Using metabolomics to understand stress responses in Lactic Acid Bacteria and their applications in the food industry.

BACKGROUND: Lactic Acid Bacteria (LAB) are commonly used as starter cultures, probiotics, to produce lactic acid and other useful compounds, and even as natural preservatives. For use in any food product however, LAB need to survive the various stresses they encounter in the environment and during processing. Understanding these mechanisms may enable direction of LAB biochemistry with potential beneficial impact for the food industry. AIM OF REVIEW: To give an overview of the use of LAB in the food industry and then generate a deeper biochemical understanding of LAB stress response mechanisms via metabolomics, and methods of screening for robust strains of LAB. KEY SCIENTIFIC CONCEPTS OF REVIEW: Uses of LAB in food products were assessed and factors which contribute to survival and tolerance in LAB investigated. Changes in the metabolic profiles of LAB exposed to stress were found to be associated with carbohydrates, amino acids and fatty acid levels and these changes were proposed to be a result of the bacteria trying to maintain cellular homeostasis in response to external conditions and minimise cellular damage from reactive oxygen species. This correlates with morphological analysis which shows that LAB can undergo cell elongation and shortening, as well as thinning and thickening of cell membranes, when exposed to stress. It is proposed that these innate strategies can be utilised to minimise negative effects caused by stress through selection of intrinsically robust strains, genetic modification and/or prior exposure to sublethal stress. This work demonstrates the utility of metabolomics to the food industry.

Exploring the potential application of alternative nuclei in NMR based metabolomics.

INTRODUCTION: Nuclear magnetic resonance (NMR) is widely used in metabolomics but it focusses on 1H over other NMR-active nuclei. OBJECTIVES: To evaluate the potential of alternative NMR-sensitive nuclei to generate useful metabolomic data. METHOD: Proton, carbon, phosphorus, and nitrogen-based NMR metabolomics was undertaken on extracts from mint and European honey bee tissue. RESULTS: Carbon NMR provided useful information but required larger sample sizes. Phosphorus produced overlapping peaks in one dimensional (1D) analysis but showed potential in 2D experiments. 15N NMR was found to not be sensitive enough for general metabolomic work. CONCLUSIONS: Alternative NMR active nuclei are useful for metabolomics.

Pelvic pain is a common prolapse symptom and improvement after ventral mesh rectopexy is more frequent than deterioration or de novo pain.

AIM: The aim of this work was to assess the relationship between pelvic pain and rectal prolapse both before prolapse surgery and in the long term after ventral mesh rectopexy (VMR). METHOD: Patients undergoing VMR between 2004 and 2017 were contacted. Outcomes including the severity of pelvic pain were recorded using a numeric rating scale. RESULTS: Four hundred and seventy eight of the 749 patients (64%) were successfully contacted. Of these, 39% reported pre-existing pelvic pain prior to VMR (group A) and 61% were pain free (group B). The median follow-up time was 8.0 years (interquartile range 5.0-10.0 years). Symptoms of obstructed defaecation were significantly more common (p = 0.002) in group A (91/187, 49%) than in group B (101/291, 35%). In contrast, faecal incontinence was more common (p = 0.007) in group B (75/291, 26%) than in group A (29/187, 15%). In group A, 76% showed improvement in pelvic pain after VMR: 61% were pain free and 39% had partial improvement in their pre-existing pelvic pain. Patients with persistent pelvic pain were younger (p = 0.01) and more likely to have revisional surgery after VMR (p = 0.0003), but there was no relation to the indication for surgery (p = 0.59). In group B, 15% reported de novo pelvic pain after VMR, and this was more common in women under 50 years old (p = 0.001), when obstructed defaecation was the indication (p = 0.03), in mesh erosion (p = <0.05) and when associated with revisional surgery (p = 0.005). CONCLUSION: Pelvic pain is common (39%) in patients undergoing prolapse surgery, and VMR improves this pain in most patients (76%). However, a significant number of patients fail to improve (12%), experience worsening of pain (12%) or develop de novo pelvic pain (15%).

The Association of Coloproctology of Great Britain and Ireland guideline on the management of anal fissure.

