Perioperative nivolumab versus observation in patients with renal cell carcinoma undergoing nephrectomy (PROSPER ECOG-ACRIN EA8143): an open-label, randomised, phase 3 study.

BACKGROUND: The standard of care for patients with intermediate-to-high risk renal cell carcinoma is partial or radical nephrectomy followed by surveillance. We aimed to investigate use of nivolumab before nephrectomy followed by adjuvant nivolumab in patients with high-risk renal cell carcinoma to determine recurrence-free survival compared with surgery only. METHODS: In this open-label, randomised, phase 3 trial (PROSPER EA8143), patients were recruited from 183 community and academic sites across the USA and Canada. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1, with previously untreated clinical stage T2 or greater or Tany N+ renal cell carcinoma of clear cell or non-clear cell histology planned for partial or radical nephrectomy. Selected patients with oligometastatic disease, who were disease free at other disease sites within 12 weeks of surgery, were eligible for inclusion. We randomly assigned (1:1) patients using permuted blocks (block size of 4) within stratum (clinical TNM stage) to either nivolumab plus surgery, or surgery only followed by surveillance. In the nivolumab group, nivolumab 480 mg was administered before surgery, followed by nine adjuvant doses. The primary endpoint was investigator-reviewed recurrence-free survival in patients with renal cell carcinoma assessed in all randomly assigned patients regardless of histology. Safety was assessed in all randomly assigned patients who started the assigned protocol treatment. This trial is registered with ClinicalTrials.gov, NCT03055013, and is closed to accrual. FINDINGS: Between Feb 2, 2017, and June 2, 2021, 819 patients were randomly assigned to nivolumab plus surgery (404 [49%]) or surgery only (415 [51%]). 366 (91%) of 404 patients assigned to nivolumab plus surgery and 387 (93%) of 415 patients assigned to surgery only group started treatment. Median age was 61 years (IQR 53-69), 248 (30%) of 819 patients were female, 571 (70%) were male, 672 (88%) were White, and 77 (10%) were Hispanic or Latino. The Data and Safety Monitoring Committee stopped the trial at a planned interim analysis (March 25, 2022) because of futility. Median follow-up was 30·4 months (IQR 21·5-42·4) in the nivolumab group and 30·1 months (21·9-41·8) in the surgery only group. 381 (94%) of 404 patients in the nivolumab plus surgery group and 399 (96%) of 415 in the surgery only group had renal cell carcinoma and were included in the recurrence-free survival analysis. As of data cutoff (May 24, 2023), recurrence-free survival was not significantly different between nivolumab (125 [33%] of 381 had recurrence-free survival events) versus surgery only (133 [33%] of 399; hazard ratio 0·94 [95% CI 0·74-1·21]; one-sided p=0·32). The most common treatment-related grade 3-4 adverse events were elevated lipase (17 [5%] of 366 patients in the nivolumab plus surgery group vs none in the surgery only group), anaemia (seven [2%] vs nine [2%]), increased alanine aminotransferase (ten [3%] vs one [<1%]), abdominal pain (four [1%] vs six [2%]), and increased serum amylase (nine [2%] vs none). 177 (48%) patients in the nivolumab plus surgery group and 93 (24%) in the surgery only group had grade 3-5 adverse events due to any cause, the most common of which were anaemia (23 [6%] vs 19 [5%]), hypertension (27 [7%] vs nine [2%]), and elevated lipase (18 [5%] vs six [2%]). 48 (12%) of 404 patients in the nivolumab group and 40 (10%) of 415 in the surgery only group died, of which eight (2%) and three (1%), respectively, were determined to be treatment-related. INTERPRETATION: Perioperative nivolumab before nephrectomy followed by adjuvant nivolumab did not improve recurrence-free survival versus surgery only followed by surveillance in patients with high-risk renal cell carcinoma. FUNDING: US National Institutes of Health National Cancer Institute and Bristol Myers Squibb.

Brain responses to intermittent fasting and the healthy living diet in older adults.

