The ESMO Tumour-Agnostic Classifier and Screener (ETAC-S): a tool for assessing tumour-agnostic potential of molecularly guided therapies and for steering drug development.

BACKGROUND: Advances in precision oncology led to approval of tumour-agnostic molecularly guided treatment options (MGTOs). The minimum requirements for claiming tumour-agnostic potential remain elusive. METHODS: The European Society for Medical Oncology (ESMO) Precision Medicine Working Group (PMWG) coordinated a project to optimise tumour-agnostic drug development. International experts examined and summarised the publicly available data used for regulatory assessment of the tumour-agnostic indications approved by the US Food and Drug Administration and/or the European Medicines Agency as of December 2023. Different scenarios of minimum objective response rate (ORR), number of tumour types investigated, and number of evaluable patients per tumour type were assessed for developing a screening tool for tumour-agnostic potential. This tool was tested using the tumour-agnostic indications approved during the first half of 2024. A taxonomy for MGTOs and a framework for tumour-agnostic drug development were conceptualised. RESULTS: Each tumour-agnostic indication had data establishing objective response in at least one out of five patients (ORR ≥ 20%) in two-thirds (≥4) of the investigated tumour types, with at least five evaluable patients in each tumour type. These minimum requirements were met by tested indications and may serve as a screening tool for tumour-agnostic potential, requiring further validation. We propose a conceptual taxonomy classifying MGTOs based on the therapeutic effect obtained by targeting a driver molecular aberration across tumours and its modulation by tumour-specific biology: tumour-agnostic, tumour-modulated, or tumour-restricted. The presence of biology-informed mechanistic rationale, early regulatory advice, and adequate trial design demonstrating signs of biology-driven tumour-agnostic activity, followed by confirmatory evidence, should be the principles for tumour-agnostic drug development. CONCLUSION: The ESMO Tumour-Agnostic Classifier (ETAC) focuses on the interplay of targeted driver molecular aberration and tumour-specific biology modulating the therapeutic effect of MGTOs. We propose minimum requirements to screen for tumour-agnostic potential (ETAC-S) as part of tumour-agnostic drug development. Definition of ETAC cut-offs is warranted.

Oncology phase I trial design and conduct: time for a change - MDICT Guidelines 2022.

In 2021, the Food and Drug Administration Oncology Center of Excellence announced Project Optimus focusing on dose optimization for oncology drugs. The Methodology for the Development of Innovative Cancer Therapies (MDICT) Taskforce met to review and discuss the optimization of dosage for oncology trials and to develop a practical guide for oncology phase I trials. Defining a single recommended phase II dose based on toxicity may define doses that are neither the most effective nor the best tolerated. MDICT recommendations address the need for robust non-clinical data which are needed to inform trial design, as well as an expert team including statisticians and pharmacologists. The protocol must be flexible and adaptive, with clear definition of all endpoints. Health authorities should be consulted early and regularly. Strategies such as randomization, intrapatient dose escalation, and real-world eligibility criteria are encouraged whereas serial tumor sampling is discouraged in the absence of a strong rationale and appropriately validated assay. Endpoints should include consideration of all longitudinal toxicity. The phase I dose escalation trial should define the recommended dose range for later testing in randomized phase II trials, rather than a single recommended phase II dose, and consider scenarios where different populations may require different dosages. The adoption of these recommendations will improve dosage selection in early clinical trials of new anticancer treatments and ultimately, outcomes for patients.

The different shapes of the fourth ventricle.

With a distinctive shape and surrounding anatomical structures, the fourth ventricle is located in the posterior cranial fossa. There are various pathologies, either developmental or acquired, that can present as a characteristic deformity of the fourth ventricle. Therefore, this paper will cover the anatomy of the fourth ventricle and correlate this to the various pathologies. The aim of this review is to improve the ability of the readers to recognise the change in shape and configuration of the fourth ventricle, enabling early detection of pathologies.

Measuring the quality of cancer care in the Barwon South Western region, Victoria, Australia.

