Prolonged Life Expectancy Research Articles

Personalized Stem Length Optimization in Hip Replacement: A Microscopic Perspective on Bone—Implant Interaction

Total hip replacement (THR) surgery involves the removal of necrotic tissue and the replacement of the natural joint with an artificial hip joint. The demand for THR is increasing due to population aging and prolonged life expectancies. However, the uniform length and shape of artificial hip joints can cause stress shielding, leading to implant loosening and femoral fractures. These issues arise because these designs fail to account for the unique anatomical and biomechanical characteristics of individual patients. Therefore, this study proposes and validates a method to optimize stem length by considering bone microstructure and daily load. The results demonstrated that the optimal stem length varies with loading conditions and significantly reduces stress in the cortical bone while maintaining an appropriate strain energy in the cancellous bone, thereby preventing bone loss. These findings underscore the importance of patient-specific stem design for improving implant stability and clinical outcomes.

Pediatric Dental Care and Antibiotics: A Comprehensive Update

Abstract Antimicrobial agents, a foundational component of contemporary medical practice, have significantly transformed the management of microbial infections, effectively protecting human well-being and prolonging life expectancy. Nevertheless, this extraordinary advancement faces a mounting challenge in the form of antimicrobial resistance (AMR). The ongoing evolution of microorganisms to withstand the impact of these substances has led to a decline in the efficacy of formerly dependable treatments, thereby presenting a critical menace to medical progress and prompting an exigent need for action. This paper undertakes a comprehensive exploration of the utilisation and correct application of antimicrobials within the context of paediatric dental healthcare. By meticulously examining the intricate interplay between therapeutic efficacy and the emergence of AMR, the overview delves into the pivotal function these agents fulfil in both preventing and treating dental infections in young patients. In addition, this update sheds light on the potential repercussions stemming from improper prescription practices, unwarranted overutilisation and insufficient adherence to established guidelines.

Potential roles of lipases and antioxidases on longevity under nutrient restriction in two Argopecten scallops with distinct lifespans

Nutrient restriction (NR) extends lifespan in many species. High latitudes are characterized by cold-water temperature and food limitations, where bivalves may mimic NR like vertebrates, which could result in a prolonged life expectancy. The long-lived Peruvian scallop (7–10 years) distributes naturally at relatively higher latitudes than the annual bay scallop. However, the relationship and the mechanism underlying the food availability and lifespan are unclear in bivalves. In this study, the genetic response to NR was first investigated in bivalves with distinct lifespans. Peruvian scallops persistently responded to NR mainly via metabolic pathways, but that began to play roles in bay scallops after 56 days. Significant down-regulated expression of long-chain saturated fatty acid synthetase in both two scallops and increased expression of SCD5 and LIPN2 in Peruvian scallops might contribute to MUFA accumulation under NR. SOD1 was more highly expressed in Peruvian scallops than in bay scallops under NR, and strong autophagy was detected only in Peruvian scallops. Peruvian scallops presented much lower MDA levels and higher SOD1 activities than bay scallops. These findings help us understanding the role of lipases and antioxidases in longevity of bivalves, and provided potential biomarkers for breeding long-lived larger scallops.

Utilizing diffusion tensor imaging as an image biomarker in exploring the therapeutic efficacy of forniceal deep brain stimulation in a mice model of Alzheimer’s disease

