Most post-colonoscopy interval colorectal cancers are proximal; serrated polyps are often precursors to these cancers and are considered difficult to detect. We assessed the safety, feasibility, and ...economic effect of chromocolonoscopy on detection of proximal serrated neoplasia.
We did an open-label, multicentre, randomised, controlled non-inferiority trial including patients from Bowel Screening Wales centres. Participants who tested positive for faecal occult blood and who were eligible for and considered fit to have colonoscopy (patients with known cases of polyposis syndromes, Lynch syndrome, and chronic inflammatory disease were excluded) were randomly assigned (1:1; with the use of minimisation, stratified by centre with an 80:20 random element) to either standard white light colonoscopy (standard group) or chromocolonoscopy (indigo carmine dye 0·2%; chromocolonoscopy group) using a secure, internet-based, computerised, randomisation system that used centralised, dynamic allocation. Participants were followed up for 1 year and data from index colonoscopies and associated clearance procedures were analysed. All proximal polyps were reviewed by an expert pathologist panel. The main outcome on which power was based was time taken to perform the colonoscopy procedure, defined as from the time when the scope was inserted to withdrawal from the anus, assessed in the per-protocol population. The non-inferiority margin was 15 min. This trial is complete and is registered with ClinicalTrials.gov, number NCT01972451.
Between Nov 20, 2014, and June 16, 2016, 741 (72%) of 1031 patients screened were eligible and consented: 360 were randomly assigned to white light colonoscopy and 381 to chromocolonoscopy. In the chromocolonoscopy group, the procedure took a mean of 36·8 min (SD 15·0), compared with a mean of 30·6 min (13·7) in the standard group (mean difference 6·3 min 95% CI 4·2-8·4 longer with chromocolonoscopy than in the standard group). The mean difference was within the prespecified non-inferiority margin. Detection rates for proximal serrated lesions were significantly higher in the chromocolonoscopy group than in the control group (45 12% of 381 patients vs 23 6% of 360 patients; odds ratio 1·96 95% CI 1·16-3·32; p=0·012). Serious adverse events (four cases of postpolypectomy bleeding two in each group, and one case of anxiety and hyperventilation in the chromocolonoscopy group), colonoscopy quality measures, comfort scores, and sedation were similar between groups.
Chromocolonoscopy is feasible within a population-based colorectal cancer screening programme, is safe, and has significantly increased detection of proximal serrated neoplasia and other polyp types compared with standard colonoscopy. Larger randomised trials of chromocolonoscopy, powered for improved detection of significant serrated polyps and for longer-term follow-up to investigate the effect on reduction of interval cancers within screening populations, are warranted.
Health and Care Research Wales (RfPPB-1021).
Parkinson's disease is a progressive neurodegenerative disorder in which loss of dopaminergic neurons in the substantia nigra results in a clinically heterogeneous group with variable motor and ...non-motor symptoms with a degree of misdiagnosis. Only 3-25% of sporadic Parkinson's patients present with genetic abnormalities that could represent a risk factor, thus environmental, metabolic, and other unknown causes contribute to the pathogenesis of Parkinson's disease, which highlights the critical need for biomarkers. In the present study, we prospectively collected and analyzed plasma samples from 194 Parkinson's disease patients and 197 age-matched non-diseased controls. N-acetyl putrescine (NAP) in combination with sense of smell (B-SIT), depression/anxiety (HADS), and acting out dreams (RBD1Q) clinical measurements demonstrated combined diagnostic utility. NAP was increased by 28% in Parkinsons disease patients and exhibited an AUC of 0.72 as well as an OR of 4.79. The clinical and NAP panel demonstrated an area under the curve, AUC = 0.9 and an OR of 20.4. The assessed diagnostic panel demonstrates combinatorial utility in diagnosing Parkinson's disease, allowing for an integrated interpretation of disease pathophysiology and highlighting the use of multi-tiered panels in neurological disease diagnosis.
Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have ...recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice in vivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to the metabolic changes that occur with physical exercise.
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•Exercise increases circulating levels of the lipokine 12,13-diHOME in humans and mice•iBAT is the tissue source for the exercise-stimulated increase in 12,13-diHOME in mice•12,13-diHOME increases fatty acid uptake and oxidation in skeletal muscle of mice
Using an MS/MSALL lipidomics platform, Stanford et al. identify 12,13-diHOME as an exercised-induced lipokine in male, female, young, and old human subjects. Murine experiments show that BAT is the tissue source of exercise-induced increases in circulating 12,13-diHOME, and that this lipokine increases fatty acid uptake in skeletal muscle in vivo.
