Stage Of Disease Research Articles

Defining the role of exertional hypoxemia and pulmonary vasoconstriction on lung function decline, morbidity, and mortality in patients with chronic obstructive lung disease – the PROSA study: rationale and study design

BackgroundChronic obstructive lung disease (COPD) has diverse molecular pathomechanisms and clinical courses which, however, are not fully mirrored by current therapy. Intermittent hypoxemia is a driver of lung function decline and poor outcome, e.g., in patients with concomitant obstructive sleep apnea. Transient hypoxemia during physical exercise has been suggested to act in a similar manner. The PROSA study is designed to prospectively assess whether the clinical course of COPD patients with or without exertional desaturation differs, and to address potential pathophysiological mechanisms and biomarkers.Methods148 COPD patients (GOLD stage 2–3, groups B or C) will undergo exercise testing with continuous pulse oximetry. They will be followed for 36 months by spirometry, echocardiography, endothelial function testing, and biomarker analyses. Exercise testing will be performed by comparing the 6-min walk test (6MWT), bicycle ergometry, and a 15-sec breath-hold test. Exertional desaturation will be defined as SpO2 < 90% or delta-SpO2 ≥ 4% during the 6MWT. The primary endpoint will be the rate of decline of FEV1(LLN) between COPD patients with and without exertional desaturation.DiscussionThe PROSA Study is an investigator-initiated prospective study that was designed to prove or dismiss the hypothesis that COPD patients with exertional desaturation have a significantly more rapid rate of decline of lung function as compared to non-desaturators. A 20% difference in the primary endpoint was considered clinically significant; it can be detected with a power of 90%. If the primary endpoint will be met, exercise testing with continuous pulse oximetry can be used as a ubiquitously available, easy screening tool to prospectively assess the risk of rapid lung function decline in COPD patients at an early disease stage. This will allow to introduce personalized, risk-adapted therapy to improve COPD outcome in the long run. PROSA is exclusively funded by public funds provided by the European Research Council through an ERC Advanced Grant. Patient recruitment is ongoing; the PROSA results are expected to be available in 2028.Trial registrationThe PROSA Study has been prospectively registered at clinicaltrials.gov (register no. NCT06265623, dated 09.02.2024).

Correlation between Corneal Volume and Corneal Biomechanics and Corneal Volume Significance in Staging and Diagnosing Keratoconus.

To investigate the relationship between corneal volume (CV) at different zones and corneal biomechanics in keratoconus (KC) along with the significance of CV in diagnosing and staging KC. This prospective clinical study included 456 keratoconic eyes (Group B) and 198 normal eyes (Group A). Using the topographic KC classification method, Group B was divided into subgroups based on severity (mild, moderate, and severe). The CVs of the 3 mm, 5 mm, and 7 mm zones and biomechanical parameters were obtained by Pentacam and Corvis ST. The diagnostic utility of multirange CVs at different disease stages and severity was determined using a receiver operating characteristic (ROC) curve analysis. The CV of the 7-mm zone had the strongest correlation with A1V, A2T, PD, DA ratio max (2 mm), DA ratio max (1 mm), ARTh, integrated radius, SPA1, and CBI (p < 0.01). The CVs of the Group B subgroups were significantly lower than those of Group A for each diameter range (p < 0.05). There were significant differences between the severe, mild, and moderate subgroups for the 3 mm zone (p < 0.05, all). The 3 mm zone CV exhibited better diagnostic ability in each group for distinguishing KC from the normal cornea (Groups A vs. B: area under the ROC curve (AUC) = 0.926, Groups A vs. B1: AUC = 0.894, Groups A vs. B2: AUC = 0.925, Groups A vs. B3: AUC = 0.953). The CV significantly decreased in keratoconic eyes. Progressive thinning in the 3 mm zone may be a valuable measurement for detecting and staging KC. Combining the CV examination with corneal biomechanical information may effectively enhance the ability to detect KC.

Novel ex-vivo calcification model for human aortic valves reveals patient-specific effect of compound