Objective.With prolonged life expectancy, the incidence of memory deficits, especially in Alzheimer's disease (AD), has increased. Although multiple treatments have been evaluated, no promising treatment has been found to date. Deep brain stimulation (DBS) of the fornix area was explored as a possible treatment because the fornix is intimately connected to memory-related areas that are vulnerable in AD; however, a proper imaging biomarker for assessing the therapeutic efficiency of forniceal DBS in AD has not been established.Approach.This study assessed the efficacy and safety of DBS by estimating the optimal intersection volume between the volume of tissue activated and the fornix. Utilizing a gold-electroplating process, the microelectrode's surface area on the neural probe was increased, enhancing charge transfer performance within potential water window limits. Bilateral fornix implantation was conducted in triple-transgenic AD mice (3 × Tg-AD) and wild-type mice (strain: B6129SF1/J), with forniceal DBS administered exclusively to 3 × Tg-AD mice in the DBS-on group. Behavioral tasks, diffusion tensor imaging (DTI), and immunohistochemistry (IHC) were performed in all mice to assess the therapeutic efficacy of forniceal DBS.Main results.The results illustrated that memory deficits and increased anxiety-like behavior in 3 × Tg-AD mice were rescued by forniceal DBS. Furthermore, forniceal DBS positively altered DTI indices, such as increasing fractional anisotropy (FA) and decreasing mean diffusivity (MD), together with reducing microglial cell and astrocyte counts, suggesting a potential causal relationship between revised FA/MD and reduced cell counts in the anterior cingulate cortex, hippocampus, fornix, amygdala, and entorhinal cortex of 3 × Tg-AD mice following forniceal DBS.Significance.The efficacy of forniceal DBS in AD can be indicated by alterations in DTI-based biomarkers reflecting the decreased activation of glial cells, suggesting reduced neural inflammation as evidenced by improvements in memory and anxiety-like behavior.

Low prevalence of peptic ulcer disease in hospitalized patients with cystic fibrosis: A national database study

BackgroundAlthough cystic fibrosis (CF) is widely considered a lung disease, the prevalence of CF-specific gastrointestinal symptoms and diseases has continued to rise. Peptic ulcer disease (PUD) has not been well-studied among people with CF (PwCF) and may be a common cause of abdominal symptoms. In PwCF, impaired bicarbonate secretion and unbuffered gastric acid production have been attributed to the development of ulcers, although ulcers remain uncommon. The objective of this study was to evaluate the prevalence of PUD in PwCF and assess for possible contributing factors. MethodsThis study utilized the National Inpatient Sample (NIS) database. All patients 18 years or older with CF were identified from 2014 to 2019. Relevant patient characteristics and procedures were identified using ICD-9 and ICD-10 codes. Linear trend, bivariate analyses, and multiple regression analysis were performed. The outcomes of interest were peptic ulcer disease, pancreatic insufficiency, and nonalcoholic steatohepatitis or NASH. All analyses accounted for complex sampling scheme of the NIS. ResultsThe total prevalence of PwCF in the National Inpatient Sample (NIS) database was 0.08 %, and the number was stable year to year from 2014 to 2019. Hispanic patients were more likely to be diagnosed with PUD than other white (aOR 1.802 [1.311,2.476]). Multiple regression analysis indicated that PUD in PwCF was strongly associated with a diagnosis of NASH (aOR 2.421[1.197, 4.898]). PUD patients were less likely to have pancreatic insufficiency compared to the non-PUD group (aOR 0.583 [0.455, 0.745]). ConclusionAlthough cystic fibrosis has been historically known as a disease of childhood, advancements in therapy have led to prolonged life expectancy and higher prevalence for cystic fibrosis-related digestive diseases. This study revealed a low prevalence of PUD in PwCF. Hispanics and those with NASH are more likely to develop peptic ulcers.

Non-Invasive Ventilation for Children Affected by Duchenne Muscular Dystrophy in Ukraine

