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PURPOSE: This study aimed to identify factors, including degree of disability, that contribute to the caregiver burden of raising children with cerebral palsy in Sri Lanka. METHODS: Participants were caregivers of children with cerebral palsy attending the pediatric neurology clinic of the only tertiary care center in southern Sri Lanka. The locally validated Caregiver Difficulties Scale (CDS) was administered, and demographic information was obtained in a structured interview. Disability data was accessed through the medical record. RESULTS: Of 163 caregivers who participated in this study, 133 (81.2%) demonstrated a moderate to high level of burden, and 91 (55.8%) were at high risk for psychological burden. In the bivariate analysis, caregiver burden significantly correlated with degree of physical disability based on the Gross Motor Function Classification System (GMFCS) and the Manual Ability Classification System (MACS), the presence of medical co-morbidities, and having two or more children. However, only the GMFCS level and number of children remained significant predictors of caregiver burden after controlling for confounding effects. CONCLUSION: Raising a child with cerebral palsy in Sri Lanka is likely to cause caregiver burden, particularly if they have a high level of disability or one or more siblings. Monitoring caregiver burden as part of routine cerebral palsy management is important, which allows targeting psychosocial support to families most in need.

Up to 20% of idiopathic interstitial lung disease is familial, referred to as Familial Pulmonary Fibrosis (FPF). We performed an integrated analysis of FPF genetic risk by comprehensively evaluating for genetic rare variants (RVs) in a large cohort of FPF kindreds.We performed whole-exome sequencing and/or candidate gene sequencing from affected individuals in 569 FPF kindreds, followed by co-segregation analysis in large kindreds, gene burden analysis, gene-based risk scoring, cell type enrichment analysis, and co-expression network construction.We found that 14.9% - 23.4% of genetic risk in kindreds could be explained by RVs in genes previously linked to FPF, predominantly telomere related genes. We identified new candidate genes in a small number of families, including SYDE1, SERPINB8, GPR87, and NETO1, and developed tools for evaluation and prioritization of RV-containing genes across kindreds. Several pathways were enriched for RV-containing genes in FPF, including focal adhesion and mitochondrial complex I assembly. By combining single cell transcriptomics with prioritized candidate genes, we discovered that expression of RV-containing genes was enriched in smooth muscle cells, type II alveolar epithelial cells, and endothelial cells.In the most comprehensive FPF genetic study to date, we defined the prevalence of RVs in known FPF-related genes and identified new candidate genes and pathways relevant to FPF. However, we did not identify new RV-containing genes shared across multiple kindreds, thereby suggesting that heterogeneous genetic variants involving a variety of genes and pathways mediate genetic risk in most FPF kindreds.

OBJECTIVE The incidence of leptomeningeal disease (LMD) has increased as treatments for brain metastases (BMs) have improved and patients with metastatic disease are living longer. Sample sizes of individual studies investigating LMD after surgery for BMs and its risk factors have been limited, ranging from 200 to 400 patients at risk for LMD, which only allows the use of conventional biostatistics. Here, the authors used machine learning techniques to enhance LMD prediction in a cohort of surgically treated BMs. METHODS A conditional survival forest, a Cox proportional hazards model, an extreme gradient boosting (XGBoost) classifier, an extra trees classifier, and logistic regression were trained. A synthetic minority oversampling technique (SMOTE) was used to train the models and handle the inherent class imbalance. Patients were divided into an 80:20 training and test set. Fivefold cross-validation was used on the training set for hyperparameter optimization. Patients eligible for study inclusion were adults who had consecutively undergone neurosurgical BM treatment, had been admitted to Brigham and Women’s Hospital from January 2007 through December 2019, and had a minimum of 1 month of follow-up after neurosurgical treatment. RESULTS A total of 1054 surgically treated BM patients were included in this analysis. LMD occurred in 168 patients (15.9%) at a median of 7.05 months after BM diagnosis. The discrimination of LMD occurrence was optimal using an XGboost algorithm (area under the curve = 0.83), and the time to LMD was prognosticated evenly by the random forest algorithm and the Cox proportional hazards model (C-index = 0.76). The most important feature for both LMD classification and regression was the BM proximity to the CSF space, followed by a cerebellar BM location. Lymph node metastasis of the primary tumor at BM diagnosis and a cerebellar BM location were the strongest risk factors for both LMD occurrence and time to LMD. CONCLUSIONS The outcomes of LMD patients in the BM population are predictable using SMOTE and machine learning. Lymph node metastasis of the primary tumor at BM diagnosis and a cerebellar BM location were the strongest LMD risk factors.