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dekker grant Background Aortic stenosis (AS) is a narrowing of the aortic valve opening due to calcification and valve thickening. There are currently no pharmacological treatments for AS, and surgical interventions are the only therapies. To understand the molecular mechanisms underlying AS and test new pharmacological agents, advanced calcification models are required. These models need to closely approach native tissue response to stimuli by maintaining the valvular interstitial cells within their native environment. We have recently developed an ex vivo culture model that fulfills this requirement and allows the induction of calcification in slices of human aortic valves. Purpose Our goal is to evaluate the applicability of our ex-vivo calcification model as a pre-clinical test system for potential therapies. Methods Diseased aortic valves were dissected, embedded in agarose, then cut into 300-500 um slices using a vibratome. The use of multiple slices from a single patient ensured proper internal controls. To induce calcification, slices were cultured with 3mM phosphate(n=12), and control slices without phosphate (n=11). To investigate molecular modulation of induced calcification, dexamethasone was added to phosphate cultures(n=9). The slices were assessed for calcification using Alizarin Red staining. ImageJ was used to quantify the percentage of alizarin red-positive area. The average thickness was determined using 3DHISTECH software. Results In the presence of phosphate, a significant increase in the calcification percentage was observed in cultured valve slices compared with cultures without phosphate (p&amp;lt;0.05). Interestingly, within the phosphate-treated group, two sub-groups could be distinguished, one sub-group exhibiting extensive calcification, while the other showed virtually no sign of calcification. Paired comparisons revealed strong effect of dexamethasone depending on the extent of calcification-inducing capability of phosphate in each patient-sample. More precisely, dexamethasone exhibited potent inhibitory effect on calcification in valvular slices from patients where calcification was stimulated in the presence of phosphate. Conversely, dexamethasone exhibited a stimulatory effect on calcification in slices that did not show a stimulation of calcification in the presence of phosphate. This differential effect was strongly correlated with valve thickness.(r=-0.884,p&amp;lt; 0.01). Conclusions Our novel ex-vivo calcification model for human aortic valves revealed potential presence of patient-specific effects of pharmacological agents. Dexamethasone can have both stimulatory and inhibitory effects on calcification levels, influenced by phosphate response and valve thickness. As thickness might be indicative of the disease stage, this correlation suggests that the direction of compound’s effect might depend on disease stage. Hence, proper understanding of potential opposite effects of compounds is crucial in developing novel therapies.

Can Laparoscopic Surgery Reduce Fatigue in Women with Endometriosis?-A Pilot Study.

Background: Fatigue is mentioned as one of the most significant symptoms of endometriosis. The impact of laparoscopic endometriosis surgeries on fatigue remains unknown. The aim of this study was to investigate, for the first time, the effect of laparoscopic surgery in endometriosis patients, with the complete removal of endometriotic lesions, on the severity of fatigue. Methods: This is a single-center prospective pilot study including 58 participants. Participants were recruited at the Tertiary Endometriosis Referral Center of the Medical University of Vienna between February 2020 and November 2021. Thirty patients with histologically proven endometriosis were compared to a control group of 28 patients who underwent a laparoscopy for benign gynecologic conditions other than endometriosis. All participants were interviewed using the Fatigue Severity Scale before their surgery and 6 months afterward. Relationships between variables were established using regression analysis and associations were quantified as odds ratios. Results: Fatigue was significantly more severe preoperatively in patients with endometriosis when compared to controls ((odds ratio (OR): 1.82; 95% confidence interval (CI): 1.24-2.67, p < 0.01). Six months postoperatively, the fatigue severity score of endometriosis patients decreased significantly (p < 0.01). In multivariate analysis, fatigue was significantly associated with endometriosis (OR: 4.50, CI: 1.14-17.8, p < 0.05), when adjusted for abdominal pain and menstrual bleeding. Fatigue in patients with endometriosis was not associated with disease stage or the presence of deep endometriosis. Conclusions: Fatigue is a frequent and bothersome symptom in patients with endometriosis. Within our study, we demonstrated for the first time that fatigue responds to surgical treatment. The management of fatigue is crucial to improving patients' quality of life.

Oropharyngeal Dysphagia Phenotypes Across Huntington’s Disease Stages: Endoscopic Findings and Tongue Pressure Analysis

Background: Oropharyngeal dysphagia (OD) is a common symptom in Huntington’s disease (HD) and is associated with severe health and psychosocial consequences. Different OD phenotypes are defined on the basis of characteristic patterns at fiberoptic endoscopic evaluation of swallowing (FEES), and they may vary during disease progression. Objective: To describe OD phenotypes in different HD stages and to analyze their association with neurological data and tongue pressure measurements. Methods: Twenty-four patients with HD at different stages of disease progression underwent a FEES. Data on penetration/aspiration, pharyngeal residue, and OD phenotypes were gained. Neurological examination was performed with the Unified Huntington’s Disease Rating Scale (UHDRS). Patient Maximum tongue pressure (MTP) and tongue endurance were measured. Results: We confirmed that the occurrence of penetration/aspiration increased with disease duration and pharyngeal residue increased from 16.7% to 100% , respectively. The most common OD phenotypes were oropharyngeal dyspraxia (91.7% ), posterior oral incontinence (87.5% ), and delayed pharyngeal phase (87.5% ). These types of dysfunctions are already detectable in &gt;80% of patients in the early disease stages. In more advanced stages, we also observed propulsion deficit (66.7% ), resistive issue (54.2% ), and protective deficit (37.5% ). Propulsion deficit was associated with higher disease stage, greater motor dysfunction (UHDRS-I), and lower MTP and tongue endurance (p &lt; 0.05). Conclusions: OD in HD results from a combination of different swallowing phenotypes. Early assessment of swallowing and periodical follow-ups are necessary to monitor OD severity and phenotypes and to revise diet recommendations.

