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Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary arterial pressures that can lead to right heart failure and death. No cure exists for this disease, but therapeutic advancements have extended its median survival from 2 to 7 years. Mechanistic research in PAH has been limited by factors including that a) animal models do not fully recapitulate the disease or provide insights into its pathogenesis, and b) cellular material from PAH patients is primarily obtained from donor lungs during autopsy or transplantation, which reflect end-stage disease. Therefore, there is a need to identify tools that can elucidate the specific mechanisms of human disease in individual patients, a critical step to guide treatment decisions based on specific pathway abnormalities. Here we demonstrate a simple method to isolate and culture circulating endothelial cells (CECs) obtained at the time of right heart catheterization in PAH patients. We tested these CECs using transcriptomics and found that they have typical traits of PAH, including those involving key treatment pathways, i.e. nitric oxide, endothelin, prostacyclin and BMP/activin pathways. CECs show important gene expression changes in other central PAH disease pathways. In summary, we present a new cellular model for the ex-vivo mechanistic evaluation of critical PAH pathways that participate in the pathogenesis of the disease and may help personalized therapeutic decisions. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DKD) is a severe diabetes complication and a leading cause of mortality. While urine microalbuminuria and eGFR are common markers, some advanced cases may exhibit normal values. The progression from microalbuminuria to overt proteinuria in DKD is gradual and requires comprehensive physiological tests for diagnosis. This study employs deep reinforcement learning to predict DKD progression based on patients’ physiological data, aiming to assist clinical diagnosis and treatment. A multivariate logistic regression algorithm is used to describe the DKD prediction probability. An optimized DKD progression prediction algorithm (DPDCD) based on deep reinforcement learning determines the best model coefficients, enabling accurate prediction of DKD progression using routine clinical data. Experimental results demonstrate that DPDCD outperforms other algorithms in predicting DKD progression, providing valuable support for clinicians. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Prion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG‐PET) imaging for this purpose.FDG‐PET were performed in 40 clinic patients with prion disease. FDG‐PET images were projected onto latent factors generated in an external dataset to yield patient‐specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data‐driven clusters, which were compared by survival time.Median age at FDG‐PET was 65.3 years (range 23–85). Median time from FDG‐PET to death was 3.7 months (range 0.3–19.0). Four data‐driven clusters were generated, termed “Neocortical” (n = 7), “Transitional” (n = 12), “Temporo‐parietal” (n = 13), and “Deep nuclei” (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG‐PET‐patterns were not associated with demographic (age and sex) or clinical (CSF total‐tau, 14‐3‐3) variables.Greater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG‐PET informs large‐scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG‐PET may enrich multimodal prion disease prognostication models. [ABSTRACT FROM AUTHOR]

Motivated by the experience of COVID‐19 trials, we consider clinical trials in the setting of an emerging disease in which the uncertainty of natural disease course and potential treatment effects makes advance specification of a sample size challenging. One approach to such a challenge is to use a group sequential design to allow the trial to stop on the basis of interim analysis results as soon as a conclusion regarding the effectiveness of the treatment under investigation can be reached. As such a trial may be halted before a formal stopping boundary is reached, we consider the final analysis under such a scenario, proposing alternative methods for when the decision to halt the trial is made with or without knowledge of interim analysis results. We address the problems of ensuring that the type I error rate neither exceeds nor falls unnecessarily far below the nominal level. We also propose methods in which there is no maximum sample size, the trial continuing either until the stopping boundary is reached or it is decided to halt the trial. [ABSTRACT FROM AUTHOR]

Background: Increased awareness of the factors contributing to the diagnostic disparities seen in bipolar disorder between individuals of different heritage is needed to achieve equity in diagnosis and treatment. One such inequity is the provision of earlier treatment. Earlier treatment of patients diagnosed with bipolar disorder may prolong time to recurrence of mood episodes and reduce functional impairment and other poor outcomes associated with disease progression. The aim of this post hoc analysis was to study the efficacy and safety of long-acting injectable aripiprazole once-monthly 400 mg (AOM 400) in patients with earlier-stage bipolar I disorder (BP-I). Data from a 52-week multicenter, double-blind, placebo-controlled, randomized withdrawal trial of AOM 400 versus placebo in patients with BP‑I (NCT01567527) were analyzed. Those patients in the lowest quartiles for age (18–≤32 years; n = 70) or disease duration (0.13–≤4.6 years; n = 67) at baseline were categorized with earlier-stage BP-I. The primary endpoint was time from randomization to recurrence of any mood episode. Other endpoints included proportion of patients with recurrence of any mood episode, and change from baseline in Young Mania Rating Scale (YMRS) and Montgomery–Åsberg Depression Rating Scale (MADRS) total scores. Results: Maintenance treatment with AOM 400 significantly delayed time to recurrence of any mood episode versus placebo in patients aged 18–≤32 years (hazard ratio [HR]: 2.46 [95% confidence interval (CI) 1.09, 5.55]; p = 0.0251) or with disease duration 0.13–≤4.6 years (HR: 3.21 [95% CI 1.35, 7.65]; p = 0.005). This was largely driven by a lower proportion of patients in the AOM 400 group with YMRS total score ≥15 or clinical worsening. Changes from baseline in MADRS total score in both earlier-stage groups indicated AOM 400 did not worsen depression versus placebo. The safety profile of AOM 400 was consistent with the original study. Note that the original study included patients who had previously been stabilized on AOM 400 monotherapy, which may have enriched the population with patients who respond to and tolerate AOM 400. Conclusions: In this post hoc analysis, AOM 400 prolonged time to recurrence of any mood episode versus placebo in earlier-stage BP-I. These findings support early initiation of maintenance treatment with AOM 400. [ABSTRACT FROM AUTHOR]

The spinal muscular atrophy (SMA) phenotype strongly correlates with the SMN2 gene copy number. However, the severity and progression of the disease vary widely even among affected individuals with identical copy numbers. This study aimed to investigate the impact of genetic variability in oxidative stress, inflammatory, and neurodevelopmental pathways on SMA susceptibility and clinical progression. Genotyping for 31 genetic variants across 20 genes was conducted in 54 SMA patients and 163 healthy controls. Our results revealed associations between specific polymorphisms and SMA susceptibility, disease type, age at symptom onset, and motor and respiratory function. Notably, the TNF rs1800629 and BDNF rs6265 polymorphisms demonstrated a protective effect against SMA susceptibility, whereas the IL6 rs1800795 was associated with an increased risk. The polymorphisms CARD8 rs2043211 and BDNF rs6265 were associated with SMA type, while SOD2 rs4880, CAT rs1001179, and MIR146A rs2910164 were associated with age at onset of symptoms after adjustment for clinical parameters. In addition, GPX1 rs1050450 and HMOX1 rs2071747 were associated with motor function scores and lung function scores, while MIR146A rs2910164, NOTCH rs367398 SNPs, and GSTM1 deletion were associated with motor and upper limb function scores, and BDNF rs6265 was associated with lung function scores after adjustment. These findings emphasize the potential of genetic variability in oxidative stress, inflammatory processes, and neurodevelopmental pathways to elucidate the complex course of SMA. Further exploration of these pathways offers a promising avenue for developing personalized therapeutic strategies for SMA patients. [ABSTRACT FROM AUTHOR]

Introduction: The objective of this study was to evaluate quality indicators of secondary health care in chronic kidney disease (CKD). Methods: This retrospective longitudinal study was conducted in an outpatient medical nephrology clinic of the Brazilian Unified Health System (UHS) and a multidisciplinary outpatient clinic of a private health plan (PHP). The inclusion criteria were age ≥ 18 years, ≥ 3 medical appointments, and follow‐up time ≥ 6 months. Results: Compared to PHP patients (n = 183), UHS patients (n = 276) were older (63.4 vs. 59.7 years, p = 0.04), had more arterial hypertension (AH) (91.7% vs. 84.7%, p = 0.02) and dyslipidemia (58.3 vs. 38.3%, p < 0.01), and had a lower estimated baseline glomerular filtration rate (eGFR) (29.9 [21.5–42.0] vs. 39.1 [28.6–54.8] mL/min/1.73 m2, p < 0.01). Compared to PHP patients, UHS patients had a lower percentage of diabetics with glycated hemoglobin < 7.5% (46.1% vs. 61.2%, p = 0.03), fewer people with potassium < 5.5 mEq/L (90.4% vs. 95.6%, p = 0.04), and fewer referrals for hemodialysis with functioning arteriovenous fistula (AVF) (9.1% vs. 54.3%, p < 0.01). The percentages of people with hypertension and blood pressure < 140 × 90 mmHg were similar between the UHS and PHP groups (59.7% vs. 66.7%; p = 0.17), as was the percentage of people with parathyroid hormone control (85.6% vs. 84.8%; p = 0.83), dyslipidemia and LDL‐cholesterol < 100 mg/dL (38.3% vs. 49.3%; p = 0.13), phosphorus < 4.5 mg/dL (78.5% vs. 72.0%; p = 0.16), and 25‐OH‐vitamin‐D > 30 ng/mL (28.4% vs. 36.5%; p = 0.11). The crude reduction in eGFR was greater in the UHS group than in PHP (2.3 [−0.1; 5.9] vs. 1.1 [−1.9; 4.6] mL/min/1.73 m2; p < 0.01). In the multivariate linear mixed‐effects model, UHS patients also showed faster CKD progression over time than PHS ones (group effect, p < 0.01; time effect, p < 0.01; interaction, p < 0.01). Conclusions: Quality of care for patients with CKD can be improved through both services, and multidisciplinary care may have a positive impact on the control of comorbidities, the progression of CKD, and the planning of the initiation of hemodialysis. [ABSTRACT FROM AUTHOR]