This study assessed classification accuracy of paper-and-pencil and computerized cognitive batteries at subacute (SA; 1-11 days) and early chronic (EC; ∼4 months) phases of pediatric mild traumatic brain injury (pmTBI). Two statistical approaches focused on single-subject performance (individual task scores, total impairments) were used to maximize clinical utility.Two hundred thirty-five pmTBI and 169 healthy controls (HC) participants aged 8-18 were enrolled, with a subset (190 pmTBI; 160 HC) returning for the EC visit. The paper-and-pencil battery included several neuropsychological tests selected from recommended common data elements, whereas computerized testing was performed with the Cogstate Brief Battery. Hierarchical logistic regressions (base model: Parental education and premorbid reading abilities; full model: Base model and cognitive testing variables) were used to examine sensitivity/specificity, with diagnosis as the dependent variable.Number Sequencing and Cogstate One-Card Learning accuracy significantly predicted SA diagnosis (full model accuracy = 71.6%-71.7%, sensitivity = 80.6%-80.8%, specificity = 59.1%-59.6%), while only immediate recall was significant at EC visit (accuracy = 68.5%, sensitivity = 74.6%, specificity = 61.5%). Other measures (Letter Fluency, Cogstate Detection, and One-Card Learning accuracy) demonstrated higher proportions of impairment for pmTBI subacutely (pmTBI: 11.5%-19.8%; HC: 3.7%-6.1%) but did not improve classification accuracy. Evidence of multiple impairments across the entire testing battery significantly predicted diagnosis at both visits (full model accuracy = 66.2%-68.6%, sensitivity = 71.2%-78.9%, specificity = 54.3%-61.5%).Current results suggest similar modest diagnostic accuracy for computerized and paper-and-pencil batteries across multiple pmTBI phases. Moreover, findings suggest the total number of impairments may be more clinically useful than any single test or cognitive domain in terms of diagnostic accuracy at both assessment points. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Intra-articular injections are routinely performed to alleviate pain and inflammation associated with osteoarthritis in horses. Intra-articular injections require accurate needle placement to optimize clinical outcomes and minimize complications. This study’s objectives were to develop and validate a three-dimensional (3D) printed model of an equine cervical articular process joint to teach ultrasound-guided injections. Five identical models of an equine cervical articular process joint were 3D printed and embedded in 10% ballistic gelatin. Experts’ and novices’ ability to successfully insert a needle into the joint space of the model using ultrasound guidance was assessed and graded using an objective structured clinical examination (OSCE). Scores from experts and novices were compared to evaluate the construct validity of the model. Participants also answered a survey assessing the face and content validity of the model. Experts required less time (22.51 seconds) for correct needle placement into the model joint space than novices (35.96 seconds); however, this difference was not significant ( p = .53). Experts’ median total OSCE score (14) was significantly higher ( p = .03) than novices’ (12), supporting the model’s construct validity. Participants agreed on the face and content validity of the model by grading all survey questions greater than 7 on a 10-point Likert-type scale. In summary, we successfully developed a 3D printed model of an equine cervical articular process joint, partially demonstrated the construct validity of the model, and proved the face and content validity of this new training tool.