Prevalence of Mild Cognitive Impairment and Alzheimer's Disease Identified in Veterans in the United States.

Diagnostic codes can be instrumental for case identification in Alzheimer's disease (AD) research; however, this method has known limitations and cannot distinguish between disease stages. Clinical notes may offer more detailed information including AD severity and can complement diagnostic codes for case identification. To estimate prevalence of mild cognitive impairment (MCI) and AD using diagnostics codes and clinical notes available in the electronic healthcare record (EHR). This was a retrospective study in the Veterans Affairs Healthcare System (VAHS). Health records from Veterans aged 65 years or older were reviewed during Fiscal Years (FY) 2010-2019. Overall, 274,736 and 469,569 Veterans were identified based on a rule-based algorithm as having at least one clinical note for MCI and AD, respectively; 201,211 and 149,779 Veterans had a diagnostic code for MCI and AD, respectively. During FY 2011-2018, likely MCI or AD diagnosis was defined by≥2 qualifiers (i.e., notes and/or codes)≥30 days apart. Veterans with only 1 qualifier were considered as suspected MCI/AD. Over the 8-year study, 147,106 and 207,225 Veterans had likely MCI and AD, respectively. From 2011 to 2018, yearly MCI prevalence increased from 0.9% to 2.2%; yearly AD prevalence slightly decreased from 2.4% to 2.1%; mild AD changed from 22.9% to 26.8%, moderate AD changed from 26.5% to 29.1%, and severe AD changed from 24.6% to 30.7. The relative distribution of AD severities was stable over time. Accurate prevalence estimation is critical for healthcare resource allocation and facilitating patients receiving innovative medicines.

The role of pyroptosis in heart failure and related traditional chinese medicine treatments.

Pyroptosis is a type of programmed cell death that is mediated by both typical and atypical pathways and ultimately leads to the lysis and rupture of cell membranes and the release of proinflammatory factors, triggering an intense inflammatory response. Heart failure (HF) is a serious and terminal stage of various heart diseases. Myocardial hypertrophy, myocardial fibrosis, ventricular remodeling, oxidative stress, the inflammatory response and cardiomyocyte ionic disorders caused by various cardiac diseases are all risk factors for and aggravate HF. Numerous studies have shown that pyroptosis can induce and exacerbate these reactions, causing progression to HF. Therefore, targeting pyroptosis is a promising strategy to treat HF. This paper summarizes the role of pyroptosis in the development of HF and the underlying mechanism involved. Recent research progress on the ability of traditional Chinese medicine (TCM) extracts and formulas to inhibit pyroptosis and treat HF was summarized, and some traditional Chinese medicine extracts and formulas can alleviate different types of HF, including heart failure with preserved ejection fraction (HFpEF), heart failure with reduced ejection fraction (HFrEF), and heart failure with midrange ejection fraction (HFmrEF), by targeting pyroptosis. These findings may provide new ideas and evidence for the treatment or adjuvant treatment of HF by targeting pyroptosis.

Gait Variability as a Potential Motor Marker of Cerebellar Disease-Relationship between Variability of Stride, Arm Swing and Trunk Movements, and Walking Speed.

Excessive stride variability is a characteristic feature of cerebellar ataxias, even in pre-ataxic or prodromal disease stages. This study explores the relation of variability of arm swing and trunk deflection in relationship to stride length and gait speed in previously described cohorts of cerebellar disease and healthy elderly: we examined 10 patients with spinocerebellar ataxia type 14 (SCA), 12 patients with essential tremor (ET), and 67 healthy elderly (HE). Using inertial sensors, recordings of gait performance were conducted at different subjective walking speeds to delineate gait parameters and respective coefficients of variability (CoV). Comparisons across cohorts and walking speed categories revealed slower stride velocities in SCA and ET patients compared to HE, which was paralleled by reduced arm swing range of motion (RoM), peak velocity, and increased CoV of stride length, while no group differences were found for trunk deflections and their variability. Larger arm swing RoM, peak velocity, and stride length were predicted by higher gait velocity in all cohorts. Lower gait velocity predicted higher CoV values of trunk sagittal and horizontal deflections, as well as arm swing and stride length in ET and SCA patients, but not in HE. These findings highlight the role of arm movements in ataxic gait and the impact of gait velocity on variability, which are essential for defining disease manifestation and disease-related changes in longitudinal observations.

