[Long-term hypomethylating agents in patients with myelodysplastic syndromes: a multi-center retrospective study].

Objective: To evaluate the efficacy and safety of hypomethylating agents (HMA) in patients with myelodysplastic syndromes (MDS) . Methods: A total of 409 MDS patients from 45 hospitals in Zhejiang province who received at least four consecutive cycles of HMA monotherapy as initial therapy were enrolled to evaluate the efficacy and safety of HMA. Mann-Whitney U or Chi-square tests were used to compare the differences in the clinical data. Logistic regression and Cox regression were used to analyze the factors affecting efficacy and survival. Kaplan-Meier was used for survival analysis. Results: Patients received HMA treatment for a median of 6 cycles (range, 4-25 cycles) . The complete remission (CR) rate was 33.98% and the overall response rate (ORR) was 77.02%. Multivariate analysis revealed that complex karyotype (P=0.02, OR=0.39, 95%CI 0.18-0.84) was an independent favorable factor for CR rate. TP53 mutation (P=0.02, OR=0.22, 95%CI 0.06-0.77) was a predictive factor for a higher ORR. The median OS for the HMA-treated patients was 25.67 (95%CI 21.14-30.19) months. HMA response (P=0.036, HR=0.47, 95%CI 0.23-0.95) was an independent favorable prognostic factor, whereas complex karyotype (P=0.024, HR=2.14, 95%CI 1.10-4.15) , leukemia transformation (P<0.001, HR=2.839, 95%CI 1.64-4.92) , and TP53 mutation (P=0.012, HR=2.19, 95%CI 1.19-4.07) were independent adverse prognostic factors. There was no significant difference in efficacy and survival between the reduced and standard doses of HMA. The CR rate and ORR of MDS patients treated with decitabine and azacitidine were not significantly different. The median OS of patients treated with decitabine was longer compared with that of patients treated with azacitidine (29.53 months vs 20.17 months, P=0.007) . The incidence of bone marrow suppression and pneumonia in the decitabine group was higher compared with that in the azacitidine group. Conclusion: Continuous and regular use of appropriate doses of hypomethylating agents may benefit MDS patients to the greatest extent if it is tolerated.

Case report: Development of clonal hematologic disorders from inherited bone marrow failure.

Introduction: Inherited bone marrow failure (IBMF) syndromes are caused by mutations forming pathologic germline variants resulting in the production of defective hematopoietic stem cells (HSC) and in congenital failure in the production of one or more blood lineages. An acquisition of subsequent somatic mutations is determining further course of the disease. Nevertheless, a certain number of patients with IBMF may escape correct diagnosis in childhood, especially those with mild cytopenia and minimal clinical features without non-hematologic symptoms. These patients usually present in the third decade of life with unexplained cytopenia or myelodysplastic syndrome (MDS). Methods and results: We report 2 patients with IBMF who were correctly diagnosed between 20 and 40 years of age when they were referred with progressive MDS with adverse prognostic factors that affected their outcome. Discussion: IBMF syndromes should be excluded in all patients below 40 years of age with unexplained cytopenia. Early hematopoietic stem cell transplantation (HSCT) is the treatment of choice in these patients.

Hereditary and Familial Traits in Urological Cancers and Their Underlying Genes.

Early recognition of hereditary urological cancers may influence diagnostic and therapeutic decision-making, and potentially alter the fate of patients and family members. Here, we introduce readers to the current knowledge on germline genetic testing and clinical practice in prostate, bladder, renal, and testicular carcinoma. Considering all urological cancer patients, routine inquiries about familial cancer history should become a standard practice in clinical settings. If suspicion arises, patients can opt for two avenues: referral to genetic counseling or undergoing genetic tests after consultation with the treating urologist. Patient summary: Tumors of the urogenital tract (prostate, kidney, bladder, and testes) can sometimes be related to genetic mutations that are present in all the cells of the body. Such mutations can be inherited and run in families. Therefore, it is relevant to obtain information on the incidence of all cancers in the family history. The information obtained may initiate genetic testing, leading to the identification of mutations that are related to cancer in the current or next generation. In addition, these mutations may offer alternative treatment options for patients.