Background: Duchenne Muscular Dystrophy (DMD) poses significant challenges, especially in Low- and Middle-Income Countries (LMIC) with limited access to Non-Invasive Mechanical Ventilation (NIV), which prolongs life expectancy. Two years after Stage 1 of the successfull “1500 years of survival” NIV programme commenced with 8 DMD boys in Ukraine in 2021, this study further explores the Stage 2 of the programme in 2023. Method: DMD patients underwent a 5-day training program at the National Children’s Clinical Hospital “Okhmatdyt” in Kyiv, Ukraine, utilizing donated second-hand bilevel intermittent positive presure ventilators. Indications for NIV included: sleep-related symptoms, high Apnea-Hypopnea Index (AHI>10 events/hour), decreased Forced Vital Capacity (FVC=50%), low minimum saturation during sleep (SpO2<88%), or age above 17 years. Parallel Masterclass on NIV was conducted for Ukrainian healthcare professionals and patients’ parents. Findings: Thirteen DMD inpatients, aged (mean ± standard deviation) 14.8±2.6 years and FVC of 1.8±0.4L (65.5±22.8% predicted value) were enrolled. Criteria for NIV initiation were: age>17 years (n: 4), FVC% =50% (n :6), AHI>10 (n :2) and SpO2<88% (n :5). Follow-up phone calls were conducted to monitor progress. Three months post-hospitalization, all 13 patients consistently adhered to nocturnal ventilator treatment with a mean use of 7.5 hours per night. Conclusions: Despite the lack of equipment and system of reimbursement, the implementation of the comprehensive Stage 2 training programme supplying NIV for DMD patients in an LMIC such as in Ukraine, was a successful experience. The next steps in the home NIV programme will take place in the coming years.

Timing of SMN replacement therapies in mouse models of spinal muscular atrophy: a systematic review and meta-analysis.

Mutations in the Survival of Motor Neuron 1 gene lead to a loss of survival motor neuron protein in patients with spinal muscular atrophy. Revolutionary advances in gene therapy have led to survival motor neuron-replacement therapies that significantly prolong life expectancy and improve neuromuscular function. However, accumulating evidence suggests that the timing of survival motor neuron-replacement therapies is a critical determinant of success. We performed a systematic review and meta-analysis of all pre-clinical studies testing survival motor neuron replacement therapies in mouse models of spinal muscular atrophy to assess the impact of timing of delivery on therapeutic effectiveness. We incorporated four databases in this pre-registered study (PROSPERO 2020 CRD42020200180): EMBASE, PubMed, Scopus and Web of Science. Inclusion criteria were; primary research article, a measure of survival analysis, use of survival motor neuron mouse model and evaluation of survival motor neuron-targeting therapy. Exclusion criteria included; use of therapies not known to directly target survival motor neuron, genetic manipulations and/or lack of appropriate controls. We screened papers using the SyRF platform. The main outcome we assessed was survival in treated groups compared to untreated groups. We performed meta-analysis of survival using median survival ratio and the random effects model and measured heterogeneity using the I 2 statistic. Subgroup analyses were performed to assess treatment efficacy based on timing of intervention (embryonic delivery, day of birth, postnatal day 2 and postnatal day 3 or later) and treatment type. If detailed in the studies, body weight compared to untreated spinal muscular atrophy models and motor neuron number were included as secondary outcomes for meta-analysis. 3469 studies were initially identified, with 78 ultimately included. Survival motor neuron-replacement therapies significantly affected survival in favour of treatment by a factor of 1.20 (95% CI 1.10-1.30, P < 0.001) with high heterogeneity (I 2 = 95%). Timing of treatment was a significant source of heterogeneity (P < 0.01), with earlier treatment having a greater impact on survival. When stratified by type of treatment, earlier treatment continued to have the strongest effect with viral vector replacement therapy and antisense oligonucleotide therapy. Secondary outcome measures of body weight and spinal motor neuron counts were also positively associated with early treatment. Earlier delivery of survival motor neuron replacement therapies is therefore a key determinant of treatment efficacy in spinal muscular atrophy.

The impact of widowhood on the quality of life of older adults: the mediating role of intergenerational support from children

BackgroundChina’s transition into an aging society is accelerated by the simultaneous decline in fertility rates and the prolonged life expectancy of older adults. The impact of widowhood, a significant stressor in old age, has emerged as a crucial factor affecting the quality of life among the elderly.MethodsThis study is based on data from the 2018 China Health and Aging Tracking Survey. Multiple linear regression models were employed to investigate the influence of widowhood on the quality of life of older adults in China. Additionally, Bootstrap mediation effects were utilized to assess the mediating role of intergenerational support, considering both financial and emotional support from children.ResultsThe findings indicate a substantial reduction in the quality of life index among older adults following widowhood. Moreover, the impact is more pronounced among older men compared to older women. Rural older adults experience a significant decline in quality of life post-widowhood, while the effect on urban counterparts is not statistically significant.ConclusionsIntergenerational financial support was identified as a partial mediator between widowhood and the quality of life among older adults. This underscores the importance of familial financial assistance in mitigating the adverse effects of widowhood on the well-being of the elderly. These results offer valuable insights into the nuanced impact of widowhood on the quality of life among older adults in China, emphasizing the need for targeted interventions, especially in rural areas.Clinical trialNot applicable.

