Standard Of Care Research Articles

Exercise in Pediatric COVID-19: A Randomized Controlled Trial.

Purpose: This study assessed the impact of a 12-week, home-based exercise training (HBET) program on health-related quality of life (HRQOL, primary outcome), cardiovascular and metabolic parameters in pediatric COVID-19 patients.Methods: In this single-center, randomized controlled trial conducted in Sao Paulo (Brazil) from October 2020 to January 2022, 32 patients (mean age 12 ± 3.3 years; median 4 months [range: 0.7-6.6] between COVID-19 diagnosis [n = 25 mild, n = 4 moderate, n = 3 severe illness] and study entry) from a tertiary hospital were randomly assigned to either HBET or standard of care (CONTROL) in a 2:1 ratio. The HBET group underwent supervised and unsupervised sessions 3 times/week for 12 weeks emphasizing aerobic and bodyweight exercises and the CONTROL group received standard care which included general advice for a healthy lifestyle with no prescribed exercise intervention. HRQOL (Pediatric Quality of Life Inventory [PedsQL], cardiopulmonary exercise test (CPET), brachial flow-mediated dilation (b-FMD) and echocardiography assessments were conducted in both groups. Statistical analysis was performed using an intention-to-treat approach (ITT) for the primary analysis and complete-case (per-protocol) as sensitivity analysis and significance was set at P ≤ 0.05 (P ≤ 0.10 were considered as trend).Results: There was no difference in HRQOL between groups. Intention-to-treat analysis showed a trend toward increased VO2 at anaerobic threshold at post-intervention for the HBET group. Additionally, a sensitivity analysis showed significant changes in peak HR, HRR1min, RER and chronotropic response and tendency towards significance in VE/MVV and chronotropic response for the HBET group. No other between-group differences were detected for CPET, b-FMD and echocardiography variables (all p > 0.05).Conclusions: In this RCT, a 12-week HBET intervention did not impact HRQOL in pediatric COVID-19 patients. However, HBET led to greater improvements in VO2 VAT, heart rate peak and one-minute recovery and in chronotropic response with no changes in other cardiovascular parameters. Further studies are needed to explore the effects of exercise on the recovery of pediatric COVID-19 patients with persistent COVID-19 symptoms.

Pragmatic implementation of low-intensity psychological treatment for children and young people: the reality.

Low-intensity psychological interventions are effective for children and young people (CYP) with mental health difficulties and can help bridge the demand-capacity gap. Despite increasing awareness, training and use of low-intensity psychological interventions, it is not yet understood what is being implemented in clinical practice in the UK and the associated evidence base. This paper presents two studies; first, a national survey (n=102) of practitioners to identify low-intensity psychological interventions currently delivered in practice and second, an exploration of the availability and the strength of empirical support (characterised as 'gold', 'silver' and 'bronze') of low-intensity CBT interventions for CYP. The first study found a wide variety of interventions being used across different services; 101/102 respondents reported using routine outcome measures. The second study identified 44 different low-intensity interventions, 28 of which were rated as having gold empirical support. However, only 13of the gold interventions were considered accessible for practitioners and only two were reported being used in routine practice. These findings highlight that these interventions have been developed and empirically tested, but many are not easily accessible, highlighting the 'research-practice' gap in the provision of low-intensity interventions. There is a need for an increase in standardisation of care and accessibility of gold interventions. This paper hopes to begin the process of creating a hub of low-intensity interventions that are accessible and empirically supported to improve equity of access and outcomes of low-intensity psychological interventions for CYP.

Decompensated Liver Cirrhosis Research Network (UK-CLIF): Building consensus for hepatology trials in the UK

Liver disease is a major, and increasing, cause of death in the UK. The UK Chronic Liver Failure network (UK-CLIF) was developed as a multi-stakeholder network with the aim to advance cirrhosis research, with emphasis on geographical areas of high disease prevalence or limited research activity. The process involved network development through dissemination and snowball sampling techniques, with monitoring of network development and connections between participants, developed over two online meetings. Network membership included representatives from patients, carers, clinicians, researchers, R&D professionals, industry representatives, and the third sector. Subsequently, two facilitated in-person workshops were conducted with network participants. World Café methodology and participant dot voting was used to develop areas of priority and consensus in: (i) research infrastructure for cirrhosis clinical trials, (ii) clinical factors affecting research delivery, and (iii) research priorities for future trials. Thematic analysis demonstrated that the need for patient-centric trial materials, a lack of resource for clinicians to participate in research, and variability in the standard of inpatient care for cirrhosis, were barriers for cirrhosis clinical trials. Future activities for UK-CLIF include participation in a process of quality standard setting for inpatient care for cirrhosis, and coordination of a James Lind Alliance Priority Setting Partnership to develop research questions for liver cirrhosis.

