Clinical Disease Research Articles

Comparison of transcriptome responses in blood cells of Atlantic salmon infected by three genotypes of Piscine orthoreovirus.

Piscine orthoreovirus (PRV) infection is common in aquaculture of salmonids. The three known PRV genotypes (PRV-1-3) have host species specificity and cause different diseases, but all infect and replicate in red blood cells (RBCs) in early infection phase. PRV-1 is the causative agent of heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon (Salmo salar), PRV-2 causes erythrocytic inclusion body syndrome (EIBS) in coho salmon (Oncorhynchus kisutch), while PRV-3 induces HSMI-like disease in farmed rainbow trout (Oncorhynchus mykiss). PRV-3 can also infect A. salmon without causing clinical disease and has been shown to cross-protect against PRV-1 infection and HSMI, while PRV-2 or inactivated adjuvanted PRV-1 vaccine only partially reduced HSMI pathologic changes. In the present work, we studied the transcriptional responses in blood cells of A. salmon two- and five-weeks post infection with PRV-1, PRV-2, PRV-3, or post injection with inactivated PRV-1 vaccine. PRV-1 and PRV-3 replicated well in A. salmon blood cells, and both induced the typical innate antiviral responses triggered by dsRNA viruses. Two weeks post infection, PRV-3 triggered stronger antiviral responses than PRV-1, despite their similar viral RNA replication levels, but after five weeks the induced responses were close to equal. PRV-2 and the InPRV-1 vaccine did not trigger the same typical antiviral responses as the replicating PRV-1 and PRV-3 genotypes, but induced genes involved in membrane trafficking and signaling pathways that may regulate physiological functions. These findings propose that the protection mediated by PRV-3 against a secondary infection by PRV-1 occur due to a potent and early activation of the same type of innate immune responses. The difference in the timing of antiviral responses may give PRV-1 an evolutionary edge, facilitating its dissemination to A. salmon heart, a critical step for HSMI development.

Danggui Buxue decoction regulates autophagy to Improve renal fibrosis in diabetes through miR-27a /PI3K/AKT pathway.

Danggui Buxue Decoction (DBD) is a classic traditional Chinese herbal formulation, composed of Astragali Radix (AR) and Angelica Sinensis Radix (ASR) in a ratio of 5:1. It is a traditional Chinese medicine classic prescription for nourishing Qi and Yin (vital energy and body fluids), and it is effective in treating various clinical diseases. Diabetic nephropathy (DN) is categorized under "thirsting," "edema," and "turbid urine" in Traditional Chinese Medicine (TCM). However, the underlying mechanisms by which DBD ameliorates diabetic nephropathy remain unclear. To explore the mechanism by which Danggui Buxue Decoction (DBD) regulates podocyte autophagy in diabetic nephropathy (DN). Male db/m mice served as controls; db/db mice were divided into the model, dapagliflozin, and high/low-dose DBD groups. After 12 weeks of gavage, body weight, fasting blood glucose, urine albumin-to-creatinine ratio, 24-h urine volume, and blood urea nitrogen were recorded. Renal autophagy was assessed by Masson staining; mRNA levels were measured by qRT-PCR; and protein expression was analyzed by Western blot. The expression of inflammatory factors in the kidney was measured by ELISA. Human renal podocytes were cultured in NG, HG, HG+Blank serum, and HG+DBD-containing serum groups for 48h; cell viability was measured by CCK-8, and autophagy was observed by transmission electron microscopy. Changes in autophagy protein and mRNA expression were observed after miR-27a transfection under high glucose conditions. DBD can ameliorate renal function and reduce the degree of renal fibrosis in DN mice, enhance the mRNA expression of Beclin-1 and ULK1, and decrease the mRNA expression of Vimentin and α-SMA. This trend mirrors protein expression, and DBD also lowers renal inflammatory factors. DBD-containing serum boosts human renal podocyte viability under high glucose, protecting cells and modulating mRNA levels of Beclin-1, ULK1, P62, and PI3K, with miR-27a-mimic reversing these effects. DBD-containing serum also enhances Beclin-1, suppresses P62, and reduces the expression of p-PI3K/PI3K and p-AKT/AKT. DBD Regulates Autophagy to Improve Renal Fibrosis in Diabetes via the miR-27a/PI3K/AKT Pathway.

A phase 2 basket study of talabostat, a small-molecule inhibitor of dipeptidyl peptidases, administered in combination with pembrolizumab in patients with advanced solid cancers.

