Global Urinary Volatolomics with (GC×)GC-TOF-MS.

Urinary volatolomics offers a noninvasive approach for disease detection and monitoring. Herein we present an improved methodology for global volatolomic profiling. Wide coverage was achieved by utilizing a multiphase sorbent for volatile organic compound (VOC) extraction. A single, midpolar column gas chromatography (GC) assay yielded substantially higher numbers of monitored VOCs compared to our previously reported single-sorbent method. Multidimensional GC (GC×GC) enhanced further biomarker discovery while data analysis was simplified by using a tile-based approach. At the same time, the required urine volume was reduced 5-fold from 2 to 0.4 mL. The applicability of the methodology was demonstrated in a pancreatic ductal adenocarcinoma cohort where previous findings were confirmed while a series of additional VOCs with diagnostic potential were discovered.

A Complete Pipeline for Untargeted Urinary Volatolomic Profiling with Sorptive Extraction and Dual Polar and Nonpolar Column Methodologies Coupled with Gas Chromatography Time-of-Flight Mass Spectrometry.

Volatolomics offers an opportunity for noninvasive detection and monitoring of human disease. While gas chromatography-mass spectrometry (GC-MS) remains the technique of choice for analyzing volatile organic compounds (VOCs), barriers to wider adoption in clinical practice still exist, including: sample preparation and introduction techniques, VOC extraction, throughput, volatolome coverage, biological interpretation, and quality control (QC). Therefore, we developed a complete pipeline for untargeted urinary volatolomic profiling. We optimized a novel extraction technique using HiSorb sorptive extraction, which exhibited high analytical performance and throughput. We achieved a broader VOC coverage by using HiSorb coupled with a set of complementary chromatographic methods and time-of-flight mass spectrometry. Furthermore, we developed a data preprocessing strategy by evaluating internal standard normalization, batch correction, and we adopted strict QC measures including removal of nonlinearly responding, irreproducible, or contaminated metabolic features, ensuring the acquisition of high-quality data. The applicability of this pipeline was evaluated in a clinical cohort consisting of pancreatic ductal adenocarcinoma (PDAC) patients (n = 28) and controls (n = 33), identifying four urinary candidate biomarkers (2-pentanone, hexanal, 3-hexanone, and p-cymene), which can successfully discriminate the cancer and noncancer subjects. This study presents an optimized, high-throughput, and quality-controlled pipeline for untargeted urinary volatolomic profiling. Use of the pipeline to discriminate PDAC from control subjects provides proof of principal of its clinical utility and potential for application in future biomarker discovery studies.

Influence of ventilatory parameters on the concentration of exhaled volatile organic compounds in mechanically ventilated patients.

Analysis of volatile organic compounds (VOC) within exhaled breath is subject to numerous sources of methodological and physiological variability. Whilst breathing pattern is expected to influence the concentrations of selected exhaled VOCs, it remains challenging to investigate respiratory rate and depth accurately in awake subjects. Online breath sampling was performed in 20 mechanically ventilated patients using proton transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). The effect of variation in respiratory rate (RR) and tidal volume (TV) on the VOC release profiles was examined. A panel of nineteen VOCs were selected, including isoprene, acetone, propofol, volatile aldehydes, acids and phenols. Variation in RR had the greatest influence on exhaled isoprene levels, with maximum and average concentrations being inversely correlated with RR. Variations in RR had a statistically significant impact on acetone, C3-C7 linear aldehydes and acetic acid. In comparison, phenols (including propofol), C8-C10 aldehydes and C3-C6 carboxylic acids were not influenced by RR. Isoprene was the only compound to be influenced by variation in TV. These findings, obtained under controlled conditions, provide useful guidelines for the optimisation of breath sampling protocols to be applied on awake patients.

The effects of prehabilitation on body composition in patients undergoing multimodal therapy for esophageal cancer.

