Efficient Cardiovascular Parameters Estimation for Fluid-Structure Simulations Using Gappy Proper Orthogonal Decomposition.

As full-scale detailed hemodynamic simulations of the entire vasculature are not feasible, numerical analysis should be focused on specific regions of the cardiovascular system, which requires the identification of lumped parameters to represent the patient behavior outside the simulated computational domain. We present a novel technique for estimating cardiovascular model parameters using gappy Proper Orthogonal Decomposition (g-POD). A POD basis is constructed with FSI simulations for different values of the lumped model parameters, and a linear operator is applied to retain information that can be compared to the available patient measurements. Then, the POD coefficients of the reconstructed solution are computed either by projecting patient measurements or by solving a minimization problem with constraints. The POD reconstruction is then used to estimate the model parameters. In the first test case, the parameter values of a 3-element Windkessel model are approximated using artificial patient measurements, obtaining a relative error of less than 4.2%. In the second case, 4 sets of 3-element Windkessel are approximated in a patient's aorta geometry, resulting in an error of less than 8% for the flow and less than 5% for the pressure. The method shows accurate results even with noisy patient data. It automatically calculates the delay between measurements and simulations and has flexibility in the types of patient measurements that can handle (at specific points, spatial or time averaged). The method is easy to implement and can be used in simulations performed in general-purpose FSI software.

Biological Rhythms Generated by a Single Activator-Repressor Loop with Inhomogeneity and Diffusion.

Common models of circadian rhythms are typically constructed as compartmental reactions of well-mixed biochemicals, incorporating a negative-feedback loop consisting of several intermediate reaction steps essentially required to produce oscillations. Spatial transport of each reactant is often represented as an extra compartmental reaction step. Contrary to this traditional understanding, in this Letter we demonstrate that a single activation-repression biochemical reaction pair is sufficient to generate sustained oscillations if the sites of both reactions are spatially separated and molecular transport is mediated by diffusion. Our proposed scenario represents the simplest configuration in terms of the participating chemical reactions and offers a conceptual basis for understanding biological oscillations and inspiring in vitro assays aimed at constructing minimal clocks.

Interpretable artificial intelligence to optimise use of imatinib after resection in patients with localised gastrointestinal stromal tumours: an observational cohort study.

BACKGROUND: Current guidelines recommend use of adjuvant imatinib therapy for many patients with gastrointestinal stromal tumours (GISTs); however, its optimal treatment duration is unknown and some patient groups do not benefit from the therapy. We aimed to apply state-of-the-art, interpretable artificial intelligence (ie, predictions or prescription logic that can be easily understood) methods on real-world data to establish which groups of patients with GISTs should receive adjuvant imatinib, its optimal treatment duration, and the benefits conferred by this therapy. METHODS: In this observational cohort study, we considered for inclusion all patients who underwent resection of primary, non-metastatic GISTs at the Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY, USA) between Oct 1, 1982, and Dec 31, 2017, and who were classified as intermediate or high risk according to the Armed Forces Institute of Pathology Miettinen criteria and had complete follow-up data with no missing entries. A counterfactual random forest model, which used predictors of recurrence (mitotic count, tumour size, and tumour site) and imatinib duration to infer the probability of recurrence at 7 years for a given patient under each duration of imatinib treatment, was trained in the MSKCC cohort. Optimal policy trees (OPTs), a state-of-the-art interpretable AI-based method, were used to read the counterfactual random forest model by training a decision tree with the counterfactual predictions. The OPT recommendations were externally validated in two cohorts of patients from Poland (the Polish Clinical GIST Registry), who underwent GIST resection between Dec 1, 1981, and Dec 31, 2011, and from Spain (the Spanish Group for Research in Sarcomas), who underwent resection between Oct 1, 1987, and Jan 30, 2011. FINDINGS: Among 1007 patients who underwent GIST surgery in MSKCC, 117 were included in the internal cohort; for the external cohorts, the Polish cohort comprised 363 patients and the Spanish cohort comprised 239 patients. The OPT did not recommend imatinib for patients with GISTs of gastric origin measuring less than 15·9 cm with a mitotic count of less than 11·5 mitoses per 5 mm2 or for those with small GISTs (<5·4 cm) of any site with a count of less than 11·5 mitoses per 5 mm2. In this cohort, the OPT cutoffs had a sensitivity of 92·7% (95% CI 82·4-98·0) and a specificity of 33·9% (22·3-47·0). The application of these cutoffs in the two external cohorts would have spared 38 (29%) of 131 patients in the Spanish cohort and 44 (35%) of 126 patients in the Polish cohort from unnecessary treatment with imatinib. Meanwhile, the risk of undertreating patients in these cohorts was minimal (sensitivity 95·4% [95% CI 89·5-98·5] in the Spanish cohort and 92·4% [88·3-95·4] in the Polish cohort). The OPT tested 33 different durations of imatinib treatment (<5 years) and found that 5 years of treatment conferred the most benefit. INTERPRETATION: If the identified patient subgroups were applied in clinical practice, as many as a third of the current cohort of candidates who do not benefit from adjuvant imatinib would be encouraged to not receive imatinib, subsequently avoiding unnecessary toxicity on patients and financial strain on health-care systems. Our finding that 5 years is the optimal duration of imatinib treatment could be the best source of evidence to inform clinical practice until 2028, when a randomised controlled trial with the same aims is expected to report its findings. FUNDING: National Cancer Institute.