OBJECTIVE: The implementation of clinical quality indicators for monitoring cancer care in regional, rural and remote areas. DESIGN: Retrospective data from a population-based Clinical Quality Registry for lung, colorectal and breast cancers. SETTING: All major health services in the Barwon South Western region, Victoria, Australia. PARTICIPANTS: All patients who were diagnosed with cancer and who presented to a health service. INTERVENTION(S): Clinical subgroups to review variations. MAIN OUTCOME MEASURES(S): Clinical quality indicators for lung, colorectal and breast cancers. RESULTS: Clinical indicators included the following: discussion at multidisciplinary meetings, the timeliness of care provided and the type of care for different stages of the disease and survival outcomes. Many of the derived clinical indicator targets were reached. However, variations led to an improvement in the tumour stage being recorded in the medical record; an improved awareness of the need for adjuvant chemotherapy for colorectal cancer; a reduction in time to treatment for lung cancer and a reduced time to surgery for breast cancer, and the 30-day mortality post-treatment for all of the tumour streams was highlighted. CONCLUSIONS: Clinical quality indicators allow for valuable insights into patterns of care. These indicators are easily reproduced and may be of use to other cancer centres and health services.

Not all swellings are lymph nodes! A case of subcutaneous panniculitis-like T-cell lymphoma.

Subcutaneous Panniculitis-like T-cell Lymphoma (SPTL) is a rare cutaneous neoplasm of mature cytotoxic T cells, first described in 1991 by Gonzalez et al. The incidence of SPTL in Asian countries ranges from 2.3% to 3%. In Malaysia, only 5 cases were reported from 2001 to 2004 in Hospital Kuala Lumpur, Malaysia. SPTL typically presents as skincoloured or erythematous subcutaneous nodules, most often on the extremities and trunk, but it can also involve the face, back and neck. Diagnosis of SPTL is made based on correlation of clinical findings and subcutaneous tissue biopsy along with immunohistochemical staining patterns.

A comparative study of ChIP-seq sequencing library preparation methods.

BACKGROUND: ChIP-seq is the primary technique used to investigate genome-wide protein-DNA interactions. As part of this procedure, immunoprecipitated DNA must undergo "library preparation" to enable subsequent high-throughput sequencing. To facilitate the analysis of biopsy samples and rare cell populations, there has been a recent proliferation of methods allowing sequencing library preparation from low-input DNA amounts. However, little information exists on the relative merits, performance, comparability and biases inherent to these procedures. Notably, recently developed single-cell ChIP procedures employing microfluidics must also employ library preparation reagents to allow downstream sequencing. RESULTS: In this study, seven methods designed for low-input DNA/ChIP-seq sample preparation (Accel-NGS® 2S, Bowman-method, HTML-PCR, SeqPlex™, DNA SMART™, TELP and ThruPLEX®) were performed on five replicates of 1 ng and 0.1 ng input H3K4me3 ChIP material, and compared to a "gold standard" reference PCR-free dataset. The performance of each method was examined for the prevalence of unmappable reads, amplification-derived duplicate reads, reproducibility, and for the sensitivity and specificity of peak calling. CONCLUSIONS: We identified consistent high performance in a subset of the tested reagents, which should aid researchers in choosing the most appropriate reagents for their studies. Furthermore, we expect this work to drive future advances by identifying and encouraging use of the most promising methods and reagents. The results may also aid judgements on how comparable are existing datasets that have been prepared with different sample library preparation reagents.

A scoring model for predicting survival following primary tumour resection in stage IV colorectal cancer patients with unresectable metastasis.

