Innovations in the Treatment of Spinal Cerebrospinal Fluid Leaks.

Spontaneous spinal cerebrospinal fluid (CSF) leaks are uncommon but can be neurologically debilitating. When initial treatments fail, definitive repair or closure of the leak is indicated. Depending upon the type of leak present, innovative strategies for their treatment have been developed. Among them are open surgical techniques using a transdural approach for the closure of ventral CSF leaks, minimally invasive tubular techniques for the reduction and repair of lateral meningeal diverticula, and endovascular embolization of CSF-venous fistulas. Illustrative cases demonstrating the indications for and implementation of these techniques are provided.

A randomised controlled trial of Standard Of Care versus RadioAblaTion in Early Stage HepatoCellular Carcinoma (SOCRATES HCC).

BACKGROUND: Therapeutic options for early-stage hepatocellular carcinoma (HCC) in individual patients can be limited by tumor and location, liver dysfunction and comorbidities. Many patients with early-stage HCC do not receive curative-intent therapies. Stereotactic ablative body radiotherapy (SABR) has emerged as an effective, non-invasive HCC treatment option, however, randomized evidence for SABR in the first line setting is lacking. METHODS: Trans-Tasman Radiation Oncology Group (TROG) 21.07 SOCRATES-HCC is a phase II, prospective, randomised trial comparing SABR to other current standard of care therapies for patients with a solitary HCC ≤ 8 cm, ineligible for surgical resection or transplantation. The study is divided into 2 cohorts. Cohort 1 will compromise 118 patients with tumors ≤ 3 cm eligible for thermal ablation randomly assigned (1:1 ratio) to thermal ablation or SABR. Cohort 2 will comprise 100 patients with tumors > 3 cm up to 8 cm in size, or tumors ≤ 3 cm ineligible for thermal ablation, randomly assigned (1:1 ratio) to SABR or best other standard of care therapy including transarterial therapies. The primary objective is to determine whether SABR results in superior freedom from local progression (FFLP) at 2 years compared to thermal ablation in cohort 1 and compared to best standard of care therapy in cohort 2. Secondary endpoints include progression free survival, overall survival, adverse events, patient reported outcomes and health economic analyses. DISCUSSION: The SOCRATES-HCC study will provide the first randomized, multicentre evaluation of the efficacy, safety and cost effectiveness of SABR versus other standard of care therapies in the first line treatment of unresectable, early-stage HCC. It is a broad, multicentre collaboration between hepatology, interventional radiology and radiation oncology groups around Australia, coordinated by TROG Cancer Research. TRIAL REGISTRATION: anzctr.org.au, ACTRN12621001444875, registered 21 October 2021.

Pediatric Electrocardiogram-Based Deep Learning to Predict Secundum Atrial Septal Defects.

Secundum atrial septal defect (ASD2) detection is often delayed, with the potential for late diagnosis complications. Recent work demonstrated artificial intelligence-enhanced ECG analysis shows promise to detect ASD2 in adults. However, its application to pediatric populations remains underexplored. In this study, we trained a convolutional neural network (AI-pECG) on paired ECG-echocardiograms (≤ 2 days apart) to detect ASD2 from patients ≤ 18 years old without major congenital heart disease. Model performance was evaluated on the first ECG-echocardiogram pair per patient for Boston Children's Hospital internal testing and emergency department cohorts using area under the receiver operating (AUROC) and precision-recall (AUPRC) curves. The training cohort comprised of 92,377 ECG-echocardiogram pairs (46,261 patients; median age 8.2 years) with an ASD2 prevalence of 6.7%. Test groups included internal testing (12,631 patients; median age 7.4 years; 6.9% prevalence) and emergency department (2,830 patients; median age 7.5 years; 4.9% prevalence) cohorts. Model performance was higher in the internal test (AUROC 0.84, AUPRC 0.46) cohort than the emergency department cohort (AUROC 0.80, AUPRC 0.30). In both cohorts, AI-pECG outperformed ECG findings of incomplete right bundle branch block. Model explainability analyses suggest high-risk limb lead features include greater amplitude P waves (suggestive of right atrial enlargement) and V1 RSR' (suggestive of RBBB). Our findings demonstrate the promise of AI-pECG to inexpensively screen and/or detect ASD2 in pediatric patients. Future multicenter validation and prospective trials to inform clinical decision making are warranted.

Patrolling the area, not ousting intruders, relates to reproductive success for territorial male Leon Springs pupfish, Cyprinodon bovinus.