Identifying Gaps in the Treatment Guidelines for Hepatitis C in Peru to Meet International Standards: A Narrative Review.

Hepatitis C virus still represents a major cause of morbidity and mortality worldwide. In Peru, two national practice guidelines for the management of this infection were published more than 5 years ago; however, the latest breakthroughs in the treatment make it necessary to update these guidelines. We reviewed the most recent recommendations of the international guidelines and compared them with the current Peruvian guidelines. We found major differences, such as the use of Glecaprevir/Pibrentasvir as a first-line therapy, which is contemplated in the World Health Organization guideline, and recommended by American and European guidelines, but is not considered in the Peruvian guidelines. Another crucial difference lies in the management of patients with chronic kidney disease, who are treated nowadays with a variety of direct-acting antivirals, with no restrictions on the use of Sofosbuvir-based regimens in first-world countries, an approach that has not been adopted in Peru. We believe that standardization of the recommendations of the Peruvian guidelines is imperative, including the new therapeutic strategies that have emerged in recent years. We also suggest conducting a cost effectiveness analysis in the Peruvian context to allow for the implementation of new antivirals, and to achieve a better control of hepatitis C in the country.

Influence of Neoadjuvant Therapy on Success of Endoscopic Vacuum Therapy in Anastomotic Leakage after Rectal Resection Because of Rectal Cancer.

Background: For locally advanced rectal cancer, neoadjuvant therapy (NT) is an established element of therapy. Endoscopic vacuum therapy (EVT) has been a relevant treatment option for anastomotic leakage after rectal resection since 2008. The aim was to evaluate the influence of NT on the duration and success of EVT in anastomotic leakage after rectal resection for rectal cancer. Methods: This was a monocentric, retrospective cohort study including patients who underwent rectal resection with primary anastomosis because of histologically proven carcinoma of the rectum in the Department for General and Visceral Surgery of Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin over a period of ten years (2012 to 2022). Results: Overall, 243 patients were included, of which 47 patients (19.3%) suffered from anastomotic leakage grade B with consecutive EVT. A total of 29 (61.7%) patients received NT and 18 patients (38.3%) did not. The median duration of EVT until the removal of the sponge did not differ between patients with and without NT: 24.0 days (95% CI 6.44-41.56) versus 20.0 days (95% CI 17.03-22.97); p = 0.273. The median duration from insertion of EVT until complete healing was 74.0 days with NT (95% CI 10.07-137.93) versus 62.0 days without NT (95% CI 45.99-78.01); p = 0.490. Treatment failure-including early persistence and late onset of recurrent anastomotic leakage-was evident in 27.6% of patients with NT versus 27.8% without NT; p = 0.989. Ostomy was reversed in 19 patients (79.2%) with NT compared to 11 patients (68.8%) without NT; p = 0.456. Overall, continuity was restored in 75% of patients in the long term after EVT. Conclusion: This trial comprised-to our knowledge-the largest study cohort to analyze the outcome of EVT in anastomotic leakage after rectal resection for rectal cancer. We conclude that neoadjuvant therapy neither prolongs EVT nor the time to healing from anastomotic leakage. The rates of treatment failure of EVT and permanent ostomy were not higher when neoadjuvant therapy was used.