Inflammatory Burden Index as a promising new marker for predicting surgical and oncological outcomes in colorectal cancer

AbstractAimsThe prognosis of colorectal cancer (CRC) has been historically reliant on the Tumor Node Metastasis (TNM) staging system, but there is variability in outcomes among patients at similar stages. Therefore, there is an urgent need for more robust biomarkers. The aim of this study was to assess the clinical feasibility of the recently reported Inflammatory Burden Index (IBI) for predicting short‐ and long‐term outcomes in patients with CRC.MethodsThis was a retrospective observational study of 555 CRC patients undergoing surgery for primary tumor resection. We determined the prognostic value of preoperative IBI for disease‐free and overall survival, and its predictive value for perioperative risk of infectious complications, including surgical site infection.ResultsIncreased preoperative IBI was significantly associated with advanced disease stage and poor oncological outcome in CRC patients. Higher IBI was independently linked to poorer disease‐free and overall survival. Similar outcomes were observed in a subanalysis focused on high‐risk stage II and stage III CRC patients. Elevated preoperative IBI was significantly correlated with an increased risk of surgical site infection and other postoperative infectious complications. Propensity score‐matching analysis validated the impact of IBI on the prognosis in CRC patients.ConclusionWe established preoperative IBI as a valuable predictive biomarker for perioperative risks and oncological outcomes in CRC patients. Preoperative IBI is useful for designing effective perioperative management and postoperative oncological follow‐up.

Investigation of the relationship between fatigue with vitamin D, disease stage, anxiety and physical activity level in patients with Parkinson's disease

Investigation of the relationship between fatigue with vitamin D, disease stage, anxiety and physical activity level in patients with Parkinson's disease

Biomarkers of inflammation and neoangiogenesis in premature rupture of membranes

BACKGROUND: Premature rupture of membranes complicates up to 2–10% of full-term pregnancies and up to 40% of all premature pregnancies. It is believed that the main cause of premature rupture of membranes is inflammation caused by both infectious agents and autoimmune processes. Numerous studies are aimed at searching for biomarkers that can predict inflammation in premature rupture of membranes. AIM: The aim of this study was to determine the levels of pro-inflammatory cytokines such as interleukin-6, -18 and procalcitonin, as well as interferon-α and soluble endoglin, in the blood serum of pregnant women with premature rupture of membranes and women in labor with timely discharge of amniotic fluid and evaluate the possibility of using these parameters to optimize obstetric tactics. MATERIALS AND METHODS: This study included 69 patients delivered at the Clinic of Obstetrics and Gynecology of the Academician I.P. Pavlov First Saint Petersburg State Medical University from January 2022 to March 2023. The main study group consisted of 53 pregnant women with premature rupture of membranes, the control group included 16 women with term labor and timely discharge of amniotic fluid, or amniotomy performed in the first stage of labor. The levels of interleukin-6, -18, interferon-α, procalcitonin and soluble endoglin in maternal peripheral blood were assessed using enzyme-linked immunosorbent assay. Pregnancies complicated by severe preeclampsia, placenta abruption and chronic maternal diseases in the acute stage were excluded from the study. RESULTS: At the time of rupture, the minimum gestational age was 33+0 weeks and the maximum age — 41+3 weeks. The median duration of the anhydrous interval was 31.8 hours. No significant differences in interleukin-6, -18, procalcitonin and soluble endoglin concentrations were revealed in the main and control groups, interferon-α level being higher in the comparison group. The median concentration of interferon-α in pregnant women with premature rupture of membranes was 1.64 pg/ml and in women with timely discharge of amniotic fluid — 4.61 pg/ml (p = 0.001). A weak direct correlation was revealed between soluble endoglin and interleukin-18 concentrations (R = 0.26; p = 0.03), as well as a moderate direct correlation between soluble endoglin and procalcitonin levels (R = 0.4; p 0.001). CONCLUSIONS: The study did not reveal differences in the concentrations of interleukin-6, -18, procalcitonin and soluble endoglin in the comparison groups. A decrease in interferon-α level in the blood in pregnant women increases the risk of developing premature rupture of membranes. The correlations between soluble endoglin and interleukin-18 or procalcitonin concentrations may indicate an association between different mechanisms of the pathogenesis of premature rupture of membranes. In this regard, an integrated approach and analysis of a combination of several cellular bioregulators are eligible to predict infectious complications in premature rupture of membranes.