Prehabilitation aims to optimize a patient's functional capacity in preparation for surgery. Esophageal cancer patients have a high incidence of sarcopenia and commonly undergo neoadjuvant therapy, which is associated with loss of muscle mass. This study examines the effects of prehabilitation on body composition during neoadjuvant therapy in esophageal cancer patients. In this cohort study, changes in body composition were compared between esophageal cancer patients who participated in prehabilitation during neoadjuvant therapy and controls who did not receive prehabilitation. Assessment of body composition was performed from CT images acquired at the time of diagnosis and after neoadjuvant therapy. Fifty-one prehabilitation patients and 28 control patients were identified. There was a significantly greater fall in skeletal muscle index (SMI) in the control group compared with the prehabilitation patients (Δ SMI mean difference = -2.2 cm2/m2, 95% CI -4.3 to -0.1, p=0.038). Within the prehabilitation cohort, there was a smaller decline in SMI in patients with ≥75% adherence to exercise in comparison to those with lower adherence (Δ SMI mean difference = -3.2, 95% CI -6.0 to -0.5, P = 0.023). A greater decrease in visceral adipose tissue (VAT) was seen with increasing volumes of exercise completed during prehabilitation (P = 0.046). Loss of VAT during neoadjuvant therapy was associated with a lower risk of post-operative complications (P = 0.017). By limiting the fall in SMI and promoting VAT loss, prehabilitation may have multiple beneficial effects in patients with esophageal cancer. Multi-center, randomized studies are needed to further explore these findings.

Assessment of Health Related Quality of Life and Digestive Symptoms in Long-term, Disease Free Survivors After Esophagectomy.

OBJECTIVE: The aim of this study was to investigate long-term HRQOL and symptom evolution in disease free patients up to 20 years after esophagectomy. BACKGROUND: Esophagectomy has been associated with decreased HRQOL and persistent gastrointestinal symptoms. METHODS: The study cohort was identified from 2 high volume centers for the management of esophageal cancer. Patients completed HRQOL and symptom questionnaires, including: Digestive Symptom Questionnaire, EORTC QLQ-C30, EORTC QLQ-OG25 Euro QoL 5D, and SF36. Patients were assessed in 3 cohorts: <1 year; 1-5 years, and; >5 years after surgery. RESULTS: In total 171 of 222 patients who underwent esophagectomy between 1991 and 2017 who met inclusion criteria and were contactable, responded to the questionnaires, corresponding to a response rate of 77%. Median age was 66.2 years, and median time from operation to survey was 5.6 years (range 0.3-23.1). Early satiety was the most commonly reported symptom in all patients irrespective of timeframe (87.4%; range 82%-92%). Dysphagia was seen to decrease over time (58% at <2 years; 28% at 2-5 years; 20% at >5 years; P = 0.013). Weight loss scores demonstrated nonstatistical improvement over time. All other symptom scores including heartburn, regurgitation, respiratory symptoms, and pain scores remained constant over time. Average HRQOL did not improve from levels 1 year after surgery compared to patients up to 23 years after esophagectomy. CONCLUSION: With the exception of dysphagia, which improved over time, esophagectomy was associated with decreased HRQOL and lasting gastrointestinal symptoms up to 20 years after surgery. Pertinently however long-term survivors after oesophagectomy demonstrated comparable to improved HRQOL compared to the general population. The impact of esophagectomy on gastrointestinal symptoms and long-term HRQOL should be considered when counseling and caring for patients undergoing esophagectomy.

Development of a Reliable Surgical Quality Assurance System for 2-stage Esophagectomy in Randomized Controlled Trials.

OBJECTIVE: The aim was to develop a reliable surgical quality assurance system for 2-stage esophagectomy. This development was conducted during the pilot phase of the multicenter ROMIO trial, collaborating with international experts. SUMMARY OF BACKGROUND DATA: There is evidence that the quality of surgical performance in randomized controlled trials influences clinical outcomes, quality of lymphadenectomy and loco-regional recurrence. METHODS: Standardization of 2-stage esophagectomy was based on structured observations, semi-structured interviews, hierarchical task analysis, and a Delphi consensus process. This standardization provided the structure for the operation manual and video and photographic assessment tools. Reliability was examined using generalizability theory. RESULTS: Hierarchical task analysis for 2-stage esophagectomy comprised fifty-four steps. Consensus (75%) agreement was reached on thirty-nine steps, whereas fifteen steps had a majority decision. An operation manual and record were created. A thirty five-item video assessment tool was developed that assessed the process (safety and efficiency) and quality of the end product (anatomy exposed and lymphadenectomy performed) of the operation. The quality of the end product section was used as a twenty seven-item photographic assessment tool. Thirty-one videos and fifty-three photographic series were submitted from the ROMIO pilot phase for assessment. The overall G-coefficient for the video assessment tool was 0.744, and for the photographic assessment tool was 0.700. CONCLUSIONS: A reliable surgical quality assurance system for 2-stage esophagectomy has been developed for surgical oncology randomized controlled trials. ETHICAL APPROVAL: 11/NW/0895 and confirmed locally as appropriate, 12/SW/0161, 16/SW/0098.Trial registration number: ISRCTN59036820, ISRCTN10386621.

