Citations

Background/Objectives: Respiratory syncytial virus (RSV) causes symptoms similar to a mild cold for adults, but in case of infants, it causes bronchitis and/or pneumonia, and in some cases, mortality. Mucosal immunity within the respiratory tract includes tissue-resident memory T (TRM) cells and tissue-resident memory B (BRM) cells, which provides rapid and efficient protection against RSV re-infection. Therefore, vaccine strategies should aim to generate mucosal immune responses. However, the interactions between RSV vaccines and mucosal immune responses within the respiratory tract are poorly understood. We evaluated a mucosal immune system following immunization by RSV vaccine with poly-sorbitol transporter (RSV-PST), a nanoparticle adjuvant. Methods: We intranasally immunized the RSV-PST and identified the systemic and mucosal immune responses. Furthermore, we challenged with RSV A2 strain after immunization and investigated the protective effects. Results: Consequently, antigen-specific CD8+ TRM cells were markedly elevated in the lung parenchyma, yet exhibited impaired cytokine expression. In contrast, humoral immunity, with systemic antibody production from serum, but not in the respiratory tract, was significantly increased by RSV-PST immunization. Interestingly, the production of respiratory mucosal antigen-specific IgG after RSV A2 challenge dramatically increased in the bronchoalveolar lavage fluid (BALF) of the RSV-PST immunized group in the presence of FTY720, and the lung-infected RSV titer was significantly lower in this group. Furthermore, after RSV A2 challenge, CD69+ IgG+ BRM cells were significantly increased in lung tissues in the RSV-PST group. Conclusions: The RSV-PST vaccine has protective effects against RSV infection by promoting both systemic and local humoral immunity rather than cellular immunity.

Importance Typical cysteine-altering NOTCH3 ( NOTCH3 cys ) variants are highly prevalent (approximately 1 in 300 individuals) and are associated with a broad spectrum of small vessel disease (SVD), ranging from early-onset stroke and dementia (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [CADASIL]) to nonpenetrance. A staging system that captures the full NOTCH3 -SVD severity spectrum is needed and currently lacking. Objective To design a simple disease severity staging system that captures the broad clinicoradiological NOTCH3 -SVD severity spectrum. Design, Setting, and Participants A cohort study was performed in which the NOTCH3 -SVD severity staging system was developed using a discovery cohort (2019-2020) and validated in independent international CADASIL cohorts (1999-2023) and the UK Biobank. Clinical and imaging data were collected from participants originating from 23 international CADASIL cohorts and from the UK Biobank. Eligibility criteria were presence of a NOTCH3 cys variant, availability of brain magnetic resonance imaging, and modified Rankin Scale score. The discovery cohort consisted of 195 NOTCH3 cys -positive cases from families with CADASIL; the validation set included 1713 NOTCH3 cys -positive cases from 15 countries. The UK Biobank cohort consisted of 101 NOTCH3 cys -positive individuals. Data from 2-year (2019-2023) and 18-year (1999-2017) follow-up studies were also analyzed. Data analysis was performed from July 2023 to August 2024. Main Outcomes and Measures Percentage of cases following the sequence of events of the NOTCH3 -SVD stages, and the association between the stages and ischemic stroke, intracerebral hemorrhage, global cognition, processing speed, brain volume, brain microstructural damage, and serum neurofilament light chain (NfL) level. Results The NOTCH3 -SVD staging system encompasses 9 disease stages or substages, ranging from stage 0 (premanifest stage) to stage 4B (end stage). Of all 1908 cases, which included 195 in the discovery cohort (mean [SD] age, 52.4 [12.2] years) and 1713 in the validation cohorts (mean [SD] age, 53.1 [13.0] years), 1789 (94%) followed the sequence of events defined by the NOTCH3 -SVD staging system. The NOTCH3 -SVD stages were associated with neuroimaging outcomes in the NOTCH3 cys -positive cases in the CADASIL cohorts and in the UK Biobank and with cognitive outcomes and serum NfL level in cases from the CADASIL cohorts. The NOTCH3 -SVD staging system captured disease progression and was associated with 18-year survival. Conclusions and Relevance The NOTCH3 -SVD staging system captures the full disease spectrum, from asymptomatic individuals with a NOTCH3 cys variant to patients with end-stage disease. The NOTCH3 -SVD staging system is a simple but effective tool for uniform disease staging in the clinic and in research.

