Demonstrating the reliability of in vivo metabolomics based chemical grouping: towards best practice.

While grouping/read-across is widely used to fill data gaps, chemical registration dossiers are often rejected due to weak category justifications based on structural similarity only. Metabolomics provides a route to robust chemical categories via evidence of shared molecular effects across source and target substances. To gain international acceptance, this approach must demonstrate high reliability, and best-practice guidance is required. The MetAbolomics ring Trial for CHemical groupING (MATCHING), comprising six industrial, government and academic ring-trial partners, evaluated inter-laboratory reproducibility and worked towards best-practice. An independent team selected eight substances (WY-14643, 4-chloro-3-nitroaniline, 17α-methyl-testosterone, trenbolone, aniline, dichlorprop-p, 2-chloroaniline, fenofibrate); ring-trial partners were blinded to their identities and modes-of-action. Plasma samples were derived from 28-day rat tests (two doses per substance), aliquoted, and distributed to partners. Each partner applied their preferred liquid chromatography-mass spectrometry (LC-MS) metabolomics workflows to acquire, process, quality assess, statistically analyze and report their grouping results to the European Chemicals Agency, to ensure the blinding conditions of the ring trial. Five of six partners, whose metabolomics datasets passed quality control, correctly identified the grouping of eight test substances into three categories, for both male and female rats. Strikingly, this was achieved even though a range of metabolomics approaches were used. Through assessing intrastudy quality-control samples, the sixth partner observed high technical variation and was unable to group the substances. By comparing workflows, we conclude that some heterogeneity in metabolomics methods is not detrimental to consistent grouping, and that assessing data quality prior to grouping is essential. We recommend development of international guidance for quality-control acceptance criteria. This study demonstrates the reliability of metabolomics for chemical grouping and works towards best-practice.

Molecular alterations and clinical prognostic factors in resectable non-small cell lung cancer.

BACKGROUND: EGFR inhibitor and immunotherapy have been approved for adjuvant treatment in resectable non-small cell lung cancer (NSCLC). Limited reports of molecular and clinical characteristics as prognostic factors in NSCLC have been published. METHODS: Medical records of patients with resectable NSCLC stage I-III diagnosed during 2015-2020 were reviewed. Real time-PCR (RT-PCR) was performed for EGFR mutations (EGFRm). Immunohistochemistry staining was conducted for ALK and PD-L1 expression. Categorical variables were compared using chi-square test and Fisher's exact test. Survival analysis was done by cox-regression method. RESULTS: Total 441 patients were included. The prevalence of EGFRm, ALK fusion, and PD-L1 expression were 57.8%, 1.9%, and 20.5% (SP263), respectively. The most common EGFRm were Del19 (43%) and L858R (41%). There was no significant difference of recurrence free survival (RFS) by EGFRm status whereas patients with PD-L1 expression (PD-L1 positive patients) had lower RFS compared to without PD-L1 expression (PD-L1 negative patients) (HR = 1.75, P = 0.036). Patients with both EGFRm and PD-L1 expression had worse RFS compared with EGFRm and PD-L1 negative patients (HR = 3.38, P = 0.001). Multivariable analysis showed higher CEA at cut-off 3.8 ng/ml, pT4, pN2, pStage II, and margin were significant poor prognostic factors for RFS in the overall population, which was similar to EGFRm population (exception of pT and pStage). Only pStage was a significant poor prognostic factor for PD-L1 positive patients. The predictive score for predicting of recurrence were 6 for all population (63% sensitivity and 86% specificity) and 5 for EGFRm population (62% sensitivity and 93% specificity). CONCLUSION: The prevalence and types of EGFRm were similar between early stage and advanced stage NSCLC. While lower prevalence of PD-L1 expression was found in early stage disease. Patients with both EGFRm and PD-L1 expression had poorer outcome. Thus PD-L1 expression would be one of the prognostic factor in EGFRm patients. Validation of the predictive score should be performed in a larger cohort.

Clinical outcomes of children with COVID-19 infection in a low-risk centre in Malaysia.