Impact of Early Jejunostomy Tube Feeding on Clinical Outcome and Parameters of Body Composition in Esophageal Cancer Patients Receiving Multimodal Therapy.

BACKGROUND: Malnutrition commonly affects patients with esophageal cancer and has the potential to negatively influence treatment outcomes. The aim of this study was to investigate the impact of early (preoperative) jejunostomy tube feeding (JTF) in nutritionally 'high risk' patients receiving multimodal therapy for esophageal cancer. METHODS: Patients were selected to undergo early JTF during neoadjuvant chemoradiotherapy (nCRT) in accordance with European Society for Clinical Nutrition and Metabolism (ESPEN) and Enhanced Recovery after Surgery (ERAS®) Society guidelines. Clinical outcomes were compared with patients who received routine JTF from the time of esophagectomy. Body composition was determined from computed tomography (CT) images acquired at diagnosis, after nCRT, and ≥ 3 months after surgery. RESULTS: In total, 81 patients received early JTF and 91 patients received routine JTF. Patients who received early JTF had lower body mass index (BMI; 26.1 ± 4.6 vs. 28.4 ± 4.9; p = 0.002), greater weight loss, and worse performance status at diagnosis. Groups were otherwise well-matched for baseline characteristics. Rate of re-intubation (8.8% vs. 1.1%; p = 0.027), pulmonary embolism (5.0% vs. 0.0%; p = 0.046), and 90-day mortality (10.0% vs. 1.1%; p = 0.010) were worse in the early JTF group; however, overall survival was equivalent for both the early and routine JTF groups (p = 0.053). Wide variation in the degree of preoperative muscle loss and total adipose tissue loss was observed across the entire study cohort. Relative preoperative muscle and adipose tissue loss in patients with early and routine JTF was equivalent. CONCLUSIONS: In patients determined to be at 'high risk' of malnutrition, early JTF may prevent excess morbidity after esophagectomy with an associated relative preservation of parameters of body composition.

Systematic review and validation of clinical models predicting survival after oesophagectomy for adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma poses a significant global health burden, yet the staging used to predict survival has limited ability to stratify patients by outcome. This study aimed to identify published clinical models that predict survival in oesophageal adenocarcinoma and to evaluate them using an independent international multicentre dataset. METHODS: A systematic literature search (title and abstract) using the Ovid Embase and MEDLINE databases (from 1947 to 11 July 2020) was performed. Inclusion criteria were studies that developed or validated a clinical prognostication model to predict either overall or disease-specific survival in patients with oesophageal adenocarcinoma undergoing surgical treatment with curative intent. Published models were validated using an independent dataset of 2450 patients who underwent oesophagectomy for oesophageal adenocarcinoma with curative intent. RESULTS: Seventeen articles were eligible for inclusion in the study. Eleven models were suitable for testing in the independent validation dataset and nine of these were able to stratify patients successfully into groups with significantly different survival outcomes. Area under the receiver operating characteristic curves for individual survival prediction models ranged from 0.658 to 0.705, suggesting poor-to-fair accuracy. CONCLUSION: This study highlights the need to concentrate on robust methodologies and improved, independent, validation, to increase the likelihood of clinical adoption of survival predictions models.

Investigating Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Surface and Air Contamination in an Acute Healthcare Setting During the Peak of the Coronavirus Disease 2019 (COVID-19) Pandemic in London.

