A microbiome-directed therapeutic food for children recovering from severe acute malnutrition.

Severe acute malnutrition (SAM), defined anthropometrically as a weight-for-length z-score more than 3 standard deviations below the mean (WLZ<-3), affects 19 million children under 5-years-old worldwide. Complete anthropometric recovery after standard inventions is rare with children often left with moderate acute malnutrition (MAM; WLZ -2 to -3). Here we conduct a randomized controlled trial (RCT), involving 12-18-month-old Bangladeshi children from urban and rural sites, who after hospital-based treatment for SAM received a 3-month intervention with a microbiota-directed complementary food (MDCF-2) or a ready-to-use supplementary food (RUSF) as they transitioned to MAM. The rate of WLZ improvement was significantly greater with MDCF-2 than the more calorically-dense RUSF, as we observed in a previous RCT of Bangladeshi children with MAM without antecedent SAM. A correlated meta-analysis of aptamer-based measurements of 4,520 plasma proteins in this and the prior RCT revealed 215 proteins positively-associated with WLZ (prominently those involved in musculoskeletal and CNS development) and 44 negatively-associated proteins (related to immune activation), with a significant enrichment in levels of the positively WLZ-associated proteins in the MDCF-2 arm. Characterizing changes in 754 bacterial metagenome-assembled genomes in serially collected fecal samples disclosed the effects of acute rehabilitation for SAM on the microbiome, its transition as each child achieves a state of MAM, and how specific strains of Prevotella copri function at the intersection between MDCF-2 glycan metabolism and the rescue of growth faltering. These results provide a rationale for further testing the generalizability of the efficacy of MDCF and identify biomarkers for defining treatment responses.

Particle-assisted formation of oil-in-liquid metal emulsions.

Gallium-based liquid metals (LM) have surface tension an order of magnitude higher than water and break up into micro-droplets when mixed with other liquids. In contrast, silicone oil readily mixes into LM foams to create oil-in-LM emulsions with oil inclusions. Previously, the LM was foamed through rapid mixing in air for an extended duration (over 2 hours). This process first results in the internalization of oxide flakes that form at the air-liquid interface. Once a critical fraction of these randomly shaped solid flakes is reached, air bubbles internalize into the LM to create foams that can internalize secondary liquids. Here, we introduce an alternative oil-in-LM emulsion fabrication method that relies on the prior addition of SiO2 micro-particles into the LM before mixing it with the silicone oil. This particle-assisted emulsion formation process provides a higher control over the composition of the LM-particle mixture before oil addition, which we employ to systematically study the impact of particle characteristics and content on the emulsions' composition and properties. We demonstrate that the solid particle size (0.8 µm to 5 µm) and volume fraction (1% to 10%) have a negligible impact on the internalization of the oil inclusions. The inclusions are mostly spherical with diameters of 20 to 100 µm diameter and are internalized by forming new, rather than filling old, geometrical features. We also study the impact of the particle characteristics on the two key properties related to the functional application of the LM emulsions in the thermal management of microelectronics. In particular, we measure the impact of particles and silicone oil on the emulsion's thermal conductivity and its ability to prevent deleterious gallium-induced corrosion and embrittlement of contacting metal substrates. .

NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer.

Nitric oxide (NO) and reactive nitrogen species (RNS) exert profound biological impacts dictated by their chemistry. Understanding their spatial distribution is essential for deciphering their roles in diverse biological processes. This review establishes a framework for the chemical biology of NO and RNS, exploring their dynamic reactions within the context of cancer. Concentration-dependent signaling reveals distinctive processes in cancer, with three levels of NO influencing oncogenic properties. In this context, NO plays a crucial role in cancer cell proliferation, metastasis, chemotherapy resistance, and immune suppression. Increased NOS2 expression correlates with poor survival across different tumors, including breast cancer. Additionally, NOS2 can crosstalk with the proinflammatory enzyme cyclooxygenase-2 (COX-2) to promote cancer progression. NOS2 and COX-2 co-expression establishes a positive feed-forward loop, driving immunosuppression and metastasis in estrogen receptor-negative (ER-) breast cancer. Spatial evaluation of NOS2 and COX-2 reveals orthogonal expression, suggesting the unique roles of these niches in the tumor microenvironment (TME). NOS2 and COX2 niche formation requires IFN-γ and cytokine-releasing cells. These niches contribute to poor clinical outcomes, emphasizing their role in cancer progression. Strategies to target these markers include direct inhibition, involving pan-inhibitors and selective inhibitors, as well as indirect approaches targeting their induction or downstream effectors. Compounds from cruciferous vegetables are potential candidates for NOS2 and COX-2 inhibition offering therapeutic applications. Thus, understanding the chemical biology of NO and RNS, their spatial distribution, and their implications in cancer progression provides valuable insights for developing targeted therapies and preventive strategies.

