCs) play crucial roles in facilitating the development of diverse immune responses essential for host protection. Here, we report that KDM5C, a histone lysine demethylase, regulates conventional or classical DC (cDC) and plasmacytoid DC (pDC) population heterogeneity and function. Mice deficient in KDM5C in DCs have increased proportions of cDC2Bs and cDC1s, which is partly dependent on type I interferon (IFN) and pDCs. Loss of KDM5C results in an increase in Ly6C - pDCs, which, compared to Ly6C + pDCs, have limited ability to produce type I IFN and more efficiently stimulate antigen-specific CD8 T cells. KDM5C-deficient DCs have increased expression of inflammatory genes, altered expression of lineage-specific genes, and decreased function. In response to Listeria infection, KDM5C-deficient mice mount reduced CD8 T cell responses due to decreased antigen presentation by cDC1s. Thus, KDM5C is a key regulator of DC heterogeneity and critical driver of the functional properties of DCs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Objective: Postoperative sore throat (POST) and hoarseness are common complications of tracheal intubation. This study aims to evaluate the efficacy of flurbiprofen administered through the subglottic port of tracheal tubes to prevent POST after cardiac surgery., Design: Single-center, prospective, randomized, double-blind, placebo-controlled trial., Setting: Tertiary Care Referral University Hospital (Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome)., Patients: Included 71 patients undergoing for elective cardiac surgery. Inclusion criteria were (a) age between 50 and 75 years, (b) NYHA class I or II, (c) surgery for myocardial revascularization or valve repair or replacement under cardiopulmonary bypass., Intervention: Patients were double blind randomized to receive flurbiprofen or saline in the subglottic port of the endotracheal tube (groups F and P). The solution was injected ten minutes after tracheal tube placement, ten minutes after ICU admission and ten minutes before tracheal tube removal., Measurements: The primary outcome was to assess the effect of topical flurbiprofen administered through the subglottic port of the tracheal tube to prevent post-operative sore throat (POST). The secondary outcomes were the presence of hoarseness safety and patient's subjective satisfaction with their recovery. We did not report any exploratory outcomes., Main Results: We analyzed 68 patients, 34 patients in each group. In group F, two patients complained of POST and hoarseness (5.9%), while all controls did. The two groups significantly differed in the severity scores (VAS and TPS for sore throat and HOAR for hoarseness) at all time points. In group P, patients reported mild to moderate symptoms that significantly improved or disappeared 36 h after tracheal tube removal. According to the multivariable model, hoarseness affected women less than men, in the control group (p = 0.002). None of the patients in either group reported any adverse effects., Conclusions: Repeated administration of flurbiprofen through the subglottic port of tracheal tubes reduced the incidence of sore throat and hoarseness after cardiac surgery without evidence of complications., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Adrenocortical carcinoma (ACC) is a malignancy of the adrenal cortex with a high morbidity and mortality. More than half of the cases are functional tumors. As different hormones can be co-secreted above physiologic levels, it causes a very broad variety of symptoms and makes differentiating from more common entities hard. Here we present a case of a patient with a newly diagnosed ACC who initially presented with acute pulmonary embolism and recurrent deep vein thromboses (DVT) in the setting of hypercortisolism. Imaging showed a left adrenal mass invading adjacent structures including a nonocclusive thrombus in the left renal vein. Intravenous anticoagulation and thrombectomy were initially performed, followed by removal of the tumor and adjacent metastatic disease. Pathology confirmed ACC. The patient underwent left adrenalectomy, left nephrectomy, splenectomy, distal pancreatectomy, and caval thrombectomy with inferior vena cava (IVC) filter placement. Intravenous anticoagulation and glucocorticoid replacement were also administered as part of the treatment plan. Unfortunately, the patient had multiple episodes of bleeding and thrombosis and was eventually discharged to hospice care. DVT in the setting of ACC can be caused by increased hypercoagulability from hypercortisolism, direct venous thrombosis, or vascular invasion. Thrombosis, especially in the inferior vena cava, has been associated with poor prognosis and survival rates. Clinicians should be aware of this rare complication given its immediate therapeutic repercussions and prognostic value., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Nava Suarez et al.)