AIM: The management of anal fissure: ACPGBI position statement was written 15 years ago. [KLR Cross et al., Colorectal Dis, 2008]. Our aim was to update the guideline and provide recommendations on the most effective treatment for patients with anal fissures utilising a multidisciplinary, rigorous guideline methodology. METHODS: The development process consisted of six phases. In phase 1 we defined the scope of the guideline. The patient population included patients with acute and chronic anal fissure. The target group was all practitioners (primary and secondary care) treating patients with fissures and, in addition, healthcare workers and patients who desired information regarding fissure management. In phase 2 we formed a guideline development group (GDG) including a methodologist. In phase 3 review questions were formulated, using a reversed PICO process, starting with possible recommendations based on the GDG's knowledge. In phase 4 a comprehensive literature search focused on existing systematic reviews addressing each review question, supplemented by more recent studies if appropriate. In phase 5 data were extracted from the included papers and checked by the GDG. If indicated, meta-analysis of systematic review data was updated by the GDG. During phase 6 the GDG members decided what recommendations could be made based on the evidence in the literature and strength of the recommendation was assessed using 'grade'. RESULTS: This guideline is divided into two sections: Primary care which includes (i) diagnosis; (ii) basic treatment; (iii) topical treatment; and secondary care which includes (iv) botulinum toxin therapy; (v) surgical intervention and (vi) special situations (including pregnancy and breast-feeding patients, children, receptive anal intercourse and low-pressure fissures). A total of 23 recommendations were formulated. A new term clinically healed was described by the GDG. CONCLUSION: This guideline provides an up-to-date evidence-based summary of the current knowledge of the management of anal fissure and may serve as a useful guide for clinicians as well as a potential reference for patients.

Macrophage-NLRP3 Activation Promotes Right Ventricle Failure in Pulmonary Arterial Hypertension.

Rationale: Pulmonary arterial hypertension (PAH) often results in death from right ventricular failure (RVF). NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3)-macrophage activation may promote RVF in PAH. Objectives: Evaluating the contribution of the NLRP3 inflammasome in RV macrophages to PAH RVF. Methods: Rats with decompensated RV hypertrophy (monocrotaline [MCT] and Sugen-5416 hypoxia [SuHx]) were compared with compensated RV hypertrophy rats (pulmonary artery banding). Echocardiography and right heart catheterization were performed. Macrophages, atrial natriuretic peptides, and fibrosis were evaluated by microscopy or flow cytometry. NLRP3 inflammasome activation and cardiotoxicity were confirmed by immunoblot and in vitro strategies. MCT rats were treated with SC-144 (a GP130 antagonist) or MCC950 (an NLRP3 inhibitor). Macrophage-NLRP3 activity was evaluated in patients with PAH RVF. Measurements and Main Results: Macrophages, fibrosis, and atrial natriuretic peptides were increased in MCT and SuHx RVs but not in left ventricles or pulmonary artery banding rats. Although MCT RV macrophages were inflammatory, lung macrophages were antiinflammatory. CCR2+ macrophages (monocyte-derived) were increased in MCT and SuHx RVs and highly expressed NLRP3. The macrophage-NLRP3 pathway was upregulated in patients with PAH with decompensated RVs. Cultured MCT monocytes showed NLRP3 activation, and in coculture experiments resulted in cardiomyocyte mitochondrial damage, which MCC950 prevented. In vivo, MCC950 reduced NLRP3 activation and regressed pulmonary vascular disease and RVF. SC-144 reduced RV macrophages and NLRP3 content, prevented STAT3 (signal transducer and activator of transcription 3) activation, and improved RV function without regressing pulmonary vascular disease. Conclusions: NLRP3-macrophage activation occurs in the decompensated RV in preclinical PAH models and patients with PAH. Inhibiting GP130 or NLRP3 signaling improves RV function. The concept that PAH RVF results from RV inflammation rather than solely from elevated RV afterload suggests a new therapeutic paradigm.

Public perspectives on inequality and mental health: A peer research study.

