Progressive Functional Impairment Research Articles

Design of Promising Thiazoloindazole-Based Acetylcholinesterase Inhibitors Guided by Molecular Docking and Experimental Insights.

Alzheimer's disease is characterized by a progressive deterioration of cognitive function and memory loss, and it is closely associated with the dysregulation of cholinergic neurotransmission. Since acetylcholinesterase (AChE) is a critical enzyme in the nervous system, responsible for breaking down the neurotransmitter acetylcholine, its inhibition holds a significant interest in the treatment of various neurological disorders. Therefore, it is crucial to develop efficient AChE inhibitors capable of increasing acetylcholine levels, ultimately leading to improved cholinergic neurotransmission. The results reported here represent a step forward in the development of novel thiazoloindazole-based compounds that have the potential to serve as effective AChE inhibitors. Molecular docking studies revealed that certain of the evaluated nitroindazole-based compounds outperformed donepezil, a well-known AChE inhibitor used in Alzheimer's disease treatment. Sustained by these findings, two series of compounds were synthesized. One series included a triazole moiety (Tl45a-c), while the other incorporated a carbazole moiety (Tl58a-c). These compounds were isolated in yields ranging from 66 to 87% through nucleophilic substitution and Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions. Among the synthesized compounds, the thiazoloindazole-based 6b core derivatives emerged as selective AChE inhibitors, exhibiting remarkable IC50 values of less than 1.0 μM. Notably, derivative Tl45b displays superior performance as an AChE inhibitor, boasting the lowest IC50 (0.071 ± 0.014 μM). Structure-activity relationship (SAR) analysis indicated that derivatives containing the bis(trifluoromethyl)phenyl-triazolyl group demonstrated the most promising activity against AChE, when compared to more rigid substituents such as carbazolyl moiety. The combination of molecular docking and experimental synthesis provides a suitable and promising strategy for the development of new efficient thiazoloindazole-based AChE inhibitors.

Extracellular Vesicles Derived from Human Liver Stem Cells Counteract Chronic Kidney Disease Development and Cardiac Dysfunction in Remnant Kidney Murine Model: The Possible Involvement of Proteases

Fibrosis is a marker of chronic kidney disease (CKD) and consists of the accumulation of the extracellular matrix (ECM) components, causing the progressive deterioration of kidney function. Human liver stem cells (HLSCs) have anti-fibrotic activity, and HLSC-derived extracellular vesicles (EVs) mediate this effect. Herein, we evaluated the ability of HLSC-EVs to reverse renal and cardiac alterations in a murine model of partial nephrectomy (PNx) that mimics human CKD development. Furthermore, we investigated the contribution of extracellular matrix remodeling-related proteases to the anti-fibrotic effect of HLSC-EVs. PNx was performed by ligation of both poles of the left kidney, followed one week later by the removal of the right kidney. EV treatment started 4 weeks after the nephrectomy, when renal and cardiac alternations were already established, and mice were sacrificed at week eight. HLSC-EV treatment improved renal function and morphology, significantly decreasing interstitial fibrosis, glomerular sclerosis, and capillary rarefaction. This improvement was confirmed by the decreased expression of pro-fibrotic genes. Moreover, EV treatment improved cardiac function and reduced cardiac fibrosis. HLSC-EVs shuttled different proteases with ECM remodeling activity, and matrix metalloproteinase 1 (MMP-1) was involved in their anti-fibrotic effect on renal tissue. HLSC-EV treatment interferes with CKD development and ameliorates cardiomyopathy in PNx mice.

Fibrosing cholestatic hepatitis as a variant of the course of hepatotropic viruses’ infection

Fibrosing cholestatic hepatitis is a special variant of infectious hepatitis, with a rapid progressive deterioration of liver function, and usually results in immunosuppression. It has also been reported in patients with immunocompetent status having viral hepatitis B and C. Fibrosing cholestatic hepatitis is diagnosed based on the histological examination of the liver tissue, which reveals severe damage to hepatocytes with pronounced ballooning over a weak inflammatory reaction, pericellular and perisinusoidal fibrosis, and intracellular and tubular cholestases. Analysis of the literature confirms the authors’ assumption that pathological changes in the liver, described as fibrosing cholestatic hepatitis, can develop in different conditions under the influence of various infectious agents. Despite the availability of effective antiviral therapy for hepatitis B and C, the outcomes of fibrosing cholestatic hepatitis are often unfavorable, particularly in cases not associated with solid-organ transplantation. Currently, because of the emergence of numerous drugs that selectively act on the immune system and the development of new areas of medicine such as hematology, rheumatology, oncology, transplantology, and infectious diseases, doctors in these specialties increasingly encounter severe liver damage in patients receiving specific therapy. The authors believe that doctors who do not work at liver transplantation centers underestimate the possibility of fibrosing cholestatic hepatitis development in patients with viral hepatitis B and C, in the clinic of infectious and internal diseases.

