Citations

Recent findings suggest that autophagy plays a role in the development of aging-related neuromuscular dysfunction; however, the contribution of autophagy impairment to the maintenance of diaphragm force generation in old age is unknown. This study shows that in old mice, chloroquine administration decreases maximal transdiaphragmatic pressure generation. These chloroquine effects suggest a susceptibility to impairments in autophagy in old age.

Extracellular vesicles (EVs) show promise for targeted drug delivery but face production challenges with low yields. Cell-derived nanovesicles (CDNVs) made by reconstituting cell membranes could serve as EV substitutes. In this study, CDNVs were generated from mesenchymal stem cells by extrusion. Their proteomic composition, in vitro and in vivo toxicity, and capacity for loading RNA or proteins were assessed. Compared with EVs, CDNVs were produced at higher yields, were comprised of a broader range of proteins, and showed no detrimental effects on cell proliferation, DNA damage, or nitric oxide production in vitro or on developmental toxicity in vivo. CDNVs could be efficiently loaded with RNA and engineered to modify surface proteins. The feasibility of generating immunomodulatory CDNVs was demonstrated by preparing CDNVs with enhanced surface expression of PD1, which could bind to PD-L1 expressing tumor cells, enhance NK and T cell degranulation, and increase immune-mediated tumor cell death. These findings demonstrate the adaptability and therapeutic promise of CDNVs as promising substitutes for natural EVs that can be engineered to enhance immunomodulation.

We report a case highlighting key clinical, CSF, and imaging findings of recurrent pleomorphic xanthoastrocytoma with leptomeningeal spread.

AbstractPulmonary hypertension (PH) is a risk factor for mortality in patients with sarcoidosis. Severe PH in chronic lung disease has previously been defined as mean pulmonary arterial pressure (mPAP) ≥ 35 mmHg or mPAP 25 ≥ mmHg with cardiac index (CI) ≤ 2 L/min/m2. However, there is no clear definition denoting severity of sarcoidosis‐associated PH (SAPH). We aimed to determine pulmonary hemodynamic cut‐off values where transplant‐free survival was worse among patients with SAPH. This was a retrospective cohort analysis of the Registry of SAPH database focusing on pulmonary hemodynamic predictors of transplant‐free survival among patients with precapillary SAPH. Cox regression was performed to determine which pulmonary hemodynamic values predicted death or lung transplantation. Kaplan−Meier survival analysis was performed on statistically significant predictors to determine pulmonary hemodynamic cut‐off values where transplant‐free survival was decreased. Decreased transplant‐free survival occurred among SAPH patients with mPAP ≥ 40 mmHg and SAPH patients with pulmonary vascular resistance (PVR) ≥ 5 Woods units (WU). Transplant‐free survival was not decreased in patients who fulfilled prior criteria of severe PH in chronic lung disease. We identified new cut‐offs with decreased transplant‐free survival in the SAPH population. Neither cut‐off of mPAP ≥ 40 mmHg nor PVR ≥ 5 WU has previously been shown to be associated with decreased transplant‐free survival in SAPH. These values could suggest a new definition of severe SAPH. Our PVR findings are in line with the most recent European Society of Cardiology/European Respiratory Society guideline definition of severe PH in chronic lung disease.

Optimal care of patients requiring long-term outpatient parenteral or oral antimicrobial therapy by infectious diseases (ID) specialists is facilitated by an accurate microbiologic diagnosis. Close collaboration between ID specialists and the clinical microbiology laboratory for routine or specialized molecular testing can result in more accurate diagnoses, streamlined antimicrobial regimens, and improved patient outcomes.

AbstractBackgroundThe prevalence of acute coronary syndrome (ACS) among young adults (premature ACS) has dramatically increased in recent years, especially in developing countries. Yet, the data on these patients' attributed risk factors and outcomes are inconsistent. In this study, we aimed to investigate these data in a cohort of premature ACS cases who underwent percutaneous coronary intervention (PCI) compared to older patients.HypothesisWe hypothesize that premature ACS patients undergoing PCI will exhibit different risk factor profiles and outcomes compared to non‐premature patients. specifically, we anticipate that premature patients do not necessarily have better outcomes than non‐premature.MethodsOverall, 3142 and 10 399 patients were included in premature and non‐premature groups, respectively. Patients' pre‐operative, post‐operative, and follow‐up data were retrieved retrospectively from the Tehran Heart Center PCI databank.ResultsThe mean age of premature and non‐premature cohorts was 48.39 and 67 years, respectively. Patients were predominantly male in both groups. Family history of coronary artery disease (CAD), dyslipidemia, smoking, and opium addiction were more prevalent among the younger cohort. After adjustment, in‐hospital mortality in younger patients was considerably higher, with all‐cause mortality and major cardiovascular and cerebrovascular events (MACCE) exhibiting no noticeable difference among the two groups.ConclusionsRisk factor profile is different in young patients, and traditional cardiovascular risk factors, such as hypertension and diabetes mellitus, are more prevalent among older adults. Younger age is not equivalent to a better prognosis; hence, similar or even more caution should be taken into consideration regarding secondary prevention for these patients.

Transatrial transcatheter mitral valve replacement is a hybrid strategy involving placing the patient on cardiopulmonary bypass and direct implantation of a transcatheter valve in a calcified annulus for mitral annular calcification. We report a rare phenomenon of systolic anterior motion of the leaflets of a transcatheter heart valve prosthesis used for mitral valve replacement causing left ventricular outflow tract obstruction. Although reported in transcatheter mitral valve replacement, we believe this is the first report of left ventricular outflow tract obstruction after transatrial mitral valve replacement and discuss the pre-disposing risk factors.

