Hematologic Cancer after Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: Gene therapy with elivaldogene autotemcel (eli-cel) consisting of autologous CD34+ cells transduced with lentiviral vector containing ABCD1 complementary DNA (Lenti-D) has shown efficacy in clinical studies for the treatment of cerebral adrenoleukodystrophy. However, the risk of oncogenesis with eli-cel is unclear. METHODS: We performed integration-site analysis, genetic studies, flow cytometry, and morphologic studies in peripheral-blood and bone marrow samples from patients who received eli-cel therapy in two completed phase 2-3 studies (ALD-102 and ALD-104) and an ongoing follow-up study (LTF-304) involving the patients in both ALD-102 and ALD-104. RESULTS: Hematologic cancer developed in 7 of 67 patients after the receipt of eli-cel (1 of 32 patients in the ALD-102 study and 6 of 35 patients in the ALD-104 study): myelodysplastic syndrome (MDS) with unilineage dysplasia in 2 patients at 14 and 26 months; MDS with excess blasts in 3 patients at 28, 42, and 92 months; MDS in 1 patient at 36 months; and acute myeloid leukemia (AML) in 1 patient at 57 months. In the 6 patients with available data, predominant clones contained lentiviral vector insertions at multiple loci, including at either MECOM-EVI1 (MDS and EVI1 complex protein EVI1 [ecotropic virus integration site 1], in 5 patients) or PRDM16 (positive regulatory domain zinc finger protein 16, in 1 patient). Several patients had cytopenias, and most had vector insertions in multiple genes within the same clone; 6 of the 7 patients also had somatic mutations (KRAS, NRAS, WT1, CDKN2A or CDKN2B, or RUNX1), and 1 of the 7 patients had monosomy 7. Of the 5 patients with MDS with excess blasts or MDS with unilineage dysplasia who underwent allogeneic hematopoietic stem-cell transplantation (HSCT), 4 patients remain free of MDS without recurrence of symptoms of cerebral adrenoleukodystrophy, and 1 patient died from presumed graft-versus-host disease 20 months after HSCT (49 months after receiving eli-cel). The patient with AML is alive and had full donor chimerism after HSCT; the patient with the most recent case of MDS is alive and awaiting HSCT. CONCLUSIONS: Hematologic cancer developed in a subgroup of patients who were treated with eli-cel; the cases are associated with clonal vector insertions within oncogenes and clonal evolution with acquisition of somatic genetic defects. (Funded by Bluebird Bio; ALD-102, ALD-104, and LTF-304 ClinicalTrials.gov numbers, NCT01896102, NCT03852498, and NCT02698579, respectively.).

Lentiviral Gene Therapy for Cerebral Adrenoleukodystrophy.

BACKGROUND: Cerebral adrenoleukodystrophy is a severe form of X-linked adrenoleukodystrophy characterized by white-matter disease, loss of neurologic function, and early death. Elivaldogene autotemcel (eli-cel) gene therapy, which consists of autologous CD34+ cells transduced with Lenti-D lentiviral vector containing ABCD1 complementary DNA, is being tested in persons with cerebral adrenoleukodystrophy. METHODS: In a phase 2-3 study, we evaluated the efficacy and safety of eli-cel therapy in boys with early-stage cerebral adrenoleukodystrophy and evidence of active inflammation on magnetic resonance imaging (MRI). The primary efficacy end point was survival without any of six major functional disabilities at month 24. The secondary end points included overall survival at month 24 and the change from baseline to month 24 in the total neurologic function score. RESULTS: A total of 32 patients received eli-cel; 29 patients (91%) completed the 24-month study and are being monitored in the long-term follow-up study. At month 24, none of these 29 patients had major functional disabilities; overall survival was 94%. At the most recent assessment (median follow-up, 6 years), the neurologic function score was stable as compared with the baseline score in 30 of 32 patients (94%); 26 patients (81%) had no major functional disabilities. Four patients had adverse events that were directly related to eli-cel. Myelodysplastic syndrome (MDS) with excess blasts developed in 1 patient at month 92; the patient underwent allogeneic hematopoietic stem-cell transplantation and did not have MDS at the most recent follow-up. CONCLUSIONS: At a median follow-up of 6 years after lentiviral gene therapy, most patients with early cerebral adrenoleukodystrophy and MRI abnormalities had no major functional disabilities. However, insertional oncogenesis is an ongoing risk associated with the integration of viral vectors. (Funded by Bluebird Bio; ALD-102 and LTF-304 ClinicalTrials.gov numbers NCT01896102 and NCT02698579, respectively.).