This study aimed to determine the responsiveness of three instruments (disease-specific, generic, and hearing-specific) assessing health-related quality of life (HRQoL) in adult patients undergoing surgery for chronic otitis media (COM).Prospective correlational study.Two otology referral centers in England, United Kingdom.Consecutive adult patients undergoing middle ear surgery for COM.HRQoL assessment and audiometry were performed preoperatively and 12 months after surgery. HRQoL was assessed using disease-specific (Chronic Otitis Media Questionnaire-12 [COMQ-12]), generic (Euro-Qol-5D-5L), and hearing-specific (Hearing Handicap Inventory for Adults [HHIA]) instruments.A total of 52 patients (mean [standard deviation {SD}] age, 47.3 [18.3] yr) were included, with 42 patients completing both preoperative and postoperative COMQ-12 forms. COMQ-12 and HHIA total scores significantly improved after surgery (COMQ-12: mean [SD], 28.3 [11.6] versus 14.8 [10.6]; p0.001; HHIA: 42.9 (28.4) versus 32.6 (27.5); p = 0.012). General HRQoL measured with the Euro-Qol-5D-5L was unaffected by surgery ( p0.05). The standardized response means for the COMQ-12 and HHIA total scores were 1.21 and 0.44, respectively. Postoperative air conduction thresholds were moderately correlated with the postoperative COMQ-12 ( r = 0.46, p = 0.005) and HHIA ( r = 0.41, p = 0.012) total scores.Middle ear surgery significantly improved both disease-specific and hearing-specific HRQoL, whereas general HRQoL did not change. Only the COMQ-12 is highly responsive to surgical intervention. This study supports the use of the COMQ-12 to monitor patient-reported outcomes in both research and routine clinical settings.

This essay attempts to answer the question of how one commemorates the event of thinking by raising it in relation to some commemorative texts. Derrida’s Demeure, Athènes provides an exemplary point of departure, but the seminars concerned with the death penalty raise the stakes in readings that deeply trouble an inheritance fixated on the determination of death, with Socrates and Oedipus as ancient figures of an enduring culture. The essay touches on Freud and Heidegger as dissenting figures and concludes by commemorating three distinctive thinkers: Lauren Berlant, Jean-Luc Nancy and Bernard Stiegler.

Alternative splicing (AS) is prevalent in cancer, generating an extensive but largely unexplored repertoire of novel immunotherapy targets. We describe I soform peptides from R NA splicing for I mmunotherapy target S creening (IRIS), a computational platform capable of discovering AS-derived tumor antigens (TAs) for T cell receptor (TCR) and chimeric antigen receptor T cell (CAR-T) therapies. IRIS leverages large-scale tumor and normal transcriptome data and incorporates multiple screening approaches to discover AS-derived TAs with tumor-associated or tumor-specific expression. In a proof-of-concept analysis integrating transcriptomics and immunopeptidomics data, we showed that hundreds of IRIS-predicted TCR targets are presented by human leukocyte antigen (HLA) molecules. We applied IRIS to RNA-seq data of neuroendocrine prostate cancer (NEPC). From 2,939 NEPC-associated AS events, IRIS predicted 1,651 epitopes from 808 events as potential TCR targets for two common HLA types (A*02:01 and A*03:01). A more stringent screening test prioritized 48 epitopes from 20 events with “neoantigen-like” NEPC-specific expression. Predicted epitopes are often encoded by microexons of ≤30 nucleotides. To validate the immunogenicity and T cell recognition of IRIS-predicted TCR epitopes, we performed in vitro T cell priming in combination with single-cell TCR sequencing. Seven TCRs transduced into human peripheral blood mononuclear cells (PBMCs) showed high activity against individual IRIS-predicted epitopes, providing strong evidence of isolated TCRs reactive to AS-derived peptides. One selected TCR showed efficient cytotoxicity against target cells expressing the target peptide. Our study illustrates the contribution of AS to the TA repertoire of cancer cells and demonstrates the utility of IRIS for discovering AS-derived TAs and expanding cancer immunotherapies.

Supplementary Methods, Figures 1-3 from Targeted Nanoparticles That Deliver a Sustained, Specific Release of Paclitaxel to Irradiated Tumors

To capitalize on the response of tumor cells to XRT, we developed a controlled-release nanoparticle drug delivery system using a targeting peptide that recognizes a radiation-induced cell surface receptor. Phage display biopanning identified Gly-Ile-Arg-Leu-Arg-Gly (GIRLRG) as a peptide that selectively recognizes tumors responding to XRT. Membrane protein extracts of irradiated glioma cells identified glucose-regulated protein GRP78 as the receptor target for GIRLRG. Antibodies to GRP78 blocked the binding of GIRLRG in vitro and in vivo. Conjugation of GIRLRG to a sustained-release nanoparticle drug delivery system yielded increased paclitaxel concentration and apoptosis in irradiated breast carcinomas for up to 3 weeks. Compared with controls, a single administration of the GIRLRG-targeted nanoparticle drug delivery system to irradiated tumors delayed the in vivo tumor tripling time by 55 days (P = 0.0001) in MDA-MB-231 and 12 days in GL261 (P < 0.005). This targeting agent combines a novel recombinant peptide with a paclitaxel-encapsulating nanoparticle that specifically targets irradiated tumors, increasing apoptosis and tumor growth delay in a manner superior to known chemotherapy approaches. Cancer Res; 70(11); 4550–9. ©2010 AACR.

