Development and validation of a claims-based algorithm to identify patients with Neuromyelitis Optica Spectrum disorder.

INTRODUCTION: No validated algorithm exists to identify patients with neuromyelitis optica spectrum disorder (NMOSD) in healthcare claims data. We developed and tested the performance of a healthcare claims-based algorithm to identify patients with NMOSD. METHODS: Using medical record data of 101 adults with NMOSD, multiple sclerosis (MS), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), we tested the sensitivity and specificity of claims-based algorithms developed through interviews with neurologists. We tested the best-performing algorithm's face validity using 2016-2019 data from IBM MarketScan Commercial and Medicare Supplemental databases. Demographics and clinical characteristics were reported. RESULTS: Algorithm inclusion criteria were age ≥ 18 years and (≥1 NMO diagnosis [or ≥ 1 transverse myelitis (TM) and ≥ 1 optic neuritis (ON) diagnosis] and ≥ 1 NMOSD drug) or (≥2 NMO diagnoses ≥90 days apart). Exclusion criteria were MS diagnosis or use of MS-specific drug after last NMO diagnosis or NMOSD drug; sarcoidosis diagnosis after last NMO diagnosis; or use of ≥1 immune checkpoint inhibitor. In medical record billing data of 50 patients with NMOSD, 30 with MS, and 21 with MOGAD, the algorithm had 82.0% sensitivity and 70.6% specificity. When applied to healthcare claims data, demographic and clinical features of the identified cohort were similar to known demographics of NMOSD. CONCLUSIONS: This clinically derived algorithm performed well in medical records. When tested in healthcare claims, demographics and clinical characteristics were consistent with previous clinical findings. This algorithm will enable a more accurate estimation of NMOSD disease burden using insurance claims datasets.

Broad host range phages target global Clostridium perfringens bacterial strains and clear infection in five-strain model systems.

Clostridium perfringens is a prevalent bacterial pathogen in poultry, and due to the spread of antimicrobial resistance, alternative treatments are needed to prevent and treat infection. Bacteriophages (phages), viruses that kill bacteria, offer a viable option and can be used therapeutically to treat C. perfringens infections. The aim of this study was to isolate phages against C. perfringens strains currently circulating on farms across the world and establish their virulence and development potential using host range screening, virulence assays, and larva infection studies. We isolated 32 phages of which 19 lysed 80%-92% of our global C. perfringens poultry strain collection (n = 97). The virulence of these individual phages and 32 different phage combinations was quantified in liquid culture at multiple doses. We then developed a multi-strain C. perfringens larva infection model, to mimic an effective poultry model used by the industry. We tested the efficacy of 16/32 phage cocktails in the larva model. From this, we identified that our phage cocktail consisting of phages CPLM2, CPLM15, and CPLS41 was the most effective at reducing C. perfringens colonization in infected larvae when administered before bacterial challenge. These data suggest that phages do have significant potential to prevent and treat C. perfringens infection in poultry. IMPORTANCE: Clostridium perfringens causes foodborne illness worldwide, and 95% of human infections are linked to the consumption of contaminated meat, including chicken products. In poultry, C. perfringens infection causes necrotic enteritis, and associated mortality rates can be up to 50%. However, treating infections is difficult as the bacterium is becoming antibiotic-resistant. Furthermore, the poultry industry is striving toward reduced antibiotic usage. Bacteriophages (phages) offer a promising alternative, and to progress this approach, robust suitable phages and laboratory models that mimic C. perfringens infections in poultry are required. In our study, we isolated phages targeting C. perfringens and found that many lyse C. perfringens strains isolated from chickens worldwide. Consistent with other published studies, in the model systems we assayed here, when some phages were combined as cocktails, the infection was cleared most effectively compared to individual phage use.

Minimal impact of proprioceptive loss on implicit sensorimotor adaptation and perceived movement outcome.

Implicit sensorimotor adaptation keeps our movements well-calibrated amid changes in the body and environment. We have recently postulated that implicit adaptation is driven by a perceptual error: the difference between the desired and perceived movement outcome. According to this perceptual re-alignment model, implicit adaptation ceases when the perceived movement outcome - a multimodal percept determined by a prior belief conveying the intended action, the motor command, and feedback from proprioception and vision - is aligned with the desired movement outcome. Here, we examined the role of proprioception in implicit motor adaptation and perceived movement outcome by examining individuals who lack proprioception. We used a modified visuomotor rotation task designed to isolate implicit adaptation and probe perceived outcome throughout the experiment. Surprisingly, implicit adaptation and perceived outcome were minimally impacted by deafferentation, posing a challenge to the perceptual re-alignment model of implicit adaptation.