INTRODUCTION: According to WHO, long-COVID or post- COVID-19 condition is defined as the continuation or development of new symptoms 3 months after the initial SARS-CoV-2 infection, with these symptoms lasting for at least 2 months with no other explanation. A systematic review and meta-analyses published in 2022, which mainly focus on the Western population, revealed that the prevalence of long COVID was 25.24%. Literature regarding long-COVID in children in Asia was scarce. The objectives of our study were to assess the long-term effect of COVID-19 infection in children and its correlation to their acute COVID- 19 infection. MATERIALS AND METHODS: This study was conducted in Hospital Kepala Batas (HKB), a district hospital in Penang State, Malaysia, which was the designated regional COVID hospital during the pandemic. It was a retrospective observational study, where children who were admitted from November 2020 to March 2021, and attended follow-up clinics from Jan 2021 to May 2021, were recruited. RESULTS: This study comprised 90 subjects, from 3 months old to 12 years old, mean of 6.5 years old. When comparing asymptomatic and symptomatic children, children with comorbidities were more likely to be symptomatic with a pvalue of 0.045 using the Pearson Chi-square test. All our patients' symptoms resolved upon discharge. During followup at 2-4 months after COVID-19 infection, all children were reported as back to their usual selves. Fifteen patients had recurrent symptoms. Most of their symptoms pointed towards an acute infection. One patient had two episodes of illness, while the rest had one. The most common symptoms were cough, fever and runny nose. The average duration of illness of these 16 episodes was 4.5 days with a standard deviation of 2.48. None of these symptoms lasted more than seven days. None of them required hospital admission. None of them had recurrent COVID-19 infections. Tweleve out of 72 children who had been going to school stopped physical school after COVID-19 infection. Our findings differed from other studies. These could be due to the limitations that we faced. CONCLUSION: Most children who contracted COVID-19 infection recovered fully after acute infection, and most of them recovered fully without long-term sequelae.

Mode of action hypothesis testing in chemical safety assessments using metabolomics as supporting evidence: Phenobarbital and cyclobutrifluram metabolomics profile comparison.

In long term rodent studies administering Cyclobutrifluram (TYMIRIUM® Technology), a new agrochemical, there was a slight elevation of incidence of hepatocellular carcinomas in male CD-1 mice that was within the historical control range but appeared to be dose responsive. Cyclobutrifluram's ability to activate mouse constitutive androstane receptor (CAR) mediated gene transcription was confirmed in vitro, therefore a 28-day dietary toxicity study was conducted in vivo in male CD-1 mice to assess the CAR activation mode of action hypothesis of Cyclobutrifluram along with phenobarbital, a known CAR activator. In addition to other end points comprehensive (polar and lipidomic) hybrid metabolomics analyses were performed on terminal plasma and liver samples following 2-, 7- and 28-days dietary exposure to cyclobutrifluram and phenobarbital. The data generation and quality assessments were performed in line with the principles of the MEtabolomics standaRds Initiative in Toxicology (MERIT).First the full annotated feature set was used to compare the metabolomic changes induced by the administration of the two test substances using Shared and Unique Structures plots. This gave a comprehensive overview of the similarity of the two effect profiles showing good correlation and demonstrated that no other, alternative effect signatures were detected. Then the phenobarbital induced differentially abundant metabolites were selected, compared to the literature and their direction of change was assessed in cyclobutrifluram profiles, finding good agreement. Both approaches concluded that the metabolomics data supports the CAR activation hypothesis. Comparison of the metabolomic effect profiles can be a line of evidence in mode of action hypothesis testing in the chemical risk assessment process.

Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID.

Long COVID patients who experienced severe acute SARS-CoV-2 infection can present with humoral autoimmunity. However, whether mild SARS-CoV-2 infection increases autoantibody responses and whether vaccination can decrease autoimmunity in long COVID patients is unknown. Here, we demonstrate that mild SARS-CoV-2 infection increases autoantibodies associated with systemic lupus erythematosus (SLE) and inflammatory myopathies in long COVID patients with persistent neurologic symptoms to a greater extent than COVID convalescent controls at 8 months post-infection. Furthermore, high titers of SLE-associated autoantibodies in long COVID patients are associated with impaired cognitive performance and greater symptom severity, and subsequent vaccination/booster does not decrease autoantibody titers. In summary, we found that mild SARS-CoV-2 infection can induce persistent humoral autoimmunity in both long COVID patients and healthy COVID convalescents, suggesting that a reappraisal of vaccination and mitigation strategies is warranted.

A National Referral Service for Paediatric Brachytherapy: An Evolving Practice and Outcomes Over 13 Years.