Talabostat, an oral small molecule inhibitor of dipeptidyl peptidases (DPP4 and DPP8/9), has shown synergistic activity with immune checkpoint inhibitors in preclinical studies. This open label, phase 2 basket trial assessed the antitumor activity of combining talabostat and pembrolizumab (anti-programmed death-1 antibody) in advanced solid tumor patients. The primary objective was assessment of dose-limiting toxicity (DLT) rates in the first six patients (lead-in stage) and response rate (efficacy stage; included cohort A [checkpoint inhibitor (ICI) naive] and cohort B [ICI pretreated]) for the study treatment using the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and immune RECIST (iRECIST). Efficacy was assessed using a Bayesian optimal phase 2 design. A total of 31 patients enrolled in this trial (14 in cohort A, 17 in cohort B). The median age was 61 years; 17 (55%) patients were male and 21 (68%) patients were White. Among 19 (61%) patients evaluable for response, the best response was stable disease in nine patients, unconfirmed progressive disease in seven patients, and clinical progressive disease in three patients based on iRECIST. Disease control rate was 47%. One patient with programmed death-ligand 1 negative, microsatellite stable endometrial cancer had unconfirmed partial response. Median progression-free survival was 2.7 months; median overall survival was 20.5 months. One patient (cohort A) experienced a grade 4 hypotension as a DLT and treatment discontinuation. The most common toxicities were hypotension (22.6%), fatigue (9.7%), diarrhea, rash, thrombocytopenia, vomiting, syncope, general disorders and administration site conditions-other, and skin and subcutaneous tissue disorders-other, each in 6.5% of patients. This study of the combination of talabostat and pembrolizumab in patients with advanced solid tumors demonstrated predictable adverse events and limited activity. The combination was shown to be safe. Efficacy data shows immune stable disease in nine of 19 evaluable patients, and an unconfirmed immune partial response in a patient with endometrial cancer.

Single-cycle neoadjuvant pembrolizumab in patients with stage I-III MMR-deficient colon cancer: Final analysis of the RESET-C study.

19 Background: Neoadjuvant treatment with immune checkpoint inhibitors has shown remarkable responses in patients with deficient mismatch repair (dMMR) colorectal cancer. However, the optimal choice and duration of treatment have yet to be established. Methods: RESET-C (NCT05662527) was an investigator-initiated, phase II, single-arm, multicenter study investigating the efficacy and safety of single-cycle neoadjuvant pembrolizumab in 85 patients with resectable stage I-III dMMR colon cancer. Additional inclusion criteria were ≥ 18 years of age, no indication for neoadjuvant therapy, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. After inclusion, patients received one cycle of pembrolizumab 4mg/kg (maximum 400mg) and underwent surgery within three to five weeks. A tumor-response evaluation was done before surgery, including blood samples, a computed tomography scan of the chest and abdomen, and a colonoscopy. The primary endpoint was the pathological complete response (pCR) rate according to Mandard tumor regression grading (Clopper-Pearson method). Secondary endpoints included surgical complications, safety of pembrolizumab, major pathological response (Mandard tumor regression grade 1 or 2), and disease-free survival. Results: Between February 2023 and March 2024, 85 patients were included. The median age was 74 years (IQR, 68-79), 72% were women, and 60% had clinical stage III disease. All patients received pembrolizumab, and 84 patients proceeded to surgery. One patient with stage I disease decided not to undergo surgery. A pCR rate of 44% (37/84; 95% CI, 33-55) and a major pathological response rate of 57% (48/84; 95% CI, 46-68) were found. A significantly higher pCR rate was seen in patients with stage I-II (20/33) versus stage III (17/51) disease (61% vs 33%; p=0.02). A total of 41 surgical complications were seen in 31 patients (37%; 95% CI, 27-48). Of these, eight complications were Clavien-Dindo grade 3a or above, including three patients with anastomotic leakages and two deaths within 30 days. The patients who died were aged 80 and 81, had ECOG performance status 1, and clinical stage IIIB and IIIC disease, respectively. Seven out of 85 patients (8%; 95% CI, 3-16) experienced grade 3 adverse events, three of which were treatment-related. No grade 4 or 5 adverse events were registered. Finally, data on the association between endoscopically evaluated clinical complete response and pCR, along with the 1-year disease-free survival rate expected in January 2025, will be reported. Conclusions: A single cycle of neoadjuvant pembrolizumab was efficacious and safe in patients with localized dMMR colon cancer. For most patients with clinical stage I-II disease, a single cycle sufficed to achieve pCR. Clinical trial information: NCT05662527 .

