Early Therapeutic Intervention Research Articles

Development of a fluorescence and quencher-based FRET assay for detection of endogenous peptide:N-glycanase/NGLY1 activity

Cytosolic peptide:N-glycanase (PNGase/NGLY1 in mammals) catalyzes deglycosylation of N-glycans on glycoproteins. A genetic disorder caused by mutations in the NGLY1 gene leads to NGLY1 deficiency, with symptoms including motor deficits and neurological problems. Effective therapies have not been established, though a recent study used the administration of an adeno-associated viral vector expressing human NGLY1 to dramatically rescue motor functions in young Ngly1–/– rats. Thus, early therapeutic intervention may improve symptoms arising from central nervous system dysfunction, and assay methods for measuring NGLY1 activity in biological samples are critical for early diagnostics. In this study, we established an assay system for plate-based detection of endogenous NGLY1 activity using a FRET-based probe. Using this method, we revealed significant changes in NGLY1 activity in rat brains during aging. This novel assay offers reliable disease diagnostics and provides valuable insights into the regulation of PNGase/NGLY1 activity in diverse organisms under different stress conditions.

534 - Incidence of venous thromboembolic events and atherosclerotic cardiovascular disease risk factors in adolescents and adults with atopic dermatitis in Denmark: a population-based cohort study

Abstract Background Atopic dermatitis (AD) is associated with substantial impairment in quality of life, including sleep disturbances, anxiety, and depression, which may increase the risk of cardiovascular disease (CVD). However, the association between CVD and AD is not well established. Objectives To evaluate incidence rates (IRs) of venous thromboembolism (VTE), deep vein thrombosis (DVT), and pulmonary embolism (PE) in patients with and without AD in a population-based cohort study in Denmark, and to assess IRs of malignancies, major adverse cardiovascular events (MACE), VTE, and the distribution of Atherosclerotic Cardiovascular Disease (ASCVD) risk factors in patients with AD and rheumatoid arthritis (RA) in a nested cohort analysis. Methods Data from all individuals aged ≥12 years (≥18 years in the nested cohort analysis) between January 1, 2000, and December 31, 2018, were extracted from the Danish National Patient Registry. Patients with ≥1 AD diagnosis during the study period were matched on sex and age with 10 individuals from the general population. The nested cohort analysis included patients diagnosed with RA as an additional comparison population. In the overall cohort, IRs of VTE, DVT, and PE were assessed; the nested cohort analysis evaluated the distribution of ASCVD risk factors and incidence of malignancies, MACE, and VTE in patients with and without ASCVD risk factors (age ≥65 years, and history of smoking, coronary artery disease, stroke, DVT, PE, and malignancy). The follow-up period was from the first diagnosis during the study period until the occurrence of death or an endpoint, the first instance of migration, or December 31, 2018. IRs are shown per 100 patient-years (PY) of exposure with 95% confidence intervals. Results The population-based cohort comprised 190,751 patients, including 17,341 patients with AD and 173,410 age- and sex-matched controls. The IR/100 PY of VTE was similar between the AD cohort (0.14 [95% CI, 0.12-0.16]) and the general population (0.11 [0.11-0.12]). The IR/100 PY for VTE was higher in patients with AD aged ≥65 years (0.71 [0.56-0.90]) than the age-matched general population (0.50 [0.46-0.54]) and lower in the younger AD cohorts (12 to <18 years, 0.02 [0.00-0.08]; 18 to <65 years, 0.12 [0.09-0.13]). The IRs/100 PY of DVT and PE were comparable between the AD cohort (DVT, 0.08 [0.06-0.09]; PE, 0.06 [0.05-0.08]) and the general population (DVT, 0.06 [0.06-0.07]; PE, 0.05 [0.05-0.05]).. The nested cohort analysis comprised 195,807 patients, including 13,432 with AD, 48,055 with RA, and 134,320 age- and sex-matched controls. Distribution of risk factors for malignancies (excluding nonmelanoma skin cancer [NMSC]), MACE, and VTE was comparable in the AD cohort and general population, but higher in patients with RA. The IR/100 PY for malignancies (excluding NMSC) was higher in patients with AD with a history of malignancy (11.41 [9.83-13.25]) than those without (0.44 [0.40-0.48]), and in those aged ≥65 years (3.09 [2.75-3.48]) versus <65 years (0.36 [0.33-0.40]). Similarly, the IR/100 PY for MACE was higher in patients with AD aged ≥65 years (2.30 [2.01-2.63]) versus <65 years (0.15 [0.13-0.17]), and patients with a history of ASCVD (5.02 [4.37-5.76]) versus without (0.15 [0.13-0.18]). Patients with AD with a history of VTE (including DVT/PE) and inherited thrombophilia had a greater risk of VTE than patients without these risk factors. Conclusions In these 2 large cohort studies of adults and adolescents with AD, IRs of VTE, DVT, and PE were comparable with the general Danish population. The risk of VTE, malignancy, and MACE was higher in patients with AD with a history of risk factors for ASCVD. This underscores the need for appropriate monitoring and reporting of cardiovascular events in patients with AD, and active management of risk factors with early and effective therapeutic intervention.

