Citations

Abstract Background Sickle cell disease (SCD) is a hemoglobinopathy with limited treatment options. Genetic modification of the patient's own hematopoietic stem cells (HSCs) offers an avenue to curative therapy using the patient's own cells. Many challenges exist in collecting sufficient numbers of starting material for manufacturing, beginning with the pre‐mobilization optimization of the patient to the mobilization, collection, and post‐collection phases. Study Design and Methods A working group within the Cellular Therapy Subcommittee of the American Society for Apheresis Clinical Applications Committee describes the challenges associated with apheresis collection of the starting material for gene therapy (GT) product manufacturing for patients with SCD and discusses potential strategies for overcoming these challenges. Results and Discussion Patients must undergo automated red blood cell exchange (RCE) to lower hemoglobin S in a relatively short window of time before apheresis collection of HSCs. The risks and benefits of transfusion as well as the logistics of providing adequate and appropriate blood products must be considered. Limited agents are available for mobilization of HSCs into the peripheral blood for collection and the timing of administration is short. Each collection cycle consists of RCE followed by at least three mobilization and apheresis collection events in addition to collecting backup cells. More than one cycle is typically needed to collect enough cells for GT drug product manufacturing. Optimization of patient factors and apheresis instrument parameters leads to better collection yields. Early and frequent ongoing coordination with all stakeholders involved is critical to developing personalized treatment plans for patients.

Peripheral T cell lymphoma (PTCL) is a heterogeneous group of postthymic T cell neoplasms, with ~40% classified as PTCL–not otherwise specified (PTCL-NOS). PTCL-GATA3, a molecularly defined subtype, associated with T helper 2 (T H 2)–like differentiation and poor prognosis, has frequent co-occurrence of TP53 loss/mutation and heterozygous PTEN loss. CD4+ T cell conditional mouse models with Trp53 mutation/deletion and Pten loss demonstrated mature T cell lymphomas (mTCLs) with T H 2-like transcriptomic and immunophenotypic profiles. Molecular studies revealed that codeletion of Trp53/Pten induced T cell receptor and Janus kinase–signal transducer and activator of transcription signaling, promoting T H 2 differentiation while inhibiting T H 1 differentiation. These findings were validated by CRISPR editing of TP53/PTEN loss in human CD4+ T cells and mechanistically evaluated the p53 binding region in intron-3 of GATA3, resulting in transcriptional repression. Transcriptomic profiles of m-TCLs recapitulated human-PTCL-GATA3 transcriptome and distinguished PTCL-NOS subtypes. Preclinical assessment of m-TCLs with PI3Kγ/δ inhibitors significantly improved survival, supporting a therapeutic approach for the p53-aberrant PTCL-GATA3.

Abstract Few medical decisions have a greater impact on the life of patients affected by either long QT syndrome (LQTS) or catecholaminergic polymorphic ventricular tachycardia (CPVT) as the one to recommend an implantable cardioverter defibrillator (ICD) or not. If the decision is correct, a life might be saved or a litany of ICD-related complications might be avoided. If it is wrong, well you can fill in the blanks. Many physicians take the fastest and simplest road by recommending an ICD which represents ‘double protection’: for the patients and for themselves. Our opinion is that this requires a very careful consideration about the pros and cons and should be taken neither lightly nor quickly. Moreover, there is another side to this moon, which also requires more thought than usually assumed. As to LQTS and CPVT, the current data strongly indicate that when high risk patients are treated with either combination drug therapy comprising beta blockers and mexiletine (LQTS) or beta blockers and flecainide (CPVT) or triple therapy with left cardiac sympathetic denervation as the treatment intensifier, mortality is close to zero and most patients have no life-threatening events. Thus, we stand by our view that most patients still do not need and should not receive an ICD. However, sometimes patients are desperately worried for the fear of dying suddenly and ask for an ICD despite being at low risk. Their request should be listened to, respected, and considered with empathy because immortality cannot be guaranteed. We believe that both expertise and compassion are quintessential to practicing the science and art of medicine.

Background: Femoroacetabular impingement (FAI) is a common cause of hip pain in female athletes. There are limited data on midterm outcomes for female athletes undergoing hip arthroscopic surgery. Purpose: To evaluate return-to-sport rates and clinical outcomes in female athletes with FAI after primary hip arthroscopic surgery with labral repair and femoral osteochondroplasty. Study Design: Case series; Level of evidence, 4. Methods: A retrospective analysis of a single institution’s database was performed to identify female athletes who underwent primary hip arthroscopic surgery with labral repair and femoral osteochondroplasty from July 2011 to October 2019 with a minimum 5-year follow-up. Preoperative radiographs were evaluated for the lateral center-edge angle, Tonnis angle, Tonnis grade, and alpha angle. Patient-reported outcome measure (PROM) scores, including those for the modified Harris Hip Score, Hip Outcome Score, Tegner Activity Scale, and visual analog scale for pain, as well as patient satisfaction with surgery were analyzed postoperatively. Results: A total of 63 hips (27 left, 36 right) in 56 female patients (mean age, 21.6 ± 8.0 years; mean body mass index, 24.7 ± 4.8 kg/m 2 ) were included and followed for a mean of 8.4 ± 2.1 years (range, 5.0-13.2 years). Preoperatively, patients participated in basketball (n = 18), dance (n = 21), hockey (n = 8), and soccer (n = 12). Of the 56 patients, 41 attempted to return to sport. There were 28 (68%) female athletes who successfully returned to their preoperative sport. Of the total cohort, 21 (38%) patients cited non–hip-related factors for discontinuing their sport. All postoperative PROM scores improved significantly compared with preoperatively ( P ≤ .002) for patients with available preoperative data. Those who returned to sport had significantly improved Hip Outcome Score values compared with those who did not return to sport ( P ≤ .010). Conclusion: Female athletes who underwent primary hip arthroscopic surgery for FAI had significant improvements in PROM scores and moderate return-to-sport rates at a minimum 5-year follow-up. Most athletes discontinued sports because of non–hip-related factors, although hip-related issues were also cited. Our analysis highlights the need for thorough perioperative counseling and establishing appropriate patient expectations for female athletes before hip arthroscopic surgery.

