Engineering Memory T Cells as a platform for Long-Term Enzyme Replacement Therapy in Lysosomal Storage Disorders.

Enzymopathy disorders are the result of missing or defective enzymes. Amongst these enzymopathies, mucopolysaccharidosis type I, is a rare genetic lysosomal storage disorder caused by mutations in the gene encoding alpha-L-iduronidase (IDUA), ultimately causes toxic build-up of glycosaminoglycans (GAGs). There is currently no cure and standard treatments provide insufficient relief to the skeletal structure and central nervous system (CNS). Human memory T cells (Tm) migrate throughout the body's tissues and can persist for years, making them an attractive approach for cellular-based, systemic enzyme replacement therapy. Here, we tested genetically engineered, IDUA-expressing Tm as a cellular therapy in an immunodeficient mouse model of MPS I. Our results demonstrate that a single dose of engineered Tm leads to detectable IDUA enzyme levels in the blood for up to 22 weeks and reduced urinary GAG excretion. Furthermore, engineered Tm take up residence in nearly all tested tissues, producing IDUA and leading to metabolic correction of GAG levels in the heart, lung, liver, spleen, kidney, bone marrow, and the CNS. Our study indicates that genetically engineered Tm holds great promise as a platform for cellular-based enzyme replacement therapy for the treatment of mucopolysaccharidosis type I and potentially many other enzymopathies and protein deficiencies.

Open, endovascular, or hybrid repair of aortic arch disease: narrative review of diverse strategies with diverse options.

OBJECTIVES AND METHODS: The management of aortic arch disease is complex. Open surgical management continues to evolve, and the introduction of endovascular repair is revolutionizing aortic arch surgery. Although these innovative techniques have generated the opportunity for better outcomes in select patients, they have also introduced confusion and uncertainty regarding best practices. In New York, we have developed a collaborative group named the New York Aortic Consortium (NYAC) as a means of crosslinking knowledge and working together to better understand and treat aortic disease. In our meeting in May 2023, regional aortic experts and invited international experts discussed the contemporary management of aortic arch disease, differences in interpretation of the available literature, as well as the integration of endovascular technology into disease management. In this review article, we summarize the current state of aortic arch surgery. RESULTS: Approaches to aortic arch repair have evolved substantially, whether it be methods to reduce cerebral ischaemia, improve hemostasis, simplify future operations, or expand options for high-risk patients with endovascular approaches. However, the transverse aortic arch remains challenging to repair. Amongst our collaborative group of cardiac/aortic surgeons, we discovered a wide disparity in our practice patterns and management strategies of patients with aortic arch disease. CONCLUSIONS: It is important to build unique institutional expertise in the context of complex and evolving management of aortic arch disease with open surgery, endovascular repair, and hybrid approaches, tailored to the risk profiles and anatomical specifics of individual patients.

Wound-Healing Effects of Common Antineoplastic Agents and Perioperative Considerations for the Orthopaedic Surgeon.

In oncologic patients, optimal postoperative wound healing is crucial for the maintenance of systemic therapies and improved survival. Although several risk factors for postoperative wound complications have been identified, the clinical effect of new antineoplastic agents on wound healing remains uncertain. The available literature on the effect of antineoplastic agents in wound healing is complex to analyze because of other confounding risk factors such as radiation therapy and certain patient-specific variables. Available perioperative drug recommendations are based on database opinion and case reports from adverse event alerts. This review highlights the characteristics of old and new antineoplastic agents commonly used in the treatment of sarcoma, carcinoma, and other cancers and their potential effects on the wound-healing process. It also aims to provide perioperative treatment cessation recommendations to guide orthopaedic surgeons and prevent drug-related wound complications to the fullest extent possible.

Characterization of treatment resistance and viral kinetics in the setting of single- versus dual-active monoclonal antibodies against SARS-CoV-2.

