DNAJB1-PRKACA fusion protein-regulated LINC00473 promotes tumor growth and alters mitochondrial fitness in fibrolamellar carcinoma.

Fibrolamellar carcinoma (FLC) is a rare liver cancer that disproportionately affects adolescents and young adults. Currently, no standard of care is available and there remains a dire need for new therapeutics. Most patients harbor the fusion oncogene DNAJB1-PRKACA (DP fusion), but clinical inhibitors are not yet developed and it is critical to identify downstream mediators of FLC pathogenesis. Here, we identify long noncoding RNA LINC00473 among the most highly upregulated genes in FLC tumors and determine that it is strongly suppressed by RNAi-mediated inhibition of the DP fusion in FLC tumor epithelial cells. We show by loss- and gain-of-function studies that LINC00473 suppresses apoptosis, increases the expression of FLC marker genes, and promotes FLC growth in cell-based and in vivo disease models. Mechanistically, LINC00473 plays an important role in promoting glycolysis and altering mitochondrial activity. Specifically, LINC00473 knockdown leads to increased spare respiratory capacity, which indicates mitochondrial fitness. Overall, we propose that LINC00473 could be a viable target for this devastating disease.

The circadian clock is disrupted in pancreatic cancer.

Disruption of the circadian clock is linked to cancer development and progression. Establishing this connection has proven beneficial for understanding cancer pathogenesis, determining prognosis, and uncovering novel therapeutic targets. However, barriers to characterizing the circadian clock in human pancreas and human pancreatic cancer-one of the deadliest malignancies-have hindered an appreciation of its role in this cancer. Here, we employed normalized coefficient of variation (nCV) and clock correlation analysis in human population-level data to determine the functioning of the circadian clock in pancreas cancer and adjacent normal tissue. We found a substantially attenuated clock in the pancreatic cancer tissue. Then we exploited our existing mouse pancreatic transcriptome data to perform an analysis of the human normal and pancreas cancer samples using a machine learning method, cyclic ordering by periodic structure (CYCLOPS). Through CYCLOPS ordering, we confirmed the nCV and clock correlation findings of an intact circadian clock in normal pancreas with robust cycling of several core clock genes. However, in pancreas cancer, there was a loss of rhythmicity of many core clock genes with an inability to effectively order the cancer samples, providing substantive evidence of a dysregulated clock. The implications of clock disruption were further assessed with a Bmal1 knockout pancreas cancer model, which revealed that an arrhythmic clock caused accelerated cancer growth and worse survival, accompanied by chemoresistance and enrichment of key cancer-related pathways. These findings provide strong evidence for clock disruption in human pancreas cancer and demonstrate a link between circadian disruption and pancreas cancer progression.

Helminth egg derivatives as proregenerative immunotherapies.

The immune system is increasingly recognized as an important regulator of tissue repair. We developed a regenerative immunotherapy from the helminth Schistosoma mansoni soluble egg antigen (SEA) to stimulate production of interleukin (IL)-4 and other type 2-associated cytokines without negative infection-related sequelae. The regenerative SEA (rSEA) applied to a murine muscle injury induced accumulation of IL-4-expressing T helper cells, eosinophils, and regulatory T cells and decreased expression of IL-17A in gamma delta (γδ) T cells, resulting in improved repair and decreased fibrosis. Encapsulation and controlled release of rSEA in a hydrogel further enhanced type 2 immunity and larger volumes of tissue repair. The broad regenerative capacity of rSEA was validated in articular joint and corneal injury models. These results introduce a regenerative immunotherapy approach using natural helminth derivatives.

Modulation of cannabinoid receptor 2 alters neuroinflammation and reduces formation of alpha-synuclein aggregates in a rat model of nigral synucleinopathy.