#3087 Phenotype of extracellular vesicles in diabetic kidney disease with albuminuria

Abstract Background and Aims Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) and affects more than 40% of patients with type 2 diabetes mellitus (T2D). The pathogenesis of CKD is multifactorial and leads to a clinical presentation with diverse phenotypes characterised by proteinuria and/or progressive deterioration of renal function, thus urging the search for new non-invasive biomarkers that allow early diagnosis and the development of new therapeutic targets. Urinary extracellular vesicles (EVs) have emerged as an alternative, as changes in their number and composition have been described in clinical conditions associated with DM and kidney disease. EVs are able to interact with neighbouring and/or distant cells by transferring their cargo, rich in proteins, lipids or nucleic acids, from progenitor cells to recipient cells, thus participating in cell-to-cell communication processes. The aim of the present study was to analyse the different phenotypes of EVs in T2D patients with different degrees of albuminuria compared to healthy controls, as well as their correlation with the degree of albuminuria. Method A cohort of 69 subjects (49 patients with T2DM and 20 healthy volunteers) was analysed. The phenotype of EVu present between the two groups was assessed, as well as the association between the different cell lines and the presence of albuminuria. Statistical analysis was performed using Spearman correlations. Analyses were performed with R software. Results A positive correlation was observed between EVu from podocytes (PODO+) and those from macrophagocytes (R = 0.3180, p-value = 0.0082), as well as a positive association between PODO+ and neutrophil EVu, both in the whole cohort and when analysing only patients with diabetes (R = 0.3225, p-value:0.0254). When assessing the association of EVu with the degree of albuminuria, we observed a direct association with proximal tubule EVu (R: 0.3158, p-value 0.0271) both in all subjects (T2D and HV) and only in those with T2D (R = 0.4200, p-value = 0.0056). When stratifying according to the degree of albuminuria (A1, A2 and A3), we still observed a dependent association of the degree of glomerular involvement with the number of EVu of TCP (A1: mean 5.5 (SD 4.1); A2: mean 12.3 (SD 30.9); A3: mean 132.5 (SD 322.8)) p-value: 0.0609. Conclusion The results presented suggest a relevant role of TCP in the glomerular involvement of patients with DKD, in line with the emergence of new therapeutic lines such as iSGLT2. The study suggests new lines of research aimed at developing therapeutic targets that assess the cellular expression of EVu.

#2923 Intracardiac vascular access as a last resort for hemodialysis in patients with exhausted traditional vascular access: a case report

