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Abstract PEGylation (the covalent attachment of one or more poly(ethylene glycol) (PEG) units to a therapeutic) is a well-established technique in the pharmaceutical industry to increase blood-residence time and decrease immunogenicity. A challenging aspect of PEGylation is the dispersity of PEGylation agents, which results in batch-to-batch variations and analytical limitations. Herein, we present an approach to overcome these limitations by manufacturing a defined molecular weight (dispersity-free) PEGylation agent. We synthesise a defined molecular weight (Mw), linear 5 kDa methoxy-PEG (mPEG) active ester in an efficient and scalable manner using an iterative liquid-phase approach based on Nanostar Sieving. We then perform a comparative study on the random PEGylation and subsequent characterisation of the protein bovine serum albumin (BSA), using both the defined Mw, dispersity-free mPEG active ester, and a commercially available disperse 5 kDa mPEG active ester. We demonstrate that the defined Mw PEG both allows for facile monitoring of chemical modification reactions during the synthesis of the PEGylation agents, and facilitates straightforward identification of the PEGylated fragments within a PEGylated protein via a simple peptide mapping approach using UPLC-MS.

Abstract Conventional spectroscopies are not sufficiently selective to comprehensively understand the behaviour of trapped carriers in perovskite solar cells, particularly under their working conditions. Here we use infrared optical activation spectroscopy (i.e., pump-push-photocurrent), to observe the properties and real-time dynamics of trapped carriers within operando perovskite solar cells. We compare behaviour differences of trapped holes in pristine and surface-passivated FA0.99Cs0.01PbI3 devices using a combination of quasi-steady-state and nanosecond time-resolved pump-push-photocurrent, as well as kinetic and drift-diffusion models. We find a two-step trap-filling process: the rapid filling (~10 ns) of low-density traps in the bulk of perovskite, followed by the slower filling (~100 ns) of high-density traps at the perovskite/hole transport material interface. Surface passivation by n-octylammonium iodide dramatically reduces the number of trap states (~50 times), improving the device performance substantially. Moreover, the activation energy (~280 meV) of the dominant hole traps remains similar with and without surface passivation.

Background: Genome-wide polygenic risk scores (PRS) have shown high specificity and sensitivity in predicting type 2 diabetes (T2D) risk in Europeans. However, the PRS-driven information and its clinical significance in non-Europeans are underrepresented. We examined the predictive efficacy and transferability of PRS models using variant information derived from genome-wide studies of Asian Indians (AIs) (PRS AI ) and Europeans (PRS EU ) using 13,974 AI individuals. Methods: Weighted PRS models were constructed and analyzed on 4602 individuals from the Asian Indian Diabetes Heart Study/Sikh Diabetes Study (AIDHS/SDS) as discovery/training and test/validation datasets. The results were further replicated in 9372 South Asian individuals from UK Biobank (UKBB). We also assessed the performance of each PRS model by combining data of the clinical risk score (CRS). Results: Both genetic models (PRS AI and PRS EU ) successfully predicted the T2D risk. However, the PRS AI revealed 13.2% odds ratio (OR) 1.80 [95% confidence interval (CI) 1.63–1.97; p = 1.6 × 10 −152 ] and 12.2% OR 1.38 (95% CI 1.30–1.46; p = 7.1 × 10 −237 ) superior performance in AIDHS/SDS and UKBB validation sets, respectively. Comparing individuals of extreme PRS (ninth decile) with the average PRS (fifth decile), PRS AI showed about two-fold OR 20.73 (95% CI 10.27–41.83; p = 2.7 × 10 −17 ) and 1.4-fold OR 3.19 (95% CI 2.51–4.06; p = 4.8 × 10 −21 ) higher predictability to identify subgroups with higher genetic risk than the PRS EU . Combining PRS and CRS improved the area under the curve from 0.74 to 0.79 in PRS AI and 0.72 to 0.75 in PRS EU . Conclusion: Our data suggest the need for extending genetic and clinical studies in varied ethnic groups to exploit the full clinical potential of PRS as a risk prediction tool in diverse study populations.

