Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and indications for postoperative ...radiotherapy are controversial. Here we develop a targeted gene expression biomarker that predicts meningioma outcomes and radiotherapy responses. Using a discovery cohort of 173 meningiomas, we developed a 34-gene expression risk score and performed clinical and analytical validation of this biomarker on independent meningiomas from 12 institutions across 3 continents (N = 1,856), including 103 meningiomas from a prospective clinical trial. The gene expression biomarker improved discrimination of outcomes compared with all other systems tested (N = 9) in the clinical validation cohort for local recurrence (5-year area under the curve (AUC) 0.81) and overall survival (5-year AUC 0.80). The increase in AUC compared with the standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval 0.07 to 0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% confidence interval 0.37 to 0.78, P = 0.0001) and suggested postoperative management could be refined for 29.8% of patients. In sum, our results identify a targeted gene expression biomarker that improves discrimination of meningioma outcomes, including prediction of postoperative radiotherapy responses.
Summary
Programmed cell death (PCD) is fundamentally important for plant development, abiotic stress responses and immunity, but our understanding of its regulation remains fragmented. Building a ...stronger research community is required to accelerate progress in this area through knowledge exchange and constructive debate. In this Viewpoint, we aim to initiate a collective effort to integrate data across a diverse set of experimental models to facilitate characterisation of the fundamental mechanisms underlying plant PCD and ultimately aid the development of a new plant cell death classification system in the future. We also put forward our vision for the next decade of plant PCD research stemming from discussions held during the 31st New Phytologist workshop, ‘The Life and Death Decisions of Plant Cells’ that took place at University College Dublin in Ireland (14–15 June 2023). We convey the key areas of significant progress and possible future research directions identified, including resolving the spatiotemporal control of cell death, isolation of its molecular and genetic regulators, and harnessing technical advances for studying PCD events in plants. Further, we review the breadth of potential impacts of plant PCD research and highlight the promising new applications of findings from this dynamically evolving field.
Real and apparent conflicts between ecosystem and human needs for fresh water are contributing to the emergence of an alternative model for conducting river science around the world. The core of this ...new paradigm emphasizes the need to forge new partnerships between scientists and other stakeholders where shared ecological goals and river visions are developed, and the need for new experimental approaches to advance scientific understanding at the scales relevant to whole-river management. We identify four key elements required to make this model succeed: existing and planned water projects represent opportunities to conduct ecosystem-scale experiments through controlled river flow manipulations; more cooperative interactions among scientists, managers, and other stakeholders are critical; experimental results must be synthesized across studies to allow broader generalization; and new, innovative funding partnerships are needed to engage scientists and to broadly involve the government, the private sector, and NGOs.
Abstract Most genome-wide association studies have explored relationships between genetic variants and plasma phospholipid fatty acid proportions, but few have examined apparent genetic influences on ...the membrane fatty acid profile of red blood cells (RBC). Using RBC fatty acid data from the Framingham Offspring Study, we analyzed over 2.5 million single nucleotide polymorphisms (SNPs) for association with 14 RBC fatty acids identifying 191 different SNPs associated with at least 1 fatty acid. Significant associations ( p <1×10−8 ) were located within five distinct 1 MB regions. Of particular interest were novel associations between (1) arachidonic acid and PCOLCE2 (regulates apoA-I maturation and modulates apoA-I levels), and (2) oleic and linoleic acid and LPCAT3 (mediates the transfer of fatty acids between glycerolipids). We also replicated previously identified strong associations between SNPs in the FADS (chromosome 11) and ELOVL (chromosome 6) regions. Multiple SNPs explained 8–14% of the variation in 3 high abundance (>11%) fatty acids, but only 1–3% in 4 low abundance (<3%) fatty acids, with the notable exception of dihomo-gamma linolenic acid with 53% of variance explained by SNPs. Further studies are needed to determine the extent to which variations in these genes influence tissue fatty acid content and pathways modulated by fatty acids.
Although lipid profiles tend to worsen with age, it is not fully known if such age-related changes are influenced primarily by body composition and lifestyle or by other aspects of aging.
We ...investigated the extent to which the fat and fat-free components of body mass index (BMI) and lifestyle factors influence patterns of change in lipids independent of age.
Serial data were analyzed using sex-specific longitudinal models. These models use serial data from individuals to assume a general pattern of change over time, while allowing baseline age and the rate of change to vary among individuals.
Serial data were obtained from 940 examinations of 269 healthy white participants (126 men, 143 women), aged 40-60 years, in the Fels Longitudinal Study.