Diet may promote brain health in metabolically impaired older individuals. In an 8-week randomized clinical trial involving 40 cognitively intact older adults with insulin resistance, we examined the effects of 5:2 intermittent fasting and the healthy living diet on brain health. Although intermittent fasting induced greater weight loss, the two diets had comparable effects in improving insulin signaling biomarkers in neuron-derived extracellular vesicles, decreasing the brain-age-gap estimate (reflecting the pace of biological aging of the brain) on magnetic resonance imaging, reducing brain glucose on magnetic resonance spectroscopy, and improving blood biomarkers of carbohydrate and lipid metabolism, with minimal changes in cerebrospinal fluid biomarkers for Alzheimer's disease. Intermittent fasting and healthy living improved executive function and memory, with intermittent fasting benefiting more certain cognitive measures. In exploratory analyses, sex, body mass index, and apolipoprotein E and SLC16A7 genotypes modulated diet effects. The study provides a blueprint for assessing brain effects of dietary interventions and motivates further research on intermittent fasting and continuous diets for brain health optimization. For further information, please see ClinicalTrials.gov registration: NCT02460783.

Is Quadriceps-Strengthening Exercises (QSE) in Medial-Compartment Knee Osteoarthritis with Neutral and Varus Malalignment a Paradox? - A Risk-Appraisal of Strength-Training on Disease Progression.

Introduction: The present inquiry seeks to investigate whether the current regimens of QSEs (Quadriceps-Strengthening Exercises) aggravate the disease while mitigating symptoms. Materials and methods: A comparative study was conducted on 32 patients with medial compartment osteoarthritis of knees. While the neutral group of 16 patients was constituted of those with an anatomical-lateral-femoro-tibial-angle (aFTA) 176-180º, varus group comprised an equal number of patients with an aFTA >180º. A home-based 12-week strength-training program involving weekly visits to hospital for supervised sessions was administered. The outcome measures were visual-analog-scale (VAS), medial patello-femoral joint tenderness (MPFJT), time-up-and-go-test (TUGT), stair-climb test, step test, WOMAC, IKDC scores, aFTA, hip-knee-ankle (HKA) angle, lateral-tibio-femoral-joint-separation (LTFJS), and horizontal-distance-from-centre-of-knee-to-Mikulicz-line. Results: There was a significant increase in quadriceps strength (p<0.01) in both groups. Values for neutral group with VAS score (p=0.01), MPFJT (p=0.01), TUGT (p=0.01), timing of the stair climb test (p=0.01), WOMAC (p<0.01), and IKDC (p=0.03) were better compared to varus group with VAS score (p=0.13), MPFJT (p=0.03), TUGT (p=0.90), timing of stair climb test (p=0.68), WOMAC (p<0.02), and IKDC (p=0.05). Varus group also showed an increase in aFTA and LTFJS in 12 patients, increase in HKA in 11, and increase in horizontal distance from the centre of knee to the Mikulicz line in 7 patients. Conclusion: The present study brings to the fore the paradoxical role played by QSEs in management of medial knee OA. While there is a radiological progression of the disease in both neutral and varus mal-aligned knees more so in the latter than the former.

Lipidomic Analysis of Plasma Extracellular Vesicles Derived from Alzheimer's Disease Patients.

Analysis of blood-based indicators of brain health could provide an understanding of early disease mechanisms and pinpoint possible intervention strategies. By examining lipid profiles in extracellular vesicles (EVs), secreted particles from all cells, including astrocytes and neurons, and circulating in clinical samples, important insights regarding the brain's composition can be gained. Herein, a targeted lipidomic analysis was carried out in EVs derived from plasma samples after removal of lipoproteins from individuals with Alzheimer's disease (AD) and healthy controls. Differences were observed for selected lipid species of glycerolipids (GLs), glycerophospholipids (GPLs), lysophospholipids (LPLs) and sphingolipids (SLs) across three distinct EV subpopulations (all-cell origin, derived by immunocapture of CD9, CD81 and CD63; neuronal origin, derived by immunocapture of L1CAM; and astrocytic origin, derived by immunocapture of GLAST). The findings provide new insights into the lipid composition of EVs isolated from plasma samples regarding specific lipid families (MG, DG, Cer, PA, PC, PE, PI, LPI, LPE, LPC), as well as differences between AD and control individuals. This study emphasizes the crucial role of plasma EV lipidomics analysis as a comprehensive approach for identifying biomarkers and biological targets in AD and related disorders, facilitating early diagnosis and potentially informing novel interventions.

Detection of ABO Blood Groups From Dentin and Pulp by Using the Absorption-Elution Technique: A Forensic Cross-Sectional Study Among the Population of the Al Jouf Province, Saudi Arabia.