AIMS: Most children requiring radiotherapy receive external beam treatment and few have tumours suitable for brachytherapy. No paediatric radiotherapy centre will treat enough patients from its own normal catchment population for expertise in brachytherapy to be developed and sustained. Following discussion and agreement in the national paediatric radiotherapy group, a service for paediatric brachytherapy in the UK has been developed. We report the process that has evolved over more than 10 years, with survival and functional outcome results. MATERIALS AND METHODS: Since 2009, potential patients have been referred to the central paediatric oncology multidisciplinary team meeting, where imaging, pathology and treatment options are discussed. Since 2013, the National Soft Tissue Sarcoma Advisory Panel has also reviewed most patients, with the principal aim of advising on the most suitable primary tumour management for complex patients. Clinical assessment and examination under anaesthetic with biopsies may be undertaken to confirm the appropriateness of brachytherapy, either alone or following conservative surgery. Fractionated high dose rate brachytherapy was delivered to a computed tomography planned volume after implantation of catheters under ultrasound imaging guidance. Since 2019, follow-up has been in a dedicated multidisciplinary clinic. RESULTS: From 2009 to 2021 inclusive, 35 patients (16 female, 19 male, aged 8 months to 17 years 6 months) have been treated. Histology was soft-tissue sarcoma in 33 patients and carcinoma in two. The treated site was pelvic in 31 patients and head and neck in four. With a median follow-up of 5 years, the local control and overall survival rates are 100%. Complications have been few, and functional outcome is good. CONCLUSION: Brachytherapy is effective for selected paediatric patients, resulting in excellent tumour control and good functional results. It is feasible to deliver paediatric brachytherapy at a single centre within a national referral service.

Factors associated with the spatial accessibility of healthcare services measured by the floating catchment area (FCA)-based method: A scoping review.

INTRODUCTION: The floating catchment area (FCA) method has emerged as the most comprehensive and accurate method for quantifying the spatial accessibility of health care services. There were variants of the FCA-based method that was continuously improvised by the researchers to suit specific local contexts and the different nature of healthcare service delivery. This scoping review identifies factors associated with the spatial accessibility of healthcare services that were specifically measured using the FCAbased method. MATERIALS AND METHODS: This scoping review was performed through electronic databases (PubMed and ScienceDirect) using keywords: 'spatial accessibility', 'floating catchment area' and 'factors'. Google Scholar and Mendeley Network were also used as additional sources to obtain relevant studies. RESULTS: A total of 32 articles were included in this review. Factors identified can be distinguished into two broad categories, which are spatial and non-spatial factors. Spatial factors were remoteness or distance from the urban centre, areas in close proximity to main roads, and some specific geographical characteristics such as mountainous and deltaic regions, whereas non-spatial factors were the degree of urbanisation, population density and various demographic profiles of the population such as socioeconomic status, health need, and minority ethnic composition. CONCLUSION: This study adds to the body of literature pertinent to the factors associated with spatial accessibility to healthcare services. These findings could give insight for researchers to consider and incorporate those additional variables to further improve the FCA-based method calculations.

The aquaculture supply chain in the time of covid-19 pandemic: Vulnerability, resilience, solutions and priorities at the global scale.

The COVID-19 global pandemic has had severe, unpredictable and synchronous impacts on all levels of perishable food supply chains (PFSC), across multiple sectors and spatial scales. Aquaculture plays a vital and rapidly expanding role in food security, in some cases overtaking wild caught fisheries in the production of high-quality animal protein in this PFSC. We performed a rapid global assessment to evaluate the effects of the COVID-19 pandemic and related emerging control measures on the aquaculture supply chain. Socio-economic effects of the pandemic were analysed by surveying the perceptions of stakeholders, who were asked to describe potential supply-side disruption, vulnerabilities and resilience patterns along the production pipeline with four main supply chain components: a) hatchery, b) production/processing, c) distribution/logistics and d) market. We also assessed different farming strategies, comparing land- vs. sea-based systems; extensive vs. intensive methods; and with and without integrated multi-trophic aquaculture, IMTA. In addition to evaluating levels and sources of economic distress, interviewees were asked to identify mitigation solutions adopted at local / internal (i.e., farm-site) scales, and to express their preference on national / external scale mitigation measures among a set of a priori options. Survey responses identified the potential causes of disruption, ripple effects, sources of food insecurity, and socio-economic conflicts. They also pointed to various levels of mitigation strategies. The collated evidence represents a first baseline useful to address future disaster-driven responses, to reinforce the resilience of the sector and to facilitate the design reconstruction plans and mitigation measures, such as financial aid strategies.