BACKGROUND: Monoclonal antibodies (mAbs) represent a crucial antiviral strategy for SARS-CoV-2 infection, but it is unclear whether combination mAbs offer a benefit over single-active mAb treatment. Amubarvimab and romlusevimab significantly reduced the risk of hospitalizations or death in the ACTIV-2/A5401 trial. Certain SARS-CoV-2 variants are intrinsically resistant against romlusevimab, leading to only single-active mAb therapy with amubarvimab in these variants. We evaluated virologic outcomes in individuals treated with single- versus dual-active mAbs. METHODS: Participants were non-hospitalized adults at higher risk of clinical progression randomized to amubarvimab plus romlusevimab or placebo. Quantitative SARS-CoV-2 RNA levels and targeted S gene next-generation sequencing was performed on anterior nasal samples. We compared viral load kinetics and resistance emergence between individuals treated with effective single- versus dual-active mAbs depending on the infecting variant. RESULTS: Study participants receiving single- and dual-active mAbs had similar demographics, baseline nasal viral load, symptom score, and symptom duration. Compared to single-active mAb, treatment with dual-active mAbs led to faster viral load decline at study day 3 (p < 0.001) and day 7 (p < 0.01). Treatment-emergent resistance mutations were more likely to be detected after amubarvimab plus romlusevimab treatment than placebo (2.6% vs 0%, P < 0.001), and more frequently detected in the setting of single-active compared to dual-active mAb treatment (7.2% vs 1.1%, p < 0.01). Single-active and dual-active mAb treatment resulted in similar decrease in rates of hospitalizations or death. CONCLUSION: Compared to single-active mAb therapy, dual-active mAbs led to similar clinical outcomes, but significantly faster viral load decline and a lower risk of emergent resistance.

A new angle on transcranial magnetic stimulation coil orientation: A targeted narrative review.

Transcranial magnetic stimulation (TMS) is used to treat several neuropsychiatric disorders including depression, where it is effective in approximately half of patients for whom pharmacological approaches have failed. Treatment response is related to stimulation parameters such as the stimulation frequency, pattern, intensity, location, total number of pulses and sessions applied, as well as target brain network engagement. One critical but underexplored component of the stimulation procedure is the orientation or yaw angle of the commonly used figure-of-eight TMS coil, which is known to impact neuronal response to TMS. However, coil orientation has remained largely unchanged since TMS was first used to treat depression and continues to be based on motor cortex anatomy which may not be optimal for the dorsolateral prefrontal cortex treatment site. This targeted narrative review evaluates experimental, clinical, and computational evidence indicating that optimizing coil orientation may potentially improve TMS treatment outcomes. The properties of the electric field induced by TMS, the changes to this field caused by the differing conductivities of head tissues, and the interaction between coil orientation and the underlying cortical anatomy are summarized. We describe evidence that the magnitude and site of cortical activation, surrogate markers of TMS dosing and brain network targeting considered central in clinical response to TMS, are influenced by coil orientation. We suggest that coil orientation should be considered when applying therapeutic TMS and propose several approaches to optimizing this potentially important treatment parameter.

CD4 T cells and CD8α+ lymphocytes are necessary for intravenous BCG-induced protection against tuberculosis in macaques.

Tuberculosis (TB) is a major cause of morbidity and mortality worldwide despite widespread intradermal (ID) BCG vaccination in newborns. We previously demonstrated that changing the route and dose of BCG vaccination from 5ξ10 5 CFU ID to 5ξ10 7 CFU intravenous (IV) resulted in prevention of infection and disease in a rigorous, highly susceptible non-human primate model of TB. Identifying the immune mechanisms of protection for IV BCG will facilitate development of more effective vaccines against TB. Here, we depleted select lymphocyte subsets in IV BCG vaccinated macaques prior to Mtb challenge to determine the cell types necessary for that protection. Depletion of CD4 T cells or all CD8α expressing lymphoycytes (both innate and adaptive) resulted in loss of protection in most macaques, concomitant with increased bacterial burdens (∼4-5 log10 thoracic CFU) and dissemination of infection. In contrast, depletion of only adaptive CD8αß+ T cells did not significantly reduce protection against disease. Our results demonstrate that CD4 T cells and innate CD8α+ lymphocytes are critical for IV BCG-induced protection, supporting investigation of how eliciting these cells and their functions can improve future TB vaccines. One Sentence Summary: Antibody depletion of lymphocytes in rhesus macques demonstrates key roles for CD4 T cells and innate-like CD8α+ lymphocytes in conferring sterilizing immunity against tuberculosis following intravenous BCG vaccination.