Background: Subclinical hypothyroidism (SCH) is characterized by elevated levels of thyroid hormone (TSH) and normal levels of free thyroxine (FT4). The outcomes of SCH patients are crucial for determining treatment plans; therefore, our aim is to summarize the existing prospective studies to understand the changes in thyroid function over time in SCH patients and the factors influencing these changes, providing references for clinical diagnosis and treatment. Methods: We searched PubMed, Embase, Cochrane Library, and Web of Science for prospective follow-up studies on natural outcomes of SCH published until September 2024. Results are presented as the overall risk ratio (RR) and 95% confidence intervals (CI). Results: We reviewed 8 prospective follow-up studies involving 1,859 individuals and extracted data from them for a meta-analysis. We found that when TSH levels are ≥ 10 mU/L, patients with SCH are more likely to progress to overt hypothyroidism (OH) (RR11.38, 95%CI 4.98–26.03, P<0.001) and were less likely to return to normal TSH levels (RR 0.20, 95%CI 0.09–0.42, P<0.001) compared to patients with TSH between 4.5 and 9.9 mU/L. In addition, patients who test positive for thyroid peroxidase antibodies (TPOAb) are more likely to progress to OH (RR 2.53, 95% CI 1.86–3.44, P < 0.001) and less likely to return to euthyroidism (RR 0.68, 95% CI 0.60–0.76, P < 0.001) compared to TPOAb-negative patients. Conclusion: The results indicated that a large proportion of patients diagnosed with SCH will return to normal TSH levels or maintain SCH. Additionally, patients with TSH levels ≥ 10 mU/L or positive for TPOAb are more likely to experience progression and should be closely monitored. However, we did not find any gender differences in the natural outcome of SCH. [ABSTRACT FROM AUTHOR]

Purpose Methods Results Conclusion Patients with exudative and nonexudative age‐related macular degeneration (AMD) can experience physical, mental, social, administrative or financial burden that are associated with the treatment of this progressive chronic disease. The role of healthcare providers in supporting patients who experience high treatment burden can be important, especially when it comes to effective communication. Despite previous research underlining the need to improve patient‐provider communication in AMD care, patient experiences with communication, and how these are related to perceived treatment burden, remain underexplored.A survey was distributed among Dutch patients with AMD, which contained questions on several aspects of communication with the patient's ophthalmologist, such as the Quality Of communication Through the patients' Eyes (QUOTE‐COMM, including task‐, affect‐ and therapy‐oriented communication) questionnaire. Patients were primarily enlisted through a patient association.A total of 162 patients completed the questionnaire, of which 133 provided fully completed responses. While patients reported positive experiences with affect‐oriented communication of their ophthalmologist, they rated task‐ and therapy‐oriented communication as below their expectations. Most patients wished to receive (additional) information on AMD‐related costs (71%), future perspectives (71%) and coping with negative emotions pertaining to the disease (68%). Both lower experience scores on task‐ and affect‐oriented communication and lower self‐efficacy were associated with higher administrative burden and mental burden among patients.Our study shows that current communication, information provision and decision‐making do not fully meet patients' needs and preferences. Enhancing patient‐provider communication seems important, as effective dialogue is likely to diminish patients' perceived treatment burden. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) encompasses a long continuum from a preclinical phase, characterized by neuropathological alterations albeit normal cognition, to a symptomatic phase, marked by its clinical manifestations. Yet, the neural mechanisms responsible for cognitive decline in AD patients remain poorly understood. Here, we posit that anosognosia, emerging from an error-monitoring failure due to early amyloid-β deposits in the posterior cingulate cortex, plays a causal role in the clinical progression of AD by preventing patients from being aware of their deficits and implementing strategies to cope with their difficulties, thus fostering a vicious circle of cognitive decline. This article advances the view of anosognosia as a driver of cognitive decline in Alzheimer's disease, due to early amyloid-β deposits in the posterior cingulate cortex, with error-monitoring failure and patients' inability to counter their deficits. [ABSTRACT FROM AUTHOR]

Background: Pemphigus is a rare autoimmune disease characterized by the formation of blisters on the skin and mucous membranes, caused by autoantibodies against desmoglein, a key protein in cell adhesion. This study aims to compare demographic and clinical criteria between male and female patients with pemphigus referred to a referral hospital, utilizing data from the pemphigus diseases registry. Method: This retrospective cross‐sectional analysis focused on several key aspects age at disease onset, severity (measured by the Pemphigus Disease Area Index [PDAI]), types of pemphigus, duration of disease, and diagnostic criteria including the presence of antidesmoglein antibodies and findings from direct immunofluorescence (DIF). By examining these variables among a cohort selected based on their diagnosis of pemphigus, the study aimed to identify significant gender differences in disease manifestation, diagnosis, and progression. This approach is crucial for tailoring more effective gender‐specific management and treatment strategies for this rare autoimmune condition. Results: In a comprehensive analysis of 1218 pemphigus patients in the year 2021 from the hospital's registry, comprising 543 males (44.6%) and 675 females (55.4%), significant gender differences were identified in 9 out of 44 variables examined. The study revealed that males had a higher age at disease onset, more frequent clinical manifestations in the head, neck, and trunk areas, and greater severity of disease as measured by the PDAI score compared to females. Conversely, females exhibited higher instances of mucosal manifestations and a higher PDAI score for mucosal erosion blister of the lower gingiva. No significant gender differences were found in 21 variables, including the overall age of patients, specific clinical manifestations across various mucous membranes, types of pemphigus, and PDAI scores for mucosal erosions in particular locations, indicating a nuanced gender impact on the presentation and severity of pemphigus that necessitates tailored clinical approaches. Conclusion: The study highlights significant gender differences in the presentation and severity of pemphigus, underscoring the importance of gender‐specific approaches in the diagnosis and management of this condition. The findings contribute valuable insights into the complex nature of pemphigus and underline the necessity for further research to understand the underlying mechanisms driving these differences. [ABSTRACT FROM AUTHOR]

Background: Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of "omics" data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF. Methods: The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell's C-index (for time-to-event outcomes) or area under the curve (for binary outcomes). Results: Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes. Conclusions: We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models. Trial registration: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.clinicaltrials.gov. [ABSTRACT FROM AUTHOR]

Background: Hepatitis B remains a significant global health concern with widespread communicability. Nevertheless, data on its burden and trends in children and adolescents were limited. We aim to evaluate the global, regional, and national trends of total burden related to hepatitis B in children and adolescents aged 0–19 years from 1990 to 2021. Methods: The age-standardized incidence, prevalence, mortality, and disability-adjusted life years (DALYs) were calculated by the Global Burden of Disease (GBD) study from 1990 to 2021. These indicators were stratified by sex, age, socio-demographic index (SDI), and disease stage. We calculated the correlation between them and SDI. The temporal trends were examined using the annual average percentage change (AAPC) and joinpoint regression. Results: The global age-standardized incidence of hepatitis B in children and adolescents decreased from 1385.20 per 100,000 population in 1990 to 418.68 per 100,000 population in 2021, with an AAPC of -3.76%. Similarly, age-standardized DALYs decreased from 70.78 per 100,000 population to 36.31 per 100,000 population, with an AAPC of -2.13%. The age-standardized prevalence (AAPC − 3.53%) and mortality (AAPC − 2.09%) of hepatitis B also decreased significantly. From 1990 to 2021, the age-standardized incidence and prevalence among males exhibited a higher trend compared to females, although both declined over time. These two indicators also decreased across all age subgroups, with consistently higher rates observed in the 15–19 age group compared to other age groups. The burden of hepatitis B demonstrated a notable reduction in countries with high-middle SDI, while it was highest in countries with low SDI. In 2021, Central sub-Saharan Africa and West sub-Saharan Africa reported the highest age-standardized incidence. For age-standardized DALYs, South Asia was the only region to experience an increase (AAPC 1.09%), while East Asia showed the largest decline (AAPC − 7.58%). Alcohol and drug use remained important risk factors for DALYs among people aged 15–19 years. Furthermore, the impact of drug use on disease burden was increasing, particularly in high-SDI countries. Conclusions: The global burden and trends of hepatitis B decreased significantly in children and adolescents, exhibiting regional and national variations. Management of alcohol and drug use remains a major challenge for people aged 15–19 years. [ABSTRACT FROM AUTHOR]