Symmetrical drug-related intertriginous and flexural exanthema like eruption associated with COVID-19 vaccination.

This is a case of symmetrical drug-related intertriginous and flexural exanthema-like eruption following ChAdOx1 nCoV-19 (AstraZeneca-Oxford) vaccination. Investigations, including repeated skin swabs, ruled out an infectious cause. He was subsequently treated with oral prednisolone, which led to a resolution of his symptoms.

Characterization of dermatological diagnoses among hospitalized patients experiencing homelessness.

While previous studies have characterized the types of dermatological disease among people experiencing homelessness (PEH) in the outpatient setting, dermatological disease among hospitalized PEH has never been evaluated. Therefore, we performed a cross-sectional analysis of hospitalized patients who received dermatology consultations at two San Francisco hospitals between March 2018 and March 2020 and compared the odds of diagnostic categories between PEH and patients with stable housing. In both unadjusted and adjusted analyses, PEH had significantly higher odds of bacterial skin infections [adjusted odds ratio (aOR) = 2.29, 95% CI 1.46-3.61], ectoparasitic disease (aOR = 9.43, 95% CI 3.79-23.47), psoriasis or seborrhoeic dermatitis (aOR = 2.50, 95% CI 1.43-4.36) and venous stasis or lymphoedema (aOR = 2.54, 95% CI 1.23-5.27) and significantly lower odds of drug reactions (aOR = 0.34, 95% CI 0.18-0.67). Overall, these findings highlight the unique dermatological challenges among hospitalized PEH and suggest potential strategies to facilitate equitable dermatology care delivery.

Genetic stress-reactivity, sex, and conditioning intensity affect stress-enhanced fear learning.

The Stress-Enhanced Fear Learning (SEFL) model of posttraumatic stress disorder (PTSD) reveals increased fear memory in animals exposed to stress prior to contextual fear conditioning (CFC), similar to the increased likelihood of developing PTSD in humans after prior stress. The present study utilized the SEFL model by exposing animals to restraint stress as the first stressor, followed by CFC using foot-shocks with 0.6 mA or 0.8 mA intensity. Adult males and females from the two nearly isogenic rat strains, the genetically more stress-reactive Wistar Kyoto (WKY) More Immobile (WMI), and the less stress-reactive WKY Less Immobile (WLI) were employed. Percent time spent freezing at acquisition and at recall differed between these strains in both prior stress and no stress conditions. The significant correlations between percent freezing at acquisition and at recall suggest that fear memory differences represent a true phenotype related to the stress-reactivity differences between the strains. This assumption is further substantiated by the lack of effect of either conditioning intensity on percent freezing in WLI males, while WMI males were affected by both intensities albeit with opposite directional changes after prior stress. Differences between the sexes in sensitivity to the two conditioning intensities became apparent by the opposite directional and inverse relationship between fear memory and the intensity of conditioning in WMI males and females. The present data also illustrate that although corticosterone (CORT) responses to prior stress are known to be necessary for SEFL, plasma CORT and percent freezing were positively correlated only in the stress less-reactive WLI strain. These differences in baseline fear acquisition, fear memory, and the percent freezing responses to the SEFL paradigm in the two genetically close inbred WMI and WLI strains provide a unique opportunity to study the genetic contribution to the variation in these phenotypes.

Microdiversity of Enterococcus faecalis isolates in cases of infective endocarditis: selection of non-synonymous mutations and large deletions is associated with phenotypic modifications.