Histone Modifications and miRNA Perturbations Contribute to Transcriptional Dysregulation of Hypertrophy in Obstructive Hypertrophic Cardiomyopathy.

Background: Recently, we demonstrated transcriptional downregulation of hypertrophy pathways in myectomy tissue derived from patients with obstructive hypertrophic cardiomyopathy (HCM) despite translational activation of hypertrophy pathways. The mechanisms and modifiers of this transcriptional dysregulation in HCM remain unexplored. We hypothesized that miRNA and post-translational modifications of histones contribute to transcriptional dysregulation in HCM. Methods: First, miRNA-sequencing and chromatin immunoprecipitation sequencing (ChIP-seq) were performed on HCM myectomy tissue and control donor hearts to characterize miRNA and differential histone marks across the genome. Next, the differential miRNA and histone marks were integrated with RNA-sequencing (RNA-seq) data. Finally, the effects of miRNA and histones were removed in silico to determine their necessity for transcriptional dysregulation of pathways. Results: miRNA-analysis identified 19 differentially expressed miRNA. ChIP-seq analysis identified 2,912 (7%) differential H3K4me3 peaks, 23,339 (21%) differential H3K9ac peaks, 33 (0.05%) differential H3K9me3 peaks, 58,837 (42%) differential H3K27ac peaks, and 853 (3%) differential H3K27me3 peaks. Univariate analysis of concordance between H3K9ac with RNA-seq data showed activation of cardiac hypertrophy signaling, while H3K27me showed downregulation of cardiac hypertrophy signaling. Similarly, miRNAs were predicted to result in downregulation of cardiac hypertrophy signaling. In silico knock-out that effects either miRNA or histones attenuated transcriptional downregulation while knocking out both abolished downregulation of hypertrophy pathways completely. Conclusion: Myectomy tissue from patients with obstructive HCM shows transcriptional dysregulation, including transcriptional downregulation of hypertrophy pathways mediated by miRNA and post-translational modifications of histones. Cardiac hypertrophy loci showed activation via changes in H3K9ac and a mix of activation and repression via H3K27ac.

State-of-the-Art Advancements in Gastroesophageal Cancer Treatment: Harnessing Biomarkers for Precision Care.

Gastroesophageal cancers (GECs) represent a significant clinical challenge. For early resectable GEC, the integration of immune checkpoint inhibitors into the perioperative chemotherapy and chemoradiation treatment paradigms are being explored and showing promising results. Frontline management of metastatic GEC is exploring the role of targeted therapies beyond PD-1 inhibitors, including anti-human epidermal growth factor receptor 2 agents, Claudin 18.2 inhibitors, and FGFR2 inhibitors, which have shown considerable efficacy in recent trials. Looking ahead, ongoing trials and emerging technologies such as bispecific antibodies, antibody-drug conjugates, and adoptive cell therapies like chimeric antigen receptor T cells are expected to define the future of GEC management. These advancements signify a paradigm shift toward personalized and immunotherapy-based approaches, offering the potential for improved outcomes and reduced toxicity for patients with GEC.

Chiral-structured heterointerfaces enable durable perovskite solar cells.

Mechanical failure and chemical degradation of device heterointerfaces can strongly influence the long-term stability of perovskite solar cells (PSCs) under thermal cycling and damp heat conditions. We report chirality-mediated interfaces based on R-/S-methylbenzyl-ammonium between the perovskite absorber and electron-transport layer to create an elastic yet strong heterointerface with increased mechanical reliability. This interface harnesses enantiomer-controlled entropy to enhance tolerance to thermal cycling-induced fatigue and material degradation, and a heterochiral arrangement of organic cations leads to closer packing of benzene rings, which enhances chemical stability and charge transfer. The encapsulated PSCs showed retentions of 92% of power-conversion efficiency under a thermal cycling test (-40°C to 85°C; 200 cycles over 1200 hours) and 92% under a damp heat test (85% relative humidity; 85°C; 600 hours).