Epicardial adipose tissue (EAT) significantly contributes to the progression of cardiovascular diseases (CVDs). However, manually quantifying EAT volume is labor-intensive and susceptible to human error. Although there have been some deep learning-based methods for automatic quantification of EAT, they are mostly uninterpretable and fail to harness the complete anatomical characteristics. In this study, we proposed an enhanced deep learning method designed for EAT quantification on coronary computed tomography angiography (CCTA) scan, which integrated both data-driven method and specific morphological information. A total of 108 patients who underwent routine CCTA examinations were included in this study. They were randomly assigned to training set (n = 60), validation set (n = 8), and test set (n = 40). We quantified and calculated the EAT volume based on the CT attenuation values within the predicted pericardium. The automatic method demonstrated strong agreement with expert manual quantification, yielding a median Dice score coefficients (DSC) of 0.916 (Interquartile Range (IQR): 0.846–0.948) for 2D slices. Meanwhile, the median DSC for the 3D volume was 0.896 (IQR: 0.874–0.908) between these two measures, with an excellent correlation of 0.980 (p < 0.001) for EAT volumes. Additionally, our model's Bland-Altman analysis revealed a low bias of -2.39 cm³. The incorporation of pericardial anatomical structures into deep learning methods can effectively enhance the automatic quantification of EAT. The promising results demonstrate its potential for clinical application. [ABSTRACT FROM AUTHOR]

Background and Objective Methods Results Conclusion Chronic obstructive pulmonary disease (COPD) exhibits diverse patterns of disease progression, due to underlying disease activity. We hypothesized that changes in static hyperinflation or KCO % predicted would reveal subgroups with disease progression unidentified by preestablished markers (FEV1, SGRQ, exacerbation history) and associated with unique baseline biomarker profiles. We explored 18‐month measures of disease progression associated with 18–54‐month mortality, including changes in hyperinflation parameters and transfer factor, in a large German COPD cohort.Analysing data of 1364 patients from the German observational COSYCONET‐cohort, disease progression and improvement patterns were assessed for their impact on mortality via Cox hazard regression models. Association of biomarkers and COPD Assessment test items with phenotypes of disease progression or improvement were evaluated using logistic regression and random forest models.Increased risk of 18–54‐month mortality was linked to decrease in KCO % predicted (7.5% increments) and FEV1 (20 mL increments), increase in RV/TLC (2% increments) and SGRQ (≥6 points), and an exacerbation grade of 2 at 18 months. Decrease in KCO % predicted ≥7.5% and an increase of RV/TLC ≥2% were the most frequent measures of 18‐month disease progression occurring in ~52% and ~46% of patients, respectively. IL‐6 and CRP thresholds exhibited significant associations with medium‐ and long‐term disease measures.In a multicentric cohort of COPD, new markers of current disease activity predicted mid‐term mortality and could not be anticipated by baseline biomarkers. [ABSTRACT FROM AUTHOR]

Aim Method Results Conclusion Recently, substantial studies have been accumulated to indicate the important role of gut microbiota in diabetic kidney disease (DKD). The abnormal change of bacterial‐derived products could imply specific injuries or play beneficial or harmful roles in DKD progression. In this study, we examined the presence and contribution of the Klebsiella oxytoca gene in the circulation of patients with DKD.We enrolled a total of 16 healthy participants, 17 patients with DKD, 5 patients with DKD requiring haemodialysis (HD), and 7 patients with CKD without diabetes. Bacterial‐derived DNA (16S rDNA and a specific K. oxytoca gene) in the blood was detected using droplet digital PCR, then investigated the relationship with clinical characteristics.We identified an increase in K. oxytoca genes in the blood of DKD patients. Interestingly, blood K. oxytoca copies and K. oxytoca/ 16S DNA ratio correlated with higher blood creatinine and BUN levels together with lower eGFR in DKD patients. K. oxytoca levels were also associated with higher neutrophil percentage, lower lymphocyte frequency, and increased neutrophil‐to‐lymphocyte ratio.Collectively, the presence of the K. oxytoca gene in the circulation could serve as a biomarker reflecting reduced renal function in DKD patients. [ABSTRACT FROM AUTHOR]

Background and Purpose Methods Results Conclusions Despite the wide use of dopamine receptor blocking agents (DRBAs) in Huntington disease (HD), neuroleptic malignant syndrome (NMS) is rarely described in this population. The aim of this study was to assess NMS prevalence in a large cohort of HD patients and explore the main associated risk factors.In 2023, an HD patient was admitted to our neurology department due to NMS. Starting from the case description, we performed a narrative review of the literature of NMS cases in HD, reviewed data from the fifth dataset of the Enroll‐HD (a longitudinal, observational, global study of families with HD) study (PDS5) selecting HD patients treated with DRBAs and/or tetrabenazine (TBZ) who presented at least one of the core symptoms of NMS (rigidity and hyperthermia), and collected data to investigate prevalence of NMS and identify risk factors.In the Enroll‐HD PDS5 dataset, we identified 5108 of 11,569 HD patients who were undergoing DRBA and/or TBZ treatment. Only one patient, a Caucasian man of 46 years, undergoing clozapine and valproate treatment, had a registered diagnosis of NMS.NMS in HD patients is seldom described. This could be due to an underestimation of this condition. There are no available objective NMS diagnostic criteria at present, and the existence of atypical forms of NMS further complicates diagnosis. Advanced disease stage, rigid–akinetic phenotype, abrupt therapy changes, polytherapy, and dehydration are key risk factors, most of which are preventable through awareness and caution in managing medications in the HD population. [ABSTRACT FROM AUTHOR]

Cytomegalovirus (CMV) commonly infects immunocompromised individuals, such as cancer patients. We present a case involving a 60‐year‐old male with Stage 3A lung adenocarcinoma and chronic obstructive pulmonary disease (COPD) diagnosed with CMV tracheobronchitis, initially suspected as cancer progression. Treatment with ganciclovir led to partial improvement in symptoms of shortness of breath and cough, as well as bronchoscopic findings. However, due to ganciclovir‐induced neutropenia, the therapy was switched to foscarnet. Distinguishing between cancer progression and infectious tracheobronchitis through physical examination and chest CT scans remains challenging. In lung cancer patients presenting with airway and bronchial narrowing along with ulcerative mucosal lesions, CMV infection should be considered. A bronchoscopic biopsy is crucial for accurate diagnosis and determining the appropriate treatment in these patients. [ABSTRACT FROM AUTHOR]

Background: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant tumors, with high incidence and poor prognosis. Revealing mechanisms of ESCC progression and developing new therapeutic targets remains crucial. The aim of this study was to elucidate the molecular mechanism of miR‐30c‐5p in regulating the malignant progression of ESCC. Methods: TCGA, GEO, and other datasets were used to analyze the differential expression of miR‐30c‐5p in ESCC and adjacent tissues, and its impact on prognosis. Then the effects of miR‐30c‐5p on the proliferation, migration, and invasion of TE‐1 and Eca9706 cells were investigated through proliferation experiments, transwell and wounding healing assays. The regulatory mechanism of miR‐30c‐5p on the PI3K/AKT signaling pathway and its interaction in cancer progression were investigated through Western blots, dual‐luciferase reporter assay, and rescue experiments. Results: miR‐30c‐5p was significantly downregulated in ESCC tissue and represented a poor prognosis. miR‐30c‐5p mimic significantly inhibited the proliferation, migration, and invasion ability of ESCC, while miR‐30c‐5p inhibitor significantly promoted tumor cell progression. Through bioinformatic analysis and experimental results, miR‐30c‐5p interacted directly with PIK3CA mRNA and inhibited subsequent signaling pathway activation. PIK3CA activator could eliminate the inhibitory effects of miR‐30c‐5p mimic on the progression of ESCC, while PIK3CA inhibitors could rescue the promoting effect of miR‐30c‐5p inhibitor group cells. Conclusions: In summary, we found that miR‐30c‐5p inhibited the proliferation, invasion and migration of ESCC by inhibiting PI3K/AKT signaling pathway for the first time, and this study is expected to provide a novel insight and potential therapeutic target for managing ESCC. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac amyloidosis is a rarely reported and potentially fatal variant of the systemic disease. Its early diagnosis could potentially lead to significantly improved clinical outcomes. Case presentation: A 56-year-old female presented with dyspnea and palpitations. Her physical exam and non-invasive evaluation with cardiac magnetic resonance imaging (CMRI) revealed restrictive cardiomyopathy, and the bone marrow biopsy results showed systemic amyloidosis. Discussion: The diagnosis of cardiac amyloidosis is not always straightforward, and delay can cause the progression of the disease and an increased risk of morbidity and mortality. Electrocardiograms, echocardiograms, cardiac magnetic resonance imaging, and histopathologic evaluation are the main methods for diagnosing cardiac amyloidosis. The treatment consists of controlling heart failure symptoms and disease-modifying interventions, including medical and surgical therapeutic methods. Clinical learning point (conclusion): Cardiac involvement is the main cause of death in systemic amyloidosis. Early suspicion, diagnosis, and treatment are crucial in improving patients' survival. CMRI can play an essential role in the diagnosis of cardiac Amyloidosis. A graphical abstract is provided for visual summary. [ABSTRACT FROM AUTHOR]