BACKGROUND: We evaluated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surface and air contamination during the coronavirus disease 2019 (COVID-19) pandemic in London. METHODS: Prospective, cross-sectional, observational study in a multisite London hospital. Air and surface samples were collected from 7 clinical areas occupied by patients with COVID-19 and a public area of the hospital. Three or four 1.0-m3 air samples were collected in each area using an active air sampler. Surface samples were collected by swabbing items in the immediate vicinity of each air sample. SARS-CoV-2 was detected using reverse-transcription quantitative polymerase chain reaction (PCR) and viral culture; the limit of detection for culturing SARS-CoV-2 from surfaces was determined. RESULTS: Viral RNA was detected on 114 of 218 (52.3%) surfaces and in 14 of 31 (38.7%) air samples, but no virus was cultured. Viral RNA was more likely to be found in areas immediately occupied by COVID-19 patients than in other areas (67 of 105 [63.8%] vs 29 of 64 [45.3%]; odds ratio, 0.5; 95% confidence interval, 0.2-0.9; P = .025, χ2 test). The high PCR cycle threshold value for all samples (>30) indicated that the virus would not be culturable. CONCLUSIONS: Our findings of extensive viral RNA contamination of surfaces and air across a range of acute healthcare settings in the absence of cultured virus underlines the potential risk from environmental contamination in managing COVID-19 and the need for effective use of personal protective equipment, physical distancing, and hand/surface hygiene.

A Bidirectional Mendelian Randomization Study to evaluate the causal role of reduced blood vitamin D levels with type 2 diabetes risk in South Asians and Europeans.

CONTEXT: Multiple observational studies have reported an inverse relationship between 25-hydroxyvitamin D concentrations (25(OH)D) and type 2 diabetes (T2D). However, the results of short- and long-term interventional trials concerning the relationship between 25(OH)D and T2D risk have been inconsistent. OBJECTIVES AND METHODS: To evaluate the causal role of reduced blood 25(OH)D in T2D, here we have performed a bidirectional Mendelian randomization study using 59,890 individuals (5,862 T2D cases and 54,028 controls) from European and Asian Indian ancestries. We used six known SNPs, including three T2D SNPs and three vitamin D pathway SNPs, as a genetic instrument to evaluate the causality and direction of the association between T2D and circulating 25(OH)D concentration. RESULTS: Results of the combined meta-analysis of eight participating studies showed that a composite score of three T2D SNPs would significantly increase T2D risk by an odds ratio (OR) of 1.24, p = 1.82 × 10-32; Z score 11.86, which, however, had no significant association with 25(OH)D status (Beta -0.02nmol/L ± SE 0.01nmol/L; p = 0.83; Z score -0.21). Likewise, the genetically instrumented composite score of 25(OH)D lowering alleles significantly decreased 25(OH)D concentrations (-2.1nmol/L ± SE 0.1nmol/L, p = 7.92 × 10-78; Z score -18.68) but was not associated with increased risk for T2D (OR 1.00, p = 0.12; Z score 1.54). However, using 25(OH)D synthesis SNP (DHCR7; rs12785878) as an individual genetic instrument, a per allele reduction of 25(OH)D concentration (-4.2nmol/L ± SE 0.3nmol/L) was predicted to increase T2D risk by 5%, p = 0.004; Z score 2.84. This effect, however, was not seen in other 25(OH)D SNPs (GC rs2282679, CYP2R1 rs12794714) when used as an individual instrument. CONCLUSION: Our new data on this bidirectional Mendelian randomization study suggests that genetically instrumented T2D risk does not cause changes in 25(OH)D levels. However, genetically regulated 25(OH)D deficiency due to vitamin D synthesis gene (DHCR7) may influence the risk of T2D.

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

BACKGROUND: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk. METHODS: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD. RESULTS: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10- 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042). CONCLUSIONS: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Long-term variation in skeletal muscle and adiposity in patients undergoing esophagectomy.