First report of Rhizoctonia blight caused by Rhizoctonia solani on Chinese cabbage (Brassica rapa subsp. chinensis) in India.

During January and February 2021, foliar blight symptoms were observed on the leaves of Chinese cabbage (Pak choi) at Lembucherra research farm, College of Agriculture, Tripura, India. The incidence of disease symptoms ranged from 5 to 10% of the plants observed in the field. The symptomatic leaves showed grayish colored water-soaked lesions with an irreguar shape and size. A total of 10 symptomatic leaves (1 leaf per plant) from Chinese cabbage infected plant were sampled, surface decontaminated with 1% NaOCl, washed twice in sterile water, plated on 2% water agar, and incubated at 25 ± 2°C. Hyphal tips from mycelium of 7-day old culture (2 isolates from two different plants) with right-angled branching were transferred to potato dextrose agar (PDA) media (SRL, India). Cream or light brown hyphae that branched at right angles, with septa near the point of the origin of hyphae, and a slight constriction at the base of the branch) were visible under a microscope. Olive-brown sclerotia were observed after 5 days of incubation. Multiple nuclei per cell were visible after staining with 4', 6-diamidino-2-phenylindole (Estandarte et al. 2016). Based on morphological characteristics (Parmeter et al. 1970) the isolates TP36 and TP37 were identified as Rhizoctonia solani. The internal transcribed spacer (ITS) region and glyceraldehyde-3-phosphate dehydrogenase gene (GAPDH) were amplified with ITS1& ITS4 (White et al. 1990) and (GAPDH F-5'- CAAGGAGAACCCAGGTGTTAAG-3' and GAPDH R- 5'-GGCGTCGAAGATAGAAGAGTGT-3') respectively for both isolates and sequenced (accession #. PP458158, PP458159, PP425343, PP425344). BLASTn analysis showed 99.26%( 668/673 nt) to 99.46% (659/664 nt) identity with R. solani sequences (GenBank MG397062.1 and KX674524.1) for ITS and 98.42% (552/562 nt) to 100% 540/540 nt)identity with R. solani sequences (GenBank HQ425709.1 and CP102644.1) for GAPDH. Isolates TP36 and TP37 were deposited in the Indian Type Culture Collection (ITCC), New Delhi as R. solani (nos. 9154 and 9319, respectively). Both isolates were amplified using (anastomosis group) AG1 subgroup specific primers (Matsumoto 2002; Prashantha et al. 2021) to identify their AG. The presence of a 265 bp amplicon for both isolates suggested that they belong to AG1-IA. A multilocus analysis of R. solani isolates from different host plants with concatenated sequences ITS and GAPH showed that TP36 and TP37 are closely related to rice isolate RS107. A pathogenicity test on five plants per treatment was conducted and repeated twice on one month old Chinese cabbage plants (hybrid, TOKITA, India) grown under glasshouse conditions in a sterilized mixture of soil and sand (3:1) at 27-28oC during January 2024 at ICAR-IARI, New Delhi. R. solani isolates TP36 and TP37 were grown on PDA and plants were inoculated by placing single sclerotia of 10-day old colony on different plant parts and covering it with moist cotton. After 7 day, typical lesions of R. solani infection were visible. No symptoms were observed on the control plants. The fungus was reisolated from the inoculated plants and identified as R. solani based on morphology. R. solani has previously been reported to cause disease on some members of Brassicaceae in different countries (Budge et al. 2009; Hua et al. 2014). Based on literature available this is the first report of R. solani infecting Chinese cabbage in India.

Stemless Anatomic and Reverse Shoulder Arthroplasty in Patients under 55 years of age with Primary Glenohumeral Osteoarthritis: An analysis of the Australian Orthopaedic Association National Joint Replacement Registry at five years.