INTRODUCTION: Associations between structural inequalities and health are well established. However, there is limited work examining this link in relation to mental health, or that centres public perspectives. This study explores people's experience and sense-making of inequality in their daily lives, with particular consideration of impacts on mental health. METHODS: We conducted a peer research study. Participants had to live in one of two London Boroughs and have an interest in inequalities and mental health. Using social media, newsletters, local organisations and our peer researchers' contacts, we recruited 30 participants who took photos representing their experience of inequality and discussed them during semi-structured interviews. Data were analysed using reflexive thematic analysis. RESULTS: Three themes were identified in this study: (1) inequalities are unjust, multilayered and intertwined with mental health. Accounts demonstrated a deep understanding of inequalities and their link to mental health outcomes, describing inequalities as 'suffering' and 'not good for anyone'. Financial, housing, immigration and healthcare problems exacerbated poor mental health, with racism, gender-based violence and job loss also contributing factors for both poor mental health and experiences of inequality; (2) inequalities exclude and have far-reaching mental health consequences, impacting personal sense of belonging and perceived societal value and (3) moving forwards-addressing long-standing inequality and poor public mental health necessitated coping and resilience strategies that are often unacknowledged and undervalued by support systems. CONCLUSION: Lived experience expertise was central in this study, creating an innovative methodological approach. To improve public mental health, we must address the everyday, painful structural inequalities experienced by many as commonplace and unfair. New policies and strategies must be found that involve communities, redistributing resources and power, building on a collective knowledge base, to coproduce actions combatting inequalities and improving population mental health. PATIENT OR PUBLIC CONTRIBUTION: This study was peer-led, designed and carried out by researchers who had experiences of poor mental health. Six authors of the paper worked as peer researchers on this study.

Outcomes of rectal prolapse surgery in patients with benign joint hypermobility syndrome.

BACKGROUND: Rectal prolapse is a debilitating disorder of the pelvic floor, and treatment outcomes are variable. Previous studies have identified underlying benign joint hypermobility syndrome (BJHS) in some patients. We sought to determine the outcomes of these patients after undergoing ventral rectopexy surgery (VMR). METHODS: All consecutive patients who were referred to the pelvic floor unit at our institution between February 2010 and December 2011 were considered for recruitment into the study. Following recruitment, they were assessed using the Beighton criteria to determine the presence or absence of benign joint hypermobility syndrome. Both groups underwent similar surgical interventions and were then followed up. The need for revisional surgery was recorded in both groups. RESULTS: Fifty-two patients [34 normal; M:F, 1:6; median age 61 (range 22-84) years; 18 BJHS; M:F, 0:1; median age 52 (range 25-79) years] were recruited. A total of 42 patients completed the full 1-year follow-up (26 normal, 16 benign joint hypermobility syndrome). Patients with benign joint hypermobility syndrome were significantly younger (median age 52 versus 61 years, p < 0.001) with male to female ratio of 0:1 versus 1:6, respectively. In addition, they were significantly more likely to require revisional surgery than those without the condition (31% versus 8% p < 0.001). In most cases, this was in the form of a posterior stapled transanal resection of the rectum procedure. CONCLUSIONS: Patients with BJHS presenting for rectal prolapse surgery were younger and are more likely to require further surgery for rectal prolapse recurrence than those without the condition.

Is substrate choice an overlooked variable in ecotoxicology experiments?

It is crucial to understand the effects caused by experimental parameters such as temperature, light, and food type on lab and field-based ecotoxicology experiments, as these variables, and combinations thereof, can affect results. The type of substrate used in exposure experiments, however, is generally assumed to have no effect. This may not always be correct. The metabolic changes in the freshwater crustacean, Austrochiltonia subtenuis exposed to copper, using three common substrates, gauze; toilet paper; and cellulose were investigated. Substrate alone did not affect survival, but each substrate elicited a different metabolic response and adult and juvenile amphipods had different substrate preferences. Several classes of metabolites were shown to change in response to different substrates and toxicant. These included disaccharides, monosaccharides, fatty acids, and tricarboxylic acid cycle intermediates. The results illustrate that metabolomic responses can differ in response to experimental factors that were previously thought not to be significant. In fact, our data indicate that substrate should be viewed as an experimental factor as important to control for as more well-known confounders such as temperature or food, thus challenging the current paradigm. Assuming substrate type has no effect on the experiment could potentially lead to errors in contaminant toxicity assessments. We propose that ideal good practise would be that all experimental factors should be evaluated for their potential influence on metabolomic profiles prior to contaminant response experiments being undertaken.

Patients' Perception of Long-term Outcome After Laparoscopic Ventral Mesh Rectopexy; Single Tertiary Center Experience.