BACKGROUND: Stage IV colorectal cancer patients with unresectable metastasis who undergo elective primary tumour resection experience heterogeneous post-operative survival. We aimed to develop a scoring model for predicting post-operative survival using pre-operative variables to identify patients who are least likely to experience extended survival following the procedure. METHODS: Survival data were collected from stage IV colorectal cancer patients who had undergone elective primary tumour resection between January 1999 and December 2007. Coefficients of significant covariates from the multivariate Cox regression model were used to compute individual survival scores to classify patients into three prognostic groups. A survival function was derived for each group via Kaplan-Meier estimation. Internal validation was performed. RESULTS: Advanced age (hazard ratio, HR 1.43 (1.16-1.78)); poorly differentiated tumour (HR 2.72 (1.49-5.04)); metastasis to liver (HR 1.76 (1.33-2.33)), lung (HR 1.37 (1.10-1.71)) and bone (HR 2.08 ((1.16-3.71)); carcinomatosis (HR 1.68 (1.30-2.16)); hypoalbuminaemia (HR 1.30 (1.04-1.61) and elevated carcinoembryonic antigen levels (HR 1.89 (1.49-2.39)) significantly shorten post-operative survival. The scoring model separated patients into three prognostic groups with distinct median survival lengths of 4.8, 12.4 and 18.6 months (p < 0.0001). Internal validation revealed a concordance probability estimate of 0.65 and a time-dependent area under receiver operating curve of 0.75 at 6 months. Temporal split-sample validation implied good local generalizability to future patient populations (p < 0.0001). CONCLUSION: Predicting survival following elective primary tumour resection using pre-operative variables has been demonstrated with the scoring model developed. Model-based survival prognostication can support clinical decisions on elective primary tumour resection eligibility.

Examining the sources of occupational stress in an emergency department.

BACKGROUND: Previous work has established that health care staff, in particular emergency department (ED) personnel, experience significant occupational stress but the underlying stressors have not been well quantified. Such data inform interventions that can reduce cases of occupational mental illness, burnout, staff turnover and early retirement associated with cumulative stress. AIMS: To develop, implement and evaluate a questionnaire examining the origins of occupational stress in the ED. METHODS: A questionnaire co-designed by an occupational health practitioner and ED management administered to nursing, medical and support staff in the ED of a large English teaching hospital in 2015. The questionnaire assessed participants' demographic characteristics and perceptions of stress across three dimensions (demand-control-support, effort-reward and organizational justice). Work-related stressors in ED staff were compared with those of an unmatched control group from the acute ear, nose and throat (ENT) and neurology directorate. RESULTS: A total of 104 (59%) ED staff returned questionnaires compared to 72 staff (67%) from the acute ENT/neurology directorate. The ED respondents indicated lower levels of job autonomy, management support and involvement in organizational change, but not work demand. High levels of effort-reward imbalance and organizational injustice were reported by both groups. CONCLUSIONS: Our findings suggest that internal ED interventions to improve workers' job control, increase support from management and involvement in organizational change may reduce work stress. The high levels of effort-reward imbalance and organizational injustice reported by both groups may indicate that wider interventions beyond the ED are also needed to address these issues.

U-PRO-CRM: designing patient-centred dose-finding trials with patient-reported outcomes.

BACKGROUND: Determining the maximum tolerated dose (MTD) remains the primary objective for the majority of dose-finding oncology trials. Whilst MTD determination often relies upon clinicians to identify dose-limiting toxicities (DLTs) experienced by patients during the trial, research suggests that clinicians may underreport patient's adverse events. Therefore, contemporary practice may be exposed to recommending intolerable doses to patients for further investigation in subsequent trials. There is increasing interest in patients self-assessing their own symptoms using patient-reported outcomes (PROs) in dose-finding trials. DESIGN: We present Utility-PRO-Continual Reassessment Method (U-PRO-CRM), a novel trial design which simultaneously uses clinician-rated and patient-rated DLTs (Clinician-DLTs and Patient-DLTs, respectively) to make dose (de-)escalation decisions and to recommend an MTD. U-PRO-CRM contains the published PRO-CRM as a special case and provides greater flexibility to trade-off the rate of Patient-DLTs and Clinician-DLTs to find an optimal dose. We present simulation results for U-PRO-CRM. RESULTS: For specified trade-offs between Clinician-DLT and Patient-DLT rate, U-PRO-CRM outperforms the PRO-CRM design by identifying the true MTD more often. In the special case where U-PRO-CRM generalises to PRO-CRM, U-PRO-CRM performs as well as its published counterpart. U-PRO-CRM minimises the number of patients overdosed whilst maintaining a similar proportion of patients allocated to the true MTD. CONCLUSIONS: By using a utility-based dose selection approach, U-PRO-CRM offers the flexibility to define a trade-off between the risk of patient-rated and clinician-rated DLTs for an optimal dose. Patient-centric dose-finding strategies, which integrate PROs, are poised to assume an ever more pivotal role in significantly advancing our understanding of treatment tolerability. This bears significant implications in shaping the future landscape of early-phase trials.