Clinical Implications of Various Electroencephalographic Patterns in Post-Stroke Seizures. The Utility of Routine Electroencephalogram.

Objective: Post-stroke seizures (PSS) are one of the major stroke-related complications. Early therapeutic interventions are critical therefore using electroencephalography (EEG) as a predictive tool for future recurrence may be helpful. We aimed to assess frequencies of different EEG patterns in patients with PSS and their association with seizure recurrence and functional outcomes. Methods: All patients admitted with PSS were included and underwent interictal EEG recording during their admission and monitored for seizure recurrence for 24 months. Results: PSS was reported in 106 patients. Generalized slow wave activity (GSWA) was the most frequent EEG pattern observed (n = 62, 58.5%), followed by Focal sharp wave discharges (FSWDs) (n = 57, 55.8%), focal slow wave activity (FSWA) (n = 56, 52.8%), periodic discharges (PDs) (n = 13, 12.3%), and ictal epileptiform abnormalities (n = 6, 5.7%). FSWA and ictal EAs were positively associated with seizure recurrence (p < .001 and p = .015 respectively) and it remained significant even after adjusting for age, sex, stroke severity, stroke subtype, or use of anti-seizure medications (ASMs). Other positive associations were status epilepticus (SE) (p = .015), and use of older ASM (p < .001). FSWA and GSWA in EEG were positively associated with severe functional disability (p = .055, p = .015 respectively). Other associations were; Diabetes Mellitus (p = .034), Chronic Kidney Disease (p = .002), use of older ASMs (p = .037), presence of late PSS (p = .021), and those with Ischemic stroke (p = .010). Conclusions: Recognition and documentation of PSS-related EEG characteristics are important, as certain EEG patterns may help to identify the patients who are at risk of developing recurrence or worse functional outcomes.

Inflammatory Biomarkers, Cognitive Functioning, and Brain Imaging Abnormalities in Bipolar Disorder: A Systematic Review.

Recent studies have pointed to neuroinflammation and neurotrophic factors as crucial mediators in the pathophysiology origins of mood disorders. The aim of this review is to assess the potential association between cognitive impairment, brain imaging abnormalities, and inflammatory biomarkers in patients affected by bipolar disorder (BD). Following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) guidelines, we systematically searched PubMed, Google Scholar, Scopus, and Web of Science databases, with no year restriction, up until August 2023, for human studies that examined the relationship between inflammatory markers and cognitive impairment in BD patients. Studies based on neuroimaging, such as MRI, DTI, and fMRI, were also included, along with those examining the moderating role of specific inflammatory markers in the alteration of the brain. 59 human clinical studies satisfied the criteria for consideration. Most of the studies reviewed concur that inflammatory state, measured by peripheral blood levels of CRP and cytokines, constitutes an important contributor to cognitive impairment observed in patients with BD. Robust evidence indicates an association between cognitive impairment and CRP, IL-1RA, IL-6, and TNF-α with its receptors, whereas there is no convincing evidence for the involvement of other neuroinflammatory biomarkers. Neuroimaging studies suggest that brain structural/functional abnormalities seen in BD could also be linked to a neuroinflammatory condition. Current data provide evidence of a link between cognitive impairments observed in BD patients and mechanisms of neuroinflammation. Emerging evidence indicates that systemic inflammation might also play an important role in the deterioration of brain structures critical to cognitive functions in patients with BD. The convergence of findings across these studies strengthens our understanding of the complex neurobiological underpinnings of these disorders. Identification of BD specific inflammatory markers may be of assistance for future early therapeutic interventions.