Molecular characterization of vaginal microbiota using a new 22-species qRT-PCR test to achieve a relative-abundance and species-based diagnosis of bacterial vaginosis.

Background: Numerous bacteria are involved in the etiology of bacterial vaginosis (BV). Yet, current tests only focus on a select few. We therefore designed a new test targeting 22 BV-relevant species. Methods: Using 946 stored vaginal samples, a new qPCR test that quantitatively identifies 22 bacterial species was designed. The distribution and relative abundance of each species, α- and ß-diversities, correlation, and species co-existence were determined per sample. A diagnostic index was modeled from the data, trained, and tested to classify samples into BV-positive, BV-negative, or transitional BV. Results: The qPCR test identified all 22 targeted species with 95 - 100% sensitivity and specificity within 8 hours (from sample reception). Across most samples, Lactobacillus iners, Lactobacillus crispatus, Lactobacillus jensenii, Gardnerella vaginalis, Fannyhessea (Atopobium) vaginae, Prevotella bivia, and Megasphaera sp. type 1 were relatively abundant. BVAB-1 was more abundant and distributed than BVAB-2 and BVAB-3. No Mycoplasma genitalium was found. The inter-sample similarity was very low, and correlations existed between key species, which were used to model, train, and test a diagnostic index: MDL-BV index. The MDL-BV index, using both species and relative abundance markers, classified samples into three vaginal microbiome states. Testing this index on our samples, 491 were BV-positive, 318 were BV-negative, and 137 were transitional BV. Although important differences in BV status were observed between different age groups, races, and pregnancy status, they were statistically insignificant. Conclusion: Using a diverse and large number of vaginal samples from different races and age groups, including pregnant women, the new qRT-PCR test and MDL-BV index efficiently diagnosed BV within 8 hours (from sample reception), using 22 BV-associated species.

Safety and Effectiveness of COVID-19 Vaccines During Pregnancy: A Living Systematic Review and Meta-analysis.

BACKGROUND: Pregnant persons are susceptible to significant complications following COVID-19, even death. However, worldwide COVID-19 vaccination coverage during pregnancy remains suboptimal. OBJECTIVE: This study assessed the safety and effectiveness of COVID-19 vaccines administered to pregnant persons and shared this evidence via an interactive online website. METHODS: We followed Cochrane methods to conduct this living systematic review. We included studies assessing the effects of COVID-19 vaccines in pregnant persons. We conducted searches every other week for studies until October 2023, without restrictions on language or publication status, in ten databases, guidelines, preprint servers, and COVID-19 websites. The reference lists of eligible studies were hand searched to identify additional relevant studies. Pairs of review authors independently selected eligible studies using the web-based software COVIDENCE. Data extraction and risk of bias assessment were performed independently by pairs of authors. Disagreements were resolved by consensus. We performed random-effects meta-analyses of adjusted relative effects for relevant confounders of comparative studies and proportional meta-analyses to summarize frequencies from one-sample studies using R statistical software. We present the GRADE certainty of evidence from comparative studies. Findings are available on an interactive living systematic review webpage, including an updated evidence map and real-time meta-analyses customizable by subgroups and filters. RESULTS: We included 177 studies involving 638,791 participants from 41 countries. Among the 11 types of COVID-19 vaccines identified, the most frequently used platforms were mRNA (154 studies), viral vector (51), and inactivated virus vaccines (17). Low to very low-certainty evidence suggests that vaccination may result in minimal to no important differences compared to no vaccination in all assessed maternal and infant safety outcomes from 26 fewer to 17 more events per 1000 pregnant persons, and 13 fewer to 9 more events per 1000 neonates, respectively. We found statistically significant reductions in emergency cesarean deliveries (9%) with mRNA vaccines, and in stillbirth (75-83%) with mRNA/viral vector vaccines. Low to very low-certainty evidence suggests that vaccination during pregnancy with mRNA vaccines may reduce severe cases or hospitalizations in pregnant persons with COVID-19 (72%; 95% confidence interval [CI] 42-86), symptomatic COVID-19 (78%; 95% CI 21-94), and virologically confirmed SARS-CoV-2 infection (82%; 95% CI 39-95). Reductions were lower with other vaccine types and during Omicron variant dominance than Alpha and Delta dominance. Infants also presented with fewer severe cases or hospitalizations due to COVID-19 and laboratory-confirmed SARS-CoV-2 infection (64%; 95% CI 37-80 and 66%; 95% CI 37-81, respectively). CONCLUSIONS: We found a large body of evidence supporting the safety and effectiveness of COVID-19 vaccines during pregnancy. While the certainty of evidence is not high, it stands as the most reliable option available, given the current absence of pregnant individuals in clinical trials. Results are shared in near real time in an accessible and interactive format for scientists, decision makers, clinicians, and the general public. This living systematic review highlights the relevance of continuous vaccine safety and effectiveness monitoring, particularly in at-risk populations for COVID-19 impact such as pregnant persons, during the introduction of new vaccines. CLINICAL TRIAL REGISTRATION: PROSPERO: CRD42021281290.