This study seeks to define long-term variation in body composition in patients undergoing esophagectomy for cancer and to associate those changes with survival. Assessment of skeletal muscle, visceral (VAT) and subcutaneous adipose tissue (SAT) was performed using computed tomography (CT) images routinely acquired: at diagnosis; after neoadjuvant therapy, and; >6 months after esophagectomy. In cases where multiple CT scans were performed >6 months after surgery, all available images were assessed. Ninty-seven patients met inclusion criteria with a median of 2 (range 1-10) postoperative CT images acquired between 0.5 and 9.7 years after surgery. Following surgical treatment of esophageal cancer, patients lost on average 13.3% of their skeletal muscle, 64.5% of their VAT and 44.2% of their SAT. Sarcopenia at diagnosis was not associated with worse overall survival (66.3% vs. 68.5%; P = 0.331). Sarcopenia 1 year after esophagectomy was however associated with lower 5-year overall survival (53.8% vs. 87.5%; P = 0.019). Survival was lower in those patients who had >10% decrease in skeletal muscle index (SMI; 33.3% vs. 72.1%; P = 0.003) and >40% decrease in SAT 1 year after surgery (40.4% vs. 67.4%; P = 0.015). On multivariate analysis, a decline in SMI 1 year after surgery was predictive of worse survival (HR 0.38, 95%CI 0.20-0.73; P = 0.004). This study provides new insight relating to long-term variation in body composition in patients undergoing esophagectomy for cancer. Findings provide further evidence of the importance of body composition, in particular depletion of skeletal muscle, in predicting survival following esophagectomy.

Large differences in the organization of palliative care in nursing homes in six European countries: findings from the PACE cross-sectional study.

BACKGROUND: To be able to provide high-quality palliative care, there need to be a number of organizational structures available in the nursing homes. It is unclear to what extent such structures are actually present in nursing homes in Europe. We aim to examine structural indicators for quality of palliative care in nursing homes in Europe and to evaluate the differences in terms of availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. METHODS: A PACE cross-sectional study (2015) of nursing homes in Belgium, England, Finland, Italy, the Netherlands and Poland. Nursing homes (N = 322) were selected in each country via proportional stratified random sampling. Nursing home administrators (N = 305) filled in structured questionnaires on nursing home characteristics. Organization of palliative care was measured using 13 of the previously defined IMPACT structural indicators for quality of palliative care covering four domains: availability of and access to palliative care, infrastructure for residents and families, multidisciplinary meetings and quality improvement initiatives. We calculated structural indicator scores for each country and computed differences in indicator scores between the six countries. Pearson's Chi-square test was used to compute the p-value of each difference. RESULTS: The availability of specialist palliative care teams in nursing homes was limited (6.1-48.7%). In Finland, Poland and Italy, specialist advice was also less often available (35.6-46.9%). Up to 49% of the nursing homes did not provide a dedicated contact person who maintained regular contact with the resident and relatives. The 24/7 availability of opioids for all nursing home residents was low in Poland (37.5%). CONCLUSIONS: This study found a large heterogeneity between countries in the organization of palliative care in nursing homes, although a common challenge is ensuring sufficient structural access to specialist palliative care services. Policymakers and health and palliative care organizations can use these structural indicators to identify areas for improvement in the organization of palliative care.

Impact of oral cleansing strategies on exhaled volatile organic compound levels.

RATIONALE: The analysis of volatile organic compounds (VOCs) within exhaled breath potentially offers a non-invasive method for the detection and surveillance of human disease. Oral contamination of exhaled breath may influence the detection of systemic VOCs relevant to human disease. This study aims to assess the impact of oral cleansing strategies on exhaled VOC levels in order to standardise practice for breath sampling. METHODS: Ten healthy volunteers consumed a nutrient challenge followed by four oral cleansing methods: (a) water, (b) saltwater, (c) toothbrushing, and (d) alcohol-free mouthwash. Direct breath sampling was performed using selected ion flow tube mass spectrometry after each intervention. RESULTS: Proposed reactions suggest that volatile fatty acid and alcohol levels (butanoic, pentanoic acid, ethanol) declined with oral cleansing interventions, predominantly after an initial oral rinse with water. Concentrations of aldehydes and phenols (acetaldehyde, menthone, p-cresol) declined with oral water rinse; however, they increased after toothbrushing and mouthwash use, secondary to flavoured ingredients within these products. No significant reductions were observed with sulphur compounds. CONCLUSIONS: Findings suggest that oral rinsing with water prior to breath sampling may reduce oral contamination of VOC levels, and further interventions for oral decontamination with flavoured products may compromise results. This intervention may serve as a simple and inexpensive method of standardisation within breath research.

