ABSTRACT
Tumor-infiltrating lymphocyte (TIL) hypofunction contributes to the progression of advanced cancers and is a frequent target of immunotherapy. Emerging evidence indicates that metabolic insufficiency drives T cell hypofunction during tonic stimulation, but the signals that initiate metabolic reprogramming in this context are largely unknown. Here, we found that Meteorin-like (METRNL), a metabolically active cytokine secreted by immune cells in the tumor microenvironment (TME), induced bioenergetic failure of CD8+ T cells. METRNL was secreted by CD8+ T cells during repeated stimulation and acted via both autocrine and paracrine signaling. Mechanistically, METRNL increased E2F-peroxisome proliferator-activated receptor delta (PPARδ) activity, causing mitochondrial depolarization and decreased oxidative phosphorylation, which triggered a compensatory bioenergetic shift to glycolysis. Metrnl ablation or downregulation improved the metabolic fitness of CD8+ T cells and enhanced tumor control in several tumor models, demonstrating the translational potential of targeting the METRNL-E2F-PPARδ pathway to support bioenergetic fitness of CD8+ TILs.
Subject(s)
CD8-Positive T-Lymphocytes , Lymphocytes, Tumor-Infiltrating , Mitochondria , Tumor Microenvironment , CD8-Positive T-Lymphocytes/immunology , Animals , Mitochondria/metabolism , Mitochondria/immunology , Mice , Tumor Microenvironment/immunology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/metabolism , Humans , Mice, Inbred C57BL , Cytokines/metabolism , Signal Transduction , Energy Metabolism , PPAR delta/metabolism , Cell Line, Tumor , Neoplasms/immunology , Glycolysis , Mice, Knockout , Oxidative PhosphorylationABSTRACT
Glioblastoma (GBM) is the deadliest form of brain cancer, with a median survival of less than 2 years despite surgical resection, radiation, and chemotherapy. GBM's rapid progression, resistance to therapy, and inexorable recurrence have been attributed to several factors, including its rapid growth rate, its molecular heterogeneity, its propensity to infiltrate vital brain structures, the regenerative capacity of treatment-resistant cancer stem cells, and challenges in achieving high concentrations of chemotherapeutic agents in the central nervous system. Escape from immunosurveillance is increasingly recognized as a landmark event in cancer biology. Translation of this framework to clinical oncology has positioned immunotherapy as a pillar of cancer treatment. Amid the bourgeoning successes of cancer immunotherapy, GBM has emerged as a model of resistance to immunotherapy. Here we review the mechanisms of immunotherapy resistance in GBM and discuss how insights into GBM-immune system interactions might inform the next generation of immunotherapeutics for GBM and other resistant pathologies.
Subject(s)
Brain Neoplasms/therapy , Drug Resistance, Neoplasm/genetics , Glioblastoma/therapy , Immunotherapy/methods , Tumor Escape/genetics , Brain Neoplasms/genetics , Central Nervous System/immunology , Glioblastoma/genetics , HumansABSTRACT
While measurements of RNA expression have dominated the world of single-cell analyses, new single-cell techniques increasingly allow collection of different data modalities, measuring different molecules, structural connections, and intermolecular interactions. Integrating the resulting multimodal single-cell datasets is a new bioinformatics challenge. Equally important, it is a new experimental design challenge for the bench scientist, who is not only choosing from a myriad of techniques for each data modality but also faces new challenges in experimental design. The ultimate goal is to design, execute, and analyze multimodal single-cell experiments that are more than just descriptive but enable the learning of new causal and mechanistic biology. This objective requires strict consideration of the goals behind the analysis, which might range from mapping the heterogeneity of a cellular population to assembling system-wide causal networks that can further our understanding of cellular functions and eventually lead to models of tissues and organs. We review steps and challenges toward this goal. Single-cell transcriptomics is now a mature technology, and methods to measure proteins, lipids, small-molecule metabolites, and other molecular phenotypes at the single-cell level are rapidly developing. Integrating these single-cell readouts so that each cell has measurements of multiple types of data, e.g., transcriptomes, proteomes, and metabolomes, is expected to allow identification of highly specific cellular subpopulations and to provide the basis for inferring causal biological mechanisms.