Context: Today, infective endocarditis (IE) caused by Enterococcus faecalis represents 10% of all IE and is marked by its difficult management and the frequency of relapses. Although the precise reasons for that remain to be elucidated, the evolution of the culprit strain under selective pressure through microdiversification could be, at least in part, involved. Material and methods: To further study the in situ genetic microdiversity and its possible phenotypic manifestations in E. faecalis IE, we sequenced and compared multiple isolates from the valves, blood culture and joint fluid of five patients who underwent valvular surgery. Growth rate and early biofilm production of selected isolates were also compared. Results: By sequencing a total of 58 E. faecalis genomes, we detected a considerable genomic microdiversity, not only among strains from different anatomical origins, but also between isolates from the same studied cardiac valves. Interestingly, deletions of thousands of bases including the well-known virulence factors ebpA/B/C, and srtC, as well as other large prophage sequences containing genes coding for proteins implicated in platelet binding (PlbA and PlbB) were evidenced. The study of mutations helped unveil common patterns in genes related to the cell cycle as well as central metabolism, suggesting an evolutionary convergence in these isolates. As expected, such modifications were associated with a significant impact on the in-vitro phenotypic heterogeneity, growth, and early biofilm production. Conclusion: Genome modifications associated with phenotypic variations may allow bacterial adaptation to both antibiotic and immune selective pressures, and thus promote relapses.

Understanding the future research needs in Postural Orthostatic Tachycardia Syndrome (POTS): Evidence mapping the POTS adult literature.

POTS is under diagnosed with an estimated prevalence of 0.2%. North American and Australian researchers, as well as patient groups have called for more research into POTS. However, there has been no comprehensive appraisal of the current POTS evidence base. AIM: To map the POTS evidence base. METHODS: Two reviewers systematically searched 12 databases until July 1st 2019 using the search term "Postural Tachycardia Syndrome" (n = 7280) and categorised the literature. Inclusion criteria included all adult published literature with no language restrictions. 779 papers are analysed and mapped. RESULTS: Seven themes were identified: symptomology and quality of life 16.8% (n = 132), biomedical topics 16.5% (n = 130), co-morbidities 10.3% (n = 81), non-pharmacological management 9.8% (n = 77), aetiologies 6.9% (n = 53), pharmacological management 6.7% (n = 53), and clinical management 6.6% (n = 52). There 45 subthemes. Quality appraisal of the research studies (n = 233) evaluated design, sample size, outcome measures, data analysis and research biases. 74.8% (n = 175) were observational designs and 25.2% (n = 59) were experimental designs (16 using a randomised controlled design, 11 of which had a sample size greater than 21). 47.4% (n = 111) of studies only measured duration of effect for <1 day. 11.5% (n = 27) of studies reported outcomes using an unvalidated subjective measurement tool. CONCLUSION: The volume of adult POTS literature is small and the validity and reliability of the research lacks rigour. The evidence map methodology provides POTS researchers with a benchmark for research thus far. This paper adds an in-depth research appraisal to the broad calls for action, highlighting the pressing need for multicentre, good quality research in POTS, to support guidelines and consensus development in the future.

Phase III, randomized trial of mirvetuximab soravtansine versus chemotherapy in patients with platinum-resistant ovarian cancer: primary analysis of FORWARD I.

BACKGROUND: Mirvetuximab soravtansine (MIRV) is an antibody-drug conjugate comprising a folate receptor alpha (FRα)-binding antibody, cleavable linker, and the maytansinoid DM4, a potent tubulin-targeting agent. The randomized, open-label, phase III study FORWARD I compared MIRV and investigator's choice chemotherapy in patients with platinum-resistant epithelial ovarian cancer (EOC). PATIENTS AND METHODS: Eligible patients with 1-3 prior lines of therapy and whose tumors were positive for FRα expression were randomly assigned, in a 2 : 1 ratio, to receive MIRV (6 mg/kg, adjusted ideal body weight) or chemotherapy (paclitaxel, pegylated liposomal doxorubicin, or topotecan). The primary endpoint was progression-free survival [PFS, Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, blinded independent central review] in the intention-to-treat (ITT) population and in the prespecified FRα high population. RESULTS: A total of 366 patients were randomized; 243 received MIRV and 109 received chemotherapy. The primary endpoint, PFS, did not reach statistical significance in either the ITT [hazard ratio (HR), 0.98, P = 0.897] or the FRα high population (HR, 0.69, P = 0.049). Superior outcomes for MIRV over chemotherapy were observed in all secondary endpoints in the FRα high population including improved objective response rate (24% versus 10%), CA-125 responses (53% versus 25%), and patient-reported outcomes (27% versus 13%). Fewer treatment-related grade 3 or higher adverse events (25.1% versus 44.0%), and fewer events leading to dose reduction (19.8% versus 30.3%) and treatment discontinuation (4.5% versus 8.3%) were seen with MIRV compared with chemotherapy. CONCLUSIONS: In patients with platinum-resistant EOC, MIRV did not result in a significant improvement in PFS compared with chemotherapy. Secondary endpoints consistently favored MIRV, particularly in patients with high FRα expression. MIRV showed a differentiated and more manageable safety profile than chemotherapy.