Healthcare utilization and direct medical costs of Huntington's disease among Medicaid beneficiaries in the United States.

AIMS: To provide more recent estimates of healthcare utilization and costs in Huntington's disease (HD) in the Medicaid population. MATERIALS AND METHODS: This retrospective analysis used administrative claims data for HD beneficiaries (≥1 HD claim; ICD-9-CM 333.4) from Medicaid Analytic eXtract data files from 1 January 2010-31 December 2014. The date of the first HD claim during the identification period (1 January 2011-31 December 2013) was assigned as the index date. If a beneficiary had multiple HD claims during the identification period, one was randomly chosen as the index date. Beneficiaries were required to be continuously enrolled in fee-for-service plans during the 1-year pre-index and post-index periods. Medicaid beneficiaries without HD were drawn from a 100% random sample and matched (3:1) to those with HD. Beneficiaries were classified by disease stage (early/middle/late). All-cause and HD-related (any utilization related to HD diagnosis or symptoms associated with HD) healthcare utilization and costs were reported. RESULTS: A total of 1,785 beneficiaries without HD were matched to 595 beneficiaries with HD (139 early-, 78 middle-, and 378 late-stage). The mean (SD) annual total costs were higher for beneficiaries with HD than beneficiaries without HD ($73,087 [$75,140] vs. $26,834 [$47,659], p <.001) and driven by inpatient costs ($45,190 [$48,185] vs. $13,808 [$39,596], p <.001). Total healthcare costs were highest among beneficiaries with late-stage HD (mean [SD] cost: $22,797 [$31,683] for early-stage HD vs. $55,294 [$129,290] for middle-stage HD vs. $95,251 [$60,197] for late-stage HD; p <.001). LIMITATIONS: Administrative claims are intended for billing purposes and subject to coding errors. This study did not address functional status, which may provide further insight to late-stage and end-of-life burden of HD, and indirect costs. CONCLUSIONS: Medicaid beneficiaries with HD have higher acute healthcare utilization and costs compared to beneficiaries without HD, which tend to increase with disease progression, indicating that HD beneficiaries at later disease stages have greater burden.

Huntington's disease (HD) is a degenerative genetic disorder marked by progressive decline in cognitive and motor functions, leading to severe disability and loss of independence. The median and mean survival time after a diagnosis of HD is 15 years. Little is known about the kinds of health services used or costs associated with HD in the United States (US) in the Medicaid population. The study objective was to estimate healthcare utilization and direct medical spending among Medicaid beneficiaries with HD. The mean annual total costs were higher for beneficiaries with HD than beneficiaries without HD ($73,087 vs. $26,834). Mean total healthcare costs were highest among beneficiaries with late-stage HD ($22,797 for early-stage HD vs. $55,294 for middle-stage HD vs. $95,251 for late-stage HD). Medicaid beneficiaries with HD have higher acute healthcare utilization and costs compared to beneficiaries without HD, with utilization and costs increasing with disease progression, indicating that HD beneficiaries at later disease stages have greater burden.

Donor bone marrow-derived macrophage engraftment into the central nervous system of patients following allogeneic transplantation.

Hematopoietic stem cell transplantation is a well-known treatment for hematologic malignancies, wherein nascent stem cells provide regenerating marrow and immunotherapy against the tumor. The progeny of hematopoietic stem cells also populate a wide spectrum of tissues, including the brain, as bone marrow-derived macrophages similar to microglial cells. We developed a sensitive and novel combined immunohistochemistry (IHC) and XY fluorescence in situ hybridization assay to detect, quantify, and characterize donor cells in the cerebral cortices of 19 female patients who underwent allogeneic stem cell transplantation. We showed that the number of male donor cells ranged from 0.14% to 3.0% of the total cells or from 1.2% to 25% of microglial cells. Using tyramide-based fluorescent IHC, we found that at least 80% of the donor cells expressed the microglial marker ionized calcium-binding adapter molecule-1, consistent with bone marrow-derived macrophages. The percentage of donor cells was related to pretransplantation conditioning; donor cells from radiation-based myeloablative cases averaged 8.1% of microglial cells, whereas those from nonmyeloablative cases averaged only 1.3%. The number of donor cells in patients conditioned with busulfan- or treosulfan-based myeloablation was similar to that in total body irradiation-based conditioning; donor cells averaged 6.8% of the microglial cells. Notably, patients who received multiple transplantations and those with the longest posttransplantation survival had the highest level of donor engraftment, with donor cells averaging 16.3% of the microglial cells. Our work represents the largest study characterizing bone marrow-derived macrophages in patients after transplantation. The efficiency of engraftment observed in our study warrants future research on microglial replacement as a therapeutic option for disorders of the central nervous system.

