Delayed Cerebral Infarction After Aneurysmal Subarachnoid Hemorrhage: Location, Distribution Patterns, Infarct Load, and Effect on Outcome.

BACKGROUND AND OBJECTIVES: Delayed cerebral ischemia (DCI) is one of the main contributing factors to poor clinical outcome after aneurysmal subarachnoid hemorrhage (SAH). Unsuccessful treatment can cause irreversible brain injury in the form of DCI-related infarction. We aimed to assess the association between the location, distribution, and size of DCI-related infarction in relation to clinical outcome. METHODS: Consecutive patients with SAH treated at 2 university hospitals between 2014 and 2019 (Helsinki, Finland) and between 2006 and 2020 (Aachen, Germany) were included. Size of DCI-related infarction was quantitatively measured as absolute volume (in milliliters). In a semiquantitative fashion, infarction in 14 regions of interest (ROIs) according to a modified Alberta Stroke Program Early CT Score (ASPECTS) was noted. The association of infarction in these ROIs along predefined regions of eloquent brain, with clinical outcome, was assessed. For this purpose, 1-year outcome was measured by the Glasgow Outcome Scale (GOS) and dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3). RESULTS: Of 1,190 consecutive patients with SAH, 155 (13%) developed DCI-related infarction. One-year outcome data were available for 148 (96%) patients. A median overall infarct volume of 103 mL (interquartile range 31-237) was measured. DCI-related infarction was significantly associated with 1-year unfavorable outcome (odds ratio [OR] 4.89, 95% CI 3.36-7.34, p < 0.001). In patients with 1-year unfavorable outcome, vascular territories more frequently affected were left middle cerebral artery (affected in 49% of patients with unfavorable outcome vs in 30% of patients with favorable outcome; p = 0.029), as well as left (44% vs 18%; p = 0.003) and right (52% vs 14%; p < 0.001) anterior cerebral artery supply areas. According to the ASPECTS model, the right M3 (OR 8.52, 95% CI 1.41-51.34, p = 0.013) and right A2 (OR 7.84, 95% CI 1.97-31.15, p = 0.003) regions were independently associated with unfavorable outcome. DISCUSSION: DCI-related infarction was associated with a 5-fold increase in the odds of unfavorable outcome, after 1 year. Ischemic lesions in specific anatomical regions are more likely to contribute to unfavorable outcome. TRIAL REGISTRATION INFORMATION: Data collection in Aachen was registered in the German Clinical Trial Register (DRKS00030505); on January 3, 2023.

CT-guided needle biopsy is not associated with increased ipsilateral pleural metastasis.

INTRODUCTION: Histological confirmation of a lung tumor is the prerequisite for treatment planning. It has been suspected that CT-guided needle biopsy (CTGNB) exposes the patient to a higher risk of pleural recurrence. However, the distance between tumor and pleura has largely been neglected as a possible confounder when comparing CTGNB to bronchoscopy. METHODS: All patients with lung cancer histologically confirmed by bronchoscopy or CTGNB between 2010 and 2020 were enrolled and studied. Patients' medical histories, radiologic and pathologic findings and surgical records were reviewed. Pleural recurrence was diagnosed by pleural biopsy, fluid cytology, or by CT chest imaging showing progressive pleural nodules. RESULTS: In this retrospective unicenter analysis, 844 patients underwent curative resection for early-stage lung cancer between 2010 and 2020. Median follow-up was 47.5 months (3-137). 27 patients (3.2 %) with ipsilateral pleural recurrence (IPR) were identified. The distance of the tumor to the pleura was significantly smaller in patients who underwent CTGNB. A tendency of increased risk of IPR was observed in tumors located in the lower lobe (HR: 2.18 [±0.43], p = 0.068), but only microscopic pleural invasion was a significant independent predictive factor for increased risk of IPR (HR: 5.33 [± 0.51], p = 0.001) by multivariate cox analysis. Biopsy by CTGNB did not affect IPR (HR: 1.298 [± 0.39], p = 0.504). CONCLUSION: CTGNB is safe and not associated with an increased incidence of IPR in our cohort of patients. This observation remains to be validated in a larger multicenter patient cohort.

sEMG as complementary tool for VFSS: A synchronized study in patients with neurogenic oropharyngeal dysphagia.