Research into the disequilibrium of microglial phenotypes has become an area of intense focus in neurodegenerative disease as a potential mechanism that contributes to chronic neuroinflammation and neuronal loss in Parkinson's disease (PD). There is growing evidence that neuroinflammation accompanies and may promote progression of alpha-synuclein (Asyn)-induced nigral dopaminergic (DA) degeneration. From a therapeutic perspective, development of immunomodulatory strategies that dampen overproduction of pro-inflammatory cytokines from chronically activated immune cells and induce a pro-phagocytic phenotype is expected to promote Asyn removal and protect vulnerable neurons. Cannabinoid receptor-2 (CB2) is highly expressed on activated microglia and peripheral immune cells, is upregulated in the substantia nigra of individuals with PD and in mouse models of nigral degeneration. Furthermore, modulation of CB2 protects against rotenone-induced nigral degeneration; however, CB2 has not been pharmacologically and selectively targeted in an Asyn model of PD. Here, we report that 7 weeks of peripheral administration of CB2 inverse agonist SMM-189 reduced phosphorylated (pSer129) Asyn in the substantia nigra compared to vehicle treatment. Additionally, SMM-189 delayed Asyn-induced immune cell infiltration into the brain as determined by flow cytometry, increased CD68 protein expression, and elevated wound-healing-immune-mediator gene expression. Additionally, peripheral immune cells increased wound-healing non-classical monocytes and decreased pro-inflammatory classical monocytes. In vitro analysis of RAW264.7 macrophages treated with lipopolysaccharide (LPS) and SMM-189 revealed increased phagocytosis as measured by the uptake of fluorescence of pHrodo E. coli bioparticles. Together, results suggest that targeting CB2 with SMM-189 skews immune cell function toward a phagocytic phenotype and reduces toxic aggregated species of Asyn. Our novel findings demonstrate that CB2 may be a target to modulate inflammatory and immune responses in proteinopathies.

Energetic trade-offs in migration decision-making, reproductive effort and subsequent parental care in a long-distance migratory bird.

Migratory species trade-off long-distance movement with survival and reproduction, but the spatio-temporal scales at which these decisions occur are relatively unknown. Technological and statistical advances allow fine-scale study of animal decision-making, improving our understanding of possible causes and therefore conservation management. We quantified effects of reproductive preparation during spring migration on subsequent breeding outcomes, breeding outcomes on autumn migration characteristics and autumn migration characteristics on subsequent parental survival in Greenland white-fronted geese (Anser albifrons flavirostris). These are long-distance migratory birds with an approximately 50% population decline from 1999 to 2022. We deployed GPS-acceleration devices on adult females to quantify up to 5 years of individual decision-making throughout the annual cycle. Weather and habitat-use affected time spent feeding and overall dynamic body acceleration (i.e. energy expenditure) during spring and autumn. Geese that expended less energy and fed longer during spring were more likely to successfully reproduce. Geese with offspring expended more energy and fed for less time during autumn, potentially representing adverse fitness consequences of breeding. These behavioural comparisons among Greenland white-fronted geese improve our understanding of fitness trade-offs underlying abundance. We provide a reproducible framework for full annual cycle modelling using location and behaviour data, applicable to similarly studied migratory animals.

Chronic adolescent stress alters GR-FKBP5 interactions in the hippocampus of adult female rats.

Chronic stress exposure during development can have lasting behavioral consequences that differ in males and females. More specifically, increased depressive behaviors in females, but not males, are observed in both humans and rodent models of chronic stress. Despite these known stress-induced outcomes, the molecular consequences of chronic adolescent stress in the adult brain are less clear. The stress hormone corticosterone activates the glucocorticoid receptor, and activity of the receptor is regulated through interactions with co-chaperones-such as the immunophilin FK506 binding proteins 5 (FKBP5). Previously, it has been reported that the adult stress response is modified by a history of chronic stress; therefore, the current study assessed the impact of chronic adolescent stress on the interactions of the glucocorticoid receptor (GR) with its regulatory co-chaperone FKBP5 in response to acute stress in adulthood. Although protein presence for FKBP5 did not differ by group, assessment of GR-FKBP5 interactions demonstrated that adult females with a history of chronic adolescent stress had elevated GR-FKBP5 interactions in the hippocampus following an acute stress challenge which could potentially contribute to a reduced translocation pattern given previous literature describing the impact of FKBP5 on GR activity. Interestingly, the altered co-chaperone interactions of the GR in the stressed female hippocampus were not coupled to an observable difference in transcription of GR-regulated genes. Together, these studies show that chronic adolescent stress causes lasting changes to co-chaperone interactions with the glucocorticoid receptor following stress exposure in adulthood and highlight the potential role that FKBP5 plays in these modifications. Understanding the long-term implications of adolescent stress exposure will provide a mechanistic framework to guide the development of interventions for adult disorders related to early life stress exposures.