We considered the relationship between the benefits and costs of territorial defense in a wild population of the Leon Springs pupfish, Cyprinodon bovinus. We defined benefit as the number of eggs deposited on an artificial substratum placed within the defender's territory. Costs included two defensive behaviors. First, males frequently "patrolled" their territories, swimming back-and-forth across their area. Second, males chased intruding Pecos gambusia (Gambusia nobilis) as well as small male and female conspecific C. bovinus from their territories. Both of these species prey on the territorial defenders' eggs; additionally, small male C. bovinus will attempt to "steal" spawns from the territorial defender by spawning with females in the territory. Our analyses revealed that only patrol frequency was related to the reproductive benefit of the territory. Neither chases against gambusia nor conspecifics were predicted by egg numbers on the breeding substrata. We speculate that the frequency of patrolling is an indicator of territorial value and note the qualitative differences in chasing behavior against the different species of intruder.

Cranial and Spinal Cerebrospinal Fluid Leaks: Foundations of Identification and Management.

Cerebrospinal fluid (CSF) leaks may occur at the skull base or along the spinal column and can cause a variety of debilitating neurological symptoms for patients. Recognizing the potential presence of a CSF leak and then identifying its source are necessary for accurate diagnosis and definitive treatment. A standardized workflow can be followed for successful leak localization, which often requires several diagnostic studies, and for definitive leak treatment, which can range from minimally invasive, needle-based approaches to a variety of surgical corrections. This review paper provides an overview of epidemiology, pathophysiology, and diagnostic workup for CSF leaks and introduces available treatment options. An illustrative case of a skull base CSF leak demonstrating diagnosis and surgical correction is provided.

Cerebrospinal Fluid Leaks: Challenges in Localizing Spontaneous Spinal Leak Sites and Minimally Invasive Treatment.

The confirmation of cerebrospinal fluid (CSF) leaks in the setting of spontaneous intracranial hypotension (SIH) by imaging involves a growing toolset of multimodal advanced spinal and skull base imaging techniques, for which exists a unique set of challenges for each CSF leak type. Furthermore, the repertoire of minimally invasive CSF leak treatment beyond nontargeted epidural blood patch administration has grown widely, with varied practices across institutions. This review describes current diagnostic imaging and treatment modalities as they apply to the challenges of CSF leak localization and management.

Behavioral interventions and behavior change techniques used to improve sleep outcomes in athlete populations: A scoping review.

BACKGROUND: Athletes display a high prevalence of undesired sleep characteristics that may affect both performance and wellbeing. OBJECTIVES: This scoping review aimed to identify and map the existing evidence of behavioral sleep interventions and their effects on sleep outcomes in athletes, and retrospectively code the behavior change techniques (BCTs) implemented using the Behavior Change Technique Taxonomy (BCTTv1). METHODS: Conducted following the JBI methodology for scoping reviews, four online databases were used to identify prospective interventions with at least one behavioral component in competitive athletes, and reporting a sleep outcome pre- and post-intervention. RESULTS: Thirty-three studies met the inclusion criteria, encompassing 892 participants with a median age of 23. Five intervention categories were identified (education, mind-body practices, direct, multi-component, and other), with each demonstrating mixed efficacy but the potential to improve sleep outcomes. The BCTs varied in type and frequency between each category, with only 18 unique BCTs identified across all studies. CONCLUSIONS: The varied efficacy of previous studies at improving sleep outcomes may be attributed to the lack of behavior change theory applied during intervention development. Designing interventions following a targeted specification of the behavioral problem, and the integration of corresponding BCTs should be considered in future research.

Use of HSC Targeted LNP to Generate a Mouse Model of Lethal α-Thalassemia and Treatment via Lentiviral Gene Therapy.

-Thalassemia (AT) is one of the most commonly occurring inherited hematological diseases. However, few treatments are available, and allogeneic bone marrow transplantation (BMT) is the only available therapeutic option for patients with severe AT. Research into AT has remained limited due to a lack of adult mouse models, with severe AT typically resulting in in utero lethality. By using a lipid nanoparticle (LNP) targeting the receptor CD117 and delivering a Cre mRNA (mRNACreLNPCD117), we were able to delete floxed -globin genes at high efficiency in hematopoietic stem cells (HSC) ex vivo. These cells were then engrafted in the absence or presence of a novel α-globin expressing lentiviral vector (ALS20I). Myeloablated mice transplanted with mRNACreLNPCD117-treated HSC showed a complete knockout of -globin genes. They demonstrated a phenotype characterized by the synthesis of hemoglobin H (-tetramers,  or HbH), aberrant erythropoiesis, and abnormal organ morphology, culminating in lethality approximately eight weeks following engraftment. Mice receiving mRNACreLNPCD117-treated HSC with at least one copy of ALS20I survived long-term with normalization of erythropoiesis, decreased the production of HbH, and ameliorated the abnormal organ morphology. Furthermore, we tested ALS20I in erythroid progenitors derived from -globin-KO CD34+ and cells isolated from patients with both deletional and non-deletional HbH disease, demonstrating improvement in -globin/-globin mRNA ratio and reduction in the formation of HbH by HPLC. Our results demonstrate the broad applicability of LNP for disease modeling, characterization of a novel severe mouse model of AT, and the efficacy of ALS20I for treating AT.