Abstract The interest around analysis of volatile organic compounds (VOCs) within breath has increased in the last two decades. Uncertainty remains around standardisation of sampling and whether VOCs within room air can influence breath VOC profiles. To assess the abundance of VOCs within room air in common breath sampling locations within a hospital setting and whether this influences the composition of breath. A secondary objective is to investigate diurnal variation in room air VOCs. Room air was collected using a sampling pump and thermal desorption (TD) tubes in the morning and afternoon from five locations. Breath samples were collected in the morning only. TD tubes were analysed using gas chromatography coupled with time-of-flight mass spectrometry (GC-TOF-MS). A total of 113 VOCs were identified from the collected samples. Multivariate analysis demonstrated clear separation between breath and room air. Room air composition changed throughout the day and different locations were characterized by specific VOCs, which were not influencing breath profiles. Breath did not demonstrate separation based on location, suggesting that sampling can be performed across different locations without affecting results.

Abstract 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.

Abstract 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.

Volatile aldehydes can be enriched in esophageal adenocarcinoma patients’ breath. Here, the authors reveal corresponding metabolic changes in EAC tumours, which may be caused by impaired detoxification of endogenous metabolites.

Analysis of salivary volatile organic compounds (VOCs) may offer a novel noninvasive modality for disease detection. This study aims to optimise saliva headspace VOC analysis and assess longitudinal variation of salivary VOCs. Whole saliva from healthy participants was acquired in order to assess four methodological parameters: saliva collection, volume, dilution, and acidification. Saliva VOCs were analysed using untargeted proton transfer reaction time-of-flight mass spectrometry. Using the optimised method, five saliva samples collected over 3 weeks assessed the longitudinal VOC variability and reproducibility with targeted selected ion flow tube-mass spectrometry analysis. The method of saliva collection influenced VOC detection and was a source of contamination. An amount of 500 µL of whole saliva by passive drool yielded optimal VOCs. Longitudinal variation was negligible with target short chain fatty acids and aldehydes. However, certain compounds showed variability suggesting the influence of potential exogenous factors. Overall, there was an acceptable range of inter- and intraindividual VOC variability. Standardisation with morning sampling after a 6 h fast is recommended demonstrating minimal intersubject variability. Future studies should seek to establish salivary VOC levels in healthy and diseased populations.

Abstract Background Influence of sarcopenia in combination with other body composition parameters and muscle strength on outcomes after oesophageal surgery for oesophageal cancer remains unclear. The objectives were (i) to describe the incidence of sarcopenia in relation to adipose tissue quantity and distribution and muscle strength; (ii) to evaluate if neoadjuvant chemoradiation (nCRTx) influences body composition and muscle strength; and (iii) to evaluate the influence of body composition and muscle strength on post‐operative morbidity and long‐term survival. Methods This retrospective study included patients with oesophageal cancer who received nCRTx followed by surgery between January 2011 and 2016. Skeletal muscle, visceral, and subcutaneous adipose tissue cross‐sectional areas were calculated based on computed tomography scans, and muscle strength was measured using hand grip tests, 30 seconds chair stand tests, and maximal inspiratory and expiratory pressure tests prior to nCRTx and after nCRTx. Results A total of 322 patients were included in this study. Sarcopenia was present in 55.6% of the patients prior to nCRTx and in 58.2% after nCRTx (P = 0.082). Patients with sarcopenia had a significantly lower muscle strength and higher fat percentage. The muscle strength and incidence of sarcopenia increased while the mean body mass index and fat percentage decreased during nCRTx. A body mass index above 25 kg/m2 was associated with anastomotic leakage (P = 0.032). Other body composition parameters were not associated with post‐operative morbidity. A lower handgrip strength prior to nCRTx was associated with pulmonary and cardiac complications (P = 0.023 and P = 0.009, respectively). In multivariable analysis, a lower number of stands during the 30 seconds chair stand test prior to nCRTx (hazard ratio 0.93, 95% confidence interval 0.87–0.99, P = 0.017) and visceral adipose tissue of >128 cm2 after nCRTx (hazard ratio 1.81, 95% confidence interval 1.30–2.53, P = 0.001) were associated with worse overall survival. Conclusions Sarcopenia occurs frequently in patients with oesophageal cancer and is associated with less muscle strength and a higher fat percentage. Body composition changes during nCRTx did not influence survival. Impaired muscle strength and a high amount of visceral adipose tissue are associated with worse survival. Therefore, patients with poor fitness might benefit from preoperative nutritional and muscle strengthening guidance, aiming to increase muscle strength and decrease visceral adipose tissue. However, this should be confirmed in a large prospective study.