Umpolung Flow Chemistry for the Synthesis of a 3-Oxo-3H-spiro[benzofuran-2,4'-piperidine] Building Block.

An efficient and scalable route to tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate, a central prochiral intermediate in the synthesis of SHP2 inhibitor GDC-1971 (migoprotafib), was achieved. Preparation of the title compound from readily available 2-fluorobenzaldehyde included formation of a modified Katritzky benzotriazole hemiaminal, which, upon deprotonation by n-butyllithium, participated in umpolung reactivity via 1,2-addition to tert-butyl 4-oxopiperidine-1-carboxylate (N-Boc-4-piperidone). Most notably, this reaction was developed as a robust plug-flow process that could be executed on multiple kilograms without the need for pilot-scale reaction vessels operating at low cryogenic temperatures. Treatment of the resulting tetrahedral intermediate with oxalic acid resulted in collapse to the corresponding 4-(2-fluorobenzoyl)-4-hydroxypiperidine, which was isolated as a solid via crystallization. The synthesis concluded with an optimized intramolecular SNAr reaction and final crystallization to generate tert-butyl 3-oxo-3H-spiro[benzofuran-2,4'-piperidine]-1'-carboxylate as a stable, high-quality intermediate suitable for further functionalization toward GDC-1971.

Understanding futility in pancreaticoduodenectomy: Insights from a national cohort.

BACKGROUND AND OBJECTIVES: Pancreaticoduodenectomy (PD), the only surgical option for right-sided pancreatic ductal adenocarcinoma (PDAC), carries significant morbidity. Not all patients may be deriving a survival benefit from this operation. We sought to identify the rate of futile PD and its associated factors in a large national cohort. METHODS: We performed a retrospective analysis using the National Cancer Database (2004-2020), including all patients who underwent PD for non-metastatic PDAC. The primary outcome was operative futility, which was defined as death within 12 months of diagnosis despite PD. Multivariable regression was used to identify factors associated with futility. We performed a subgroup analysis on patients who received neoadjuvant systemic therapy. RESULTS: Data from 66 326 patients were analyzed, and 16 772 (25.3%) underwent PD that met criteria for futility. Macroscopically positive margins (odds ratio [OR]: 2.87; 95% confidence interval [CI]: 2.36-3.48), poor tumor differentiation (OR: 2.44; 95% CI: 2.25-2.65), and N2 nodal stage (OR: 2.09; 95% CI: 1.98-2.20) were associated with the greatest odds of futility. Meanwhile, receipt of any systemic therapy (OR: 0.33; 95% CI: 0.31-0.34), receipt of any radiation (OR: 0.60; 95% CI: 0.57-0.63), and receipt of neoadjuvant systemic therapy (OR: 0.62; 95% CI: 0.57-0.66) were associated with the lowest odds of futility. In the neoadjuvant subgroup, a longer diagnosis-to-surgery interval was associated with lower odds of futility. CONCLUSION: PD was futile in about one quarter of patients. Futility was associated with higher age and worse tumor biology. Receipt of neoadjuvant therapy resulted in fewer futile operations.

Untangling the relationship between BMI and academic achievement in the elementary years.

Although the negative relationship between BMI and academic achievement (AA) is well documented, no prior studies have investigated the potential bi-directional relationship between BMI and AA in childhood. We investigated the longitudinal relationships between child BMI and AA across different school subjects (reading, math and science) and sexes. To do so, we employed the Early Childhood Longitudinal Study kindergarten cohort (2011), which is a nationally representative sample of American children who entered kindergarten in 2010-2011. We utilised the kindergarten-fifth grade longitudinal sample (n 17 480) and applied cross-lagged panel models with fixed effects to address unobserved heterogeneity. Our results showed significant but small reciprocal relationships between BMI and math/science achievement for girls (n 8540) (year-to-year effect sizes ranged from -0·01 to -0·04), but not for reading. In contrast, we did not find any evidence of reciprocal relationships between BMI and AA for boys (n 8940). Our results reveal that early weight status and academic performance may be jointly responsible for a vicious cycle of poor AA and unhealthy weight. Breaking the cycle from AA may complement existing obesity prevention strategies, particularly for girls in the science, technology, engineering and mathematics field.