Subject(s)
Computational Biology , Research Design , Single-Cell Analysis , Systems Integration , Animals , Gene Expression Profiling , Humans , Metabolomics , ProteomicsABSTRACT
Pathogenic variants that disrupt human mitochondrial protein synthesis are associated with a clinically heterogeneous group of diseases. Despite an impairment in oxidative phosphorylation being a common phenotype, the underlying molecular pathogenesis is more complex than simply a bioenergetic deficiency. Currently, we have limited mechanistic understanding on the scope by which a primary defect in mitochondrial protein synthesis contributes to organelle dysfunction. Since the proteins encoded in the mitochondrial genome are hydrophobic and need co-translational insertion into a lipid bilayer, responsive quality control mechanisms are required to resolve aberrations that arise with the synthesis of truncated and misfolded proteins. Here, we show that defects in the OXA1L-mediated insertion of MT-ATP6 nascent chains into the mitochondrial inner membrane are rapidly resolved by the AFG3L2 protease complex. Using pathogenic MT-ATP6 variants, we then reveal discrete steps in this quality control mechanism and the differential functional consequences to mitochondrial gene expression. The inherent ability of a given cell type to recognize and resolve impairments in mitochondrial protein synthesis may in part contribute at the molecular level to the wide clinical spectrum of these disorders.
Subject(s)
Oxidative Phosphorylation , Protein Biosynthesis , Mitochondrial Proteins/genetics , Mitochondrial Proton-Translocating ATPases/genetics , Mutation , PhenotypeABSTRACT
Progressive myoclonus epilepsies (PMEs) comprise a group of clinically and genetically heterogeneous rare diseases. Over 70% of PME cases can now be molecularly solved. Known PME genes encode a variety of proteins, many involved in lysosomal and endosomal function. We performed whole-exome sequencing (WES) in 84 (78 unrelated) unsolved PME-affected individuals, with or without additional family members, to discover novel causes. We identified likely disease-causing variants in 24 out of 78 (31%) unrelated individuals, despite previous genetic analyses. The diagnostic yield was significantly higher for individuals studied as trios or families (14/28) versus singletons (10/50) (OR = 3.9, p value = 0.01, Fisher's exact test). The 24 likely solved cases of PME involved 18 genes. First, we found and functionally validated five heterozygous variants in NUS1 and DHDDS and a homozygous variant in ALG10, with no previous disease associations. All three genes are involved in dolichol-dependent protein glycosylation, a pathway not previously implicated in PME. Second, we independently validate SEMA6B as a dominant PME gene in two unrelated individuals. Third, in five families, we identified variants in established PME genes; three with intronic or copy-number changes (CLN6, GBA, NEU1) and two very rare causes (ASAH1, CERS1). Fourth, we found a group of genes usually associated with developmental and epileptic encephalopathies, but here, remarkably, presenting as PME, with or without prior developmental delay. Our systematic analysis of these cases suggests that the small residuum of unsolved cases will most likely be a collection of very rare, genetically heterogeneous etiologies.
Subject(s)
Dolichols/metabolism , Mutation/genetics , Myoclonic Epilepsies, Progressive/genetics , Adolescent , Adult , Age of Onset , Child , Child, Preschool , Cohort Studies , DNA Copy Number Variations/genetics , Female , Glycosylation , Humans , Introns/genetics , Male , Middle Aged , Myoclonic Epilepsies, Progressive/classification , Exome Sequencing , Young AdultABSTRACT
BACKGROUND: Patients with advanced neuroendocrine tumors (NETs) have multiple treatment options. Ideally, treatment decisions are shared between physician and patient; however, previous studies suggest that oncologists and patients place different value on treatment attributes such as adverse event (AE) rates. High-quality information on NET patient treatment preferences may facilitate patient-centered decision making by helping clinicians understand patient priorities. METHODS: This study used 2 discrete choice experiments (DCE) to elicit preferences of NET patients regarding advanced midgut and pancreatic NET (pNET) treatments. The DCEs used the "potentially all pairwise rankings of all possible alternatives" (PAPRIKA) method. The primary objective was to determine relative utility rankings for treatment attributes, including progression-free survival (PFS), treatment modality, and AE rates. Ranking of attribute profiles matching specific treatments was also determined. Levels for treatment attributes were obtained from randomized clinical trial data of NET treatments. RESULTS: One hundred and 10 participants completed the midgut NET DCE, and 132 completed the pNET DCE. Longer PFS was the highest ranked treatment attribute in 64.5% of participants in the midgut NET DCE, and in 59% in the pNET DCE. Approximately, 40% of participants in both scenarios prioritized lower AE rates or less invasive treatment modalities over PFS. Ranking of treatment profiles in the midgut NET scenario identified 60.9% of participants favoring peptide receptor radionuclide therapy (PRRT), and 30.0% somatostatin analogue dose escalation. CONCLUSION: NET patients have heterogeneous priorities when choosing between treatment options based on the results of 2 independent DCEs. These results highlight the importance of shared decision making for NET patients.