Real-world use of immune checkpoint inhibitors in advanced or recurrent endometrial cancer.

OBJECTIVE: The aim of this study was to describe real-world use of immune checkpoint inhibitors for women with advanced or recurrent endometrial cancer. METHODS: Adult women with advanced or recurrent endometrial cancer who received at least one line of systemic treatment between January 1, 2014 and November 1, 2020, then followed to May 31, 2021 in a nationwide electronic health record-derived de-identified database. Chi-Squared test or Welch's 2-sample t-tests were used to compare patient and clinical factors associated with immune checkpoint inhibitor treatment. Time to next treatment analyses were performed based on the treatment line of the immune checkpoint inhibitor. Sankey plots depicted patient-level temporal systemic treatment. RESULTS: During our study period, 326 women received their first immune checkpoint inhibitor treatment, increasing from 12 patients in 2016 to 148 in 2020. Factors associated with ever receiving immune checkpoint inhibitors included disease stage (p=0.002), mismatch repair (MMR)/microsatellite instability (MSI) status (p<0.001), performance status (p=0.001), and prior radiation receipt (p<0.001) and modality (p=0.003). The most common immune checkpoint inhibitor regimen was pembrolizumab (47.9%) followed by pembrolizumab and lenvatinib (34.7%). Immune checkpoint inhibitors were given as first, second, and third or greater lines of therapy in 24.5%, 41.7%, and 46.1% of evaluable patients. The median time to next treatment was significantly longer if given as an earlier line of treatment (p=0.008). There were significant differences in treatment line of immune checkpoint inhibitor by region (p=0.004), stage (p<0.001), and prior radiation receipt (p=0.014) and modality (p=0.009). Among 326 patients who received immune checkpoint inhibitors, 114 (34.9%) received subsequent treatment including chemotherapy (43.9%), additional immune checkpoint inhibitors (29.8%), and other (26.3%) with no differences in demographic or clinical characteristics based on the type of post-immune checkpoint inhibitor treatment. CONCLUSION: In an observational retrospective real-world database study, immune checkpoint inhibitors were used in 14.7% of patients with advanced or recurrent endometrial cancer across multiple lines of treatment, including after initial immune checkpoint inhibitor treatment.

Resumen: Consenso internacional para la nomenclatura y clasificación de la válvula aórtica bicúspide congénita y su aortopatía, con fines clínicos, quirúrgicos, intervencionistas y de investigación / Summary: International consensus statement on nomenclature and classification of the congenital bicuspid aortic valve and its aortopathy, for clinical, surgical, interventional and research purposes

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Abstract This consensus of nomenclature and classification for congenital bicuspid aortic valve and its aortopathy is evidence-based and intended for universal use by physicians (both pediatricians and adults), echocardiographers, advanced cardiovascular imaging specialists, interventional cardiologists, cardiovascular surgeons, pathologists, geneticists, and researchers spanning these areas of clinical and basic research. In addition, as long as new key and reference research is available, this international consensus may be subject to change based on evidence-based data1.

Immunomethylomic profiles of long-term head and neck squamous cell carcinoma survivors on immune checkpoint inhibitors.

Aim: This study addresses the challenge of predicting the response of head and neck squamous cell carcinoma (HNSCC) patients to immunotherapy. Methods: Using DNA methylation cytometry, we analyzed the immune profiles of six HNSCC patients who showed a positive response to immunotherapy over a year without disease progression. Results: There was an initial increase in CD8 T memory cells and natural killer cells during the first four cycles of immunotherapy, which then returned to baseline levels after a year. Baseline CD8 T cell levels were lower in HNSCC immunotherapy responders but became similar to those in healthy subjects after immunotherapy. Conclusion: These findings suggest that monitoring fluctuations in immune profiles could potentially identify biomarkers for immunotherapy response in HNSCC patients.

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FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer.