Extracting Critical Information from Unstructured Clinicians' Notes Data to Identify Dementia Severity Using a Rule-Based Approach: Feasibility Study.

BACKGROUND: The severity of Alzheimer disease and related dementias (ADRD) is rarely documented in structured data fields in electronic health records (EHRs). Although this information is important for clinical monitoring and decision-making, it is often undocumented or "hidden" in unstructured text fields and not readily available for clinicians to act upon. OBJECTIVE: We aimed to assess the feasibility and potential bias in using keywords and rule-based matching for obtaining information about the severity of ADRD from EHR data. METHODS: We used EHR data from a large academic health care system that included patients with a primary discharge diagnosis of ADRD based on ICD-9 (International Classification of Diseases, Ninth Revision) and ICD-10 (International Statistical Classification of Diseases, Tenth Revision) codes between 2014 and 2019. We first assessed the presence of ADRD severity information and then the severity of ADRD in the EHR. Clinicians' notes were used to determine the severity of ADRD based on two criteria: (1) scores from the Mini Mental State Examination and Montreal Cognitive Assessment and (2) explicit terms for ADRD severity (eg, "mild dementia" and "advanced Alzheimer disease"). We compiled a list of common ADRD symptoms, cognitive test names, and disease severity terms, refining it iteratively based on previous literature and clinical expertise. Subsequently, we used rule-based matching in Python using standard open-source data analysis libraries to identify the context in which specific words or phrases were mentioned. We estimated the prevalence of documented ADRD severity and assessed the performance of our rule-based algorithm. RESULTS: We included 9115 eligible patients with over 65,000 notes from the providers. Overall, 22.93% (2090/9115) of patients were documented with mild ADRD, 20.87% (1902/9115) were documented with moderate or severe ADRD, and 56.20% (5123/9115) did not have any documentation of the severity of their ADRD. For the task of determining the presence of any ADRD severity information, our algorithm achieved an accuracy of >95%, specificity of >95%, sensitivity of >90%, and an F1-score of >83%. For the specific task of identifying the actual severity of ADRD, the algorithm performed well with an accuracy of >91%, specificity of >80%, sensitivity of >88%, and F1-score of >92%. Comparing patients with mild ADRD to those with more advanced ADRD, the latter group tended to contain older, more likely female, and Black patients, and having received their diagnoses in primary care or in-hospital settings. Relative to patients with undocumented ADRD severity, those with documented ADRD severity had a similar distribution in terms of sex, race, and rural or urban residence. CONCLUSIONS: Our study demonstrates the feasibility of using a rule-based matching algorithm to identify ADRD severity from unstructured EHR report data. However, it is essential to acknowledge potential biases arising from differences in documentation practices across various health care systems.

What we've learnt about autoimmune neurological diseases from neuropathology.