Background and objective Human teeth have a significant forensic importance. As they are the hardest of all human tissues, they are not just chemically stable but also their characteristics are maintained for a long time after death even in the most harsh environmental conditions. Despite the advances made in DNA analysis, fingerprinting, etc., ABO blood grouping still plays a significant role in the forensic practice in the field of personal identification, paternity disputes, and several other scenarios including the identification of mass disaster victims. The term blood groups refers to inherited antigens on the surface of red blood cells (RBCs) detected by specific antibodies. Since tooth pulp contains numerous blood vessels, blood group antigens are most certainly bound to be present in tooth pulp. Various studies have shown that blood group antigens in the pulp and dentin are preserved as long as up to two years after the demise of an individual. Absorption-elution technique has been proven to be the most sensitive, reliable, and consistent method to determine the ABO blood group from both the pulp and dentine. This study aimed to ascertain the ABO blood group from both the hard (dentin) as well as the soft tissue (pulp) of the tooth by using the absorption-elution (AE) technique and also to determine if there are any variations in identifying the blood groups from the teeth based on age and gender. Material and methods After obtaining due consent, we included patients of both genders aged between 16-60 years visiting the outpatient department (OPD) clinics at the College of Dentistry for periodontal or orthodontic extractions. One patient's blood type was determined by using the slide agglutination technique before any capillary blood extraction was performed; this patient served as a control. For this investigation, we used the pulp and powdered dentin samples taken from the dental extractions to test for the presence of ABO and Rhesus (Rh) factor antigens by using the AE method. The study samples were compared with the control for blood group determination. Statistical analysis was carried out using the chi-square test with Monte Carlo (MC) simulation to check for any correlation of blood grouping with age and gender. Results The dentin and pulp were shown to have positive blood group antigens for the ABO and Rh factors. While neither pulp nor dentin performed significantly differently in identifying the blood group antigens, pulp showed marginally higher accuracy. There was no discernible difference regarding gender or age in the dentin or pulp of any of the 45 samples studied. Conclusions For determining an individual's blood type and Rh factor, both the hard (dentin) and soft (pulp) tissues of a tooth are valid sources. This is particularly helpful in forensic medicine cases where teeth are the only remains that can be viably used to find out a person's identity.

Weight-Drop Method for Inducing Closed Head Diffuse Traumatic Brain Injury.

Traumatic brain injury (TBI) is one of the foremost causes of disability and death globally. Prerequisites for successful therapy of disabilities associated with TBI involved improved knowledge of the neurobiology of TBI, measurement of quantitative changes in recovery dynamics brought about by therapy, and the translation of quantitative methodologies and techniques that were successful in tracking recovery in preclinical models to human TBI. Frequently used animal models of TBI in research and development include controlled cortical impact, fluid percussion injury, blast injury, penetrating blast brain injury, and weight-drop impact acceleration models. Preclinical models of TBI benefit from controlled injury settings and the best prospects for biometric quantification of injury and therapy-induced gradual recovery from disabilities. Impact acceleration closed head TBI paradigm causes diffuse TBI (DTBI) without substantial focal brain lesions in rats. DTBI is linked to a significant rate of death, morbidity, and long-term disability. DTBI is difficult to diagnose at the time of hospitalization with imaging techniques making it challenging to take prompt therapeutic action. The weight-drop method without craniotomy is an impact acceleration closed head DTBI model that is used to induce mild/moderate diffuse brain injuries in rodents. Additionally, we have characterized neuropathological and neurobehavioral outcomes of the weight-drop model without craniotomy for inducing closed head DTBI of graded severity with a range of mass of weights (50-450 gm). This chapter also discusses techniques and protocols for measuring numerous functional disabilities and pathological changes in the brain brought on by DTBI.

Attempted repair of chest wall injury following penetrating injury with surgical stabilization rib and autologous bone graft: A case report.

Rib fractures are one of the most common injuries following blunt trauma. When associated with penetrating trauma, the projectile velocity and immense energy transfer cause significant rib fracture displacement and fragmentation. As a result, these patients are potentially exposed to an even higher risk of complications compared to those seen in more simple rib fractures. Unfortunately, there is limited research regarding technical considerations for surgical stabilization of rib fractures (SSRF) in severely displaced rib fractures with bone loss following penetrating injury. We present the case of a 21-year-old male gunshot wound victim with severely displaced and comminuted rib fractures in which we utilized an autologous bone graft bridge during SSRF to enhance fracture unionization, chest wall stability, and cosmesis. Unfortunately, the bone graft failed to incorporate into surrounding tissue.