Position paper on essential strategies for healthy aging: focus on preventing sarcopenia and cardiovascular diseases from the 38&lt;sup&gt;th&lt;/sup&gt; National Congress of the Italian Society of Geriatrics Hospital and Territory (SIGOT)

Italy’s demographic setting is rapidly evolving and is characterized by a substantial increase in the older population segment. This trend, driven by prolonged life expectancy and declining birth rates, positions Italy as a leader in global aging patterns. The 38th National Congress of the Società Italiana di Geriatria Ospedale e Territorio (SIGOT), held in Rome, underlined the importance of addressing the health needs of this aging population, particularly focusing on preventing sarcopenia and cardiovascular diseases. Recent data challenge the notion of functional decline as an inevitable consequence of aging, highlighting the interplay of genetic, environmental, and lifestyle factors in modulating health outcomes. Sarcopenia, a prevalent condition and biological substrate of frailty, significantly impacts physical function and mortality rates, necessitating behavioral interventions to mitigate its effects. Physical exercise emerges as a key strategy for maintaining cardiovascular health and reducing the risk of arrhythmias, prevalent in older age groups. However, the complex relationship between physical activity intensity, age, and cardiovascular risk underlines the importance of tailored interventions and preliminary screenings. Looking ahead, proactive measures such as enhanced screening, promoting lifelong healthy habits, research and innovation, robust community support systems, and adaptable policies are essential to address the multifaceted challenges posed by an aging population. With this consensus paper, we aimed to summarize the key messages from the three intensive days of the SIGOT National Congress.

The Role of Oxidative Stress in Hypertension: The Insight into Antihypertensive Properties of Vitamins A, C and E.

Hypertension stands as a pervasive global health challenge, contributing significantly to mortality rates worldwide. Various factors, including lifestyle choices and dietary habits, contribute to the development of hypertension. In recent years, oxidative stress has garnered significant attention as a factor influencing hypertension risk, prompting a shift in research focus towards exploring it as a potential target for prevention and treatment. Antioxidants found in our diet, such as vitamins C, E and carotenoids exhibit the ability to neutralize reactive oxygen species, thereby mitigating oxidative stress. In addition, Vitamin A has an antioxidant effect despite not being an antioxidant itself. Consequently, supplementation or increased intake of these antioxidants has been hypothesized to potentially lower blood pressure levels and aid in the management of hypertension, thereby potentially prolonging life expectancy. Research findings regarding this effect have been diverse. This paper examines the existing literature demonstrating favorable outcomes associated with antioxidant supplementation.

Systematic review of long-term effectiveness of endoscopic gastrojejunostomy in patients presenting with gastric outlet obstruction from periampullary malignancies.

Recently, endoscopic ultrasound-guided (EUS) gastrojejunostomy (GJ) has emerged as an alternative option to surgical palliation and endoscopic duodenal stenting for malignant gastric outlet obstruction (GOO). Although early success rates are commonly reported with the technique, there is a paucity of data regarding the long-term efficacy of this approach. In this study, we investigated long-term outcomes in patients that underwent EUS-guided GJ for palliation of periampullary malignancies. From a total of 192 studies that were reviewed, 6 studies with a follow-up time frame of a minimum of 5months were analyzed, totaling 238 patients. Outcome variables included technical success rate, clinical success rate, adverse events, symptom recurrence, and re-intervention rates. The cohort of 238 patients had a technical success rate of 93.7% and a clinical success rate of 92.9%. A total of 25 patients (10.5%) experienced adverse events associated with EUS-GJ. A total of 14 patients (5.9%) experienced recurrence of GOO symptoms within 5months. A total of 14 patients (5.9%) underwent re-intervention with the first 5months. This systematic review shows that data are scarce regarding long-term effectiveness of EUS-guided GJ. Even though early success rates have been reported, further studies are needed to focus on long-term efficacy of this approach. Until such studies become available, surgical palliation should continue to be the treatment of choice for patients with malignant GOO with a prolonged life expectancy.