BACKGROUND: Primary glenohumeral osteoarthritis in young patients poses challenging treatment decisions. Arthroplasty options have different failure profiles and implant survivorship patterns. This registry study aims to analyze the cumulative per cent revision rate (CPR) of different types of arthroplasties conducted for primary osteoarthritis in patients under 55 years of age. METHODS: This comparative observational national registry study included all shoulder arthroplasty for osteoarthritis in patients under 55 years of age undertaken between January 1st, 2005, and December 31st, 2022. Partial hemi resurfacing and hemi stemless procedures were excluded. The cumulative percentage of revision (CPR) was determined using Kaplan-Meier estimates of survivorship and hazard ratios (HR) from Cox proportional hazard models adjusted for gender. Reasons for revision of each type of arthroplasty and cumulative incidence of revision diagnoses were analyzed. RESULTS: 2111 primary shoulder arthroplasties were compared. Glenoid erosion is the predominant cause of revision for humeral resurfacing (29.8%) and hemiarthroplasty (35.5%). Instability is the predominant cause of revision for stemmed anatomic total shoulder arthroplasty (ATSA) and reverse total shoulder arthroplasty (RTSA), while loosening is the predominant cause of revision for stemless ATSA. The 6-year CPR is 12.8% for humeral resurfacing (HRA), 14.1% for hemiarthroplasty (HA), 12.4% for stemmed (ATSA), 7.0% for stemless ATSA, and 6.5% for (RTSA). Stemmed ATSA had a higher revision rate than RTSA (entire period HR=2.04 (95% confidence interval (CI) 1.16, 3.57), p=0.012). In contrast, the revision rate of stemless ATSA was not different from RTSA (HR =1.05 (95% CI 0.51, 2.19), p=0.889). Males outnumber females for all shoulder arthroplasty categories. DISCUSSION: RTSA and stemless ATSA are viable options in young patients with primary osteoarthritis. Their short-to medium-term revision rates are comparable to those of older patients and lower than those associated with HRA, HA, and stemmed ATSA. CONCLUSION: In the predominantly male patient population under the age of 55, reverse shoulder arthroplasty and stemless ATSA have a lower short-term revision risk than stemmed ATSA.

Clinical Significance of Platelet Indices (Mean Platelet Volume and Mean Platelet Volume-to-lymphocyte Ratio) in Acute Coronary Syndrome: A Hospital-based Observational Study.

BACKGROUND: The role of platelet indices, such as mean platelet volume (MPV) and MPV-to-lymphocyte ratio (MPVLR), in diagnosing, and predicting the severity, and fatality in acute coronary syndrome (ACS) has not been extensively studied, particularly in Indian patients. Therefore, the study aimed to investigate the clinical significance of MPV and MPVLR in ACS. MATERIALS AND METHODS: This hospital-based observational study was conducted from 2020 to 2022. It included 110 ACS cases and an equal number of age- and sex-matched controls with chest pain of noncardiac origin. The primary objective was to compare MPV and MPVLR in ACS patients and controls. Secondary objectives included examining the associations between MPV, MPVLR, and different ACS types, as well as their correlation with the global registry of acute coronary events (GRACE) risk score and inhospital major adverse cardiovascular events (MACE). RESULTS: Higher MPV and MPVLR were observed in ACS cases compared to controls [(11.1 ± 1.1 fL; 10.6 ± 1.3 fL, p < 0.01), (7.63 ± 4.9 fL/mm3; 4.74 ± 1.6 fL/mm3, p < 0.01) respectively]. Significant associations were found between platelet indices (MPV, MPVLR) and various ACS types (p < 0.01). Both indices positively correlated with the severity of heart failure, GRACE score, and inhospital MACE (p < 0.01). MPVLR showed a positive correlation with the duration of hospital stay [(r: 0.21; p = 0.03), but MPV did not (r: 0.13; p = 0.17)]. The GRACE score demonstrated the highest discriminating capacity in predicting inhospital mortality compared to platelet indices. Additionally, MPV serves as a more effective prognostic marker than MPVLR in predicting inhospital mortality. CONCLUSION: Both MPV and MPVLR are higher in ACS than in healthy individuals. Therefore, both may be used as discriminating markers for differentiating cardiac and noncardiac chest pain when cardiac biomarkers are not available. Additionally, both have good sensitivity for predicting the severity of the disease, inhospital mortality, and MACE in ACS.

Eosinopenia in patients with acute myocardial infarction- longitudinal imaging insights from the CAPRI study.

Eosinophils are recruited to the heart during acute myocardial infarction (MI) and are considered part of the inflammatory response associated with adverse clinical outcomes. We assessed the impact of eosinopenia on cardiac imaging biomarkers in patients presenting with ST-segment elevation MI. This is a post-hoc analysis of the Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention (CAPRI) trial. Patients underwent cardiac MRI within 1 week and 12 weeks and low eosinophil was defined as less than 40 cells/ml. The study included 52 patients and 38% had low eosinophil. Ciclosporin administration was comparable between patients with low versus normal eosinophils. The ischaemia time was significantly longer in low eosinophil patients [262 (205-325) vs. 138 (102-195) minutes, P < 0.001]. At 12 weeks, patients with eosinopenia had larger infarct size [9.8% (5.7-18.4) vs. 7.4% (1.9-10.2), P = 0.045], larger left ventricle (LV) end systolic volume (89 ± 28 vs. 68 ± 23, P = 0.02), and lower LV ejection fraction (EF) (49 ± 9 vs. 58 ± 7, P < 0.001). After adjustments for significant predictors, including ischaemia time, low eosinophil count was an independent predictor of worse LVEF at 12 weeks [-5.78, 95% CI (-11.22 to -0.34), P = 0.038] but not infarct size [1.83, 95% CI (-2.77 to 6.43), P = 0.43]. Patients with low eosinophil count had larger infarct size and LV volumes and worse adverse remodeling compared to those with normal eosinophil count. At 12 weeks, eosinopenia was an independent predictor of worse LVEF but not infarct size.