Brown adipose tissue (BAT) is an important tissue for thermogenesis, making it a potential target to decrease the risks of obesity, type 2 diabetes, and cardiovascular disease, and recent studies ...have also identified BAT as an endocrine organ. Although BAT has been implicated to be protective in cardiovascular disease, to this point there are no studies that identify a direct role for BAT to mediate cardiac function.
To determine the role of BAT on cardiac function, we utilized a model of BAT transplantation. We then performed lipidomics and identified an increase in the lipokine 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME). We utilized a mouse model with sustained overexpression of 12,13-diHOME and investigated the role of 12,13-diHOME in a nitric oxide synthase type 1 deficient (NOS1
) mouse and in isolated cardiomyocytes to determine effects on function and respiration. We also investigated 12,13-diHOME in a cohort of human patients with heart disease.
Here, we determined that transplantation of BAT (+BAT) improves cardiac function via the release of the lipokine 12,13-diHOME. Sustained overexpression of 12,13-diHOME using tissue nanotransfection negated the deleterious effects of a high-fat diet on cardiac function and remodeling, and acute injection of 12,13-diHOME increased cardiac hemodynamics via direct effects on the cardiomyocyte. Furthermore, incubation of cardiomyocytes with 12,13-diHOME increased mitochondrial respiration. The effects of 12,13-diHOME were absent in
mice and cardiomyocytes. We also provide the first evidence that 12,13-diHOME is decreased in human patients with heart disease.
Our results identify an endocrine role for BAT to enhance cardiac function that is mediated by regulation of calcium cycling via 12,13-diHOME and NOS1.
Abstract
Prostate-specific antigen (PSA) screening for prostate cancer (PCa) is limited by the lack of specificity but is further complicated in the benign prostatic hyperplasia (BPH) population ...which also exhibit elevated PSA, representing a clear unmet need to distinguish BPH from PCa. Herein, we evaluated the utility of FLNA IP-MRM, age, and prostate volume to stratify men with BPH from those with PCa. Diagnostic performance of the biomarker panel was better than PSA alone in discriminating patients with negative biopsy from those with PCa, as well as those who have had multiple prior biopsies (AUC 0.75 and 0.87 compared to AUC of PSA alone 0.55 and 0.57 for patients who have had single compared to multiple negative biopsies, respectively). Of interest, in patients with PCa, the panel demonstrated improved performance than PSA alone in those with Gleason scores of 5–7 (AUC 0.76 vs. 0.56) and Gleason scores of 8–10 (AUC 0.74 vs. 0.47). With Gleason scores (8–10), the negative predictive value of the panel is 0.97, indicating potential to limit false negatives in aggressive cancers. Together, these data demonstrate the ability of the biomarker panel to perform better than PSA alone in men with BPH, thus preventing unnecessary biopsies.
Low molecular-mass aliphatic carboxylic acids are critically important for intermediate metabolism and may serve as important biomarkers for metabolic homeostasis. Here in, we focused on multiplexed ...method development of aliphatic carboxylic analytes, including methylsuccinic acid (MSA), ethylmalonic acid (EMA), and glutaric acid (GA). Also assessed was their utility in a population's health as well as metabolic disease screening in both plasma and urine matrices. MSA, EMA, and GA are constitutional isomers of dicarboxylic acid with high polarity and poor ionization efficiency, resulting in such challenges as poor signal intensity and retention, particularly in reversed-phase liquid chromatography with electrospray mass spectrometry (RP-LC-ESI-MS/MS). Derivatization using n-butanol was performed in the sample preparation to enhance the signal intensity accompanied with a positive charge from ionization in complicated biomatrices as well as to improve the separation of these isomers with optimal retention. Fit-for-purpose method validation results demonstrated quantitative ranges for MSA/EMA/GA from 5/10/20 ng/mL to 400 ng/mL in plasma analysis, and 100/200/100 ng/mL to 5000/10000/5000 ng/mL in urine analysis. This validated method demonstrates future utility when exploring population health analysis and biomarker development in metabolic diseases.
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•Small aliphatic carboxylates identified as biomarkers in metabolic diseases.•The sensitivity was improved by derivatized dicarboxylates in LC-MS/MS.•Three dicarboxylates of constitutional isomer were separated without isobaric effect.•Quantification methods using LC-MS/MS for dicarboxylate isomers were validated here.•The validated methods are promised in diagnosis of metabolic disease biomarkers.