Colorectal Cancer Screening Participation and Health Belief Levels of Public Hospital Patients in Türkiye.

Colorectal cancer can be diagnosed early with screening tests; therefore, patients' beliefs regarding colorectal cancer screening are closely related to clinical and pathological disease stages at the time of diagnosis. This study aimed to determine participation in colorectal cancer screening programs and health beliefs related to protection from colorectal cancer among patients aged 40-70years and evaluate factors affecting their participation in such screening programs. This descriptive study was conducted in a state hospital in Türkiye between May 2021 and December 2021 with the participation of 1,016 patients. Study data were collected through face-to-face interviews using a questionnaire consisting of an "Introductory Information Form" and the "Health Belief Model Scale for Prevention of Colorectal Cancer." Signed voluntary consent was obtained from all participants, as well as ethics committee approval and institutional permission from the hospital. The mean age of the participants was 50.12±9.29years, 54% were 40-50years old, 55.5% were female, 87.3% were married, 6.8% had a primary education or below, and 39.3% were employed. The internal consistency was low for the health motivation subscale and relatively high for other subscales of the Health Belief Model Scale for Prevention of Colorectal Cancer.

Cardiac matrix-bound Nanovesicles provide insight into mechanisms of clinical heart disease progression to failure.

Remodeling of the extracellular matrix (ECM) is critical for effective wound healing and maintaining organ homeostasis. The ECM of soft tissues, including cardiac, contains embedded nanovesicles; or matrix-bound nanovesicles (MBV). The luminal cargo of MBV consists of lipids, microRNAs (miRNAs), and proteins that influence the function of immune and stromal cells. ECM remodeling is extensive during heart disease, yet it is unknown if MBV are altered during the development of heart disease. We conducted the present study to answer this question. MBV were isolated from de-identified human left ventricle (LV) tissue samples from: 1) non-ischemic, failing hearts (failing) and 2) non-failing, non-ischemic hearts (control). MBV morphology was analyzed and the protein and miRNA cargo were quantified. Immunomodulatory capacity of MBV was assessed on macrophages. Failing and control heart tissue had similar concentrations of MBV, however, their size and cargo differed. MBV from failing tissue had increased levels of Apolipoprotein A-1 and decreased levels of C-Reactive Protein. Over 600 unique miRNA were detected. Of these, 5% showed significantly different levels, with most being downregulated in MBV from failing heart tissue. Ex vivo stimulation of human macrophages with MBV isolated from control ventricular tissue, but not failing ventricles, induced gene expression suggesting increased reparative functions. These data reveal that MBV are present within the human heart and suggests that disease progression alters MBV cargo (lipids, microRNAs, and proteins). Furthermore, it is suggested that alterations in local MBV cargo may perpetuate pathology when their capacity to modulate reparative immune cells is diminished.

Ultraviolet-Induced Fluorescence Dermoscopy, a Novel Diagnostic Technique in Dermatological Practice: A Systematic Review.

Ultraviolet-induced fluorescence dermoscopy (UVF dermoscopy) is a novel diagnostic technique for identifying and diagnosing numerous skin tumors, inflammatory dermatoses, and infectious diseases. The ultraviolet (UV) band has a wavelength ranging from 10 to 400 nm. When intense UV radiation with shorter wavelengths strikes a target chromophore, visible light (VL) with a longer wavelength and lower energy is produced in the skin. This VL is apparent to the naked eye and is referred to as fluorescence. The current review compares ultraviolet fluorescence dermoscopy (UVFD) and polarized dermoscopy (PD) features in various dermatological disorders. This review was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Metanalyses) guidelines. A comprehensive search of the literature was carried out through the PubMed and Google Scholar electronic databases from inception to 25th December 2023 using the following search terms: "UV dermoscopy" OR "ultraviolet fluorescence dermoscopy" OR "ultraviolet-induced fluorescence dermoscopy" OR "Ultraviolet-induced fluorescent dermoscopy". Titles, abstracts, and full texts were screened by two independent reviewers to select papers dealing with UVF-dermoscopy. A total of 23 relevant articles were included in this systematic review, including a total of 313 patients. Pigmented skin tumors included 209 patients, Fordyce spot mimickers (13), scabies (57), biopsy site (20), psoriasis (3), corynebacterium infections (2), fungal infections (4), vitiligo (3), acne folliculitis (1) and glomus tumors (1). Levels of evidence (LoE) was 3 and 4 in only two included studies; the rest had a LoE of 5. UVF dermoscopy is a new diagnostic and prognostic tool for neoplastic and non-neoplastic dermatological conditions. This is the first systematic review of its sort that compares and categorizes dermoscopic findings in UVF and polarized light in dermatological practice. As UVFD does not penetrate deeper skin layers, we observed that it is a better way to distinguish features restricted to the skin's superficial layers in neoplastic diseases. As a result, tumor-free margins and improved surgical outcomes can be achieved. More favorable outcomes for evaluation and treatment were seen with non-neoplastic conditions. Limitations included a lack of studies with a high level of evidence, control groups, and larger sample sizes. We concluded that UVFD will improve clinical diagnosis, disease management, and outcomes. More clinical trials with larger sample sizes are recommended to better understand this novel and intriguing new diagnostic tool.