Abstract Introduction The dysfunction of vascular access (VA) constitutes one of the main problems faced by nephrologists and patients in chronic hemodialysis (HD). This challenge becomes particularly worrying in patients who have depleted their upper extremity venous resources and have no longer arteriovenous fistula available, requiring the placement of a central venous catheters. It leads to an increase in morbidity and mortality and a higher of infections, thrombosis and exhaustion of access points. In such cases, alternatives to conventional VA are limited, with intracardiac access being an emerging option, albeit with very limited documented experience. Case Report We describe the case of a 68-year-old male with a history of hypertension, nasopharyngeal carcinoma in 2012 treated with chemotherapy and radiotherapy. In 2018 he was diagnosed with low-grade urothelial bladder carcinoma (PT1G1) that infiltrated the subepithelial corion while sparing the muscular layer. He also had severe hydronephrosis with impaired renal function, requiring radical cystoprostatectomy with Bricker bladder reconstruction and subsequent bilateral nephrostomy due to persistent dilatation and progressive deterioration of renal function. He began chronic HD in June 2020 through a left femoral catheter due to the inability to access the upper thoracic vascular tree due to stenosing fibrosis from previous radiotherapy. He was placed on the waiting list for a kidney transplant (KT) in the right iliac fossa but experienced multiple catheter dysfunction episodes, requiring the placement of a right femoral venous catheter to continue with his HD sessions. Additionally, peritoneal dialysis was not considered due to previous urological surgery. Considering the limitation of VA and the possibility of KT as its best alternative, we opted for the insertion of a tunnelled intracardiac catheter at the right atrium. This procedure was conducted by the Cardiac Surgery Department on 03/12/2021 through a median sternotomy in the 4th intercostal space. A permanent hemodialysis catheter was inserted in the right atrium through the 3rd intercostal space and fixed with a purse-string suture. It was then tunnelled under the breast to the 2nd intercostal space through a counter-incision. The cuff was appropriately placed in the subcutaneous tissue (Figs 1 and 2). The intervention proceeded without any complication and the catheter exhibited normal functionality. After that, the patient received anticoagulation with enoxaparin the days between dialysis sessions. Consequently, the right femoral catheter was safely removed. Two weeks later, the patient successfully received a KT from a deceased donor. He was discharged on the day 11st post-KT with any complication and maintains a good renal function after 2 years of follow-up with a serum creatinine 1.7 mg/dL (eGFR: 39 ml/min). The intracardiac catheter was removed one month later through a mini-thoracotomy. Conclusions Intracardiac VA is an unusual and high-risk resource that seems an alternative in patients with exhausted VA with no alternative emergency renal replacement therapy, so it should be considered as the last resort. In the case of our patient, the implantation of this catheter allowed for the continuation of dialysis and access to KT.

Continuous Markov Models for Analyzing the Effect of Environmental Personal Exposure on Multiple Sclerosis Progression.

Multiple sclerosis (MS) is an inflammatory autoimmune demyelinating disorder of the central nervous system, leading to progressive functional impairments. Predicting disease progression with a probabilistic and time-dependent approach might help suggest interventions for a better management of the disease. Recently, there has been increasing focus on the impact of air pollutants as environmental factors influencing disease progression. This study employs a Continuous-Time Markov Model (CMM) to explore the impact of air pollution measurements on MS progression using longitudinal data from MS patients in Italy between 2013 and 2022. Preliminary findings indicate a relationship between air pollution and MS progression, with pollutants like Particulate Matter with a diameter of 10 micrometers (PM10) or 2.5 micrometers (PM2.5), Nitrogen Dioxide (NO2), and Carbon Monoxide (CO) showing potential effects on disease activity.

Revealing novel biomarkers for diagnosing chronic kidney disease in pediatric patients

Pediatric chronic kidney disease (CKD) is a clinical condition characterized by progressive renal function deterioration. CKD diagnosis is based on glomerular filtration rate, but its reliability is limited, especially at the early stages. New potential biomarkers (citrulline (CIT), symmetric dimethylarginine (SDMA), S-adenosylmethionine (SAM), n-butyrylcarnitine (nC4), cis-4-decenoylcarnitine, sphingosine-1-phosphate and bilirubin) in addition to creatinine (CNN) have been proposed for early diagnosis. To verify the clinical value of these biomarkers we performed a comprehensive targeted metabolomics study on a representative cohort of CKD and healthy pediatric patients. Sixty-seven children with CKD and forty-five healthy children have been enrolled in the study. Targeted metabolomics based on liquid chromatography-triple quadrupole mass spectrometry has been used for serum and plasma samples analysis. Univariate data analysis showed statistically significant differences (p < 0.05) in the concentration of CNN, CIT, SDMA, and nC4 among healthy and CKD pediatric patients. The predictive ability of the proposed biomarkers was also confirmed through specificity and sensitivity expressed in Receiver Operating Characteristic curves (AUC = 0.909). In the group of early CKD pediatric patients, AUC of 0.831 was obtained, improving the diagnostic reliability of CNN alone. Moreover, the models built on combined CIT, nC4, SDMA, and CNN allowed to distinguish CKD patients from healthy control regardless of blood matrix type (serum or plasma). Our data demonstrate potential biomarkers in the diagnosis of early CKD stages.