Subject(s)
Neuroectodermal Tumors, Primitive , Neuroendocrine Tumors , Humans , Neuroendocrine Tumors/pathology , Patient Preference , Somatostatin/therapeutic use , Randomized Controlled Trials as TopicABSTRACT
BACKGROUND: Lung cancer is a deadly cancer. Early diagnosis and access to timely treatment are essential to maximizing the likelihood of survival. Indigenous peoples experience enduring disparities in lung cancer survival, and disparities in access to and through lung cancer services is one of the important drivers of these disparities. In this manuscript, we aimed to examine the current evidence on disparities in Indigenous access to services along the lung cancer treatment pathway. METHODS: A narrative literature review was conducted for all manuscripts and reports published up until July 20, 2022, using Medline, Scopus, Embase, and Web of Science. Following the identification of eligible literature, full-text versions were scanned for relevance for inclusion in this review, and relevant information was extracted. After scanning 1,459 documents for inclusion, our final review included 36 manuscripts and reports that included information on lung cancer service access for Indigenous peoples relative to non-Indigenous peoples. These documents included data from Aotearoa New Zealand, Australia, Canada, and the USA (including Hawai'i). RESULTS: Our review found evidence of disparities in access to, and the journey through, lung cancer care for Indigenous peoples. Disparities were most obvious in access to early detection and surgery, with inconsistent evidence regarding other components of the pathway. CONCLUSION: These observations are made amid relatively scant data in a global sense, highlighting the need for improved data collection and monitoring of cancer care and outcomes for Indigenous peoples worldwide. Access to early detection and guideline-concordant treatment are essential to addressing enduring disparities in cancer survival experienced by Indigenous peoples globally.
ABSTRACT
OBJECTIVES: Endothelial protein C receptor (EPCR) is highly expressed in synovial tissues of patients with RA, but the function of this receptor remains unknown in RA. This study investigated the effect of EPCR on the onset and development of inflammatory arthritis and its underlying mechanisms. METHODS: CIA was induced in EPCR gene knockout (KO) and matched wild-type (WT) mice. The onset and development of arthritis was monitored clinically and histologically. T cells, dendritic cells (DCs), EPCR and cytokines from EPCR KO and WT mice, RA patients and healthy controls (HCs) were detected by flow cytometry and ELISA. RESULTS: EPCR KO mice displayed >40% lower arthritis incidence and 50% less disease severity than WT mice. EPCR KO mice also had significantly fewer Th1/Th17 cells in synovial tissues with more DCs in circulation. Lymph nodes and synovial CD4 T cells from EPCR KO mice expressed fewer chemokine receptors CXCR3, CXCR5 and CCR6 than WT mice. In vitro, EPCR KO spleen cells contained fewer Th1 and more Th2 and Th17 cells than WT and, in concordance, blocking EPCR in WT cells stimulated Th2 and Th17 cells. DCs generated from EPCR KO bone marrow were less mature and produced less MMP-9. Circulating T cells from RA patients expressed higher levels of EPCR than HC cells; blocking EPCR stimulated Th2 and Treg cells in vitro. CONCLUSION: Deficiency of EPCR ameliorates arthritis in CIA via inhibition of the activation and migration of pathogenic Th cells and DCs. Targeting EPCR may constitute a novel strategy for future RA treatment.