The influence of acute lifestyle changes on NAFLD evolution in a multicentre cohort: a matter of body composition.

Unhealthy lifestyles represent a key element fueling Non-alcoholic fatty liver disease (NAFLD) onset and worsening. We aimed to evaluate the effects of forced acute lifestyle changes on NAFLD evolution. 187 NAFLD patients were followed two years pre- and two years during the lockdown social restrictions in three Italian medical centers. For each patient, biochemical, clinical, non-invasive liver fibrosis, nutritional, and body composition data were collected. An increase in fats and carbohydrate intake associated with impaired weekly physical activity during the lockdown was demonstrated as well as an increase in body mass index and waist-hip-ratio (p < 0.0001 for all). Total cholesterol, low-density lipoprotein, high-density lipoprotein, triglycerides, glucose, insulin, homeostatic model assessment for insulin resistance, and transaminases worsened during the lockdown (glucose: p = 0.0007; p < 0.0001 for the others). Moreover, NAFLD fibrosis score, liver stiffness, and controlled attenuation parameter were also impaired during the same period (p < 0.0001 for all). The bioelectrical impedance analysis (BIA) evidenced an increase of fat mass (FM), and a reduction of free fat mass (FFM) and body cell mass (BCM) (p < 0.0001 for all). The lockdown overall hepatocellular carcinoma (HCC) and Milan-out HCC occurrence revealed Hazard Ratio (HR): 2.398, 95% Confidence Interval (CI):1.16-5, p = 0.02, and HR:5.931, CI:2-17.6, p = 0.008 respectively. A liver disease stage and comorbidities independent association between both the assessed outcomes and body composition analysis in terms of mean values and variation (T1-T2 Δ) was demonstrated. The acute lifestyle changes impacted NAFLD evolution via body composition modifications negatively influencing the HCC occurrence.

The serum tenascin C level is a marker of metabolic disorder-related inflammation affecting pancreatic cancer prognosis

Obesity is a risk factor for pancreatic cancer development, partly due to the tissue environment of metabolic disorder-related inflammation. We aimed to detect a tissue environment marker triggered by obesity-related metabolic disorders related to pancreatic cancer progression. In murine experiments, Bl6/j mice fed a normal diet (ND) or a high-fat diet (HFD) were orthotopically injected with mPKC1, a murine-derived pancreatic cancer cell line. We used stocked sera from 140 pancreatic cancer patients for analysis and 14 colon polyp patients as a disease control. Compared with ND-fed mice, HFD-fed mice exhibited obesity, larger tumors, and worse prognoses. RNA sequencing of tumors identified tenascin C (TNC) as a candidate obesity-related serum tissue environment marker with elevated expression in tumors of HFD-fed mice. Serum TNC levels were greater in HFD-fed mice than in ND-fed mice. In pancreatic cancer patients, serum TNC levels were greater than those in controls. The TNC-high group had more metabolic disorders and greater CA19-9 levels than did the TNC-low group. There was no relationship between serum TNC levels and disease stage. Among 77 metastatic patients treated with chemotherapy, a high serum TNC concentration was an independent poor prognostic factor. Pancreatic cancer patients with high serum TNC levels experienced progression more rapidly.

Expression of CD44 is associated with aggressiveness in seminomas

BackgroundTesticular germ cell tumors (TGCTs) exhibit diverse biological and pathological features and are divided in two main types, seminomas and nonseminomatous germ cell tumors (NSGCTs). CD44 is a cell surface receptor, which is highly expressed in malignancies and is implicated in tumorigenesis affecting cell-matrix interactions and cell signaling.Methods and resultsHere, we examined the expression of CD44 in tumor cell lines and in patients’ material. We found that CD44 is over-expressed in TGCTs compared to normal tissues. Immunohistochemical staining in 71 tissue specimens demonstrated increased expression of CD44 in some patients, whereas CD44 was absent in normal tissue. In seminomas, a high percentage of tumor and stromal cells showed cytoplasmic and/or cell surface staining for CD44 as well as increased staining for CD44 in the tumor stroma was found in some cases. The increased expression of CD44 either in tumor cells or in stromal components was associated with tumor size, nodal metastasis, vascular/lymphatic invasion, and disease stage only in seminomas. The increased stromal expression of CD44 in TGCTs was positively associated with angiogenesis.ConclusionsCD44 may exhibit diverse biological functions in seminomas and NSGCTs. The expression of CD44 in tumor cells as well as in tumor stroma fosters an aggressive phenotype in seminomas and should be considered in disease treatment.