Modified pustulotic arthro-osteitis diagnostic guidance 2022 - Modified Sonozaki criteria - Secondary publication.

The concept of pustulotic arthro-osteitis (PAO) was first reported by Sonozaki et al. in 1979, with diagnostic criteria (Sonozaki criteria) proposed in 1981. These criteria have served as the gold standard for PAO diagnosis for over 40 years. In recent years, there has been an increasing emphasis on maximizing the quality of life of patients with PAO. This is achieved by striving for clinical remission, structural remission, and functional remission through early diagnosis and appropriate therapeutic intervention from an early stage. This article is an English translation of a summary of the 'Modified PAO Diagnostic Guidance 2022', edited by the Japan Ministry of Health, Labour and Welfare's Research Group on improvement of medical standard and quality of life of patients with spondyloarthritis and related diseases represented by ankylosing spondylitis and the Japan Spondyloarthritis Society. This guidance is intended to be helpful to both Japanese and global communities in rheumatology and spondyloarthritis.

Assessment Of The Status And Challenges Of The Linkage Between Universities And Industries In Ethiopia: The Case Of Two Universities And Six Industries

The primary objective is to report and document the case of a collodion baby, a rare congenital condition, emphasizing the importance of early and appropriate therapeutic intervention. By presenting this infrequent incidence, the aim is to contribute to the existing medical knowledge regarding the clinical symptoms and complications associated with collodion baby syndrome. Specifically, the goal is to highlight the significance of prompt and adequate management in minimizing potential complications due to skin barrier disruption. This involves implementing a treatment approach focused on eliminating scaling and reducing xerosis without causing excessive irritation to the delicate skin of the affected newborn. Furthermore, the report seeks to enhance clinical awareness among healthcare professionals, providing valuable insights into the symptoms that should be monitored closely and the multidisciplinary care required. Collaboration between pediatricians, dermatologists, otorhinolaryngologists, ophthalmologists, plastic surgeons, and physiotherapists is crucial for comprehensive care, addressing immediate concerns, and ensuring long-term survival and well-being. In summary, the objective is twofold: first, to contribute to the medical literature by documenting a rare collodion baby syndrome, and second, to underscore the importance of early intervention and multidisciplinary care in managing this congenital condition and minimizing associated complications.

Fabry App: the value of a portable technology in recording day-to-day patient monitored information in patients with Fabry disease