Safety and efficacy of an innovative external support device for de novo arterio-venous fistula creation: a French bicentric experience.

The aim of this study was to evaluate the safety and efficacy of VasQTM, a permanent extravascular nitinol vascular support device, implanted around the anastomosis of de novo arteriovenous fistulas (AVF), in consecutive patients. This was a French prospective bicentric study. All patients with an indication for creation of a distal or proximal end to side AVF performed by supervised trainee were eligible. Follow-up was performed clinically and by Duplex scan at 6 weeks and 6 months post fistula creation. Primary endpoint was functional maturation at 6 weeks defined as successful use for dialysis via 2-needle cannulation in dialysis patients or a flow rate of ≥600 mL/min and a target vein diameter ≥6 mm for pre-dialysis patients. Overall functional success for dialysis patients was assessed as well. Between March and November 2022, 21 patients received the VasQTM device and were followed for an average of 165 days. Median age was 61. Eleven patients (52%) were on dialysis at the time of implantation. AVFs were created with distal radial (N.=8), proximal radial (N.=5), brachial cephalic (N.=4) or brachial basilic (N.=4) arteries with 100% technical success . Functional maturation at 6-weeks was achieved in 81% (17/21). Functional success was 80% (12/15) with unassisted functional success of 67% (10/15) at 6 months for patients requiring dialysis at that time point. Two reoperations were performed within the device, one thrombectomy and one angioplasty, both were successful. Freedom from access-related interventions occurred in 71% (15/21) of the study population at 6-months. This study demonstrates that the VasQTM AVFs achieved high rates of maturation at 6-weeks, without the need to modify standards of care. VasQTM can successfully assist in achieving excellent results at the introduction of the device to a new center.

Pilot Trial of Perampanel on Peritumoral Hyperexcitability in Newly Diagnosed High-grade Glioma.

Glutamatergic neuron-glioma synaptogenesis and peritumoral hyperexcitability promote glioma growth in a positive feedback loop. The objective of this study was to evaluate the feasibility and estimated effect sizes of the targeted AMPA receptor antagonist perampanel on peritumoral hyperexcitability. An open-label trial was performed comparing perampanel with standard of care (SOC) in patients undergoing resection of newly diagnosed radiologic high-grade glioma. Perampanel was administered as a preoperative loading dose followed by maintenance therapy until progressive disease or up to 12 months. SOC treatment involved levetiracetam for 7 days or as clinically indicated. The primary outcome of hyperexcitability was defined by intraoperative electrocorticography high-frequency oscillation (HFO) rates. Seizure freedom and overall survival were estimated by the Kaplan-Meier method. Tissue concentrations of perampanel, levetiracetam, and correlative biomarkers were measured by mass spectrometry. HFO rates were similar between patients treated with perampanel and levetiracetam. The trial was terminated early after a planned interim analysis, and outcomes assessed in 11 patients (seven perampanel treated; four treated with SOC). Over a median 281 days of postenrollment follow-up, 27% of patients had seizures, including 14% maintained on perampanel and 50% treated with SOC. Overall survival in perampanel-treated patients was similar to that in a glioblastoma reference cohort. Glutamate concentrations in surface biopsies were positively correlated with HFO rates in adjacent electrode contacts and were not significantly associated with treatment assignment or drug concentrations. Glioma peritumoral glutamate concentrations correlated with high-gamma oscillation rates. Targeting glutamatergic activity with perampanel achieved similar electrocorticographic hyperexcitability levels as in levetiracetam-treated patients.

Capivasertib augments chemotherapy via Akt inhibition in preclinical small cell lung cancer models.