Collapse of late endosomal pH elicits a rapid Rab7 response via V-ATPase and RILP.

Endosomal-lysosomal trafficking is accompanied by the acidification of endosomal compartments by the H+-V-ATPase to reach low lysosomal pH. Disruption of proper pH impairs lysosomal function and the balance of protein synthesis and degradation (proteostasis). We used the small dipeptide LLOMe, which is known to permeabilize lysosomal membranes, and find that LLOMe also impacts late endosomes (LEs) by neutralizing their pH without causing membrane permeabilization. We show that LLOMe leads to hyper-activation of Rab7 and disruption of tubulation and mannose-6-phosphate receptor (CI-M6PR) recycling on pH-neutralized LEs. Either pH neutralization (NH4Cl) or Rab7 hyper-active mutants alone can phenocopy the alterations in tubulation and CI-M6PR trafficking. Mechanistically, pH neutralization increases the assembly of the V1G1 subunit of the V-ATPase on endosomal membranes, which stabilizes GTP-bound Rab7 via RILP, a known interactor of Rab7 and V1G1. We propose a novel pathway by which V-ATPase and RILP modulate LE pH and Rab7 activation in concert. This pathway might broadly contribute to pH control during physiologic endosomal maturation or starvation and during pathologic pH neutralization, which occurs via lysosomotropic compounds or in disease states.

Accrual and statistical power failure in published adjuvant phase III oncology trials: a comprehensive analysis from 2013 to 2023.

BACKGROUND: In a competitive landscape with many ongoing adjuvant randomised controlled trials (RCTs), the prevalence of trials that failed to recruit their targeted sample size and were inadequately powered is unclear. The aims of the study are (i) to determine the percentage of trials with accrual and statistical power failure and (ii) to evaluate their potential impact on the drug development process. MATERIALS AND METHODS: A systematic review was carried out to identify adjuvant phase III oncology RCTs reported between 2013 and 2023 across all solid tumours. No restrictions were applied regarding the type of intervention or journal of publication. The percentage of trials with accrual failure and power failure was estimated as well as their association with the efficacy endpoints. Logistic regression models were used to estimate the odds ratio (OR) and its 95% confidence interval (CI). RESULTS: A total of 282 RCTs met the inclusion criteria with a median sample size of 661 patients and a median accrual period of 4.3 years. Most of these studies were superiority trials (83.0%). Accrual failure was observed in 22.0% of the studies, finishing recruitment without achieving the targeted sample size. Overall, 39.7% of the studies experienced power failure, having less power than specified in the protocol at the date of the read-out. Among superiority RCTs evaluating intermediate survival endpoints, only 31.1% presented statistically significant results. Trials with power failure were less likely to present statistically significant results (37.9% versus 21.9%, P = 0.04). The association was consistent across all cancer types. In the subset of non-inferiority trials, 35.0% formally demonstrated non-inferiority of the experimental arm. CONCLUSIONS: Nearly 40% of adjuvant phase III RCTs experienced power failure, and the reduction in power significantly impacted the final study results. There is a need for procedural refinements in the design and implementation of future adjuvant RCTs to mitigate these fallacies.

The Utility of Sirolimus Eluting Balloons in the Setting of Chronic Limb Threatening Ischaemia in Asian Patients from Singapore - 12 Months Results of the PRISTINE Registry.