Subject(s)
Arthritis, Experimental , Arthritis, Rheumatoid , Animals , Humans , Mice , Arthritis, Experimental/metabolism , Arthritis, Rheumatoid/metabolism , Dendritic Cells/metabolism , Endothelial Protein C Receptor/metabolism , Synovial Membrane/pathology , Th17 Cells/metabolismABSTRACT
Diabetic striatopathy (DS) is an uncommon complication of diabetes characterized by hemiballismus-hemichorea, often accompanied by reversible striatal hyperintensity on neuroimaging. Diabetes is the most common metabolic cause of hemiballismus and hemichorea. However, it is underreported as clinicians do not always consider it in the diagnosis of new movement abnormalities. The prognosis is generally excellent, and management involves glycemic control and anti-chorea medications. We present a case of a patient with bilateral chorea and ballismus and classic MRI findings of DS, though his history of diabetes and substance use confounds the clinical picture of DS.
ABSTRACT
Acute cerebral ischemia triggers a profound inflammatory response. While macrophages polarized to an M2-like phenotype clear debris and facilitate tissue repair, aberrant or prolonged macrophage activation is counterproductive to recovery. The inhibitory immune checkpoint Programmed Cell Death Protein 1 (PD-1) is upregulated on macrophage precursors (monocytes) in the blood after acute cerebrovascular injury. To investigate the therapeutic potential of PD-1 activation, we immunophenotyped circulating monocytes from patients and found that PD-1 expression was upregulated in the acute period after stroke. Murine studies using a temporary middle cerebral artery (MCA) occlusion (MCAO) model showed that intraperitoneal administration of soluble Programmed Death Ligand-1 (sPD-L1) significantly decreased brain edema and improved overall survival. Mice receiving sPD-L1 also had higher performance scores short-term, and more closely resembled sham animals on assessments of long-term functional recovery. These clinical and radiographic benefits were abrogated in global and myeloid-specific PD-1 knockout animals, confirming PD-1+ monocytes as the therapeutic target of sPD-L1. Single-cell RNA sequencing revealed that treatment skewed monocyte maturation to a non-classical Ly6Clo, CD43hi, PD-L1+ phenotype. These data support peripheral activation of PD-1 on inflammatory monocytes as a therapeutic strategy to treat neuroinflammation after acute ischemic stroke.
Subject(s)
Brain Edema , Ischemic Stroke , Humans , Mice , Animals , Monocytes/metabolism , Brain Edema/metabolism , Programmed Cell Death 1 Receptor/metabolism , B7-H1 Antigen/metabolism , Infarction, Middle Cerebral Artery/metabolismABSTRACT
PURPOSE: There is limited literature describing care coordination for patients with glioblastoma (GBM). We aimed to investigate the impact of primary care and electronic health information exchange (HIE) between neurosurgeons, oncologists, and primary care providers (PCP) on GBM treatment patterns, postoperative outcomes, and survival. METHODS: We identified adult GBM patients undergoing primary resection at our institution (2007-2020). HIE was defined as shared electronic medical information between PCPs, oncologists, and neurosurgeons. Multivariate logistic regression analyses were used to determine the effect of PCPs and HIE upon initiation and completion of adjuvant therapy. Kaplan-Meier and multivariate Cox regression models were used to evaluate overall survival (OS). RESULTS: Among 374 patients (mean age ± SD: 57.7 ± 13.5, 39.0% female), 81.0% had a PCP and 62.4% had electronic HIE. In multivariate analyses, having a PCP was associated with initiation (OR: 7.9, P < 0.001) and completion (OR: 4.4, P < 0.001) of 6 weeks of concomitant chemoradiation, as well as initiation (OR: 4.0, P < 0.001) and completion (OR: 3.0, P = 0.007) of 6 cycles of maintenance temozolomide thereafter. Having a PCP (median OS [95%CI]: 14.6[13.1-16.1] vs. 10.8[8.2-13.3] months, P = 0.005) and HIE (15.40[12.82-17.98] vs. 13.80[12.51-15.09] months, P = 0.029) were associated with improved OS relative to counterparts in Kaplan-Meier analysis and in multivariate Cox regression analysis (hazard ratio [HR] = 0.7, [95% CI] 0.5-1.0, P = 0.048). In multivariate analyses, chemoradiation (HR = 0.34, [95% CI] 0.2-0.7, P = 0.002) and maintenance temozolomide (HR = 0.5, 95%CI 0.3-0.8, P = 0.002) were associated with improved OS relative to counterparts. CONCLUSION: Effective care coordination between neurosurgeons, oncologists, and PCPs may offer a modifiable avenue to improve GBM outcomes.