Small cell lung cancer (SCLC) is a highly aggressive type of lung cancer for which platinum-based chemotherapy is the standard of care. Despite an initial response to this therapy, patients eventually develop resistance to the chemotherapy. To investigate the potential of capivasertib, an approved drug for advanced breast cancer, to enhance the efficacy of cisplatin in preclinical SCLC models and explore the underlying mechanisms. SCLC cell lines were treated with capivasertib and cisplatin, alone or in combination, to assess cell viability, proliferation, colony formation, and apoptosis. Next, capivasertib's effects, alone and combined with cisplatin, were evaluated in an SCLC mouse model. Mechanistic studies focused on Akt and MYC signaling, with constitutively active Akt overexpression used to assess its role. Capivasertib is active against a panel of SCLC cell lines regardless of cellular origin and genetic profiling with IC50 at a clinically achievable range. Particularly, capivasertib inhibits proliferation and anchorage-independent colony formation and induces apoptosis in SCLC cells. It significantly augments cisplatin's inhibitory effects in all tested cell lines. Importantly, capivasertib at a non-toxic dose is effective in delaying SCLC growth in mice and its combination with cisplatin achieves nearly complete tumor growth inhibition. Mechanistic studies confirm that capivasertib inhibits Akt and MYC signaling, and furthermore, that overexpression of constitutively active Akt reversed anti-SCLC activity of capivasertib. Our work is the first to reveal that Akt inhibition can augment chemotherapy in SCLC, and capivasertib is a useful addition to the treatment armamentarium for SCLC.

Oxygen supplementation and cognitive function in long-COVID.

Patients can experience persistent cognitive complaints and deficits in long-COVID. Inflammation and capillary damage may contribute to symptoms by interfering with tissue oxygenation. This was an exploratory pilot crossover study designed to describe the effects of supplemental oxygen (portable oxygen concentrator, POC) on cognitive performance and peripheral and cerebral oxygen saturation at rest and exercise. Participants with long-COVID (n = 21) were randomized 1:1 to: 1) POC (3h/day) for 2 weeks followed by standard of care (Control) for 2 weeks or 2) Control for 2 weeks then POC (3h/day) for 2 weeks, with a 1-week washout. Cognitive assessment (global cognition [Montreal Cognitive Assessment, MoCA], episodic memory [Hopkins], working memory [Digit Span], executive function [Verbal fluency]) was performed at baseline and after each treatment period. Patient Health Questionnaire (PHQ-9) and Generalized Anxiety Disorder-7 were completed. Peripheral and cerebral oxygen saturation were measured at rest and exercise (treadmill) at baseline and after each treatment period. Statistical analyses were descriptive without formal testing. MoCA scores were similar under POC (26.45±2.31) and Control (26.37±2.85); overall POC-Control difference was -0.090 (95% CI [-1.031, 0.850]). Because of a learning effect, post-hoc analyses were performed for Period 1, where the MoCA score difference was 1.705 [0.140, 3.271]. MoCA subscores suggested better performance with POC for Visuospatial/executive (0.618 [-0.106, 1.342]) and Attention (0.975 [0.207, 1.743]). POC trended to have better scores on Digit Span backward (difference: 0.822 [-0.067, 1.711]) and self-reported depressive symptoms (difference: -1.335 [-3.166, 0.495]). For specific PHQ-9 items, POC tended to have lower (better) scores for Q1 (Little interest/pleasure) and Q7 (Trouble concentrating). Cerebral oxygen saturations at end of exercise showed no difference between POC and Control. Peripheral saturations during exercise were similar under POC and Control (difference: 0.519% [-1.675, 2.714]). An advantage of POC over Control was observed for global cognition, attention, visuospatial/executive performance and depressive symptoms. Results need to be validated in a larger study.

Longitudinal Study of Transcriptomic Changes Occurring over Six Weeks of CHOP Treatment in Canine Lymphoma Identifies Prognostic Subtypes

The majority of canine lymphoma patients treated with the standard of care, the CHOP chemotherapy protocol, initially achieve remission but eventually relapse with a multi-drug-resistant phenotype. This study assesses gene expression profiles of canine lymphoma tumor cell populations using RNA-Seq data from 15 matched patient samples taken prior to treatment and again six weeks into treatment with CHOP. Two distinct clusters were present in the t-SNE dimensionality reduction of the gene expression profiles. There was a significant difference in progression-free survival (PFS) between the cluster groups, with a median of 43.5 days in a group of six patients and 185 days in another group of nine patients. Comparing the group with shorter PFS to the group with longer PFS, we identified 265 significantly enriched GO:BP terms in 3874 significantly up-regulated genes and 740 significantly enriched GO:BP terms in 3236 significantly down-regulated genes. Comparing the six-week timepoint against the initial timepoint, in the group with longer PFS, we identified 277 significantly enriched GO:BP terms in 413 significantly up-regulated genes and 222 significantly enriched GO:BP terms in 267 significantly down-regulated genes. In the group with shorter PFS, we only identified 27 significantly differentially expressed genes, for this comparison. We found DNA damage response genes to be enriched in the down-regulated genes in both comparisons. These results identify and characterize two transcriptionally distinct groups of canine lymphoma patients with significantly different responses to CHOP chemotherapy.