Antibody-associated autoimmune neurological diseases are a group of disorders with various immune effector mechanisms that result in significant differences in disease course and prognosis. Paraneoplastic or idiopathic autoimmune encephalitis associated with antibodies against intracellular antigens are mostly characterized by a T-cell-dominated inflammation with neuronal loss, astrogliosis, and microglial nodules. In anti-Yo paraneoplastic cerebellar degeneration CD8+/granzymeB+ T cells were demonstrated in close apposition to neurons along with a nuclear upregulation of the activator of transcription 1, suggesting an important role of interferon-gamma in disease pathogenesis. Early and late disease stages may show different lesion types. For example, tissue samples from patients with temporal lobe epilepsy associated with antiglutamic acid decarboxylase 65 antibodies in early disease stages show numerous infiltrating T cells targeting hippocampal neurons and high numbers of B cells and plasma cells, while in chronic stages inflammation gets less and is followed by hippocampal sclerosis. Similarly, antiglial fibrillary acidic protein meningoencephalomyelitis may show loss of astrocytes only in the very early lesions, whereas in subacute and chronic stages astrocytes can get replenished most likely due to their high regeneration potential. In contrast, neuropathology of autoimmune neurological diseases mediated by surface antibodies is mostly characterized by a dysfunction of neurons in the absence of immune-mediated neuronal damage. The interaction of surface antibodies with their target antigen and the resulting downstream mechanisms are variable and can range from an internalization of the receptor in well-preserved neurons in anti-N-methyl-D-aspartate receptor encephalitis to an irreversible internalization and blocking of the receptor that may be associated with an accumulation of phosphorylated tau in specific brain regions in anti-IgLON5 disease. Interestingly, anti-IgLON5 patients with short disease duration were shown to present prominent deposition of IgG4 in the neuropil and on neuronal membranes in the absence of neuronal tau deposits, suggesting that the immune mechanisms precede neurodegeneration. Knowledge about pathomechanisms and patterns of tissue damage in different disease stages of antibody-associated autoimmune diseases will help to identify novel biomarkers and can give important clues for possible therapeutic interventions.

Real-World Study of the Burden of Myelodysplastic Syndromes in Patients and Their Caregivers in Europe and the United States.

INTRODUCTION: Myelodysplastic syndromes (MDS) are characterized by bone marrow failure, peripheral blood cytopenias and a high risk of progression to acute myeloid leukemia (AML), which is associated with a poor prognosis and low survival rates. This study combined surveys with patient chart reviews to document real-world clinical practice and burden of MDS, including perspectives of physicians, patients and caregivers and underlying discrepancies. METHODS: Physicians in major European countries and the US provided information on 1445 patients, stratified into lower- (LR) and higher-risk (HR) MDS. Patients had the opportunity to complete questionnaires describing the impact of MDS. Caregivers had the option to report on the burden of caring for a patient with MDS. RESULTS: While supportive treatment was common, mainly with erythropoietins (52%), anti-AML agents were more frequently used in HR than in LR patients (70% vs 20%), while HR patients generally received more transfusions (48% vs 36%). Symptoms with the largest discordance between patient vs physician reporting were excessive bruising (30% vs 14%), GI side effects (19% vs 6%) and feeling tired or fatigued (68% vs 56%). A bigger impact of fatigue was reported on the European Organization for the Research and Treatment of Cancer Quality of Life questionnaire (EORTC QLQ-C30) for HR vs LR patients (43.2 vs 36.5 on a scale from 0 to 100). There was discordance between caregivers vs physicians on reporting of weekly caregiver hours (45.4 vs 29.2) with a Zarit Burden Interview score (ZBI, score 0-88) of 25.4. CONCLUSIONS: Patients reported a higher frequency than their physicians of top symptoms, with MDS-related disruptions in daily life for both patients and caregivers. There is a need for new therapeutic strategies, along with shared understanding and decision making among patients, caregivers and physicians, to optimize disease management and improve quality of life in people living with MDS.

The risk of geriatric syndromes in older COVID-19 survivors among the nonvaccinated population: a real world retrospective cohort study.