Use of Wearables in Frail Institutionalized Older Adults While Ambulating in Different Environments

(1) Prolonged life expectancy often leads to declining health, reduced physical activity, and dependence, especially in institutionalized elderly. Frailty, obesity, limited functionality, and cognitive impairment are common. Physical activity programs for this demographic can increase weekly energy expenditure and improve frailty. Understanding differences in walking indoors versus outdoors is crucial for tailored programs. This study aimed to compare time, energy expenditure, and perceived exertion in institutionalized elderly walking indoors versus outdoors. It also explored how body mass index and cognitive levels affected these factors. (2) Employing a cross-sectional descriptive observational approach, the study gathered data on height, weight, accelerometers, the modified Borg Scale, the Timed Up and Go test, and the Lobo Cognitive Mini-Exam from a sample of 30 institutionalized older adults. (3) Walking outdoors leads to shorter walking times, higher energy expenditure, and increased perceived effort. Overweight individuals expend more energy in both settings, while cognitive impairment does not significantly impact walking preferences. (4) The study concludes that indoor walking is preferable for frail elderly due to lower perceived exertion, but outdoor walking is recommended for overweight individuals. Cognitive status does not influence the choice of walking environment.

Disparities in the prevalence of anxiety and major depressive disorder in patients with lung cancer and the associated risk factors: A retrospective analysis.

e22544 Background: Cancer is a leading cause of mortality and has been associated with an increasing prevalence of psychological disorders. Previous studies indicate that approximately 1 in 8 individuals diagnosed with lung cancer also experience symptoms of depression. Our study aimed to assess the disparities in the prevalence and association of Anxiety and Major depressive disorder (MDD) in lung cancer patients. Methods: Using the National Inpatient Sample 2017-2020, we identified lung cancer patients with regional and advanced metastatic disease. They were divided into two groups - with and without concomitant Anxiety and MDD. Baseline demographic characteristics were analyzed to assess disparities in prevalence, and multivariate logistic regression was used to evaluate the association of Anxiety and MDD in these patients. Results: A total of 461975 patients had lung cancer, and 25780(5%) had concurrent diagnoses of Anxiety and MDD. The anxiety + MDD group had 70% females and 30% males (p &lt; 0.001).Females had an increased likelihood of MDD + Anxiety (OR = 2.36 (2.21-2.52); p &lt; 0.001). Compared to younger patients, older patients were less likely to have MDD + Anxiety ( &gt; 65: OR = 0.45(0.25-0.81); p = 0.008). Compared to the white population, patients of other races had a decreased likelihood of MDD + Anxiety (Black: OR = 0.41( 0.36-0.47), p &lt; 0.001; Hispanic: OR = 0.65( 0.55-0.77), p &lt; 0.001; Other races OR = 0.60(0.48-0.76), p &lt; 0.001). Private insurance and patients without insurance were less likely to have MDD + Anxiety (OR = 0.74(0.67-0.81) and OR = 0.56(0.44-0.71), p &lt; 0.001, respectively). Patients admitted to teaching and large hospitals had an increased likelihood of MDD + Anxiety compared to smaller and nonteaching hospitals (OR = 1.13(1.03-1.24), p = 0.006 and OR = 1.14(1.03-1.25), p = 0.007, respectively). Patients with Hyperlipidemia, Hypertension, COPD, and Obesity were more likely to have MDD + Anxiety (OR = 1.39(1.30-1.48), p &lt; 0.001; OR = 1.11(1.03-1.18), p = 0.002; OR = 1.29(1.21-1.38), p &lt; 0.001 and OR = 1.33(1.22-1.45), p &lt; 0.001 respectively). In contrast, patients with Diabetes had a decreased likelihood of concomitant Anxiety + Depression (OR = 0.92(0.85-0.99), p = 0.04). Lung cancer patients with concurrent Anxiety + MDD had a higher total cost of hospitalization. (+$ 2611(66-5156); p = 0.04). Conclusions: Female lung cancer patients and white individuals had an increased risk of anxiety and depression. Patients with private insurance had decreased risk, and those admitted to larger and teaching hospitals had increased association with these psychological disorders. Devising comprehensive strategies to effectively control underlying psychiatric conditions is crucial for improving outcomes in lung cancer patients, aiming to enhance quality of life and prolong life expectancy.

Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.

Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001). These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

The Impact of Immune System Aging on Infectious Diseases.

Immune system aging is becoming a field of increasing public health interest because of prolonged life expectancy, which is not paralleled by an increase in health expectancy. As age progresses, innate and adaptive immune systems undergo changes, which are defined, respectively, as inflammaging and immune senescence. A wealth of available data demonstrates that these two conditions are closely linked, leading to a greater vulnerability of elderly subjects to viral, bacterial, and opportunistic infections as well as lower post-vaccination protection. To face this novel scenario, an in-depth assessment of the immune players involved in this changing epidemiology is demanded regarding the individual and concerted involvement of immune cells and mediators within endogenous and exogenous factors and co-morbidities. This review provides an overall updated description of the changes affecting the aging immune system, which may be of help in understanding the underlying mechanisms associated with the main age-associated infectious diseases.

Clinical studies with drugs and biologics aimed at slowing or reversing normal aging processes—emerging results and future perspectives

Five families of investigational products are in clinical investigation to slow or reverse normal aging processes [longevity candidates, mesenchymal stem cells, senolytics drugs, sirtuin activators, and nicotinamide adenine dinucleotide (NAD)+ precursors]. The longevity candidates, vitamin D and metformin, appear to significantly reduce all-cause mortality and prolong life expectancy. This should be confirmed by interventional studies. The mesenchymal stem cell family is the most advanced in clinical trial development [phase 2b randomized controlled trial (RCT)]. An allogeneic bone marrow stem cell preparation (Lomecel-B) reduced locomotor frailty in older people. The improvement in locomotion was modest. In the future, attempts could be made to improve potency through a precondition or genetic modification of naive bone marrow stem cells. Autologous adipose stem cell-assisted fat grafting increased graft survival, facial volume, and skin quality. The association of the senolytic drugs dasatinib and quercetin was well tolerated, with low brain penetration of dasatinib and undetectable levels of quercetin. The sirtuin-1 activator resveratrol (combined with physical exercise) improved physical function in older adults with physical limitations. The NAD+ precursor nicotinamide riboside improved physical exercise performance. In conclusion, Lomecel-B is the most advanced agent in clinical trial development for normal aging processes (phase 2b for locomotion frailty), followed by resveratrol and nicotinamide riboside.