Immune checkpoint inhibitors (ICIs) are an important class of cancer treatment. Endocrine immune-related adverse events (E-irAEs) account for a significant proportion of irAEs in ICI-treated patients. Diagnosing E-irAEs accurately and timely can be challenging in the absence of clear categorization and standardization across oncology, endocrinology and other specialties. While existing guidelines provide some broad directions to diagnosis and management, they lack clarity on irAE-specific symptom evaluation and work-up, as well as assessment of severity. These limitations can then impact triage, time-sensitive management and care escalation to specialists such as oncoendocrinologists. The objective of this study was to develop consensus-based statements on disease definitions for E-irAEs. A core working group of endocrinologists with expertise in the oncoendocrinology field drafted a survey with statements outlining the general approach to E-irAEs, disease definition and management approach of six specific diagnoses: ir-thyroiditis thyrotoxic phase, ir-thyroiditis hypothyroidism, ir-Graves’ disease, ir-hypophysitis, ir-adrenalitis and ir-type 1 diabetes mellitus. Severity grading tables were drafted for three disease categories—“thyroid”, “pituitary and adrenal”, and “diabetes mellitus”. A two-round modified Delphi process, using the RAND/University of California Los Angeles (RAND/UCLA) Appropriateness Method, was employed. In this process, a 25-member voting panel consisting of endocrinologists, oncologists and other specialists and healthcare providers with experience in management of ICI-treated patients and irAEs was recruited. The panel rated anonymously on usability, accuracy, appropriateness or agreement of 41 items on a 9-point scale in Survey 1, after which a meeting was convened. Statements were modified based on voting results from Survey 1 and Meeting 1, and the process was repeated in Survey 2 and Meeting 2. At the end of this process, consensus was achieved for all statements. Our study findings address the gap in standardized nomenclature, clinical, laboratory and radiological evaluations, and management principles of E-irAEs. With consensus achieved from a panel of experts from a variety of disciplines, we anticipate that the statements can form the basis for standardization of the diagnostic process and improvement of patient care.

Abstract Our understanding of Alzheimer's disease (AD) and related dementias (ADRD) has grown exponentially, thanks to significant investments by the National Institute on Aging (NIA). This article celebrates the 40th anniversary of the NIA's Alzheimer's Disease Research Centers, highlighting the pivotal role of neuropathology as the bedrock for neurodegeneration research. Neuropathology has championed the key principles of proteinopathy, selective vulnerability, and stereotypic spread. Furthermore, neuropathologic studies advanced our understanding of ADRD prevalence, heterogeneity, clinical–pathological correlations, and genetic underpinnings, spurring biomarker development for target engagement and disease monitoring. Disease‐modifying therapies for AD were inspired and informed by neuropathology. The neuropathology community is poised to refine diagnostics, leveraging digital pathology and integrating genetics and pathomics to enhance subtyping for novel precision medicine approaches. Despite some common misconceptions and logistical challenges, neuropathology continues to be a critical component of the ADRD research infrastructure, serving as a key bridge between allied basic and clinical sciences. Highlights We celebrate 40 years of NIA‐funded ADRCs and their contributions through neuropathology studies that have significantly advanced our understanding and treatment of ADRD. Neuropathology uncovers principles of neurodegenerative disease: proteinopathy, selective vulnerability, and stereotypic spread, informing diagnostics and therapies. Development of AD biomarkers with reference to neuropathology enhances accuracy in diagnosis and monitoring, paving the way for targeted disease‐modifying therapies. Integration of digital pathology, genetics, and novel tools in neurodegeneration research promises advanced precision medicine approaches and refined diagnostics. Misconceptions and logistical challenges to neuropathological research are addressed to improve understanding and collaboration.

OBJECTIVE: To review currently available devices on pressure injury (PI) early detection, summarize challenges and opportunities to clinical implementation, and propose evaluation standards for device categories. DATA SOURCES: PubMed and US Food and Drug Administration (FDA) databases. STUDY SELECTION: Published in English from peer-reviewed journals with full text available. Excluded if opinion statements, lack of empirical data, or unrelated to project’s objective. DATA EXTRACTION: For both clinical device and research equipment: measurement mechanisms, measurement types, outcome/output, FDA classification, and indications for use. Addition data were extracted for clinical devices: instruction for use, end user, order requirement, and billable code. DATA SYNTHESIS: The 4 clinical devices are ultrasound, long-wave infrared thermography, subepidermal moisture assessment, and nearinfrared spectroscopy. The 3 research devices are laser Doppler flowmetry, laser speckle contrast imaging, and colorimetry. CONCLUSIONS: The measurement mechanisms of all devices are unique and different from each other. One commonality is that they could measure the nonvisual signs of PI (eg, inflammation, edema, ischemia, and hypoxia) except colorimeter. Some clinical devices are promising to assist with early identification of PIs, especially in individuals with dark skin tones. Currently, there is no reimbursement available for early detection of PI. Current evidence did not support replacing the standard skin assessment of visual inspection and palpation with the devices reviewed, rather using validated devices to augment the current practice standard. This is especially recommended for individuals identified as high risk for a PI on admission to a facility.