BackgroundFabry disease is a rare inherited disorder resulting from deficient α-galactosidase A enzyme activity. Common disease manifestations are sweating abnormalities, neuropathic pain, gastrointestinal symptoms and fatigue. Challenges are faced by health care professionals in evaluating symptom burden in the current clinical setting, and the demand for alternative methods for monitoring disease-specific symptoms has seen an acceleration in recent years. Smartphone technologies offer the potential for continuity of care and surveillance. As a part of a quality improvement project, a disease specific app was developed in collaboration with a software company (Health Touch Ltd) and made available for patient use in May 2018. The Fabry mobile app records five categories: pain, gastrointestinal symptoms, sweating, activity levels, medications. Fabry disease patients with gastrointestinal and pain symptoms attending the Lysosomal Storage Disorders Unit of the Royal Free London NHS Foundation Trust were reviewed to assess eligibility and invited to download the app for recording their symptoms (activity, sweating, pain and gastrointestinal) and medications. Patient-generated data were transmitted to a secure website for clinicians to review.ResultsOne-hundred and thirty-nine symptomatic Fabry disease patients who had a smartphone (iPhone or android) were invited to download the app. Sixty-seven patients (26 males and 41 females; median age, 49 years [range, 20–81]) downloaded and tracked the Fabry App at least once. The median frequency of use per patient was 6 (range, 1–629). Pain in the hands and abdominal pain were significantly higher (p = 0.009 and p = 0.007, respectively) in patients with classic phenotype compared with patients with non-classic phenotypes.ConclusionsWe demonstrated the feasibility and acceptability of a smartphone app to facilitate the remote assessment and monitoring of Fabry disease symptom burden on a daily/weekly basis, as an alternative to the current standard of care that requires patients to recall their symptoms during 6 to 12 monthly annual clinic visits. Patients who were more likely to use the app had greater disease burden. This innovation has the potential to assess disease progression, early therapeutic intervention, thereby decreasing the burden of morbidity and mortality among Fabry patients, and to record long-term effects of Fabry-specific therapies.

MarsGT: Multi-omics analysis for rare population inference using single-cell graph transformer

Rare cell populations are key in neoplastic progression and therapeutic response, offering potential intervention targets. However, their computational identification and analysis often lag behind major cell types. To fill this gap, we introduce MarsGT: Multi-omics Analysis for Rare population inference using a Single-cell Graph Transformer. It identifies rare cell populations using a probability-based heterogeneous graph transformer on single-cell multi-omics data. MarsGT outperforms existing tools in identifying rare cells across 550 simulated and four real human datasets. In mouse retina data, it reveals unique subpopulations of rare bipolar cells and a Müller glia cell subpopulation. In human lymph node data, MarsGT detects an intermediate B cell population potentially acting as lymphoma precursors. In human melanoma data, it identifies a rare MAIT-like population impacted by a high IFN-I response and reveals the mechanism of immunotherapy. Hence, MarsGT offers biological insights and suggests potential strategies for early detection and therapeutic intervention of disease.

E. Coli LPS-induced calcium signaling regulates the expression of hypoxia-inducible factor 1α in periodontal ligament fibroblasts in a non-hypoxia-dependent manner

Periodontitis, an inflammatory disease, can cause significant damage to the oral tissues which support the teeth. During the early development of periodontitis, periodontal ligament fibroblasts (PDLFs) undergo metabolic reprogramming regulated by hypoxia-inducible factor 1α (HIF-1α), which is strongly linked to the progression of inflammation. However, the precise mechanisms by which PDLFs regulate HIF-1α and its associated metabolic reprogramming during early inflammation remain unclear. This study illustrated that brief and low-dose exposure to Escherichia coli (E. coli) lipopolysaccharide (LPS) can serve as a non-hypoxic stimulus, effectively replicating early periodontal inflammatory reactions. This is evidenced by the upregulation of HIF-1α expression and the activation of HIF-1α-mediated crucial glycolytic enzymes, namely lactate dehydrogenase a, pyruvate kinase, and hexokinase 2, concomitant with an augmentation in the inflammatory response within PDLFs. We observed that the effects mentioned and their impact on macrophage polarization were notably attenuated when intracellular and extracellular stores of Ca2+ were depleted using BAPTA-AM and Ca2+-free medium, respectively. Mechanistically, our findings demonstrated that the transcriptional process of HIF-1α is regulated by Ca2+ during E. coli LPS stimulation, mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. Additionally, we observed that the stabilization of intracellular HIF-1α proteins occurs via the endothelin (ET)-1-endothelin A receptor pathway, independent of hypoxia. Taken together, our research outcomes underscore the pivotal involvement of Ca2+ in the onset of early periodontitis by modulating HIF-1α and glycolysis, thereby presenting novel avenues for early therapeutic interventions.