Hypoparathyroidism in Patients Older than 10 Years of Age with Beta-thalassemia

Abstract: BACKGROUND: Despite prolonged life expectancy in patients with beta-thalassemia due to modern chelation therapy and planned blood transfusions, they still suffer from multisystem complications of this chronic hemolytic anemia, including endocrine system dysfunction. Under-recognized parathyroid hormone (PTH) dysfunction in these patients can manifest as bone pain and fractures. OBJECTIVE: The objective of the study was to evaluate PTH in patients with beta-thalassemia &gt;10 years of age. METHODS: A cross-sectional study was performed on 76 randomly selected patients &gt;10 years old with beta-thalassemia (including both thalassemia major and thalassemia intermedia) in the Al-Kut Hereditary Blood Disease Center in Wasit province, Iraq. The study covered the period from November 2021 to April 2022. Data were collected from patients’ files after written consent, including sex, age, ferritin level, mean hemoglobin level, type of chelation therapy, frequency of transfusion, mean calcium level, and whether the patients were splenectomized or not. RESULTS: Of the 76 patients enrolled in the study, 39 (51.3%) were males. There were 63 (82.9%) who had thalassemia major. The majority of cases (n = 55, 71%) were from the age group &gt;15 years. Fifteen (19.7%) patients had low PTH levels. The age group &gt;15 years had a higher frequency of having low PTH levels (P = 0.01 and Pearson factor - 0.29). The study found a positive correlation between low calcium and low PTH levels (P = 0.001, Pearson factor = 0.1). High ferritin levels had no significant correlation with PTH levels (P = 0.4). CONCLUSIONS: Beta-thalassemia patients can have a low PTH level. It can occur more often in patients &gt;15 years old, which necessitates close monitoring for older thalassemia patients. A declining calcium level in these patients can correlate with a low PTH level.

29 Cardio-Omentopexy to Reduce Myocardial Scarring and Promote Regeneration

OBJECTIVES/GOALS: While the current management of single ventricle repairs has drastically prolonged life expectancy, the repair fails over time primarily through pathologic inflammation and fibrosis. Our goal is to demonstrate that cardio-omentopexy can decrease inflammation and fibrosis in swine after cryoinjury. METHODS/STUDY POPULATION: A cryoinjury is created using a liquid nitrogen cooled probe to the right ventricle of 15-20kg swine for three minutes. In half the groups the omentum is attached to the heart over the area of the injury. The swine are recovered and monitored for 4 or 8 weeks at which time they are euthanized. The injured area is evaluated via histological and immunohistochemical testing for markers of inflammation and scarring including collagen type, scar area, macrophage activity. RESULTS/ANTICIPATED RESULTS: Currently, we have successfully validated the animal model to create myocardial scar validated by histological testing. We anticipate that the addition of omentopexy to cryoinjury will decrease scar area, fibrosis and markers of chronic inflammation. Additionally, we expect an increase in myocytes in the area of injury. We expect that this will occur through the anti-inflammatory and protective mechanism of the omentum. DISCUSSION/SIGNIFICANCE: Cardio-omentopexy, if able to decrease fibrosis and preserve myocytes, may provide a useful adjunct to the treatment of single ventricle repair by prolonging the longevity of the repair. Additionally, as these repairs often require a ventriculotomy, decreasing the operative scar may preserve myocardial function.

Abstract 7250: Serial assessment of GEN2, a retroviral vector for gene transfer of an optimized thymidine kinase and GM-CSF, for genomic integration into peripheral blood mononuclear cells (PBMCs) in a Phase 1 clinical trial in adult patients with solid tumors