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.

Invasive pneumococcal disease in Latin America and the Caribbean: Serotype distribution, disease burden, and impact of vaccination. A systematic review and meta-analysis.

BACKGROUND: Invasive pneumococcal diseases (IPD) are associated with high morbidity, mortality, and health costs worldwide, particularly in Latin America and the Caribbean (LAC). Surveillance about the distribution of serotypes causing IPD and the impact of pneumococcal vaccination is an important epidemiological tool to monitor disease activity trends, inform public health decision-making, and implement relevant prevention and control measures. OBJECTIVES: To estimate the serotype distribution for IPD and the related disease burden in LAC before, during, and after implementing the pneumococcal vaccine immunization program in LAC. METHODS: Systematic literature review following Cochrane methods of studies from LAC. We evaluated the impact of the pneumococcal vaccine on hospitalization and death during or after hospitalizations due to pneumococcal disease and serotype-specific disease over time. We also analyzed the incidence of serotyped IPD in pneumococcal conjugate vaccine PCV10 and PCV13. The protocol was registered in PROSPERO (ID: CRD42023392097). RESULTS: 155 epidemiological studies were screened and provided epidemiological data on IPD. Meta-analysis of invasive diseases in children <5 years old found that 57%-65% of causative serotypes were included in PCV10 and 66%-84% in PCV13. After PCV introduction, vaccine serotypes declined in IPD, and the emergence of non-vaccine serotypes varied by country. CONCLUSIONS: Pneumococcal conjugate vaccines significantly reduced IPD and shifted serotype distribution in Latin America and the Caribbean. PCV10/PCV13 covered 57-84% of serotypes in children under 5, with marked decline in PCV serotypes post-vaccination. Continuous surveillance remains crucial for monitoring evolving serotypes and informing public health action.

A critical appraisal of the current landscape of resectable BRAF mutated colorectal liver metastases: a systematic review.

BACKGROUND: Patients with surgically resectable BRAF-mutated colorectal liver metastases (CRLM) or limited extrahepatic disease constitute a highly selective subgroup among BRAF-mutated patients, characterized by a more indolent disease biology. This is evident in their suitability for surgical resection. However, initial studies from a decade ago presented a discouraging outlook for these patients, citing early, frequent, multifocal recurrences and a very limited median overall survival (OS) of less than two years. Our objective was to provide an updated, comprehensive, and critically assessed review of the current literature on the prognostic impact of BRAF variants in CRLM, as well as to explore optimal treatment strategies for these patients through a systematic search. METHODS: A systematic literature search of the Medline, Scopus, and CENTRAL databases for studies reporting long-term outcomes of patients with a known BRAF status was performed. RESULTS: A total of 386 unique studies were screened during the study selection process. After applying the exclusion criteria, a total of 18 studies published between 2012 and 2023 were deemed eligible for inclusion. CONCLUSIONS: In contrast to older studies, more recent studies, with larger sample sizes, have revealed that the rate of extrahepatic recurrence is comparable between BRAF-mutated and wild-type patients. Furthermore, they have reported significantly improved survival outcomes, with OS extending up to 52 months. Notably, patients with non-V600E BRAF mutations may even achieve outcomes comparable to those with wild-type BRAF CRLM. Additionally, a few recent studies have compared surgery and systemic therapies, indicating that surgery is associated with improved survival rates, even for patients with the V600E mutation. This challenges the previous belief that BRAF mutations are absolute contraindications to surgical treatment. Surgical denial for technically resectable patients may now be reserved for specific clinical scenarios, such as the presence of a BRAF V600E mutation and concurrent extrahepatic disease.