Measurements included age, the fat (FMI) and fat-free mass (FFMI) components of BMI, high-density lipoprotein (HDL-C), low-density lipoprotein (LDL-C), triglycerides (TG), total cholesterol (TC), fasting glucose and insulin, physical activity, alcohol use and smoking, and women's menopausal status and estrogen use.
In both sexes, increased FMI was significantly associated with increased LDL-C, TG and TC, and decreased HDL-C. Increased FFMI was significantly related to decreased HDL-C and increased TG. Independent age effects remained significant only for LDL-C and TC in men and TC in women. Increased insulin was significantly related to increased TG in women. Moderate alcohol consumption was associated with higher HDL-C in men. Physical activity lowered male LDL-C and TC levels, and increased female HDL-C levels. Menopause was associated with increases in LDL-C. Premenopausal women not using estrogen had significantly lower HDL-C, TG, and TC than postmenopausal women taking estrogen.
(1) Age is an important independent predictor for LDL-C and TC in men, and TC in women, but it is not as influential as body composition and lifestyle on HDL-C and TG in men and women, and LDL-C in women. (2) Increasing FMI is the major contributor to elevated TC, LDL-C and TG levels, and decreased HDL-C levels in men and women. (3) FFMI significantly influences HDL and TG levels in both sexes. (4) Maintaining a lower BMI via a reduced fat component may be more beneficial in lowering CVD risks than other factors.
Neoplasia is common in pet dogs but accurate figures for the incidence of tumours in this, as in other species, are sparse. The purpose of this study was to document the occurrence of tumours in a ...defined population of dogs. From a database of 130,684 insured dogs, claims relating to the investigation or treatment of tumours or tumour‐like lesions during a 12‐month period were accessed and followed up. A total of 2546 claims were tumour related and were classified according to tumour site and type. Because the demographics of the insured population were skewed towards younger animals, a standard population, as described in the veterinary literature, was used in the calculation of tumour incidence rates. The skin and soft tissues were the most common sites for tumour development, with a standardised incidence rate of 1437 per 100,000 dogs per year, followed by alimentary (210), mammary (205), urogenital (139), lymphoid (134), endocrine (113) and oropharyngeal (112). Canine cutaneous histiocytoma was the most common single tumour type, with a standardised incidence rate of 337 per 100,000 dogs per year, followed by lipoma (318), adenoma (175), soft tissue sarcoma (142), mast cell tumour (129) and lymphosarcoma (114). These data are unique and provide a valuable basis for future research into the aetiology and epidemiology of canine tumours.
Deceased donor skin possesses many of the properties of the ideal biological dressing, and a well-stocked skin bank has become a critically important asset for the modern burn surgeon. Without it, ...managing patients with extensive burns and wounds becomes far more challenging, and outcomes are significantly worse. With the recent establishment of such a bank in South Africa, the challenge facing the medical fraternity is to facilitate tissue donation so that allograft skin supply can match the enormous demand.
Patients with advanced renal disease randomized to the very low-protein diet group in the Modification of Diet in Renal Disease (MDRD) Study had a marginally (
P = 0.066) slower mean glomerular ...filtration rate (GFR) decline compared with patients randomized to the low-protein diet group. The objective of these secondary analyses was to determine the relationship between achieved, in addition to prescribed, dietary protein intake and the progression of advanced renal disease. A randomized controlled trial was conducted in patients with chronic renal diseases of diverse etiology. The average follow-up was 2.2 years. Fifteen university hospital outpatient nephrology practices participated in the study, which comprised 255 patients aged 18 to 70 years with a baseline GFR 13 to 24 mL/min/1.73 m
2 who participated in MDRD Study B. Patients with diabetes requiring insulin were excluded. The patients were given a low-protein (0.58 g/kg/d) or very low-protein (0.28 g/kg/d) diet supplemented with keto acids-amino acids (0.28 g/kg/d). Outcomes were measured by comparisons of protein intake from food or from food and supplement between randomized groups, and correlations of protein intake with rate of decline in GFR and time to renal failure or death. Comparison of the randomized groups showed that total protein intake from food and supplement was lower (
P < 0.001) among patients randomized to the very low-protein diet (0.66 g/kg/ d) compared with protein intake from food only in patients randomized to the low-protein diet (0.73 g/kg/d). In correlational analyses, we combined patients assigned to both diets and controlled for baseline factors associated with a faster progression of renal disease. A 0.2 g/kg/d lower achieved total protein intake (including food and supplement) was associated with a 1.15 mL/min/yr slower mean decline in GFR (
P = 0.011), equivalent to 29% of the mean GFR decline. After adjusting for achieved total protein intake, no independent effect of prescription of the keto acid-amino acid supplement to slow the GFR decline could be detected. If the GFR decline is extrapolated until renal failure, a patient with a 29% reduction in the rate of GFR decline would experience a 41% prolongation in the time to renal failure. Additional analyses confirmed a longer time to renal failure in patients with lower total protein intake. In conclusion, these secondary analyses of the MDRD Study suggest that a lower protein intake, but not the keto acid-amino acid supplement, retards the progression of advanced renal disease. In patients with GFR less than 25 mL/min/1.73 m
2, we suggest a prescribed dietary protein intake of 0.6 g/kg/d.