Healthcare resource utilization and cost among individuals with late-onset versus adult-onset Huntington's disease: a claims­based retrospective cohort study.

AIMS: Quantify healthcare resource utilization (HRU) and costs for individuals with late-onset Huntington's disease (LoHD) and compare these with adult-onset HD (AoHD) and non-HD controls. METHODS: This retrospective cohort study used US healthcare claims data from the IBM MarketScan Commercial and Medicare Supplemental Databases. Individuals newly diagnosed with HD between 1/1/2009 and 12/31/2017 were selected (index date was first HD claim). Individuals ≥60 years of age at the index date were categorized as having LoHD while individuals 21-59 years of age were categorized as having AoHD. Non­HD controls were exact matched 2:1 to LoHD and AoHD cohorts. Individuals were required to have continuous enrollment for ≥12 months pre- and post-index. Twelve-month all-cause HRU and healthcare costs were assessed for each cohort. RESULTS: In total, 763 individuals with LoHD and 1,073 individuals with AoHD were matched with 3,762 non-HD controls. Unadjusted all-cause HRU in the 12 months post-index was higher for individuals with LoHD and AoHD compared with non-HD controls across most service categories. Adjusted all-cause HRU for the LoHD cohort was significantly higher compared with non-HD controls across all service categories. In the 12 months post-index, mean total costs for the LoHD cohort ($29,055) were significantly higher than for non-HD controls (≥60 years old: $17,286; 21-59 years old: $12,688; p <.001) and similar to total costs in the AoHD cohort ($31,701; p =.47). LIMITATIONS: It was not possible to control for differences in HD stage but regression models were adjusted for baseline HRU. Evaluations of costs did not include indirect costs, which are known to be significant components of the wider HD burden. CONCLUSIONS: This study provides the first analysis of HRU and costs in LoHD, demonstrating that individuals with LoHD experience a significantly higher healthcare burden compared with non-HD controls and a similarly high burden compared with individuals with AoHD.

Huntington's disease (HD) usually develops between the ages of 30­50 but can develop earlier/later. This study looked at healthcare use in people who developed HD at age 60 or later in the United States. Researchers found that people who develop HD at age 60 or later have similar health needs to people with adult-onset HD. Furthermore, they have much greater health needs than people of a similar age who do not have HD.

A bacteriophage cocktail delivered in feed significantly reduced Salmonella colonization in challenged broiler chickens.

Nontyphoidal Salmonella spp. are a leading cause of human gastrointestinal infections and are commonly transmitted via the consumption of contaminated meat. To limit the spread of Salmonella and other food-borne pathogens in the food chain, bacteriophage (phage) therapy could be used during rearing or pre-harvest stages of animal production. This study was conducted to determine if a phage cocktail delivered in feed is capable of reducing Salmonella colonization in experimentally challenged chickens and to determine the optimal phage dose. A total of 672 broilers were divided into six treatment groups T1 (no phage diet and unchallenged); T2 (phage diet 106 PFU/day); T3 (challenged group); T4 (phage diet 105 PFU/day and challenged); T5 (phage diet 106 PFU/day and challenged); and T6 (phage diet 107 PFU/day and challenged). The liquid phage cocktail was added to mash diet with ad libitum access available throughout the study. By day 42 (the concluding day of the study), no Salmonella was detected in faecal samples collected from group T4. Salmonella was isolated from a small number of pens in groups T5 (3/16) and T6 (2/16) at ∼4 × 102 CFU/g. In comparison, Salmonella was isolated from 7/16 pens in T3 at ∼3 × 104 CFU/g. Phage treatment at all three doses had a positive impact on growth performance in challenged birds with increased weight gains in comparison to challenged birds with no phage diet. We showed delivering phages via feed was effective at reducing Salmonella colonization in chickens and our study highlights phages offer a promising tool to target bacterial infections in poultry.

Synthesis, characterisation, DNA binding, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and molecular docking studies of metal(II) complexes with 1,10-phenanthroline scaffold.