A Systematic Review of Patient Selection Criteria for Outpatient Total Shoulder Arthroplasty.

The utilization of total shoulder arthroplasty (TSA) is increasing, driving associated annual health care costs higher. Opting for outpatient over inpatient TSA may provide a solution by reducing costs. However, there is no single set of accepted patient selection criteria for outpatient TSA. Here, the authors identify and systematically review 14 articles to propose evidence-based criteria that merit postoperative admission. Together, the studies suggest that patients with limited ability to abmluate independently or a history of congestive heart failure may benefit from postoperative at least one night of hospital based monitoring and treatment.

Establishing the diagnosis of radial tunnel syndrome: a systematic review of published clinical series.

PURPOSE: Radial tunnel syndrome (RTS) is a controversial diagnosis due to non-specific exam findings and frequent absence of positive electromyography (EMG) and nerve conduction study (NCS) findings. The purpose of this study was to identify the methods used to diagnose RTS in the literature. METHODS: We queried PubMed, Embase, Web of Science, and Cochrane databases per PRISMA guidelines. Extracted data included article and patient characteristics, diagnostic assessments utilized and their respective findings, and treatments. Objective data were summarized descriptively. The relationship between reported diagnostic findings (i.e., physical exam and diagnostic tests) and treatments was assessed via a descriptive synthesis. RESULTS: Our review included 13 studies and 391 upper extremities. All studies utilized physical exam in diagnosing RTS; most commonly, patients had tenderness over the radial tunnel (381/391, 97%). Preoperative EMG/NCS was reported by 11/13 studies, with abnormal findings in 8.9% (29/327) of upper extremities. Steroid and/or lidocaine injection for presumed lateral epicondylitis was reported by 9/13 studies (46/295 upper extremities, 16%), with RTS being diagnosed after patients received little to no relief. It was also common to inject the radial tunnel to make the diagnosis (218/295, 74%). The most common reported intraoperative finding was narrowing of the PIN (38/137, 28%). The intraoperative compressive site most commonly reported was the arcade of Frohse (142/306, 46%). CONCLUSIONS: There is substantial heterogeneity in modalities used to diagnose RTS and the reported definition of RTS. This, in conjunction with many patients having concomitant lateral epicondylitis, makes it difficult to compare treatment outcomes for RTS. LEVEL OF EVIDENCE: Level III. Systematic review of retrospective and prospective cohort studies.

Segmental Agenesis of the Corpus Callosum With Pituitary Hypoplasia.

We report a 3-year-old male with findings of segmental agenesis of the corpus callosum, pituitary hypoplasia, and Chiari I malformation. The patient was born at 33 weeks and spent five weeks in the NICU for hypoglycemia, hypotension, and dyspnea. In infancy, the patient passed an adrenocorticotropic hormone stimulation test, while cortisol, growth hormone, and insulin-like growth factor levels were within reference range. Following height and weight percentile regression the patient underwent arginine and clonidine stimulation testing at 3 years of age, prompting pituitary evaluation via MRI. The results provided exemplary neuroimaging of segmental callosal agenesis, in which the genu and splenium form despite the absence of the callosal body. This finding adds support to a newer theory of embryological callosal development where progression does not occur linearly in the rosto-caudal direction.

National and regional trends in fentanyl seizures in the United States, 2017-2023.