Type 1 Diabetes in care homes: A practical guide on management.

The primary purpose of the original NAPCHD project was to develop a national Strategic Document of Diabetes Care for Care Homes which has now been completed and well received as a worthwhile, sustainable, and effective guidance for delivering quality diabetes care in the UK. A Working Group of NAPCHD was established to produce a Position Statement on type 1 diabetes in care homes since this area was recommended as a topic to further develop. There are currently limited data on the prevalence and clinical outcomes associated with type 1 diabetes in care homes and management policies have been non-existent in the UK. Communication among all key stakeholders involved in direct care of residents with type 1 diabetes is generally fragmented and lacks coordination. This is compounded by a slowly growing utilisation of diabetes technology and the absence of a standard/agreed community-based model of interdisciplinary collaboration. The Rationale and Objectives were defined prior to commencing the work and a work plan with individual tasks was initially set out. After multiple correspondences and Team calls over a period of 9 months, the Group successfully generated a first draft in October 2023. This draft was then finalised the following month and circulated among stakeholders for feedback. Nine chapters have been provided including minimum standards of diabetes care, insulin regimens, avoiding hospitalisation and discharge planning. A scheme for a community-based model of care for type 1 diabetes has been included. Eight key messages were developed. In addition, an Appendix has been created which includes key assessments such as nutritional assessment, detection of frailty, sick day rules and foot risk stratification (available online).

The American Headache Society First Contact-Headache in Primary Care program: Current metrics, knowledge assessments, and direction for future initiatives.

This study examines the American Headache Society First Contact-Headache in Primary Care program metrics to date in order to assess the program's reach and provide direction for future initiatives. Approximately 4 million primary care office visits annually are headache-specific encounters. Therefore, it is important that primary care providers are knowledgeable about headache management. Recognizing the need, the American Headache Society First Contact designed the comprehensive First Contact-Headache in Primary Care program with input from an advisory board comprised of a diverse group of physicians and advanced practice providers with backgrounds in family and internal medicine, pediatrics, obstetrics and gynecology, and neurology. This is the first study to assess the reach of the program and critically examine how to best meet the needs of clinicians and patients going forward. We report descriptive statistics for the First Contact website metrics from October 2020 to June 2023 and grand rounds program data from May 2020 to December 2023. We also conducted a cross-sectional analysis of survey data from presentations conducted at two large national family medicine symposia, as well as a thematic analysis of the question: "Please indicate what areas of your practice could be enhanced or improved with additional education?" The First Contact program homepage was the second most visited page on the American Headache Society website (>100,000 views). A total of 20 podcast episodes were created for the program (>3500 plays). The First Contact program held 99 events (72 institutional grand rounds, 22 State-level meetings, and five national meetings), reaching >7000 clinicians. The institutional grand rounds and state-level meetings were held across 27 States and Washington D.C. Only 31.9% (30/94) of First Contact program events (excluding national meetings) occurred in the West census region, which has the fewest headache subspecialists and lowest headache subspecialist density in the United States. When examining survey data of participants who attended the two virtual national family medicine symposia (39.3% response rate, N = 636/1620), 85.7% (544/635) reported being "completely confident" or "veryconfident" in their ability to recognize and accurately diagnose patients presenting with a primary complaint of headache and 81.5% (517/634) reported being "completely confident" or "very confident" in their ability to develop evidence-based treatment plans that are tailored to the needs of individual patients. The use of diagnostic tools to recognize patients with migraine (60.4%, 384/636) and translating standards of care to the practice setting (42.5%, 270/636) were the most reported intended changes by participants. Most participants reported that program content was of clinical relevance and would improve their patients' outcomes (90.5% [571/631] and 90.6% [572/631], respectively). Over three-quarters (77.8%, 495/636) of participants reported areas of their practice that can be improved by additional education specifically regarding workflow, diagnosis, and management. This study evaluates one of the first national initiatives for primary care education. Data from the two First Contact Family Medicine national symposia indicate the program is generally well received with most participants reporting improved confidence and intention to implement key changes in practice to improve care for patients with headache; however, there remain areas of exploration for education that could further enhance participant experience and expand the reach of the initiatives. Areas for future programming include continued education on multifactorial approaches to headache treatment and suggestions for addressing cost, insurance, and time constraints. Also, future work may examine where the First Contact program might focus initiatives based on specific areas of need in headache care, such as geographic "desert" areas, racial and ethnic disparities, and uninsured/underinsured populations.