A series of metal complexes containing Phenanthroline scaffold [ML] (L-1,10-Phenanthroline derivative comprises conjugated aromatic core and selenol group); M = Cu(II), Zn(II), Co(II) and Zn(II) ions were designed and synthesised to obtain effective anti-cholinesterase efficiencies of metal chelates. Analytical and spectroscopic studies were used to determine the structural features. An octahedral structure with moderate distortion was attributed to the above metal chelates based on spectroscopic data. The distorted octahedral geometry of copper(II) complex to DNA (Kb = 4.05 × 105 M-1) is stronger than that of ethidium bromide (EB) to DNA (Kb = 3.2 × 105 M-1), other metal complexes, respectively. The synthesised 1,10-Phenanthroline derivative had the best inhibitory effects against acetylcholinesterase (AChE) and butyrylcholinesterase, with IC50 values of 0.45 and 3.6 M, respectively, which were lower than the reference molecules. As a result, nitrogen-containing heterocyclic compounds (H2L) showed significant inhibitory profiles against the metabolic enzymes. Therefore, we believe that these experimental results may contribute to the development of new drug molecules particularly in the treatment of neurological disorders including glaucoma, Alzheimer's disease (AD) and diabetes. Docking, AChE and BuChE inhibition activities results revealed that ligand may be used for AD. The prepared 1,10-phenanthroline analogue, which has a high selectivity for AChE, may be studied further to find potential candidates for treating early-stage Alzheimer's symptoms.Communicated by Ramaswamy H. Sarma.

Therapeutic targeting of PRAME with mTCRCAR T cells in acute myeloid leukemia.

Preferentially Expressed Antigen in Melanoma (PRAME), a cancer-testis antigen, provides an ideal target for immunotherapy in acute myeloid leukemia (AML). We have shown expression of PRAME in a significant subset of childhood and adult AML and lack of expression in normal hematopoiesis. Although an intracellular antigen, we developed a novel approach to target PRAME using a chimeric antigen receptor (CAR) construct encoding a targeting domain based on T-cell receptor (TCR) mimic antibodies that target the peptide-HLA complex. We used the antibody sequence from a previously designed TCR mimic (mTCR) antibody, Pr20, that recognizes the PRAME ALY peptide in complex with HLA-A∗02 and verified expression of PRAME in AML cell lines and primary AML blasts. Using the Pr20 antibody sequence, we developed CAR T cells (PRAME mTCRCAR T) to be tested against primary samples from patients with AML and AML cell lines that express the PRAME antigen in the context of HLA-A2 expression. In contrast to appropriate controls, PRAME mTCRCAR T cells demonstrate target-specific and HLA-mediated in vitro activity in OCI-AML2 and THP-1 cell lines, HLA-A2 cell lines expressing the PRAME antigen, and against primary AML patient samples. In vivo cell-derived xenograft models treated with PRAME mTCRCAR T cells demonstrated potent leukemia clearance and improved survival compared with unmodified T-cell controls. Furthermore, the cytolytic activity of PRAME mTCRCAR T cells was enhanced by treating the target cells with interferon gamma, which increases PRAME antigen expression. These results demonstrate the feasibility and efficacy of targeting PRAME with novel PRAME mTCRCAR T cells.

Adherence and Persistence to Nusinersen for Spinal Muscular Atrophy: A US Claims-Based Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a genetic, neuromuscular disease caused by deletions and/or mutations in the survival of motor neuron 1 (SMN1) gene leading to reduced SMN protein levels. Nusinersen, an intrathecally administered antisense oligonucleotide therapy that increases SMN protein levels, is approved for use in adult and pediatric patients with SMA. Data to inform real-world patient adherence and persistence to nusinersen are limited, with disparities in the population with SMA, study design, and results. The objective of this study is to characterize real-world nusinersen adherence and persistence in patients with SMA. METHODS: This retrospective study examined nusinersen adherence and persistence over a 2-year period in patients with SMA in the USA from the IQVIA PharMetrics Plus claims database. Patients were followed from the date of first evidence of nusinersen treatment (occurring after 1 July 2017) until the end of the study period (31 December 2019) or end of continuous pharmacy and medical benefit enrollment, whichever came first. Subgroup analyses for nusinersen adherence and persistence were performed on the basis of age and presence or absence of spinal complications. RESULTS: The final cohort consisted of 179 patients with SMA treated with nusinersen. Adherence to nusinersen treatment was 41% at 56 weeks and 39% at 104 weeks. In the base-case persistence analysis, there was a decrease in persistence before 6 months (67%) and further decline at 1 (57%) and 2 years (55%). Patients with spinal complication versus without had numerically higher persistence with nusinersen. CONCLUSIONS: The findings suggest that adherence and persistence to nusinersen treatment appear low. Demographic (age ≥ 18 years) and clinical factors (no spinal complications) may contribute to nusinersen treatment discontinuation. Future research should explore possible reasons for low adherence and persistence to nusinersen treatment, such as clinical or logistical factors, patient preferences, and payer restrictions.