Modeling of electromagnetic propagation inside jet engine environment using statistical electromagnetic approach.

In this paper, the distribution of the electromagnetic field inside a complex jet engine environment is analyzed using statistical electromagnetics. The jet engine environment is an extremely complex geometry and exhibits random behavior due to the presence of moving metallic parts. This renders traditional analytical and simulation modeling techniques highly inefficient. To address this issue, two different approaches are proposed to model the propagation characteristics of the jet engine environment. The first is an innovative dynamic system approach based on dynamic system simulation which is inspired by the analysis of mechanically stirred reverberation chambers. In the dynamic system simulation the dynamic system, which is characterized by the rotation of a distinct set of blades, is primarily studied through the simulation program. A dimension scaling method is also introduced along with the dynamic system simulation to solve the complex jet engine environment. In the second approach, a novel statistical excitation method is applied to develop an equivalent model for the dynamic jet engine system. The studied jet engine is considered as a static jet engine system without blade rotation (static blades), but with a random excitation.A small signal analysis method is used to integrate the static and dynamic system parameters to generate random excitation characteristics of the static system. The extracted electric field values from the dynamic jet engine simulation environment and the static system field values from the small signal analysis have been analyzed statistically to prove the statistical equality between the two systems. The numerical results of the static system model are presented and verified through comparison with finite element method simulation packages.

Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma.

BACKGROUND: Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. METHODS: Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009-2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging-defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990-2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. RESULTS: Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. CONCLUSIONS: In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.

Characterization of tumor microenvironment in glioblastoma multiforme identifies ITGB2 as a key immune and stromal related regulator in glial cell types.

Glioblastoma multiforme (GBM) is the most aggressive form of brain tumor characterized by inter and intra-tumor heterogeneity and complex tumor microenvironment. To uncover the molecular targets in this milieu, we systematically identified immune and stromal interactions at the glial cell type level that leverages on RNA-sequencing data of GBM patients from The Cancer Genome Atlas. The perturbed genes between the high vs low immune and stromal scored patients were subjected to weighted gene co-expression network analysis to identify the glial cell type specific networks in immune and stromal infiltrated patients. The intramodular connectivity analysis identified the highly connected genes in each module. Combining it with univariable and multivariable prognostic analysis revealed common vital gene ITGB2, between the immune and stromal infiltrated patients enriched in microglia and newly formed oligodendrocytes. We found following unique hub genes in immune infiltrated patients; COL6A3 (microglia), ITGAM (oligodendrocyte precursor cells), TNFSF9 (microglia), and in stromal infiltrated patients, SERPINE1 (microglia) and THBS1 (newly formed oligodendrocytes, oligodendrocyte precursor cells). To validate these hub genes, we used external GBM patient single cell RNA-sequencing dataset and this identified ITGB2 to be significantly enriched in microglia, newly formed oligodendrocytes, T-cells, macrophages and adipocyte cell types in both immune and stromal datasets. The tumor infiltration analysis of ITGB2 showed that it is correlated with myeloid dendritic cells, macrophages, monocytes, neutrophils, B-cells, fibroblasts and adipocytes. Overall, the systematic screening of tumor microenvironment components at glial cell types uncovered ITGB2 as a potential target in primary GBM.

Neuron-derived extracellular vesicles to examine brain mTOR target engagement with sirolimus in patients with multiple system atrophy.