The neurogenic oropharyngeal dysphagia is a prevalent functional swallowing disorder resulting from neurological causes. The conventional diagnosis involves ionizing radiation in Videofluoroscopy Swallowing Studies (VFSS). Surface electromyography (sEMG) offers a non-invasive alternative by recording muscle activity. This research compares bolus passage timing through anatomical structures using VFSS and sEMG-related activation times. Fifty confirmed oropharyngeal dysphagia patients underwent synchronized VFSS and sEMG, evaluating muscle groups during cracker and fluid ingestion. sEMG revealed activation patterns in masseters, suprahyoid, and infrahyoid muscles, occurring before bolus passage through the mandibular line and concluding near the upper esophageal sphincter complex. sEMG identified differences in dysphagia severity (EAT-10 score), age, and diagnosis, contrasting VFSS results. Results indicate potential complementarity between sEMG and VFSS for dysphagia screening, diagnosis, and monitoring.

Increased water intake dilutes protective uromodulin levels in urine and results in increased rates of pyelonephritis in a murine model.

AIM: Urinary tract infections (UTIs) rank among the most prevalent infections in humans, carrying substantial implications for public health. Women experiencing recurrent UTIs are often advised to boost their fluid intake to help eliminate bacteria. In this study, we explored the impact of elevated fluid consumption during UTIs using a mouse model of pyelonephritis. METHODS: UTI was induced in 8-10 w female BALB/cJ-mice by surgically injecting Escherichia coli (O6:K13:H1) into the bladder whereafter mice were randomized to gel food (GF) or regular chow. Immune response and infection severity were determined 24-h post-infection. In vitro bacterial growth (OD600) was determined in urine from mice or from human volunteers. RESULTS: Gel feeding increased urine output (1.40 ± 0.77 µL min-1, p < 0.01) and diluted the urine (668.7 ± 177 mOsmol kg-1, p < 0.0001) compared to controls on regular chow (urine output: 0.34 ± 0.27 µL min-1, osmolality: 1439 ± 473.5 mOsmol kg-1). Mice on GF had a higher risk of pyelonephritis (87.5%) and more severe infections (26.22 ± 9.88 CFU mg-1 tissue) compared to controls (43.75%; 3.87 ± 3.56 CFU mg-1, p < 0.01). Correspondingly, the growth of E. coli was markedly reduced at osmolalities above 1200 mOsmol kg-1 compared to 600 mOsmol kg-1 and GF mice had lower urine levels of uromodulin (13.70 ± 1.89 µg mL-1, p < 0.01) compared to controls (24.65 ± 2.70 µg mL-1). CONCLUSION: Increased water intake and urine flow in mice will markedly increase the risk of pyelonephritis. The increased risk may reflect reduced urine uromodulin combined with optimized growth conditions for E. coli. The study does not immediately support the notion that established UTIs can be eliminated by increased water intake.

Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors.

BACKGROUND: Pediatric gastroenteropancreatic neuroendocrine tumors are exceedingly rare, resulting in most pediatric treatment recommendations being based on data derived from adults. Trametinib is a kinase inhibitor that targets MEK1/2 and has been employed in the treatment of cancers harboring mutations in the Ras pathway. METHODS: We utilized an established human pediatric gastroenteropancreatic neuroendocrine-like tumor patient-derived xenograft (PDX) with a known NRAS mutation to study the effects of MEK inhibition. We evaluated the effects of trametinib on proliferation, motility, and tumor growth in vivo. We created an intraperitoneal metastatic model of this PDX, characterized both the phenotype and the genotype of the metastatic PDX and again, investigated the effects of MEK inhibition. RESULTS: We found target engagement with decreased ERK1/2 phosphorylation with trametinib treatment. Trametinib led to decreased in vitro cell growth and motility, and decreased tumor growth and increased animal survival in a murine flank tumor model. Finally, we demonstrated that trametinib was able to significantly decrease gastroenteropancreatic neuroendocrine intraperitoneal tumor metastasis. CONCLUSIONS: The results of these studies support the further investigation of MEK inhibition in pediatric NRAS mutated solid tumors.

Immunomodulation as a treatment for parkinson's disease in current trials: a systematic review and meta-analysis.

