TREM1 disrupts myeloid bioenergetics and cognitive function in aging and Alzheimer disease mouse models.

Human genetics implicate defective myeloid responses in the development of late-onset Alzheimer disease. A decline in peripheral and brain myeloid metabolism, triggering maladaptive immune responses, is a feature of aging. The role of TREM1, a pro-inflammatory factor, in neurodegenerative diseases is unclear. Here we show that Trem1 deficiency prevents age-dependent changes in myeloid metabolism, inflammation and hippocampal memory function in mice. Trem1 deficiency rescues age-associated declines in ribose 5-phosphate. In vitro, Trem1-deficient microglia are resistant to amyloid-ß42 oligomer-induced bioenergetic changes, suggesting that amyloid-ß42 oligomer stimulation disrupts homeostatic microglial metabolism and immune function via TREM1. In the 5XFAD mouse model, Trem1 haploinsufficiency prevents spatial memory loss, preserves homeostatic microglial morphology, and reduces neuritic dystrophy and changes in the disease-associated microglial transcriptomic signature. In aging APPSwe mice, Trem1 deficiency prevents hippocampal memory decline while restoring synaptic mitochondrial function and cerebral glucose uptake. In postmortem Alzheimer disease brain, TREM1 colocalizes with Iba1+ cells around amyloid plaques and its expression is associated with Alzheimer disease clinical and neuropathological severity. Our results suggest that TREM1 promotes cognitive decline in aging and in the context of amyloid pathology.

State Cannabis Legalization and Psychosis-Related Health Care Utilization.

Importance: Psychosis is a hypothesized consequence of cannabis use. Legalization of cannabis could therefore be associated with an increase in rates of health care utilization for psychosis. Objective: To evaluate the association of state medical and recreational cannabis laws and commercialization with rates of psychosis-related health care utilization. Design, Setting, and Participants: Retrospective cohort design using state-level panel fixed effects to model within-state changes in monthly rates of psychosis-related health care claims as a function of state cannabis policy level, adjusting for time-varying state-level characteristics and state, year, and month fixed effects. Commercial and Medicare Advantage claims data for beneficiaries aged 16 years and older in all 50 US states and the District of Columbia, 2003 to 2017 were used. Data were analyzed from April 2021 to October 2022. Exposure: State cannabis legalization policies were measured for each state and month based on law type (medical or recreational) and degree of commercialization (presence or absence of retail outlets). Main Outcomes and Measures: Outcomes were rates of psychosis-related diagnoses and prescribed antipsychotics. Results: This study included 63 680 589 beneficiaries followed for 2 015 189 706 person-months. Women accounted for 51.8% of follow-up time with the majority of person-months recorded for those aged 65 years and older (77.3%) and among White beneficiaries (64.6%). Results from fully-adjusted models showed that, compared with no legalization policy, states with legalization policies experienced no statistically significant increase in rates of psychosis-related diagnoses (medical, no retail outlets: rate ratio [RR], 1.13; 95% CI, 0.97-1.36; medical, retail outlets: RR, 1.24; 95% CI, 0.96-1.61; recreational, no retail outlets: RR, 1.38; 95% CI, 0.93-2.04; recreational, retail outlets: RR, 1.39; 95% CI, 0.98-1.97) or prescribed antipsychotics (medical, no retail outlets RR, 1.00; 95% CI, 0.88-1.13; medical, retail outlets: RR, 1.01; 95% CI, 0.87-1.19; recreational, no retail outlets: RR, 1.13; 95% CI, 0.84-1.51; recreational, retail outlets: RR, 1.14; 95% CI, 0.89-1.45). In exploratory secondary analyses, rates of psychosis-related diagnoses increased significantly among men, people aged 55 to 64 years, and Asian beneficiaries in states with recreational policies compared with no policy. Conclusions and Relevance: In this retrospective cohort study of commercial and Medicare Advantage claims data, state medical and recreational cannabis policies were not associated with a statistically significant increase in rates of psychosis-related health outcomes. As states continue to introduce new cannabis policies, continued evaluation of psychosis as a potential consequence of state cannabis legalization may be informative.

Liposomes as Versatile Platform for Cancer Theranostics: Therapy, Bio-imaging, and Toxicological Aspects.