Evaluation of stem cell therapies in companion animal disease models: A concise review (2015-2023).

Companion animals in veterinary medicine develop multiple naturally occurring diseases analogous to human conditions. We previously reported a comprehensive review on the feasibility, safety, and biologic activity of using novel stem cell therapies to treat a variety of inflammatory conditions in dogs and cats (2008-2015) [1]. The purpose of this review is to provide an updated summary of current studies in companion animal disease models that have evaluated stem cell therapeutics that are relevant to human disease. Here we have reviewed the literature from 2015 to 2023 for publications on stem cell therapies that have been evaluated in companion animals, including dogs, cats, and horses. The review excluded case reports or studies performed in experimentally induced models of disease, studies involving cancer, or studies in purpose-bred laboratory species such as rodents. We identified 45 manuscripts meeting these criteria, an increase from 19 that were described in the previous review [1]. The majority of studies were performed in dogs (n=28), with additional studies in horses (n=9) and cats (n=8). Disease models included those related to musculoskeletal disease (osteoarthritis, tendon/ligament injury), neurologic disease (canine cognitive dysfunction, intervertebral disc disease, spinal cord injury) gingival/dental disease (gingivostomatitis), dermatologic disease (atopic dermatitis), chronic multi-drug resistant infections, ophthalmic disease (keratoconjunctivitis sicca, eosinophilic keratitis, immune mediated keratitis), cardiopulmonary disease (asthma, degenerative valve disease, dilated cardiomyopathy), gastrointestinal disease (inflammatory bowel disease, chronic enteropathy) and renal disease (chronic kidney disease). The majority of studies reported beneficial responses to stem cell treatment, with the exception of those related to more chronic processes such as spinal cord injury and chronic kidney disease. However, it should also be noted that 22 studies were open-label, baseline-controlled trials and only 12 studies were randomized and controlled, making overall study interpretation difficult. As noted in the previous review, improved regulatory oversight and consistency in manufacturing of stem cell therapies is needed. Enhanced understanding of the temporal course of disease processes using advanced -omics approaches may further inform mechanisms of action and help define appropriate timing of interventions. Future directions of stem cell-based therapies could include use of stem-cell derived extracellular vesicles, or cell conditioning approaches to direct cells to specific pathways that are tailored to individual disease processes and stages of illness.

The impact of treatment for childhood classical Hodgkin lymphoma according to the EuroNet-PHL-C2 protocol on serum anti-Müllerian Hormone.