Mass-Spectrometry Analysis of Mixed-Breath, Isolated-Bronchial-Breath, and Gastric-Endoluminal-Air Volatile Fatty Acids in Esophagogastric Cancer.

A noninvasive breath test has the potential to improve survival from esophagogastric cancer by facilitating earlier detection. This study aimed to investigate the production of target volatile fatty acids (VFAs) in esophagogastric cancer through analysis of the ex vivo headspace above underivatized tissues and in vivo analysis within defined anatomical compartments, including analysis of mixed breath, isolated bronchial breath, and gastric-endoluminal air. VFAs were measured by PTR-ToF-MS and GC-MS. Levels of VFAs (acetic, butyric, pentanoic, and hexanoic acids) and acetone were elevated in ex vivo experiments in the headspace above esophagogastric cancer compared with the levels in samples from control subjects with morphologically normal and benign conditions of the upper gastrointestinal tract. In 25 patients with esophagogastric cancer and 20 control subjects, receiver-operating-characteristic analysis for the cancer-specific VFAs butyric acid ( P < 0.001) and pentatonic acid ( P = 0.005) within in vivo gastric-endoluminal air gave an area under the curve of 0.80 (95% confidence interval of 0.65 to 0.93, P = 0.01). Compared with mixed- and bronchial-breath samples, all examined VFAs were found in highest concentrations within esophagogastric-endoluminal air. In addition, VFAs were higher in all samples derived from cancer patients compared with in the controls. Equivalence of VFA levels within the mixed and bronchial breath of cancer patients suggests that their origin within breath is principally derived from the lungs and, by inference, from the systemic circulation as opposed to direct passage from the upper gastrointestinal tract. These findings highlight the potential to utilize VFAs for endoluminal-gas biopsies and noninvasive mixed-exhaled-breath testing for esophagogastric-cancer detection.

Obesity genetics and cardiometabolic health: Potential for risk prediction.

The increasing burden of obesity worldwide and its effect on cardiovascular disease (CVD) risk is an opportunity for evaluation of preventive approaches. Both obesity and CVD have a genetic background and polymorphisms within genes which enhance expression of variant proteins that influence CVD in obesity. Genome-based prediction may therefore be a feasible strategy, but the identification of genetically driven risk factors for CVD manifesting as clinically recognized phenotypes is a major challenge. Clusters of such risk factors include hyperglycaemia, hypertension, ectopic liver fat, and inflammation. All involve multiple genetic pathways having complex interactions with variable environmental influences. The factors that make significant contributions to CVD risk include altered carbohydrate homeostasis, ectopic deposition of fat in muscle and liver, and inflammation, with contributions from the gut microbiome. A futuristic model depends on harnessing the predictive power of plausible genetic variants, phenotype reversibility, and effective therapeutic choices based on genotype-phenotype interactions. Inverting disease phenotypes into ideal cardiovascular health metrics could improve genetic and epigenetic assessment, and form the basis of a future model for risk detection and early intervention.

The other explanation for dyspnea: giant paraesophageal hiatal hernia repair routinely improves pulmonary function.