A structured pathway for developing your complex abdominal hernia service: our York pathway.

PURPOSE: Clinical pathways are widely prevalent in health care and may be associated with increased clinical efficacy, improved patient care, streamlining of services, while providing clarity on patient management. Such pathways are well established in several branches of healthcare services but, to the authors' knowledge, not in complex abdominal wall reconstruction (CAWR). A stepwise, structured and comprehensive approach to managing complex abdominal wall hernia (CAWH) patients, which has been successfully implemented in our practice, is presented. METHODS: A literature search of common databases including Embase® and MEDLINE® for CAWH pathways identified no comprehensive pathway. We therefore undertook a reiterative process to develop the York Abdominal Wall Unit (YAWU) through examination of current evidence and logic to produce a pragmatic redesign of our own pathway. Having introduced our pathway, we then performed a retrospective analysis of the complexity and number of abdominal wall cases performed in our trust over time. RESULTS: We describe our pathway and demonstrate that the percentage of cases and their complexity, as defined by the VHWG classification, have increased over time in York Abdominal Wall Unit. CONCLUSION: A structured pathway for complex abdominal wall hernia service is one way to improve patient experience and streamline services. The relevance of pathways for the hernia surgeon is discussed alongside this pathway. This may provide a useful guide to those wishing to establish similar personalised pathways within their own units and allow them to expand their service.

A multistage process leading to the development of a structured consent form and patient information leaflet for complex abdominal wall reconstruction (CAWR).

PURPOSE: Informed consent is vital in surgery. The General Medical Council, UK and Royal College of Surgeons of England provide clear guidance on what constitutes the process of informed patient consent. Despite this, evidence suggests that the consent process may not be performed well in surgery. We utilised a staged patient-centred approach and rigorous methodology to develop a standardised patient information leaflet (PIL) and pre-written structured consent form for complex abdominal wall reconstruction (CAWR). METHODS: We utilised the principles of Deming's Plan-Do-Study-Act (PDSA) cycles to approach the process. Buzan's mind maps were used to identify the stakeholders and deficiencies in the consent process ('Plan' phase). The content of the PIL and pre-written consent form was then developed in collaboration with stakeholders ('Do' phase). Multidisciplinary and multidepartmental feedback was obtained on the proposed content and amendments were made ('Study' and 'Act' phases). RESULTS: We successfully produced a clear, focused PIL and structured consent form, in Plain English, presenting accurate, relevant and detailed information in a highly understandable way. The PIL had a Flesch Reading Ease score of > 80, demonstrating a high level of readability and comprehensibility, with positive implications for informed patient decision making and preparedness for surgery. CONCLUSION: Through sharing the process that we undertook, we aim to support other abdominal wall units who wish to develop and improve their own consent process.

The relationship between resting heart rate and new-onset microalbuminuria in people with type 2 diabetes: An 8-year follow-up study.

AIMS: Microalbuminuria is an indicator of adverse cardiovascular events and chronic kidney disease. Studies have described an elevated resting heart rate as a risk factor for microalbuminuria in people with cardiovascular disease, but none have clarified its role in microalbuminuria development in people with type 2 diabetes. Therefore, this study investigated the relationship between resting heart rate and new-onset microalbuminuria in type 2 diabetes. METHODS: A total of 788 people from a glycaemic control trial in Taiwan were enrolled. Microalbuminuria was defined as a fasting urine albumin-to-creatinine ratio ≥30 mg/g in two consecutive urine tests. Resting heart rate and other covariates were measured at baseline. The quartile of resting heart rates, categorized as <70, 70-74, 75-80 and >80 beats/min, was used for analysis. Cox proportional hazard models were used to evaluate the association between resting heart rate and risk of microalbuminuria. RESULTS: During the follow-up period, 244 people (31%) developed microalbuminuria. Those who developed microalbuminuria had a longer diabetes duration (median = 3.0 vs. 2.0 years, p < 0.001), higher rate of hypertension (77% vs. 66%, p = 0.003), higher rate of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker treatment (50% vs. 38%, p = 0.001) and higher baseline HbA1c level (70 vs. 64 mmol/mol, 8.6 vs. 8.0%, p < 0.001). After adjusting for demographics, metabolic profiles and inflammatory markers, developing microalbuminuria was significantly associated with baseline resting heart rate of 70-74, 75-80 and >80 beats/min (with hazard ratios [95% CI] of 2.05 [1.32, 3.18], 2.10 [1.32, 3.32] and 1.62 [1.01, 2.59], respectively) compared to resting heart rates <70 beats/min. An average increased risk of microalbuminuria for increment of 10 beats/min was about 24% among those with hypertension (with hazard ratios of 1.24 [1.05, 1.47] in the multivariable Cox model). CONCLUSIONS: This prospective cohort study showed that resting heart rate may be an associative risk factor for developing microalbuminuria in type 2 diabetes.