Abstract GEN2 is a non-replicating retroviral gene transfer vector encoding a sequence-optimized herpes simplex thymidine kinase (HSV-TK), which activates the antiherpetic pro-drug ganciclovir (GCV), resulting in chain termination during DNA replication, triggering cancer cell apoptosis and release of neoantigens (NA). GEN2 also encodes hGM-CSF, which may augment antitumor immunity by enhancing NA presentation to immune effector cells. GEN2 in combination with valganciclovir (an oral formulation of GCV) was evaluated in a dose-escalating Phase 1 clinical trial in 61 adult patients (pts) with an advanced solid tumor (NCT04313868), with serial assessment of PBMCs to detect any GEN2 integration and replication competent retrovirus (RCR). Methods: PBMCs were obtained in Cycle 1 (following 1st/3rd dose), prior to and 2 hours after Cycle 2, and thereafter at 6-month intervals for 15 years, or until death or withdrawal of consent. Digital droplet PCR (ddPCR) for psi and envelope gene sequences in extracted genomic DNA from PBMCs was used to detect vector genome integration and replication competent retrovirus (RCR), respectively. Results: All 82 samples obtained from the intravenous cohorts 1-12 were below LOD (Limit of Detection) for RCR. All results for integration were BLOQ (Below Limit of Quantitation), whereas 4 samples collected at two hours following the end of infusion were above LOD, likely resulting from non-integrated cDNA. GEN2 continues to be studied in clinical trials in adult patients with solid tumors. Per the 2020 FDA Guidance for Industry (Long Term Follow-Up After Administration of Human Gene Therapy Products), serial assessment of vector integration is mandated throughout a pt’s participation in a gene therapy clinical trial and for 15 years following the last dose. These guidance documents were originally conceived when gene therapy was developed for treatment of rare hereditary diseases in pediatric pts; however, adult pts enrolled in early-stage clinical trials for cancer typically do not have a prolonged life expectancy (BMC Cancer 2011 11:426). In the context of proper and warranted usage of pts’ blood for testing, attention should be drawn to the limited expectation for a 2nd malignancy within the lifespan of this pt population, and the absence of detectable RCR in cancer patients receiving retroviral vectors over decades. A recent review noted no evidence of RCR in 1,595 post-treatment PBMCs obtained from 60 clinical trials (Mol Ther 2023 31(3):801). Our results confirm that GEN2 also shows negligible genotoxic risk for gene therapy of cancer at doses tested to date. Citation Format: Alison L. Hannah, Noriyuki Kasahara, Li Liu, Allen Wang, Joe McNulty, Robert G. Johnson. Serial assessment of GEN2, a retroviral vector for gene transfer of an optimized thymidine kinase and GM-CSF, for genomic integration into peripheral blood mononuclear cells (PBMCs) in a Phase 1 clinical trial in adult patients with solid tumors [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 7250.

CARDIOVASCULAR COMPLICATIONS IN PATIENTS ON RENAL REPLACEMENT THERAPY

Introduction. A progressive decrease in the rate of glomerular filtration is an independent risk factor for cardiovascular complications, as well as a marker of an unfavorable prognosis of cardiovascular diseases. Cardiovascular complications arising against the background of end-stage renal failure are the main cause of mortality in patients undergoing renal replacement therapy.&#x0D; The aim of the study was to determine the features and prevalence of cardiovascular complications in patients undergoing renal replacement therapy.&#x0D; Materials and methods. A retrospective study was conducted of 114 medical records of nephrology patients who were treated in the center of nephrology and dialysis of Poltava Regional Clinical Hospital n.a. M.V. Sklifosovsky. Patients were divided into three groups: two experimental and one control group. The first experimental group consisted of 44 (38.6%) patients who were on RRT by the method of programmed hemodialysis. The second experimental group consisted of 21 (18.4%) patients who were also undergoing RRT, but by the method of peritoneal dialysis. The control group consisted of 49 (43.0%) patients with CKD stages I-II. Analysis of laboratory data of traditional risk factors for cardiovascular complications (lipidogram), as well as non-traditional ones (level of calcium and phosphorus) was carried out. The frequency of cardiovascular complications in patients on renal replacement therapy was studied.&#x0D; Results. A statistically significant difference was found between the indicators of the atherogenicity index in the groups GD1 with CG1 (р=0.001) and GD2 with CG2 (р=0.031), PD1 and CG1 (р=0.005) and PD2 with CG2 (р=0.027). When analyzing the correlations between indicators of mineral metabolism in the experimental and control groups, it was found that weak and medium inverse correlations were observed in the experimental groups (GD1: -0.4703, GD2: -0.3219, PD1: -0,2146, PD2: -0.2784, respectively), while in the control groups a direct weak correlation was found (CG1 0.1975, CG2 0.2031, respectively). Chronic heart failure was detected in 75.0% of patients in the GD1 group, in 66.6% – in GD2, and in 100.0% of PD1 and PD2 patients. Valve calcification was observed in 35.0%, 29.1%, 33.3%, and 20.0%, respectively.&#x0D; Conclusions. Studying the features of cardiovascular complications, control of risk factors, which in any case occur in patients on dialysis therapy, is one of the main directions of controlling the underlying disease, reducing the risk of dangerous cardiovascular complications, prolonging life expectancy and its quality.