ABSTRACT Sarcopenia, as a disease characterized by progressive decline of quality, strength, and function of muscles, has posed an increasingly significant threat to the health of middle‐aged and elderly individuals in recent years. With the continuous deepening of studies, the concept of gut–muscle axis has attracted widespread attention worldwide, and the occurrence and development of sarcopenia are believed to be closely related to the composition and functional alterations of gut microbiota. In this review, combined with existing literatures and clinical reports, we have summarized the role and impacts of gut microbiota on the muscle, the relevance between gut microbiota and sarcopenia, potential mechanisms of gut microbiota in the modulation of sarcopenia, potential methods to alleviate sarcopenia by modulating gut microbiota, and relevant advances and perspectives, thus contributing to adding more novel knowledge to this research direction and providing certain reference for future related studies. [ABSTRACT FROM AUTHOR]

Enteric glia are a heterogeneous population of peripheral glia within the enteric nervous system and play pivotal roles in gut homeostasis, tissue integrity, coordination of motility, and intestinal immune responses. Under physiological conditions, they communicate with enteric neurons to control intestinal motility. In contrast, enteric glia undergo reactive changes in response to inflammatory signals during enteric neuroinflammation and participate in immune control. In this state, these glia are called reactive enteric glia, which promote cytokine and chemokine secretion and perpetuate immune cell recruitment, thereby affecting disease progression. Interestingly, reactive glia exhibit a huge plasticity and adapt to or shape the immune environment towards a resolving phenotype during inflammation and neuropathies. Recent studies revealed a bidirectional communication between enteric glia and resident and infiltrating immune cells under healthy conditions and in the context of inflammation‐based intestinal disorders and neuropathies. While recent reviews give a superb general overview of enteric glial reactivity, we herein discuss the latest evidence on enteric glial reactivity in two prominent inflammatory conditions: acute postoperative inflammation, resulting in postoperative ileus, and chronic inflammation in inflammatory bowel diseases. We define their plasticity during inflammation and the interplay between reactive enteric glia and intestinal macrophages. Finally, we sketch important questions that should be addressed to clarify further the impact of enteric glial reactivity on intestinal inflammation. [ABSTRACT FROM AUTHOR]

Background Objectives Methods Results Conclusions Huntington's Disease is a rare neurodegenerative disorder in which appropriate medication management is essential. While many medications are prescribed based on expert knowledge, overviews of actual medication use in HD are sparse.We provide a detailed overview of medication use and associated indications across HD disease stages, considering sex and regional differences.Data from the largest observational HD study, ENROLL‐HD, were used. We created HD‐related medication and indication classes to identify medication trends in manifest, premanifest and control subjects. We studied medication use in adult, childhood‐ and adolescent‐onset HD, incorporating disease stage (including phenoconverters), sex and regional differences.In 8546 manifest HD patients, 84.6% used medication (any type), with the average number of medications per user rising from 2.5 in premanifest HD to 5.2 in end stage disease. Antipsychotics (29.2%), SSRIs (27.5%) and painkillers (21.8%) were most often used. Medication use varied with disease progression. Several differences were observed between the sexes, and notably between Europe and Northern America as well. Medication use increased after phenoconversion (from 64.8% to 70.6%, P < 0.05), with the largest difference in antipsychotic use (4.4%–7.8%, P < 0.05). Medication patterns were different in childhood‐onset HD, with no use of painkillers, less use of anti‐chorea and antidepressant drugs, and more for aggression and irritability.Medication use in HD increases with disease progression, with varying types of medications prescribed based on disease stage, sex, and region of living. Recognizing these medication trends is vital for further personalized HD management. [ABSTRACT FROM AUTHOR]

Introduction: Early-onset Alzheimer's disease (EOAD) is sporadic, highly heterogeneous, and its underlying pathogenic mechanisms remain largely elusive. Proteomics research aims to uncover the biological processes and key proteins involved in disease progression. However, no proteomic studies to date have specifically focused on EOAD brain tissue. Method: We integrated proteomic data from brain tissues of two Alzheimer's disease (AD) cohorts and constructed a protein co-expression network using weighted gene co-expression network analysis (WGCNA). We identified modules associated with EOAD, conducted functional enrichment analysis to understand the biological processes involved in EOAD, and pinpointed potential key proteins within the core modules most closely linked to AD pathology. Results: In this study, we identified a total of 2,749 proteins associated with EOAD. Through protein co-expression network analysis, we discovered 41 distinct co-expression modules. Notably, the proteins within the core module most closely linked to AD pathology were significantly enriched in neutrophil degranulation. Additionally, we identified two potential key proteins within this core module that have not been previously reported in AD and validated their expression levels in 5xFAD mice. Conclusion: In summary, through a protein co-expression network analysis, we identified EOAD-related biological processes and molecular pathways, and screened and validated two key proteins, ERBB2IP and LSP1. These proteins may play an important role in the progression of EOAD, suggesting they could serve as potential therapeutic targets for the disease. [ABSTRACT FROM AUTHOR]

Introduction: Parkinson's Disease affects over 8.5 million people and there are currently no medications approved to treat underlying disease. Clinical trials for disease modifying therapies (DMT) are hampered by a lack of sufficiently sensitive measures to detect treatment effect. Reliable digital assessments of motor function allow for frequent at-home measurements that may be able to sensitively detect disease progression. Methods: Here, we estimate the test-retest reliability of a suite of at-home motor measures derived from raw triaxial accelerometry data collected from 44 participants (21 with confirmed PD) and use the estimates to simulate digital measures in DMT trials. We consider three schedules of assessments and fit linear mixed models to the simulated data to determine whether a treatment effect can be detected. Results: We find at-home measures vary in reliability; many have ICCs as high as or higher than MDS-UPDRS part III total score. Compared with quarterly in-clinic assessments, frequent at-home measures reduce the sample size needed to detect a 30% reduction in disease progression from over 300 per study arm to 150 or less than 100 for bursts and evenly spaced at-home assessments, respectively. The results regarding superiority of at-home assessments for detecting change over time are robust to relaxing assumptions regarding the responsiveness to disease progression and variability in progression rates. Discussion: Overall, at-home measures have a favorable reliability profile for sensitive detection of treatment effects in DMT trials. Future work is needed to better understand the causes of variability in PD progression and identify the most appropriate statistical methods for effect detection. [ABSTRACT FROM AUTHOR]

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis (ALS) affect millions and present significant challenges in healthcare and treatment costs. The debate in the field pivots around two hypotheses: synaptic spread and selective vulnerability. Pioneers like Virginia Lee and John Trojanowski have been instrumental in identifying key proteins (tau, alpha-synuclein, TDP-43) central to these diseases. The synaptic spread hypothesis suggests a cell-to-cell propagation of pathogenic proteins across neuronal synapses, influencing disease progression, with studies highlighting the role of proteins like alpha-synuclein and amyloid-beta in this process. In contrast, the selective vulnerability hypothesis proposes inherent susceptibility of certain neurons to degeneration due to factors like metabolic stress, leading to protein aggregation. Recent advancements in neuroimaging, especially PET/MRI hybrid imaging, offer new insights into these mechanisms. While both hypotheses offer substantial evidence, their relative contributions to neurodegenerative processes remain to be fully elucidated. This uncertainty underscores the necessity for continued research, with a focus on these hypotheses, to develop effective treatments for these devastating diseases. [ABSTRACT FROM AUTHOR]