BACKGROUND: Rates of synthetic opioid-related deaths over time and across regions have been compared within the US, but other indicator data could help inform prevention and harm reduction as well. We compared regional trends in fentanyl seizures to examine potential shifts in illicit fentanyl availability. METHODS: Annual trends in fentanyl seizures were examined using data from High Intensity Drug Trafficking Areas for the US overall and by region from 2017 through 2023. Multiple measures included the number of seizures, the number of powder seizures, the number of pill seizures, the total weight of seizures, the number of pills seized, and the percentage of the number of pill seizures relative to the number of total seizures. RESULTS: The percentage of seizures in pill form in the US increased from 10.3 % in 2017 to 49.0 % in 2023 (adjusted annual percentage change [AAPC]=25.2, 95 % CI: 17.6, 33.2), with 115.6 million individual pills seized in 2023. Pill weight related to total seizure weight also increased from 0.4 % to 54.5 % (AAPC=112.6, 95 % CI: 78.6, 153.2). In 2023, the plurality of seizures was in the West, in seven out of eight of our measures, with 77.8 % of seizures in the West being in pill form. Although the Midwest had lower prevalence of seizures than the West, there were notable increases in the Midwest in the number of pill seizures (AAPC=142.2, 95 % CI: 91.9, 205.8) and number of pills seized (AAPC=421.0, 95 % CI: 272.7, 628.4). Total weight of fentanyl seized increased the most in the West (AAPC=84.6, 95 % CI: 72.3, 97.8). CONCLUSIONS: The number and size of fentanyl seizures is increasing in the US, with the majority of seizures, especially in pill form, in the West. Continued monitoring of regional shifts in the fentanyl supply can help inform targeted prevention and public health response.

Safety, Efficacy, and Pharmacokinetics of Combination SARS-CoV-2 Neutralizing Monoclonal Antibodies BMS-986414 (C135-LS) and BMS-986413 (C144-LS) Administered Subcutaneously in Non-Hospitalized Persons with COVID-19 in a Phase 2 Trial.

Background: Outpatient COVID-19 monoclonal antibody (mAb) treatment via subcutaneous delivery, if effective, overcomes the logistical burdens of intravenous administration. Methods: ACTIV-2/A5401 was a randomized, masked placebo-controlled platform trial where participants with COVID-19 at low risk for progression were randomized 1:1 to subcutaneously administered BMS-986414 (C135-LS) 200 mg, plus BMS-986413 (C144-LS) 200 mg, (BMS mAbs), or placebo. Coprimary outcomes were time to symptom improvement through 28 days; nasopharyngeal SARS-CoV-2 RNA below the lower limit of quantification (LLoQ) on days 3, 7, or 14; and treatment-emergent grade 3 or higher adverse events (TEAEs) through 28 days. Results: A total of 211 participants (105 BMS mAbs and 106 placebo) initiated study product. Time to symptom improvement favored the active therapy but was not significant (median 8 vs 10 days, P=0.19). There was no significant difference in the proportion with SARS-CoV-2 RNA

Teaching Ultrasound-Guided Venous Cannulation to Newly Qualified Doctors.

Background Venous cannulation is an essential task that allows the intravenous administration of fluids and medications. In the United Kingdom, this task is often performed by newly qualified Foundation Year 1 (FY1) doctors; however, difficulties are commonly encountered. The usage of ultrasound increases the chance of successful cannulation, provided the operator has been trained. Some medical schools now include ultrasound in their undergraduate curricula, though this is far from universal. Methods Forty-eight FY1s received a one-hour teaching session on ultrasound-guided venous cannulation, delivered by near-peer Education Fellows. FY1s completed questionnaires immediately after the teaching session, and a follow-up questionnaire three months later. Findings 44.44% of FY1s felt "fairly" or "very" confident in ultrasound-guided venous cannulation at follow-up, compared to 6.66% before the session. Sixty-three attempts were made in the month before the follow-up survey, compared to six in the month prior to the teaching session. The success rate at follow-up was 60% (38/63), up from 50% (3/6) prior to the session. One third fewer cannulas were escalated to senior doctors (72 vs 48), although there was little change in escalations to anesthetists, from 15 vs 18. FY1s identified the lack of ultrasound machines on the wards as a barrier to using ultrasound-guided venous cannulation more often. Conclusion A short, near-peer teaching session can improve FY1s' confidence, usage, and success rates in ultrasound-guided venous cannulation.

Serum ferritin and risk of colonic neoplasia: Implications for the workup and treatment of iron deficiency.