A unique approach to address avoided crossings in the charge stabilization curve for LUMO identification.

In quantum chemistry, Lowest Unoccupied Molecular Orbital (LUMO) is important for studying various chemical processes, including photochemical reactions, electron attached states, and electron excites states. Recently, an effective method has been introduced that involves the use of the Parametric Equation of Motion (PEM) in conjunction with the nuclear charge stabilization method for precise identification of true LUMO. However, the inclusion of extra diffuse functions in the basis set, which is necessary for describing electron-attached and electron-excited states, can cause issues due to the presence of the same symmetry states, leading to avoided crossing. Identifying the true LUMO among these avoided crossings is challenging due to the mixing of states and the exchange of their orbital character. This article introduces a modification of the PEM to identify the true LUMO by preventing the stabilization of specific states involved in avoided crossings. The present method is highly effective and requires minimal computational cost.

Prevalence and natural history of gibbus deformity in patients with Hurler syndrome.

INTRODUCTION: Gibbus deformity has been documented as a common musculoskeletal abnormality in mucopolysaccharidosis type I (Hurler syndrome, MPS IH), and its recognition often leads to the diagnosis of MPS IH. While the incidence has been described, the progression of gibbus deformities is not well known. Here we describe the natural history of gibbus deformity in a single center patient population using serial spinal MRI scans. METHODS: All spinal MRI scans in MPS IH patients were retrospectively reviewed. The presence, spinal location, and angulation of the gibbus deformities were collected. The angles between the superior endplate of the superior normal vertebral body and the inferior endplate of the inferior normal vertebral body were measured. RESULTS: 24 of 47 patients (51%) were found to have cervico-thoracic deformity on their cervical MRI scans, and 19 of those 24 (79%) patients were found to have progressive cervico-thoracic deformity with average change of angle of 17.1 degrees [range 3.9, 62.8] over 5.3 years. 7 of 8 patients who had thoraco-lumbar MRI were found to have thoraco-lumbar deformity, and 4 of those 7 patients (57%) were found to have progressive thoraco-lumbar deformity with the average increase angle of 16.7 degrees [range 3.3, 47.1] over an average of 4.1 years. CONCLUSION: We found out that baseline spinal measurement cannot reliably predict the progression as multiple patients with normal alignment eventually developed severe deformity, whereases patients with severe deformity did not progress to require surgical intervention.

Machine Learning to Enhance Electronic Detection of Diagnostic Errors.

This cohort study examines whether machine learning (ML) can enhance the ability of electronic triggers to identify possible missed opportunities in diagnosis.

Effect of Age, Deboning Time of Carcass, and Different Cooking Conditions on the Woody Breast Myopathies in Chicken: A Meta-Analysis.

This meta-analysis review undertakes a comprehensive examination of various approaches for identifying myopathic fillets and meticulously evaluates the effects of bird age, deboning time, and different cooking and storage conditions on woody breast (WB) myopathic conditions in broiler deboned fillets. The data, meticulously collected from 20 articles based on predefined inclusion criteria sourced from various databases and online resources, reveal significant insights. For instance, the analysis uncovers that deboning time significantly affects Meullenet-Owens Razor Shear (MORS), Blunt Meullenet-Owens Razor Shear (BMORS), and descriptive analysis values (p < 0.001). Instrumentation techniques, such as compression force and shear force, along with different cooking conditions, strongly impact BMORS shear force values (R2 = 86.80%), with significance levels ranging from 0.01 to 0.001. Deboning time also substantially impacts MORS shear force values (R = 64.03%). In contrast, the effects of deboning time, bird age, and cooking conditions on descriptive sensory evaluation are minimal when compared to woody breast fillets (age of birds: R2 = 26.53%; cooking conditions: R2 = 32.57%; deboning time: R2 = 10.06%). The overall effect of bird age on chicken breast meat quality shows significant differences for the evaluated parameters (Hedges' g [95% CI] = -0.72 [0.17, 1.26], I2 = 93%, p < 0.01). The sous vide cooking method significantly affects shear force energies and sensory descriptive evaluation for woody breast fillets (Hedges' g [95% CI] = 5.30 [-50.30, 83.40], I2 = 98%, p < 0.01). These findings, with their significant implications, provide valuable insights for optimizing processing conditions in the poultry industry to reduce woody breast occurrences and enhance meat quality, instilling confidence in the robustness of the research.