Background: Immunomodulatory drugs and immunotherapies are being evaluated in clinical trials for the treatment of neuroinflammation, as the latter is an essential mechanism for the development and progression of Parkinson's disease. Objective: The objective of the study is to review recent evidence on the evaluation of immunomodulators in randomized controlled clinical trials measuring improvement of motor symptoms. Methods: A meta-analysis of Movement Disorder Society-Unified Parkinson's disease Rating Scale (MDS-UPDRS III) scores extracted from seven articles selected after an online search of PubMed, Cochrane Library, and Clarivate's Web of Science for randomized controlled clinical trials published between 2000 and July 2023 was performed. The selected articles reported clinical trials evaluating the effects of specific immunomodulators or treatments with known effects on the immune system and inflammation. MDS-UPDRS III scores were reported in these studies, and the results of the placebo groups were compared with those of the treatment groups. Results: A total of 590 patients treated with immunomodulators and 622 patients treated with placebo were included. A test for heterogeneity yielded an I2 value > 50%. The mean standard difference for change in MDS-UPDR III score was -0.46 (CI [95%] = -0.90 - -0.02, p < 0.01). No significant differences were found in the change in mean MDS-UPDR III score between the treatment and placebo groups; however, two studies showed a trend toward separation from the mean. Conclusion: The immunomodulatory treatments included in this study showed no efficacy in improving motor symptoms in Parkinson's disease patients. Further clinical trials with larger patient populations are needed.

Repeated horizontal acquisition of lagriamide-producing symbionts in Lagriinae beetles.

Microbial symbionts associate with multicellular organisms on a continuum from facultative associations to mutual codependency. In some of the oldest intracellular symbioses there is exclusive vertical symbiont transmission, and co-diversification of symbiotic partners over millions of years. Such symbionts often undergo genome reduction due to low effective population sizes, frequent population bottlenecks, and reduced purifying selection. Here, we describe multiple independent acquisition events of closely related defensive symbionts followed by genome erosion in a group of Lagriinae beetles. Previous work in Lagria villosa revealed the dominant genome-eroded symbiont of the genus Burkholderia produces the antifungal compound lagriamide and protects the beetle's eggs and larvae from antagonistic fungi. Here, we use metagenomics to assemble 11 additional genomes of lagriamide-producing symbionts from seven different host species within Lagriinae from five countries, to unravel the evolutionary history of this symbiotic relationship. In each host species, we detected one dominant genome-eroded Burkholderia symbiont encoding the lagriamide biosynthetic gene cluster (BGC). Surprisingly, however, we did not find evidence for host-symbiont co-diversification, or for a monophyly of the lagriamide-producing symbionts. Instead, our analyses support at least four independent acquisition events of lagriamide-encoding symbionts and subsequent genome erosion in each of these lineages. By contrast, a clade of plant-associated relatives retained large genomes but secondarily lost the lagriamide BGC. In conclusion, our results reveal a dynamic evolutionary history with multiple independent symbiont acquisitions characterized by high degree of specificity. They highlight the importance of the specialized metabolite lagriamide for the establishment and maintenance of this defensive symbiosis.

Incremento del riesgo hemorrágico en pacientes con fibrilación auricular y enfermedad renal crónica en hemodiálisis tratados con anticoagulantes. Serie de cuatro centros / Increased risk of bleeding in patients with atrial fibrillation and chronic kidney disease on hemodialysis treated with anticoagulants. A four center series

Resumen Objetivo: El objetivo de este estudio fue estimar si el uso de anticoagulantes se asociaba con una diferencia en la frecuencia de trombosis de cualquier sitio, hemorragia mayor y mortalidad en adultos con coexistencia de ambas patologías. Método: Se realizó un estudio de cohorte retrospectivo en cuatro centros de alta complejidad. Se incluyeron mayores de 18 años con ERC en hemodiálisis y FA no valvular, con indicación de anticoagulación (CHA2DS2VASc ≥ 2). El desenlace primario fue la ocurrencia de sangrado mayor, evento trombótico (accidente vascular cerebral, infarto agudo al miocardio o enfermedad tromboembólica venosa) o muerte. Se realizó ajuste por variables de confusión por regresión logística. Resultados: De los 158 pacientes incluidos, el 61% (n = 97) recibieron anticoagulante. El desenlace principal se encontró en el 84% de quienes recibieron anticoagulación y en el 70% de quienes no la recibieron (OR: 2.12, IC95%: 0.98-4.57; luego del ajuste OR: 2.13, IC95%: 1.04-4.36). De los desenlaces mayores se presentaron sangrado en el 52% vs. el 34% (OR: 2.03; IC95%: 1.05-3.93), trombosis en el 35% vs. el 34% (OR: 1.03; IC95%: 0.52-2.01) y muerte en el 46% vs. el 41% (OR: 1.25; IC95%: 0.65-2.38). Conclusiones: Los resultados de este estudio sugieren un incremento en el riesgo de sangrado en los pacientes con FA y ERC en hemodiálisis que reciben anticoagulación, sin disminución del riesgo de eventos trombóticos ni de muerte.