Introduction: Diabetic Kidney Disease (DKD) is the main cause of end-stage renal disease in the developed world. The current treatment of the DKD with reninangiotensin system (RAS) blockade does not totally halt the progression to end stage kidney disease. Currently, several drugs have shown to delay DKD progression such as sodium-glucose co-transporter-2 inhibitors (SGLT2i) and glucagon-like-1 receptor agonists (GLP-1RA). We hypothesized that by combining several drugs that prevent DKD progression on top of RAS blockade a synergistic effect would be achieved in terms of cardiorenal protection. In the present study, we analysed if the combination of a RAS blocker (ramipril) with a SGLT2i (empagliflozin) and/or GLP-1RA (semaglutide) in a type 2 diabetic mouse model could have add-on effects in kidney and heart protection. Methods: Male and female uninephrectomized type 2 diabetic db/db mice were treated with empagliflozin and/or semaglutide on top of ramipril during 8 weeks. During the study body weight, water and food intake were weekly monitored, glycaemia biweekly and albuminuria and glomerular filtration rate (GFR) before and after the treatment. At the end of the experiment, kidney and heart were isolated for histological and gene expression studies as well as for intrarenal RAS state assessment. Results: Semaglutide combined with ramipril and/or empagliflozin significantly decreased albuminuria but only when combined with both compounds, semaglutide further decreased blood glucose, glomerular hyperfiltration in male mice and glomerular mesangial matrix expansion. In kidney, only the triple treatment with empagliflozin, semaglutide and ramipril reduced the expression of the proinflammatory and profibrotic genes ccl2 and TGFß1. In addition, the combination of empagliflozin and semaglutide on top of RAS blockade was superior in decreasing cardiomyocyte hypertrophy and heart fibrosis in db/db mice. Discussion: Our results suggest that the combination of SGLT2i with GLP-1RA is superior in cardiorenal protection in DKD than the drugs administered alone on top of RAS blockade. [ABSTRACT FROM AUTHOR]

Introduction: The majority of patients with mycosis fungoides (MF) have an indolent disease course, but a substantial fraction (20-30%) of patients progress to advanced stages - usually with a grave prognosis. Early differentiation between indolent and aggressive types of MF is important for the choice of treatment regimen and monitoring of the individual patient. Good biomarkers are therefore desired. Methods: Here, we used spatial transcriptomics on skin samples at time-of-diagnosis to enable prediction of patients who later progressed to advanced stages of MF. Formalin-fixed, paraffin-embedded skin biopsies at time of diagnosis from six patients with MF who progressed to advanced stages of disease within 4 months to 12 years after diagnosis, and nine patients who remained in early-stage disease over 9 to 27 years were analyzed using the GeoMx Digital Spatial Profiler to capture spatially resolved high-plex RNA gene expression data. Five different regions of interest (the epidermis, the basal layer of epidermis, CD4+ T-cells and neighboring cells, and Pautrier's microabscesses) were profiled for further assessment. Results and discussion: Interestingly, RUNX2, SHMT2, and MCM7 were upregulated in the enriched population of malignant T-cells in Pautrier's microabscesses in patients who later developed advanced stages of disease. Expression of RUNX2, SHMT2 and MCM7 in malignant T-cells was confirmed in a subset of patients in MF skin using scRNA-seq datasets across multiple studies and correlating with stage of disease. Taken together, we provide first evidence that RUNX2 has potential as a biomarker to identify MF patients progressing to advanced stage disease. As RUNX2 has not previously been linked to MF, our data also shows the analytical strength of combining spatial transcriptomics with scRNA-seq analysis. [ABSTRACT FROM AUTHOR]

The brain is a complex non-equilibrium system capable of expressing many different dynamics as well as the transitions between them. We hypothesized that the level of non-equilibrium can serve as a signature of a given brain state, which was quantified using the arrow of time (the level of irreversibility). Using this thermodynamic framework, the irreversibility of emergent cortical activity was quantified from local field potential recordings in male Lister-hooded rats at different anesthesia levels and during the sleep-wake cycle. This measure was carried out on five distinct brain states: slow-wave sleep, awake, deep anesthesia–slow waves, light anesthesia–slow waves, and microarousals. Low levels of irreversibility were associated with synchronous activity found both in deep anesthesia and slow-wave sleep states, suggesting that slow waves were the state closest to the thermodynamic equilibrium (maximum symmetry), thus requiring minimum energy. Higher levels of irreversibility were found when brain dynamics became more asynchronous, for example, in wakefulness. These changes were also reflected in the hierarchy of cortical dynamics across different cortical areas. The neural dynamics associated with different brain states were characterized by different degrees of irreversibility and hierarchy, also acting as markers of brain state transitions. This could open new routes to monitoring, controlling, and even changing brain states in health and disease. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the agreement of ocular biometry measured using a swept-source optical coherence (Casia 2) and a dual Scheimpflug (Galilei G6) tomography in keratoconus. Methods: This retrospective study included 102 eyes from 102 keratoconus patient examined using both devices. Parameters compared included flat (Kf) and steep (Ks) keratometry, astigmatism of anterior, posterior, and total keratometry, central (CCT) and thinnest (TCT) corneal thickness. To assess the agreement, intraclass coefficient (ICC) and Bland-Altman analysis with 95% limits of agreement (LoA) were used. Results: Anterior and total Ks and Kf showed moderate or good agreement with 95% limits of agreement (LoA) range over 9.75 D. Posterior Ks and Kf were lower in the Galilei G6 (all p < 0.001). Astigmatism showed moderate, poor, and moderate agreement for anterior, posterior, and total keratometry, respectively. CCT and TCT showed excellent agreement; however, the 95% LoA range was over 60 μm. Conclusion: The agreement between the two devices was not excellent for most parameters used to diagnose keratoconus and assess disease progression, and the differences were clinically significant. Therefore, the measurements from these two devices are not interchangeable for patients with keratoconus. [ABSTRACT FROM AUTHOR]

The study was to evaluate the clinical outcomes of azvudine versus nirmatrelvir-ritonavir against omicron strains of coronavirus disease 2019 infections and determine their comparative effectiveness. This retrospective study included 716 patients who received nirmatrelvir-ritonavir (NR group) or azvudine (FNC group) at Peking Union Medical College Hospital between 1 November 2022 and 27 February 2023. Patients in the FNC group (n = 304) were younger, exhibited less severe symptoms, started antiviral therapy later, received corticosteroids more frequently, and used tocilizumab less frequently than patients in the NR group (n = 412). Within 28 d of therapy, 40 (9.7%) and 20 (6.6%) deaths were in the NR and FNC groups, respectively. No differences were observed between drugs and mortality rates (odds ratio [OR] 0.78, 95% CI 0.40–1.5, P = 0.45), clinical improvement (OR 0.79, 95% CI 0.79–1.3, P = 0.38), and clinical progression (OR 1.0, 95% CI 0.58–1.8, P = 0.96). More patients in the NR group experienced platelet decline than those in the FNC group (17.6% vs. 8.9%, P = 0.034). This study indicated that the effectiveness and safety of azvudine were comparable to those of nirmatrelvir-ritonavir. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an age-related neurodegenerative disorder with regulatory RNAs playing significant roles in its etiology. Circular RNAs (CircRNA) are enriched in human brains and contribute to AD progression. Many circRNA isoforms derived from same gene loci share common back splicing sites, thus often form clusters and work as a group to additively regulate their downstream targets. Unfortunately, the coordinated role of clustered circRNAs is often overlooked in individual circRNA differential expression (DE) analysis. To address these challenges, we develop circMeta2, a computational tool designed to perform DE analysis focused on circRNA clusters, equipped with modules tailored for both a small sample of biological replicates and a large-scale population study. Using circMeta2, we identify brain region-specific circRNA clusters from six distinct brain regions in the ENCODE datasets, as well as brain region-specific alteration of circRNA clusters signatures associated with AD from Mount Sinai brain bank (MSBB) AD study. We also illustrate how AD-associated circRNA clusters within and across different brain regions work coordinately to contribute to AD etiology by impacting miRNA-mediated gene expression and identified key circRNA clusters that associated with AD progression and severity. Our study demonstrates circMeta2 as a highly accuracy and robust tool for analyzing circRNA clusters, offering valuable molecular insights into AD pathology. circMeta2 performs differential expression analysis for clustered circRNAs. Using this tool, the authors identify brain region-specific circRNA clusters in healthy controls, as well as their key dysregulations associated with Alzheimer's Disease progression. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation Despite the advances in treatments for multiple sclerosis (MS), unremitting neurodegeneration continues to drive disability and disease progression. Smoldering/slowly expanding lesions (SELs) and dysfunction of the RNA binding protein (RBP) heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) are pathologic hallmarks of MS cortex and intricately tied to disability and neurodegeneration, respectively. We hypothesized that neuronal hnRNP A1 dysfunction contributes to neurodegeneration and is exacerbated by smoldering/SELs in progressive MS.Neuronal hnRNP A1 pathology (nucleocytoplasmic mislocalization of hnRNP A1) was examined in healthy control and MS brains using immunohistochemistry. MS cases were stratified by severity of hnRNP A1 pathology to examine the link between RBP dysfunction, demyelination, and neurodegeneration.We found that smoldering/SELs were only present within a subset of MS tissues characterized by elevated neuronal hnRNP A1 pathology (MS‐A1high) in adjacent cortical gray matter. In contrast to healthy controls and MS with low hnRNP A1 pathology (MS‐A1low), MS‐A1high showed elevated markers of neurodegeneration, including neuronal loss and injury, brain atrophy, axonal loss, and axon degeneration. Additionally, we discovered a subpopulation of morphologically intact neurons lacking expression of NeuN, a neuron‐specific RBP, in cortical projection neurons in MS‐A1high cases.hnRNP A1 dysfunction contributes to neurodegeneration and may be exacerbated by smoldering/SELs in progressive MS. The discovery of NeuN‐negative neurons suggests that some cortical neurons may only be injured and not lost. By characterizing RBP pathology in MS cortex, this study has important implications for understanding the pathogenic mechanisms driving neurodegeneration, the substrate of disability and disease progression. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