Parent experiences with genetic testing for pediatric hearing loss.

The purpose of the current study was to assess parent perceptions and experiences of genetic testing, as well as barriers for not undergoing testing in a sample of families of children with hearing loss. A 44-item questionnaire, The Parent Perception of Genetic Testing Questionnaire developed by the research study team was administered. Participants were recruited from a pediatric otolaryngology/audiology practice and social media. A total of 146 parents of children with hearing loss participated. Approximately 47.6% of the children in our sample underwent genetic testing, 44.8% did not, and 7.6% of parents were unsure. For those that did not undergo testing, reasons included: unaware (6.2%), not interested (8.9%), cost (8.9%), time (3.4%), fearful of results (2.7%), and never offered (15.1%). For those that did undergo testing, over half of the parents reported that they did not receive counseling before (55.1%) and 41.7% reported they received counseling after the testing. Furthermore, parents were confused about the results with 18.3% reporting they were Very Confused, 28.3% Somewhat Confused, 20% A Little Confused, and 33.3% Not Confused at All about the variant of uncertain or unknown significance. Notably, less than half of parents (43.4%) remembered what they were told about the mode of inheritance. Overall, our study highlighted the low adoption rate of genetic testing and lack of integration into standard of care for otology/audiology practices. Collaboration between hearing healthcare professionals and geneticists is warranted to determine how to reduce barriers to access while improving pre- and post-counseling.

A real‑world study of clinical characteristics, treatment sequence and outcomes of patients with non-small cell lung cancer and EGFR exon 20 insertion mutations.

EGFR exon 20 insertion (EGFRex20ins) mutations are found in up to 4% of all patients with non-small cell lung cancer (NSCLC). These patients are often insensitive to EGFR-tyrosine kinase inhibitors (TKIs) and have worse prognosis than patients with more common EGFR mutations. In this multicenter, retrospective, real-world study, we sought to determine whether the administration of recently approved treatments that specifically target EGFRex20ins mutations could significantly improve outcomes in this patient population. We evaluated the clinical features of 41 patients diagnosed with NSCLC and EGFRex20ins mutations, their evolution, and response to treatments received across 7 hospitals in the Valencian Community, Spain, between 31st December 2012 and 31st December 2022. 32 patients (72%) developed metastatic disease, and 29 (71%) of them received oncological treatment. We found that administering a targeted therapy against EGFRex20ins mutations (amivantamab, mobocertinib and/or sunvozertinib) at some point during the course of treatment, significantly increased the median OS of metastatic patients from 8months (95% CI 0-21.7) to 30months (95% CI 11.1-48.8; Hazard ratio = 0.297, p = 0.02). Our findings contribute to the evolving standard of care for this specific population and highlight the clinical benefits of targeted cancer therapies.

Mitochondrial Iron Metabolism as a Potential Key Mediator of PD-L1 Thermal Regulation

Glioblastoma (GBM) is the most common primary brain malignancy in the U.S. with a 5-year overall survival < 5% despite an aggressive standard of care. Laser interstitial thermal therapy (LITT) is a surgical approach to treating GBM that has gained traction, providing a safe option for reducing intracranial tumor burden. LITT is believed to potentially modulate GBM immune responses; however, the biochemical mechanisms underlying the modulation of immune checkpoints in GBM cells have been poorly characterized. The present study aimed to preliminarily evaluate the effects of thermal therapy and radiation on PD-L1 modulation in vitro, as a function of IDH mutational status. U87 cells and their IDH-mutant counterpart (U87R132H), which was generated using a crispr-cas9 knock-in approach, were utilized for this preliminary evaluation. Cell heating was achieved by harvesting with trypsin centrifugation where the cell pellets were treated on a heat block for the associated time and temperature. Following thermal therapy, cells were resuspended and irradiated using a 37-Cesium irradiator at 0.6 Gy min−1. Immediately following treatment, cells were either plated as single cells to allow colonies to form, and stained with Coomassie blue to be counted approximately 10–14 days later or harvested for Western blot analysis. Cell lysates were analyzed for PD-L1 expression with respect to various iron metabolic parameters (mortalin (HSPA9), transferrin receptor, and ferritin heavy chain) using a Western blotting approach. In both U87 and U87R132H cell lines, thermal therapy showed a temperature-dependent cell-killing effect, but U87R132H cells appeared more sensitive to thermal treatment when treated at 43 °C for 10 min. Moreover, thermal therapy had minimal effects on cell responses to 2 Gy irradiation. Treatment with thermal therapy downregulated PD-L1 expression in U87R132H cells, which was associated with increased expression of the mitochondrial iron metabolic enzyme, HSPA9. Thermal therapy reversed the radiation-induced overexpression of PD-L1, transferrin receptor, and ferritin heavy chain in U87R132H cells. No effects were observed in wild-type U87 cells. Moreover, Ga(NO3)3 depleted mitochondrial iron content which, in turn, significantly enhanced the sensitivity of U87R132H cells to thermal therapy and 2 Gy irradiation and caused a significant increase in PD-L1 expression. These results suggest that thermal therapy alone can modulate the immune checkpoint PD-L1. This effect was more pronounced when thermal therapy was combined with radiation. Mechanistically, mitochondrial iron trafficking through HSPA9 may coordinate the regulation of PD-L1 in the context of thermal therapy and ionizing radiation, which can be targeted with gallium-based therapy. These novel, preliminary findings warrant further mechanistic investigations in pre-clinical models of LITT.

