Modified Broström vs suture tape augmentation: A systematic review.

Ankle sprains are common musculoskeletal injuries which can develop into residual chronic lateral ankle instability. When non-surgical treatments fail, surgical intervention is often indicated. We performed a systematic review of the literature comparing outcome measures of modified Broström repair to suture tape augmentation for lateral ankle stabilization. All studies available in PubMed up to July 2023 were screened. Three randomized controlled trials involving 235 patients met inclusion criteria. All the studies reported on Foot and Ankle Ability Measure, two of the three studies found higher postoperative Sports Activity scores in the suture tape group. Two of the studies reported Foot and Ankle Outcome Score, neither were found to be significantly different. The third study analyzed return to pre-injury level of activity between the two surgical techniques and found a faster return to activity for suture tape compared to modified Broström procedure. Overall, outcome measures show no significant difference between modified Broström and suture tape augmentation.

Human Papillomavirus (HPV)-Related Multiphenotypic Sinonasal Carcinoma With Intracranial Extension and Rapid Recurrence: A Case Report.

HPV-related multiphenotypic sinonasal carcinoma (HMSC) is a rare malignancy of the nasal cavity or paranasal sinuses that often presents with indolent behavior despite aggressive histologic appearance. Herein, we present an unusual case of a patient with HMSC presenting with rapid local recurrence, highlighting the histopathology and diagnostic and therapeutic strategies surrounding HMSC.

The Patterns of Failure and Prognostic Impact of Tumor Location in Patients Undergoing Reirradiation for Glioblastoma.

Introduction  RTOG 1205 is the only randomized study to evaluate the safety and efficacy of reirradiation (reRT) in recurrent glioblastoma (GBM). While this study showed that reRT was safe and improves progression-free survival (PFS), an improved approach to reRT is still needed. In this study, we report on patterns of failure and outcomes in a cohort of patients with recurrent GBM who underwent reRT. We hypothesize that patients at high risk of leptomeningeal spread (LMS) are not good candidates for reRT due to the risk of treatment-related toxicity without clinical benefit. Methods In this retrospective study, patients with recurrent GBM who underwent reRT at a single institution from 2015-2023 were included. Sociodemographic, treatment, and outcomes data were collected via chart review. Time to progression was defined as the time from the start of reRT to progression per the Response Assessment in Neuro-Oncology (RANO) criteria. Overall survival (OS) was defined as the time from the start of reRT to death. PFS and OS were estimated using the Kaplan-Meier method. Results Thirteen patients with recurrent GBM who underwent reRT were identified. The median age at diagnosis was 58 years. Six patients (46.2%) had tumors that were O6-methylguanine-DNA methyltransferase (MGMT) methylated, four (30.8%) were MGMT unmethylated, and three (23.11%) had unknown MGMT status. Eight patients underwent repeat resection after recurrence and before reRT. Most patients (n=7) received 35 Gy in 10 fractions with concurrent bevacizumab, while other patients were treated with 25-40 Gy in 5-15 fractions with grade 1 or less acute toxicity. Three patients were treated with tumor-treating fields. The median follow-up was five months. Median PFS was three months [95% confidence interval (95% CI): one to four months] and median OS was five months (95% CI, 1-8 months) as compared to 7.1 months and 10.1 months, respectively, on RTOG 1205. Five patients developed LMS after reRT, one patient died before progression, and the remaining seven patients all developed progression within one centimeter of the recurrent tumor. Of the patients who developed LMS, all had tumors abutting the ventricles and three underwent resection 2-17 months before reRT. Conclusion Patterns of failure suggest a potential treatment selection approach for patients with recurrent GBM, in which patients at high risk of LMS (tumor abutting ventricles with or without recent surgery) should not undergo reRT, while patients at low risk of LMS are good candidates for reRT. Furthermore, reRT could be administered with reduced margins given that all non-LMS recurrences were within 1cm of the original tumor. Additional studies are needed to validate this approach.

Langerhans Cell Histiocytosis Masked by Constipation: A Case Report and Literature Review.