Healthcare utilisation and quality of life according to atrial fibrillation burden, episode frequency and duration.

BACKGROUND: We aimed to evaluate the association between atrial fibrillation (AF) burden, duration and number of episodes with healthcare utilisation and quality of life in patients with early paroxysmal AF without a history of AF. METHODS: In this observational cohort study, we included 417 patients with paroxysmal AF from the Reappraisal of Atrial Fibrillation: interaction between hyperCoagulability, Electrical remodelling and Vascular destabilisation in the progression of AF (RACE V) Study. Patients were monitored with an insertable cardiac monitor for 1 year. Outcomes collected were healthcare utilisation, and quality of life assessed using the Atrial Fibrillation Severity Scale and EuroQol EQ-5D-5L questionnaires. RESULTS: During 1 year of follow-up, 63 973 AF episodes were detected in 353 (85%) patients. The median AF burden was 0.7% (IQR 0.1-4.0%). AF ablation was performed more frequently in patients with intermediate-to-high AF burdens (>0.2%) (16.2% vs 5.9%, p=0.01) and longer AF episode duration (>1 hour) (15.8% vs 2.0%, p=0.01), whereas cardioversions were more frequent in patients with longer episode duration (>1 hour) (9.5% vs 0%, p=0.04) and intermediate (0.2-1.9%) (but not high) AF burdens (13.6% vs 4.2%, p=0.01). Patients with many episodes (>147) reported higher symptom severity (p=0.001). No differences in symptom severity nor in EQ-5D-5L scores according to AF burden or duration were observed. CONCLUSION: In patients with early paroxysmal AF, higher AF burden and longer episode duration were associated with increased rates of healthcare utilisation but not with symptoms and quality of life. Patients with a higher number of episodes experienced more severe symptoms. TRIAL REGISTRATION NUMBER: NCT02726698.

KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis.

Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth-promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression.

Orbital trochleitis: Literature review.

Trochleitis is clinically and/or radiologically evidenced inflammation of the trochlea or orbital pulley. Clinically it is characterized by pain and hypersensitivity in the superomedial orbital angle, which is increased or triggered by direct palpation of the area and/or eye movements. During the REM (rapid eye movements) phase of sleep, patients with trochleitis suffer from nocturnal micro-awakenings that impede their rest, and pain is often associated with visual symptoms (diplopia or Brown's syndrome). The lack of common guidelines for diagnosis and treatment of this disease, its low prevalence and the lack of knowledge of the different entities associated with trochlear pain, leads to underdiagnosis or misdiagnosis. It is essential to know the characteristics of this pathology and to diagnose it correctly, differentiating it from other trochlear pain entities, in order to be able to carry out an adequate therapeutic and prognostic approach. The lack of consensus on the therapeutic protocol means that various treatments are used, in different order and often with a combination of several without a firm scientific basis. This comprehensive review of previous studies concludes that nonsteroidal anti-inflammatory drugs (NSAIDs) achieve an overall complete cure rate of 77%, although this rate decreases to 30% in case of motility restriction or diplopia. Intratrochlear corticosteroid injection achieves an overall complete cure rate of 86%, even in the worst prognosis trochleitis, being the only effective option in NSAID-refractory trochleitis and currently being questioned as the first treatment option.

ENTEROBACTER CLOACAE CARDIAC IMPLANTABLE ELECTRONIC DEVICE INFECTION.