Age-dependent dynamics of neuronal VAPBALS inclusions in the adult brain

Amyotrophic Lateral Sclerosis (ALS) is a relentlessly progressive and fatal disease, caused by the degeneration of upper and lower motor neurons within the brain and spinal cord in the ageing human. The dying neurons contain cytoplasmic inclusions linked to the onset and progression of the disease. Here, we use a Drosophila model of ALS8 (VAPP58S) to understand the modulation of these inclusions in the ageing adult brain.The adult VAPP58S fly shows progressive deterioration in motor function till its demise 25 days post-eclosion. The density of VAPP58S-positive brain inclusions is stable for 5–15 days of age. In contrast, adding a single copy of VAPWT to the VAPP58S animal leads to a large decrease in inclusion density with concomitant rescue of motor function and lifespan. ER stress, a contributing factor in disease, shows reduction with ageing for the disease model. Autophagy, rather than the Ubiquitin Proteasome system, is the dominant mechanism for aggregate clearance.We explored the ability of Drosophila Valosin-containing protein (VCP/TER94), the ALS14 locus, which is involved in cellular protein clearance, to regulate age-dependent aggregation. Contrary to expectation, TER94 overexpression increased VAPP58S punctae density, while its knockdown led to enhanced clearance. Expression of a dominant positive allele, TER94R152H, further stabilised VAPP58S puncta, cementing roles for an ALS8-ALS14 axis. Our results are explained by a mechanism where autophagy is modulated by TER94 knockdown.Our study sheds light on the complex regulatory events involved in the neuronal maintenance of ALS8 aggregates, suggesting a context-dependent switch between proteasomal and autophagy-based mechanisms as the larvae develop into an adult. A deeper understanding of the nucleation and clearance of the inclusions, which affect cellular stress and function, is essential for understanding the initiation and progression of ALS.

Late Presentation of Pulmonary Hypertension Crisis Concurrent with Atrial Arrhythmia after Atrial Septal Defect Device Closure

Background: ASD occurs when there is a septal defect between the right and left atria, resulting in a left-to-right shunt that increases the volume of the right heart and pulmonary circulation. Increased pulmonary resistance can lead to pulmonary hypertension (PH), resulting in progressive deterioration of right ventricular function, leading to right heart failure and death. Prolonged elevation of atrial pressure induces progressive atrial dilatation and electrophysiological remodelling. Together with autonomic modulation, this leads to atrial arrhythmias (AAs). Patients with significant shunts leading to ventricular volume overload are considered for ASD closure. However, in some cases, PH occurs after ASD closure.  Case Presentation: We report a 21 yo man diagnosed with ASD Secundum Post Closure with Device (September 1th, 2023) and Pulmonary Hypertension Crisis. The left atria (LA), right atria (RA) and right ventricle (RV) were dilated. We also found moderate mitral regurgitation, severe tricuspid regurgitation, and mild to moderate pulmonary regurgitation. There was a decline in systolic function in the right ventricle, and grade III diastolic dysfunction in left ventricle. There was a well-seated device with no residual shunt on interatrial septal. The pulmonary arteries were confluence and dilated. From ECG we found atrial flutter with variable conduction. This patient was transferred to HCU. This patient treated with digoxin, furosemide, milrinon, ceftriaxone, miniaspi, sildenafil, electrophysiology, and 3D ablation.  Conclusion: Pulmonary hypertension can occur in cases of congenital heart defects, such as ASD. The operative management of ASD is closure of the ASD, but in some unique groups, this can lead to pulmonary hypertensive crisis after its closure.

Loss of LpqM proteins in Mycobacterium abscessus is associated with impaired intramacrophage survival.

Mycobacterium abscessus causes persistent infections in patients with underlying pulmonary diseases, resulting in progressive lung function deterioration. The rough (R) morphotype is well-established as associated with chronic and more aggressive infections in patients. In this study, we individually and simultaneously deleted the MAB_1470c and MAB_1466c genes in M. abscessus S, without observing changes in colony morphotypes. However, these mutants exhibited a severe impairment in their ability to survive within human macrophages, highlighting the critical role of these two lipoproteins in M. abscessus virulence.