PURPOSE: The aim of PRISTINE was to evaluate the 6 and 12 months safety and efficacy of the Selution Sustained Limus Release (SLR)™ sirolimus-coated balloon for treatment of complex lower limb occlusive lesions (TASC II C & D) in patients with chronic limb threatening ischemia (CLTI) from Singapore. METHODS: PRISTINE was a prospective, non-randomized, single arm, observational, multi-investigator, single-center clinical study. Complication-free survival at 30 days was the safety clinical endpoint. Immediate technical success (ability to cross and dilate the lesion and achieve residual angiographic stenosis < 30%), 6-month primary vessel patency, limb salvage, clinically driven target lesion revascularization (TLR) and amputation free survival (AFS) were the efficacy endpoints of interest. RESULTS: Seventy five patients were included. There were 50 (68.0%) males; mean age, 69.0 ± 10.7 years. CLTI severity was based on the Rutherford Scale (R5 = 51; R6 = 17). Significant co-morbidities included diabetes mellitus (n = 68; 91.0%) and end-stage renal failure (n = 28; 37.0%). 112 atherosclerotic lesions were treated (TASC II D = 58 (52%); 76 (67%) de novo). There was 100% technical success. Mean lesion length treated was 22.4 ± 13.9 cm. Primary vessel patencies at 6 and 12 months were 64/86 (74%) and 43/74 (58%) and freedom from clinically driven TLR were 72/86 (84%) and 55/74 (74%) respectively. AFS was 61/73 (84.0%; five deaths and seven major lower extremity amputation) at 6-months. Mean Rutherford score improved from 5.1 ± 0.55 at baseline to 1.1 ± 2.05 (p < 0.05) at one year and there was a wound healing rate of 38/48 (79%) at the same timepoint. CONCLUSIONS: The Selution SLR™ drug eluting balloon is safe and efficacious in treating highly complex infra-inguinal atherosclerotic lesions in an otherwise challenging frail population of CLTI patients with a high incidence of diabetes and end-stage renal failure. It is associated with highly satisfactory acute technical and clinical success, 12-month target lesion patency and AFS. LEVEL OF EVIDENCE: Level 2b, Individual Cohort Study.

Amperometric nitric oxide sensor based on nanoporous platinum phthalocyanine modified electrodes.

This article describes the fabrication of electropolymerized Metallo 4', 4″, 4‴, 4'''' tetra-amine phthalocyanine (poly-MTAPc) modified electrodes for the detection of nitric oxide (NO) in phosphate-buffered saline (PBS) at pH 7.4. A two-step synthetic protocol using a laboratory microwave reactor was adopted to provide three MTAPc complexes bearing different metal centers (M = Cu(2+): CuTAPc, M = Zn(2+): ZnTAPc, and M = Pt(2+): PtTAPc). The MTAPc complexes and the intermediates were characterized by MALDI-TOF mass spectrometry, UV-vis spectroscopy, (1)H NMR spectroscopy, and elemental analysis. The MTAPc products were separately electropolymerized either onto a glassy carbon (GC) electrode as a thin-film or within the pores of Anodisc nanoporous alumina membrane as a densely packed array of poly-MTAPc nanotubes to produce two electrode systems. In the latter system, the surface area enhancement provided by the nanotube-arrayed morphology of the poly-MTAPc enabled a high faradaic (signal) to capacitative (background) current during NO electro-oxidation. Amperometric detection of NO using these two electrode systems shows that the sensitivity and linear ranges were insensitive to the metal centers (M = Cu(2+), Zn(2+), and Pt(2+)) of the poly-MTAPc material.

An investigation of arsenic contamination in Peninsular Malaysia based on Centella asiatica and soil samples.

The first objective of this study was to provide data of arsenic (As) levels in Peninsular Malaysia based on soil samples and accumulation of As in Centella asiatica collected from 12 sampling sites in Peninsular Malaysia. The second objective was to assess the accumulation of As in transplanted C. asiatica between control and semi-polluted or polluted sites. Four sites were selected which were UPM (clean site), Balakong (semi-polluted site), Seri Kembangan (semi-polluted site) and Juru (polluted site). The As concentrations of plant and soil samples were determined by Instrumental Neutron Activation Analysis. The As levels ranged from 9.38 to 57.05 µg/g dw in soils, 0.21 to 4.33 µg/g dw in leaves, 0.18 to 1.83 µg/g dw in stems and 1.32-20.76 µg/g dw in roots. All sampling sites had As levels exceeding the CCME guideline (12 µg/g dw) except for Kelantan, P. Pauh, and Senawang with P. Klang having the highest As in soil (57.05 µg/g dw). In C. asiatica, As accumulation was highest in roots followed by leaves and stems. When the As level in soils were higher, the uptake of As in plants would also be increased. After the transplantation of plants to semi-polluted and polluted sites for 3 weeks, all concentration factors were greater than 50 % of the initial As level. The elimination factor was around 39 % when the plants were transplanted back to the clean sites for 3 weeks. The findings of the present study indicated that the leaves, stems and roots of C. asiatica are ideal biomonitors of As contamination. The present data results the most comprehensive data obtained on As levels in Malaysia.