Relationship Between Hemorrhage Type and Development of Emotional and Behavioral Dyscontrol After Hemorrhagic Stroke.

OBJECTIVE: Emotional and behavioral dyscontrol (EBD), a neuropsychiatric complication of stroke, leads to patient and caregiver distress and challenges to rehabilitation. Studies of neuropsychiatric sequelae in stroke are heavily weighted toward ischemic stroke. This study was designed to compare risk of EBD following intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH) and to identify risk factors for EBD following hemorrhagic stroke. METHODS: The authors conducted a prospective cohort study of patients hospitalized for nontraumatic hemorrhagic stroke between 2015 and 2021. Patients or legally authorized representatives completed the Quality of Life in Neurological Disorders (Neuro-QOL) EBD short-form inventory 3 months after hospitalization. Univariable and multivariable analyses identified risk factors for EBD after hemorrhagic stroke. RESULTS: The incidence of EBD was 21% (N=15 of 72 patients) at 3 months after hemorrhagic stroke. Patients with ICH were more likely to develop EBD; 93% of patients with EBD (N=14 of 15) had ICH compared with 56% of patients without EBD (N=32 of 57). The median Glasgow Coma Scale (GCS) score at hospital admission was lower among patients who developed EBD (13 vs. 15 among those without EBD). Similarly, admission scores on the National Institutes of Health Stroke Scale (NIHSS) and the Acute Physiology and Chronic Health Evaluation II (APACHE II) were higher among patients with EBD (median NIHSS score: 7 vs. 2; median APACHE II score: 17 vs. 11). Multivariable analyses identified hemorrhage type (ICH) and poor admission GCS score as predictors of EBD 3 months after hemorrhagic stroke. CONCLUSIONS: Patients with ICH and a low GCS score at admission are at increased risk of developing EBD 3 months after hemorrhagic stroke and may benefit from early intervention.

Cervical orthosis does not improve postoperative pain following posterior cervical fusion: a randomized controlled trial.

PURPOSE: To determine whether postoperative neck pain in the first 4 weeks following multi-level posterior cervical fusion (PCF) with orthosis is equivalent to multi-level PCF without orthosis. METHODS: Patients were randomly assigned in a 1:1 ratio to postoperative orthosis (CO) for 6 weeks or no orthosis (NO). Randomization was stratified by indication (traumatic vs. degenerative), and preoperative opioid use. A model of longitudinal regression for repeated measures was used. The two-sided 95% confidence interval (CI) was used to test equivalence. If the CI lay between the pre-determined margin of equivalence (-2.0 to + 2.0 pain score) the two groups were considered equivalent. A multiple imputation procedure was used to replace missing data. RESULTS: Thirty-one patients were enrolled in each group. At baseline, the CO group had more neck pain (5.3 vs. 3.2, p = 0.013). The Four week post-operative neck pain intensity score was 4.6 ± 0.3 for the CO group vs. 4.9 ± 0.3 for the NO group. The 95% confidence interval (-1.2 to 0.6) was within the pre-determined equivalence margin. Neck Disability Index, quality-of-life scores, and arm pain were similar. Eleven patients in the CO group and 12 patients in the NO group had an adverse event. The CO group had reduced range of motion at 6 weeks. CONCLUSION: Pain scores over the first 4 weeks after surgery were equivalent for patients undergoing multi-level PCF treated with or without a cervical orthosis. Our findings do not support the routine use of a postoperative cervical orthosis for postoperative pain control. Clinical Trials Registration Number NCT04308122, April 22, 2020.

Modular complement assemblies for mitigating inflammatory conditions.