Background: Hypertriglyceridemia is as an independent risk factor for cardiovascular disease (CVD). Apolipoprotein C-III (ApoC-III) is known to regulate triglyceride (TG) metabolism. However, the causal association between ApoC-III and CVD development is unclear. The objectives were to examine the impact of ApoC-III concentration on TG and lipoproteins and investigate the role of known rare loss-of-function APOC3 variants for modulating ApoC-III, TG concentrations and CVD risk in different ethnic groups. Methods: Plasma ApoC-III levels were measured in a multiethnic sample of 518 individuals comprising 271 Asian Indians (Sikhs), 87 Caucasians, 80 African Americans, and 80 Hispanics. Results: ApoC-III levels showed a robust association with TG in Asian Indians (r = 0.5, p = 1.1 × 10−23), Caucasians (r = 0.4, p = 7.2 × 10−4), and Hispanics (r = 0.9, p = 2.7x × 10−28). African Americans had lowest ApoC-III and TG concentrations and highest (44%) prevalence of coronary artery disease (CAD). ApoC-III levels correlated with fasting blood glucose (r = 0.25, p = 6.1 × 10−5) in Asian Indians and central adiposity in Hispanics (waist: r = 0.22, p = 0.05; waist-hip ratio: r = 0.24, p = 0.04). The carriers of rare variants IVS1-2G-A (rs373975305); A43T (rs147210663) and IVS3 + 1G-T (rs140621530) showed high TG but not low ApoC-III levels in Asian Indians and Caucasians. Conclusion: These results highlight the challenges of generalizing antisense ApoC-III inhibition for treating atherosclerotic disease in dyslipidemia that may benefit only specific sub-populations. The observed ethnic differences in ApoC-III concentrations and CAD risk factors, emphasize in-depth genetic and metabolomics evaluations on diverse ancestries.

Introduction Three-dimensional (3D) reconstruction describes the generation of either virtual or physically printed anatomically accurate 3D models from two-dimensional medical images. Their implementation has revolutionised medical practice. Within surgery, key applications include growing roles in operative planning and procedures, surgical education and training, as well as patient engagement and education. In comparison to other surgical specialties, oesophagogastric surgery has been slow in their adoption of this technology. Herein the authors outline a scoping review protocol that aims to analyse the current role of 3D modelling in oesophagogastric surgery and highlight any unexplored avenues for future research.Methods and analysis The protocol was generated using internationally accepted methodological frameworks. A succinct primary question was devised, and a comprehensive search strategy was developed for key databases (MEDLINE, Embase, Elsevier Scopus and ISI Web of Science). These were searched from their inception to 1 June 2020. Reference lists will be reviewed by hand and grey literature identified using OpenGrey and Grey Literature Report. The protocol was registered to the Open Science Framework (osf.io/ta789).Two independent reviewers will screen titles, abstracts and perform full-text reviews for study selection. There will be no methodological quality assessment to ensure a full thematic analysis is possible. A data charting tool will be created by the investigatory team. Results will be analysed to generate descriptive numerical tabular results and a thematic analysis will be performed.Ethics and dissemination Ethical approval was not required for the collection and analysis of the published data. The scoping review report will be disseminated through a peer-reviewed publication and international conferences.Registration details The scoping review protocol has been registered on the Open Science Framework (https://osf.io/ta789).

The analysis of volatile organic compounds (VOCs) can provide important clinical information (entirely non-invasively); however, the exact extent to which VOCs from human skin can be signatures of health and disease is unknown. This systematic review summarises the published literature concerning the methodology, application, and volatile profiles of skin VOC studies. An online literature search was conducted in accordance with the preferred reporting items for systematic reviews and meta-analysis, to identify human skin VOC studies using untargeted mass spectrometry (MS) methods. The principal outcome was chemically verified VOCs detected from the skin. Each VOC was cross-referenced using the CAS number against the Human Metabolome and KEGG databases to evaluate biological origins. A total of 29 studies identified 822 skin VOCs from 935 participants. Skin VOCs were commonly sampled from the hand (n = 9) or forearm (n = 7) using an absorbent patch (n = 15) with analysis by gas chromatography MS (n = 23). Twenty-two studies profiled the skin VOCs of healthy subjects, demonstrating a volatolome consisting of aldehydes (18%), carboxylic acids (12%), alkanes (12%), fatty alcohols (9%), ketones (7%), benzenes and derivatives (6%), alkenes (2%), and menthane monoterpenoids (2%). Of the VOCs identified, 13% had putative endogenous origins, 46% had tentative exogenous origins, and 40% were metabolites from mixed metabolic pathways. This review has comprehensively profiled the human skin volatolome, demonstrating the presence of a distinct VOC signature of healthy skin, which can be used as a reference for future researchers seeking to unlock the clinical potential of skin volatolomics. As significant proportions of identified VOCs have putative exogenous origins, strategies to minimise their presence through methodological refinements and identifying confounding compounds are discussed.