Liposomes are nano-sized formulations having the benefits of site-specificity, biocompatibility, and biodegradability, which make them useful for the therapy and diagnosis of major diseases like cancer. In this review, various synthetic strategies of liposomes and their biomedical application in special concern to cancer are discussed. In context to the biomedical application, this article gives a detailed insight into subcellular targeted therapy and several therapeutic modifications like immunotherapy, receptor-based therapy, phototherapy, and combination therapy. The review also describes the liposome-based imaging platforms and the toxicity associated with liposomes. Owing to a significant amount of benefits of this carrier system, several products have been approved to be launched in the market and several others have already been marketed for clinical use.

Randomized Controlled Trials in Functional Neurosurgery-Association of Device Approval Status and Trial Quality.

INTRODUCTION: Randomized controlled trials (RCTs) have been critical in evaluating the safety and efficacy of functional neurosurgery interventions. Given this, we sought to systematically assess the quality of functional neurosurgery RCTs. METHODS: We used a database of neurosurgical RCTs (trials published from 1961 to 2016) to identify studies of functional neurosurgical procedures (N = 48). We extracted data on the design and quality of these RCTs and quantified the quality of trials using Jadad scores. We categorized RCTs based on the device approval status at the time of the trial and tested the association of device approval status with trial design and quality parameters. RESULTS: Of the 48 analyzed functional neurosurgery RCTs, the median trial size was 34.5 patients with a median age of 51. The most common indications were Parkinson's disease (N = 20), epilepsy (N = 10), obsessive-compulsive disorder (N = 4), and pain (N = 4). Most trials reported inclusion and exclusion criteria (95.8%), sample size per arm (97.9%), and baseline characteristics of the patients being studied (97.9%). However, reporting of allocation concealment (29.2%), randomization mode (66.7%), and power calculations (54.2%) were markedly less common. We observed that trial quality has improved over time (Spearman r, 0.49). We observed that trials studying devices with humanitarian device exemption (HDE) and experimental indications (EI) tended to be of higher quality than trials of FDA-approved devices (p = 0.011). A key distinguishing quality characteristic was the proportion of HDE and EI trials that were double-blinded, compared to trials of FDA-approved devices (HDE, 83.3%; EI, 69.2%; FDA-approved, 35.3%). Although more than one-third of functional neurosurgery RCTs reported funding from industry, no significant association was identified between funding source and trial quality or outcome. CONCLUSION: The quality of RCTs in functional neurosurgery has improved over time but reporting of specific metrics such as power calculations and allocation concealment requires further improvement. Device approval status but not funding source was associated with trial quality.

Peripheral TREM1 responses to brain and intestinal immunogens amplify stroke severity.

Stroke is a multiphasic process in which initial cerebral ischemia is followed by secondary injury from immune responses to ischemic brain components. Here we demonstrate that peripheral CD11b+CD45+ myeloid cells magnify stroke injury via activation of triggering receptor expressed on myeloid cells 1 (TREM1), an amplifier of proinflammatory innate immune responses. TREM1 was induced within hours after stroke peripherally in CD11b+CD45+ cells trafficking to ischemic brain. TREM1 inhibition genetically or pharmacologically improved outcome via protective antioxidant and anti-inflammatory mechanisms. Positron electron tomography imaging using radiolabeled antibody recognizing TREM1 revealed elevated TREM1 expression in spleen and, unexpectedly, in intestine. In the lamina propria, noradrenergic-dependent increases in gut permeability induced TREM1 on inflammatory Ly6C+MHCII+ macrophages, further increasing epithelial permeability and facilitating bacterial translocation across the gut barrier. Thus, following stroke, peripheral TREM1 induction amplifies proinflammatory responses to both brain-derived and intestinal-derived immunogenic components. Critically, targeting this specific innate immune pathway reduces cerebral injury.

Guidelines for diagnostic flexible bronchoscopy in adults: Joint Indian Chest Society/National College of chest physicians (I)/Indian association for bronchology recommendations.