Targeting complement C3a receptor resolves mitochondrial hyperfusion and subretinal microglial activation in progranulin-deficient frontotemporal dementia.

Mutations in progranulin ( GRN ) cause frontotemporal dementia ( GRN -FTD) due to deficiency of the pleiotropic protein progranulin. GRN -FTD exhibits diverse pathologies including lysosome dysfunction, lipofuscinosis, microgliosis, and neuroinflammation. Yet, how progranulin loss causes disease remains unresolved. Here, we report that non-invasive retinal imaging of GRN -FTD patients revealed deficits in photoreceptors and the retinal pigment epithelium (RPE) that correlate with cognitive decline. Likewise, Grn -/- mice exhibit early RPE dysfunction, microglial activation, and subsequent photoreceptor loss. Super-resolution live imaging and transcriptomic analyses identified RPE mitochondria as an early driver of retinal dysfunction. Loss of mitochondrial fission protein 1 (MTFP1) in Grn -/- RPE causes mitochondrial hyperfusion and bioenergetic defects, leading to NF-kB-mediated activation of complement C3a-C3a receptor signaling, which drives further mitochondrial hyperfusion and retinal inflammation. C3aR antagonism restores RPE mitochondrial integrity and limits subretinal microglial activation. Our study identifies a previously unrecognized mechanism by which progranulin modulates mitochondrial integrity and complement-mediated neuroinflammation.

Outcomes and Pattern of Care for Spinal Myxopapillary Ependymoma in the Modern Era-A Population-Based Observational Study.

(1) Background: Myxopapillary ependymoma (MPE) is a rare tumor of the spine, typically slow-growing and low-grade. Optimal management strategies remain unclear due to limited evidence given the low incidence of the disease. (2) Methods: We analyzed data from 1197 patients with spinal MPE from the Surveillance, Epidemiology, and End Results (SEER) database (2000-2020). Patient demographics, treatment modalities, and survival outcomes were examined using statistical analyses. (3) Results: Most patients were White (89.9%) with a median age at diagnosis of 42 years. Surgical resection was performed in 95% of cases. The estimated 10-year overall survival was 91.4%. Younger age (hazard ratio (HR) = 1.09, p < 0.001) and receipt of surgery (HR = 0.43, p = 0.007) were associated with improved survival. Surprisingly, male sex was associated with worse survival (HR = 1.86, p = 0.008) and a younger age at diagnosis compared to females. (4) Conclusions: This study, the largest of its kind, underscores the importance of surgical resection in managing spinal MPE. The unexpected association between male sex and worse survival warrants further investigation into potential sex-specific pathophysiological factors influencing prognosis. Despite limitations, our findings contribute valuable insights for guiding clinical management strategies for spinal MPE.

IMPDH Inhibition Decreases TERT Expression and Synergizes the Cytotoxic Effect of Chemotherapeutic Agents in Glioblastoma Cells.

IMP dehydrogenase (IMPDH) inhibition has emerged as a new target therapy for glioblastoma multiforme (GBM), which remains one of the most refractory tumors to date. TCGA analyses revealed distinct expression profiles of IMPDH isoenzymes in various subtypes of GBM and low-grade glioma (LGG). To dissect the mechanism(s) underlying the anti-tumor effect of IMPDH inhibition in adult GBM, we investigated how mycophenolic acid (MPA, an IMPDH inhibitor) treatment affected key oncogenic drivers in glioblastoma cells. Our results showed that MPA decreased the expression of telomerase reverse transcriptase (TERT) in both U87 and U251 cells, and the expression of O6-methylguanine-DNA methyltransferase (MGMT) in U251 cells. In support, MPA treatment reduced the amount of telomere repeats in U87 and U251 cells. TERT downregulation by MPA was associated with a significant decrease in c-Myc (a TERT transcription activator) in U87 but not U251 cells, and a dose-dependent increase in p53 and CCCTC-binding factor (CTCF) (TERT repressors) in both U87 and U251 cells. In U251 cells, MPA displayed strong cytotoxic synergy with BCNU and moderate synergy with irinotecan, oxaliplatin, paclitaxel, or temozolomide (TMZ). In U87 cells, MPA displayed strong cytotoxic synergy with all except TMZ, acting primarily through the apoptotic pathway. Our work expands the mechanistic potential of IMPDH inhibition to TERT/telomere regulation and reveals a synthetic lethality between MPA and anti-GBM drugs.