Single-cell and Spatial Transcriptomics Reveals Ferroptosis as The Most Enriched Programmed Cell Death Process in Hemorrhage Stroke-induced Oligodendrocyte-mediated White Matter Injury.

Intracerebral hemorrhage (ICH) is a severe stroke subtype with limited therapeutic options. Programmed cell death (PCD) is crucial for immunological balance, and includes necroptosis, pyroptosis, apoptosis, ferroptosis, and necrosis. However, the distinctions between these programmed cell death modalities after ICH remain to be further investigated. We used single-cell transcriptome (single-cell RNA sequencing) and spatial transcriptome (spatial RNA sequencing) techniques to investigate PCD-related gene expression trends in the rat brain following hemorrhagic stroke. Ferroptosis was the main PCD process after ICH, and primarily affected mature oligodendrocytes. Its onset occurred as early as 1 hour post-ICH, peaking at 24 hours post-ICH. Additionally, ferroptosis-related genes were distributed in the hippocampus and choroid plexus. We also elucidated a specific interaction between lipocalin-2 (LCN2)-positive microglia and oligodendrocytes that was mediated by the colony stimulating factor 1 (CSF1)/CSF1 receptor pathway, leading to ferroptosis induction in oligodendrocytes and subsequent neurological deficits. In conclusion, our study highlights ferroptosis as the primary PCD mechanism, emerging as early as 1 hour post-ICH. Early therapeutic intervention via the suppression of microglial LCN2 expression may alleviate ferroptosis-induced damage in oligodendrocytes and associated neurological deficits, thus offering a promising neuroprotective strategy following ICH.

The Correlation of MicroRNA-21 With the Nephrin, Podocin, and Urinary Albumin-Creatinine Ratio in Patients With Type 2 Diabetes and Albuminuria: A Cross-Sectional Study.

Diabetic kidney disease (DKD) is the most common and deranging microvascular complication of diabetes mellitus (DM). Podocytopathy is a key component of glomerular damage in DKD. Micro RNA-21 (miRNA-21) is an epigenetic regulator that plays a role in podocyte damage; however, the results of previous studies have not resolved the controversy about the role of miRNA-21 in the pathogenesis of DKD. The objective was to investigate the correlation between miRNA-21 levels and urinary nephrin, podocin, and urinary albumin-creatinine ratio (UACR) in patients with type 2 DM and albuminuria. This is a cross-sectional study. This study was carried out in internal medicine outpatient clinic of Cipto Mangunkusumo Hospital Jakarta, Indonesia. This study consisted of 42 adults with type 2 DM and albuminuria. The measurements include (1) Serum miRNA-21; (2) urinary podocin, nephrin, and albumin-creatinine ratio; and (3) serum miRNA-21 correlated to urinary podocin, nephrin, and albumin-creatinine ratio. The Spearman bivariate analysis to assess the correlation of miRNA-21 with nephrin, podocin, and UACR. The mean relative expression of miRNA-21 was 0.069 (0.024), the median for nephrin, podocin, and UACR was 35.5 (15.75-51.25) ng/mL, 0.516 (0.442-0.545) ng/mL, and 150 (94.56-335.75) ng/mL, respectively. A correlation between miRNA-21 and nephrin was observed (r = 0.598; P < .0001). There was a correlation between miRNA-21 and UACR (r = 0.604; P < .0001). No correlation was found between miRNA-21 and podocin. A lack of non-DM and non-albuminuric control population and small sample size. We could not exclude concurrent disease, and all other potential confounding variables, particularly those related to inflammation. The miRNA-21 can be considered an early biomarker for podocytopathy and albuminuria in DM, highlighting its potential for early diagnostic and therapeutic interventions. Further research is required to confirm these findings and explore their clinical applications, which could significantly alter management strategies for DKD.