Inhibition of GPX4 enhances CDK4/6 inhibitor and endocrine therapy activity in breast cancer.

CDK4/6 inhibition in combination with endocrine therapy is the standard of care for estrogen receptor (ER+) breast cancer, and although cytostasis is frequently observed, new treatment strategies that enhance efficacy are required. Here, we perform two independent genome-wide CRISPR screens to identify genetic determinants of CDK4/6 and endocrine therapy sensitivity. Genes involved in oxidative stress and ferroptosis modulate sensitivity, with GPX4 as the top sensitiser in both screens. Depletion or inhibition of GPX4 increases sensitivity to palbociclib and giredestrant, and their combination, in ER+ breast cancer models, with GPX4 null xenografts being highly sensitive to palbociclib. GPX4 perturbation additionally sensitises triple negative breast cancer (TNBC) models to palbociclib. Palbociclib and giredestrant induced oxidative stress and disordered lipid metabolism, leading to a ferroptosis-sensitive state. Lipid peroxidation is promoted by a peroxisome AGPAT3-dependent pathway in ER+ breast cancer models, rather than the classical ACSL4 pathway. Our data demonstrate that CDK4/6 and ER inhibition creates vulnerability to ferroptosis induction, that could be exploited through combination with GPX4 inhibitors, to enhance sensitivity to the current therapies in breast cancer.

Pathophysiology of vascular ageing and the effect of novel cardio-renal protective medications in preventing progression of chronic kidney disease in people living with diabetes.

Among people with diabetes those with chronic kidney disease (CKD) have a reduced life expectancy with increased risk of cardiovascular disease (CVD) a major contributor to morbidity and mortality. CKD related to diabetes is growing worldwide and is one of the leading causes of kidney failure globally. Diabetes is associated with accelerated vascular ageing and the related mechanisms and mediators that drive the progression of CKD and CVD disease in people with diabetes may help provide insights into the pathophysiology of cardio-renal complications and guide treatment interventions in people with diabetes. We conducted a narrative review of the literature using PubMed for English language articles that contained keywords that related to diabetes, chronic or diabetic kidney disease, ageing, cellular senescence, arterial stiffness, Klotho and sirtuins, sodium-glucose co-transporter-2 (SGLT-2) inhibitors, renin angiotensin aldosterone system (RAAS) and glucagon-like peptide-1 (GLP-1) receptor agonists. Progressive kidney disease in diabetes is associated with accelerated ageing driven in part by multiple processes such as cellular senescence, inflammation, oxidative stress and circulating uremic toxins. This accelerated ageing phenotype contributes to increased arterial stiffness, endothelial dysfunction, cognitive decline and muscle wasting, thereby elevating morbidity and mortality in individuals with diabetes and CKD. Deficiency of the kidney-derived anti-ageing hormone Klotho and reduced sirtuin levels play pivotal roles in these ageing pathways. Dietary, lifestyle and pharmacological interventions targeting vascular ageing may help reduce the progression of CKD and associated CVD in people with diabetes. The current standard of care and pillars of treatment for kidney disease such as RAAS inhibitors, SGLT-2 inhibitors and GLP-1 receptor agonists all influence pathways involved in vascular ageing. A multifactorial intervention to prevent the development of CKD by targeting traditional risk factors as well as treatment with novel agents with cardio-renal beneficial effects can prevent accelerated ageing and extend lifespan in people with diabetes.