Review of impaired immune parameters in RSV infections in the elderly.

Respiratory syncytial virus (RSV) infections in elderly individuals are associated with increased rates of severe clinical disease and mortality compared to younger adults. Age-associated declines in numerous innate and adaptive immune parameters during RSV infection contribute to infection susceptibility, impaired viral clearance, and distorted cytokine profiles in the elderly. Impaired immune responses in this age group also adversely affect longevity of RSV immunity following vaccination in experimental settings. This review summarizes the effects of aging on cellular immune responses to RSV in humans and animal models, molecular mechanisms for these impaired responses where they have been elucidated, and the clinical consequences of impaired immunity in the elderly.

Motor neuron diseases are not exclusively motor; the SSR paradigm.

Motor Neuron Diseases (MNDs), familial and sporadic, are progressive neurodegenerative disorders that, for an extended period in the past, were considered purely motor disorders. During the course of the disease, however, some patients exhibit concomitant non-motor signs; thus, MNDs are currently perceived as multisystem disorders. Assessment of non-motor symptoms is usually performed clinically, although laboratory tests can also be routinely used to objectively evaluate these symptoms. Sympathetic Skin Response (SSR) is an example of a neurophysiological test that has been used in cases of Amyotrophic Lateral Sclerosis, Spinal Muscular Atrophy, and Monomelic Atrophy, mostly to assess Autonomic Nervous System (ANS) disorders. Dysautonomia affects quality of life and life expectancy, as it is involved in cardiovascular events and incidents of sudden death. SSR abnormalities are present even in subclinical involvement of the ANS in MNDs. In this review, we present published research examining SSR findings in various MNDs, and discuss the correlation of SSR findings with clinical symptoms and disease severity, as well as the potential sources of abnormal findings. The aim of this study is to raise clinician awareness of autonomic dysfunction in MNDs and present the benefits of SSR examination in patient care.

Identification of patient demographic, clinical, and SARS-CoV-2 genomic factors associated with severe COVID-19 using supervised machine learning: a retrospective multicenter study

BackgroundDrivers of COVID-19 severity are multifactorial and include multidimensional and potentially interacting factors encompassing viral determinants and host-related factors (i.e., demographics, pre-existing conditions and/or genetics), thus complicating the prediction of clinical outcomes for different severe acute respiratory syndrome coronavirus (SARS-CoV-2) variants. Although millions of SARS-CoV-2 genomes have been publicly shared in global databases, linkages with detailed clinical data are scarce. Therefore, we aimed to establish a COVID-19 patient dataset with linked clinical and viral genomic data to then examine associations between SARS-CoV-2 genomic signatures and clinical disease phenotypes.MethodsA cohort of adult patients with laboratory confirmed SARS-CoV-2 from 11 participating healthcare institutions in the Greater Toronto Area (GTA) were recruited from March 2020 to April 2022. Supervised machine learning (ML) models were developed to predict hospitalization using SARS-CoV-2 lineage-specific genomic signatures, patient demographics, symptoms, and pre-existing comorbidities. The relative importance of these features was then evaluated.ResultsComplete clinical data and viral whole genome level information were obtained from 617 patients, 50.4% of whom were hospitalized. Notably, inpatients were older with a mean age of 66.67 years (SD ± 17.64 years), whereas outpatients had a mean age of 44.89 years (SD ± 16.00 years). SHapley Additive exPlanations (SHAP) analyses revealed that underlying vascular disease, underlying pulmonary disease, and fever were the most significant clinical features associated with hospitalization. In models built on the amino acid sequences of functional regions including spike, nucleocapsid, ORF3a, and ORF8 proteins, variants preceding the emergence of variants of concern (VOCs) or pre-VOC variants, were associated with hospitalization.ConclusionsViral genomic features have limited utility in predicting hospitalization across SARS-CoV-2 diversity. Combining clinical and viral genomic datasets provides perspective on patient specific and virus-related factors that impact COVID-19 disease severity. Overall, clinical features had greater discriminatory power than viral genomic features in predicting hospitalization.

