Citations

Mutations in the PINK1 and PRKN genes are the most frequent genetic cause of early-onset Parkinson disease. The pathogenic p.R275W substitution in PRKN is the most frequent substitution observed in patients, and thus far has been characterized mostly through overexpression models that suggest a possible gain of toxic misfunction. However, its effects under endogenous conditions are largely unknown. We used patient fibroblasts, isogenic neurons, and post-mortem human brain samples from carriers with and without PRKN p.R275W to assess functional impact. Immunoblot analysis and immunofluorescence were used to study mitophagy activation, and mitophagy execution was analyzed by flow cytometry of the reporter mitoKeima. The functional analysis was accompanied by structural investigation of PRKN p.R275W. We observed lower PRKN protein in fibroblasts with compound heterozygous p.R275W mutations. Isogenic neurons showed an allele-dose dependent decrease in PRKN protein. Lower PRKN protein levels were accompanied by diminished phosphorylated ubiquitin and decreased MFN2 modification. Mitochondrial degradation was also allele-dose dependently impaired. Consistently, PRKN protein levels were drastically reduced in human brain samples from p.R275W carriers. Finally, structural simulations showed significant changes in the closed form of PRKN p.R275W. Our data suggest that under endogenous conditions the p.R275W mutation results in a loss-of-function by destabilizing PRKN.

Abstract Mounting evidence indicates the involvement of peripheral immunity in the regulation of brain function, influencing aspects such as neuronal development, emotion, and cognitive abilities. Previous studies from our laboratory have revealed that neonatal hepatitis B vaccination can downregulate hippocampal neurogenesis, synaptic plasticity and spatial learning memory. In the current post-epidemic era characterized by universal vaccination, understanding the impact of acquired immunity on neuronal function and neuropsychiatric disorders, along with exploring potential underlying mechanisms, becomes imperative. We employed hepatitis B vaccine-induced CD3 positive T cells in immunodeficient mice to investigate the key mechanisms through which T cell subsets modulate hippocampal neurogenesis and anxiety-like behaviours. Our data revealed that mice receiving hepatitis B vaccine-induced T cells exhibited heightened anxiety and decreased hippocampal cell proliferation compared to those receiving phosphate-buffered saline-T cells or wild-type mice. Importantly, these changes were predominantly mediated by infiltrated CD8+ T cells into the brain, rather than CD4+ T cells. Transcriptome profiling of CD8+ T cells unveiled that C-X-C motif chemokine receptor 6 positive (CXCR6+) CD8+ T cells were recruited into the brain through microglial and astrocyte-derived C-X-C motif chemokine ligand 16 (CXCL16). This recruitment process impaired neurogenesis and induced anxiety-like behaviour via tumour necrosis factor-α-dependent mechanisms. Our findings highlight the role of glial cell derived CXCL16 in mediating the recruitment of CXCR6+CD8+ T cell subsets into the brain. This mechanism represents a potential avenue for modulating hippocampal neurogenesis and emotion-related behaviours after hepatitis B vaccination.

Objective Visual assessments of amyloid-β PET, used for Alzheimer’s disease (AD) diagnosis and treatment evaluation, require a careful approach when different PET ligands are utilized. Because the gray matter (GM) and white matter (WM) ligand bindings vary with age, the objective was to investigate the agreement between visual reads of 11C- and 18F-PET scans. Methods Cognitively unimpaired (CU) younger adults (N = 30; 39.5 ± 6.0 years), CU older adults (N = 30; 68.6 ± 5.9 years), and adults with AD (N = 22; 67.0 ± 8.5 years) underwent brain MRI, 11C-Pittsburgh compound-B (PiB)-PET, and 18F-flutemetamol-PET. Amyloid-β deposition was assessed visually by two nuclear medicine specialists on 11C-PiB-PET and 18F-flutemetamol-PET, and quantitatively by PET centiloids. Results Seventy-two 11C-PiB-PET and 18F-flutemetamol-PET visual reads were concordant. However, 1 18F-flutemetamol-PET and 9 11C-PiB-PET were discordant with quantitative values. In four additional cases, while 11C-PiB-PET and 18F-flutemetamol-PET visual reads were concordant, they were discordant with quantitative values. Disagreements in CU younger adults were only with 11C-PiB-PET visual reads. The remaining disagreements were with CU older adults. Conclusion Age, GM/WM binding, amyloid-β load, and disease severity may affect visual assessments of PET ligands. Increase in WM binding with age causes a loss of contrast between GM and WM on 11C-PiB-PET, particularly in CU younger adults, leading to false positivity. In CU older adults, increased WM signal may bleed more into cortical regions, hiding subtle cortical uptake, especially with 18F-flutemetamol, whereas 11C-PiB can detect true regional positivity. Understanding these differences will improve patient care and treatment evaluation in clinic and clinical trials.