Abstract Objective: The aim of this study was to estimate whether the consumption of anticoagulants was associated with a difference in the frequency of thrombosis of any site, major bleeding and mortality, in adults with both diseases. Method: A retrospective cohort study was carried out in four high complexity centers. Patients older than 18 years with CKD on hemodialysis and non-valvular AF, with an indication for anticoagulation (CHA2DS2VASc ≥ 2), were included. The primary outcome was the occurrence of: major bleeding, thrombotic event (cerebrovascular accident, acute myocardial infarction or venous thromboembolic disease) or death. Adjustment for confounding variables was performed using logistic regression. Results: From 158 patients included, 61% (n = 97) received an anticoagulant. The main outcome was found in 84% of those who received anticoagulation and 70% of those who did not (OR: 2.12, 95%CI: 0.98-4.57; after the adjusted analysis OR: 2.13, 95%CI: 1.04-4.36). Separate outcomes were bleeding in 52% vs. 34% (OR: 2.03; 95%CI: 1.05-3.93), thrombosis in 35% vs. 34% (OR: 1.03; 95%CI: 0.52-2-01) and death in 46% vs. 41% (OR: 1.25; 95%CI: 0.65-2.38). Conclusions: The results of this study suggest an increased risk of bleeding in patients with AF and CKD on hemodialysis receiving anticoagulation, without a decrease in the risk of thrombotic events or all-cause mortality.

Metabolic Signaling in Cancer.

Metabolic reprogramming in cancer allows cells to survive in harsh environments and sustain macromolecular biosynthesis to support proliferation. In addition, metabolites play crucial roles as signaling molecules. Metabolite fluctuations are detected by various sensors in the cell to regulate gene expression, metabolism, and signal transduction. Metabolic signaling mechanisms contribute to tumorigenesis by altering the physiology of cancer cells themselves, as well as that of neighboring cells in the tumor microenvironment. In this review, we discuss principles of metabolic signaling and provide examples of how cancer cells take advantage of metabolic signals to promote cell proliferation and evade the immune system, thereby contributing to tumor growth and progression.

Comparing Outcomes of Post-Cardiotomy Cardiogenic Shock Patients: On-Site Cannulation vs. Retrieval for V-A ECMO Support.

Background: Post-cardiotomy cardiogenic shock (PCCS) remains a life-threatening complication after cardiac surgery. Extracorporeal membrane oxygenation (ECMO) represents the mainstay of mechanical circulatory support for PCCS; however, its availability is limited to larger experienced centers, leading to a mismatch between centers performing cardiac surgery and hospitals offering ECMO management beyond cannulation. We sought to evaluate the outcomes and complications of PCCS patients requiring veno-arterial (V-A) ECMO cannulated at our hospital compared to those cannulated at referral hospitals. Methods: A retrospective analysis of PCCS patients requiring V-A ECMO was conducted between October 2014 to December 2022. Results: A total of 121 PCCS patients required V-A ECMO support, of which 62 (51%) patients were cannulated at the referring institutions and retrieved (retrieved group), and 59 (49%) were cannulated at our hospital (on-site group). The baseline demographics and pre-ECMO variables were similar between groups, except retrieved patients had higher lactic acid levels (retrieved group: 8.5 mmol/L ± 5.8 vs. on-site group: 6.6 ± 5; p = 0.04). Coronary artery bypass graft was the most common surgical intervention (51% in the retrieved group vs. 47% in the on-site group). There was no difference in survival-to-discharge rates between the groups (45% in the retrieved group vs. 51% in the on-site group; p = 0.53) or in the rate of patient-related complications. Conclusions: PCCS patients retrieved on V-A ECMO can achieve similar outcomes as those cannulated at experienced centers. An established network in a hub-and-spoke model is critical for the PCCS patients managed at hospitals without ECMO abilities to improve outcomes.