What is the impact of the EuroNet-PHL-C2 treatment protocol for children with classical Hodgkin lymphoma (cHL) on gonadal function in girls, based on assessment of serum anti-Müllerian hormone (AMH)? Serum AMH levels decreased after induction chemotherapy and increased during subsequent treatment and 2 years of follow-up, with lowest levels in patients treated for advanced stage cHL. Treatment for cHL, particularly alkylating agents and pelvic irradiation, can be gonadotoxic and result in premature reduction of primordial follicles in females. The current EuroNet-PHL-C2 trial aims to reduce the use of radiotherapy in standard childhood cHL treatment, by intensifying chemotherapy. This study aims to assess the gonadotoxic effect of the EuroNet-PHL-C2 protocol. This international, prospective, multicenter cohort study is embedded in the EuroNet-PHL-C2 trial, an European phase-3 treatment study evaluating the efficacy of standard cHL treatment with OEPA-COPDAC-28 (OEPA: vincristine, etoposide, prednisone, and doxorubicin; COPDAC-28: cyclophosphamide, vincristine, prednisone, and dacarbazine) versus intensified OEPA-DECOPDAC-21 (DECOPDAC-21: COPDAC with additional doxorubicin and etoposide and 25% more cyclophosphamide) in a randomized setting. Participants were recruited between January 2017 and September 2021. Female patients aged ≤18 years, treated according to the EuroNet-PHL-C2 protocol for cHL were recruited across 18 sites in the Netherlands, Belgium, Germany, Austria, and Czech Republic. All parents and patients (aged ≥12 years old) provided written informed consent. Serum AMH levels and menstrual cycle characteristics were evaluated over time (at diagnosis, one to three times during treatment and 2 up to 5 years post-diagnosis) and compared between treatment-levels (TL1, TL2, and TL3) and treatment-arms (OEPA-COPDAC-28 and OEPA-DECOPDAC-21). Serum samples obtained from patients after receiving pelvic radiotherapy were excluded from the main analyses. A total of 104 females, with median age at diagnosis of 15.6 years (IQR 13.7; 17.0), were included in the analysis. Ninety-nine were (post)pubertal. Eighteen girls were diagnosed with an early stage of cHL (TL1) and 86 with intermediate or advanced stage disease (50 TL2 and 36 TL3, 66% received COPDAC-28 and 34% DECOPDAC-21). Five patients received pelvic radiotherapy. Median AMH level at diagnosis was 1.7 µg/l (IQR 0.9; 2.7). After two courses of OEPA chemotherapy, AMH levels decreased substantially in all patients (98% <0.5 µg/l), followed by a significant increase during the consolidation treatment and follow-up. After 2 years, 68% of patients reached their baseline AMH value, with overall median recovery of 129% (IQR 75.0; 208.9) compared to baseline measurement. Five patients (7%) had AMH <0.5 µg/l. In patients treated for advanced stage disease, AMH levels remained significantly lower compared to early- or intermediate stage disease, with median serum AMH of 1.3 µg/l (IQR 0.8; 2.1) after 2 years. Patients who received DECOPDAC-21 consolidation had lower AMH levels during treatment than patients receiving COPDAC-28, but the difference was no longer statistically significant at 2 years post-diagnosis. Of the 35 postmenarchal girls who did not receive hormonal co-treatment, 19 (54%) experienced treatment-induced amenorrhea, two girls had persisting amenorrhea after 2 years. The studied population comprises young girls with diagnosis of cHL often concurring with pubertal transition, during which AMH levels naturally rise. There was no control population, while the interpretation of AMH as a biomarker during childhood is complex. The state of cHL disease may affect AMH levels at diagnosis, potentially complicating assessment of AMH recovery as a comparison with baseline AMH. The current analysis included data up to 2-5 years post-diagnosis. The current PANCARE guideline advises to use the cyclophosphamide-equivalent dose score (CED-score, as an estimation of cumulative alkylating agent exposure) with a cut-off of 6000 mg/m2 to identify females aged <25 years at high risk of infertility. All treatment-arms of the EuroNet-PHL-C2 protocol remain below this cut-off, and based on this guideline, girls treated for cHL should therefore be considered low-risk of infertility. However, although we observed an increase in AMH after chemotherapy, it should be noted that not all girls recovered to pre-treatment AMH levels, particularly those treated for advanced stages of cHL. It remains unclear how our measurements relate to age-specific expected AMH levels and patterns. Additional (long-term) data are needed to explore clinical reproductive outcomes of survivors treated according to the EuroNet-PHL-C2 protocol. The fertility add-on study was funded by the Dutch charity foundation KiKa (project 257) that funds research on all forms of childhood cancer. C.M-K., D.K., W.H.W., D.H., M.C., A.U., and A.B. were involved in the development of the EuroNet-PHL-C2 regimen. The other authors indicated no potential conflicts of interest. N/A.

CircRNA Interference Pathway: A New Target for Intervention in Different Stages of Heart Failure.

Cardio-cerebrovascular disease has seen a rapid rise in recent years, with Heart Failure (HF) -- a terminal stage of various cardiovascular diseases -- also on the rise. HF has a complex pathogenesis involving multiple factors, such as inflammation, fibrosis, and oxidative stress. Due to its unique reverse shear mechanism, HF exhibits distinct expression patterns across different diseases. CircRNA has been linked to conditions like cancer, diabetes, and osteoarthritis. This article briefly introduces the mechanisms of circRNA biogenesis and its associated biological functions, focusing on CircSLC8A1-1, CircRNA_000203, and others at the early stage of HF, CircRNA PAN3, CircRNA (ACR), and others during the progression of HF, and CircHIPK3, CircNfix, and others at the end stage of HF. These circRNAs play a participatory role in the exact mechanism. As a research method, circRNA can be utilized to study the pathogenesis of heart failure and serve as a target for drug discovery and development. Therefore, circRNA's ability to mark the disease at different stages has significant guiding implications for HF monitoring, treatment, and prognosis.