Role of Noninvasive Urinary Prothrombin Fragment 1 + 2 to Measure Blood Coagulation Indices and Dose of Acenocoumarol.

PF1 + 2 plasma levels are a crucial indicator for assessing anticoagulant action in individuals receiving anticoagulant treatment. Urine also has PF1 + 2 levels due to its molecular size. Hence, the present study aims to measure urinary prothrombin fragment 1 + 2 (uPF1 + 2) in patients taking anticoagulants in order to divulge a noninvasive surrogate marker of PT-INR of blood coagulopathy. A total of 205 people participated in the study: 104 patients on acenocoumarol (AC) and 101 healthy controls (HC). Clinical parameters, including PT-INR, urinary creatinine, etc., were measured in all subjects. To evaluate uPF1 + 2 in samples, MALDI-TOF-MS, Western blot analysis, and ELISA tests were used. The MALDI-TOF-MS results showed the presence of uPF1 + 2 in both AC and HC urine samples. The Western blot, ELISA experiment, and unpaired t test results displayed that the patients with AC had significantly increased levels of uPF1 + 2 compared to HC. A regression study showed a strong positive relation between blood-based PT-INR and uPF1 + 2. ROC validation also revealed the clinical efficacy of uPF1 + 2. For the goal to monitor anticoagulant medication, the present study highlights PF1 + 2, which describes the overall hemostatic capacity and might be utilized in addition to or instead of PT-INR.

Assessment of Psychiatric Illness among Pulmonary Tuberculosis Patients at a Tertiary Care Center in India.

INTRODUCTION: Tuberculosis (TB) is a chronic infectious multisystemic disease caused by Mycobacterium tuberculosis and is one of the leading causes of mortality worldwide. Both common mental disorders (CMD) and TB are global public health problems that have a considerable impact on human health. Moreover, TB and CMDs share common risk factors including poverty, drug addiction, and homelessness and the coexistence of CMD and TB leads to difficult management of TB. MATERIALS AND METHODS: This was a hospital-based longitudinal study, carried out between June 2021 and December 2022. In this study, 147 pulmonary TB patients were included as per inclusion and exclusion criteria, and psychiatric illness was evaluated by the Brief Psychiatric Rating Scale. RESULTS: The mean age of study participants was 37.59 ± 15.37 years, there were 99 (67.3%) were male and 48 (32.7%) were female. Psychiatric illness was found in 77 (52.38%) pulmonary TB patients. Among psychiatric illness, anxiety was found in 33 (22.4%) participants and 21 (14.3%) participants had depression. Mixed anxiety and depression were found in 20 (13.6%) patients and 03 (2%) participants had severe psychosis. The association of psychiatric illness with age group and gender was not significant ( P = 0.734, 0.203, respectively). There were 105 (71.40%) patients who had <12 standard education and 42 (28.60%) had >12 standard education and their association with psychiatric illness was statistically significant ( P = 0.044). Adverse drug reactions were found among 80 (54.42%) patients and the association between adverse drug reactions and psychiatric illness was significant ( P = 0.031). CONCLUSION: Psychiatric illness is one of the important domains to be evaluated in timely manner in TB patients and early intervention is needed for better management of the TB because the severity, social factors, and chronicity of the disease make them susceptible to develop psychiatric illness.