Linked article: This Correspondence comments on Deslandes and Leonardi. Click here to view the article.

AbstractA 57-year-old male patient who underwent an open hemiarch repair with a femoral–femoral crossover bypass and right lower extremity fasciotomies for an acute Type A aortic dissection with limb ischemia presented 5 weeks' postrepair with a 20-pound weight loss due to intermittent hemodynamic collapse of the dissection flap over the origin of the superior mesenteric artery. This case highlights the challenges a dissection flap can cause after an urgent Type A aortic dissection repair.

Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive, malignant embryonal tumor with dismal long-term survival despite aggressive multimodal therapy. While this tumor typically presents in infancy or early childhood, there are published case reports of adult-onset ATRT. Making prognostic conclusions or therapeutic decisions for this older patient population remains challenging due to the paucity of these reports. A 25-year-old female with Down syndrome presented with dysphagia and facial droop and was found to have an avidly enhancing, cerebellopontine angle mass. Histology demonstrated sheets of rhabdoid cells with loss of INI1 expression, pathognomonic for ATRT. Further sequencing detected a frameshift SMARCB1 mutation and methylation profiling matched with high confidence to the MYC subclass of ATRT. The patient was treated with subtotal surgical resection and focal proton beam irradiation, followed by chemotherapy on a modified regimen due to concern for heightened risk of treatment-related toxicity. On most recent follow-up 22 months from diagnosis, the patient remains without evidence of disease. This report represents the first known case of ATRT in a young adult patient with Down syndrome, offering unique mechanistic insight into the tumorigenesis of ATRT. Further studies are needed to define an appropriate risk-adapted and standardized therapeutic approach for this patient population.

Background: Adolescents and young adults (AYAs) living with advanced cancer may experience a heightened risk for existential distress. Addressing AYAs’ hopes can stimulate a dialogue about their concerns, values, and goals, provide a path to holistically support their existential needs, and potentially alleviate their distress. This study aimed to evaluate hope's role in a sample of AYAs living with advanced cancer. Method: This study used a Husserlian phenomenology-informed descriptive qualitative research design to elicit AYAs’ experiences with hope while living with advanced cancer. Participants were virtually recruited from an academic medical center and an online non-profit organization. Thematic analyses were performed across the data set to identify final themes. Results: Fifteen AYAs aged 12–21 years diagnosed with advanced hematological (80%) or solid (20%) malignancies participated in this study. A main theme of Simple Supports of Hope with a subtheme of Diversion was identified. Participants described music as a form of diversion, which supported their hope. Participants found listening to music calming and comforting and helped them cope with their distress. Performing music provided a creative outlet for negative feelings associated with cancer treatment. Participants reported creating music transformed and deintensified the treatment environment and helped spread hope to healthcare staff. Discussion: AYAs may intentionally use music to improve emotional expression, empowerment, connection, and coping strategies throughout the treatment process for cancer. Additional research needs to be conducted exploring the use of music interventions such as therapeutic songwriting or compositional music therapy to assist AYAs with building coping strategies during treatment for cancer.

PURPOSE BRAF and MEK inhibitors are standard treatments in histiocytic disorders, such as Erdheim-Chester disease (ECD). Some patients lack MAPK-pathway alterations, making these treatments less effective. METHODS We describe three patients with histiocytic disorders who have novel non-MAPK pathway alterations. These alterations were studied through genomic and in silico analyses when applicable, then treated with off-label medications rationally selected on the basis of genomic alterations. RESULTS Patient 1 had rapidly progressive ECD involving the CNS. A CSF1R in-frame deletion (p.S560_P566del) was identified, and in silico modeling predicted a gain-of-function mutation. This alteration was targeted with pexidartinib, which led to a clinical complete response (CR) within 2 months, and a partial response (PR) on imaging after 3 months. After 15 months, the disease became resistant to pexidartinib and transformed to histiocytic sarcoma. Patient 2 has skin-only involvement of a xanthogranuloma disorder. A KIF5B-FGFR1 fusion was identified on RNA sequencing and targeted with pemigatinib. At 24 months of follow-up, she remains in a clinical PR. Patient 3 has ECD involving the bone marrow, gastrointestinal tract, and subcutaneous tissues. A MEF2C-FLT3 fusion was identified and targeted with sorafenib. He achieved a clinical CR and radiographic PR within 3 months, which has continued for 30 months. CONCLUSION We report three patients with histiocytic disorders harboring novel alterations who had sustained responses to off-label kinase inhibitors specific to their histiocytic disorder. Pathogenic variants outside of the MAPK pathway, including variants of unknown significant, may be targeted with readily available small molecules.