Peripheral neuropathy associated with severe glial fibrillary acidic protein (GFAP) astrocytopathy: a case report

A 44-year-old man was admitted due to a fever. He developed unconsciousness and respiratory failure, necessitating mechanical ventilation. After the administration of methylprednisolone and intravenous immunoglobulin for suspected autoimmune encephalitis, his consciousness and respiratory state improved. However, he exhibited pronounced tetraparalysis and impaired sensation below the neck. A spinal MRI revealed swelling of the entire spinal cord, indicating myelitis. Deep tendon reflexes were diminished in all extremities, and a nerve conduction study confirmed motor-dominant axonal polyneuropathy. Subsequently, he developed a fever and headache. Brain MRI demonstrated FLAIR hyperintensities in the basal ganglia and brain stem. CSF analysis for anti-glial fibrillary acidic protein (GFAP) antibody turned out positive, leading to the diagnosis of GFAP astrocytopathy. Although the steroid re-administration improved muscle strength in his upper limbs and reduced the range of diminished sensation, severe hemiparalysis remained. Severe GFAP astrocytopathy can be involved with polyneuropathy. Early detection and therapeutic intervention for this condition may lead to a better prognosis.

Serum Amyloid A3 Fuels a Feed-Forward Inflammatory Response to the Bacterial Amyloid Curli in the Enteric Nervous System

BackgroundMounting evidence suggests a role for the gastro-intestinal microbiome as a determinant of peripheral immunity and central neurodegeneration, but the local disease mechanisms remain unknown. Given its potential relevance for early diagnosis and therapeutic intervention, we set out to map the pathogenic changes induced by bacterial amyloids in the gastro-intestinal tract and its enteric nervous system. MethodsTo examine the early response, we challenged primary murine myenteric networks with curli, the prototypic bacterial amyloid, and performed shotgun RNA sequencing and multiplex ELISA. Using enteric neurosphere-derived glial and neuronal cell cultures, as well as in vivo curli injections into the colon wall, we further scrutinized curli-induced pathogenic pathways. ResultsCurli induced a pro-inflammatory response, with marked upregulation of Serum Amyloid A3 (Saa3) and the secretion of several cytokines. This pro-inflammatory state was primarily induced in enteric glia, was accompanied by elevated levels of DNA damage and replication, and triggered the influx of immune cells in vivo. The addition of recombinant SAA3 was sufficient to recapitulate this specific pro-inflammatory phenotype while Saa3 knock-out attenuated curli-induced DNA damage and replication. Like curli, recombinant SAA3 caused a strong upregulation of Saa3 transcripts, indicating a feed-forward loop. Colonization of curli-producing Salmonella and Dextran Sulphate Sodium (DSS)-induced colitis caused a significant increase in Saa3 transcripts, indicating a central role for SAA3 in enteric dysfunction. Inhibition of dual leucine zipper kinase (DLK), an upstream regulator of the c-Jun N-terminal kinase (JNK) pathway responsible for SAA3 production, attenuated curli- and SAA3-induced Saa3 upregulation, DNA damage and replication in enteric glia. ConclusionsOur results position SAA3 as an important mediator of gastro-intestinal vulnerability towards bacterial-derived amyloids and demonstrate the potential of DLK inhibition to dampen enteric pathology.

Prognostic Factors of In-hospital Mortality in Patients without Human Immunodeficiency Virus Infection with Pneumocystis Pneumonia: A Retrospective Cohort Study.

Objective This study explored the prognostic factors of in-hospital mortality in patients with Pneumocystis pneumonia (PCP) without human immunodeficiency virus (HIV) infection, using a Japanese nationwide inpatient database. Methods We extracted the data of patients with PCP without HIV infection between July 2010 and March 2022 from the Diagnosis Procedure Combination database. We performed multivariable logistic regression analyses to identify the prognostic factors of in-hospital mortality in with PCP without HIV infection. Results We identified 1,704 patients with PCP without HIV infection and 404 (23.7%) in-hospital deaths. Higher in-hospital mortality was associated with advanced age, male sex (odds ratio [OR], 1.45; 95% confidence interval [CI], 1.06-2.00), a low Barthel index score, non-hematological malignancy (OR, 1.81; 95% CI, 1.22-2.70), receipt of mechanical ventilation (OR, 2.49; 95% CI, 1.47-4.21), and administration of antibiotics (OR, 1.52; 95% CI, 1.12-2.06) and antifungal drugs (OR, 1.83; 95% CI, 1.26-2.67). Lower in-hospital mortality was associated with connective tissue disease and vasculitis (OR, 0.55; 95% CI, 0.37-0.81), hematological malignancy (OR, 0.59; 95% CI, 0.38-0.93), and early trimethoprim-sulfamethoxazole treatment (OR, 0.63; 95% CI, 0.44-0.90). Conclusions These findings will help physicians identify patients who may benefit from early aggressive therapeutic interventions.