Flexible bronchoscopy (FB) is commonly performed by respiratory physicians for diagnostic as well as therapeutic purposes. However, bronchoscopy practices vary widely across India and worldwide. The three major respiratory organizations of the country supported a national-level expert group that formulated a comprehensive guideline document for FB based on a detailed appraisal of available evidence. These guidelines are an attempt to provide the bronchoscopist with the most scientifically sound as well as practical approach of bronchoscopy. It involved framing appropriate questions, review and critical appraisal of the relevant literature and reaching a recommendation by the expert groups. The guidelines cover major areas in basic bronchoscopy including (but not limited to), indications for procedure, patient preparation, various sampling procedures, bronchoscopy in the ICU setting, equipment care, and training issues. The target audience is respiratory physicians working in India and well as other parts of the world. It is hoped that this document would serve as a complete reference guide for all pulmonary physicians performing or desiring to learn the technique of flexible bronchoscopy.

Surgical outcomes of pediatric spinal cord astrocytomas: systematic review and meta-analysis.

OBJECTIVE: Pediatric spinal astrocytomas are rare spinal lesions that pose unique management challenges. Therapeutic options include gross-total resection (GTR), subtotal resection (STR), and adjuvant chemotherapy or radiation therapy. With no randomized controlled trials, the optimal management approach for children with spinal astrocytomas remains unclear. The aim of this study was to conduct a systematic review and meta-analysis on pediatric spinal astrocytomas. METHODS: The authors performed a systematic review of the PubMed/MEDLINE electronic database to investigate the impact of histological grade and extent of resection on overall survival among patients with spinal cord astrocytomas. They retained publications in which the majority of reported cases included astrocytoma histology. RESULTS: Twenty-nine previously published studies met the eligibility criteria, totaling 578 patients with spinal cord astrocytomas. The spinal level of intramedullary spinal cord tumors was predominantly cervical (53.8%), followed by thoracic (40.8%). Overall, resection was more common than biopsy, and GTR was slightly more commonly achieved than STR (39.7% vs 37.0%). The reported rates of GTR and STR rose markedly from 1984 to 2015. Patients with high-grade astrocytomas had markedly worse 5-year overall survival than patients with low-grade tumors. Patients receiving GTR may have better 5-year overall survival than those receiving STR. CONCLUSIONS: The authors describe trends in the management of pediatric spinal cord astrocytomas and suggest a benefit of GTR over STR for 5-year overall survival.

Brainstem Dose Constraints in Nonisometric Radiosurgical Treatment Planning of Trigeminal Neuralgia: A Single-Institution Experience.

BACKGROUND: CyberKnife stereotactic radiosurgery (SRS) for trigeminal neuralgia (TGN) administers nonisometric, conformational high-dose radiation to the trigeminal nerve with risk of subsequent hypoesthesia. METHODS: We performed a retrospective, single-institution review of 66 patients with TGN treated with CyberKnife SRS to compare outcomes from 2 distinct treatment periods: standard dosing (n = 38) and reduced dosing (n = 28). Standard and reduced dosing permitted a maximum brainstem dose of 45 Gy and 25 Gy, respectively, each with a prescription dose of 60 Gy. Primary and secondary outcomes were Barrow Neurologic Institute pain and numbness scores. Maximum brainstem dose, prepontine nerve length, and treatment history were recorded for their predictive contributions by logistic regression. RESULTS: After matching, patients in the standard dosing and reduced dosing groups were followed for a median of 25 months and 19.5 months, respectively. Mean trigeminal nerve length was 8.55 mm in the standard dosing group and 9.46 mm in the reduced dosing group. Baseline rates of poorly controlled pain were 97% and 88%, respectively, which improved to 23.4% and 8.3%, respectively (P < 0.001 for both). The baseline rates of bothersome numbness were null in both groups, and increased to 25% in the standard group (P = 0.006) and to 21% in the reduced group (P = 0.07). Regression analyses suggested that reduced brainstem exposure (P = 0.01), as well as a longer trigeminal nerve (P = 0.01), were predictive of durable pain control. CONCLUSIONS: These outcomes demonstrate that a lower maximum brainstem dose can provide excellent pain control without affecting facial numbness. Longer nerves may achieve better long-term outcomes and help optimize individual plans.

Diagnosis and treatment options for sequelae following radiation treatment of brain tumors.