BACKGROUND: We aimed to analyse the differences in the risk of geriatric syndromes between older adults with and without coronavirus disease 2019 (COVID-19). METHODS: We conducted a retrospective cohort study of patients from the US Collaborative Network in the TriNetX between January 1, 2020, and December 31, 2022. We included individuals aged older than 65 years with at least 2 health care visits who underwent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) polymerase chain reaction (PCR) tests during the study period. We excluded those with SARS-CoV-2 vaccination, diagnosis with neoplasm and geriatric syndromes before the index date, and death within 30 days after the index date. The index date was defined as the first date of the PCR test for SARS-CoV-2 during the study period. Hazard ratios (HRs) and 95% confidence intervals (CIs) for eight geriatric syndromes were estimated for propensity score-matched older adults with and without COVID-19. Subgroup analyses of sex and age were also performed. RESULTS: After propensity score matching, 315 826 patients were included (mean [standard deviation] age, 73.5 [6.4] years; 46.7% males and 51.7% females). The three greatest relative increases in the risk of geriatric syndromes in the COVID-19 cohort were cognitive impairment (HR: 3.13; 95% CI: 2.96-3.31), depressive disorder (HR: 2.72; 95% CI: 2.62-2.82) and pressure injury (HR: 2.52; 95% CI: 2.34-2.71). CONCLUSIONS: The risk of developing geriatric syndromes is much higher in the COVID-19 cohort. It is imperative that clinicians endeavour to prevent or minimise the development of these syndromes in the post-COVID-19 era.

Obstructive sleep apnea illness perception relative to other common chronic conditions.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a common chronic medical condition that results in impaired daytime functioning. While the link between OSA and cardiovascular disease is important, there has been increasing recognition of the impact of OSA on daytime functioning and experience. Better insight into illness perceptions can help better understand how to initiate and maintain treatment. METHODS: Data from two OSA clinical trials were examined. The baseline Respiratory Event Index (REI) was obtained from diagnostic sleep testing. The Brief Illness Perception Questionnaire (BIPQ) assesses the cognitive and emotional representation of illness and was administered at baseline along with the Epworth Sleepiness Scale (ESS) and the Pittsburgh Sleep Quality Index (PSQI). RESULTS: 523 patients diagnosed with OSA were studied. The sample had a mean age of 51.1 ± 16.6, mean REI of 28.6 ± 17.9/h, and mean body mass index of 32.8 ± 15.5 kg/m^2. The mean BIPQ total score at baseline was 43.3 ± 11.3. BIPQ scores were significantly correlated with sleepiness and sleep quality but not with REI. Relative to other common chronic conditions with major comorbidities, BIPQ scores for patients with OSA were higher on consequences, identity, concern, and emotional representation dimensions. CONCLUSIONS: The study shows that Veterans with OSA report elevated illness perceptions across several dimensions at levels as high, or higher, than other common chronic conditions. Implications for clinical practice are that it is important to ask patients about their understanding of illness across several dimensions to appreciate better patient needs and preferences.

Diagnostic value of six plasma biomarkers in progressive supranuclear palsy, multiple system atrophy, and Parkinson's disease.

OBJECTIVES: This study aimed to evaluate the diagnostic ability of six plasma biomarkers in progressive supranuclear palsy (PSP), multiple system atrophy (MSA), and different subtypes of Parkinson's disease (PD). METHODS: Neurofilament light chain (NfL), phosphorylated tau-181, glial fibrillary acidic protein (GFAP), amyloid-ß 42 (Aß42), and amyloid-ß 40 (Aß40) levels were measured using the single-molecule array (Simoa) technique in a cohort of patients with PSP, MSA, different subtypes of PD, and healthy controls (HCs). RESULTS: Plasma NfL and GFAP levels were beneficial in discriminating between the disease groups and HCs. Plasma NfL, Aß42, and Aß40 could distinguish atypical Parkinsonian syndrome (APS) from PD and its subtypes. GFAP could discriminate APS from tremor dominant PD but could not discriminate APS from postural instability and gait disorder dominant PD. The efficacy of differentiation improved when a combination of multiple plasma biomarkers was applied. CONCLUSIONS: In this study, the plasma biomarkers NfL, GFAP, Aß42, and Aß40 exhibited high discriminatory diagnostic value in PD and APS, and could be used as clinically potential diagnostic biomarkers. Plasma biomarker combinations could improve the differential diagnostic efficacy in the comparisons of PD and APS.

Predictive model for left main coronary artery or triple vessel disease in patients with chronic coronary syndromes.