Spinal muscular atrophy (SMA) is a rare, genetic disease that causes patients to lose motor neurons over time. This makes tasks that involve movement control like walking and talking more difficult. SMA can be treated, but it is important that patients receive their scheduled doses of medicine as prescribed and stay on treatment. Nusinersen (SPINRAZA^®) is a treatment for SMA that is given as an intrathecal injection into the cerebrospinal fluid of the spine. Patients receive six doses of nusinersen in the first year. After the first year, patients receive three doses every year for life.This study looked at whether patients received their scheduled doses, also called adherence, and how many patients remained on treatment, or persistence, over two years. This study involved 179 nusinersen-treated patients with SMA and used data from US health insurance plans. After 56 weeks of treatment, 41% of patients were adherent. After 104 weeks, 39% were adherent. After 6 months, 67% of patients were still on treatment. After 1 year, 57% were still on treatment. After 2 years, 55% of patients were still on treatment. The study showed that a low number of patients with SMA, particularly those older than 18 years with no spinal problems, remained on nusinersen for the intended time and received the treatment as prescribed. Future studies will look at possible reasons for low adherence and persistence to nusinersen, which may include difficulties traveling to a clinic or scheduling a visit, patient preference, or insurance restrictions.

A Methodical and Performance-based Investigation of Alzheimer Disease Detection on Magnetic Resonance and Multimodal Images.

BACKGROUND: In recent years, Alzheimer's Disease (AD) has received more attention in the field of medical imaging, which leads to cognitive disorders. Physicians mainly rely on MRI imaging to examine memory impairment, thinking skills, judge functional abilities, and detect behavioral abnormalities for diagnosing Alzheimer's disease. OBJECTIVE: Early diagnosis of AD has become a challenging and strenuous task with conventional methods. The diagnostic procedure becomes complicated due to the structure and heterogeneous dimensions of the brain. This paper visualizes and analyzes the publications on AD and furnishes a detailed review based on the stages involved in the early detection of the disease. METHODS: This paper also focuses on assorted stages of disease detection such as image preprocessing, segmentation, feature extraction, classification, and optimization techniques that have been used in the diagnosis of AD during the past five years. It also spotlights the deep learning models used in assorted stages of detection. This paper also highlights the benefits of each method for assorted modalities of images. RESULTS: AD has been analyzed with various computational methods on a few datasets, which leads to high computation time and loss of important features. Hybrid methods can perform better in every diagnosis stage of AD than others. Finally, the assorted datasets used for the diagnosis and investigation of Alzheimer's disease were analyzed and explored using a computerized system for future scope. CONCLUSION: From the review papers, we can conclude that DNN has greater accuracy in MR images and CNN +AEC has the best accuracy in the multimodal images.

Diversity, Dynamics and Therapeutic Application of Clostridioides difficile Bacteriophages.

Clostridioides difficile causes antibiotic-induced diarrhoea and pseudomembranous colitis in humans and animals. Current conventional treatment relies solely on antibiotics, but C. difficile infection (CDI) cases remain persistently high with concomitant increased recurrence often due to the emergence of antibiotic-resistant strains. Antibiotics used in treatment also induce gut microbial imbalance; therefore, novel therapeutics with improved target specificity are being investigated. Bacteriophages (phages) kill bacteria with precision, hence are alternative therapeutics for the targeted eradication of the pathogen. Here, we review current progress in C. difficile phage research. We discuss tested strategies of isolating C. difficile phages directly, and via enrichment methods from various sample types and through antibiotic induction to mediate prophage release. We also summarise phenotypic phage data that reveal their morphological, genetic diversity, and various ways they impact their host physiology and pathogenicity during infection and lysogeny. Furthermore, we describe the therapeutic development of phages through efficacy testing in different in vitro, ex vivo and in vivo infection models. We also discuss genetic modification of phages to prevent horizontal gene transfer and improve lysis efficacy and formulation to enhance stability and delivery of the phages. The goal of this review is to provide a more in-depth understanding of C. difficile phages and theoretical and practical knowledge on pre-clinical, therapeutic evaluation of the safety and effectiveness of phage therapy for CDI.

Health care resource utilization and costs among individuals with vs without Huntington disease in a US population.