Enterobacter cloacae cardiac implantable electronic device infections are rare but can be associated with significant morbidity and mortality. We report an 11-year-old female with Enterobacter cloacae infection of a dual-chamber transvenous pacemaker pocket. The report is supplemented by a comprehensive review of the literature on Enterobacter cloacae cardiac implantable electronic device infections.

Prostate Cancer Risk Stratification by Digital Histopathology and Deep Learning.

PURPOSE: Prostate cancer (PCa) represents a highly heterogeneous disease that requires tools to assess oncologic risk and guide patient management and treatment planning. Current models are based on various clinical and pathologic parameters including Gleason grading, which suffers from a high interobserver variability. In this study, we determine whether objective machine learning (ML)-driven histopathology image analysis would aid us in better risk stratification of PCa. MATERIALS AND METHODS: We propose a deep learning, histopathology image-based risk stratification model that combines clinicopathologic data along with hematoxylin and eosin- and Ki-67-stained histopathology images. We train and test our model, using a five-fold cross-validation strategy, on a data set from 502 treatment-naïve PCa patients who underwent radical prostatectomy (RP) between 2000 and 2012. RESULTS: We used the concordance index as a measure to evaluate the performance of various risk stratification models. Our risk stratification model on the basis of convolutional neural networks demonstrated superior performance compared with Gleason grading and the Cancer of the Prostate Risk Assessment Post-Surgical risk stratification models. Using our model, 3.9% of the low-risk patients were correctly reclassified to be high-risk and 21.3% of the high-risk patients were correctly reclassified as low-risk. CONCLUSION: These findings highlight the importance of ML as an objective tool for histopathology image assessment and patient risk stratification. With further validation on large cohorts, the digital pathology risk classification we propose may be helpful in guiding administration of adjuvant therapy including radiotherapy after RP.

Effect of dimethyl fumarate on mitochondrial metabolism in a pediatric porcine model of asphyxia-induced in-hospital cardiac arrest.

Neurological and cardiac injuries are significant contributors to morbidity and mortality following pediatric in-hospital cardiac arrest (IHCA). Preservation of mitochondrial function may be critical for reducing these injuries. Dimethyl fumarate (DMF) has shown potential to enhance mitochondrial content and reduce oxidative damage. To investigate the efficacy of DMF in mitigating mitochondrial injury in a pediatric porcine model of IHCA, toddler-aged piglets were subjected to asphyxia-induced CA, followed by ventricular fibrillation, high-quality cardiopulmonary resuscitation, and random assignment to receive either DMF (30 mg/kg) or placebo for four days. Sham animals underwent similar anesthesia protocols without CA. After four days, tissues were analyzed for mitochondrial markers. In the brain, untreated CA animals exhibited a reduced expression of proteins of the oxidative phosphorylation system (CI, CIV, CV) and decreased mitochondrial respiration (p < 0.001). Despite alterations in mitochondrial content and morphology in the myocardium, as assessed per transmission electron microscopy, mitochondrial function was unchanged. DMF treatment counteracted 25% of the proteomic changes induced by CA in the brain, and preserved mitochondrial structure in the myocardium. DMF demonstrates a potential therapeutic benefit in preserving mitochondrial integrity following asphyxia-induced IHCA. Further investigation is warranted to fully elucidate DMF's protective mechanisms and optimize its therapeutic application in post-arrest care.

Efficacy in diet-induced obese mice of the hepatotropic, peripheral cannabinoid 1 receptor inverse agonist TM38837.