Chronic disease prevalence and preventive care among Ontario social housing residents compared with the general population: a population-based cohort study

BackgroundOlder adults living in social housing report poor health and access to healthcare services. This study aimed to estimate the prevalence of chronic diseases, influenza vaccination and cancer screenings among...

'Diagnosis and Treatment of Hypersensitivity Pneumonitis' S2k Guideline of the German Respiratory Society and the German Society for Allergology and Clinical Immunology.

German recommendations for the diagnosis of hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis (EAA), were last published in 2007 [1]. The current S2k Guideline for the Diagnosis and Treatment of Hypersensitivity Pneumonitis (HP) replaces these diagnostic recommendations. They were supplemented by the aspect of chronic, and in particular of the chronic fibrotic phenotype of HP, and also, as first HP guideline, include treatment recommendations. Based on current scientific evidence and on expert opinion 12 consensus recommendations were developed. They include important statements summarizing the diagnostic process, the treatment indication and therapeutic strategies for patients with HP. Particular emphasis was placed on the different clinical courses (acute and chronic) and their characteristics (inflammatory and/or fibrotic pattern), which present differential diagnostic challenges and ultimately result in different treatment approaches. In addition to general information (diagnosis, classification, clinical disease course, epidemiology, pathogenesis, risk factors, prognosis and special aspects associated with occupational disease), the guideline will present the various clinical disease entities of HP, some in detail, others in tabular form. A major focus is on the various diagnostic steps and the different treatment approaches. The background information serves to provide a deeper understanding and inform the implementation of the recommendations. In particular, other current international guidelines for the diagnosis of HP as well as German guidelines for the diagnosis of Interstitial lung diseases (ILDs) (Leitlinien zur Diagnostik interstitieller Lungenerkrankungen) in general and for the pharmacotherapy of fibrotic ILDs were integrated and considered in this guideline [2-6].

19-Year Follow-up on Patients with Axenfeld-Rieger Anomaly or Syndrome and Fuchs' Endothelial Dystrophy Including the 6th Generation in a Pedigree.

Nineteen-year follow-up after initial examination on patients with Axenfeld-Rieger anomaly or syndrome (ARAS) and coexisting Fuchs' endothelial dystrophy (FED). All individuals had previously been tested positive for the PITX2 (g.20 913 G>T) mutation. Additionally, we addressed their descendants for phenotype and genotype examination to determine their penetrance into the next generations. Twenty-nine patients (9 patients and 20 of their descendants) participated in this prospective observational study. Nine patients were examined and tested positive for the PITX variant (g.20 913 G>T) in our previous study in 2001. Fourteen descendants were genetically and clinically examined. Six descendants were not available for clinical examination but donated saliva samples for genetic analysis. Ophthalmic examination was performed, consisting of visual acuity (VA) testing, applanation tonometry, gonioscopy, and anterior segment and central fundus biomicroscopy. Peripapillary optical coherence tomography (pOCT) was performed, and endothelial cell density (ECD) and central corneal thickness (CCT) were measured. Clinical disease progression in patients with a positive PITX2 mutation, genetic defect transmission, and clinical penetrance in subsequent third to sixth generations were the main outcome measures. Ten out of twenty descendants tested positive for the PITX2 variant (g.20 913 G>T). Eight were identified as being affected by ARAS. FED was found in six patients. All of them showed ARAS. Third generation patients (mean age 82) progressed significantly in both coexisting diseases. Four of six eyes ended up in corneal edema, with VA below 0.2. Glaucoma assessment was compromised due to corneal edema. Fourth generation patients (mean age 43) showed a mean CCT of 611 µm, ECD of 1230, and intraocular pressure (IOP) of 17.5 mmHg and thinning of the peripapillary nerve fiber layer. One eye was newly diagnosed with glaucoma, elevated IOP, and mild corneal edema. Fifth generation patients (mean age 27) presented with a mean CCT of 564 µm, ECD of 2802, and IOP of 14.4 mmHg. Genetic analysis confirmed the PITX2 (g.20 913 G>T) mutation was associated with Axenfeld-Rieger and FED in 10 of 20 descendants in this family. This matches the autosomal dominant inheritance pattern with a probability of 50%. Glaucoma and corneal decompensation were progressive over 19 years, with variable expression and early onset in subsequent pedigree members.