Résumé Introduction:La tuberculose (TB) est une maladie infectieuse multisystémique chronique causée par Mycobacterium tuberculosis et constitue l'une des principales causes de mortalité dans le monde. Les troubles mentaux courants (CMD) et la tuberculose sont des problèmes de santé publique mondiaux qui ont un impact considérable sur la santé humaine. De plus, la tuberculose et les troubles mentaux courants (CMD) partagent des facteurs de risque communs, notamment la pauvreté, la toxicomanie et l'itinérance, et la coexistence des CMD et de la tuberculose rend difficile la gestion de la tuberculose.Méthodes:Il s'agissait d'une étude longitudinale en milieu hospitalier, réalisée entre juin 2021 et décembre 2022. Dans cette étude, 147 patients atteints de tuberculose pulmonaire ont été inclus selon les critères d'inclusion et d'exclusion et la maladie psychiatrique a été évaluée par une brève échelle d'évaluation psychiatrique (BPRS).Résultats:L'âge moyen des participants à l'étude était de 37,59 ± 15,37 ans, il y avait 99 (67,3 %) hommes et 48 (32,7 %) femmes. Une maladie psychiatrique a été trouvée chez 77 (52,38 %) patients atteints de tuberculose pulmonaire. Parmi les maladies psychiatriques, l'anxiété a été constatée chez 33 (22,4 %) participants et 21 (14,3 %) participants souffraient de dépression. Une anxiété et une dépression mixtes ont été trouvées chez 20 (13,6 %) patients et 03 (2 %) participants souffraient d'une psychose sévère. L'association entre la maladie psychiatrique et le groupe d'âge et le sexe n'était pas significative (valeur P = 0,734, 0,203 respectivement). Il y avait 105 (71,40 %) patients ayant <12 niveaux d'éducation standard et 42 (28,60 %) avaient >12 niveaux d'éducation standard et leur association avec une maladie psychiatrique était statistiquement significative ( P = 0,044). Des effets indésirables du médicament ont été observés chez 80 (54,42 %) patients et l'association entre l'effet indésirable du médicament et la maladie psychiatrique était significative. ( P = 0,031).Conclusion:La maladie psychiatrique est l'un des domaines importants à évaluer en temps opportun chez les patients tuberculeux et une intervention précoce est nécessaire pour une meilleure prise en charge de la tuberculose car la gravité, les facteurs sociaux et la chronicité de la maladie les rendent susceptibles de développer une maladie psychiatrique.

Secondary failure of lentiviral vector gene therapy in a cerebral adrenoleukodystrophy patient with an ABCD1 whole-gene deletion.

A 9-year-old boy with adrenoleukodystrophy due to ABCD1 whole-gene deletion was diagnosed with active cerebral adrenoleukodystrophy characterized by demyelination and gadolinium enhancement on brain MRI. He underwent hematopoietic cell transplant (HCT) with autologous CD34+ cells transduced with an ABCD1-expressing lentiviral vector (eli-cel [elivaldogene autotemcel]) as part of the ALD-104 clinical trial. Fifty days after HCT, the patient's MRI showed gadolinium resolution; the whole-blood vector copy number (VCN) was 0.666 copies/mL. Six months following HCT, an MRI showed re-emergence of gadolinium enhancement; the VCN had decreased to 0.029 copies/mL. Polyclonal antibodies to the ABCD1 gene product were detectable 9 months after transplant, showing reactivity to peroxisomes, suggesting an immune response; however, no antibody binding to human CD34+ cells could be shown. The patient underwent a successful allogeneic HCT 12 months after gene therapy with resultant gadolinium resolution, cerebral disease stabilization, and the disappearance of antibodies. The coincident VCN loss and appearance of antibody to the ABCD1 gene product is of interest, and we postulate that it is related to the patient's whole ABCD1 gene deletion. We suggest close monitoring of loss of gene therapy efficacy due to immune response in patients with full deletions who are considering gene therapy.

Diffusion Tensor Imaging in Boys With Adrenoleukodystrophy: Identification of Cerebral Disease and Association With Neurocognitive Outcomes.