Subject(s)
Brain Neoplasms , Glioblastoma , Health Information Exchange , Primary Health Care , Humans , Female , Glioblastoma/therapy , Glioblastoma/mortality , Male , Middle Aged , Brain Neoplasms/therapy , Brain Neoplasms/mortality , Primary Health Care/statistics & numerical data , Health Information Exchange/statistics & numerical data , Retrospective Studies , Aged , Adult , Patient Acceptance of Health Care/statistics & numerical data , Survival Rate , Follow-Up Studies , Prognosis , Treatment OutcomeABSTRACT
Various preclinical and clinical studies have demonstrated the robust wound healing capacity of the natural anticoagulant activated protein C (APC). A bioengineered APC variant designated 3K3A-APC retains APC's cytoprotective cell signalling actions with <10% anticoagulant activity. This study was aimed to provide preclinical evidence that 3K3A-APC is efficacious and safe as a wound healing agent. 3K3A-APC, like wild-type APC, demonstrated positive effects on proliferation of human skin cells (keratinocytes, endothelial cells and fibroblasts). Similarly it also increased matrix metollaproteinase-2 activation in keratinocytes and fibroblasts. Topical 3K3A-APC treatment at 10 or 30 µg both accelerated mouse wound healing when culled on Day 11. And at 10 µg, it was superior to APC and had half the dermal wound gape compared to control. Further testing was conducted in excisional porcine wounds due to their congruence to human skin. Here, 3K3A-APC advanced macroscopic healing in a dose-dependent manner (100, 250 and 500 µg) when culled on Day 21. This was histologically corroborated by greater collagen maturity, suggesting more advanced remodelling. A non-interference arm of this study found no evidence that topical 3K3A-APC caused either any significant systemic side-effects or any significant leakage into the circulation. However the female pigs exhibited transient and mild local reactions after treatments in week three, which did not impact healing. Overall these preclinical studies support the hypothesis that 3K3A-APC merits future human wound studies.
Subject(s)
Endothelial Cells , Protein C , Female , Humans , Animals , Mice , Swine , Protein C/pharmacology , Protein C/metabolism , Protein C/therapeutic use , Endothelial Cells/metabolism , Wound Healing , Fibrinolytic Agents/therapeutic use , Anticoagulants/pharmacology , Anticoagulants/therapeutic useABSTRACT
PURPOSE: Centralisation of lung cancer treatment can improve outcomes, but may result in differential access to care for those who do not reside within treatment centres. METHODS: We used national-level cancer registration and health care access data and used Geographic Information Systems (GIS) methods to determine the distance and time to access first relevant surgery and first radiation therapy among all New Zealanders diagnosed with lung cancer (2007-2019; N = 27,869), and compared these outcomes between ethnic groups. We also explored the likelihood of being treated at a high-, medium-, or low-volume hospital. Analysis involved both descriptive and adjusted logistic regression modelling. RESULTS: We found that Maori tend to need to travel further (with longer travel times) to access both surgery (median travel distance: Maori 57 km, European 34 km) and radiation therapy (Maori 75 km, European 35 km) than Europeans. Maori have greater odds of living more than 200 km away from both surgery (adjusted odds ratio [aOR] 1.83, 95% CI 1.49-2.25) and radiation therapy (aOR 1.41, 95% CI 1.25-1.60). CONCLUSIONS: Centralisation of care may often improve treatment outcomes, but it also makes accessing treatment even more difficult for populations who are more likely to live rurally and in deprivation, such as Maori.
Subject(s)
Health Services Accessibility , Lung Neoplasms , Travel , Humans , Australasian People , Lung Neoplasms/radiotherapy , Lung Neoplasms/surgery , Maori People , New ZealandABSTRACT
Mitochondrial translation occurs on the mitochondrial ribosome, also known as the mitoribosome. The assembly of mitoribosomes is a highly coordinated process. During mitoribosome biogenesis, various assembly factors transiently associate with the nascent ribosome, facilitating the accurate and efficient construction of the mitoribosome. However, the specific factors involved in the assembly process, the precise mechanisms, and the cellular compartments involved in this vital process are not yet fully understood. In this study, we discovered a crucial role for GTP-binding protein 8 (GTPBP8) in the assembly of the mitoribosomal large subunit (mt-LSU) and mitochondrial translation. GTPBP8 is identified as a novel GTPase located in the matrix and peripherally bound to the inner mitochondrial membrane. Importantly, GTPBP8 is specifically associated with the mt-LSU during its assembly. Depletion of GTPBP8 leads to an abnormal accumulation of mt-LSU, indicating that GTPBP8 is critical for proper mt-LSU assembly. Furthermore, the absence of GTPBP8 results in reduced levels of fully assembled 55S monosomes. This impaired assembly leads to compromised mitochondrial translation and, consequently, impaired mitochondrial function. The identification of GTPBP8 as an important player in these processes provides new insights into the molecular mechanisms underlying mitochondrial protein synthesis and its regulation.