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplastic disorder that presents in all age groups, although it often affects young children. Patients typically present with lytic bone lesions and an erythematous rash, though other systems such as the digestive, endocrine, lymphatic, and respiratory systems can be involved.  We present a case of LCH that was masked by symptoms of constipation. The patient was a three-year-old female who presented with a primary complaint of constipation accompanied by abdominal and back pain. Further investigation identified an L3 lesion on lumbar spine magnetic resonance imaging, for which a pediatric neurosurgeon performed an open reduction and internal fixation. Pathology confirmed the diagnosis of LCH. This was followed by one year of chemotherapy. To date, she has not had a recurrence of LCH.  This case demonstrates the importance of generating a broad differential diagnosis and determining and treating the etiology of a patient's symptoms rather than the symptoms alone. Physicians must maintain a high index of suspicion for rare diagnoses when symptoms have persisted and more common etiologies have been ruled out. A thorough neurological exam should be performed for all patients with constipation due to an unknown etiology, especially when accompanied by back pain. Although the patient did not present with gastrointestinal (GI) involvement of LCH, nonspecific GI symptoms such as diffuse abdominal pain and bloody diarrhea have been associated with this rare diagnosis. We thoroughly review the literature regarding both GI involvement of LCH and cases of LCH that present with accompanying GI symptoms. Additionally, we highlight the clinical treatment options of LCH.

2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association.

AIM: The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke. METHODS: A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed. STRUCTURE: Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.

Alkynes to (Free) Carbenes to Polycyclic Cyclopropanes.

Carbenes and carbenoids are commonly employed for the synthesis of cyclopropane-containing compounds. Here we report the metal-free, intramolecular cyclopropanation of tethered alkenes by free carbenes derived from alkynes to construct structurally unique multicyclic cyclopropanes with perfect atom economy. The nature of the tether influences both the rate of carbene formation and subsequent competing reaction events. Some of the substrates lead to metastable cyclopropane intermediates that further fragment to furnish interesting isomeric products by mechanistically novel processes. A removable siloxane tether can be utilized to achieve formal intermolecular cyclopropanations and to access cyclopropanol derivatives.

Counting on Change: Conquering Challenges in Teaching Pharmaceutical Calculations.

All pharmacists are expected to accurately perform pharmaceutical calculations to ensure patient safety. In recent years, there have been trends in declining performance on the North American Pharmacist Licensure Examination related to calculations. Understanding the cause of this decline and determining methods to correct underlying issues could benefit pharmacy administration, faculty, students, and patients. The aims of this commentary are to present the factors impacting the students' pharmaceutical calculations abilities, discuss the consequences of declining math skills, and provide a call to action for scholarship of teaching and learning pertaining to calculations, as well as increased administrative support to rectify this challenge.

PHF6 cooperates with SWI/SNF complexes to facilitate transcriptional progression.

Genes encoding subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in nearly 25% of cancers. To gain insight into the mechanisms by which SWI/SNF mutations drive cancer, we contributed ten rhabdoid tumor (RT) cell lines mutant for SWI/SNF subunit SMARCB1 to a genome-scale CRISPR-Cas9 depletion screen performed across 896 cell lines. We identify PHF6 as specifically essential for RT cell survival and demonstrate that dependency on Phf6 extends to Smarcb1-deficient cancers in vivo. As mutations in either SWI/SNF or PHF6 can cause the neurodevelopmental disorder Coffin-Siris syndrome, our findings of a dependency suggest a previously unrecognized functional link. We demonstrate that PHF6 co-localizes with SWI/SNF complexes at promoters, where it is essential for maintenance of an active chromatin state. We show that in the absence of SMARCB1, PHF6 loss disrupts the recruitment and stability of residual SWI/SNF complex members, collectively resulting in the loss of active chromatin at promoters and stalling of RNA Polymerase II progression. Our work establishes a mechanistic basis for the shared syndromic features of SWI/SNF and PHF6 mutations in CSS and the basis for selective dependency on PHF6 in SMARCB1-mutant cancers.

A Narrative Review of Pain in Pediatric Oncology: The Opioid Option.