The outcome of haematopoietic stem cell transplantation in a patient with STAT1 gain-of-function: a case report

Background: The human signal transducer and activator of transcription 1 (STAT1) is a latent cytoplasmic transcription factor and one of seven members of the STAT family. Autosomal dominant (AD) STAT1 gain-of-function (GOF), characterized by enhanced phosphorylation of the tyrosine-701 residue and STAT1 activation, is commonly associated with chronic mucocutaneous candidiasis (CMCC), immunodeficiency, aneurysms, malignancies, and autoimmune phenomena. The best management strategies for patients with STAT1 GOF remain unclear. Typically, the standard care includes supportive treatments such as antimicrobial prophylaxis, either alone or combined with immunoglobulin replacement therapy. Biological therapies such as JAK inhibitors have been shown to alleviate symptoms of infection and autoimmune disorders in patients with STAT1 GOF mutations. However, there is a lack of long-term outcome data for JAK inhibition. Hematopoietic stem cell transplantation (HSCT) is an alternative treatment option for a subset who experience a persistent disease course despite conventional therapy. However, the effectiveness of HSCT for this condition is not yet well established. Methods: Our patient’s medical records were analyzed retrospectively, including her medical history. Results: We present the outcome of HSCT performed on a 27-year-old female with STAT1 GOF, conducted as a treatment for acute myeloid leukemia (AML). Conclusion: HSCT may serve as an alternative and potentially curative treatment for certain STAT1 GOF patients with progressive, life-threatening conditions that do not respond to conventional therapies. Additional research is needed to improve the management of these patients. Statement of Novelty: We present a novel case study of HSCT as a treatment for AML in a 27-year-old patient with STAT1 GOF, highlighting the potential for curative outcomes in progressive, life-threatening conditions unresponsive to conventional therapies. This case contributes to the limited body of evidence supporting the efficacy and challenges of HSCT in STAT1 GOF patients.

Diagnosing and Characterizing Chronic Kidney Disease with Machine Learning: The Value of Clinical Patient Characteristics as Evidenced from an Open Dataset

Applying artificial intelligence (AI) and machine learning for chronic kidney disease (CKD) diagnostics and characterization has the potential to improve the standard of patient care through accurate and early detection, as well as providing a more detailed understanding of the condition. This study employed reproducible validation of AI technology with public domain software applied to CKD diagnostics on a publicly available CKD dataset acquired from 400 patients. The approach presented includes patient-specific symptomatic variables and demonstrates performance improvements associated with this approach. Our best-performing AI models, which include patient symptom variables, achieve predictive accuracies ranging from 99.4 to 100% across both hold-out and 5-fold validation with the light gradient boosting machine. We demonstrate that the exclusion of patient symptom variables reduces model performance in line with the literature on the same dataset. We also provide an unsupervised learning cluster analysis to help interpret variability among, and characterize the population of, patients with CKD.

Additive Effects of Cu-ATSM and Radiation on Survival of Diffuse Intrinsic Pontine Glioma Cells.

Diffuse intrinsic pontine gliomas (DIPG) are highly aggressive and treatment-resistant childhood primary brainstem tumors with a median survival of less than one year after diagnosis. The prevailing standard of care for DIPG, radiation therapy, does not prevent fatal disease progression, with most patients succumbing to this disease 3-8 months after completion of radiation therapy. This underscores the urgent need for novel combined-modality approaches for enhancing therapy responses. This study demonstrates that the cellular redox modulating drug, copper (II)-diacetyl-bis(N4-methylthiosemicarbazone) (Cu-ATSM) dose-dependently (1-3 μM) decreased clonogenic cell survival in SU-DIPG50 and SU-DIPG36 cell lines during 6 h of exposure but had no significant effect on survival in normal human astrocytes (NHA). Additional significant (>90%) decreases in DIPG clonogenic survival were observed at 24 h of Cu-ATSM exposure. However, NHAs also began to show dose-dependent 10-70% survival decreases at this point. Notably, 3 μM Cu-ATSM for 6 h resulted in additive clonogenic cell killing of DIPG lines when combined with radiation, which was not seen in NHAs and was partially inhibited by the copper chelator, bathocuproinedisulfonic acid. Cu-ATSM toxicity in DIPG cells was also inhibited by overexpression of mitochondrial-targeted catalase. These results support the hypothesis that Cu-ATSM is selectively cytotoxic to DIPGs by a mechanism involving H2O2 generation and copper and being additively cytotoxic with ionizing radiation.