• Entropy encompasses a popular set of methods for nonlinear brain data analysis. • Alzheimer's disease is associated with changes in brain activity patterns. • Entropy-based features could be valuable to screen Alzheimer's disease patients. Alzheimer's disease (AD) is a prevalent and debilitating neurodegenerative disease that leads to substantial loss of quality of life. Therapies currently available for AD do not modify the disease course and have limited efficacy in symptom control. As such, novel and precise therapies tailored to individual patients' neurophysiologic profiles are needed. Functional neuroimaging tools have demonstrated substantial potential to provide quantifiable insight into brain function in various neurologic disorders, particularly AD. Entropy, a novel analysis for better understanding the nonlinear nature of neurophysiological data, has demonstrated consistent accuracy in disease detection. This literature review characterizes the use of entropy-based analyses from functional neuroimaging tools, including electroencephalography (EEG) and magnetoencephalography (MEG), in patients with AD for disease detection, therapeutic response measurement, and providing clinical insights. [ABSTRACT FROM AUTHOR]

Progressive Supranuclear Palsy (PSP) is a rare and fatal neurodegenerative tauopathy which, with a rapid clinical progression coupled to a strong degree of clinico-pathologic correlation, has been suggested to be a "frontrunner" in translational development for neurodegenerative proteinopathies. Elegant studies in animals have contributed greatly to our understanding of disease pathogenesis in PSP. However, presently no animal model replicates the key anatomical and cytopathologic hallmarks, the spatiotemporal spread of pathology, progressive neurodegeneration, or locomotor and cognitive symptoms that characterize PSP. Current models therefore likely fail to recapitulate the key mechanisms that underly the pathological progression of PSP, impeding their translational value. Here we review what we have learned about PSP from work in animals to date, examine the gaps in modeling the disease and discuss strategies for the development of refined animalmodels that will improve our understanding of disease pathogenesis and provide a critical platform for the testing of novel therapeutics for this devastating disease. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune encephalitis (AE) comprises a group of inflammatory brain disorders mediated by autoimmune responses. Anti-N-methyl-Daspartate receptor (NMDAR) encephalitis, anti-leucine-rich glioma-inactivated 1 (LGI1) encephalitis, and anti-g-aminobutyric acid-B receptor (GABABR) encephalitis are the most prevalent forms, characterized by the presence of antibodies against neuronal cell-surface antigens. Efgartigimod, an antagonist of the neonatal Fc receptor, has proven efficacy in myasthenia gravis treatment. This clinical case report describes the clinical progression and functional outcomes of AE in three patients who received efgartigimod treatment. Case presentations: Case 1 was a 60-year-old man exhibiting memory impairment and psychiatric disturbances over 11 days. Case 2 was a 38-yearold man with a 1-month history of rapid cognitive decline and seizures. Case 3 was a 68-year-old woman with mental behavioral changes and seizures for 4 months. Anti-GABABR, anti-LGI1, and anti-NMDAR antibodies were confirmed in the respective patients' cerebrospinal fluid or serum. All three patients experienced marked and swift symptomatic relief after four cycles of efgartigimod treatment, with no complication. Conclusion: Current first-line and second-line treatments for AE have limitations, and efgartigimod has demonstrated potential in the rapid and efficacious treatment of AE, emerging as a promising option for the management of this disease. [ABSTRACT FROM AUTHOR]

This narrative review aims specifically to explore the relationship between tobacco exposure and systemic sclerosis (SSc), idiopathic inflammatory myositis (IIM), and systemic lupus erythematosus (SLE). Relevant articles were obtained by searching key terms such as "tobacco," "smoking," "scleroderma," "myositis," "lupus," and "Sjögren's" in PubMed and Google Scholar databases. The selected articles ranged from the years 2010 to 2023. Inclusion criteria were based on the relevance and contribution to the field of study. Systemic sclerosis is a complex condition involving multiple immune cell lines that can be influenced by tobacco. However, the existing literature does not provide sufficient evidence to support an increased risk of SSc in smokers or the impact on treatment options. Cigarette smoking does increase the risk of skin ulcerations in SSc patients. In addition, cigarette smoking has been associated with IIM through genetic and molecular mechanisms. Smokers with dermatomyositis or polymyositis are at an elevated risk of atherosclerosis and interstitial lung disease. Similarly, smoking in patients with SLE increases the risk of organ damage, thrombosis, and disease severity compared with non-smokers. Smokers with SLE also have more difficulty in controlling disease flares compared with non-smokers. Tobacco exposure can lead to secondary complications in patients with IIM and SLE, although the course of treatment may not differ significantly. No definitive conclusions can be drawn to the clear relationship between tobacco smoking and Sjögren's's syndrome. [ABSTRACT FROM AUTHOR]

Background: There has been significant improvement in treating metastatic non–small-cell lung cancer (mNSCLC) over the past 2 decades. The aim of this study is to describe the use of tyrosine kinase inhibitors (TKIs) in Qatar. This study focuses on the objective response rate (ORR) and reported adverse drug events (ADEs) of TKIs used for the management of patients with mNSCLC. Methods: This is a descriptive retrospective cohort study. All non–small-cell lung cancers (NSCLCs) with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) mutations who received TKIs between 2015 and 2019 in Qatar were included. The TKIs used during this period include EGFR inhibitors such as afatinib, erlotinib, gefitinib, and osimertinib and ALK inhibitors such as alectinib and crizotinib. The response on each TKI was identified by reporting the ORR (as the sum of the complete response [CR] and the partial response [PR]), in addition stable disease (SD) and disease progression (DP) were reported. While ADEs were reported using the National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Results: A total of 63 patients were included, of which 36 cases (57.1%) expressed EGFR mutation, and 27 patients (42.9%) expressed ALK rearrangement. The ORR in EGFR inhibitors was as follows: osimertinib 40%, gefitinib 33%, afatinib 22%, and erlotinib 18%. However, the response to the ALK-targeted therapy was 43% with alectinib and 40% with crizotinib. A total of 112 ADEs were reported. They were distributed as 63.4% (71 of 112) with the anti-EGFR and 36.6% (41 of 112) ADEs with the ALK inhibitors. In the anti-EGFR group, the most common types of ADEs were dermatological toxicity 30%, whereas, in the anti-ALK group, gastrointestinal toxicity was the most common (29%). Conclusions: The EGFR-targeted and ALK-targeted therapies appear to have acceptable clinical response rate and safety profile in our population. Close and frequent monitoring of adverse events is advised to ensure a good quality of life and prevent serious complications. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) affects the hippocampus during its progression, but the specific observable changes of hippocampal subfields during disease progression remain poorly understood. In this study, we employed an event‐based model (EBM) to determine the sequence of occurrence of hippocampal subfield atrophy in mild cognitive impairment (MCI) and AD cohorts. Subjects (207) were included: 86 MCI, 53 AD, and 68 healthy controls from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Participants underwent structural magnetic resonance imaging (MRI) scans to analyse the hippocampal subfields. We assigned each patient to a specific EBM stage, based on the number of their abnormal subfields. A combination of 2‐year follow‐up MRI scans were applied to demonstrate the longitudinal consistency and utility of the model's staging system. The model estimated that the earliest atrophy occurs in the hippocampal fissure, then spreading to other subregions in both MCI and AD. We identified a marked divergence between the sequences of left and right hippocampal subfields atrophy, so inter‐hemispheric asymmetry pattern was further analysed. The sequence of asymmetry index (AI) increases beginning in the molecular and granule cell layers of the dentate gyrus (GC‐ML‐DG), cornus ammonis (CA) 4, and the molecular layer (ML). Longitudinal analysis confirms the efficacy of the model. In addition, the model stages were significantly correlated with patients' memory scores (p <.05). Collectively, we used a data‐driven method to provide new insight into AD hippocampal progression. The present model could aid in understanding of the disease stages, as well as tracking memory decline. [ABSTRACT FROM AUTHOR]