Opioid therapy is the mainstay for managing pain in pediatric oncology. This narrative review describes the current literature regarding opioids for pediatric cancer pain. The review explores the multifaceted landscape of opioid utilization in this population, including the role of opioids in certain clinical circumstances, modalities of opioid delivery, unique opioids, outpatient and at-home pain management strategies, and other key concepts such as breakthrough pain. This review highlights the importance of individualized dosing and multimodal approaches to enhance efficacy and minimize adverse effects. Drawing from a wide range of evidence, this review offers insights to optimize pediatric oncology pain management.

A fibroblast-dependent TGF-ß1/sFRP2 noncanonical Wnt signaling axis promotes epithelial metaplasia in idiopathic pulmonary fibrosis.

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGF-ß1 signaling inhibitor epigallocatechin gallate (EGCG) to interstitial lung disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA-Seq on spare tissue. Biopsies from untreated patients showed higher fibroblast TGF-ß1 signaling compared with nondisease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGF-ß1 signaling and several proinflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzled-related protein 2 (sFRP2), an unrecognized TGF-ß1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision-cut lung slices (PCLSs) from nondiseased donors, we found TGF-ß1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature cytokeratin 5+ (Krt5+) basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGF-ß1 signaling in ILD and the therapeutic potential of EGCG in reducing idiopathic pulmonary fibrosis-related (IPF-related) transcriptional changes and identify TGF-ß1/noncanonical Wnt pathway crosstalk via sFRP2 as a mechanism for dysfunctional epithelial signaling in IPF/ILD.

Measurement Properties of Backward Walking and Its Sensitivity and Feasibility in Predicting Falls in People With Multiple Sclerosis.

BACKGROUND: People with multiple sclerosis (MS) experience mobility impairments that elevate fall risk, increasing the need to identify clinical measures that accurately predict falls. Backward walking (BW) better differentiates fallers from nonfallers in MS. However, no studies have reported the measurement properties of the backward walking Timed 25-Foot Walk (B-T25-FW) and BW metrics, like BW velocity. Additionally, it is unknown whether BW can predict future falls in MS or its link to activity levels. This study assessed the reliability and responsiveness of B-T25-FW and BW metrics, including BW velocity. It also examined whether BW could predict falls at 3 and 6 months and its association with activity levels. METHODS: During 2 separate visits, 23 people with MS completed the forward walking Timed 25-Foot Walk (F-T25-FW) and B-T25-FW, as well as forward walking and BW assessments in which spatiotemporal measures were recorded. Test-retest reliability was determined with intraclass correlation coefficients, and minimum detectable changes were calculated. Correlation analyses explored the relationship between BW velocity, B-T25-FW, prospective falls, and activity levels. RESULTS: B-T25-FW and BW velocity exhibited excellent test-retest reliability. Large effect sizes to interpret clinically meaningful change in the B-T25-FW and BW velocity were also found. Both metrics demonstrated modest negative correlations with falls at 3 and 6 months and correlated strongly with very active minutes at 3- and 6-months post study. CONCLUSIONS: The B-T25-FW and BW velocity are effective and reliable in clinical use for evaluating functional mobility in people with MS, are sensitive enough to detect subtle changes, and may be a meaningful marker for tracking disease progression and treatment efficacy.

Congenital lymphatic dysplasia and severe bone disease in a term neonate with a novel homozygous PIEZO1 variant.

We report a patient with nonimmune fetal hydrops and multiple pathologic fractures. RNA analysis revealed a novel PIEZO1 variant. This report is the first to elucidate PIEZO1's role as a critical regulator of bone mass and strength.

Spatial lipidomics maps brain alterations associated with mild traumatic brain injury.

Traumatic brain injury (TBI) is a global public health problem with 50-60 million incidents per year, most of which are considered mild (mTBI) and many of these repetitive (rmTBI). Despite their massive implications, the pathologies of mTBI and rmTBI are not fully understood, with a paucity of information on brain lipid dysregulation following mild injury event(s). To gain more insight on mTBI and rmTBI pathology, a non-targeted spatial lipidomics workflow utilizing high resolution mass spectrometry imaging was developed to map brain region-specific lipid alterations in rats following injury. Discriminant multivariate models were created for regions of interest including the hippocampus, cortex, and corpus callosum to pinpoint lipid species that differentiated between injured and sham animals. A multivariate model focused on the hippocampus region differentiated injured brain tissues with an area under the curve of 0.99 using only four lipid species. Lipid classes that were consistently discriminant included polyunsaturated fatty acid-containing phosphatidylcholines (PC), lysophosphatidylcholines (LPC), LPC-plasmalogens (LPC-P) and PC potassium adducts. Many of the polyunsaturated fatty acid-containing PC and LPC-P selected have never been previously reported as altered in mTBI. The observed lipid alterations indicate that neuroinflammation and oxidative stress are important pathologies that could serve to explain cognitive deficits associated with rmTBI. Therapeutics which target or attenuate these pathologies may be beneficial to limit persistent damage following a mild brain injury event.