ACR Appropriateness Criteria® Dizziness and Ataxia: 2023 Update.

Diagnostic evaluation of a patient with dizziness or vertigo is complicated by a lack of standardized nomenclature, significant overlap in symptom descriptions, and the subjective nature of the patient's symptoms. Although dizziness is an imprecise term often used by patients to describe a feeling of being off-balance, in many cases dizziness can be subcategorized based on symptomatology as vertigo (false sense of motion or spinning), disequilibrium (imbalance with gait instability), presyncope (nearly fainting or blacking out), or lightheadedness (nonspecific). As such, current diagnostic paradigms focus on timing, triggers, and associated symptoms rather than subjective descriptions of dizziness type. Regardless, these factors complicate the selection of appropriate diagnostic imaging in patients presenting with dizziness or vertigo. This document serves to aid providers in this selection by using a framework of definable clinical variants. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Cerebrovascular Diseases-Stroke and Stroke-Related Conditions.

Cerebrovascular disease encompasses a vast array of conditions. The imaging recommendations for stroke-related conditions involving noninflammatory steno-occlusive arterial and venous cerebrovascular disease including carotid stenosis, carotid dissection, intracranial large vessel occlusion, and cerebral venous sinus thrombosis are encompassed by this document. Additional imaging recommendations regarding complications of these conditions including intraparenchymal hemorrhage and completed ischemic strokes are also discussed. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

A shared group of bacterial taxa in the duodenal microbiota of undernourished Pakistani children with environmental enteric dysfunction.

Environmental enteric dysfunction (EED) is a subclinical syndrome of altered small intestinal function postulated to be an important contributor to childhood undernutrition. The role of small intestinal bacterial communities in the pathophysiology of EED is poorly defined due to a paucity of studies where there has been a direct collection of small intestinal samples from undernourished children. Sixty-three members of a Pakistani cohort identified as being acutely malnourished between 3 and 6 months of age and whose wasting (weight-for-length Z-score [WLZ]) failed to improve after a 2-month nutritional intervention underwent esophagogastroduodenoscopy (EGD). Paired duodenal luminal aspirates and duodenal mucosal biopsies were obtained from 43 children. Duodenal microbiota composition was characterized by sequencing bacterial 16S rRNA gene amplicons. Levels of bacterial taxa (amplicon sequence variants [ASVs]) were referenced to anthropometric indices, histopathologic severity in biopsies, expression of selected genes in the duodenal mucosa, and fecal levels of an immunoinflammatory biomarker (lipocalin-2). A "core" group of eight bacterial ASVs was present in the duodenal samples of 69% of participants. Streptococcus anginosus was the most prevalent, followed by Streptococcus sp., Gemella haemolysans, Streptococcus australis, Granulicatella elegans, Granulicatella adiacens, and Abiotrophia defectiva. At the time of EGD, none of the core taxa were significantly correlated with WLZ. Statistically significant correlations were documented between the abundances of Granulicatella elegans and Granulicatella adiacens and the expression of duodenal mucosal genes involved in immune responses (dual oxidase maturation factor 2, serum amyloid A, and granzyme H). These results suggest that a potential role for members of the oral microbiota in pathogenesis, notably Streptococcus, Gemella, and Granulicatella species, warrants further investigation.IMPORTANCEUndernutrition among women and children is a pressing global health problem. Environmental enteric dysfunction (EED) is a disease of the small intestine (SI) associated with impaired gut mucosal barrier function and reduced capacity for nutrient absorption. The cause of EED is ill-defined. One emerging hypothesis is that alterations in the SI microbiota contribute to EED. We performed a culture-independent analysis of the SI microbiota of a cohort of Pakistani children with undernutrition who had failed a standard nutritional intervention, underwent upper gastrointestinal tract endoscopy, and had histologic evidence of EED in their duodenal mucosal biopsies. The results revealed a shared group of bacterial taxa in their duodenums whose absolute abundances were correlated with levels of the expression of genes in the duodenal mucosa that are involved in inflammatory responses. A number of these bacterial taxa are more typically found in the oral microbiota, a finding that has potential physiologic and therapeutic implications.

PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival.

NK cell therapeutics have gained significant attention as a potential cancer treatment. Towards therapeutic use, NK cells need to be activated and expanded to attain high potency and large quantities for an effective dosage. This is typically done by ex vivo stimulation with cytokines to enhance functionality or expansion for 10-14 days to increase both their activity and quantity. Attaining a robust methodology to produce large doses of potent NK cells for an off-the-shelf product is highly desirable. Notably, past reports have shown that stimulating NK cells with IL-12, IL-15, and IL-18 endows them with memory-like properties, better anti-tumor activity, and persistence. While this approach produces NK cells with clinically favorable characteristics supported by encouraging early results for the treatment of hematological malignancies, its limited scalability, variability in initial doses, and the necessity for patient-specific production hinder its broader application. In this study, stimulation of NK cells with PM21-particles derived from K562-41BBL-mbIL21 cells was combined with memory-like induction using cytokines IL-12, IL-15, and IL-18 to produce NK cells with enhanced anti-tumor function. The use of cytokines combined with PM21-particles (cytokine and particle, CAP) significantly enhanced NK cell expansion, achieving a remarkable 8,200-fold in 14 days. Mechanistically, this significant improvement over expansion with PM21-particles alone was due to the upregulation of receptors for key stimulating ligands (4-1BBL and IL-2), resulting in a synergy that drives substantial NK cell growth, showcasing the potential for more effective therapeutic applications. The therapeutic potential of CAP-NK cells was demonstrated by the enhanced metabolic fitness, persistence, and anti-tumor function both in vitro and in vivo. Finally, CAP-NK cells were amenable to current technologies used in developing therapeutic NK cell products, including CRISPR/Cas9-based techniques to generate a triple-gene knockout or a gene knock-in. Taken together, these data demonstrate that the addition of cytokines enhanced the already effective method of ex vivo generation of therapeutic NK cells with PM21-particles, yielding a superior NK cell product for manufacturing efficiency and potential therapeutic applications.

Mechanical Ventilation in Older Adults With Dementia: Opportunities to Promote Goal-Concordant Care.

CONTEXT: Recent studies show increasing use of mechanical ventilation among people living with dementia. There are concerns that this trend may not be driven by patient preferences. OBJECTIVES: To better understand decision-making regarding mechanical ventilation in people living with dementia. METHODS: This was an electronic health record-based retrospective cohort study of older adults with dementia (n = 295) hospitalized at one of two teaching hospitals between 2015 and 2019 who were supported with mechanical ventilation (n = 191) or died without mechanical ventilation (n = 104). Multivariable logistic regression was used to examine associations between patient characteristics and mechanical ventilation use. RESULTS: The median age was 78 years (IQR 71-86), 41% were female, 28% resided in a nursing home, and 58% had clinical markers of advanced dementia (dehydration, weight loss, mobility limitations, or pressure ulcers). Among patients supported with mechanical ventilation, 70% were intubated within 24 hours of presentation, including 31% intubated before hospital arrival. Younger age, higher illness acuity, and absence of a treatment-limiting Physician Orders for Life-Sustaining Treatment document were associated with mechanical ventilation use; nursing home residence and clinical markers of advanced dementia were not. Most patients (89%) had a documented goals of care discussion (GOCD) during hospitalization. CONCLUSION: Future efforts to promote goal-concordant care surrounding mechanical ventilation use for people living with dementia should involve identifying barriers to goal-concordant care in pre-hospital settings, assessing the timeliness of in-hospital GOCD, and developing strategies for in-the-moment crisis communication across settings.

Individual and community empowerment improve resource users' perceptions of community-based conservation effectiveness in Kenya and Tanzania.