Background: A commonly used guideline for community-acquired pneumonia (CAP) is the joint American Thoracic Society and Infectious Diseases Society of America practice guideline. We aimed to investigate the effect of guideline-concordant therapy in the treatment of CAP., Methods: We systematically searched MEDLINE, Embase, CENTRAL, Web of Science, and Scopus from 2007 to December 2023. We screened citations, extracted data, and assessed risk of bias in duplicate. Primary outcomes were mortality rates, intensive care unit (ICU) admission, and length of stay. Secondary outcomes were guideline adherence, readmission, clinical cure rate, and adverse complications. We performed random-effect meta-analysis to estimate the overall effect size and assessed heterogeneity using the I 2 statistics., Results: We included 17 observational studies and 82 240 patients, of which 10 studies were comparative and pooled in meta-analysis. Overall guideline adherence rate was 65.2%. Guideline-concordant therapy was associated with a statistically significant reduction in 30-day mortality rate (crude odds ratio [OR], 0.49 [95% confidence interval .34-.70; I 2 = 60%]; adjusted OR, 0.49 [.37-.65; I 2 = 52%]) and in-hospital mortality rate (crude OR, 0.63 [.43-.92]; I 2 = 61%). Due to significant heterogeneity, we could not assess the effect of guideline-concordant therapy on length of stay, ICU admission, readmission, clinical cure rate, and adverse complications., Conclusions: In hospitalized patients with CAP, guideline-concordant therapy was associated with a significant reduction in mortality rate compared with nonconcordant therapy; however, there was limited evidence to support guideline-concordant therapy for other clinical outcomes. Future studies are needed to assess the clinical efficacy and safety of current guideline recommendations., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objective: This retrospective, multicenter, observational study aimed to refine patient selection criteria for secondary cytoreductive surgery in recurrent endometrial cancer. The objective was to identify preoperative predictors of complete cytoreduction, assess surgical complexity, and propose a preoperative predictive scoring system to identify suitable candidates for secondary cytoreductive surgery., Methods: Data from 331 women with recurrent endometrial cancer were analyzed across three Italian centers from January 2010 to December 2021. Patients were categorized based on treatment received (medical treatment, diagnostic laparoscopy/examination under anesthesia, or secondary cytoreductive surgery). Preoperative predictors, surgical complexity, complications, and a predictive scoring system were assessed. Logistic regression and receiver operating characteristic analysis were used for statistical evaluation., Results: Of the cohort, 56.2% underwent debulking surgery, 17.2% had diagnostic laparoscopy, and 26.6% received medical treatment. Patients undergoing secondary cytoreductive surgery were younger, with a lower body mass index, better performance status, and fewer comorbidities. Single site locoregional relapse was common in secondary cytoreductive surgery patients. Age <65 years, single site relapse, lymph node, and hematogenous relapse were independent predictors of complete cytoreduction. A predictive scoring system demonstrated a clear relationship between the score and the likelihood of complete cytoreduction., Conclusion: This study identified age <65 years, single site recurrence, as well as nodal and hematogenous recurrence, as predictive factors for achieving optimal cytoreduction. A predictive scoring system incorporating these factors has been proposed to identify optimal candidates for secondary cytoreductive surgery in recurrent endometrial cancer. The scoring system showed promising predictive accuracy and could aid in refining the decision making process, ensuring appropriate patient selection for secondary cytoreductive surgery. Further prospective studies are warranted to validate and enhance the predictive model., Competing Interests: Competing interests: None declared., (© IGCS and ESGO 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: The valve-in-valve transcatheter-aortic-valve-implantation (VIV-TAVI) represents an emerging procedure for the treatment of degenerated aortic bio-prostheses, and the occurrence of patient-prosthesis mismatch (PPM) after VIV-TAVI might affect its clinical efficacy. This study aimed to test a multimodal imaging approach to predict PPM risk during the TAVI planning phase and assess its clinical predictivity in VIV-TAVI procedures., Methods: Consecutive patients undergoing VIV-TAVI procedures at our Institution over 6 years were screened and those treated by self-expandable supra-annular valves were selected. The effective orifice area (EOA) was calculated with a hybrid Gorlin equation combining echocardiographic data with invasive hemodynamic assessment. Severe PPM was defined according to such original multimodality assessment as EOAi≤0.65 cm 2 /m 2 (if BMI < 30 kg/m 2 ) or < 0.55 cm 2 /m 2 (if BMI ≥ 30 kg/m 2 ). The primary endpoint was a composite of all-cause mortality and valve-related re-hospitalization during the clinical follow-up., Results: A total of 40 VIV-TAVI was included in the analysis. According to the pre-specified multimodal imaging modality assessment, 18 patients (45.0 %) had severe PPM. Among all baseline clinical and anatomical characteristics, estimated glomerular filtration rate before VIV-TAVI (OR 0.872, 95%CI[0.765-0.994],p = 0.040), the echocardiographic pre-procedural ≥moderate AR (OR 0.023, 95%CI[0.001-0.964],p = 0.048), the MSCT-derived effective internal area (OR 0.958, 95%CI[0.919-0.999],p = 0.046) and the implantation depth (OR 2.050, 95%CI[1.028-4.086],p = 0.041) resulted as independent predictors of severe PPM at multivariable logistic analysis. At a mean follow-up of 630 days, patients with severe PPM showed a higher incidence of the primary