Subject(s)
Mitochondria , Mitochondrial Membranes , Mitochondria/metabolism , Mitochondrial Membranes/metabolism , Mitochondrial Ribosomes/chemistry , Mitochondrial Ribosomes/metabolism , Protein Biosynthesis , GTP-Binding Proteins/genetics , GTP-Binding Proteins/metabolism , Mitochondrial Proteins/metabolism , Ribosomal Proteins/genetics , Ribosomal Proteins/metabolismABSTRACT
BACKGROUND: Health economic modelling indicates that referral to a behavioural weight management programme is cost saving and generates QALY gains compared with a brief intervention. The aim of this study was to conduct a cross-model validation comparing outcomes from this cost-effectiveness analysis to those of a comparator model, to understand how differences in model structure contribute to outcomes. METHODS: The outcomes produced by two models, the School for Public Health Research diabetes prevention (SPHR) and Health Checks (HC) models, were compared for three weight-management programme strategies; Weight Watchers (WW) for 12 weeks, WW for 52 weeks, and a brief intervention, and a simulated no intervention scenario. Model inputs were standardised, and iterative adjustments were made to each model to identify drivers of differences in key outcomes. RESULTS: The total QALYs estimated by the HC model were higher in all treatment groups than those estimated by the SPHR model, and there was a large difference in incremental QALYs between the models. SPHR simulated greater QALY gains for 12-week WW and 52-week WW relative to the Brief Intervention. Comparisons across socioeconomic groups found a stronger socioeconomic gradient in the SPHR model. Removing the impact of treatment on HbA1c from the SPHR model, running both models only with the conditions that the models have in common and, to a lesser extent, changing the data used to estimate risk factor trajectories, resulted in more consistent model outcomes. CONCLUSIONS: The key driver of difference between the models was the inclusion of extra evidence-based detail in SPHR on the impacts of treatments on HbA1c. The conclusions were less sensitive to the dataset used to inform the risk factor trajectories. These findings strengthen the original cost-effectiveness analyses of the weight management interventions and provide an increased understanding of what is structurally important in the models.
Subject(s)
Public Health , Humans , Glycated Hemoglobin , Risk Factors , Cost-Benefit Analysis , Quality-Adjusted Life YearsABSTRACT
BACKGROUND: Both stereotactic radiosurgery (SRS) and percutaneous glycerol rhizotomy are excellent options to treat TN in patients unable to proceed with microvascular decompression. However, the influence of prior SRS on pain outcomes following rhizotomy is not well understood. METHODS: We retrospectively reviewed all patients undergoing percutaneous rhizotomy at our institution from 2011 to 2022. Only patients undergoing percutaneous glycerol rhizotomy following SRS (SRS-rhizotomy) or those undergoing primary glycerol rhizotomy were considered. We collected basic demographic, clinical, and pain characteristics for each patient. Additionally, we characterized pain presentation and perioperative complications. Immediate failure of procedure was defined as presence of TN pain symptoms within 1-week of surgery, and short-term failure was defined as presence of TN pain symptoms within 3-months of surgery. A multivariate logistic regression model was used to evaluate the relationship of a history SRS and failure of procedure following percutaneous glycerol rhizotomy. RESULTS: Of all patients reviewed, 30 had a history of SRS prior to glycerol rhizotomy whereas 371 underwent primary percutaneous glycerol rhizotomy. Patients with a history of SRS were more likely to endorse V3 pain symptoms, p = 0.01. Additionally, patients with a history of SRS demonstrated higher preoperative BNI pain scores, p = 0.01. Patients with a history of SRS were more likely to endorse preoperative numbness, p < 0.0001. A history of SRS was independently associated with immediate failure [OR = 5.44 (2.06-13.8), p < 0.001] and short-term failure of glycerol rhizotomy [OR = 2.41 (1.07-5.53), p = 0.03]. Additionally, increasing age was found to be associated with lower odds of short-term failure of glycerol rhizotomy [OR = 0.98 (0.97-1.00), p = 0.01] CONCLUSIONS: A history of SRS may increase the risk of immediate and short-term failure following percutaneous glycerol rhizotomy. These results may be of use to patients who are poor surgical candidates and require multiple noninvasive/minimally invasive options to effectively manage their pain.