Background: Data about prediction of left main coronary artery disease (LMCAD)/three-vessel disease (TVD) in patients with chronic coronary syndromes (CCS) are lacking. Objectives: This study aimed to develop a model for predicting patients at risk of LMCAD/TVD. Methods: This study used retrospective data from patients with CCS scheduled for invasive coronary angiography (ICA) and who were retrospectively recruited between January 2018 and December 2020. Predictors were obtained and analyzed by using logistic regression analysis, and generated the prediction score. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. The cut-off value and area under the curve (AUC) were analyzed by using the receiver operating characteristic (ROC) curve. Results: We recruited 162 patients with CCS. There were 75 patients in the non-LMCAD/TVD and 87 patients in the LMCAD/TVD groups. After the multivariate analysis, new onset of heart failure (HF) or left ventricular systolic dysfunction (LVSD) and suspected CAD, ST elevation (STE) in aVR, STE in V1 and lateral ST depression (STD) were associated with increased risk of LMCAD/TVD. Based on these 4 predictors, the prediction score was created. The cut-off value of the prediction score by using ROC curve analysis was 3.0. The sensitivity, specificity, PPV, and NPV were 71.26%, 86.67%, 86.11%, and 72.22%, respectively, with an AUC of 0.855. Conclusions: The CCS patients with new onset of HF or LVSD and suspected CAD, STE in aVR, and STE in V1 and lateral STD were associated with increased risk of LMCAD/TVD. The novel prediction score could predict LMCAD/TVD in those patients with acceptable sensitivity, specificity, PPV, and NPV.

Insight Into Uncommon Territory: Exploring Internuclear Ophthalmoplegia in Artery of Percheron Infarct.

Internuclear ophthalmoplegia (INO), a neurological disorder is characterized by horizontal gaze palsy because of a lesion in the medial longitudinal fasciculus, a neural pathway that is mainly responsible for coordinating the movements of the eye. INO presents with diplopia and impaired adduction of the affected eye, accompanied by abducting eye nystagmus. The condition also arises from different etiologies which include multiple sclerosis, encephalitis, Lyme disease, HIV, and herpes zoster. Artery of Percheron (AOP) infarction is a subtype of bilateral thalamic infarction that poses a unique form of diagnostic perplexity due to its varied and often non-specific clinical manifestations such as altered responsiveness, memory disturbances, and oculomotor deficits. Here we discuss a 53-year-old female who presented with INO in the context of an AOP infarct. Under this context, the clinical finding includes some paradigms like nystagmus, anisocoria, and bilateral ptosis. Magnetic resonance imaging confirmed an acute infarct in the AOP territory, which supplies the rostral midbrain and paramedian thalami. This case emphasizes the critical importance of meticulous clinical evaluation and the utilization of advanced imaging techniques in diagnosing rare stroke syndromes like AOP infarction. Management of the patient included dual antiplatelet therapy to prevent further thromboembolic events and supportive care to address the immediate neurological deficits. Early recognition and prompt treatment are crucial for better patient outcomes. Long-term management focuses on the secondary prevention of stroke through lifestyle modifications, medical therapy, and regular monitoring. Education on uncommon stroke syndromes and continued research are essential for enhancing the accuracy of diagnosis and efficacy of treatment which ultimately leads to better patient care and prognosis.

Quantitative sensory testing and chronic pain syndromes: a cross-sectional study from TwinsUK.