Converging cytokine and metabolite networks shape asymmetric T cell fate at the term human maternal-fetal interface.

Placentation presents immune conflict between mother and fetus, yet in normal pregnancy maternal immunity against infection is maintained without expense to fetal tolerance. This is believed to result from adaptations at the maternal-fetal interface (MFI) which affect T cell programming, but the identities (i.e., memory subsets and antigenic specificities) of T cells and the signals that mediate T cell fates and functions at the MFI remain poorly understood. We found intact recruitment programs as well as pro-inflammatory cytokine networks that can act on maternal T cells in an antigen-independent manner. These inflammatory signals elicit T cell expression of co-stimulatory receptors necessary for tissue retention, which can be engaged by local macrophages. Although pro-inflammatory molecules elicit T cell effector functions, we show that additional cytokine (TGF-ß1) and metabolite (kynurenine) networks may converge to tune T cell function to those of sentinels. Together, we demonstrate an additional facet of fetal tolerance, wherein T cells are broadly recruited and restrained in an antigen-independent, cytokine/metabolite-dependent manner. These mechanisms provide insight into antigen-nonspecific T cell regulation, especially in tissue microenvironments where they are enriched.

Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.

Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.

Characterization of time toxicity in older patients with metastatic breast cancer.

PURPOSE: Recognizing that receiving healthcare can be time intensive and burdensome, time toxicity has been conceptualized as the time spent by patients seeking healthcare. This study investigates the association between age at diagnosis and time toxicity for patients with Metastatic Breast Cancer (MBC) and identifies major components of care that confer the greatest time toxicity. METHODS: We conducted a retrospective cohort study among patients with MBC aged 67 or older using the SEER-Medicare database. We assessed time toxicity using the number of encounter days patients interacted with the healthcare system per 100 days, within the first year of starting cancer treatment. We used a Poisson model to analyze the association between age and encounter days, adjusting for clinical and sociodemographic factors. We stratified the mean encounter days for each age cohort by treatment types. FINDINGS: The final sample included 2949 patients; 51.4% were between 70 and 79 years old, and 81.3% were white. Although unadjusted analysis showed an association between older age and more encounter days (Rate Ratio (RR) 1.12; 95% CI 1.02, 1.22), there was no significant association after adjusting for comorbidities and treatment type. Patients with more than three comorbidities had significantly higher encounter days compared to those without comorbidities [RR 1.36 (95% CI 1.26, 1.46)]. Receipt of radiotherapy [RR: 1.45 95% CI (1.37, 1.54)] was associated with more encounter days compared to not receiving radiotherapy, while receipt of bone-modifying agents was associated with fewer encounter days compared to not using Bone modifying agents [RR 0.75 (95% CI 0.70, 0.79)]. CONCLUSION: Our study identified comorbidities and cancer treatment modality, including radiotherapy, as the factors affecting time toxicity in older patients with MBC. Assessment of an individual's comorbid medical conditions and types of treatment planned are crucial to understanding age-related impacts on encounter days and to support shared decision making in older patients.

Impact of Maternal Exercise on Mice Offspring Development, Pulmonary Hypertension, and Vascular Remodeling in Chronic Hypoxia.

PURPOSE: Chronic, high-altitude hypoxic exposure increases the risk of high-altitude pulmonary hypertension (PH). Emerging evidence shows maternal exercise may improve offspring resistance to disease throughout life. The purpose of this study is to determine if maternal exercise mitigates chronic hypoxic-induced changes in the offspring indicative of high-altitude pulmonary hypertension development. METHODS: Female adult C57BL/6 J mice were randomly allocated to nonexercise or exercise conditions. Exercise consisted of voluntary running wheel exercise for four weeks during the perinatal period. Three days after birth, the pups remained at low altitude (normoxia) or were exposed to hypobaric hypoxia of 450 mmHg to simulate ~4500 m altitude exposure until 8 weeks of age. The study consisted of 4 groups: Hypoxia + Nonexercise pregnancy, Hypoxia + Exercise, or the respective, normoxia conditions (Normoxia + Nonexercise or Normoxia + Exercise). Offspring body size, motor function, right ventricular systolic pressure (RVSP), and cardiopulmonary morphology were assessed after 8 weeks in normoxia or hypoxia. RESULTS: Both hypoxic groups had smaller body sizes, reduced motor function, increased hematocrit, RVSP, muscularization in medium-sized pulmonary arteries, as well as right ventricular hypertrophy and contractility compared to the normoxic groups ( p < 0.05). CONCLUSIONS: Chronic hypoxia simulating 4500 m attenuated growth, lowered motor function, and elicited PH development. Voluntary maternal exercise did not significantly decrease RVSP in the offspring, which aligned with a lack of effect to attenuate abnormal body size and cardiopulmonary development due to chronic hypoxia. These findings are preliminary in nature and more powered studies through larger group sizes are required to generalize the results to the population.