A ratiometric fluorescent probe for sensitively tracking peroxynitrite during drug-induced hepatotoxicity.

As one of the essential components of reactive oxygen species (ROS), peroxynitrite (ONOO-) plays an indispensable role in redox homeostasis and signal transduction processes, and its deviant levels are associated with numerous clinical diseases. Therefore, accurate and rapid detection of intracellular ONOO- levels is crucial for revealing its role in physiological and pathological processes. Herein, we constructed a ratiometric fluorescent probe to detect ONOO- levels in biological systems. The probe represents fast reaction rate (within 15 min), outstanding selectivity, good sensitivity (LOD = 13.32 nM) and stability to ONOO-, and it was successfully used for visualizing endogenous ONOO- in living cells. More importantly, it has also been used for tracking the changes of intracellular ONOO- during drug-induced hepatotoxicity with ratiometric fluorescence.

Altered medial temporal lobe subregion volumes in systemic lupus erythematosus patients with neuropsychiatric symptoms

BackgroundSystemic lupus erythematosus (SLE) often presents with neuropsychiatric (NP) involvement, including cognitive impairment and depression. Past magnetic resonance imaging (MRI) research in SLE patients showed smaller hippocampal volumes but did not investigate other medial temporal lobe (MTL) regions. Our study aims to compare MTL subregional volumes in SLE patients to healthy individuals (HI) and explore MTL subregional volumes in relation to neuropsychiatric SLE (NPSLE) manifestations.MethodsA total of 70 SLE patients and 25 HI underwent clinical evaluation, cognitive testing, and 3 tesla MRI imaging. T1-weighted MRI images were analyzed using the Automatic Segmentation of Hippocampal Subfields-T1 software. Analyses of Covariance were used to compare MTL subregion volumes between SLE and HI, and between NPSLE and non-NPSLE patients according to three models: the American College of Rheumatology (ACR) model defined by the ACR case definitions for NPSLE (n = 42), the more stringent Systemic Lupus International Collaborating Clinics (SLICC) B model (n = 21), and the most stringent SLICC A model (n = 15). Additionally, we explored the relation between MTL subregion volumes, cognitive functions, and depression scores in SLE patients using partial correlation analyses.ResultsSignificantly smaller volumes of bilateral whole hippocampus, anterior hippocampus, posterior hippocampus, and Brodmann Area 35 were demonstrated in NPSLE compared to non-NPSLE patients according to the ACR model (p = 0.01, p = 0.03, p = 0.04, and p = 0.01 respectively). The differences did not reach significance according to the SLICC B and SLICC A models. No significant differences in MTL subregional volumes between SLE patients and HI were found. Partial correlation analyses showed a significant positive correlation between left Brodmann Area 35 volume and complex attention scores in SLE patients. No significant associations between MTL subregion volumes and depression scores were demonstrated.ConclusionsNPSLE patients display significantly smaller volumes in various subregions of the MTL compared to non-NPSLE patients. These findings are suggestive of neuronal damage in MTL subregions in NPSLE patients on a group level.

The impact of imprecise case definitions in electronic health record research: a melanoma case-study from the Million Veteran Program.

Cases for a disease can be defined broadly using diagnostic codes, or narrowly using gold-standard confirmation that often is not available in large administrative datasets. These different definitions can have significant impacts on the results and conclusions of studies. We conducted this study to assess how using melanoma phecodes versus histologic confirmation for invasive or in situ melanoma impacts the results of a genome-wide association study (GWAS) using the Million Veteran Program. Melanoma status was determined three ways: (1) by the presence of two or more phecodes, (2) histologically-confirmed invasive melanoma, and (3) histologically-confirmed melanoma in situ. We conducted a GWAS for variants with minor allele frequencies of 1% or greater. There were 45,665 cases in the phecode cohort, 5364 cases in the confirmed invasive melanoma cohort, and 4792 cases in the confirmed melanoma in situ cohort. There were 20,457 variants significant at the genome-wide level in the phecode cohort, 2582 in the invasive melanoma cohort, and 1989 in the melanoma in situ cohort. Most of the variants identified in the phecode cohort did not replicate in the histologically-confirmed cohorts. The different case definitions led to large differences in sample size and variants associated at the genome-wide level. Unvalidated and imprecise case definitions can lead to less accurate results. Investigators should use validated phenotypes when gold-standard definitions are not available.