INTRODUCTION: Impaired autophagy is a pathogenic mechanism in the synucleinopathies. Sirolimus, a potent mTOR inhibitor and autophagy activator, had no beneficial effects in a randomized placebo-controlled trial in patients with multiple system atrophy (MSA). Whether sirolimus effectively inhibited brain mTOR activity was unknown. We aimed to evaluate if patients with MSA treated with sirolimus had evidence of inhibited brain mTOR pathways by measuring neuron-derived serum extracellular vesicles (NEVs). METHODS: Serum samples were collected from participants of the sirolimus-MSA trial, which randomized patients to sirolimus (2-6 mg/day) or placebo for 48 weeks. NEVs were immunoprecipitated with three antibodies-against neurons. Brain mTOR engagement was quantified as the change in the NEV phosphorylated mTOR (p-mTOR) to total-mTOR (tot-mTOR) ratio after 48 weeks of sirolimus. RESULTS: Samples from 27 patients [mean (±SD) age, 59.2±7 years, 15 (55.5%) men] were analyzed (19 sirolimus, 8 placebo). Treated- and placebo-patients had similar p-mTOR:tot-mTOR ratio at 24 (placebo: 0.248 ± 0.03, sirolimus: 0.289 ± 0.02; P = 0.305) and 48 weeks (placebo: 0.299 ± 0.05, sirolimus: 0.261 ± 0.03; P = 0.544). The tot-mTOR, p-mTOR, or their ratio levels were not associated with Unified MSA Rating Scale (UMSARS) worsening. DISCUSSION: These results are consistent with no brain mTOR engagement by oral sirolimus up to 6 mg/day. NEV-based biomarkers are a rational approach to investigating target engagement in clinical trials of brain-targeted therapeutics.

Is Follow-up Co-Morbidity Assessment via Laboratory Investigations in Older High Energy Trauma Patients Justified? - A Prospective-Retrospective Study.

Introduction: The objective of the current study was to test our hypothesis that older patients sustaining high energy trauma need to be evaluated for their comorbidities similar to geriatric patients sustaining low energy trauma. Materials and methods: This study was a retrospective-prospective analysis of 173 patients of more than 50 years of age enrolled between November 2017 and December 2018. Herewith, we have compared retrospectively collected laboratory investigations of 124 fragility fracture patients with prospectively collected laboratory investigations of 49 patients with high energy trauma. The laboratory investigations, including the liver function tests, renal function tests, indices of calcium metabolism, serum electrolytes, complete blood counts, and bone mineral density (BMD) scores. Results: Both groups were similar to each other as far as baseline demographic characteristics were concerned. The proportion of female patients and patients with non-osteoporotic range BMD (T-score >-2.5) was significantly higher in the high-energy fracture group (P value <0.05). Hypoalbuminemia (<3.4gm/dl) 17.3%, abnormalities sodium (<135mmol/L or >148mmol/L) 23.2%, Anaemia (<10g/dl) 12.7%, Hypercalcemia (>10.4mg/dl) 16.3%, Vitamin D deficiency (<20ng/ml) 17.3% are the common laboratory abnormality found in study population. No statistically significant difference was found among the two groups in terms of laboratory investigation abnormalities. Conclusion: The laboratory investigation abnormality in an older patient with a clinical fracture is independent of the mechanism of injury. The results of the current study emphasise the need for a comprehensive laboratory workup in older patients with either high- energy fractures or fragility fractures.

Surface area change detection of snow/ice cover over Zemu Glacier of Sikkim Himalaya.

This study assessed the snow/ice surface area changes over the Zemu Glacier in the Eastern Himalayas. Zemu is considered to be the largest glacier in the Eastern Himalayas located in the Sikkim State of India. Change detection in the snow/ice surface areal extent of the Zemu Glacier was delineated from the year 1945 using US Army Map Service-Topographical Sheets and Landsat imageries available from 1987 to 2020. The results obtained solely focus on surface-change delineation using remote sensing satellite data and GIS software. Landsat imagery of the years 1987, 1997, 2009, 2018, and 2020 was used for snow and ice pixel extraction. Normalized Difference Snow Index (NDSI), Snow Cover Index (S3), and new band ratio index were used to extract the pure snow and ice pixels, fresh snow, and debris-covered snow/ice area and pixels mixed with shadow to demarcate the surface area changes. Manual delineation was required and undertaken for better results. A slope raster image was generated from Shuttle Radar Topography Mission (SRTM) digital elevation model (DEM) data to delineate the slope and hill shade. The results illustrate that the snow/ice surface covering the glacier had an area of 113.5 km2 in the year 1945 which was reduced to 78.31 km2 in the year 2020 indicating a total snow/ice surface area loss of 31% in 75 years. A loss of 11.45% was observed from 1945 to 1987 in the areal extent, while from 1987 to 2009, a decadal loss of approximately 7% was observed. The surface area loss of 8.46% from 2009 to 2018 led to infer the maximum loss of snow and ice over the glacier body at a rate of 0.94% per year. Between the years 2018 and 2020, the glacier lost 1.08% of its surface area. The Accumulation Area Ratio (AAR) considering the accumulation and ablation areas of the glacier indicated a gradual decline of the accumulation zone in the recent years. Global Land Ice Measurement from Space (GLIMS) program data with RGI version 6.0 was used as a reference to demarcate the areal extent of Zemu Glacier. The study gained above 80% of overall accuracy by generating a confusion matrix in ArcMap. The analysis of this seasonal snow/ice cover showed that there has been a drastic decline in the surface snow/ice cover area over the Zemu Glacier over the years 1987 to 2020 and NDSI; S3 analysis provided improved results to delineate snow/ice cover area over such steep terrain topography of Sikkim Himalaya.