BACKGROUND AND OBJECTIVES: Childhood cerebral adrenoleukodystrophy (C-ALD) is a severe inflammatory demyelinating disease that must be treated at an early stage to prevent permanent brain injury and neurocognitive decline. In standard clinical practice, C-ALD lesions are detected and characterized by a neuroradiologist reviewing anatomical MRI scans. We aimed to assess whether diffusion tensor imaging (DTI) is sensitive to the presence and severity of C-ALD lesions and to investigate associations with neurocognitive outcomes after hematopoietic cell therapy (HCT). METHODS: In this retrospective cohort study, we analyzed high-resolution anatomical MRI, DTI, and neurocognitive assessments from boys with C-ALD undergoing HCT at the University of Minnesota between 2011 and 2021. Longitudinal DTI data were compared with an age-matched group of boys with ALD and no lesion (NL-ALD). DTI metrics were obtained for atlas-based regions of interest (ROIs) within 3 subdivisions of the corpus callosum (CC), corticospinal tract (CST), and total white matter (WM). Between-group baseline and slope differences in fractional anisotropy (FA) and axial (AD), radial (RD), and mean (MD) diffusivities were compared using analysis of covariance accounting for age, MRI severity (Loes score), and lesion location. RESULTS: Among patients with NL-ALD (n = 14), stable or increasing FA, stable AD, and stable or decreasing RD and MD were generally observed during the 1-year study period across all ROIs. In comparison, patients with mild posterior lesions (Loes 1-2; n = 13) demonstrated lower baseline FA in the CC splenium (C-ALD 0.50 ± 0.08 vs NL-ALD 0.58 ± 0.04; pBH = 0.022 adjusted Benjamini-Hochberg p-value), lower baseline AD across ROIs (e.g., C-ALD 1.34 ± 0.03 ×10-9 m2/s in total WM vs NL-ALD 1.38 ± 0.04 ×10-9 m2/s; pBH = 0.005), lower baseline RD in CC body and CST, and lower baseline MD across ROIs except CC splenium. Longitudinal slopes in CC splenium showed high sensitivity and specificity in differentiating early C-ALD from NL-ALD. Among all patients with C-ALD (n = 38), baseline Loes scores and DTI metrics were associated with post-HCT neurocognitive functions, including processing speed (e.g., FA WM Spearman correlation coefficient R = 0.64) and visual-motor integration (e.g., FA WM R = 0.71). DISCUSSION: DTI was sensitive to lesion presence and severity as well as clinical neurocognitive effects of C-ALD. DTI metrics quantify C-ALD even at an early stage.

Qualitative analysis of the Supraspinatus muscle fatty infiltration on MRI - Correlation of the Tangent sign with Goutallier grade at the Y view and Medial Scapular border in large retracted rotator cuff tears.

BACKGROUND: Surgically repairing rotator cuff tears with a higher extent of fatty infiltration is controversial. Current evidence supports performing rotator cuff repair in patients exhibiting Goutallier stage 3-4 fatty infiltration. However, the presence of retraction complicates accurate assessment using the Goutallier Classification, particularly on the lateral Y-view. A shift towards classifying fatty infiltration in more medial regions may enhance the precision of tissue quality quantification. The objective of this study was to analyze the uniformity of fatty infiltration within the entire supraspinatus muscle using the Goutallier Classification across three scapular Y-view sections and to examine the association between Goutallier grade, tangent sign, and modified Patte stage. METHODS: A retrospective evaluation was conducted on preoperative magnetic resonance imaging (MRI) scans from a consecutive series of 97 patients who had previously undergone arthroscopic rotator cuff repairs. Three supraspinatus sections on the MRI sagittal plane were identified: the lateral Y-view (section one), a medial section at the suprascapular notch anatomical landmark (section two), and a section 3 cm medial from the suprascapular notch Medial Scapular Body (section three). Goutallier grade, tangent sign, and modified Patte stage were used to evaluate fatty infiltration, muscle atrophy, and tendon retraction, respectively. RESULTS: Section one had the highest Goutallier grade, while section three had the lowest. Intra-observer rest retest reliability analysis showed excellent consistency in all sections with section one (ICC=0.920, 95% CI), section two (ICC=0.917, 95% CI), and section three (ICC=0.923, 95% CI) for Goutallier grade. Inter-observer reliability analysis also revealed excellent consistency in sections one (ICC=0.951, 95% CI), section two (ICC=0.949, 95% CI), and section three (ICC=0.922, 95% CI) for Goutallier grade. A strong correlation was observed between Goutallier grade and modified Patte stage (τb=0.43-0.56, p=0.001), and between Goutallier grade and tangent sign (τb=0.43-0.54, p=0.001) across all sections. CONCLUSION: The severity of fatty infiltration within the supraspinatus muscle belly is inconsistent, with the lateral portion being the most severe and the medial portion the least severe. Goutallier grade demonstrates a strong correlation with tangent sign and modified Patte stage. This suggests that tendon retraction results in a potential overestimation in the amount of fatty infiltration defining some tears unjustly irreparable when measuring at the traditionally described lateral Y-view position compared with 3cm medial.

Probing and gauging of D-Penicillamine xenobiotics in hepatic Wilson disease patients.