Phospholipid isotope tracing suggests ß-catenin-driven suppression of phosphatidylcholine metabolism in hepatocellular carcinoma.

Activating mutations in the CTNNB1 gene encoding ß-catenin are among the most frequently observed oncogenic alterations in hepatocellular carcinoma (HCC). Profound alterations in lipid metabolism, including increases in fatty acid oxidation and transformation of the phospholipidome, occur in HCC with CTNNB1 mutations, but it is unclear what mechanisms give rise to these changes. We employed untargeted lipidomics and targeted isotope tracing to measure phospholipid synthesis activity in an inducible human liver cell line expressing mutant ß-catenin, as well as in transgenic zebrafish with activated ß-catenin-driven HCC. In both models, activated ß-catenin expression was associated with large changes in the lipidome including conserved increases in acylcarnitines and ceramides and decreases in triglycerides. Lipid isotope tracing analysis in human cells revealed a reduction in phosphatidylcholine (PC) production rates as assayed by choline incorporation. We developed lipid isotope tracing analysis for zebrafish tumors and observed reductions in phosphatidylcholine synthesis by both the CDP-choline and PEMT pathways. The observed changes in the ß-catenin-driven HCC phospholipidome suggest that zebrafish can recapitulate conserved features of HCC lipid metabolism and may serve as a model for identifying future HCC-specific lipid metabolic targets.

Heart-to-heart: infant heart rate at 3 months is linked to infant-directed speech, mother-infant interaction, and later language outcomes.

Introduction: Previous studies underscore the importance of speech input, particularly infant-directed speech (IDS) during one-on-one (1:1) parent-infant interaction, for child language development. We hypothesize that infants' attention to speech input, specifically IDS, supports language acquisition. In infants, attention and orienting responses are associated with heart rate deceleration. We examined whether individual differences in infants' heart rate measured during 1:1 mother-infant interaction is related to speech input and later language development scores in a longitudinal study. Methods: Using a sample of 31 3-month-olds, we assessed infant heart rate during mother-infant face-to-face interaction in a laboratory setting. Multiple measures of speech input were gathered at 3 months of age during naturally occurring interactions at home using the Language ENvironment Analysis (LENA) system. Language outcome measures were assessed in the same children at 30 months of age using the MacArthur-Bates Communicative Development Inventory (CDI). Results: Two novel findings emerged. First, we found that higher maternal IDS in a 1:1 context at home, as well as more mother-infant conversational turns at home, are associated with a lower heart rate measured during mother-infant social interaction in the laboratory. Second, we found significant associations between infant heart rate during mother-infant interaction in the laboratory at 3 months and prospective language development (CDI scores) at 30 months of age. Discussion: Considering the current results in conjunction with other converging theoretical and neuroscientific data, we argue that high IDS input in the context of 1:1 social interaction increases infants' attention to speech and that infants' attention to speech in early development fosters their prospective language growth.

Exploring Gut Microbiota Alterations with Trimethoprim-Sulfamethoxazole and Dexamethasone in a Humanized Microbiome Mouse Model.