Effects of antifouling compounds on the growth of macroalgae Undaria pinnatifida.

Seaweeds are some of the principal primary producers of marine environments, and they are important ecological elements of coastal ecosystems. The effects of harmful chemicals on seaweeds may adversely affect coastal ecosystems, hence we aimed to develop a new phytotoxicity test using the gametophytes of a common temperate kelp species, Undaria pinnatifida (KU-1630), for the widely used antifouling chemical substances Cybutryne, Diuron, Cu2+, and Zn2+. Toxicity to gametophytes of U. pinnatifida was assessed by comparing the relative growth rate (RGR) at the logarithmic growth phase. Fragmentation method, initial algal biomass, photon irradiance, and adhesive period were investigated for developing optimal test conditions. Cybutryne exposure tests were performed with seven replicates and control, the RGR ranging from 0.17 to 0.19, while mean 7-day EC50 and no observed effect concentration (NOEC) were 5.1 µg/L and 1.8 µg/L, respectively. The 7-day EC50 for other antifoulants was 14 µg/L for Diuron, 17 µg/L for Cu2+, and 1500 µg/L for Zn2+. This test method demonstrated high sensitivity and reproducibility, and it may be added to the routine methods used for toxicity evaluation of hazardous chemicals.

Exploring the expression and potential function of follicle stimulating hormone receptor in extragonadal cells related to abdominal aortic aneurysm.

INTRODUCTION: Follicle stimulating hormone (FSH) is identified to play a role in postmenopausal disease and hypothesized to affect abdominal aortic aneurysm (AAA) onset/progression in postmenopausal women. We aimed to detect FSHR gene expression in AAA tissue and cell types involved in AAA formation. METHODS: FSH stimulation of human umbilical cord endothelial cells (HUVECs), smooth muscle cells (HUCs) and PMA-differentiated macrophages to assess gene expression of FSHR and various markers. Human macrophages activated with various stimuli were assessed for FSHR gene expression. AAA dataset, AAA tissue samples and AAA-derived smooth muscle cells (SMC) obtained from elderly female donors were assessed for FSHR gene expression. AAA-SMCs were stimulated with FSH to assess its effect on gene expression. Lastly, oxidized low-density-lipoprotein (ox-LDL) uptake and abundance of cell surface protein markers were assessed by flow cytometry after FSH stimulation of human monocytes. RESULTS: FSH stimulation showed similar levels of gene expression in HUVECs and HUCs. Only ACTA2 was downregulated in HUCs. In PMA-differentiated macrophages, gene expression of inflammation markers was unchanged after FSH stimulation. FSHR gene expression was found to be low in the AAA datasets. Female AAA-SMCs show occasional FSHR gene expression at a very low level, yet stimulation with FSH did not affect gene expression of SMC- or inflammation markers. FSH stimulation did not impact ox-LDL uptake or alter cell surface protein expression in monocytes. While FSHR gene expression was detected in human testis tissue, it was below quantification level in all other investigated cell types, even upon activation of macrophages with various stimuli. CONCLUSION: Despite previous reports, we did not detect FSHR gene expression in various extragonadal cell types, except in occasional female AAA-SMCs. No clear effect on cell activation was observed upon FSH stimulation in any cell type. Our data suggest that a direct effect of FSH in AAA-related extragonadal cells is unlikely to influence AAA.

Concentrations of heavy metals (Cu, Cd, Zn and Ni) and PAHs in Perna viridis collected from seaport and non-seaport waters in the Straits of Johore.