Objectives To examine the feasibility and acceptability of breath research in primary care.Design Non-randomised, prospective, mixed-methods cross-sectional observational study.Setting Twenty-six urban primary care practices.Participants 1002 patients aged 18–90 years with gastrointestinal symptoms.Main outcome measures During the first 6 months of the study (phase 1), feasibility of patient enrolment using face-to-face, telephone or SMS-messaging (Short Message Service) enrolment strategies, as well as processes for breath testing at local primary care practices, were evaluated. A mixed-method iterative study design was adopted and outcomes evaluated using weekly Plan-Do-Study-Act cycles, focus groups and general practitioner (GP) questionnaires.During the second 6 months of the study (phase 2), patient and GP acceptability of the breath test and testing process was assessed using questionnaires. In addition a ‘single practice’ recruitment model was compared with a ‘hub and spoke’ centralised recruitment model with regards to enrolment ability and patient acceptability.Throughout the study feasibility of the collection of a large number of breath samples by clinical staff over multiple study sites was evaluated and quantified by the analysis of these samples using mass spectrometry.Results 1002 patients were recruited within 192 sampling days. Both ‘single practice’ and ‘hub and spoke’ recruitment models were effective with an average of 5.3 and 4.3 patients accrued per day, respectively. The ‘hub and spoke’ model with SMS messaging was the most efficient combined method of patient accrual. Acceptability of the test was high among both patients and GPs. The methodology for collection, handling and analysis of breath samples was effective, with 95% of samples meeting quality criteria.Conclusions Large-scale breath testing in primary care was feasible and acceptable. This study provides a practical framework to guide the design of Phase III trials examining the performance of breath testing in primary care.

Hybrid halide perovskites materials have the potential for both photovoltaic and light-emitting devices. Relatively little has been reported on the kinetics of charge relaxation upon intense excitation. In order to evaluate the illumination power density dependence on the charge recombination mechanism, we have applied a femtosecond transient mid-IR absorption spectroscopy with strong excitation to directly measure the charge kinetics via electron absorption. The irradiance-dependent relaxation processes of the excited, photo-generated charge pairs were quantified in polycrystalline MAPbI3, MAPbBr3, and (FAPbI3)0.97(MAPbBr3)0.03 thin films that contain either methylamonium (MA) or formamidinium (FA). This report identifies the laser-generated charge species and provides the kinetics of Auger, bimolecular and excitonic decay components. The inter-band electron-hole (bimolecular) recombination was found to dominate over Auger recombination at very high pump irradiances, up to the damage threshold. The kinetic analysis further provides direct evidence for the carrier field origin of the vibrational Stark effect in a formamidinium containing perovskite material. The results suggest that radiative excitonic and bimolecular recombination in MAPbI3 at high excitation densities could support light-emitting applications.

Kevin R Short, Piers R Blackett, Andrew W Gardner, Kenneth C CopelandDepartment of Pediatrics, Section of Diabetes and Endocrinology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAAbstract: The foundations for cardiovascular disease in adults are laid in childhood and accelerated by the presence of comorbid conditions, such as obesity, diabetes, hypertension, and dyslipidemia. Early detection of vascular dysfunction is an important clinical objective to identify those at risk for subsequent cardiovascular morbidity and events, and to initiate behavioral and medical interventions to reduce risk. Typically, cardiovascular screening is recommended for young adults, especially in people with a family history of cardiovascular conditions. Children and adolescents were once considered to be at low risk, but with the growing health concerns related to sedentary lifestyle, poor diet and obesity, cardiovascular screening may be needed earlier so that interventions to improve cardiovascular health can be initiated. This review describes comorbid conditions that increase cardiovascular risk in youth, namely obesity and diabetes, and describes noninvasive methods to objectively detect vascular disease and quantify vascular function and structure through measurements of endothelial function, arterial compliance, and intima-media thickness. Additionally, current strategies directed toward prevention of vascular disease in these populations, including exercise, dietary interventions and pharmacological therapy are described.Keywords: endothelial function, arterial compliance, intimal medial thickness, inflammation, intervention