Neuro-regression Assessment- A Case Report

Introduction: Neuro-regression can occur for various reasons, including neurodegenerative diseases such as Alzheimer's disease, certain genetic disorders, brain injuries, infections, toxic exposures, or metabolic disorders. It is often characterized by a progressive deterioration of neurological function over time. Neuro-regression can be caused by a variety of factors, including, Neurodegenerative diseases, Genetic disorders, Brain injuries, Infections, Toxic exposures, and Metabolic disorders. Objective: The goal of this case report is to highlight the difference between developmental delay and developmental regression also known as Neuro-Regression in terms of differential diagnosis. Case Report: A 2.2-year-old male child, with a background of developmental delay and epilepsy was admitted with multiple episodes of breakthrough seizures. Developmental milestones were age-appropriate till 11 months of age (before the seizure). After the seizure, the child’s motor development regressed and the child was not able to sit, or stand. The speech and language milestones were appropriate to the age before the seizure and regressed after the seizure. Conclusion: In our study, it's very clear that the child experiencing neuro-regression which is evident based on the parents’ report, previous and present clinical assessments as well and clinical observation. Regression is an indication that more investigation is necessary and team members like a Developmental Paediatrician, Neurologist, and Clinical Psychologist should be involved.

Population longitudinal analysis of Gait Profile Score and North Star Ambulatory Assessment in children with Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) is a rare X-linked recessive disorder characterized by loss-of-function mutations in the gene encoding dystrophin. These mutations lead to progressive functional deterioration including muscle weakness, respiratory insufficiency, and musculoskeletal deformities. Three-dimensional gait analysis (3DGA) has been used as a tool to analyze gait pathology through the quantification of altered joint kinematics, kinetics, and muscle activity patterns. Among 3DGA indices, the Gait Profile Score (GPS), has been used as a sensitive overall measure to detect clinically relevant changes in gait patterns in children with DMD. To enhance our understanding of the clinical translation of 3DGA, we report here the development of a population nonlinear mixed-effect model that jointly describes the disease progression of the 3DGA index, GPS, and the functional endpoint, North Star Ambulatory Assessment (NSAA). The final model consists of a quadratic structure for GPS progression and a linear structure for GPS-NSAA correlation. Our model was able to capture the improvement in function in GPS and NSAA in younger subjects, as well as the decline of function in older subjects. Furthermore, the model predicted NSAA (CFB) at 1 year reasonably well for DMD subjects ≤7 years old at baseline. The model tended to slightly underpredict the decline in NSAA after 1 year for those >7 years old at baseline, but the prediction summary statistics were well maintained within the standard deviation of observed data. Quantitative models such as this may help answer clinically relevant questions to facilitate the development of novel therapies in DMD.

Abstract 3411: Health-related quality of life trajectories in older breast cancer survivors and noncancerous controls over ten years: SEER-MHOS analysis

Abstract Background: The adverse effects of cancer treatment on health-related quality of life (HRQOL) are the primary concern of older women diagnosed with breast cancer. The interplay of transient and progressive functional impairments caused by cancer therapies alongside the accelerated physical declines associated with the normal aging process are all negatively correlated to HRQL, yet it remains unclear whether this is an effect of cancer or solely aging; therefore, this study examined HRQL trajectory over ten years after diagnosis between cancer cases and controls. Methods: The cancer group included 1467 women (age ≥ 65) diagnosed with primary breast cancer in 1998 - 2012, registered in the Surveillance, Epidemiology, End Results (SEER) cancer registry, and completed Medical Health Outcomes (MHO) surveys before and after cancer diagnosis. Propensity score-matched controls were randomly selected with a 1:1 ratio. Participants reported their HRQOL using SF-36/VR-12. It was summarized into two summary scores (Physical Component Summary [PCS] and mental component summary [MCS]) and eight domain scores (physical functioning [PF], role limitation due to physical health [RP], bodily pain [BP], general health [GH], vitality [VT], social functioning [SF], mental health [MH], and role limitation due to emotional problem [RE]). Hierarchical linear modeling was utilized to assess the main effects of time and group and the interaction effect between time and group on HRQOL trajectory. Results: At diagnosis, cases fared worse than controls for all HRQOL domains and summary scores. Over the ten years, PCS, PF, GH, RP, SF, and VT worsened over time (all P for time &amp;lt; 0.05), while MCS, MH, and RE remained relatively constant over time (all P for time ≥ 0.05). Older women with breast cancer had lower HRQL over time than controls in PCS, GH, and RP domains, while they showed higher HRQOL than controls post 4 - 7 years in PF, SF, RE, and VT domains (all P for group &amp;lt; 0.05). However, only RE showed a statistically significant interaction effect (P =0.035), improving over time in cases but worsening in controls. Conclusions: This research shows both older women with breast cancer and propensity-matched controls experiencing deterioration of HRQOL, particularly physical health domains, over ten years after baseline, with cases’ HRQOL kept lower than controls over time. Needs assessment and more efficient interventions to improve physical health HRQOL among older women are warranted. Citation Format: Eunkyung Lee, Maria Azevedo Daruge, Katia Ferdowsi, Jianbin Zhu. Health-related quality of life trajectories in older breast cancer survivors and noncancerous controls over ten years: SEER-MHOS analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3411.