Abstract Gastric volvulus has been rarely associated with diaphragmatic paralysis or eventration. In this article, we present the case of a patient with idiopathic paralysis of the left hemidiaphragm that underwent treatment with a robotic thoracoscopic diaphragm plication, which was complicated by massive gastric volvulus resulting in such significant intra-abdominal hypertension that the ipsilateral diaphragm ruptured anterior to the plication suture line.

Abstract: The integration of artificial intelligence (AI) and big data in anterior segment (AS) imaging represents a transformative approach to glaucoma diagnosis and management. This article explores various AS imaging techniques, such as AS optical coherence tomography, ultrasound biomicroscopy, and goniophotography, highlighting their roles in identifying angle-closure diseases. The review focuses on advancements in AI, including machine learning and deep learning, which enhance image analysis and automate complex processes in glaucoma care, and provides current evidence on the performance and clinical applications of these technologies. In addition, the article discusses the integration of big data, detailing its potential to revolutionize medical imaging by enabling comprehensive data analysis, fostering enhanced clinical decision-making, and facilitating personalized treatment strategies. In this article, we address the challenges of standardizing and integrating diverse data sets and suggest that future collaborations and technological advancements could substantially improve the management and research of glaucoma. This synthesis of current evidence and new technologies emphasizes their clinical relevance, offering insights into their potential to change traditional approaches to glaucoma evaluation and care.

Introduction: The spinal rehabilitation process plays a crucial role in SCI patients’ lives, and recent developments in VR have the potential to efficiently engage SCI patients in therapeutic activities and promote neuroplasticity. Objective: The primary objective of this study is to assess a complete review of the extended impacts of VR-assisted training on spine rehabilitation in SCI patients. Methods: This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) through a single database search in PubMed/Medline between the dates 1 January 2010 and 1 February 2024. MESH terms and keywords were combined in the following search strategy: (Augmented Reality OR VR OR Virtual Reality) AND (Spine OR Spinal) AND Rehabilitation. Included articles were written in English, involved adults with SCI, included an intervention with VR, AR, or any mixed reality system, and assessed changes in outcomes after the intervention. Results: The search produced 257 articles, and 46 of them were allocated for data extraction to evaluate 652 patients. Both when VR training was analyzed and reviewed separately, and when compared to traditional training, the findings exhibited predominantly promising outcomes, reflecting a favorable trend in the study. VR technologies were used in different settings and customizations, and the medium total time of VR training among the studies was 60.46 h per patient. Conclusions: This auspicious outcome of the study further motivates the intervention of VR and AR in the rehabilitation of SCI patients along with ameliorating their overall holistic well-being.

Abstract Aims Quantitative methods have shown clinically significant heterogeneity in blood volume (BV) profiles across heart failure (HF) phenotypes. These profiles extend from hypovolaemia to normal BV and to variable degrees of BV hypervolaemia, frequently with similar clinical presentations. However, a comprehensive survey of BV profiles providing practical clinical guidance for the interpretation and management of quantitative plasma volume (PV) and red blood cell (RBC) mass findings has not been reported. The intent of this study is to advance this concept through a multicentre analysis. Methods and results A retrospective analysis of clinical and BV data was undertaken in stable NYHA class II–III HF patients (N = 546). BV was quantitated using established nuclear medicine indicator-dilution methodology. Differing combinations of PV and RBC mass were identified contributing to marked heterogeneity in overall BV profiles. A quantitatively normal BV was identified in 32% of the cohort but of these only ~1/3 demonstrated a true normal BV (i.e., normal PV + normal RBC mass). The remaining portion of normal BV profiles reflected balanced combinations of compensatory PV expansion with RBC mass deficit (anaemia) (14% of cohort) and PV contraction with RBC mass excess (erythrocythemia) (6% of cohort). Main contributors to BV hypervolaemia were PV excess with a normal RBC mass (21% of cohort; 23% female) and PV excess with erythrocythemia (24% of cohort; 26% female). Hypovolaemia was predominately defined by RBC mass deficit with a normal PV (6% of cohort; 57% female) or RBC mass deficit with PV contraction (5% of cohort; 48% female). Conclusions Findings support the clinical relevance of identifying and accurately interpreting the varying combinations of PV and RBC mass in patients with chronic HF. This in turn helps guide appropriate individualized patient management strategies. A practical volume-based guideline is provided in an effort to aid clinician interpretation.