BACKGROUND: Quantifying the extent of health care resource utilization (HCRU) and costs associated with Huntington disease (HD) is vital for providers, decisionmakers, and payers to understand unmet treatment needs and to ensure limited resources can be used to benefit the maximum number of people with HD. OBJECTIVE: To quantify HCRU and costs for people with HD, overall and by disease stage, and compare these with non-HD controls. METHODS: This was a retrospective cohort study using administrative claims data from the IBM MarketScan Commercial, Multi-State Medicaid, and Medicare Supplemental Databases from January 1, 2009, to December 31, 2018. People with an HD claim between January 1, 2010, and December 31, 2017, were selected for this analysis and matched with non-HD controls for comparison. The HD cohort and the non-HD controls were exact matched on their follow-up duration and propensity score matched 1:4 to create the final analytical cohort. Index date was the first HD diagnosis for the HD cohort (proxy index date assigned to controls), and all individuals were required to have continuous enrollment for 12 or more months pre-index (baseline) and 3 or more months post-index. Proportions of all-cause HCRU (ie, outpatient visits, inpatient visits, emergency department visits, pharmacy fills, radiology visits, and physical/occupational therapy visits) in the 6-months post-index and HCRU counts and costs per patient per month (PPPM) over the entire follow-up were calculated for each cohort. RESULTS: A total of 2,473 individuals with HD and 9,522 matched non-HD controls were identified. HCRU in 6 months post-index was significantly greater in people with HD compared with non-HD controls for all health care service categories; P < 0.0001. The mean number of HCRU PPPM for all measured healthcare services was significantly higher in people with HD compared with non-HD controls (P < 0.001). Mean total costs (2018 USD PPPM) for the HD cohort ($2,260 [SD = $4,682]) were twice the total costs in the non-HD cohort ($1,056 [SD = $3,078]) (P < 0.0001) and were highest across all disease stages. CONCLUSIONS: This study provides current comprehensive HCRU and cost estimates in individuals with HD relative to those without the disease, thus demonstrating the high economic burden imposed by HD. DISCLOSURES: Dr Ta: Employment with Genentech (at time of study) and stock options with Roche; Dr To: Employment and stock options/dividends with Genentech; Dr Patel: Employment and stock options with Roche/Genentech; Dr Fuller: Employment with CHDI Management/CHDI Foundation; Mr Surinach: Employment with Genesis Research (which receives consulting fees from Genentech/Roche); Dr Abbass: Employment and stock options with Genentech; Dr Exuzides: Employment and stock options with Roche/Genentech; and Ms Luo: Employment with CHDI Management/CHDI Foundation. This study was funded by Genentech Inc. The authors thank Greg Rowe of Chrysalis Medical Communications for providing medical writing support, which was funded by F. Hoffmann-La Roche Ltd, in accordance with Good Publication Practice (GPP3) guidelines (http://www.ismpp.org/gpp3).

CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target.

The CBFA2T3-GLIS2 (C/G) fusion is a product of a cryptic translocation primarily seen in infants and early childhood and is associated with dismal outcome. Here, we demonstrate that the expression of the C/G oncogenic fusion protein promotes the transformation of human cord blood hematopoietic stem and progenitor cells (CB HSPCs) in an endothelial cell coculture system that recapitulates the transcriptome, morphology, and immunophenotype of C/G acute myeloid leukemia (AML) and induces highly aggressive leukemia in xenograft models. Interrogating the transcriptome of C/G-CB cells and primary C/G AML identified a library of C/G-fusion-specific genes that are potential targets for therapy. We developed chimeric antigen receptor (CAR) T cells directed against one of the targets, folate receptor α (FOLR1), and demonstrated their preclinical efficacy against C/G AML using in vitro and xenograft models. FOLR1 is also expressed in renal and pulmonary epithelium, raising concerns for toxicity that must be addressed for the clinical application of this therapy. Our findings underscore the role of the endothelial niche in promoting leukemic transformation of C/G-transduced CB HSPCs. Furthermore, this work has broad implications for studies of leukemogenesis applicable to a variety of oncogenic fusion-driven pediatric leukemias, providing a robust and tractable model system to characterize the molecular mechanisms of leukemogenesis and identify biomarkers for disease diagnosis and targets for therapy.

Healthcare resource utilization and costs in individuals with Huntington's disease by disease stage in a US population.