Paraesophageal hiatal hernias (PEHs) are most commonly associated with gastrointestinal symptoms; less widely appreciated is their potentially important influence on respiratory function. We hypothesize that surgical repair of PEH will significantly improve not only gastrointestinal symptoms, but also preoperative dyspnea and spirometry scores. A prospective Institutional Review Board-approved database was used to review all patients undergoing PEH repair from 2000 to 2016. Patients with pre- and postoperative pulmonary function tests assessed by spirometry were included. Postoperative changes in spirometry measurements were compared to PEH size as reflected by the percentage of intrathoracic stomach observed on preoperative contrast studies. Patients were stratified according to improvement in forced expiratory volume in 1 second (FEV1). Patients with >12% ('significant') improvement in FEV1 after surgery were compared to the remaining patient population. In total, 299 patients met the inclusion criteria. Symptomatic improvement in respiratory function was noted in all patients after PEH repair. Age, gender, BMI, presenting symptoms, Charlson comorbidity index as well as preoperative comorbidities did not significantly impact the functional outcome. Spirometry results improved in 80% of the patients, 21% of whom showed an improvement of >20% compared to the preoperative level. 'Significant' improvement in respiratory function was seen in 122 of 299 (41%) patients. Patients presenting with moderate and severe preoperative pulmonary obstruction demonstrated 'significant' improvement in FEV1 in 48% and 40% of cases, respectively. Large PEHs, characterized by a percentage of intrathoracic stomach >75%, was strongly associated with 'significant' improvement in FEV1 (P = 0.001). PEHs can impact subjective and objective respiratory status and surgical repair can result in a significant improvement in dyspnea and pulmonary function score that is independent of preoperative pulmonary disease. Gastric herniation of more than 75% was associated with higher possibility for improvement of pulmonary function tests. Patients with persistent and unexplained dyspnea and coexistent PEH should be assessed by an experienced surgeon for consideration of elective repair.

Redefining the stress cortisol response to surgery.

BACKGROUND: Cortisol levels rise with the physiological stress of surgery. Previous studies have used older, less-specific assays, have not differentiated by severity or only studied procedures of a defined type. The aim of this study was to examine this phenomenon in surgeries of varying severity using a widely used cortisol immunoassay. METHODS: Euadrenal patients undergoing elective surgery were enrolled prospectively. Serum samples were taken at 8 am on surgical day, induction and 1 hour, 2 hour, 4 hour and 8 hour after. Subsequent samples were taken daily at 8 am until postoperative day 5 or hospital discharge. Total cortisol was measured using an Abbott Architect immunoassay, and cortisol-binding globulin (CBG) using a radioimmunoassay. Surgical severity was classified by POSSUM operative severity score. RESULTS: Ninety-three patients underwent surgery: Major/Major+ (n = 37), Moderate (n = 33) and Minor (n = 23). Peak cortisol positively correlated to severity: Major/Major+ median 680 [range 375-1452], Moderate 581 [270-1009] and Minor 574 [272-1066] nmol/L (Kruskal-Wallis test, P = .0031). CBG fell by 23%; the magnitude of the drop positively correlated to severity. CONCLUSIONS: The range in baseline and peak cortisol response to surgery is wide, and peak cortisol levels are lower than previously appreciated. Improvements in surgery, anaesthetic techniques and cortisol assays might explain our observed lower peak cortisols. The criteria for the dynamic testing of cortisol response may need to be reduced to take account of these factors. Our data also support a lower-dose, stratified approach to dosing of steroid replacement in hypoadrenal patients, to minimize the deleterious effects of over-replacement.

Vitamin D Status, Gender Differences, and Cardiometabolic Health Disparities.

BACKGROUND: Vitamin D deficiency is an unrecognized epidemic found in India and also worldwide. Despite the high prevalence of diabetes among Indians, there is a paucity of data showing the relationship between vitamin D status and cardiometabolic disparities. In this study, we have examined the relationship between vitamin D and cardiometabolic traits in a population from India. METHODS: Circulating 25(OH)D levels were measured in 3,879 participants from the Asian Indian Diabetic Heart Study using ELISA kits. RESULTS: Vitamin D levels were significantly reduced (p < 0.0001) in both men and women with obesity. However, compared to women, serum vitamin D was consistently lower in men (p < 0.02), irrespective of the presence of obesity and type 2 diabetes. Multivariate regression revealed strong interaction of vitamin D with body mass index that resulted in increased fasting glucose (p = 0.001) and reduced homeostasis model assessment of ß-cell function (HOMA-B; p = 0.01) in normoglycemic individuals. However, in gender-stratified analysis, this association was restricted to men for both fasting glucose (p = 2.4 × 10-4) and HOMA-B (p = 0.001). CONCLUSIONS: Our findings suggest that vitamin D deficiency may significantly enhance the risk of cardiometabolic disease among Asian Indians. Future randomized trials and genetic studies are expected to clarify the underlying mechanisms for gender differences in vitamin D deficiency, and whether vitamin D-driven improvement in testosterone may contribute to beneficial cardiometabolic outcomes in men.