On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro®, Bristol Myers Squibb Corporation), for the treatment of adult patients with locally advanced or metastatic ROS1-positive non-small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter "ROS1-positive") NSCLC, (NCT03093116), who were either treatment naïve or had received prior ROS1 TKI and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors (RECIST) version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI 68, 88); median duration of response was 34.1 months (95% CI 26, NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI 25, 52). The median duration of response was 14.8 months (95% CI 7.6, NE) BICR-assessed responses were observed in CNS metastases in patients in both cohorts, and in patients who developed resistance mutations following prior TKI therapy. The most common (> 20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.

Within-host influenza viral diversity in the pediatric population as a function of age, vaccine, and health status.

Seasonal influenza virus predominantly evolves through antigenic drift, marked by the accumulation of mutations at antigenic sites. Because of antigenic drift, influenza vaccines are frequently updated, though their efficacy may still be limited due to strain mismatches. Despite the high levels of viral diversity observed across populations, most human studies reveal limited intrahost diversity, leaving the origin of population-level viral diversity unclear. Previous studies show host characteristics, such as immunity, might affect within-host viral evolution. Here we investigate influenza A viral diversity in children aged between 6 months and 18 years. Influenza virus evolution in children is less well characterized than in adults, yet may be associated with higher levels of viral diversity given the lower level of pre-existing immunity and longer durations of infection in children. We obtained influenza isolates from banked influenza A-positive nasopharyngeal swabs collected at the Children's Hospital of Philadelphia during the 2017-18 influenza season. Using next-generation sequencing, we evaluated the population of influenza viruses present in each sample. We characterized within-host viral diversity using the number and frequency of intrahost single-nucleotide variants (iSNVs) detected in each sample. We related viral diversity to clinical metadata, including subjects' age, vaccination status, and comorbid conditions, as well as sample metadata such as virus strain and cycle threshold. Consistent with previous studies, most samples contained low levels of diversity with no clear association between the subjects' age, vaccine status, or health status. Further, there was no enrichment of iSNVs near known antigenic sites. Taken together, these findings are consistent with previous observations that the majority of intrahost influenza virus infection is characterized by low viral diversity without evidence of diversifying selection.

Novel Transcriptional and DNA Methylation Abnormalities of SORT1 Gene in Non-Small Cell Lung Cancer.

Sortilin is an important regulator with potential tumour-suppressor function by limiting EGFR signalling. In this study, we undertook a comprehensive expression analysis of sortilin transcript variants and the DNA methylation status of their corresponding promoters in human non-small cell carcinomas (NSCLCs). RNA/DNA was extracted from 81 NSCLC samples and paired normal tissue. mRNA expression was measured by qPCR and DNA methylation determined by pyrosequencing. BigDye-terminator sequencing was used to confirm exon-8 alternative splicing. Results demonstrated that both SORT1A and SORT1B variants were downregulated in lung tumours. The SORT1A/SORT1B expression ratio was higher in tumours compared to normal tissue. SORT1B promoter hypermethylation was detected in lung tumours compared to normal lung (median difference 14%, Mann-Whitney test p = 10-6). Interestingly, SORT1B is hypermethylated in white blood cells, but a small and very consistent drop in methylation (6%, p = 10-15) was observed in the lung cancer cases compared to control subjects. We demonstrate that the SORT1B exon-8 splice variation, reported in sequence databases, is also a feature of SORT1A. The significantly altered quantitative and qualitative characteristics of sortilin mRNA in NSCLC indicate a significant involvement in tumour pathogenesis and may have significant impact for its utility as a predictive marker in lung cancer management.

Enhancement of Filtration Performance Characteristic of Glass Fiber-Based Filter Media, Part 2: Chemical Modification with Surface-Active Treatment.

Standard glass fiber filter media were chemically modified with suitably chosen surface-active agents. The aim of these modifications was to improve the three fundamental filtration performance characteristics, namely, to increase the separation efficiency, reduce the differential pressure (∆P) and increase the dirt holding capacity (DHC). The increase in separation efficiency was considered quantitatively in terms of changes in the work of adhesion between the contaminant and the modified media substrate derived from the contact angle measurements. The experimental confirmation of this behavior was demonstrated by an improved separation efficiency especially for particles in the smaller size ranges, well below the mean porosity of the original substrate. In addition, the effect of different surface modifications, especially those of the opposite ends of the surface energy values, has clearly manifested itself in the experimental results of separation efficiency derived from the multipass evaluations. Collectively, the obtained contact angle (surface energy) and separation efficiency results are strongly indicative of a wide range of filtration performance enhancements that can be achieved through suitably chosen surface-active modification of standard substrate materials.

Metabolomics Simultaneously Derives Benchmark Dose Estimates and Discovers Metabolic Biotransformations in a Rat Bioassay.