Anti-IgLON5 disease is a unique condition that bridges autoimmunity and neurodegeneration. Since its initial description 10 years ago, an increasing number of autopsies has led to the observation of a broader spectrum of neuropathologies underlying a particular constellation of clinical symptoms. In this study, we describe the neuropathological findings in 22 patients with anti-IgLON5 disease from 9 different European centers. In 15 patients (68%), we observed a hypothalamic and brainstem-predominant tauopathy of varying severity in which the original research neuropathological criteria were readily applicable. This pathology was observed in younger patients (median age at onset 61 years) with a long disease duration (median 9 years). In contrast, in 7 (32%) patients, the originally described brainstem tauopathy was nearly absent or only minimal in the form of delicate threads, despite mild-to-moderate neurodegenerative features, consistent clinical symptoms and the presence of anti-IgLON5 antibodies in CSF and serum. These patients were older at onset (median 79 years) and had shorter disease duration (median < 1 year). Overall, about one-third of the patients showed concomitant TDP-43 pathology within the regions affected by tau pathology and/or neurodegeneration. Based on these observations and in view of the spectrum of the tau burden in the core regions involved in the disease, we propose a simple staging system: stage 1 mild neurodegeneration without overt or only minimal tau pathology, stage 2 moderate neurodegeneration and mild/ moderate tauopathy and stage 3 prominent neurodegeneration and tau pathology. This staging intends to reflect a potential (age- and time-dependent) progression of tau pathology, supporting the current notion that tau accumulation is a secondary phenomenon related to the presence of anti-IgLON5 antibodies in the CNS. Finally, we adapt the original research criteria of the anti-IgLON5 disease-related tauopathy to include the spectrum of pathologies observed in this larger postmortem series. [ABSTRACT FROM AUTHOR]

Photoexcitation of cellular as well as isolated DNAs upon exposure to the UV portion of sunlight or other UV sources can lead to the covalent dimerization of adjacent intra‐strand stacked pyrimidine nucleobase rings (i.e., at 5′‐Py‐p‐Py‐3′ sites). These modifications generate, in mammalian DNA as well as the DNA of all other forms of life, lesions such as cyclobutane pyrimidine dimers (CPDs) and pyrimidine (6‐4) pyrimidone photoproducts (6‐4PPs); and, in bacterial endospores, spore photoproducts (SPs). Importantly, the lesions formed in higher organisms can lead to disease states including cancer. While the formation, structure, and biological outcomes of pyrimidine dimer lesions have been the focus of much research, less has been known about their fundamental chemical properties until recently. Such an understanding of these lesions may lead to novel means to chemically identify and quantitate their presence in the genome. This review is intended to provide an overview of intra‐strand pyrimidine dimer lesions derived from 5′‐T‐p‐T sites with a focus on presenting what is currently known about their individual in vitro alkaline chemical reactivities. Included here are descriptions of investigations of the DNA lesions CPD, 6‐4PP, and SP, and, for comparison, the monomeric pyrimidine lesion 5,6‐dihydo‐2′‐deoxyuridine (dHdU). Of interest, the alkaline hydrolyses of these various lesions are all found to be centered on the loss of aromaticity of a lesion Py ring (T) leading to a carbonyl “hot spot,” the focal point of initial hydrolytic attack. [ABSTRACT FROM AUTHOR]

Objective Methods Results Interpretation To investigate the longitudinal dynamics of serum glial fibrillary acidic protein (sGFAP) and serum neurofilament light chain (sNfL) levels in people with multiple sclerosis (pwMS) under B‐cell depleting therapy (BCDT) and their capacity to prognosticate future progression independent of relapse activity (PIRA) events.A total of 362 pwMS (1,480 samples) starting BCDT in the Swiss Multiple Sclerosis (MS) Cohort were included. sGFAP levels in 2,861 control persons (4,943 samples) provided normative data to calculate adjusted Z scores.Elevated sGFAP levels (Z score >1) at 1 year were associated with a higher hazard for PIRA (hazard ratio [HR]: 1.80 [95% CI: 1.17–2.78]; p = 0.0079) than elevated sNfL levels (HR, 1.45 [0.95–2.24], p = 0.0886) in a combined model. Independent of PIRA events, sGFAP levels longitudinally increased by 0.49 Z score units per 10 years follow‐up (estimate, 0.49 [0.29, 0.69], p < 0.0001). In patients experiencing PIRA, sGFAP Z scores were 0.52 Z score units higher versus stable patients (0.52 [0.22, 0.83], p = 0.0009). Different sNfL Z score trajectories were found in pwMS with versus without PIRA (interaction p = 0.0028), with an average decrease of 0.92 Z score units per 10 years observed without PIRA (−0.92 [−1.23, −0.60], p < 0.0001), whereas levels in patients with PIRA remained high.Elevated sGFAP and lack of drop in sNfL after BCDT start are associated with increased risk of future PIRA. These findings provide a rationale for combined monitoring of sNfL and sGFAP in pwMS starting BCDT to predict the risk of PIRA, and to use sGFAP as an outcome in clinical trials aiming to impact on MS progressive disease biology. ANN NEUROL 2024 [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a chronic inflammatory multisystemic disease. Monitoring disease activity thoughtout the disease course is important for effective management and assessment of disease outcome. Objective: To assess whether the pan-immune inflammation value (PIIV) at diagnosis could predict organ involvement and disease activity in childhood SLE (cSLE) patients after 12 months of disease onst. Methods: This is an observational retrospective multicenter study that comprised cSLE patients seen and followed at the participating centers between January 2010 and December 2022. All patients met the EULAR/ACR-19 criteria, were immunosuppressive drug-naïve at the time of SLE diagnosis and had a minimal follow-up period of 12 months. The data included clinical and laboratory findings and disease activity using the SLEDAI-2K. Receiver operating characteristic (ROC) curves were employed to determine the optimal cut-off value of PIIV and assess its predictive potential for disease activity, and organ involvement. Results: A total of 125 patients (104 female) with a median age of 16.0 (IQR 5.6) years, a median age at disease onset of 10.9 (IQR 3.0) years, and a median disease duration of 4.8 (IQR 5.3) years were included. The most frequent involved organs at diagnosis were hematological (89.6%), musculoskeletal (68.8%), mucocutaneous (63.2%), and renal (58.4%). However, at a 12-month follow-up visit, the most frequent involved organs were renal (40.0%), hematological (39.2%), musculoskeletal (15.2%), and mucocutaneous (10.4%). The median PIIV at diagnosis was 139 (IQR 229.6), while the median SLEDAI was 12 (IQR 6.5) and 3.5 (IQR 7.0) at diagnosis and 12 months, respectively. An optimal PIIV cut-off of 250 was found to be a predicative for disease activity, with a sensitivity of 45% and a specificity of 86%. The study revealed that the PIIV successfully predicted four systems in our cohort of patients. Conclusion: Our work suggests the PIIV might be a reasonable predictor for organ involvement and disease activity in newly diagnosed cSLE, though further research, particularly larger studies, is required to validate these findings, especially regarding organ involvement. [ABSTRACT FROM AUTHOR]

Our previous research revealed a close association between the acetylation of peroxisome proliferator-activated receptor γ (PPARγ) histone H3K27 and the adipogenic differentiation of bone marrow mesenchymal stem cells (BMSCs). We preliminarily explored the epigenetic mechanism of steroid-induced avascular necrosis of the femoral head (SANFH) development, but the specific histone deacetylase (HDAC) involved in this regulatory process remains unknown. In this study, we combined cell, animal, and clinical specimen experiments to screen for specific HDAC genes that could regulate BMSC adipogenic differentiation and to explore their roles. The results showed that dexamethasone (DEX) significantly exacerbated the imbalance between the adipogenic and osteogenic differentiation of BMSCs, and there were differences in HDAC expression in the adipogenic differentiation cell models, with histone deacetylase 10 (HDAC10) showing the most significant decrease in expression. Subsequent use of a chromatin immunoprecipitation assay kit and quantitative polymerase chain reaction (ChIP‒qPCR) revealed a decrease in HDAC10 expression at predicted potential sites within the PPARγ promoter, indicating a significant decrease in HDAC10 enrichment in the PPARγ promoter region of BMSCs, thereby promoting sustained PPARγ expression. Additionally, immunohistochemistry of samples collected from mice and humans with SANFH and normal femoral heads revealed an imbalance between adipogenic and osteogenic differentiation in the necrotic area of femoral heads, with a significant decrease in the relative expression of HDAC10 in the necrotic area of femoral heads with SANFH. In summary, we speculate that HDAC10 affects the progression of SANFH by regulating BMSC adipogenic differentiation, a process possibly related to PPARγ histone acetylation. These findings provide a promising direction for the treatment of SANFH. [ABSTRACT FROM AUTHOR]