Along with the standard therapies for glioblastoma, patients are commonly prescribed trimethoprim-sulfamethoxazole (TMP-SMX) and dexamethasone for preventing infections and reducing cerebral edema, respectively. Because the gut microbiota impacts the efficacy of cancer therapies, it is important to understand how these medications impact the gut microbiota of patients. Using mice that have been colonized with human microbiota, this study sought to examine how TMP-SMX and dexamethasone affect the gut microbiome. Two lines of humanized microbiota (HuM) Rag1-/- mice, HuM1Rag and HuM2Rag, were treated with either TMP-SMX or dexamethasone via oral gavage once a day for a week. Fecal samples were collected pre-treatment (pre-txt), one week after treatment initiation (1 wk post txt), and three weeks post-treatment (3 wk post txt), and bacterial DNA was analyzed using 16S rRNA-sequencing. The HuM1Rag mice treated with TMP-SMX had significant shifts in alpha diversity, beta diversity, and functional pathways at all time points, whereas in the HuM2Rag mice, it resulted in minimal changes in the microbiome. Likewise, dexamethasone treatment resulted in significant changes in the microbiome of the HuM1Rag mice, whereas the microbiome of the HuM2Rag mice was mostly unaffected. The results of our study show that routine medications used during glioblastoma treatment can perturb gut microbiota, with some microbiome compositions being more sensitive than others, and these treatments could potentially affect the overall efficacy of standard-of-care therapy.

External validation of the SI2NCAL2C score for outcomes following cerebral venous thrombosis.

OBJECTIVES: Prognostication for cerebral venous thrombosis (CVT) remains difficult. We sought to validate the SI2NCAL2C score in an international cohort. MATERIALS AND METHODS: The SI2NCAL2C score was originally developed to predict poor outcome (modified Rankin Scale (mRS) 3-6) at 6 months, and mortality at 30 days and 1 year using data from the International CVT Consortium. The SI2NCAL2C score uses 9 variables: the absence of any female-sex-specific risk factors, intracerebral hemorrhage, central nervous system infection, focal neurological deficits, coma, age, lower level of hemoglobin, higher level of glucose, and cancer. The ACTION-CVT study was an international retrospective study that enrolled consecutive patients across 27 centers. The poor outcome score was validated using 90-day mRS due to lack of follow-up at the 6-month time-point in the ACTION-CVT cohort. Model performance was evaluated using the area under the receiver operating characteristic curve (AUC) and calibration plots. Missing data were imputed using the additive regression and predictive mean matching methods. Bootstrapping was performed with 1000 iterations. RESULTS: Mortality data were available for 950 patients and poor outcome data were available for 587 of 1,025 patients enrolled in ACTION-CVT. Compared to the International CVT Consortium, the ACTION-CVT cohort was older, less often female, and with milder clinical presentation. Mortality was 2.5% by 30 days and 6.0% by one year. At 90-days, 16.7% had a poor outcome. The SI2NCAL2C score had an AUC of 0.74 [95% CI 0.69-0.79] for 90-day poor outcome, 0.72 [0.60-0.82] for mortality by 30 days, and 0.82 [0.76-0.88] for mortality by one year. CONCLUSIONS: The SI2NCAL2C score had acceptable to good performance in an international external validation cohort. The SI2NCAL2C score warrants additional validation studies in diverse populations and clinical implementation studies.

Mercury and selenium distribution in human brain tissue using synchrotron micro-X-ray fluorescence.

Mercury is a well-recognized environmental contaminant and neurotoxin, having been associated with a number of deleterious neurological conditions including neurodegenerative diseases, such as Alzheimer's disease. To investigate how mercury and other metals behave in the brain, we used synchrotron micro-X-ray fluorescence to map the distribution pattern and quantify concentrations of metals in human brain. Brain tissue was provided by the Rush Alzheimer's Disease Center and samples originated from individuals diagnosed with Alzheimer's disease and without cognitive impairment. Data were collected at the 2-ID-E beamline at the Advanced Photon Source at Argonne National Laboratory with an incident beam energy of 13 keV. Course scans were performed at low resolution to determine gross tissue features, after which smaller regions were selected to image at higher resolution. The findings revealed (1) the existence of mercury particles in the brain samples of two subjects; (2) co-localization and linear correlation of mercury and selenium in all particles; (3) co-localization of these particles with zinc structures; and (4) association with sulfur in some of these particles. These results suggest that selenium and sulfur may play protective roles against mercury in the brain, potentially binding with the metal to reduce the induced toxicity, although at different affinities. Our findings call for further studies to investigate the relationship between mercury, selenium, and sulfur, as well as the potential implications in Alzheimer's disease and related dementias.