Benchmark dose (BMD) modeling estimates the dose of a chemical that causes a perturbation from baseline. Transcriptional BMDs have been shown to be relatively consistent with apical end point BMDs, opening the door to using molecular BMDs to derive human health-based guidance values for chemical exposure. Metabolomics measures the responses of small-molecule endogenous metabolites to chemical exposure, complementing transcriptomics by characterizing downstream molecular phenotypes that are more closely associated with apical end points. The aim of this study was to apply BMD modeling to in vivo metabolomics data, to compare metabolic BMDs to both transcriptional and apical end point BMDs. This builds upon our previous application of transcriptomics and BMD modeling to a 5-day rat study of triphenyl phosphate (TPhP), applying metabolomics to the same archived tissues. Specifically, liver from rats exposed to five doses of TPhP was investigated using liquid chromatography-mass spectrometry and 1H nuclear magnetic resonance spectroscopy-based metabolomics. Following the application of BMDExpress2 software, 2903 endogenous metabolic features yielded viable dose-response models, confirming a perturbation to the liver metabolome. Metabolic BMD estimates were similarly sensitive to transcriptional BMDs, and more sensitive than both clinical chemistry and apical end point BMDs. Pathway analysis of the multiomics data sets revealed a major effect of TPhP exposure on cholesterol (and downstream) pathways, consistent with clinical chemistry measurements. Additionally, the transcriptomics data indicated that TPhP activated xenobiotic metabolism pathways, which was confirmed by using the underexploited capability of metabolomics to detect xenobiotic-related compounds. Eleven biotransformation products of TPhP were discovered, and their levels were highly correlated with multiple xenobiotic metabolism genes. This work provides a case study showing how metabolomics and transcriptomics can estimate mechanistically anchored points-of-departure. Furthermore, the study demonstrates how metabolomics can also discover biotransformation products, which could be of value within a regulatory setting, for example, as an enhancement of OECD Test Guideline 417 (toxicokinetics).

Enteral Nutrition in Operated-On Gastric Cancer Patients: An Update.

It is well established that the preoperative nutritional status of gastric cancer (GC) patients significantly affects the prognosis of the operated patients, their overall survival, as well as the disease-specific survival. Existing data support that preoperative assessment of nutritional status and early correction of nutritional deficiencies exert a favorable effect on early postoperative outcomes. A variety of relevant indices are used to assess the nutritional status of GC patients who are candidates for surgery. The guidelines of almost all international organizations recommend the use of oral enteral nutrition (EN). Oncologically acceptable types of gastrectomy and methods of patient rehabilitation should take into account the expected postoperative nutritional status. The majority of data support that perioperative EN reduces complications and hospital stay, but not mortality. Oral EN in the postoperative period, albeit in small amounts, helps to reduce the weight loss that is a consequence of gastrectomy. Iron deficiency with or without anemia and low serum levels of vitamin B12 are common metabolic sequelae after gastrectomy and should be restored. EN also significantly helps patients undergoing neoadjuvant or adjuvant antineoplastic therapy. The occurrence of the so-called "postgastrectomy syndromes" requires dietary modifications and drug support. This review attempts to highlight the benefits of EN in GC patients undergoing gastrectomy and to emphasize the type of necessary nutritional management, based on current literature data.

The Biting Colon: An Unfortunate Nightmare for a Healthy but Anxious Patient.

A 48-year-old female with no significant past medical history presented to the emergency department with an uncommon scenario after accidentally ingesting a three-unit dental bridge, leading to its impaction within the lower gastrointestinal tract. Despite initial conservative management with laxatives aimed at facilitating spontaneous passage, the foreign body remained lodged in the colon. Subsequently, the patient underwent endoscopic intervention via colonoscopy, during which the dental bridge was successfully extracted. This case highlights the complexity of managing foreign body ingestions, particularly when impaction occurs in uncommon locations, such as the colon. We emphasize the importance of individualized care strategies and recognize the potential of endoscopic procedures in resolving clinical scenarios involving foreign body ingestions.

Sleep, Nutrition, and Health Maintenance in Cardiothoracic Surgery.

Cardiothoracic surgeons work in high-intensity environments starting in surgical training and throughout their careers. They deal with critical patients. Their routine procedures are delicate, require extensive attention to detail, and can have detrimental effects on patients' lives. Cardiothoracic surgeons are required to perform at their best capacity incessantly. To do this, they must safeguard their mental and physical well-being. Preserving health through sleep, nutrition, exercise, and routine medical checkups ensures a cardiothoracic surgeon's well-being. Great personal effort and discipline is required to maintain health in a busy schedule. We offer our best recommendations from expert peers in the field.