Radiation serves an important role in the treatment of metastatic and primary brain tumors. Radiation carries a risk of post radiation treatment effects, such as pseudoprogression and radiation necrosis. The ability to differentiate between radiation necrosis, pseudoprogression, and tumor recurrence remains a diagnostic conundrum with varying treatment options. In this review, we will discuss the pathophysiology, diagnostic imaging modalities, and treatments of these post-radiation treatment effects. We focus on the latest developments in magnetic resonance imaging (MRI) modalities including imaging biomarkers and the newest therapeutics such as VEGF inhibitors, Hyperbaric Oxygen Therapy, sensitized cytotoxic T cells, and Laser Interstitial Thermal Therapy (LITT).

Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery.

Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their transcriptome including changes to the VEGF-A pathway and genes involved in cell survival, inflammatory response, and synaptic remodeling. In our experiments, exogenous hNPCs were electrically stimulated (electrically preconditioned) via the scaffold 1 day prior to implantation. After in vitro stimulation, hNPCs on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. Electrically preconditioned hNPCs improved functional outcomes compared to unstimulated hNPCs or hNPCs where VEGF-A was blocked during in vitro electrical preconditioning. The ability to manipulate hNPCs via a conductive scaffold creates a new approach to optimize stem cell-based therapy and determine which factors (such as VEGF-A) are essential for stroke recovery.

Sclerosing liposarcoma of the anterior mediastinum: An unusual case.

Liposarcomas are extremely rare in the mediastinum. Patients usually present late due to the compressive effect of the tumor on the adjacent structures. Severity of the symptoms depend mainly on the size of the tumor and the structure it infiltrates. Well differentiated slow growing liposarcomas are the most common ones in the mediastinum followed by dedifferentiated and poorly differentiated ones. These tumors have bad prognosis because of incomplete surgical excision due to its inaccessible location. Hence these patients should be kept under close follow up because of high recurrent rates. Here we are presenting a rare case of anterior mediastinal sclerosing liposarcoma in a 77 year old male.

Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path forward to critically evaluate and improve animal models of human disease.

The genomic landscape of pediatric Ewing sarcoma.

UNLABELLED: Pediatric Ewing sarcoma is characterized by the expression of chimeric fusions of EWS and ETS family transcription factors, representing a paradigm for studying cancers driven by transcription factor rearrangements. In this study, we describe the somatic landscape of pediatric Ewing sarcoma. These tumors are among the most genetically normal cancers characterized to date, with only EWS-ETS rearrangements identified in the majority of tumors. STAG2 loss, however, is present in more than 15% of Ewing sarcoma tumors; occurs by point mutation, rearrangement, and likely nongenetic mechanisms; and is associated with disease dissemination. Perhaps the most striking finding is the paucity of mutations in immediately targetable signal transduction pathways, highlighting the need for new therapeutic approaches to target EWS-ETS fusions in this disease. SIGNIFICANCE: We performed next-generation sequencing of Ewing sarcoma, a pediatric cancer involving bone, characterized by expression of EWS-ETS fusions. We found remarkably few mutations. However, we discovered that loss of STAG2 expression occurs in 15% of tumors and is associated with metastatic disease, suggesting a potential genetic vulnerability in Ewing sarcoma.

SYK is a critical regulator of FLT3 in acute myeloid leukemia.

Cooperative dependencies between mutant oncoproteins and wild-type proteins are critical in cancer pathogenesis and therapy resistance. Although spleen tyrosine kinase (SYK) has been implicated in hematologic malignancies, it is rarely mutated. We used kinase activity profiling to identify collaborators of SYK in acute myeloid leukemia (AML) and determined that FMS-like tyrosine kinase 3 (FLT3) is transactivated by SYK via direct binding. Highly activated SYK is predominantly found in FLT3-ITD positive AML and cooperates with FLT3-ITD to activate MYC transcriptional programs. FLT3-ITD AML cells are more vulnerable to SYK suppression than FLT3 wild-type counterparts. In a FLT3-ITD in vivo model, SYK is indispensable for myeloproliferative disease (MPD) development, and SYK overexpression promotes overt transformation to AML and resistance to FLT3-ITD-targeted therapy.