A Drosophila model for mechanistic investigation of tau protein spread.

Brain protein aggregates are a hallmark of neurodegenerative disease. Previous work indicates that specific protein components of these aggregates are toxic, including tau in Alzheimer's disease and related tauopathies. Increasing evidence also indicates that these toxic proteins traffic between cells in a prion-like fashion, thereby spreading pathology from one brain region to another. However, the mechanisms involved in trafficking are poorly understood. We therefore developed a transgenic Drosophila model to facilitate rapid evaluation of candidate tau trafficking modifiers. Our model uses the bipartite Q system to drive co-expression of tau and GFP in the fly eye. We find age-dependent tau spread into the brain, represented by detection of tau, but not GFP in the brain. We also found that tau trafficking was attenuated upon inhibition of the endocytic factor dynamin or the kinase glycogen synthase kinase-3ß ( GSK-3ß ). Further work revealed that dynamin promotes tau uptake in recipient tissues, whereas GSK-3ß appears to promote tau spread via direct phosphorylation of tau. Our robust and flexible system will promote the identification of tau trafficking components involved in the pathogenesis of neurodegenerative diseases. SUMMARY STATEMENT: The trafficking of toxic proteins in neurodegenerative disease is well-known but poorly understood. Our model will allow rapid and new insight into molecular mechanisms underlying this process.

ACLY alternative splicing correlates with cancer phenotypes.

ATP-citrate lyase (ACLY) links carbohydrate and lipid metabolism and provides nucleocytosolic acetyl-CoA for protein acetylation. ACLY has two major splice isoforms: the full-length canonical "long" isoform and an uncharacterized "short" isoform in which exon 14 is spliced out. Exon 14 encodes 10 amino acids within an intrinsically disordered region and includes at least one dynamically phosphorylated residue. Both isoforms are expressed in healthy tissues to varying degrees. Analysis of human transcriptomic data revealed that the percent spliced in (PSI) of exon 14 is increased in several cancers and correlated with poorer overall survival in a pan-cancer analysis, though not in individual tumor types. This prompted us to explore potential biochemical and functional differences between ACLY isoforms. Here, we show that there are no discernible differences in enzymatic activity or stability between isoforms or phosphomutants of ACLY in vitro. Similarly, both isoforms and phosphomutants were able to rescue ACLY functions, including fatty acid synthesis and bulk histone acetylation, when re-expressed in Acly knockout cells. Deletion of Acly exon 14 in mice did not overtly impact development or metabolic physiology nor did it attenuate tumor burden in a genetic model of intestinal cancer. Notably, expression of epithelial splicing regulatory protein 1 (ESRP1) is highly correlated with ACLY PSI. We report that ACLY splicing is regulated by ESRP1. In turn, both ESRP1 expression and ACLY PSI are correlated with specific immune signatures in tumors. Despite these intriguing patterns of ACLY splicing in healthy and cancer tissues, functional differences between the isoforms remain elusive.

Combination of calretinin, MALAT1, and GAS5 as a potential prognostic biomarker to predict disease progression in surgically treated mesothelioma patients.

BACKGROUND: The role of cytoreductive surgery for epithelioid pleural mesothelioma within a multimodal treatment approach remains controversial. Carefully selected patients benefit from cytoreductive surgery and adjuvant chemotherapy, but there is no established biomarker to predict tumor recurrence or progression during the course of the disease. The aim of this study was to identify potential biomarkers to predict therapeutic response in terms of progression-free survival. METHODS: Between 03/2014 and 08/2022, preoperative blood samples were collected from 76 patients with epithelioid pleural mesothelioma who underwent cytoreductive surgery as part of a multimodal treatment approach. Identification of potential biomarkers was performed by determination of mesothelin and calretinin, as well as specific long non-coding RNAs and microRNAs. Receiver operating characteristic analysis, Kaplan-Meier survival analysis, and Cox regression were used to assess the association between biomarker concentrations and patient recurrence status and survival. RESULTS: MALAT1, GAS5, and calretinin showed statistically significant increased biomarker levels in patients with recurrence in contrast to recurrence-free patients after surgical treatment (p < 0.0001, p = 0.0190, and p = 0.0068, respectively). The combination of the three biomarkers resulted in a sensitivity of 68 % and a specificity of 89 %. CONCLUSION: MALAT1, GAS5, and calretinin could be potential biomarkers for the prediction of tumor recurrence, improving the benefit from multimodal treatment including cytoreductive surgery.