Impact of Blood Pressure Control on Graft Survival in Kidney Transplant Recipients.

BACKGROUND: Cardiovascular disease is the primary driver of morbidity and mortality in kidney transplant recipients. Hypertension is an important risk factor for development of cardiovascular disease in this population. Despite its important role in post-transplant outcomes, the blood pressure goals for kidney transplant recipients remain elusive. Current guidelines are based on observational data or data extrapolated from the chronic kidney disease population. METHODS: We followed 5-year blood pressure control of 378 kidney-alone transplant recipients at a single center and evaluated patient survival, graft survival, proteinuria, and rate of decline of kidney graft function. RESULTS: We found that a mean systolic blood pressure (BP) of 121 to 130 mm Hg was associated with better graft survival, slower decline of kidney allograft function, and lower degree of proteinuria when compared with a mean systolic BP ≤120 or >130 mm Hg. CONCLUSION: This study provides evidence for strict blood pressure control, systolic BP between 121 and 130 mm Hg, and also cautions against intensive control of systolic BP <120 mm Hg in kidney transplant recipients.

Patient-reported outcomes of laparoscopic versus robotic primary ventral and incisional hernia repair: a systematic review and meta-analysis.

BACKGROUND: Patient-Reported Outcome Measures (PROM's) are increasingly used to assess surgical outcomes in low-risk surgeries such as minimally invasive primary ventral and incisional hernia repair. The purpose of this meta-analysis was to systematically summarize the available evidence for the effect of laparoscopic versus robotic primary ventral and incisional hernia repair on PROM's. METHODS: A systematic review and meta-analysis were performed in accordance with PRISMA guidelines. Randomised control trials, retrospective and prospective studies were included. Medline, Embase, SCOPUS, Web of Science, and Cochrane CENTRAL, and two trial registers were searched. Pooled effect sizes and 95% confidence intervals were calculated using the Mantel-Haenszel method. The overall quality of evidence was assessed using GRADE. RESULTS: Of the 2728 titles screened, eight studies involving 41,205 participants were included. Return to activities of daily living, return to work day and recurrence rate were statistically better in the robotic group. Length of stay, readmission, postoperative pain, quality of life, body image, and patient satisfaction were similar in both groups. The GRADE rating of the quality of evidence was moderate for postoperative pain and low to very low for the quality of life, length of stay, recurrence and readmission. CONCLUSION: The available data of PROM's of laparoscopic and robotic primary ventral and incisional hernia repair is scarce and highly heterogeneous, thus making it difficult to assess the superiority of the laparoscopic technique over the robotic technique. Further studies with uniform reporting of PROM's in laparoscopic and robotic primary ventral and incisional hernia repair are needed.

Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease.