AbstractIntroductionOlder adults are at high risk of adverse health outcomes in the post–emergency department (ED) discharge period. Prior work has shown that discharged older adults have variable understanding of their discharge instructions which may contribute to these outcomes. To identify discharge comprehension gaps amenable to future interventions, we utilize meta‐analysis to determine patient comprehension across five domains of discharge instructions: diagnosis, medications, self‐care, routine follow‐up, and return precautions.MethodsUsing Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines, two reviewers sourced evidence from databases including Medline (PubMed), EMBASE, Web of Science, CINAHL, and Google Scholar (for gray literature). Publications or preprints appearing before April 2024 were included if they focused on geriatric ED discharge instructions and reported a proportion of patients with comprehension of at least one of five predefined discharge components. Meta‐analysis of eligible studies for each component was executed using random‐effects modeling to describe the proportion of geriatric ED cases understanding the discharge instructions; where appropriate we calculated pooled estimates, reported as percentages with 95% confidence interval (CI).ResultsOf initial records returned (N = 2898), exclusions based on title or abstract assessment left 51 studies for full‐text review; of these, seven constituted the study set. Acceptable heterogeneity and absence of indication of publication bias supported pooled estimates for proportions comprehending instructions on medications (41%, 95% CI 31%–50%, I2 = 43%), self‐care (81%, 95% CI 76%–85%, I2 = 43%), and routine follow‐up (76%, 95% CI 72%–79%, I2 = 25%). Key findings included marked heterogeneity with respect to comprehending two discharge parameters: diagnosis (I2 = 73%) and return precautions (I2 = 95%).ConclusionsOlder patients discharged from the ED had greater comprehension of self‐care and follow‐up instructions than about their medications. These findings suggest that medication instructions may be a priority domain for future interventions.

Background: Although previous literature shows tumor location as a prognostic factor in upper tract urothelial carcinoma (UTUC), there remains uninvestigated regarding the impact of tumor location on grade concordance and discrepancies between ureteroscopic (URS) biopsy and final radical nephroureterectomy (RNU) pathology. Methods: In this international study, we retrospectively reviewed the records of 1,498 patients with UTUC who underwent diagnostic URS with concomitant biopsy followed by RNU between 2005 and 2020. Tumor location was divided into four sections: the calyceal-pelvic system, proximal ureter, middle ureter, and distal ureter. Patients with multifocal tumors were excluded from the study. We performed multiple comparison tests and logistic regression analyses. Results: Overall, 1,154 patients were included; 54.4% of those with low-grade URS biopsies were upgraded on RNU. In the multiple comparison tests, middle ureter tumors exhibited the highest probability of upgrading, meanwhile pelvicalyceal tumors exhibited the lowest probability of upgrading (73.7% vs 48.5%, p = 0.007). Downgrading was comparable across all tumor locations. On multivariate analyses, middle ureteral location was significantly associated with a low probability of grade concordance (odds ratio [OR] 0.59; 95% confidence interval [CI], 0.35–1.00; p = 0.049) and an increased risk of upgrading (OR 2.80; 95% CI, 1.20–6.52; p = 0.017). The discordance did not vary regardless of caliceal location, including the lower calyx. Conclusions: Middle ureteral tumors diagnosed to be low grade had a high probability to be undergraded. Our data can inform providers and their patients regarding the likelihood of undergrading according to tumor location, facilitating patient counseling and shared decision making regarding the choice of kidney sparing vs RNU.