Community-based conservation has been increasingly recognized as critical to achieve both conservation and socio-economic development goals worldwide. However, the long-term sustainability of community-based conservation programs is dependent on a broadly shared perception among community members that management actions are achieving their stated goals. Thus, understanding the underlying factors driving differences in perceptions of management effectiveness can help managers prioritize the processes and outcomes most valued by resource users and thereby promote sustained support for conservation efforts. Here, we utilize large-scale interview survey data and machine learning to identify the factors most strongly associated with differences in perceived management effectiveness between resource users engaged in marine community-based conservation programs in Kenya and Tanzania. Perceptions of management effectiveness were generally favorable in both countries, and the most important predictors of positive perceptions were associated with community and individual empowerment in resource management and use, but within disparate focal domains. Improved perceptions of management effectiveness in Kenya were closely related to increases in women's empowerment in community-based conservation programs, while inclusionary and transparent governance structures were the most important factors driving improved perceptions in Tanzania. Additionally, the strongest predictors of differences between individuals in both countries often interacted synergistically to produce even higher rates of perceived effectiveness. These findings can help future initiatives in the region tailor management to match community-level priorities and emphasize the need for community-based conservation programs to understand local context to ensure that metrics of "success" are aligned with the needs and desires of local resource users.

Prevotella copri and microbiota members mediate the beneficial effects of a therapeutic food for malnutrition.

Microbiota-directed complementary food (MDCF) formulations have been designed to repair the gut communities of malnourished children. A randomized controlled trial demonstrated that one formulation, MDCF-2, improved weight gain in malnourished Bangladeshi children compared to a more calorically dense standard nutritional intervention. Metagenome-assembled genomes from study participants revealed a correlation between ponderal growth and expression of MDCF-2 glycan utilization pathways by Prevotella copri strains. To test this correlation, here we use gnotobiotic mice colonized with defined consortia of age- and ponderal growth-associated gut bacterial strains, with or without P. copri isolates closely matching the metagenome-assembled genomes. Combining gut metagenomics and metatranscriptomics with host single-nucleus RNA sequencing and gut metabolomic analyses, we identify a key role of P. copri in metabolizing MDCF-2 glycans and uncover its interactions with other microbes including Bifidobacterium infantis. P. copri-containing consortia mediated weight gain and modulated energy metabolism within intestinal epithelial cells. Our results reveal structure-function relationships between MDCF-2 and members of the gut microbiota of malnourished children with potential implications for future therapies.

Pediatric thoracic outlet syndrome: a systematic review and meta-analysis.

OBJECTIVE: Thoracic outlet syndrome (TOS) is a complex disorder affecting the neurovascular structures of the upper extremity as they traverse from the neck and thorax to the upper extremity. This systematic review and meta-analysis focuses on pediatric TOS, offering insights into its clinical presentation, etiology, treatment modalities, and outcomes in contrast to those reported in adult TOS. METHODS: A comprehensive search for pediatric TOS in the PubMed database using PRISMA guidelines identified 6 relevant studies published between 2008 and 2022. In total, 227 pediatric TOS cases in 216 patients were analyzed. Data categories explored for TOS in pediatric patients included study design, number of patients included, mean age and sex of patients, TOS type, laterality, bony abnormalities, time to surgery, symptoms, treatment modalities, initial surgical technique, surgical complications, percent lost to follow-up, mean follow-up period, and treatment outcome. RESULTS: The results from the 6 studies of 216 patients show a distinct pattern in pediatric TOS, with a 1.84:1 female-to-male ratio, a mean age of 15.49 years, and a lower prevalence of neurogenic TOS (75%, 95% CI 0.41-0.93; I2 = 86%, p < 0.01) compared with the prevailing literature on adults (87.5%-99%). Venous and arterial TOS accounted for a higher proportion of cases in pediatric patients than in adults, challenging the traditional adult-oriented perspective. Right-sided presentations were more common, reflecting right-arm dominance in most individuals. Additionally, bony abnormalities were more common in adults (30%) than in children (10.65%). Treatments involved mixed methods, predominantly using combinations of muscle resection (95.26%), neurolysis (78.02%), and bone resection (72.41%). Patients had high rates of symptom improvement (89%, 95% CI 0.67-0.97; I2 = 85%, p < 0.01) following surgery, with improvement of symptoms ranging from slight to complete relief. Complications were infrequent (5.66%), and most patients reported positive outcomes. The limitations of this analysis include subjective diagnostic and reporting criteria for TOS given its broad range of presentations. CONCLUSIONS: This systematic review and meta-analysis brings to light the distinctive characteristics of pediatric TOS and underscores the importance of recognizing these differences to ensure accurate diagnosis and effective treatment in this patient population. Further research is needed to understand the predictive value of conservative treatments, especially in pediatric TOS cases.