Modelling control strategies for pneumococcal meningitis outbreaks in the African meningitis belt.

INTRODUCTION: Pneumococcal meningitis outbreaks occur sporadically in the African meningitis belt. Outbreak control guidelines and interventions are well established for meningococcal but not pneumococcal meningitis. Mathematical modelling is a useful tool for assessing the potential impact of different pneumococcal control strategies. This work aimed to estimate the impact of reactive vaccination with pneumococcal conjugate vaccine (PCV) had it been implemented in past African meningitis belt outbreaks and assess their efficiency relative to existing routine infant immunisation with PCV. METHODS & RESULTS: Using recent pneumococcal meningitis outbreaks in Burkina Faso, Chad, and Ghana as case studies, we investigated the potential impact of reactive vaccination. We calculated the number needed to vaccinate to avert one case (NNV) in each outbreak setting and over all outbreaks and compared this to the NNV for existing routine infant vaccination. We extended previous analyses of reactive vaccination by considering longer-term protection in vaccinees over five years, incorporating a proxy for indirect effects. We found that implementing reactive vaccination in previous pneumococcal meningitis outbreaks could have averted up to 10-20 % of outbreak cases, with the biggest potential impact in Brong Ahafo, Ghana (2015-2016) and Goundi, Chad (2009). The NNV, and hence the value of reactive vaccination, varied greatly. 'Large' (80 + cumulative modelled cases per 100,000 population) and/or 'prolonged' (exceeding a response threshold of 10 suspected cases per 100,000 per week for four weeks or more) outbreaks had NNV estimates under 10,000. For routine infant vaccination with PCV, the estimated NNV ranged from 3,100-5,600 in Burkina Faso and 1,500-2,600 in Ghana. IMPLICATIONS: This analysis provides evidence to inform the design of pneumococcal meningitis outbreak response guidelines. Countries should consider reactive vaccination in each outbreak event, together with maintaining routine infant vaccination as the primary intervention to reduce pneumococcal disease burden and outbreak risk.

Fertility Knowledge and Educational Experiences of Graduating Medical Students: A Multi-Institution Survey.

Objective: Our goal was to assess the fertility knowledge and educational experiences of graduating U.S. medical students to evaluate areas of improvement for future educational interventions. Design: Web-based cross-sectional survey. Subjects: Medical students graduating in 2023 from the University of Miami Miller School of Medicine (SOM), New York University (NYU) Grossman SOM, Wayne State University SOM, Perelman SOM at the University of Pennsylvania, and Mayo Clinic Alix SOM. Main Outcome Measures: Fertility-related knowledge and educational experiences of U.S. medical students in their final year of school. Results: In total, 117 students (14.4%) completed the survey. The average knowledge score was 78%. Twenty-three (22%) overestimated the age of most precipitous fertility decline, and 50 (52%) overestimated the chance of getting pregnant for a 40-year-old person with ovaries. One-third of students (30, 32%) incorrectly believe that physicians have equivalent infertility rates to the general population. Students were less cognizant of male fertility issues, incorrectly believing there was no negative impact on male fertility by age (43, 42%) among other factors. Seventy-five (81%) reported less than 5 hours of fertility-related education in medical school. Only one-third (32%) were satisfied or very satisfied with the fertility education they received. In an open-response question, students expressed interest in additional education on transgender and cancer patient care, fertility preservation, assisted reproductive technologies, and reproductive life planning in medicine. Conclusions: There is a need and an opportunity for medical education programs to enhance fertility education. Giving students and trainees the knowledge required to make informed decisions for their family-building purposes and improving their ability to counsel patients adequately should be a goal of future educational endeavors. The data collected in this study will serve as a guide for the development of fertility-related learning modules for medical students and trainees.