Abstract Ageing‐related neuromuscular dysfunction is associated with reduced tropomyosin‐related kinase receptor subtype B (TrkB) signalling and accumulation of damaged cytoplasmic aggregates in motor neurons. Autophagy functions to remove these damaged aggregates, and we previously reported increased cervical motor neuron expression of LC3 and p62 in old age. We hypothesized that inhibition of TrkB kinase activity results in an increase in the relative expression of both LC3 and p62 in cervical motor neurons, consistent with impaired progression of autophagy. TrkB F616A mice, which possess a mutation that renders TrkB kinase activity susceptible to rapid inhibition by 1NMPP1, were treated at 6, 18 or 24 months of age with vehicle or 1NMPP1 for 7 days. Immunofluorescence intensity was measured to determine LC3 and p62 expression in choline acetyltransferase‐positive motor neurons in the cervical spinal cord. The effect of inhibiting TrkB kinase activity on progression of autophagy was age dependent. In 6‐month‐old mice, inhibiting TrkB kinase activity increased cervical motor neuron expression of LC3 by 11% ( P < 0.001) and p62 by 8% ( P = 0.019) compared with vehicle treatment. In 18‐ and 24‐month‐old mice, there was no effect of inhibiting TrkB kinase activity on motor neuron LC3 or p62 expression. We provide evidence that inhibition of TrkB signalling impairs progression of autophagy in motor neurons of young mice, similar to the response to ageing. Accordingly, a reduction of TrkB signalling in old age might contribute to neuromuscular dysfunction by impairing progression of autophagy in motor neurons.

Background A multidisciplinary approach improves guideline‐directed medical therapy in systolic heart failure (HF), but its efficacy in patients with HF due to cardiac sarcoidosis is unreported. Methods and Results In a retrospective cohort study, we reviewed 848 patients from our institutional cardiac sarcoidosis clinics, identifying those with a cardiac sarcoidosis diagnosis, HF (left ventricular ejection fraction <50%) at index evaluation, and echocardiograms within 90 days and 11 to 36 months. Patients were stratified by participation in a pharmacist‐led medication therapy management (MTM) program for guideline‐directed medical therapy optimization (MTM versus non‐MTM [NMTM]) without randomization. Demographics, left ventricular ejection fraction, guideline‐directed medical therapy (quantified by Kansas City Medical Optimization score), and immunosuppressive therapy were assessed. Primary outcomes included changes in Kansas City Medical Optimization score, left ventricular ejection fraction, and cardiovascular event–free survival (unplanned HF hospitalization, left ventricular assist device /heart transplant, or death). The final cohort included 111 patients (median age, 57 years; 34% women; 64% New York Heart Association class I–II); 43 (39%) were MTM and 68 (61%) were NMTM. Mean Kansas City Medical Optimization score was similar at index evaluation (MTM, 23.2; NMTM, 29.6; P =0.83). At follow‐up (median, 16 months), the Kansas City Medical Optimization score increased significantly in both groups (MTM, 23.2 to 74.8; P <0.001; NMTM, 29.6 to 58.7; P <0.001) but was higher in MTM ( P =0.001). Mean left ventricular ejection fraction trended toward higher values in MTM (44.4% versus 40.0%, P =0.05). The primary clinical outcome occurred in 1 MTM (2.3%) and 16 NMTM (23.5%) patients, with higher risk in NMTM (hazard ratio, 11.97 [95% CI, 1.58–90.54]; P =0.002). Conclusions In this retrospective cohort study, a pharmacist‐led MTM program was associated with favorable guideline‐directed medical therapy optimization and lower risk of adverse cardiovascular outcomes in patients with cardiac sarcoidosis with HF.