D-penicillamine (PA) is the primary chelator of choice to treat Wilson disease (WD). There are limitations in obtaining comprehensive data on PA metabolites in biological specimens by conventional approaches. Hence, the aim of the present was to identify the major hepatic PA metabolites and draw clear conclusions of the drug's xenobiotic in WD. Urine samples were collected from children with hepatic WD (n = 63, aged 14.8 ± 4 years) 5 h after PA administration (16.3 ± 3.8 mg/kg/day) and age-matched healthy volunteers comprised as controls (n = 30). High-resolution 800 MHz nuclear magnetic resonance spectroscopy (NMR) and mass spectrometry was applied to reveal unambiguous appraisals of different excretory by-products of PA metabolism. Four new products comprising penicillamine disulphide (PD), penicillamine cysteine disulphide (PCD), S-methyl penicillamine (SMP), and N-acetyl penicillamine (NAP) of PA xenobiotic metabolites were identified using high-resolution NMR spectroscopy. Quantitative levels of PCD and SMP were approximately three-fold higher than those of PD and NAP, respectively. High-resolution NMR identifies the major PA metabolites with certainty. Reduction, sulfation, and methylation are the predominant pathways of PA metabolism. There is a potential application for assessing therapeutic monitoring of chelation in hepatic WD.

Advances in Nickel-Containing High-Entropy Alloys: From Fundamentals to Additive Manufacturing.

High-entropy alloys (HEAs) are recognized as a class of advanced materials with outstanding mechanical properties and corrosion resistance. Among these, nickel-based HEAs stand out for their impressive strength, ductility, and oxidation resistance. This review delves into the latest advancements in nickel-containing HEAs, covering their fundamental principles, alloy design strategies, and additive manufacturing techniques. We start by introducing HEAs and their unique properties, emphasizing the crucial role of nickel. This review examines the complex relationships between alloy composition, valence electron concentration (VEC), and the resulting crystal structures. This provides insights into design principles for achieving desired microstructures and mechanical properties. Additive manufacturing (AM) techniques like selective laser melting (SLM), electron beam melting (EBM), and laser metal deposition (LMD) are highlighted as powerful methods for fabricating intricate HEA components. The review addresses the challenges of AM processes, such as porosity, fusion defects, and anisotropic mechanical properties, and discusses strategies to mitigate these issues through process optimization and improved powder quality. The mechanical behavior of AM-processed nickel-based HEAs is thoroughly analyzed, focusing on compressive strength, hardness, and ductility. This review underscores the importance of microstructural features, including grain size, phase composition, and deformation mechanisms, in determining the mechanical performance of these alloys. Additionally, the influence of post-processing techniques, such as heat treatment and hot isostatic pressing (HIP) on enhancing mechanical properties is explored. This review also examines the oxidation behavior of nickel-containing HEAs, particularly the formation of protective oxide scales and their dependence on aluminum content. The interplay between composition, VEC, and oxidation resistance is discussed, offering valuable insights for designing corrosion resistant HEAs. Finally, this review outlines the potential applications of nickel-based HEAs in industries such as aerospace, automotive, and energy, and identifies future research directions to address challenges and fully realize the potential of these advanced materials.

Developmental delay can precede neurologic regression in early onset metachromatic leukodystrophy.

OBJECTIVE: Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disorder. Emerging therapies are most effective in the presymptomatic phase, and thus defining this window is critical. We hypothesize that early development delay may precede developmental plateau. With the advent of presymptomatic screening platforms and transformative therapies, it is essential to define the onset of neurologic disease. METHODS: The specific ages of gain and loss of developmental milestones were captured from the medical records of individuals affected by MLD. Milestone acquisition was characterized as: on target (obtained before the age limit of 90th percentile plus 2 standard deviations compared to a normative dataset), delayed (obtained after 90th percentile plus 2 standard deviations), or plateau (skills never gained). Regression was defined as the age at which skills were lost. LI-MLD was defined by age at onset before 2.5 years. RESULTS: Across an international cohort, 351 subjects were included (n = 194 LI-MLD subcohort). The median age at presentation of the LI-MLD cohort was 1.4 years (25th-75th %ile: 1.0-1.5). Within the LI-MLD cohort, 75/194 (39%) had developmental delay (or plateau) prior to MLD clinical presentation. Among the LI-MLD cohort with a minimum of 1.5 years of follow-up (n = 187), 73 (39.0%) subjects never attained independent ambulation. Within LI-MLD + delay subcohort, the median time between first missed milestone target to MLD decline was 0.60 years (maximum distance from delay to onset: 1.9 years). INTERPRETATION: Early developmental delay precedes regression in a subset of children affected by LI-MLD, defining the onset of neurologic dysfunction earlier than previously appreciated. The use of realworld data prior to diagnosis revealed an early deviation from typical development. Close monitoring for early developmental delay in presymptomatic individuals may help in earlier diagnosis with important consequences for treatment decisions.