AIMS: To quantify healthcare resource utilization (HRU) and costs by disease stage in individuals with Huntington's disease (HD) in a US population. MATERIALS AND METHODS: This retrospective cohort study used administrative claims data from the IBM MarketScan Commercial, Multi-State Medicaid, and Medicare Supplemental Databases between 1 January 2009 and 31 December 2018. Individuals with an HD claim between 1 January 2010 and 31 December 2017 were selected. Index date was the date of first HD diagnosis. Individuals were required to have continuous enrollment for ≥ 12 months pre-index, 3 months post-index, and have no pre-index HD claims. All-cause HRU and costs per patient per month (PPPM) (overall and stratified by disease stage) were assessed for individuals with HD. RESULTS: A total of 2,669 individuals with HD were identified. Of these, 1,432 (53.7%), 689 (25.8%), and 548 (20.5%) had early-, middle-, and late-stage HD at baseline, respectively. Mean HRU PPPM by post-index HD stage increased with disease stage for outpatient visits, pharmacy claims, and HD-related pharmacy claims (p < 0.05 for all). Mean inpatient visits and emergency room visits PPPM were highest in individuals with middle-stage HD (p <0.05 for all). Mean total all-cause healthcare cost PPPM for individuals with HD was $2,889, and it was significantly higher in middle-stage individuals, at $7,988, compared with early- and late-stage individuals, at $3,726 and $5,125, respectively; p <0.0001. LIMITATIONS: In the absence of disease staging information in administrative claims data, staging was based on the presence of clinical markers in claims. Our evaluations didn't include the indirect costs of HD, which may be substantial as HD typically affects people at their peak earning potential. CONCLUSIONS: HRU and costs of care are high among individuals with HD, particularly among those with middle- and late-stage disease. This indicates that the disease burden in HD increases with disease stage, highlighting the need for interventions that can slow or prevent disease progression.

Prophylactic Delivery of a Bacteriophage Cocktail in Feed Significantly Reduces Salmonella Colonization in Pigs.

Nontyphoidal Salmonella spp. are a leading cause of human food poisoning and can be transmitted to humans via consuming contaminated pork. To reduce Salmonella spread to the human food chain, bacteriophage (phage) therapy could be used to reduce bacteria from animals' preslaughter. We aimed to determine if adding a two-phage cocktail to feed reduces Salmonella colonization in piglets. This first required spray drying phages to allow them to be added as a powder to feed, and phages were spray dried in different excipients to establish maximum recovery. Although laboratory phage yields were not maintained during scale up in a commercial spray dryer (titers fell from 3 × 108 to 2.4 × 106 PFU/g respectively), the phage titers were high enough to progress. Spray dried phages survived mixing and pelleting in a commercial feed mill, and sustained no further loss in titer when stored at 4°C or barn conditions over 6 months. Salmonella-challenged piglets that were prophylactically fed the phage-feed diet had significantly reduced Salmonella colonization in different gut compartments (P < 0.01). 16S rRNA gene sequencing of fecal and gut samples showed phages did not negatively impact microbial communities as they were similar between healthy control piglets and those treated with phage. Our study shows delivering dried phages via feed effectively reduces Salmonella colonization in pigs. IMPORTANCE Infections caused by Salmonella spp. cause 93.8 million cases of human food poisoning worldwide, each year of which 11.7% are due to consumption of contaminated pork products. An increasing number of swine infections are caused by multidrug-resistant (MDR) Salmonella strains, many of which have entered, and continue to enter the human food chain. Antibiotics are losing their efficacy against these MDR strains, and thus antimicrobial alternatives are needed. Phages could be developed as an alternative approach, but research is required to determine the optimal method to deliver phages to pigs and to determine if phage treatment is effective at reducing Salmonella colonization in pigs. The results presented in this study address these two aspects of phage development and show that phages delivered via feed prophylactically to pigs reduces Salmonella colonization in challenged pigs.

Epidemiology of Huntington's Disease in the United States Medicare and Medicaid Populations.

INTRODUCTION: Huntington's disease (HD) is a rare, genetic, and ultimately fatal neurodegenerative disease, with a devastating impact on individuals and families across generations. Few estimates of HD epidemiology in the United States (US) exist. METHODS: This study employed a retrospective cross-sectional design to examine the epidemiology of HD in the US Medicare and Medicaid beneficiary populations using 2016-2017 claims data from the Medicare 100% Research Identifiable Files (RIFs) and 2014 claims data from the Medicaid Analytic eXtract (MAX) files for 17 states. Medicare beneficiaries ≥65 years with a diagnosis of HD (≥1 claim with ICD-10-CM code G10) in 2017 and Medicaid beneficiaries <65 years with a diagnosis of HD (≥1 claim with ICD-9-CM code 333.4) in 2014 were identified. The study outcomes included the 2017 prevalence proportion and incidence rate of HD in the Medicare population and the 2014 prevalence proportion of HD in the Medicaid population. RESULTS: In the Medicare population, 1,941 prevalent and 819 incident cases of HD were identified in 2017, corresponding to a prevalence proportion of 13.1 per 100,000 persons and incidence rate of 6.1 per 100,000 person-years. In the Medicaid population, 353 prevalent cases of HD were identified in 2014, corresponding to a prevalence proportion of 15.2 per 100,000 persons. CONCLUSION: This study suggests that prevalence and incidence of HD in the US may be higher than previously estimated. This has important implications in raising awareness of HD among providers and payers and ensuring availability of and access to services for HD patients and care partners in the Medicare and Medicaid populations.