Complement protein C3dg, a key linkage between innate and adaptive immunity, is capable of stimulating both humoral and cell-mediated immune responses, leading to considerable interest in its use as a molecular adjuvant. However, the potential of C3dg as an adjuvant is limited without ways of controllably assembling multiple copies of it into vaccine platforms. Here, we report a strategy to assemble C3dg into supramolecular nanofibers with excellent compositional control, using ß-tail fusion tags. These assemblies were investigated as therapeutic active immunotherapies, which may offer advantages over existing biologics, particularly toward chronic inflammatory diseases. Supramolecular assemblies based on the Q11 peptide system containing ß-tail-tagged C3dg, B cell epitopes from TNF, and the universal T cell epitope PADRE raised strong antibody responses against both TNF and C3dg, and prophylactic immunization with these materials significantly improved protection in a lethal TNF-mediated inflammation model. Additionally, in a murine model of psoriasis induced by imiquimod, the C3dg-adjuvanted nanofiber vaccine performed as well as anti-TNF monoclonal antibodies. Nanofibers containing only ß-tail-C3dg and lacking the TNF B cell epitope also showed improvements in both models, suggesting that supramolecular C3dg, by itself, played an important therapeutic role. We observed that immunization with ß-tail-C3dg caused the expansion of an autoreactive C3dg-specific T cell population, which may act to dampen the immune response, preventing excessive inflammation. These findings indicate that molecular assemblies displaying C3dg warrant further development as active immunotherapies.

Reprint of: An assessment of a sleep aid and sleep promotion practices in hospitalized medical patients.

BACKGROUND: Half of patients admitted to medicine units report sleep disruption, which increases the risk of sleep deprivation. Non-pharmacological interventions are the first step to improving sleep. However, utilization of sleep aids continues to be prevalent. Limited data are available on sleep aid prescribing practices across transitions of care. OBJECTIVES: The aim of this study was to describe the current practices for assessing sleep and prescribing pharmacologic agents to promote sleep in the adult medicine population. METHODS: This study was designed as a single-center, retrospective, observational cohort study of all patients discharged by the general medicine teams over a 3-month period (September 2019- November 2019). Prior to admission, inpatient and discharge prescriptions for sleep aids were recorded, and documentation of sleep assessments and non-pharmacological interventions were evaluated. RESULTS: Of 754 patients included, 211 (28%) were prescribed a sleep aid while inpatient. During hospitalization, 124 (16%) patients had at least one documented sleep assessment, and only 22 (3%) were ordered the institutional non-pharmacological sleep promotion order set. The most prescribed sleep aid in inpatients was melatonin (50%), as well as prior to admission (35%) and at discharge (25%). Overall, the relative reduction in sleep aid prescriptions between admission and discharge was 67%. CONCLUSION: Inpatient sleep aid prescribing is common in medical patients. Despite this, sleep assessments and the standard of care of non-pharmacological interventions are rarely utilized. Future efforts should focus on implementation of strategies to make sleep assessments and non-pharmacological sleep promotion routine and consistent in the inpatient setting.

An assessment of a sleep aid and sleep promotion practices in hospitalized medical patients.

BACKGROUND: Half of patients admitted to medicine units report sleep disruption, which increases the risk of sleep deprivation. Non-pharmacological interventions are the first step to improving sleep. However, utilization of sleep aids continues to be prevalent. Limited data are available on sleep aid prescribing practices across transitions of care. OBJECTIVES: The aim of this study was to describe the current practices for assessing sleep and prescribing pharmacologic agents to promote sleep in the adult medicine population. METHODS: This study was designed as a single-center, retrospective, observational cohort study of all patients discharged by the general medicine teams over a 3-month period (September 2019- November 2019). Prior to admission, inpatient and discharge prescriptions for sleep aids were recorded, and documentation of sleep assessments and non-pharmacological interventions were evaluated. RESULTS: Of 754 patients included, 211 (28%) were prescribed a sleep aid while inpatient. During hospitalization, 124 (16%) patients had at least one documented sleep assessment, and only 22 (3%) were ordered the institutional non-pharmacological sleep promotion order set. The most prescribed sleep aid in inpatients was melatonin (50%), as well as prior to admission (35%) and at discharge (25%). Overall, the relative reduction in sleep aid prescriptions between admission and discharge was 67%. CONCLUSION: Inpatient sleep aid prescribing is common in medical patients. Despite this, sleep assessments and the standard of care of non-pharmacological interventions are rarely utilized. Future efforts should focus on implementation of strategies to make sleep assessments and non-pharmacological sleep promotion routine and consistent in the inpatient setting.

NCCN Guidelines® Insights: Biliary Tract Cancers, Version 2.2023.