Iron deficiency is the most common extraintestinal sign of colonic neoplasia, including colorectal cancer (CRC) and other lower gastrointestinal pathology. Both upper endoscopy and colonoscopy is usually recommended in the work-up of patients with unexplained iron deficiency, particularly in men and postmenopausal women. As the incidence of early-onset CRC (age <50 years) rises in the United States, there is an increasing need to identify risk predictors to aid in the early detection of CRC. It remains unknown if serum ferritin (SF), and what specific threshold, can be used as a marker to stratify those at risk for CRC and other lower gastrointestinal pathology. In this current review of the literature, we aimed to review guidelines for diagnostic workup of colonic neoplasia in the setting of iron deficiency and examine the association and specific thresholds of SF and risk of CRC by age. Some of the published findings are conflicting, and conclusions specific to younger patients are limited. Though further investigation is warranted, the cumulative findings suggest that SF, in addition to considering the clinical context and screening guidelines, may have potential utility in the assessment of colonic neoplasia.

The passive biomechanics of the thumb carpometacarpal joint: An in vitro study.

The thumb carpometacarpal (CMC) joint facilitates multidirectional motion of the thumb and affords prehensile power and precision. Traditional methods of quantifying thumb CMC kinematics have been largely limited to range-of-motion (ROM) measurements in 4 orthogonal primary directions (flexion, extension, abduction, adduction) due to difficulties in capturing multidirectional thumb motion. However, important functional motions (e.g., opposition) consist of combinations of these primary directions, as well as coupled rotations (internal and external rotation) and translations. Our goal was to present a method of quantifying the multidirectional in vitro biomechanics of the thumb CMC joint in 6 degrees-of-freedom. A robotic musculoskeletal simulation system was used to manipulate CMC joints of 10 healthy specimens according to specimen-specific joint coordinate systems calculated from computed tomography bone models. To determine ROM and stiffness (K), the first metacarpal (MC1) was rotated with respect to the trapezium (TPM) to a terminal torque of 1 Nm in the four primary directions and in 20 combinations of these primary directions. ROM and K were also determined in internal and external rotation. We found multidirectional ROM was greatest and K least in directions oblique to the primary directions. We also found external rotation coupling with adduction-flexion and abduction-extension and internal rotation coupling with abduction-flexion and adduction-extension. Additionally, the translation of the proximal MC1 was predominantly radial during adduction and predominantly ulnar during abduction. The findings of this study aid in understanding thumb CMC joint mechanics and contextualize pathological changes for future treatment improvement.

Efficacy and Safety of the Melphalan/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study.

BACKGROUND: Uveal melanoma (UM) has a poor prognosis once liver metastases occur. The melphalan/Hepatic Delivery System (melphalan/HDS) is a drug/device combination used for liver-directed treatment of metastatic UM (mUM) patients. The purpose of the FOCUS study was to assess the efficacy and safety of melphalan/HDS in patients with unresectable mUM. METHODS: Eligible patients with mUM received treatment with melphalan (3.0 mg/kg ideal body weight) once every 6 to 8 weeks for a maximum of six cycles. The primary end point was the objective response rate (ORR). The secondary end points included duration of response (DOR), overall survival (OS), and progression-free survival (PFS). RESULTS: The study enrolled 102 patients with mUM. Treatment was attempted in 95 patients, and 91 patients received treatment. In the treated population (n = 91), the ORR was 36.3 % (95 % confidence interval [CI], 26.44-47.01), including 7.7 % of patients with a complete response. Thus, the study met its primary end point because the lower bound of the 95 % CI for ORR exceeded the upper bound (8.3 %) from the benchmark meta-analysis. The median DOR was 14 months, and the median OS was 20.5 months, with an OS of 80 % at 1 year. The median PFS was 9 months, with a PFS of 65 % at 6 months. The most common serious treatment-emergent adverse events were thrombocytopenia (15.8 %) and neutropenia (10.5 %), treated mostly on an outpatient basis with observation. No treatment-related deaths were observed. CONCLUSION: Treatment with melphalan/HDS provides a clinically meaningful response rate and demonstrates a favorable benefit-risk profile in patients with unresectable mUM (study funded by Delcath; ClinicalTrials.gov identifier: NCT02678572; EudraCT no. 2015-000417-44).