Electrocardiographic features in the early differential diagnosis of cardiac amyloidosis from cardiac sarcoidosis

Abstract Introduction Amyloidosis and sarcoidosis are both systemic infiltrative diseases which can cause cardiac involvement. Differentiating early-stage cardiac amyloidosis (CA) from cardiac sarcoidosis (CS) is still challenging, although hypertrophy for CA and septal thinning for CS are characteristic echocardiographic findings in each late-stage. The diagnosis is a time-sensitive issue, given the therapies for CA and CS likely to be effective at early disease stages. Purpose We aimed to evaluate the utility of electrocardiography (ECG) for distinguishing CA from CS before or early in the course of cardiomyopathy. Methods This study enrolled 36 consecutive patients (20 male, 75±13 years) diagnosed with transthyretin-CA in 25 (CA group) and isolated CS in 11 patients (CS group) according to accepted criteria at our institute from July 2014 to July 2023. We retrospectively reviewed electrocardiographic characteristics and clinical outcomes of early-stage CA and CS. Results The CS group were younger than the CA group at the time of diagnosis (59±9 vs 83±7 years, P&amp;lt;0.01) and had a shorter period between the date of their first ECG recording at our institute and the date of diagnosis (18±3 vs 62±67 months, P=0.012). Furthermore, the CA group showed specific P-waves with longer duration (142±19 vs 126±8 ms, P=0.003) and more notches and/or fragmentation (91% vs 33%, P=0.003) in the limb leads on the initial ECG than the CS group, although prolonged PR-interval is common in both CA and CS (191±44 vs. 208±43 ms, P=0.359). Unexpectedly, the CA group had a shorter QRS duration (103±25 vs 123±31 ms, P=0.047) and a higher R-wave in V5 (2.0±0.9 vs 1.3±1.1 mV, P=0.039) than the CS group. In addition, the low voltage in all limb leads, pseudoinfarct pattern and bundle branch block morphology characteristic of CA patients did not differ between diagnosis and initial examination. There were also no differences in atrial and ventricular arrhythmias. During the follow-up period, 5 patients (20%) in the CA group, but no patients in the CS group died. Conclusion CA and CS shares several electrocardiographic features. Prolonged P-wave with notches and fragmentation, suggesting atrial conduction disturbance, may be associated with amyloid deposition in CA. This finding might be useful in the early differential diagnosis for CA from CS.

Proteomic dissection of vanishing white matter pathogenesis

Vanishing white matter (VWM) is a leukodystrophy caused by biallelic pathogenic variants in eukaryotic translation initiation factor 2B. To date, it remains unclear which factors contribute to VWM pathogenesis. Here, we investigated the basis of VWM pathogenesis using the 2b5ho mouse model. We first mapped the temporal proteome in the cerebellum, corpus callosum, cortex, and brainstem of 2b5ho and wild-type (WT) mice. Protein changes observed in 2b5ho mice were then cross-referenced with published proteomic datasets from VWM patient brain tissue to define alterations relevant to the human disease. By comparing 2b5ho mice with their region- and age-matched WT counterparts, we showed that the proteome in the cerebellum and cortex of 2b5ho mice was already dysregulated prior to pathology development, whereas proteome changes in the corpus callosum only occurred after pathology onset. Remarkably, protein changes in the brainstem were transient, indicating that a compensatory mechanism might occur in this region. Importantly, 2b5ho mouse brain proteome changes reflect features well-known in VWM. Comparison of the 2b5ho mouse and VWM patient brain proteomes revealed shared changes. These could represent changes that contribute to the disease or even drive its progression in patients. Taken together, we show that the 2b5ho mouse brain proteome is affected in a region- and time-dependent manner. We found that the 2b5ho mouse model partly replicates the human disease at the protein level, providing a resource to study aspects of VWM pathogenesis by highlighting alterations from early to late disease stages, and those that possibly drive disease progression.

Simplifying the Creation of the Ulnar Basilic Arteriovenous Fistula: The Royal Wave Position – A Case Series

ABSTRACT While the radio-cephalic arterio-venous fistula (RCAVF) remains the procedure of choice for hemodialysis, the value of the ulnar-basilic arterio-venous fistula (UBAVF) is perhaps underappreciated. The challenge of placing the forearm in a suitable and comfortable position for both the surgeon and the patient during the creation of the UBAVF may be an important factor inhibiting its use. We present a new method of hand positioning in the creation of the UBAVF that we have termed the “Royal Wave” position, which facilitates both patient comfort and surgical access intraoperatively. Patients suffering from chronic kidney disease stage -V were operated upon for the creation of UBAVF following the standardized protocol in the Royal Wave position. Patency (by Color Doppler) was recorded before discharge. Patients were clinically followed up for a period of 3 months. A total of five patients (four males) with the age range of 43–66 years were studied. The position was found to be comfortable for patients and suitable for surgeons. All five patients had successful creation of fistulas that remained patent, which was documented by Doppler report prior to discharge. The patients were followed up till 3 months post fistula creation. Thrombosis was not seen in any patient, and the basilic veins arterialized and were used for dialysis in all five patients. This innovation in positioning, the “Royal Wave” position improves the comfort of both the operator and the patient during surgery, and merits consideration when creating a UBAVF.