Understanding the Burdens Associated with Huntington's Disease in Manifest Patients and Care Partners-Comparing to Parkinson's Disease and the General Population.

BACKGROUND: The study provides real-world data on the impact of Huntington's disease (HD) from the perspective of individuals with HD (IHD) and care partners (HD-CP) and contextualizes these results relative to Parkinson's disease (PD) and the general population (GP). METHODS: Cross-sectional survey of IHD and HD-CP in the US (July 2019-August 2019) conducted using the Rare Patient Voice panel. Data for individuals with Parkinson's Disease (IPD), the general population (GP), and respective care partners (PD-CP; GP-CP) came from the 2018 US National Health and Wellness Survey. Outcomes included demographics, mental health, clinical characteristics, and health-related quality of life (HRQoL). RESULTS: IHD had greater comorbid anxiety (IHD = 51.2%, IPD = 28.8%, GP = 2.0%), and HD-CP had greater comorbid anxiety (HD-CP = 52.5%, PD-CP = 28.6%, GP-CP = 19.6%) and depression (HD-CP = 65.0%, PD-CP = 29.9%, GP-CP = 19.6%), relative to other cohorts (p < 0.05). Respective of their GP cohorts, IHD exhibited lower HRQoL (EQ-5D: 0.66 ± 0.21 vs. 0.81 ± 0.17) and greater depression (PHQ-9: 11.59 ± 7.20 vs. 5.85 ± 6.71), whereas HD-CP exhibited greater depression only (PHQ-9: 6.84 ± 6.38 vs. 4.15 ± 5.58) (p < 0.001). No differences were observed between HD/HD-CP and PD/PD-CP cohorts on PHQ-9 or HRQoL. CONCLUSIONS: HD has a significant burden on patients and care partners, which is higher than GP. Notably, anxiety and depression were greater among HD vs. PD, despite similar HRQoL.

Development of a Phage Cocktail to Target Salmonella Strains Associated with Swine.

Infections caused by multidrug resistant Salmonella strains are problematic in swine and are entering human food chains. Bacteriophages (phages) could be used to complement or replace antibiotics to reduce infection within swine. Here, we extensively characterised six broad host range lytic Salmonella phages, with the aim of developing a phage cocktail to prevent or treat infection. Intriguingly, the phages tested differed by one to five single nucleotide polymorphisms. However, there were clear phenotypic differences between them, especially in their heat and pH sensitivity. In vitro killing assays were conducted to determine the efficacy of phages alone and when combined, and three cocktails reduced bacterial numbers by ~2 × 103 CFU/mL within two hours. These cocktails were tested in larvae challenge studies, and prophylactic treatment with phage cocktail SPFM10-SPFM14 was the most efficient. Phage treatment improved larvae survival to 90% after 72 h versus 3% in the infected untreated group. In 65% of the phage-treated larvae, Salmonella counts were below the detection limit, whereas it was isolated from 100% of the infected, untreated larvae group. This study demonstrates that phages effectively reduce Salmonella colonisation in larvae, which supports their ability to similarly protect swine.

Disparities affecting incarcerated burn-injured patients: Insight from the National Burn Repository.

OBJECTIVE: Incarcerated patients are a vulnerable population and little is known regarding the epidemiology of burn injury and subsequent outcomes. This study utilizes a national database to assess disparities in care affecting this understudied population. METHODS: The National Burn Repository was queried for adult patients discharged into custody. Patients discharged to jail were compared to those with other dispositions. Additional analysis of the incarcerated patients compared those injured while in custody to those injured prior to incarceration. RESULTS: Between 2002-2011, 809 patients were discharged to jail with 283 (35.0%) sustaining these injuries while in custody. Patients were predominantly male (86.2%) and White (52.3%), with median age 35.7 years (IQR 27.7-45.9). Incarcerated patients had significantly higher rates of drug abuse and psychiatric illness. They had significantly smaller burns (2.0% vs. 3.8%, p < 0.001) and were less likely to undergo an operation but had comparable lengths of stay in the hospital. CONCLUSIONS: Although incarcerated burn-injured patients sustain smaller injuries and receive fewer operations they remain hospitalized for similar durations as non-incarcerated patients. Enhanced understanding of burn etiologies and injury characteristics as well as improved insight into the impact of psychosocial factors such as substance abuse and prevalence of psychiatric disorders may help improve care.