Albuminocytologic Dissociation and the Impact of Age-Adjusted Cerebrospinal Fluid Protein Levels in Guillain–Barré Syndrome

Background: This study examined the impact of age-adjusted cerebrospinal fluid (CSF) protein levels on clinical characteristics, disease severity, and outcomes in Guillain–Barré Syndrome (GBS) patients. Methods: This retrospective study included 71 GBS patients at UTMB Galveston. Albuminocytologic dissociation (ACD) was defined as CSF–total protein (CSF-TP) >0.45 g/L with a cell count of <50 cells/L. Patients were grouped using the conventional cutoff (>0.45 g/L) and age-adjusted upper limits (URLs) for CSF-TP levels, comparing clinical, CSF, and electrophysiological characteristics across groups. Results: The mean age was 50 years (SD = 14.5). The mean age of patients with a CSF-TP > 45 g/L was higher (53 vs. 39 years, p = 0.000), whereas no such difference was noted using age-dependent URLs. Using age-adjusted CSF-TP URLs reduced the sensitivity for detecting ACD by 20%. CSF-TP > age-adjusted URLs were associated with lower MRC sum scores (39 vs. 47.43, p = 0.000), higher ICU admission rates (34% vs. 20%, p = 0.003), and the need for second-line treatment (41% vs. 17%, p = 0.049), and the trends were not observed with the conventional cutoff of 0.45 g/L. CSF-TP was an independent predictor of lower MRC sum scores (p = 0.009, 95% CI −0.058, −0.009) and higher GBS disability scores (p = 0.015, 95% CI 0.000, 0.004). Conclusions: ACD is a common finding in GBS, but normal protein levels do not exclude the diagnosis. Using age-adjusted URLs might improve specificity but reduce sensitivity for ACD detection, potentially increasing false negatives. CSF-TP levels exceeding age-adjusted URLs were more strongly associated with greater disease severity and poorer outcomes compared to the conventional cutoff of 0.45 g/L.

Developing predictive nomogram models using quantitative electroencephalography for brain function in type a aortic dissection: a prospective observational study.

Type A aortic dissection (TAAD) remains a significant challenge in cardiac surgery, presenting high risks of adverse outcomes such as permanent neurological dysfunction and mortality despite advances in medical technology and surgical techniques. This study investigates the use of quantitative electroencephalography (QEEG) to monitor and predict neurological outcomes during the perioperative period in TAAD patients. This prospective observational study was conducted at the hospital, involving patients undergoing TAAD surgery from February 2022 to January 2023. QEEG parameters, including the dynamic amplitude-integrated electroencephalography (aEEG) grade, which assesses changes in brain function over time, alongside aEEG and relative band power (RBP), were monitored and analyzed to assess brain function preoperatively, intraoperatively, and within 2hours postoperatively. A predictive nomogram model was developed using these QEEG metrics along with other clinical variables to forecast neurological outcomes. In this study, we analyzed the factors contributing to adverse outcomes (AO) and transient neurological dysfunction (TND) following TAAD surgery. For AO, multivariable analysis identified pre-mental status (odds ratio [OR]=4.652, 95% confidence interval [CI]=2.316-10.074, P < 0.001), cardiopulmonary bypass time (OR=1.014, 95% CI=1.006-1.023, P =0.001), and dynamic aEEG grade (OR=9.926, 95% CI=4.493-25.268, P < 0.001) as independent risk factors. The AO model showed high discriminative ability with an area under the curve of 0.888 (95% CI=0.818-0.960) and good calibration (Brier score=0.0728). For TND, significant preoperative differences included dynamic aEEG grade (P < 0.001) and Log(Post-RBP Alpha%) (6.00 vs. 4.00, P < 0.001). Multivariable analysis identified cardiopulmonary bypass time (OR=1.014, 95% CI=1.006-1.023, P =0.001), Post-RBP Alpha% (OR=0.263, 95% CI=0.121-0.532, P < 0.001), and dynamic aEEG grade (OR=12.444, 95% CI=5.337-30.814, P < 0.001) as independent risk factors. The TND model had an area under the curve of 0.893 (95% CI=0.844-0.941) and good calibration (Brier score=0.125). These findings highlight the role of QEEG in predicting postoperative neurological dysfunction in TAAD patients. Through perioperative QEEG monitoring of TAAD patients, combined with clinical indicators such as cardiopulmonary bypass time and preoperative mental status, we developed clinical predictive models for AO and TND after surgery. These models allow for early detection of postoperative brain function impairment, as assessed by QEEG parameters monitored intraoperatively and during the first 2hours after surgery, a period chosen based on clinical definitions of delayed awakening and supported by the findings of this study. This study provides evidence supporting postoperative brain function monitoring in TAAD patients, with potential clinical implications for improved outcomes.