Neuroprotective effects of rutin against cuprizone-induced multiple sclerosis in mice

Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative disease of the central nervous system that injures the myelin sheath, provoking progressive axonal degeneration and functional impairments. No efficient therapy is available at present to combat such insults, and hence, novel safe and effective alternatives for MS therapy are extremely required. Rutin (RUT) is a flavonoid that exhibits antioxidant, anti-inflammatory, and neuroprotective effects in several brain injuries. The present study evaluated the potential beneficial effects of two doses of RUT in a model of pattern-III lesion of MS, in comparison to the conventional standard drug; dimethyl fumarate (DMF). Demyelination was induced in in male adult C57BL/6 mice by dietary 0.2% (w/w) cuprizone (CPZ) feeding for 6 consecutive weeks. Treated groups received either oral RUT (50 or 100 mg/kg) or DMF (15 mg/kg), along with CPZ feeding, for 6 consecutive weeks. Mice were then tested for behavioral changes, followed by biochemical analyses and histological examinations of the corpus callosum (CC). Results revealed that CPZ caused motor dysfunction, demyelination, and glial activation in demyelinated lesions, as well as significant oxidative stress, and proinflammatory cytokine elevation. Six weeks of RUT treatment significantly improved locomotor activity and motor coordination. Moreover, RUT considerably improved remyelination in the CC of CPZ + RUT-treated mice, as revealed by luxol fast blue staining and transmission electron microscopy. Rutin also significantly attenuated CPZ-induced oxidative stress and inflammation in the CC of tested animals. The effect of RUT100 was obviously more marked than either that of DMF, regarding most of the tested parameters, or even its smaller tested dose. In silico docking revealed that RUT binds tightly within NF-κB at the binding site of the protein-DNA complex, with a good negative score of −6.79 kcal/mol. Also, RUT-Kelch-like ECH-associated protein 1 (Keap1) model clarifies the possible inhibition of Keap1–Nrf2 protein–protein interaction. Findings of the current study provide evidence for the protective effect of RUT in CPZ-induced demyelination and behavioral dysfunction in mice, possibly by modulating NF-κB and Nrf2 signaling pathways. The present study may be one of the first to indicate a pro-remyelinating effect for RUT, which might represent a potential additive benefit in treating MS.Graphical

Phase 2 study of the efficacy and safety of ponsegromab in patients with cancer cachexia: PROACC-1 study design.