In 2023, the NCCN Guidelines for Hepatobiliary Cancers were divided into 2 separate guidelines: Hepatocellular Carcinoma and Biliary Tract Cancers. The NCCN Guidelines for Biliary Tract Cancers provide recommendations for the evaluation and comprehensive care of patients with gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The multidisciplinary panel of experts meets at least on an annual basis to review requests from internal and external entities as well as to evaluate new data on current and emerging therapies. These Guidelines Insights focus on some of the recent updates to the NCCN Guidelines for Biliary Tract Cancers as well as the newly published section on principles of molecular testing.

Outcomes of Nonvariceal Upper Gastrointestinal Bleeding in Patients With Cirrhosis: A National Analysis.

GOALS: We sought to evaluate hospital outcomes of cirrhosis patients with nonvariceal upper gastrointestinal bleeding (NVUGIB). BACKGROUND: NVUGIB is common in patients with cirrhosis. However, national outcome studies of these patients are lacking. STUDY: We utilized the 2014 Nationwide Readmission Database to evaluate NVUGIB in patients with cirrhosis, further stratified as no cirrhosis (NC), compensated cirrhosis (CC), or decompensated cirrhosis (DC). Validated International Classification of Diseases, Ninth Revision, Clinical Modification codes captured diagnoses and interventions. Outcomes included 30-day readmission rates, index admission mortality rates, health care utilization, and predictors of readmission and mortality using multivariable regression analysis. RESULTS: Overall, 13,701 patients with cirrhosis were admitted with NVUGIB. The 30-day readmission rate was 20.8%. Patients with CC were more likely to undergo an esophagogastroduodenoscopy (EGD) within 1 calendar day of admission (74.1%) than patients with DC (67.9%) or NC (69.4%). Patients with DC had longer hospitalizations (4.1 d) and higher costs of care ($11,834). The index admission mortality rate was higher in patients with DC (6.2%) than in patients with CC (1.7%, P <0.001) or NC (1.4%, P <0.001). Predictors of 30-day readmission included performing an EGD >1 calendar day from admission (OR: 1.21; 95% CI, 1.00 to 1.46) and DC (OR: 1.78; 95% CI, 1.54 to 2.06). DC was a predictor of index admission mortality (OR: 3.68; 95% CI, 2.67 to 5.05). CONCLUSIONS: NVUGIB among patients with DC is associated with higher readmission rates, mortality rates, and health care utilization compared with patients with CC and NC. Early EGD is a modifiable variable associated with reduced readmission rates. Early identification of high-risk patients and adherence to guidelines may improve clinical outcomes.

Optimizing HIV PrEP Persistence: Does Your Pharmacy Matter?

Persistence to human immunodeficiency virus (HIV) pre-exposure prophylaxis (PrEP) is integral to preventing new HIV infections. Previous studies have shown real-world PrEP persistence is low and insight is needed into PrEP delivery strategies that improve persistence. This single-center, retrospective, cohort study measured persistence in patients filling PrEP through an integrated health-system specialty pharmacy (HSSP) compared to those filling at external pharmacies. The Kaplan-Meier estimates for persistence probability at 6, 12, and 18 months were 0.87 (95% CI 0.79-0.95), 0.75 (95% CI 0.66-0.86), and 0.64 (95% CI 0.53-0.76) for the HSSP cohort compared to 0.65 (95% CI 0.51-0.83), 0.41 (95% CI 0.28-0.62), and 0.32 (95% CI 0.2-0.53), respectively, for the non-HSSP cohort (log-rank p < 0.001, [Formula: see text] = 11.2). Cox PH modeling showed that patients using a non-HSSP were 2.7 times more likely to be non-persistent than HSSP patients (HR 2.7, 95% CI 1.6-4.7, p < 0.001, [Formula: see text] = 12.61), demonstrating patients were better maintained on PrEP therapy when their prescriptions were filled with the HSSP.

Occipital Nocardia Abscess Presenting With Positive Visual Phenomenon and Quadrantanopsia.