Pencil Beam Scanning Proton Therapy Case Selection for Paediatric Abdominal Neuroblastoma: Effects of Tumour Location and Bowel Gas.

AIMS: Pencil beam scanning (PBS) proton therapy is an increasingly used radiation modality for childhood malignancies due to its ability to minimise dose to surrounding organs. However, the dosimetry is extremely sensitive to anatomical and density changes. The aims of this study were to investigate if there is a dosimetric benefit or detriment with PBS for paediatric abdominal neuroblastoma, assess gastrointestinal air variability and its dosimetric consequences, plus identify if there are factors that could assist case selection for PBS referral. MATERIALS AND METHODS: Twenty neuroblastoma cases were double-planned with PBS and intensity-modulated arc therapy (IMAT). Cases were divided into unilateral, midline unilateral and midline bilateral locations in relation to the kidneys. Plans were recalculated after the gastrointestinal volume was simulated as air (Hounsfield Units -700) and water (Hounsfield Units 0), then compared with nominal plans (recalculated - nominal, ΔD). Forty-three weekly cone beam computed tomography scans were analysed to quantify gastrointestinal air variability during treatment. RESULTS: PBS reduced the mean dose to normal tissues at all tumour locations, particularly unilateral tumours. However, 15% had better dosimetry with IMAT, all of which were midline tumours. Increased gastrointestinal air caused significant compromises to PBS versus IMAT plans for midline tumours [median/maximum ΔD95% clinical target volume (CTV) -2.4%/-15.7% PBS versus 1.4%/0% IMAT, P = 0.003], whereas minimal impact was observed for unilateral tumours (ΔD95% CTV -0.5%/-1.9% PBS versus 0.5%/-0.5% IMAT, P = 0.008). D95% CTV was significantly decreased in PBS plans if planning target volume (PTV) ≥400 cm3 (median -4.1%, P = 0.001) or PTV extension ≥60% anterior to vertebral body (-2.1%, P = 0.002). A larger variation in gastrointestinal air was observed in patients treated under general anaesthesia (median 38.4%) versus awake (11.5%); P = 0.004. CONCLUSION: In this planning study, tumours at the unilateral location consistently showed improved dose reductions to normal tissue with minimal dose degradation from increased gastrointestinal air with PBS plans. Tumour location, PTV volume and anterior extension of PTV are useful characteristics in facilitating patient selection for PBS.

Non-invasive spectroscopic and imaging systems for prediction of beef quality in a meat processing pilot plant.

This study evaluated a range of diffuse reflectance spectroscopic (Vis-NIR spectrophotometers) and imaging (Hyperspectral imaging cameras) instruments for predicting pH, IMF and shear force values of beef in a meat processing pilot plant. A total of 364 beef striploin samples were evaluated and prediction models were developed using PLSR. Models for pH and IMF (except Vis snapshot camera) showed good fit with high Rcv2 (0.29-0.92) and low SECV values. Good prediction accuracy with high Rp2 (0.44-0.90), RPD and low SEP values was also observed. While low values of Rp2 for shear force was observed, the expected curvilinear relationship between predicted values of shear force and predicted values of pH was observed suggesting that spectroscopic measurements were able detect biophysical factors associated to these two attributes. Overall, it can be concluded that diffuse reflectance spectroscopy combined with chemometrics has a great potential to be used as an on/in-line quality monitoring system for the meat processing industry.