endpoint (9.1%vs.44.4 %;p = 0.023)., Conclusion: In VIV-TAVI using self-expandable supra-annular valves, a multimodal imaging approach might improve clinical outcome predicting severe PPM occurrence., Competing Interests: Declaration of competing interest F. Bianchini received a research grant from Abbott. E. Romagnoli received speaker fees from Abbott Vascular and Terumo. F. Burzotta and C. Trani received speaker fees from Abbott Vascular, Abiomed, Medtronic, and Terumo. C. Aurigemma received speaker fees from Abbott Vascular, Abiomed, Medtronic, Terumo and Daiichi Sankyo. All other authors have no conflicts of interest to declare in relation to this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Stroke affects the interconnection between the nervous and immune systems, leading to a down-regulation of immunity called stroke-induced immunosuppression (SII). The primary aim of this study is to investigate SII role as a predictor of functional, neurological, and motor outcomes in the neurorehabilitation setting (NRB). We conducted a prospective observational study enrolling post-acute stroke patients hospitalized for neurorehabilitation. At NRB admission (T 0 ) and discharge (T 1 ), we assessed presence of SII (defined by a neutrophil-to-lymphocyte ratio ≥ 5) and we evaluated functional independence (Functional Independence Measure-FIM, Barthel Index-BI), motor performances (Tinetti Score, Hauser Ambulation Index) and neurological impairment (NIHSS). We enrolled 96 patients (45.8% females, 70.6 ± 13.9 years, 88.5% ischemic stroke). At T 0 , 15.6% of patients (15/96) had SII. When compared to immunocompetent patients (IC), the SII group was characterized by worse baseline functional independence, motor performances and neurological disability. The same was confirmed at T 1 (FIM p = 0.012, BI p = 0.007, Tinetti p = 0.034, NIHSS p = 0.001). Neurological disability demonstrated a less pronounced improvement in SII (ΔNIHSS: SII: - 2.1 ± 2.3 vs. IC: - 3.1 ± 2.5, p = 0.035). SII group presented a higher percentage of infectious complications during the neurorehabilitation period (SII 80% vs. IC 25.9%; p = 0.001). SII may represent a negative prognostic factor in the neurorehabilitation setting. SII patients were characterized by poorer functional, motor, neurological performances and higher risk of infectious complications. ClinicaTrial registration: NCT05889169., (© 2024. The Author(s).)

Background: The burden and disability associated with headaches are conceptualized and measured differently at patients' and populations' levels. At the patients' level, through patient-reported outcome measures (PROMs); at population level, through disability weights (DW) and years lived with a disability (YLDs) developed by the Global Burden of Disease Study (GBD). DW are 0-1 coefficients that address health loss and have been defined through lay descriptions. With this literature review, we aimed to provide a comprehensive analysis of disability in headache disorders, and to present a coefficient referring to patients' disability which might inform future GBD definitions of DW for headache disorders., Methods: We searched SCOPUS and PubMed for papers published between 2015 and 2023 addressing disability in headache disorders. The selected manuscript included a reference to headache frequency and at least one PROM. A meta-analytic approach was carried out to address relevant differences for the most commonly used PROMs (by headache type, tertiles of medication intake, tertiles of females' percentage in the sample, and age). We developed a 0-1 coefficient based on the MIDAS, on the HIT-6, and on MIDAS + HIT-6 which was intended to promote future DW iterations by the GBD consortium., Results: A total of 366 studies, 596 sub-samples, and more than 133,000 single patients were available, mostly referred to cases with migraine. Almost all PROMs showed the ability to differentiate disability severity across conditions and tertiles of medication intake. The indexes we developed can be used to inform future iterations of DW, in particular considering their ability to differentiate across age and tertiles of medication intake., Conclusions: Our review provides reference values for the most commonly used PROMS and a data-driven coefficient whose main added value is its ability to differentiate across tertiles of age and medication intake which underlie on one side the increased burden due to aging (it is likely connected to the increased impact of common comorbidities), and by the other side the increased burden due to medication consumption, which can be considered as a proxy for headache severity. Both elements should be considered when describing disability of headache disorders at population levels., (© 2024. The Author(s).)

Immune cells must adapt to different environments during the course of an immune response. Here we study the adaptation of CD8 + T cells to the intestinal microenvironment and how this process shapes the establishment of the CD8 + T cell pool. CD8 + T cells progressively remodel their transcriptome and surface phenotype as they enter the gut wall, and downregulate expression of mitochondrial genes. Human and mouse intestinal CD8 + T cells have reduced mitochondrial mass, but maintain a viable energy balance to sustain their function. We find that the intestinal microenvironment is rich in prostaglandin E 2 (PGE 2 ), which drives mitochondrial depolarization in CD8 + T cells. Consequently, these cells engage autophagy to clear depolarized mitochondria, and enhance glutathione synthesis to scavenge reactive oxygen species (ROS) that result from mitochondrial depolarization. Impairing PGE 2 sensing promotes CD8 + T cell accumulation in the gut, while tampering with autophagy and glutathione negatively impacts the T cell pool. Thus, a PGE 2 -autophagy-glutathione axis defines the metabolic adaptation of CD8 + T cells to the intestinal microenvironment, to ultimately influence the T cell pool., (© 2024. The Author(s).)