Cancer cachexia is a multifactorial metabolic wasting syndrome characterized by anorexia, unintentional loss of weight involving both skeletal muscle and adipose tissues, progressive functional impairment and reduced survival. Therapeutic strategies for this serious condition are very limited. Growth differentiation factor 15 (GDF-15) is a cytokine that is implicated in cancer cachexia and may represent both a biomarker of cancer cachexia and a potential therapeutic target. Ponsegromab is a potent and selective humanized monoclonal antibody that inhibits GDF-15-mediated signalling. Preclinical and preliminary phase 1 data suggest that ponsegromab-mediated inactivation of circulating GDF-15 may lead to improvement in key characteristics of cachexia. The primary objective of this phase 2 study is to assess the effect of ponsegromab on body weight in patients with cancer, cachexia and elevated GDF-15 concentrations. Secondary objectives include assessing physical activity, physical function, actigraphy, appetite, nausea and vomiting, fatigue and safety. Exploratory objectives include evaluating pharmacokinetics, pharmacodynamics, immunogenicity, lumbar skeletal muscle index and Response Evaluation Criteria in Solid Tumors. Approximately 168 adults with non-small-cell lung, pancreatic or colorectal cancers who have cachexia and elevated GDF-15 concentrations will be randomized in a double-blind, placebo-controlled study (NCT05546476). Participants meeting eligibility criteria will be randomized 1:1:1:1 to one of three dose groups of ponsegromab (100, 200 or 400mg) or matching placebo administered subcutaneously every 4weeks for an initial 12-week treatment period. This is followed by optional open-label treatment with ponsegromab of 400mg administered every 4weeks for up to 1year. The primary endpoint is mean change from baseline in body weight at Week 12. A mixed model for repeated measures followed by a Bayesian Emax model will be used for the primary analysis. Secondary endpoints include physical activity, physical function and actigraphy measured by remote digital sensors; patient-reported appetite-related symptoms assessed by Functional Assessment of Anorexia-Cachexia Therapy subscale scores; anorexia/appetite, nausea and vomiting, and fatigue evaluated according to questions from the Cancer-Related Cachexia Symptom Diary; and incidence of adverse events, safety laboratory tests, vital signs and electrocardiogram abnormalities. Cancer-related cachexia is an area of significant unmet medical need. This study will support the clinical development of ponsegromab as a novel inhibitor of GDF-15, which may ameliorate key pathologies of cancer cachexia to improve patient symptoms, functionality and quality of life. ClinicalTrials.gov ID: NCT05546476.

Perioperative and long-term results of ultrasonography-guided single- and multiple-tract percutaneous nephrolithotomy for staghorn calculi.

It is possible that this condition will lead to urosepsis and progressive deterioration of renal function in the absence of surgical intervention. Several recent clinical studies have shown that multi-tract percutaneous nephrolithotomy (M-PCNL) has a similar stone free rate (SFR) as standard percutaneous nephrolithotomy (S-PCNL). As a result, M-PCNL was also recommended as a treatment option for staghorn calculi. To examine the perioperative and long-term results of ultrasonography-guided single- and M-PCNL. This was a retrospective cohort study. Between March 2021 and January 2022, the urology department of our hospital selected patients for the treatment of staghorn calculi using percutaneous nephrolithotomy. The primary outcomes were complication rate and SFR, and the characteristics of patients, operative parameters, laboratory measurements were also collected. In total, 345 patients were enrolled in the study (186 in the S-PCNL group and 159 in the M-PCNL group). The SFR in the M-PCNL group was significantly higher than that in the S-PCNL group (P = 0.033). Moreover, the incidence rates of hydrothorax (P = 0.03) and postoperative infection (P = 0.012) were higher in the M-PCNL group than in the S-PCNL group. Logistic regression analysis demonstrated that post-operative white blood cell count (OR = 2.57, 95%CI: 1.90-3.47, P < 0.001) and stone size (OR = 1.59, 95%CI: 1.27-2.00, P < 0.001) were associated with a higher overall complication rate in the S-PCNL group. Body mass index (OR = 1.22, 95%CI: 1.06-1.40, P = 0.004) and stone size (OR = 1.70, 95%CI: 1.35-2.15, P < 0.001) were associated with increased overall complications in the M-PCNL group. Multiple access tracts can facilitate higher SFR while slightly increasing the incidence of acceptable complications.

Severe acyclovir induced neurotoxicity in an elderly woman with end-stage renal disease and herpes zoster : A case report

Acyclovir (ACV) is a widely utilized antiviral medication for treating herpes simplex virus, cytomegalovirus, and varicella-zoster virus (VZV). Despite its usefulness, ACV can lead to adverse effects like acute renal impairment. ACV is predominantly eliminated through the kidneys, and in cases of renal impairment, there exists a potential for elevated levels, posing a risk of subsequent neurotoxicity. This case highlights the challenges posed by ACV use in patients with compromised renal function. A 64-year-old female presented with unconsciousness persisting for several hours. She had recently self-administered acyclovir (5x800 mg) to manage a herpes zoster outbreak. She had history of Chronic Kidney Disease (CKD) Stage V but refused hemodialysis. She had irregular heart rate of 140-180 beats per minute (with EKG confirming Atrial Fibrillation Rapid Response), a respiratory rate of 26 breaths per minute. Other vital sign was stable. Physical examination identified herpes zoster lesions on the right abdomen. Laboratory results shown blood urea nitrogen of 266 mg/dL, creatinine 13.2 mg/dL, and potassium of 6.9 mmol/L . A month earlier, the level of blood urea nitrogen was 100 mg/dL and creatinine was 7.9 mg/dL, indicating a progressive deterioration in renal function. Given the severity of the patient's condition, hemodialysis was initiated. Over the course of five days, there was a notable improvement in both the patient's clinical condition and level of consciousness.