Cardiac morphology in human athletes is known to differ, depending on the sports-specific endurance component of their events, whereas anecdotes abound about superlative athletes with large hearts. ...As the heart determines stroke volume and maximum O(2) uptake in mammals, we undertook a study to test the hypothesis that the morphology of the equine heart would differ between trained horses, depending on race type, and that left ventricular size would be greatest in elite performers. Echocardiography was performed in 482 race-fit Thoroughbreds engaged in either flat (1,000-2,500 m) or jump racing (3,200-6,400 m). Body weight and sex-adjusted measures of left ventricular size were largest in horses engaged in jump racing over fixed fences, compared with horses running shorter distances on the flat (range 8-16%). The observed differences in cardiac morphologies suggest that subtle differences in training and competition result in cardiac adaptations that are appropriate to the endurance component of the horses' event. Derived left ventricular mass was strongly associated with published rating (quality) in horses racing over longer distances in jump races (P < or = 0.001), but less so for horses in flat races. Rather, left ventricular ejection fraction and left ventricular mass combined were positively associated with race rating in older flat racehorses running over sprint (<1,408 m) and longer distances (>1,408 m), explaining 25-35% of overall variation in performance, as well as being closely associated with performance in longer races over jumps (23%). These data provide the first direct evidence that cardiac size influences athletic performance in a group of mammalian running athletes.
Postoperative delirium is an important public health concern without effective prevention strategies. This study tested the hypothesis that perioperative epidural use would be associated with ...decreased risk of delirium through postoperative day 3.
This was a secondary, observational, nonrandomized analysis of data from The Prevention of Delirium and Complications Associated With Surgical Treatments Trial (PODCAST; NCT01690988). The primary outcome of the current study was the incidence of delirium (ie, any positive delirium screen, postanesthesia care unit through postoperative day 3) in surgical patients (gastrointestinal, hepatobiliary-pancreatic, gynecologic, and urologic) receiving postoperative epidural analgesia compared to those without an epidural. As a secondary outcome, all delirium assessments were then longitudinally analyzed in relation to epidural use throughout the follow-up period. Given the potential relevance to delirium, postoperative pain, opioid consumption, sleep disturbances, and symptoms of depression were also analyzed as secondary outcomes. A semiparsimonious multivariable logistic regression model was used to test the association between postoperative epidural use and delirium incidence, and generalized estimating equations were used to test associations with secondary outcomes described. Models included relevant covariates to adjust for confounding.
In total, 263 patients were included for analysis. Epidural use was not independently associated with reduced delirium incidence (adjusted odds ratio, 0.65 95% CI, 0.32-1.35; P = .247). However, when analyzing all assessments over the follow-up period, epidural patients were 64% less likely to experience an episode of delirium (adjusted odds ratio, 0.36 95% CI, 0.17-0.78; P = .009). Adjusted pain scores (visual analog scale, 0-100 mm) were significantly lower in the epidural group on postoperative day 1 (morning, -16 95% CI, -26 to -7, P < .001; afternoon, -15 95% CI, -25 to -5, P < .01) and postoperative day 3 (morning, -13 95% CI, -20 to -5, P < .01). Adjusted mean oral and IV morphine equivalents were also significantly lower on postoperative day 1 in the epidural group (74% lower 95% CI, 55%-85%; P < .0001). Finally, postoperative epidural use was not significantly associated with new sleep disturbances or changes in depression symptoms.
Postoperative epidural use was not associated with a reduced overall incidence of delirium. However, longitudinal analysis revealed reduced adjusted odds of experiencing an episode of delirium in the epidural group. Epidural use was also associated with reduced postoperative pain and opioid consumption. An appropriately designed follow-up study is warranted to further analyze the relationship among epidural use, postoperative delirium, and related outcomes.
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