To extract climatically relevant chemical signals from the deepest, oldest Antarctic ice, we must first understand the degree to which chemical ions diffuse within solid ice. Volcanic sulfate peaks are the ideal target for such an investigation because they are high amplitude, short duration (~3 years) events with a quasi-uniform structure. Here we present analysis of the EPICA Dome C sulfate record over the last 450 kyr. We identify volcanic peaks and isolate them from the non-sea salt sulfate background to reveal the effects of diffusion: amplitude damping and broadening of peaks in the time domain with increasing depth/age. Sulfate peak shape is also altered by the thinning of ice layers with depth that results from ice flow. Both processes must be simulated to derive effective diffusion rates. This is achieved by running a forward model to diffuse idealised sulfate peaks at different rates while also accounting for ice thinning. Our simulations suggest a median effective diffusion rate of sulfate ions of 2.4 ± 1.7 x 10-7 m2 yr-1 in the Holocene ice, slightly faster than suggested by previous work. The effective diffusion rate observed in deeper ice is significantly lower, and the Holocene ice shows the highest rate of the last 450 kyr. Beyond the Holocene, there is no systematic difference between the effective diffusion rates of glacial and interglacial periods despite variations in soluble ions concentrations, dust loading and ice grain radii. Effective diffusion rates for 40 to 200 ka are relatively constant, on the order of 1 x 10-8 m2 yr-1. Our results suggests that the diffusion of sulfate ions within volcanic peaks is relatively fast initially, perhaps through the inter-connected vein network, but slows significantly after 40 kyr. In the absence of clear evidence for a controlling environmental factor on sulfate diffusivity with depth/age, we hypothesize that the rapid decrease in diffusion rate from the time of deposition to ice of 50 ka age may be due to a switch in the mechanism of diffusion resulting from the changing location of sulfate ions within the ice microstructure. [ABSTRACT FROM AUTHOR]

Understanding the kinetic competition between charge extraction and recombination, and how this is impacted by mobile ions, remains a key challenge in perovskite solar cells (PSCs). Here, this issue is addressed by combining operando photoluminescence (PL) measurements, which allow the measurement of real‐time PL spectra during current–voltage (J–V) scans under 1‐sun equivalent illumination, with the results of drift‐diffusion simulations. This operando PL analysis allows direct comparison between the internal performance (recombination currents and quasi‐Fermi‐level‐splitting (QFLS)) and the external performance (J–V) of a PSC during operation. Analyses of four PSCs with different electron transport materials (ETMs) quantify how a deeper ETM LUMO induces greater interfacial recombination, while a shallower LUMO impedes charge extraction. Furthermore, it is found that a low ETM mobility leads to charge accumulation in the perovskite under short‐circuit conditions. However, thisalone cannot explain the remarkably high short‐circuit QFLS of over 1 eV which is observed in all devices. Instead, drift‐diffusion simulations allow this effect to be assigned to the presence of mobile ions which screen the internal electric field at short‐circuit and lead to a reduction in the short‐circuit current density by over 2 mA cm−2 in the best device. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Introduction: Boerhaave syndrome is a rare condition associated with high morbidity and mortality. Prompt intervention greatly improves outcomes, with surgery traditionally being the mainstay of management. Recent advances in therapeutic endoscopy have led to increasing interest in endoluminal vacuum therapy (EVT), a minimally invasive technique, allowing wound debridement and drainage, encouraging granulation tissue formation. EVT has been associated with positive clinical outcomes, including lower mortality rates compared to surgery and stenting for the management of anastomotic leaks, and to a lesser extent, oesophageal perforations. EVT has been adopted into practice across Europe; however, only few cases have been reported from the UK. Case Presentations: We report three cases of Boerhaave syndrome, successfully managed with EVT, using the Eso-SPONGE ® (B.Braun Medical Ltd, Sheffield, UK). EVT involves the placement of a polyurethane sponge into the wound cavity. The cavity is initially assessed, then an overtube is introduced through which the sponge is inserted, and then the overtube is removed. Sponge position is confirmed and adjusted if necessary. The sponge is connected via a trans-nasal drain to continuous negative pressure suction and is changed every 3–5 days. Having been deemed surgically unfit, all 3 patients were referred for EVT. All patients made excellent recovery and were discharged home. Conclusion: EVT is an effective management strategy for surgically unfit Boerhaave syndrome patients. Eso-SPONGE use aided drainage of the septic focus and closure of the defect, leading to complete recovery. Our findings support the existing evidence that EVT is a promising solution for Boerhaave syndrome.