Background: Huanglianjiedu decoction (HLJDD) is a classical Traditional Chinese Medicine (TCM) prescription with thousand years of clinical use against various malignancies, including pancreatic adenocarcinoma (PAAD). However, its potential bioactive component and molecular mechanism remains unclear. Aims: This study is to inspect the HLJDD mechanisms of action against PAAD via integrated computational and pharmacochemistry strategy, in vivo and in vitro experiments to validate associated targets and pathways. Methods: A PAAD xenograft model was established by subcutaneous injecting Panc02 cells into C57BL/6 mice. Ultra-high performance liquid chromatography with tandem mass spectrometry (UHPLC-MS/MS) was engaged to determine constituents of HLJDD and assessed for pharmacokinetic scheme using the TCM Systems Pharmacology Platform (TCM-SP). Differentially expressed genes (DEGs) of PAAD was retrieved from the transcriptome dataset GSE43795, followed by recognizing overlapping targets the oncogenes and target genes of PAAD and HLJDD, respectively. Putative signaling pathways of HLJDD in treating PAAD were enriched using KEGG and GO analyses. The anti-PAAD effects of HLJDD was assessed in vivo and in vitro, besides, the potential mechanism was validated using immunoblotting and immunohistochemical assays. Results: HLJDD significantly suppressed the growth of transplanted PAAD tumors, constrained PAAD progression, and induced apoptosis and S-phase arrest. Seventy-five active components meeting the drug-likeness criteria and 278 target genes of HLJDD were identified. KEGG analysis indicated that the top three enriched pathways were cancer, AGE-RAGE signaling, and IL-17 signaling pathways. Disease enrichment analysis highlighted immune, pharmacological, and cancer-related diseases as the top three categories. A total of 47 potential target genes were identified. Immunoblotting revealed that HLJDD inhibited PI3K and MAPK-related signaling pathways, while immunohistochemical staining confirmed that HLJDD suppressed the expression of phosphorylated MAPK and ERK1/2. Conclusion: HLJDD inhibited PAAD in vitro and in vivo via the modulation of multiple mechanisms, including regulation of PI3K/AKT/mTOR and MAPK/ERK1/2 signaling pathways. [ABSTRACT FROM AUTHOR]

Background: Systemic sclerosis (SSc) is a complex auto-immune disease characterized by vascular damage, inflammation, fibrosis and calcinosis, where pulmonary involvement is the leading cause of mortality. Calciprotein particles (CPPs) are increasingly formed upon disbalance of the physiological mineral buffering system and induce pro-inflammatory effects. This exploratory study investigated whether functional indicators of the endogenous mineral buffering system are dysregulated in SSc and linked to disease activity. Methods: T50 (calciprotein crystallization test or serum calcification propensity) and hydrodynamic radius of secondary CPPs (CPP2) were determined in serum samples from 78 SSc patients and 44 controls without SSc, and were associated with disease activity markers of SSc. Results: T50 was reduced and CPP2 radius was increased in SSc patients as compared to controls, indicating a deranged mineral buffering system. This was accompanied by slightly higher serum phosphate and PTH levels in SSc patients, while iFGF23 was not significantly modified. Longitudinally, all parameters remained unchanged over time in SSc patients, only iFGF23 increased. While the modified Rodnan skin score showed some inconsistent correlations with mineral buffering indicators, their association was not independent of other factors. However, lower T50 was significantly correlated to reduced lung diffusion capacity and this association remained significant in a multivariate linear regression model. Conclusion: This study provides indications for a disturbed mineral buffering system in SSc. Increased serum calcification propensity (lower T50) is correlated with impaired lung diffusion capacity, suggesting a possible role of deranged mineral buffering in disease progression. Further studies are required to confirm these observations in larger cohorts and to investigate a putative functional relevance. [ABSTRACT FROM AUTHOR]

Protein aggregation is a common pathological occurrence in neurodegenerative diseases. This often leads to neuroinflammation, which exacerbates the aggregation and progression of diseases like Parkinson's and Alzheimer's. Here, we focus on immune responses and neurotoxicity in a Parkinson's disease model in Drosophila. Mutations in the SNCA gene that encodes the alpha (a)-Synuclein protein have been linked to familial Parkinson's disease, disrupting autophagy regulation in neuronal cells and promoting the formation of Lewy bodies, a hallmark of Parkinson's pathology. This results in the loss of dopaminergic neurons, manifesting as movement disorders. a-Synuclein aggregation triggers innate immune responses by activating microglial cells, leading to phagocytic activity and the expression of neuroprotective antimicrobial peptides (AMPs). However, sustained AMP expression or chronic inflammation resulting from inadequate microglial phagocytosis can induce neuronal toxicity and apoptosis, leading to severe dopaminergic neuron loss. This review underscores the mechanistic connection between immune response pathways and a-Synuclein-mediated neurodegeneration using Drosophila models. Furthermore, we extensively explore factors influencing neuroinflammation and key immune signaling pathways implicated in neurodegenerative diseases, particularly Parkinson's disease. Given the limited success of traditional treatments, recent research has focused on therapies targeting inflammatory signaling pathways. Some of these approaches have shown promising results in animal models and clinical trials. We provide an overview of current therapeutic strategies showing potential in treating neurodegenerative diseases, offering new avenues for future research and treatment development. [ABSTRACT FROM AUTHOR]

Macroautophagy/autophagy is an intracellular degradation pathway that has an important effect on both healthy and diseased pancreases. It protects the structure and function of the pancreas by maintaining organelle homeostasis and removing damaged organelles. A variety of pancreas-related diseases, such as diabetes, pancreatitis, and pancreatic cancer, are closely associated with autophagy. Genetic studies that address autophagy confirm this view. Loss of autophagy homeostasis (lack or overactivation) can lead to a series of adverse reactions, such as oxidative accumulation, increased inflammation, and cell death. There is growing evidence that stimulating or inhibiting autophagy is a potential therapeutic strategy for various pancreatic diseases. In this review, we discuss the multiple roles of autophagy in physiological and pathological conditions of the pancreas, including its role as a protective or pathogenic factor. [ABSTRACT FROM AUTHOR]

Inflammation plays a pivotal role in the pathogenesis of primary and post-essential thrombocythemia or post-polycythemia vera myelofibrosis (MF) in close cooperation with the underlying molecular drivers. This inflammatory state is induced by a dynamic spectrum of inflammatory cytokines, although recent evidence points to the participation of additional soluble inflammatory mediators. Damage-associated molecular patterns (DAMPs) represent endogenous signals released upon cell death or damage which trigger a potent innate immune response. We assessed the contribution of two prototypical DAMPs, HMGB1 and S100A8/A9, to MF inflammation. Circulating HMGB1 and S100A8/A9 were elevated in MF patients in parallel to the degree of systemic inflammation and levels increased progressively during advanced disease stages. Patients with elevated DAMPs had higher frequency of adverse clinical features, such as anemia, and inferior survival, suggesting their contribution to disease progression. Monocytes, which are key players inMF inflammation, were identified as a source of S100A8/A9 but not HMGB1 release, while both DAMPs correlated with cell death parameters, such as serumLDH and cell-free DNA, indicating that passive release is an additional mechanism leading to increased DAMPs. HMGB1 and S100A8/A9 promote inflammation through binding to Toll-like receptor (TLR) 4, whereas the former also binds TLR2. Monocytes from MF patients were shown to be hyperactivated at baseline, as reflected by higher CD11b and tissue factor exposure and increased expression levels of proinflammatory cytokines IL-1b and IL-6. Patient monocytes showed preserved TLR4 and TLR2 expression and were able to mount normal or even exacerbated functional responses and cytokine upregulation following stimulation of TLR4 and TLR2. Elevated levels of endogenous TLR ligands HMGB1 and S100A8/A9 coupled to the finding of preserved or hyperreactive TLR-triggered responses indicate that DAMPs may promote monocyte activation and cytokine production in MF, fueling inflammation. Plasma IL-1b and IL-6 were elevated in MF and correlated with DAMPs levels, raising the possibility that DAMPs could contribute to cytokine generation in vivo. In conclusion, this study highlights that, in cooperation with classic proinflammatory cytokines, DAMPs represent additional inflammatory mediators that may participate in the generation of MF inflammatory state, potentially providing novel biomarkers of disease progression and new therapeutic targets. [ABSTRACT FROM AUTHOR]