Position Paper of the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) and the German Roentgen Society (DRG) on Structural and Professional Requirements in Interventional Oncology.

Interventional oncology (IO) employs various techniques to enable minimally invasive, image-guided treatment of tumor diseases with both curative and palliative goals. Additionally, it significantly contributes to managing tumor-related and perioperative complications, offering diverse supportive procedures for patients at all stages of their diseases. The execution of IO procedures places unique demands on the equipment, personnel, and structural organization of radiological clinics, necessitating specific expertise from interventional radiologists.This position paper aims to comprehensively outline the multifaceted aspects of IO and discuss the requisite criteria for hospitals, radiological clinics, and interventional radiologists (IRs). Furthermore, it underscores overarching considerations of quality assurance that clinics and professional societies should prioritize.The requirements for hospitals, radiological clinics, and IRs are varied and demand not only a high level of proficiency in performing IO procedures but also in-depth knowledge of the differential therapy for various tumor diseases. This expertise is essential for effectively serving as clinical partners in the interdisciplinary treatment of oncologic patients. Additionally, a thorough understanding and safe handling of ionizing radiation technologies, along with proficiency in radiation protection methods, which are fundamental aspects of radiological specialist training, is crucial for ensuring the safety of IO procedures for both patients and staff. The Deutsche Gesellschaft für Interventionelle Radiologie und minimal-invasive Therapie (DeGIR) and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) have long-established dedicated quality management programs, accrediting radiology clinics and certifying IRs. These initiatives aim to uphold the highest standards of care and meet the quality expectations set by politics in healthcare system, particularly in the realm of interventional radiology. · The various procedures in the field of interventional oncology (IO) are complex medical interventions that require not only the most advanced technical equipment but also adequate human resources, particularly specialized expertise in interventional radiology, diagnostic imaging, oncology, and radiation protection.. · This expertise is an integral part of the specialized medical training in radiology and is certified by professional societies such as the German Society for Interventional Radiology (DeGIR) and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).. · Professional societies like DeGIR, CIRSE, and the American Society of Interventional Radiology (SIR) establish the necessary quality assurance framework for comprehensive, high-quality IO therapy through quality assurance (QA) registries, standard operating procedure (SOP) documents, and participation in guideline development.. · Currently, radiology is the only discipline that provides physicians with the theoretical and practical knowledge, skills, and competencies required to perform the demanding procedures in the field of IO through specialized training programs and tailored certification processes.. · Isfort P, Sommer CM, Bruners P et al. Position Paper of the German Society for Interventional Radiology and Minimally Invasive Therapy (DeGIR) and the German Roentgen Society (DRG) on Structural and Professional Requirements in Interventional Oncology. Fortschr Röntgenstr 2024; DOI 10.1055/a-2373-1013.

Osteoblast Growth in Quaternized Silicon Carbon Nitride Coatings for Dental Implants

The demand for dental implants has increased, establishing them as the standard of care for replacing missing teeth. Several factors contribute to the success or failure of an implant post-placement. Modifications to implant surfaces can enhance the biological interactions between bone cells and the implant, promoting better outcomes. Surface coatings have been developed to electrochemically alter implant surfaces, aiming to reduce healing time, enhance bone growth, and prevent bacterial adhesion. Quaternized silicon carbon nitride (QSiCN) is a novel material with unique electrochemical and biological properties. This study aimed to assess the influence of QSiCN, silicon carbide nitride (SiCN), and silicon carbide (SiC) coatings on the viability of osteoblast cells on nanostructured titanium surfaces. The experiment utilized thirty-two titanium sheets with anodized TiO2 nanotubes featuring nanotube diameters of 50 nm and 150 nm. These sheets were divided into eight groups (n = 4): QSiCN-coated 50 nm, QSiCN-coated 150 nm, SiCN-coated 50 nm, SiCN-coated 150 nm, SiC-coated 50 nm, SiC-coated 150 nm, non-coated 50 nm, and non-coated 150 nm. Preosteoblast MC3T3-E1 Subclone 4 cells (ATCC, USA) were used to evaluate osteoblast viability. After three days of cell growth, samples were assessed using scanning electron microscopy (SEM). The results indicated that QSiCN coatings significantly increased osteoblast proliferation (p < 0.005) compared to other groups. The enhanced cell adhesion observed with QSiCN coatings is likely due to the positive surface charge imparted by N+.