OBJECTIVE: The chronic pain syndromes (CPS) include syndromes such as chronic widespread pain (CWP), dry eye disease (DED) and irritable bowel syndrome (IBS). Highly prevalent and lacking pathognomonic biomarkers, the CPS are known to cluster in individuals in part due to their genetic overlap, but patient diagnosis can be difficult. The success of quantitative sensory testing (QST) and inflammatory biomarkers as phenotyping tools in conditions such as painful neuropathies warrant their investigation in CPS. We aimed to examine whether individual QST modalities and candidate inflammatory markers were associated with CWP, DED or IBS in a large, highly phenotyped population sample. DESIGN: Cross-sectional study. SETTING: Community-dwelling cohort. PARTICIPANTS: Twins from the TwinsUK cohort PRIMARY AND SECONDARY OUTCOME MEASURES: We compared 10 QST modalities, measured in participants with and without a CWP diagnosis between 2007 and 2012. We investigated whether inflammatory markers measured by Olink were associated with CWP, including interleukin-6 (IL-6), IL-8, IL-10, monocyte chemoattractant protein-1 and tumour necrosis factor. All analyses were repeated in DED and IBS with correction for multiple testing. RESULTS: In N=3022 twins (95.8% women), no association was identified between individual QST modalities and CPS diagnoses (CWP, DED and IBS). Analyses of candidate inflammatory marker levels and CPS diagnoses in n=1368 twins also failed to meet statistical significance. CONCLUSION: Our findings in a large population cohort suggest a lack of true association between singular QST modalities or candidate inflammatory markers and CPS.

Role of mitochondria in reno-cardiac diseases: A study of bioenergetics, biogenesis, and GSH signaling in disease transition.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are global health burdens with rising prevalence. Their bidirectional relationship with cardiovascular dysfunction, manifesting as cardio-renal syndromes (CRS) types 3 and 4, underscores the interconnectedness and interdependence of these vital organ systems. Both the kidney and the heart are critically reliant on mitochondrial function. This organelle is currently recognized as a hub in signaling pathways, with emphasis on the redox regulation mediated by glutathione (GSH). Mitochondrial dysfunction, including impaired bioenergetics, redox, and biogenesis pathways, are central to the progression of AKI to CKD and the development of CRS type 3 and 4. This review delves into the metabolic reprogramming and mitochondrial redox signaling and biogenesis alterations in AKI, CKD, and CRS. We examine the pathophysiological mechanisms involving GSH redox signaling and the AMP-activated protein kinase (AMPK)-sirtuin (SIRT)1/3-peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) axis in these conditions. Additionally, we explore the therapeutic potential of GSH synthesis inducers in mitigating these mitochondrial dysfunctions, as well as their effects on inflammation and the progression of CKD and CRS types 3 and 4.

Into the storm: the imbalance in the yin-yang immune response as the commonality of cytokine storm syndromes.

There is a continuous cycle of activation and contraction in the immune response against pathogens and other threats to human health in life. This intrinsic yin-yang of the immune response ensures that inflammatory processes can be appropriately controlled once that threat has been resolved, preventing unnecessary tissue and organ damage. Various factors may contribute to a state of perpetual immune activation, leading to a failure to undergo immune contraction and development of cytokine storm syndromes. A literature review was performed to consider how the trajectory of the immune response in certain individuals leads to cytokine storm, hyperinflammation, and multiorgan damage seen in cytokine storm syndromes. The goal of this review is to evaluate how underlying factors contribute to cytokine storm syndromes, as well as the symptomatology, pathology, and long-term implications of these conditions. Although the recognition of cytokine storm syndromes allows for universal treatment with steroids, this therapy shows limitations for symptom resolution and survival. By identifying cytokine storm syndromes as a continuum of disease, this will allow for a thorough evaluation of disease pathogenesis, consideration of targeted therapies, and eventual restoration of the balance in the yin-yang immune response.

Self-Limited Epilepsy With Autonomic Seizures: A Case Report.

This case report describes a six-year-old girl without relevant personal or family history, who had a seizure at awakening with loss of muscle tone, sialorrhea and ocular retroversion. The episode lasted >5 minutes, with vomiting and post-ictal confusion. Upon the hospital visit, she was misdiagnosed with acute gastroenteritis and discharged with symptomatic treatment. After another seizure, she was diagnosed with Panayiotopoulos syndrome and started receiving treatment. Since then, the child has been followed up through neuropediatric appointments and by her family doctor. The psychological assessment revealed normal general intellectual functioning with vulnerability in the language area.