Subject(s)
Glycerol , Radiosurgery , Rhizotomy , Treatment Failure , Trigeminal Neuralgia , Humans , Trigeminal Neuralgia/surgery , Rhizotomy/methods , Female , Male , Middle Aged , Aged , Radiosurgery/methods , Retrospective Studies , Adult , Treatment OutcomeABSTRACT
OBJECTIVES: In the United States, falls are the leading cause of fatal and nonfatal injuries for geriatric patients. With a growing aging population, medical trainees must gain experience with geriatric assessments, including fall risk and prevention. To the authors' knowledge, no prior studies have explored who most often initiates fall discussions between Internal Medicine (IM) residents and geriatric (age 65 years and older) patients. Our objective was to determine who most often initiates fall discussions between IM residents and geriatric patients and the barriers to having these discussions. METHODS: This 2023 quantitative needs assessment used surveys distributed to ambulatory geriatric patients, IM residents, and attending physicians within an urban IM resident continuity clinic. We used the Stopping Elderly Accidents, Death & Injuries assessment from the Centers for Disease Control and Prevention to determine patient fall risk. RESULTS: Response rates were 46%, 51%, and 67% for patients, residents, and attendings, respectively. Of the 39 patients who were assessed, 51% were at risk of falling. Eighty-seven percent of patients have had a fall discussion with their residents, and 59% reported these were resident initiated; however, 75% of 28 residents reported initiating fall conversations rarely, and all 4 attendings said that they started these discussions most of the time while staffing patients with residents. Modifiable resident-identified barriers to discussing falls included forgetfulness and lack of knowledge regarding completing a fall risk assessment. CONCLUSIONS: Most patients have conversations about falling with their physicians, but discrepancies exist regarding who initiates them. Data from this study suggest that attendings may be instrumental in starting these conversations. Reminder systems and fall risk didactic curricula may increase resident-initiated fall discussions.
Subject(s)
Internship and Residency , Patients , Humans , United States , Aged , Needs Assessment , Risk Assessment , Curriculum , Communication , Geriatric AssessmentABSTRACT
Endothelial protein C receptor (EPCR) is a receptor for the natural anti-coagulant activated protein C (aPC). It mediates the anti-inflammatory and barrier-protective functions of aPC through the cleavage of protease-activated receptor (PAR)1/2. Allergic contact dermatitis is a common skin disease characterized by inflammation and defective skin barrier. This study investigated the effect of EPCR and 3K3A-aPC on allergic contact dermatitis using a contact hypersensitivity (CHS) model. CHS was induced using 1-Fluoro-2,4-dinitrobenzene in EPCR-deficient (KO) and matched wild-type mice and mice treated with 3K3A-aPC, a mutant form of aPC with diminished anti-coagulant activity. Changes in clinical and histological features, cytokines, and immune cells were examined. EPCRKO mice displayed more severe CHS, with increased immune cell infiltration in the skin and higher levels of inflammatory cytokines and IgE than wild-type mice. EPCR, aPC, and PAR1/2 were expressed by the skin epidermis, with EPCR presenting almost exclusively in the basal layer. EPCRKO increased the epidermal expression of aPC and PAR1, whereas in CHS, their expression was reduced compared to wild-type mice. 3K3A-aPC reduced CHS severity in wild-type and EPCRKO mice by suppressing immune cell infiltration/activation and inflammatory cytokines. In summary, EPCRKO exacerbated CHS, whereas 3K3A-aPC could reduce the severity of CHS in both EPCRKO and wild-type mice.