ABSTRACT: A 74-year-old man with chronic obstructive pulmonary disease, glaucoma, and Stage IIIB squamous cell lung cancer experienced several minutes of flashing lights in his right visual hemifield, followed by onset of a right visual field defect. On examination, the patient had a right homonymous hemianopsia that was most dense inferiorly by confrontation testing. Emergent CT scan of the head revealed a 2.5 × 3 cm hypodensity in the left occipital lobe, which was interpreted as an acute stroke. Continuous EEG monitoring captured left posterior quadrant seizures that were temporally correlated to the positive visual phenomena. Subsequent MRI of the brain with and without contrast revealed a conglomerate of centrally necrotic and peripherally enhancing mass lesions. On biopsy, a thick purulent material was drained and Gram stain of the sample revealed gram-positive beaded rods, which speciated to Nocardia farcinica . The patient was treated with a six-week course of intravenous meropenem and a one-year course of oral trimethroprim-sulfamethoxazole. On follow-up, the patient experienced resolution of the right visual field deficit.

Titanium vs. carbon fiber-reinforced intramedullary nailing for humeral bone tumors.

BACKGROUND: Multiple techniques have been described to treat humeral diaphyseal bone tumors requiring curettage or excision. Recent studies have suggested that carbon fiber-reinforced polyetheretherketone (CFR-PEEK) intramedullary nails (IMNs) may be preferable to titanium IMNs for patients with musculoskeletal tumors due to CFR-PEEK's high tensile strength, radiolucency, a modulus of elasticity closer to native bone, and improved postoperative surveillance/radiation dosing. In this study, we describe the rate of fixation failure for both CFR-PEEK and titanium humeral IMNs when used for humeral diaphyseal bone tumors requiring curettage or excision. METHODS: This was a single-institution retrospective cohort study including 81 patients (27 CFR-PEEK and 54 titanium) treated for a humeral diaphyseal bone tumor using an IMN ± methylmethacrylate between January 2017 and December 2022. Primary outcome was revision surgery due to soft tissue complications, nonunions, structural complications such as periprosthetic fracture or IMN breakage, periprosthetic infection, tumor progression, and implant failure due to rejection or fatigue. RESULTS: No failures were observed in either patients treated with titanium nails or patients treated with CFR-PEEK not requiring curettage. Fixation failure due to implant failure was observed in 2 cases-at 214 days and 469 days after surgery-where CFR-PEEK IMN was used for stabilization after a wide segmental resection for oncologic control with a cement spacer reconstruction. In both cases, the resection was larger than 6 cm, the remaining distal humerus was less than 5 cm, and failures occurred at the interface of the residual bone and spacer. Both patients were revised using a titanium distal posterolateral humeral plate fixed with screws and cables without any subsequent complications. One additional CFR-PEEK IMN required revision surgery after 744 days due to progression of the tumor and subsequent nonunion. One revision surgery was observed after 63 days for the titanium IMN because of nonunion and tumor progression. CONCLUSIONS: Humeral diaphyseal bone tumors requiring large segmental resection with small residual bone and a large cement spacer may fail via tension due to bending forces at the distal portion. In this clinical scenario, the use of larger-diameter CFR-PEEK IMNs may be indicated when available. In the interim, use of intercalary allografts instead of cement spacers, additional fixation with a titanium plate distally, or the use of a titanium nail when using a cement spacer may be considered.

The Road to Achieving the European Commission's Chemicals Strategy for Nanomaterial Sustainability-A PATROLS Perspective on New Approach Methodologies.

The European Green Deal outlines ambitions to build a more sustainable, climate neutral, and circular economy by 2050. To achieve this, the European Commission has published the Chemicals Strategy for Sustainability: Towards a Toxic-Free Environment, which provides targets for innovation to better protect human and environmental health, including challenges posed by hazardous chemicals and animal testing. The European project PATROLS (Physiologically Anchored Tools for Realistic nanOmateriaL hazard aSsessment) has addressed multiple aspects of the Chemicals Strategy for Sustainability by establishing a battery of new approach methodologies, including physiologically anchored human and environmental hazard assessment tools to evaluate the safety of engineered nanomaterials. PATROLS has delivered and improved innovative tools to support regulatory decision-making processes. These tools also support the need for reducing regulated vertebrate animal testing; when used at an early stage of the innovation pipeline, the PATROLS tools facilitate the safe and sustainable development of new nano-enabled products before they reach the market.