AbstractBackgroundDiabetes mellitus (DM) in children and adolescents is typically caused by type 1 DM, followed by type 2 DM and maturity‐onset diabetes of the young (MODY). We report an unusual Asian Indian family in which three members presented with DM at ages 15, 20, and 30, but not fitting the typical clinical picture of type 1 DM, type 2 DM, or MODY. The primary objective was to elucidate the molecular genetic basis of DM in this family.MethodsThe proband, a 22‐year‐old man, had short stature, gray hair, osteoporosis, and markedly reduced subcutaneous fat on the body, especially on the extremities along with acanthosis nigricans, and developed myxoid malignant peripheral nerve sheath tumor. Detailed family history revealed multiple loops of consanguinity. The proband underwent whole‐genome sequencing, and seven relatives underwent whole‐exome sequencing.ResultsThe proband and three additional family members were found to have the homozygous c.561A>G nucleotide variant of WRN RecQ‐like helicase (WRN) gene consistent with the diagnosis of Werner's syndrome. The c.561A>G variant induces a new splicing site on exon 6 resulting in a truncated WRN protein, p.Lys187Trpfs*13.ConclusionOur report brings to attention the onset of DM during childhood or early adulthood in patients with Werner's syndrome who typically develop type 2 DM around the age of 30–40 years. Presence of consanguinity among parents, dysmorphic features, and malignancy should prompt consideration of diagnosis of Werner's syndrome.

Background: Early diagnosis of significant valvular heart disease (VHD) enables appropriate implementation of the best therapeutic strategy and follow-up. Cardiac auscultation remains suboptimal in early detection of VHD. The aim of this study was to evaluate the utility of point-of-care ultrasound (POCUS) for early detection of VHD and its severity. Methods: All consecutive patients with VHD who did not have a standard echocardiogram prior to first outpatient cardiology consultation underwent history and physical examination followed by POCUS study by an experienced physician in a general cardiology clinic from June 2017 to August 2022 at our institution. Subsequent standard transthoracic echocardiography (sTTE) was performed as the gold standard. Comparison was performed between POCUS and sTTE for the presence and severity of VHD. sTTE was performed by registered cardiac sonographers and interpreted by another cardiologist blinded to the POCUS results. Results: A total of 77 patients were studied (ge 72 ± 11 years, 58.4% males). A total of 89 significant valvular abnormalities were diagnosed. There were 39 (43.8%) cases of regurgitant VHD, 16 (18.0%) of stenotic VHD and 34 (38.2%) had evaluation for prosthetic valve function. The sensitivity (90.9%; 82.4%; 83.3%; 100%) and specificity (100%; 96.7%; 100%; 100%) were high for detecting ≥ moderate aortic regurgitation (AR), mitral regurgitation (MR), aortic stenosis (AS) and prosthetic valvular abnormality, respectively. The weighted κ coefficient between POCUS and sTTE for the assessment of ≥ moderate MR, AR and AS was 0.81 (95% CI, 0.65–0.97), 0.94 (95% CI, 0.84–1.00) and 0.88 (95% CI, 0.76–1.0), respectively, indicating excellent agreement. Conclusions: POCUS can identify patients with significant VHD and may serve as a powerful screening tool for early detection of significant VHD in the outpatient clinical practice with downstream impact on clinical management of significant VHD.

AbstractBackgroundPrevious literature on cutaneous squamous cell carcinoma (cSCC) suggests that the incidence, rate of metastasis, and tumour severity of cSCC are higher in immunosuppressed patients than in immunocompetent patients. However, current literature lacks an extensive comparison of cSCC clinical characteristics and outcomes in immunosuppressed patients.ObjectivesWe compared cSCC tumour characteristics and disease‐related outcomes to help guide the clinical management of immunosuppressed patients.MethodsWe conducted a retrospective review of histopathologic and clinical data from 935 cSCC cases (19.5% immunosuppressed) from the Mayo Clinic.ResultsImmunosuppression was associated with younger age (69.3 vs. 74.8 years old, p < 0.0001), male gender (78.6% vs. 67.2%, p = 0.003), and higher grade cSCC tumour characterized by moderate or poor differentiation (25.7% vs. 15.8%, p = 0.009; 9.2% vs. 7.2%, p = 0.009, respectively). No significant differences were found in other tumour characteristics, including clinical tumour dimension, Brigham and Women's Hospital tumour staging or cumulative risk of metastasis and recurrence. Immunosuppressed patients had an increased risk of disease‐specific death on univariate analysis (hazard ratio [HR] [95% confidence interval, CI] 2.05 [1.13–3.74], p = 0.0128). Overall survival in the immunosuppressed population was worse (adjusted HR [95% CI] 1.83 [1.42–2.35], p < 0.001) and, notably, solid organ transplant recipients had the lowest overall survival when stratifying immunosuppressed patients by immunosuppression type (HR [95% CI] 1.62 [1.17–2.24], p < 0.0001).ConclusionsIn our study, immunosuppression status was predictive of poor differentiation of tumours and a reduction in overall and cSCC‐specific survival. Current staging systems for cSCC do not include immunosuppression as a risk factor and incorporating immune status may be beneficial for accurate risk stratification.