Simple Summary: Oesophagogastric cancer is the fifth most common cancer worldwide, with poor survival outcomes. Emerging data suggest that bacteria specific to cancer may play a role in earlier disease detection and treatment strategies. This study aimed to evaluate all microbiome studies identifying bacteria enriched in oesophagogastric cancer and appraisal of the methods. Eighty-nine studies demonstrated an enrichment of five bacteria in gastric cancer (Lactobacillus, Streptococcus, Prevotella, Fusobacterium, Veillonella) and three bacteria in oesophageal squamous cell carcinoma (Streptococcus, Prevotella, Fusobacterium). No differences were observed in oesophageal adenocarcinoma. Functional analysis supports the role of immune cells, localised inflammation and cancer-specific pathways in cancer progression. There is evidence that batch effects and contamination in sample analysis are poorly reported. The STORMS checklist provides a framework for high-quality microbiome studies. Whole-genome sequencing is recommended to provide key metabolic and functional pathway analysis of potentially important bacteria influencing cancer progression. Objective. Oesophagogastric cancer is the fifth most common cancer worldwide, with poor survival outcomes. The role of bacteria in the pathogenesis of oesophagogastric cancer remains poorly understood. Design. A systematic search identified studies assessing the oesophagogastric cancer microbiome. The primary outcome was to identify bacterial enrichment specific to oesophagogastric cancer. Secondary outcomes included appraisal of the methodology, diagnostic performance of cancer bacteria and the relationship between oral and tissue microbiome. Results. A total of 9295 articles were identified, and 87 studies were selected for analysis. Five genera were enriched in gastric cancer: Lactobacillus, Streptococcus, Prevotella, Fusobacterium and Veillonella. No clear trends were observed in oesophageal adenocarcinoma. Streptococcus, Prevotella and Fusobacterium were abundant in oesophageal squamous cell carcinoma. Functional analysis supports the role of immune cells, localised inflammation and cancer-specific pathways mediating carcinogenesis. STORMS reporting assessment identified experimental deficiencies, considering batch effects and sources of contamination prevalent in low-biomass samples. Conclusions. Functional analysis of cancer pathways can infer tumorigenesis within the cancer–microbe–immune axis. There is evidence that study design, experimental protocols and analytical techniques could be improved to achieve more accurate and representative results. Whole-genome sequencing is recommended to identify key metabolic and functional capabilities of candidate bacteria biomarkers. [ABSTRACT FROM AUTHOR]

Analysis of salivary volatile organic compounds (VOCs) may offer a novel noninvasive modality for disease detection. This study aims to optimise saliva headspace VOC analysis and assess longitudinal variation of salivary VOCs. Whole saliva from healthy participants was acquired in order to assess four methodological parameters: saliva collection, volume, dilution, and acidification. Saliva VOCs were analysed using untargeted proton transfer reaction time-of-flight mass spectrometry. Using the optimised method, five saliva samples collected over 3 weeks assessed the longitudinal VOC variability and reproducibility with targeted selected ion flow tube-mass spectrometry analysis. The method of saliva collection influenced VOC detection and was a source of contamination. An amount of 500 µL of whole saliva by passive drool yielded optimal VOCs. Longitudinal variation was negligible with target short chain fatty acids and aldehydes. However, certain compounds showed variability suggesting the influence of potential exogenous factors. Overall, there was an acceptable range of inter- and intraindividual VOC variability. Standardisation with morning sampling after a 6 h fast is recommended demonstrating minimal intersubject variability. Future studies should seek to establish salivary VOC levels in healthy and diseased populations. [ABSTRACT FROM AUTHOR]