Factors Associated with Costly Hospital Care among Patients with Dementia and Acute Respiratory Failure.

Rationale: Understanding contributors to costly and potentially burdensome care for patients with dementia is of interest to healthcare systems and may facilitate efforts to promote goal-concordant care. Objective: To identify risk factors, in particular whether an early goals-of-care discussion (GOCD) took place, for high-cost hospitalization among patients with dementia and acute respiratory failure. Methods: We conducted an electronic health record-based retrospective cohort study of 298 adults with dementia hospitalized with respiratory failure (receiving ⩾48 h of mechanical ventilation) within an academic healthcare system. We collected demographic and clinical characteristics, including clinical markers of advanced dementia (weight loss, pressure ulcers, hypernatremia, mobility limitations) and intensive care unit (ICU) service (medical, surgical, neurologic). We ascertained whether a GOCD was documented within 48 hours of ICU admission. We used logistic regression to identify patient characteristics associated with high-cost hospitalization measured using the hospital system accounting database and defined as total cost in the top third of the sample (⩾$145,000). We examined a path model that included hospital length of stay as a final mediator between exposure variables and high-cost hospitalization. Results: Patients in the sample had a median age of 71 (IQR, 62-79) years. Approximately half (49%) were admitted to a medical ICU, 29% to a surgical ICU, and 22% to a neurologic ICU. More than half (59%) had a clinical indicator of advanced dementia. A minority (31%) had a GOCD documented within 48 hours of ICU admission; those who did had a 50% lower risk of a high-cost hospitalization (risk ratio, 0.50; 95% confidence interval, 0.2-0.8). Older age, limited English proficiency, and nursing home residence were associated with a lower likelihood of high-cost hospitalization, whereas greater comorbidity burden and admission to a surgical or neurologic ICU compared with a medical ICU were associated with a higher likelihood of high-cost hospitalization. Conclusions: Early GOCDs for patients with dementia and respiratory failure may promote high-value care by ensuring aggressive and costly life support interventions are aligned with patients' goals. Future work should focus on increasing early palliative care delivery for patients with dementia and respiratory failure, in particular in surgical and neurologic ICU settings.

Definitive single fraction spine stereotactic radiosurgery for metastatic sarcoma: Simultaneous integrated boost is associated with high tumor control and low vertebral fracture risk.

INTRODUCTION: Sarcoma spinal metastases (SSM) are particularly difficult to manage given their poor response rates to chemotherapy and inherent radioresistance. We evaluated outcomes in a cohort of patients with SSM uniformly treated using single-fraction simultaneous-integrated-boost (SIB) spine stereotactic radiosurgery (SSRS). MATERIALS AND METHODS: A retrospective review was conducted at a single tertiary institution treated with SSRS for SSM between April 2007-April 2023. 16-24 Gy was delivered to the GTV and 16 Gy uniformly to the CTV. Kaplan-Meier analysis was conducted to assess time to progression of disease (PD) with proportionate hazards modelling used to determine hazard ratios (HR) and respective 95 % confidence intervals (CI). RESULTS: 70 patients with 100 lesions underwent SSRS for SSM. Median follow-up was 19.3 months (IQR 7.7-27.8). Median age was 55 years (IQR42-63). Median GTV and CTVs were 14.5 cm3 (IQR 5-32) and 52.7 cm3 (IQR 29.5-87.5) respectively. Median GTV prescription dose and biologically equivalent dose (BED) [α/ß = 10] was 24 Gy and 81.6 Gy respectively. 85 lesions received 24 Gy to the GTV. 27 % of patients had Bilsky 1b or greater disease. 16 of 100 lesions recurred representing a crude local failure rate of 16 % with a median time to failure of 10.4 months (IQR 5.7-18) in cases which failed locally. 1-year actuarial local control (LC) was 89 %. Median overall survival (OS) was 15.3 months (IQR 7.7-25) from SSRS. Every 1 Gy increase in GTV absolute minimum dose (DMin) across the range (5.8-25 Gy) was associated with a reduced risk of local failure (HR = 0.871 [95 % CI 0.782-0.97], p = 0.009). 9 % of patients developed vertebral compression fractures at a median of 13 months post SSRS (IQR 7-25). CONCLUSION: This study represents one of the most homogenously treated and the largest cohorts of patients with SSM treated with single-fraction SSRS. Despite inherent radioresistance, SSRS confers durable and high rates of local control in SSM without unexpected long-term toxicity rates.