Prostate cancer represents a significant health risk to aging men, in which diagnostic challenges to the identification of aggressive cancers remain unmet. Prostate cancer screening is driven by the ...prostate-specific antigen (PSA); however, in men with benign prostatic hyperplasia (BPH) due to an enlarged prostate and elevated PSA, PSA's screening utility is diminished, resulting in many unnecessary biopsies. To address this issue, we previously identified a cleaved fragment of Filamin A (FLNA) protein (as measured with IP-MRM mass spectrometry assessment as a prognostic biomarker for stratifying BPH from prostate cancer and subsequently evaluated its expanded utility in Caucasian (CA) and African American (AA) men. All men had a negative digital rectal examination (DRE) and PSA between 4 and 10 ng/mL and underwent prostate biopsy. In AA men, FLNA serum levels exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.71 AUC and 12.2 OR in 48 men with BPH and 60 men with PCa) and outperformed PSA (0.50 AUC, 2.2 OR). In CA men, FLNA serum levels also exhibited diagnostic utility for stratifying BPH from patients with aggressive prostate cancer (0.74 AUC and 19.4 OR in 191 men with BPH and 109 men with PCa) and outperformed PSA (0.46 AUC, 0.32 OR). Herein, we established FLNA alone as a serum biomarker for stratifying men with BPH vs. those with high Gleason (7-10) prostate cancers compared to the current diagnostic paradigm of using PSA. This approach demonstrates clinical actionability of FLNA alone without the requirement of prostate volume measurement as a test with utility in AA and CA men and represents a significant opportunity to decrease the number of unnecessary biopsies in aggressive prostate cancer diagnoses.
Background
The COVID‐19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 ...weeks of peak disruption due to COVID‐19.
Methods
A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β‐regression model was used to estimate 12‐week cancellation rates for 190 countries. Elective surgical case‐mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country‐level surgical volumes. The 12‐week cancellation rates were then applied to these figures to calculate the total number of cancelled operations.
Results
The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID‐19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12‐week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID‐19 disruption.
Conclusion
A very large number of operations will be cancelled or postponed owing to disruption caused by COVID‐19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely.
Antecedentes
La pandemia de COVID‐19 ha interrumpido los servicios hospitalarios habituales a nivel mundial. En este estudio se calculó el número total de operaciones electivas para adultos que se cancelarían en todo el mundo durante las 12 semanas de interrupción máxima debido a COVID’19.
Métodos
Se realizó un estudio global de respuestas de expertos para obtener proyecciones sobre la proporción de cirugía electiva que se cancelaría o pospondría durante las 12 semanas del pico máximo de disrupción. Se usó un modelo bayesiano de regresión beta para estimar las tasas de cancelación durante 12 semanas en 190 países. Se determinaron los datos de la casuística de casos quirúrgicos electivos, estratificados por especialidad e indicación (cáncer versus cirugía benigna). Esta casuística de casos se aplicó a volúmenes quirúrgicos a nivel de país. Las tasas de cancelación de las 12 semanas se aplicaron a estas cifras para calcular el total de operaciones suspendidas.
Resultados
La mejor estimación fue que 28.404.603 operaciones hubieran sido canceladas o pospuestas durante las 12 semanas del pico de disrupción por COVID‐19 (2.367.050 operaciones por semana). La mayoría hubieran sido operaciones por enfermedad benigna (90,2%, 25.638.922/28. 404. 603). La tasa de cancelación general en 12 semanas sería del 72,3%. A nivel mundial, el 81,7% (25.638.921/31.378.062) de la cirugía benigna, el 37,7% (2. 324.069/6.162.311) de la cirugía por cáncer y el 25,4% (441.611/1.735.483) de las cesáreas electivas hubieran sido canceladas o pospuestas. Si los países aumentan su volumen quirúrgico normal en un 20% después de la pandemia, se tardaría una mediana de 45 semanas para eliminar la acumulación de operaciones resultantes de la disrupción por COVID’19.
Conclusión
Se cancelará o pospondrá un número muy grande de operaciones debido a la disrupción causada por COVID‐19. Los gobiernos deberían mitigar esta importante carga para los pacientes mediante el desarrollo de planes de recuperación e implementando estrategias para reiniciar de manera segura la actividad quirúrgica.
A very large number of operations will be cancelled or postponed owing to disruption caused by COVID‐19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely.
A mountain to climb
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