Navigating the cancer care continuum: A comparative study of Black and White breast cancer patients.

Despite improvements in early detection and therapeutic interventions, the mortality rate for Black breast cancer patients is still significantly higher than that of White breast cancer patients. This study seeks to understand differences in the patient experience that lead to this disparity. Semi-structured interviews were conducted to understand the breast cancer treatment process and patient experiences. This study collected health services and timeline data from medical records. Based on these two data sources, the patient's journey in breast cancer treatment was mapped and a thematic analysis was conducted to identify challenges and barriers in the process. The cancer care continuum consists of four stages-diagnosis, surgery, chemotherapy/radiation, and follow-up care. The themes contributing to patient experiences and challenges were identified and compared in each stage for both Black and White patients. Both Black and White participants faced challenges related to financial constraints, treatment changes, lack of autonomy, and insufficient emotional support. However, Black participants additionally faced significant barriers in terms of cultural concordance, effective patient-provider communication, and delay in diagnosis. This study highlights the importance of incorporating effective provider-patient communication, navigation, and emotional support, especially for Black breast cancer patients throughout the cancer care continuum to address healthcare disparities.

Incorporating a new disease in the newborn screening programs in Europe: the spinal muscular atrophy case study

Patient advocacy organizations have a forefront role in ensuring that patients’ voices and needs are embedded as a constitutive basis in drug development, diagnosis, and policy recommendations in the healthcare ecosystem. Their sustained involvement in accelerating the policy changes for inclusion of additional diseases in the newborn screening (NBS) programs, supporting harmonization in terms of number of screened diseases across the European Union, constitutes a driving force for advancing the quality of care and the management of rare diseases by aligning NBS policies and practices internationally. In the current European landscape, NBS varies significantly across regions and countries. Patient advocacy organizations are acting to alert healthcare authorities of the existing inequity in NBS and recommending that additional diseases be added to the national NBS programs. Here, we describe the state of play for Spinal Muscular Atrophy (SMA) as a model for advancing NBS for rare diseases where a treatment regime is available. Ultimately, a broad understanding of NBS for SMA will additionally serve as a means to understand the financial impact of early therapeutic intervention for a rare disease.

Polygenic risk for Alzheimer's disease is associated with neuroaxonal damage before onset of clinical symptoms.

Establishing valid diagnostic strategies is a precondition for successful therapeutic intervention in Alzheimer's disease (AD). One hundred forty-four healthy 75-year-old participants from the Vienna-Transdanube-Aging longitudinal cohort study were tested for neuroaxonal damage by single molecular array (Simoa) plasma neurofilament light chain (NfL) levels at baseline, 30, 60, and 90 months, and onset of AD dementia. Individual risk for sporadic AD was estimated by continuous shrinkage polygenic risk score (PRS-CS, genome-wide association study). Nineteen participants developed AD after a median of 60 months (interquartile range 30). In participants with AD, baseline NfL plasma levels correlated with PRS-CS (r=0.75, p<0.001; difference to controls: Fisher's r-to-z: z=3.89, p<0.001). PRS-CS combined with baseline plasma NfL predicted onset of AD (p<0.01). Our data suggest that polygenic risk for AD and plasma NfL closely interact years before onset of clinical symptoms. Peripheral NfL may serve as a diagnostic measure supporting early therapeutic intervention and secondary prevention in AD.

Chronic thromboembolic pulmonary hypertension: the diagnostic assessment.