Atrial Fibrillation and Early Vascular Aging: Clinical Implications, Methodology Issues and Open Questions-A Review from the VascAgeNet COST Action.

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with adverse CV outcomes. Vascular aging (VA), which is defined as the progressive deterioration of arterial function and structure over a lifetime, is an independent predictor of both AF development and CV events. A timing identification and treatment of early VA has therefore the potential to reduce the risk of AF incidence and related CV events. A network of scientists and clinicians from the COST Action VascAgeNet identified five clinically and methodologically relevant questions regarding the relationship between AF and VA and conducted a narrative review of the literature to find potential answers. These are: (1) Are VA biomarkers associated with AF? (2) Does early VA predict AF occurrence better than chronological aging? (3) Is early VA a risk enhancer for the occurrence of CV events in AF patients? (4) Are devices measuring VA suitable to perform subclinical AF detection? (5) Does atrial-fibrillation-related rhythm irregularity have a negative impact on the measurement of vascular age? Results showed that VA is a powerful and independent predictor of AF incidence, however, its role as risk modifier for the occurrence of CV events in patients with AF is debatable. Limited and inconclusive data exist regarding the reliability of VA measurement in the presence of rhythm irregularities associated with AF. To date, no device is equipped with tools capable of detecting AF during VA measurements. This represents a missed opportunity to effectively perform CV prevention in people at high risk. Further advances are needed to fill knowledge gaps in this field.

Effect of cancer cachexia on first-line chemotherapy in patients with advanced pancreatic cancer: a claims database study in Japan

BackgroundCancer cachexia is a multifactorial syndrome leading to progressive functional impairment. How cachexia affects the treatment course of chemotherapy in patients with pancreatic cancer has not been well understood.MethodsThis is an exploratory, retrospective, observational cohort study using the Japanese medical claims database from Medical Data Vision Co., Ltd. The study population included patients diagnosed with pancreatic cancer in whom first-line FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (GnP) was initiated between October 1, 2018, and September 30, 2020. In this study, we defined patients with cancer cachexia as those who had a weight loss of ≥ 5% in the preceding 6 months. The primary outcome was time-to-treatment failure (TTF). The observation period was six months from the initiation of first-line FFX or GnP treatment.ResultsA total of 1897 patients (421 patients into the cachexia group; 1476 patients into the non-cachexia group) were analyzed in this study. The median TTF was 121 days (95% confidence interval [CI] 94–146) in the cachexia group and 143 days (95% CI 134–152) in the non-cachexia group. The hazard ratio for TTF of the cachexia versus non-cachexia group was 1.136 (95% CI 0.979–1.319). The median number of doses was two doses fewer in the cachexia group than in the non-cachexia group for both FFX and GnP.ConclusionCancer cachexia was suggested to be associated with shorter TTF and a reduced number of doses in patients with pancreatic cancer who received first-line FFX or GnP treatment.Clinical Trial Registration clinicaltrials.jp: UMIN000045820.

Transradial access embolization of carotid-cavernous fistulae: Case report.

Carotid-Cavernous sinus fistula (CCF) represents a misdiagnosed condition with potential repercussion in functional, neurological, and social roles of patients with this disease. Earlier reports remark on the efficiency and safety of endovascular therapy with resolution of the symptoms were performed appropriately. We present a case of a male patient from a developing country, with gunshot wound head trauma history and short-term progressive functional and neurological impairment in the presence of intracranial hypertension and ocular symptoms who developed a large CFF, subsequently treated by transradial access embolization. We aim to describe the real-world experience in diagnosis and treatment of CCFs, emphasizing on the scope and outcomes of the endovascular treatment. This case supports worldwide experience, positioning endovascular therapy as an effective strategy in the resolution of CFFs, and the relevance of suspecting this disease in the presence of typical symptoms, even if they are rapidly progressive.