Augmenting Neutrophil Extracellular Traps with Carbonized Polymer Dots: A Potential Treatment for Bacterial Sepsis.

Sepsis is a life-threatening condition that can progress to septic shock as the body's extreme response to pathogenesis damages its own vital organs. Staphylococcus aureus (S. aureus) accounts for 50% of nosocomial infections, which are clinically treated with antibiotics. However, methicillin-resistant strains (MRSA) have emerged and can withstand harsh antibiotic treatment. To address this problem, curcumin (CCM) is employed to prepare carbonized polymer dots (CPDs) through mild pyrolysis. Contrary to curcumin, the as-formed CCM-CPDs are highly biocompatible and soluble in aqueous solution. Most importantly, the CCM-CPDs induce the release of neutrophil extracellular traps (NETs) from the neutrophils, which entrap and eliminate microbes. In an MRSA-induced septic mouse model, it is observed that CCM-CPDs efficiently suppress bacterial colonization. Moreover, the intrinsic antioxidative, anti-inflammatory, and anticoagulation activities resulting from the preserved functional groups of the precursor molecule on the CCM-CPDs prevent progression to severe sepsis. As a result, infected mice treated with CCM-CPDs show a significant decrease in mortality even through oral administration. Histological staining indicates negligible organ damage in the MRSA-infected mice treated with CCM-CPDs. It is believed that the in vivo studies presented herein demonstrate that multifunctional therapeutic CPDs hold great potential against life-threatening infectious diseases.

New Advances in Rapid Pretreatment for Small Dense LDL Cholesterol Measurement Using Shear Horizontal Surface Acoustic Wave (SH-SAW) Technology.

Atherosclerosis is an inflammatory disease of the arteries associated with alterations in lipid and other metabolism and is a major cause of cardiovascular disease (CVD). LDL consists of several subclasses with different sizes, densities, and physicochemical compositions. Small dense LDL (sd-LDL) is a subclass of LDL. There is growing evidence that sd-LDL-C is associated with CVD risk, metabolic dysregulation, and several pathophysiological processes. In this study, we present a straightforward membrane device filtration method that can be performed with simple laboratory methods to directly determine sd-LDL in serum without the need for specialized equipment. The method consists of three steps: first, the precipitation of lipoproteins with magnesium harpin; second, the collection of effluent from a 100 nm filter; and third, the quantification of sd-LDL-ApoB in the effluent with an SH-SAW biosensor. There was a good correlation between ApoB values obtained using the centrifugation (y = 1.0411x + 12.96, r = 0.82, n = 20) and filtration (y = 1.0633x + 15.13, r = 0.88, n = 20) methods and commercially available sd-LDL-C assay values. In addition to the filtrate method, there was also a close correlation between sd-LDL-C and ELISA assay values (y = 1.0483x - 4489, r = 0.88, n = 20). The filtration treatment method also showed a high correlation with LDL subfractions and NMR spectra ApoB measurements (y = 2.4846x + 4.637, r = 0.89, n = 20). The presence of sd-LDL-ApoB in the effluent was also confirmed by ELISA assay. These results suggest that this filtration method is a simple and promising pretreatment for use with the SH-SAW biosensor as a rapid in vitro diagnostic (IVD) method for predicting sd-LDL concentrations. Overall, we propose a very sensitive and specific SH-SAW biosensor with the ApoB antibody in its sensitive region to monitor sd-LDL levels by employing a simple delay-time phase shifted SH-SAW device. In conclusion, based on the demonstration of our study, the SH-SAW biosensor could be a strong candidate for the future measurement of sd-LDL.

Incremental Utility of First-Pass Perfusion CMR for Prognostic Risk Stratification of Cancer-Associated Cardiac Masses.