Besides motor symptoms, many individuals with Parkinson's disease develop cognitive impairment perhaps due to coexisting α-synuclein and Alzheimer's disease pathologies and impaired brain insulin signalling. Discovering biomarkers for cognitive impairment in Parkinson's disease could help clarify the underlying pathogenic processes and improve Parkinson's disease diagnosis and prognosis. This study used plasma samples from 273 participants: 103 Parkinson's disease individuals with normal cognition, 121 Parkinson's disease individuals with cognitive impairment (81 with mild cognitive impairment, 40 with dementia) and 49 age- and sex-matched controls. Plasma extracellular vesicles enriched for neuronal origin were immunocaptured by targeting the L1 cell adhesion molecule, then biomarkers were quantified using immunoassays. α-Synuclein was lower in Parkinson's disease compared to control individuals (P = 0.004) and in cognitively impaired Parkinson's disease individuals compared to Parkinson's disease with normal cognition (P < 0.001) and control (P < 0.001) individuals. Amyloid-ß42 did not differ between groups. Phosphorylated tau (T181) was higher in Parkinson's disease than control individuals (P = 0.003) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and controls (P < 0.001). Total tau was not different between groups. Tyrosine-phosphorylated insulin receptor substrate-1 was lower in Parkinson's disease compared to control individuals (P = 0.03) and in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and controls (P = 0.01), and also decreased with increasing motor symptom severity (P = 0.005); serine312-phosphorylated insulin receptor substrate-1 was not different between groups. Mechanistic target of rapamycin was not different between groups, whereas phosphorylated mechanistic target of rapamycin trended lower in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.05). The ratio of α-synuclein to phosphorylated tau181 was lower in Parkinson's disease compared to controls (P = 0.001), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P < 0.001) and decreased with increasing motor symptom severity (P < 0.001). The ratio of insulin receptor substrate-1 phosphorylated serine312 to insulin receptor substrate-1 phosphorylated tyrosine was higher in Parkinson's disease compared to control individuals (P = 0.01), in cognitively impaired compared to cognitively normal Parkinson's disease individuals (P = 0.02) and increased with increasing motor symptom severity (P = 0.003). α-Synuclein, phosphorylated tau181 and insulin receptor substrate-1 phosphorylated tyrosine contributed in diagnostic classification between groups. These findings suggest that both α-synuclein and tau pathologies and impaired insulin signalling underlie Parkinson's disease with cognitive impairment. Plasma neuronal extracellular vesicles biomarkers may inform cognitive prognosis in Parkinson's disease.

Stereoselective total synthesis of Aspergillide D.

The total synthesis of the 16-membered Polyhydroxylated macrolide, Aspergillide D has been accomplished utilizing the Grignard reaction, Sharpless asymmetric epoxidation Regioselective ring opening of epoxy alcohol, Wittig olefination and Yamaguchi macrolactonisation as key steps. 3-butene-1-ol has been utilized as the starting material.

Oral nicotinamide riboside raises NAD+ and lowers biomarkers of neurodegenerative pathology in plasma extracellular vesicles enriched for neuronal origin.

Declining nicotinamide adenine dinucleotide (NAD+ ) concentration in the brain during aging contributes to metabolic and cellular dysfunction and is implicated in the pathogenesis of aging-associated neurological disorders. Experimental therapies aimed at boosting brain NAD+ levels normalize several neurodegenerative phenotypes in animal models, motivating their clinical translation. Dietary intake of NAD+ precursors, such as nicotinamide riboside (NR), is a safe and effective avenue for augmenting NAD+ levels in peripheral tissues in humans, yet evidence supporting their ability to raise NAD+ levels in the brain or engage neurodegenerative disease pathways is lacking. Here, we studied biomarkers in plasma extracellular vesicles enriched for neuronal origin (NEVs) from 22 healthy older adults who participated in a randomized, placebo-controlled crossover trial (NCT02921659) of oral NR supplementation (500 mg, 2x /day, 6 weeks). We demonstrate that oral NR supplementation increases NAD+ levels in NEVs and decreases NEV levels of Aß42, pJNK, and pERK1/2 (kinases involved in insulin resistance and neuroinflammatory pathways). In addition, changes in NAD(H) correlated with changes in canonical insulin-Akt signaling proteins and changes in pERK1/2 and pJNK. These findings support the ability of orally administered NR to augment neuronal NAD+ levels and modify biomarkers related to neurodegenerative pathology in humans. Furthermore, NEVs offer a new blood-based window into monitoring the physiologic response of NR in the brain.

Reversible Modulation of Aptamer-Ligand Binding in RNA Light-Up Aptamers Containing G-Quadruplex Using Chemical Stimuli.

Regulating a system in equilibrium transiently to out-of-equilibrium by using certain stimuli is the strategy used by natural biomolecules to function. Herein, we showed that the interaction of synthetic RNA aptamers, having a G-quadruplex core structure, with their corresponding ligands could be regulated from their equilibrium state to non-equilibrium state in a reversible manner using simple chemical stimuli (Ag+ and cysteine). The approach would be useful for designing aptamer regulators that work in a dynamic nucleic acid network, where a strict control on aptamer-ligand interaction is needed. In addition, to the best of our knowledge, this is the first report which shows that RNA G-quadruplexes can be disrupted by the addition of silver ions. This would be useful not only in designing RNA-based sensors or regulators but would also be useful for understanding the role of metal ions in RNA folding and catalysis.