Subject(s)
Dermatitis, Allergic Contact , Protein C , Recombinant Proteins , Animals , Mice , Protein C/metabolism , Endothelial Protein C Receptor/metabolism , Receptor, PAR-1/metabolism , Signal Transduction , Cytokines/pharmacology , Dermatitis, Allergic Contact/drug therapyABSTRACT
BACKGROUND: Criticisms have emerged that cancer medicines offer modest benefits at increasingly high prices. Reimbursement decisions made by health technology assessment (HTA) agencies have become a complex endeavour for cancer medicines. Most high-income countries (HICs) use HTA criteria to identify high-value medicines for reimbursement under public drug coverage plans. We compared HTA criteria specific for cancer medicines in economically similar HICs, to understand how these criteria contribute to reimbursement decisions. METHODS: We did an international, cross-sectional analysis in collaboration with author investigators across eight HICs, from the Group of Seven (known as G7; Canada, England, France, Germany, Italy, and Japan) and Oceania (Australia and New Zealand). Publicly available data from HTA agency reports and official documentation were extracted and analysed between Aug 15, 2021, and July 31, 2022. We collected data pertaining to the decision-making criteria used by the national HTA agency; HTA reimbursement status for 34 medicine-indication pairs corresponding to 15 unique US top-selling cancer medicines; and HTA reimbursement status for 18 cancer medicine-indication pairs (13 unique medicines) with minimal clinical benefit (score of 1 on the European Society of Medical Oncology Magnitude of Clinical Benefit Scale). Descriptive statistics were used to compare HTA decision criteria and drug reimbursement recommendations (or for Germany and Japan, final reimbursement status) across the eight countries. FINDINGS: Therapeutic impact related to clinical outcomes of the new medicine was a uniform criterion across the eight countries, whereas quality of evidence (under the remit of therapeutic impact assessment) and equity were infrequently cited criteria. Only the German HTA agency mandated that surrogate endpoints be validated in therapeutic impact assessment. All countries except Germany included formal cost-effectiveness analyses within HTA reports. England and Japan were the only countries that specified a cost-effectiveness threshold. Of the 34 medicine-indication pairs corresponding to US top-selling cancer medicines, Germany reimbursed the maximum (34 [100%]), followed by Italy (32 [94%] recommended for reimbursement), Japan (28 [82%] reimbursed), Australia, Canada, England, and France (27 [79%] recommended for reimbursement), and New Zealand (12 [35%] recommended for reimbursement). Of the 18 cancer medicine-indication pairs with marginal clinical benefit, Germany reimbursed 15 (83%) and Japan reimbursed 12 (67%). France recommended nine (50%) for reimbursement, followed by Italy (seven [39%]), Canada (five [28%]), and Australia and England (three [17%] each). New Zealand did not recommend any medicine-indications with marginal clinical benefit for reimbursement. Considering the overall cumulative proportion across the eight countries, 58 (21%) of 272 indications for the US top-selling medicines and 90 (63%) of 144 marginally beneficial medicine-indications were not recommended for reimbursement or reimbursed. INTERPRETATION: Our findings indicate discordance in public reimbursement decisions across economically similar countries, despite overlapping HTA decision criteria. This suggests a need for improved transparency around the nuances of the criteria to ensure improved access to high-value cancer medicines, and deprioritisation of low-value cancer medicines. Health systems have opportunities to improve their HTA decision-making processes by learning from the systems in other countries. FUNDING: None.
Subject(s)
Neoplasms , Technology Assessment, Biomedical , Humans , Cross-Sectional Studies , France , Neoplasms/drug therapy , OceaniaABSTRACT
Identifying linked cases of infection is a critical component of the public health response to viral infectious diseases. In a clinical context, there is a need to make rapid assessments of whether cases of infection have arrived independently onto a ward, or are potentially linked via direct transmission. Viral genome sequence data are of great value in making these assessments, but are often not the only form of data available. Here, we describe A2B-COVID, a method for the rapid identification of potentially linked cases of COVID-19 infection designed for clinical settings. Our method combines knowledge about infection dynamics, data describing the movements of individuals, and evolutionary analysis of genome sequences to assess whether data collected from cases of infection are consistent or inconsistent with linkage via direct transmission. A retrospective analysis of data from two wards at Cambridge University Hospitals NHS Foundation Trust during the first wave of the pandemic showed qualitatively different patterns of linkage between cases on designated COVID-19 and non-COVID-19 wards. The subsequent real-time application of our method to data from the second epidemic wave highlights its value for monitoring cases of infection in a clinical context.