BACKGROUND: Cardiac magnetic resonance (CMR) differentiates cardiac metastasis (CMET) and cardiac thrombus (CTHR) based on tissue characteristics stemming from vascularity on late gadolinium enhancement (LGE). Perfusion CMR can assess magnitude of vascularity; utility for cardiac masses (CMASS) is unknown. OBJECTIVES: This study sought to determine if perfusion CMR provides diagnostic and prognostic utility for CMASS beyond binary differentiation of CMET and CTHR. METHODS: The population comprised adult cancer patients with CMASS on CMR; CMET and CTHR were defined using LGE-CMR: CMASS+ patients were matched to CMASS- control subjects for cancer type/stage. First-pass perfusion CMR was interpreted visually and semiquantitatively for CMASS vascularity, including contrast enhancement ratio (CER) (plateau vs baseline) and contrast uptake rate (CUR) (slope). Follow-up was performed for all-cause mortality. RESULTS: A total of 462 cancer patients were studied, including patients with (CMET = 173, CTHR = 69) and without CMASS on LGE-CMR. On perfusion CMR, CER and CUR were higher within CMET vs CTHR (P < 0.001); CUR yielded better performance (AUC: 0.89-0.93) than CER (AUC: 0.66-0.72) (both P < 0.001) to differentiate LGE-CMR-evidenced CMET and CTHR, although both CUR (P = 0.10) and CER (P = 0.01) typically misclassified CMET with minimal enhancement. During follow-up, mortality among CMET patients was high but variable; 47% of patients were alive 1 year post-CMR. Patients with semiquantitative perfusion CMR-evidenced CMET had higher mortality than control subjects (HR: 1.42 [95% CI: 1.06-1.90]; P = 0.02), paralleling visual perfusion CMR (HR: 1.47 [95% CI: 1.12-1.94]; P = 0.006) and LGE-CMR (HR: 1.52 [95% CI: 1.16-2.00]; P = 0.003). Among patients with CMET on LGE-CMR, mortality was highest among patients (P = 0.002) with lesions in the bottom perfusion (CER) tertile, corresponding to low vascularity. Among CMET and cancer-matched control subjects, mortality was equivalent (P = NS) among patients with lesions in the upper CER tertile (corresponding to higher lesion vascularity). Conversely, patients with CMET in the middle (P = 0.03) and lowest (lowest vascularity) (P = 0.001) CER tertiles had increased mortality. CONCLUSIONS: Perfusion CMR yields prognostic utility that complements LGE-CMR: Among cancer patients with LGE-CMR defined CMET, mortality increases in proportion to magnitude of lesion hypoperfusion.

Bioactive glycans in a microbiome-directed food for children with malnutrition.

Evidence is accumulating that perturbed postnatal development of the gut microbiome contributes to childhood malnutrition1-4. Here we analyse biospecimens from a randomized, controlled trial of a microbiome-directed complementary food (MDCF-2) that produced superior rates of weight gain compared with a calorically more dense conventional ready-to-use supplementary food in 12-18-month-old Bangladeshi children with moderate acute malnutrition4. We reconstructed 1,000 bacterial genomes (metagenome-assembled genomes (MAGs)) from the faecal microbiomes of trial participants, identified 75 MAGs of which the abundances were positively associated with ponderal growth (change in weight-for-length Z score (WLZ)), characterized changes in MAG gene expression as a function of treatment type and WLZ response, and quantified carbohydrate structures in MDCF-2 and faeces. The results reveal that two Prevotella copri MAGs that are positively associated with WLZ are the principal contributors to MDCF-2-induced expression of metabolic pathways involved in utilizing the component glycans of MDCF-2. The predicted specificities of carbohydrate-active enzymes expressed by their polysaccharide-utilization loci are correlated with (1) the in vitro growth of Bangladeshi P. copri strains, possessing varying degrees of polysaccharide-utilization loci and genomic conservation with these MAGs, in defined medium containing different purified glycans representative of those in MDCF-2, and (2) the levels of faecal carbohydrate structures in the trial participants. These associations suggest that identifying bioactive glycan structures in MDCFs metabolized by growth-associated bacterial taxa will help to guide recommendations about their use in children with acute malnutrition and enable the development of additional formulations.