Chronic Thromboembolic Pulmonary Hypertension (CTEPH) presents a significant diagnostic challenge due to its complex and often nonspecific clinical manifestations. This review outlines a comprehensive approach to the diagnostic assessment of CTEPH, emphasizing the importance of a high index of suspicion in patients with unexplained dyspnea or persistent symptoms post-acute pulmonary embolism. We discuss the pivotal role of multimodal imaging, including echocardiography, ventilation/perfusion scans, CT pulmonary angiography, and magnetic resonance imaging, in the identification and confirmation of CTEPH. Furthermore, the review highlights the essential function of right heart catheterization in validating the hemodynamic parameters indicative of CTEPH, establishing its definitive diagnosis. Advances in diagnostic technologies and the integration of a multidisciplinary approach are critical for the timely and accurate diagnosis of CTEPH, facilitating early therapeutic intervention and improving patient outcomes. This manuscript aims to equip clinicians with the knowledge and tools necessary for the efficient diagnostic workflow of CTEPH, promoting awareness and understanding of this potentially treatable cause of pulmonary hypertension.

Role of carotid-femoral (aortic) pulse wave velocity measurement in the evaluation of cardiovascular risk in children with idiopathic nephrotic syndrome

Introduction and objective: The study was aimed to evaluate carotid-femoral (aortic) pulse wave velocity (cfPWV) in children with idiopathic nephrotic syndrome. Materials and methods: A total of 48 children with idiopathic nephrotic syndrome were enrolled in the study, including 35 patients in acute phase and 32 in remission. In 19 patients, measurements were performed twice: in relapse and in remission. The control group consisted of 22 healthy children. In all children, cfPWV measurements were performed. Selected clinical, biochemical parameters and fetuin-A concentrations were determined. Results: The patients with idiopathic nephrotic syndrome had significantly higher cfPWV both in relapse and in remission, as compared to the control group. Fetuin-A levels were significantly lower in both phases of the disease than in the healthy controls. cfPWV in relapse positively correlated with body weight, body mass index, systolic, diastolic, mean and pulse pressure. cfPWV in remission positively correlated with body weight, residual proteinuria, and total and low-density lipoproteins cholesterol. Systolic blood pressure in relapse, body weight, and total cholesterol in remission were found to be independent risk factors for increased cfPWV. Total cholesterol in remission was an independent risk factor for an increase of cfPWV to height rate. Conclusions: Increased cfPWV in children with idiopathic nephrotic syndrome indicates the possibility of premature cardiovascular complications. Significant effects of the modifiable risk factors, such as arterial pressure, body weight and disturbances of lipid metabolism, on arterial stiffness may contribute to early diagnostic and therapeutic interventions to improve the prognosis in patients with idiopathic nephrotic syndrome. Measurements of cfPWV may be useful in the assessment of cardiovascular risk in children with idiopathic nephrotic syndrome.

Akut mastoidite ikincil nadir görülen bir otojenik beyin apsesi tablosu

Otogenic brain abscess, precipitated by acute mastoiditis, is a rare but potentially fatal condition. It constitutes an intracranial complication that can further develop due to meningitis and sigmoid sinus thrombosis. This case underscores the critical importance of early detection and therapeutic intervention, which often pose substantial clinical challenges. This report elucidates the case of a 35-year-old female who arrived with severe otalgia, noted predominantly on the right side, coupled with discharge and vertigo. Subsequent neuroimaging unveiled the presence of basal meningitis in the right cerebellar hemisphere, accompanied by an extradural abscess and coalescent mastoid air cells. The patient's treatment protocol entailed a rigorous antibiotic regimen, continually adjusted based on symptomatic improvement. The rapid diagnosis and immediate treatment of otogenic brain abscesses are paramount. As observed in our case, factors such as limited medical knowledge, oversight in medical care, and socio-economic disadvantages contributed to the severity of the intracranial complication. These elements highlight the necessity of addressing systemic factors in healthcare to ensure effective prevention and management of such conditions.