BACKGROUND AND PURPOSE: The cannabinoid CB1 receptor has a well-established role in appetite regulation. Drugs antagonizing central CB1 receptors, most notably rimonabant, induced weight loss and improved the metabolic profile in obese individuals but were discontinued due to psychiatric side effects. However, metabolic benefits were only partially attributable to weight loss, implying a role for peripheral receptors, and peripherally restricted CB1 receptor antagonists have since been of interest. Herein, we describe the evaluation of the peripherally restricted potent CB1 receptor inverse agonists TM38837 and TM39875, with acidic functionality, which were administered daily to diet-induced obese (DIO) mice for 5 weeks at doses for which CNS-mediated effects were minimal. EXPERIMENTAL APPROACH: Compounds were tested in dose-response in acute studies to compare efficacy (gastric transport) and extent of CNS exposure (hypothermia and satiety sequence) to demonstrate peripheral restriction and select doses for the subsequent chronic DIO study. KEY RESULTS: TM38837 but not TM39875 produced considerable (26%) weight loss, linked to a sustained reduction in food intake, together with improvements in plasma markers of inflammation and glucose homeostasis. Pharmacokinetic analysis indicated high plasma and low brain levels for both compounds with high liver levels for TM38837 (but not TM39875) due to hepatic uptake. CONCLUSION AND IMPLICATIONS: Weight loss and metabolic benefits of TM38837 are likely not CNS-mediated but could be linked to enhanced liver exposure, which implicates intracellular CB1 receptors in hepatocytes as a possible driver of obesity and co-morbidities.

hnRNPAB inhibits Influenza A virus infection by disturbing polymerase activity.

Influenza A virus (IAV) continuously poses a considerable threat to global health through seasonal epidemics and recurring pandemics. IAV RNA-dependent RNA polymerases (FluPol) mediate the transcription of RNA and replication of the viral genome. Searching for targets that inhibit viral polymerase activity helps us develop better antiviral drugs. Here, we identified heterogeneous nuclear ribonucleoprotein A/B (hnRNPAB) as an anti-influenza host factor. hnRNPAB interacts with NP of IAV to inhibit the interaction between PB1 and NP, which is dependent on the 5-amino-acid peptide of the hnRNPAB C-terminal domain (aa 318-322). We further found that the 5-amino-acid peptide blocks the interaction between PB1 and NP to destroy the FluPol activity. In vivo studies demonstrate that hnRNPAB-deficient mice display higher viral burdens, enhanced cytokine production, and increased mortality after influenza infection. These data demonstrate that hnRNPAB perturbs FluPol complex conformation to inhibit IAV infection, providing insights into anti-influenza defense mechanisms.

Deciphering the Transcription Factor Landscape in Neuroendocrine Prostate Cancer Progression: A Novel Approach to Understand NE Transdifferentiation.

Background and Objective: Prostate cancer (PCa) is a leading cause of cancer mortality in men, with neuroendocrine prostate cancer (NEPC) representing a particularly resistant subtype. The role of transcription factors (TFs) in the progression from prostatic adenocarcinoma (PRAD) to NEPC is poorly understood. This study aims to identify and analyze lineage-specific TF profiles in PRAD and NEPC and illustrate their dynamic shifts during NE transdifferentiation. Methods: A novel algorithmic approach was developed to evaluate the weighted expression of TFs within patient samples, enabling a nuanced understanding of TF landscapes in PCa progression and TF dynamic shifts during NE transdifferentiation. Results: unveiled TF profiles for PRAD and NEPC, identifying 126 shared TFs, 46 adenocarcinoma-TFs, and 56 NEPC-TFs. Enrichment analysis across multiple clinical cohorts confirmed the lineage specificity and clinical relevance of these lineage-TFs signatures. Functional analysis revealed that lineage-TFs are implicated in pathways critical to cell development, differentiation, and lineage determination. Novel lineage-TF candidates were identified, offering potential targets for therapeutic intervention. Furthermore, our longitudinal study on NE transdifferentiation highlighted dynamic TF expression shifts and delineated a three-phase hypothesis for the process comprised of de-differentiation, dormancy, and re-differentiation. and proposing novel insights into the mechanisms of PCa progression. Conclusion: The lineage-specific TF profiles in PRAD and NEPC reveal a dynamic shift in the TF landscape during PCa progression, highlighting three distinct phases of NE transdifferentiation.

Facility- and patient-level factors associated with implementation of contact precautions in hospitalized VA patients with positive CRE cultures.

Decreasing the time to contact precautions (CP) is critical to carbapenem-resistant Enterobacterales (CRE) prevention. Identifying factors associated with delayed CP can decrease the spread from patients with CRE. In this study, a shorter length of stay was associated with being placed in CP within 3 days.