In this study, the ranges of pollutants found in the soft tissues of Perna viridis collected from Kg. Masai and Kg. Sg. Melayu, both located in the Straits of Johore, were 0.85-1.58 µg/g dry weight (dw) for Cd, 5.52-12.2 µg/g dw for Cu, 5.66-8.93 µg/g dw for Ni and 63.4-72.3 µg/g dw for Zn, and 36.4-244 ng/g dry weight for ∑PAHs. Significantly (p < 0.05) higher concentrations of Cd, Cu, Ni, Zn and ∑PAHs in the mussels were found in the water of a seaport site at Kg. Masai than a non-seaport site at Kg. Sg. Melayu population. The ratios of low molecular weight/high molecular weight hydrocarbons (2.94-3.42) and fluoranthene/pyrene (0.43-0.45) in mussels from both sites indicated the origin of the PAHs to be mainly petrogenic. This study has demonstrated the utility of using the soft tissues of P. viridis as a biomonitor of PAH contamination and bioavailability in the coastal waters of Peninsular Malaysia.

Environmental enrichment preserves hippocampal neurons in diabetes and stressed rats.

This study evaluated the effect of Environmental Enrichment (EE) on neuron morphology in the CA1, CA3 and dentate hilus (DH) regions of the hippocampus by quantitating the total dendritic arborizations. EE is a potential intervention for stress and diabetes. It is capable of mitigating diabetes and stress-induced cognitive and memory deficit. Diabetes and stress were induced in male Wistar rats (4-5 weeks). Diabetic and stressed rats were exposed to EE on Day 2 post STZ injection and subsequently once daily for 30 days. All animals were sacrificed on Day 30. The hippocampus was dissected and processed for Golgi staining to quantitate dendritic arborizations at the CA1, CA2 and DH regions. Diabetes (D) and Diabetes+stress (D+S) groups had significantly fewer apical and basal dendritic branching points (ADBP, BDBP) at CA1 (p<0.01), CA3 (p<0.001) and DH (p<0.001) relative to control group (NC). Diabetes and stressed rats exposed to EE: [D+EE and D+S+EE groups] exhibited significantly denser ADBP and BDBP at all regions relative to D (p<0.001) and (D+S+EE) (p<0.001) groups respectively. EE significantly preserved neuronal arborizations in hippocampus of diabetic and stressed rats, suggesting a potential entity of diabetes and stress management.

Utility of sirolimus coated balloons in the peripheral vasculature - a review of the current literature.

Sirolimus-coated balloons (SCB) have demonstrated much promise as an alternative drug eluting device to the existing paclitaxel coated balloon platforms for the treatment of peripheral arterial disease (PAD). They have been well tested pre-clinically and have demonstrated anti-restenotic effects as well as clinical safety in its use for treatment of coronary artery disease. The existing approved SCBs have thus far demonstrated good short-term patency (12-months) and did not exhibit any major adverse events or device related shortcomings in its use for treatment of PAD. There are several studies ongoing which aim to further investigate the efficacy of existing SCBs and establish a direct comparison of its outcomes compared with plain balloon angioplasty. Also, SCB utility to salvage failing arteriovenous fistulas for haemodialysis patients has also been explored. We review the current progress made in the establishment of SCB in the treatment of PAD as well as highlight ongoing studies investigating the role of SCB in various settings.

Accessory Vein Obliteration and Balloon-Assisted Maturation for Immature Arteriovenous Fistulas for Haemodialysis: A Systematic Review and Meta-Analysis.

PURPOSE: This study aims to examine outcomes of immature arteriovenous fistula salvage using balloon angioplasty (PTA) without and with accessory vein obliteration (PTA + VO). MATERIALS AND METHODS: PubMed and Embase were accessed on 21 September 2020 to retrieve cohort studies on adult patients with end-stage renal failure (ESRF) requiring dialysis. Risk of bias was assessed using Newcastle-Ottawa Scale. Studies were pooled into PTA or PTA + VO arms, with outcomes (technical/clinical success, primary/secondary post-intervention patency until 12 months) reported as event rates with 95% confidence intervals. Random-effects model and maximum likelihood meta-regression were used for meta-analysis. RESULTS: Fourteen studies (1030 participants) were included. The between-subgroup difference in outcomes was largely non-significant (p > 0.050). CONCLUSION: The evidence does not support balloon angioplasty with concomitant accessory vein obliteration for immature fistula salvage.