In eukaryotic cells, intron lariats produced by the spliceosome contain a 2′5′ phosphodiester linkage. The RNA lariat debranching enzyme, Dbr1, is the only enzyme known to hydrolyze this bond. Dbr1 is a member of the metallophosphoesterase (MPE) family of enzymes, and recent X-ray crystal structures and biochemistry data demonstrate that Dbr1 from Entamoeba histolytica uses combinations of Mn2+, Zn2+, and Fe2+ as enzymatic cofactors. Here, we examine the kinetic properties and metal dependence of the Dbr1 homolog from Saccharomyces cerevisiae (yDbr1). Elemental analysis measured stoichiometric quantities of Fe and Zn in yDbr1 purified following heterologous expression E. coli. We analyzed the ability of Fe2+, Zn2+, and Mn2+ to reconstitute activity in metal-free apoenzyme. Purified yDbr1 was highly active, turning over substrate at 5.6 sec−1, and apo-yDbr1 reconstituted with Fe2+ was the most active species, turning over at 9.2 sec−1. We treated human lymphoblastoid cells with the iron-chelator deferoxamine and measured a twofold increase in cellular lariats. These data suggest that Fe is an important biological cofactor for Dbr1 enzymes.

Amniotic products are potent immunomodulators used clinically to repair tissue injury. Little information exists regarding the potential of cell-free human amniotic fluid (hAF) to treat cardiovascular disease. Herein, we sought to determine the influence and efficacy of acellular hAF on myocardial ischemia-reperfusion injury. Processed hAF was obtained from volunteer donors at the time of elective caesarean section and manufactured using proprietary methods. Left anterior descending coronary artery ligation was performed on rats for 60 min. Thirty minutes after release and reperfusion, either saline or hAF was injected intramyocardially. Serial echocardiography revealed that compared with saline-injected rats, hAF animals maintained their ejection fraction and did not adversely remodel through the 4-wk period. This preserved ventricular function correlated with decreased infarct size, less fibrosis, and reduced expression of cytokines and infiltrating inflammatory cells. Comparative arrays of different donor hAF lots confirmed the presence of a wide array of immunomodulatory and host-defense proteins. The observed functional cardioprotection was furthermore evident when given intravenously and across multiple hAF donors. In conclusion, our data demonstrate, for the first time, the cardioprotective effect of acellular hAF on myocardial injury. These observations spanned across diverse donors and likely result from the mixture of a plethora of naturally produced cytokines, chemokines, and immune-modulating proteins rather than a single, defined mechanistic culprit. The ubiquitous availability of hAF as a cell-free solution further suggests its potential for widespread adoption as a therapy for myocardial ischemia-reperfusion injury.

The Mendelian inheritance pattern of acute intermittent porphyria, hereditary coproporphyria, and variegate porphyria is autosomal dominant, but the clinical phenotype is heterogeneous. Within the general population, penetrance is low, but among first-degree relatives of a symptomatic proband, penetrance is higher. These observations suggest that genetic factors, in addition to mutation of the specific enzyme of the biosynthetic pathway of heme, contribute to the clinical phenotype. Recent studies by others suggested that the genotype of the transporter protein ABCB6 contribute to the porphyria phenotype. Identifying the molecule(s) that are transported by ABCB6 has been problematic and has led to uncertainty with respect to how or if variants/mutants contribute to phenotypic heterogeneity. Knockout mouse models of Abcb6 have not provided a direction for investigation as homozygous knockout animals do not have a discrete phenotype. To address the proposed link between ABC6 genotype and porphyria phenotype, a large cohort of patients with acute hepatic porphyria and erythropoietic protoporphyria was analyzed. Our studies showed that ABCB6 genotype did not correlate with disease severity. Therefore, genotyping of ABCB6 in patients with acute hepatic porphyria and erythropoietic protoporphyria is not warranted.