Presentation and Surgical Outcomes of Primary Hyperparathyroidism After Radioactive Iodine Therapy.

Radioactive iodine (RAI) is a common treatment for various thyroid diseases. Previous studies have suggested susceptibility of parathyroid glands to the mutagenic effect of RAI and the development of primary hyperparathyroidism (PHPT). We tested the possible link between prior RAI treatment, disease presentation, and treatment outcomes. A retrospective analysis of 704 individuals who underwent parathyroidectomy for PHPT at a tertiary care center between the years 2015 and 2023 was performed. Preoperative and postoperative parameters, including demographic characteristics, biochemical markers, imaging data, and surgical and pathology findings were collected and analyzed to compare differences in patients who had previous RAI treatment and those who did not (non-RAI). Univariate statistical analyses were performed. Twenty-nine patients had a history of RAI treatment. Indications for RAI treatment included hyperthyroidism (n=18), papillary thyroid cancer (n=6), subacute thyroiditis (n=1), follicular cancer (n=1), and toxic goiter (n=1). Average latency time between RAI exposure and development of PHPT was 18.4ys. On comparison of the two groups, there was no difference in age, sex, race/ethnicity, day of surgery body mass index, preoperative parathyroid hormone, calcium, glomerular filtration rate, creatinine, vitamin D, or phosphate levels. There was also no difference in preoperative diagnosis of osteoporosis or nephrolithiasis. Postoperatively, there was no difference in parathyroid hormone, calcium, or creatinine levels, or in rate of cure. There was significantly higher chance of unilateral exploration in the operating room (75.9% RAI, 54.1% non-RAI, P=0.02) and increased rate of single-gland disease in the RAI group, although the latter finding was not statistically significant (79.3% RAI, 65.2% non-RAI, P=0.12). There was no difference in adenoma size as noted on the pathology report (greatest dimension 1.7cm RAI, 1.7cm non-RAI, P=0.28). Subgroup analysis of the RAI group based on reason for RAI treatment (cancer versus hyperthyroidism) showed no statistically significant differences in the examined demographic or clinical data. There does not seem to be a relationship between prior RAI treatment and the clinical presentation of PHPT. Additionally, differences in RAI dose do not appear to be associated with a change in clinical presentation. Our study revalidates that age and latency are inversely related, which is a previously shown finding. Clinicians may be reassured that patients with prior RAI history may not have differences in clinical characteristics, disease presentation, or treatment outcomes.

Brain connectivity, neural networks, and resilience in aging and neurodegeneration.

The importance of complex systems has become increasingly evident in recent years. The nervous system is one such example with neural networks sitting at the intersection of complex networks and biology. A particularly exciting feature is the resilience of complex systems. For example, the ability of the nervous system to perform even in the face of challenges that include neuronal loss, neuroinflammation, protein accumulation, axonal disruptions, and metabolic stress is an intriguing and exciting line of investigation. In neurodegenerative diseases, neural network resilience is responsible for the time between the earliest disease-linked changes and clinical symptom onset and disease diagnosis. In this way, connectivity resilience of neurons within the complex network of cells that make up the nervous system has significant implications. This review provides an overview of relevant concepts related to complex systems with a focus on the connectivity of the nervous system. It discusses the development of the neural network and how a delicate balance determines how this complex system responds to injury with examples illustrating maladaptive plasticity. The review then addresses the implications of these concepts, methods to understand brain connectivity and neural networks, and recent research efforts aimed at understanding neurodegeneration from this perspective. The authors aim to provide foundational knowledge and an overview of current research directions in this evolving and exciting area of neuroscience.