OBJECTIVE: To assess patients' long-term outcome and satisfaction after laparoscopic ventral mesh rectopexy (LVMR). SUMMARY OF BACKGROUND DATA: Data on the long-term outcome and satisfaction of patients undergoing LVMR are limited. METHODS: Patients who underwent LVMR between 2004 and 2017 were identified from a prospectively maintained database. We attempted to contact all patients by telephone for an interview using a standardized questionnaire to record pre-LVMR symptoms, long-term outcome, and overall satisfaction. RESULTS: Total number of patients who underwent LVMR was 848 and 99(12%) were deceased at follow-up. In the end, 544 (64%) patients were contacted successfully and 478 (56%) were able to complete the questionnaire. Median time elapsed since surgery was 7 years and mean age was 62 years. Patients' reported preoperative symptoms were obstructed defecation syndrome in 40%, fecal incontinence in 22%, combination of obstructed defecation syndrome and fecal incontinence in 21% and other conditions in 17%. Bowel symptoms were reported as improved by 69% of patients and worse by 12%. Pelvic pain was reported to be improved in 47% of the patients after LVMR but new onset of pelvic pain appeared in 15%. Sexual function was reported to be better and worse with equal frequency. Overall, 63% of the patients were satisfied with the outcome and 76% would recommend this procedure to others with similar symptoms. CONCLUSION: LVMR offers acceptable long-term outcomes and satisfaction. There is a mixed impact on pelvic pain and sexual function which requires careful consideration in counseling patients for this procedure.

PINK1-induced phosphorylation of mitofusin 2 at serine 442 causes its proteasomal degradation and promotes cell proliferation in lung cancer and pulmonary arterial hypertension.

Impaired mitochondrial fusion, due in part to decreased mitofusin 2 (Mfn2) expression, contributes to unrestricted cell proliferation and apoptosis-resistance in hyperproliferative diseases like pulmonary arterial hypertension (PAH) and non-small cell lung cancer (NSCLC). We hypothesized that Mfn2 levels are reduced due to increased proteasomal degradation of Mfn2 triggered by its phosphorylation at serine 442 (S442) and investigated the potential kinase mediators. Mfn2 expression was decreased and Mfn2 S442 phosphorylation was increased in pulmonary artery smooth muscle cells from PAH patients and in NSCLC cells. Mfn2 phosphorylation was mediated by PINK1 and protein kinase A (PKA), although only PINK1 expression was increased in these diseases. We designed a S442 phosphorylation deficient Mfn2 construct (PD-Mfn2) and a S442 constitutively phosphorylated Mfn2 construct (CP-Mfn2). The effects of these modified Mfn2 constructs on Mfn2 expression and biological function were compared with those of the wildtype Mfn2 construct (WT-Mfn2). WT-Mfn2 increased Mfn2 expression and mitochondrial fusion in both PAH and NSCLC cells resulting in increased apoptosis and decreased cell proliferation. Compared to WT-Mfn2, PD-Mfn2 caused greater Mfn2 expression, suppression of proliferation, apoptosis induction, and cell cycle arrest. Conversely, CP-Mfn2 caused only a small increase in Mfn2 expression and did not restore mitochondrial fusion, inhibit cell proliferation, or induce apoptosis. Silencing PINK1 or PKA, or proteasome blockade using MG132, increased Mfn2 expression, enhanced mitochondrial fusion and induced apoptosis. In a xenotransplantation NSCLC model, PD-Mfn2 gene therapy caused greater tumor regression than did therapy with WT-Mfn2. Mfn2 deficiency in PAH and NSCLC reflects proteasomal degradation triggered by Mfn2-S442 phosphorylation by PINK1 and/or PKA. Inhibiting Mfn2 phosphorylation has potential therapeutic benefit in PAH and lung cancer.

Laparoscopic Sacral Mesh Fixation for Ventral Rectopexy: Clinical Implications From a Cadaver Study.

BACKGROUND: Correct tack placement at the sacral promontory for mesh fixation in ventral mesh rectopexy is crucial to avoid bleeding, nerve dysfunction, and spondylodiscitis. OBJECTIVE: The present cadaver study was designed to assess the true location of tacks after mesh fixation during laparoscopic ventral mesh rectopexy in relation to vascular and nerve structures and bony landmarks. DESIGN: This was an interventional cadaver study. SETTING: This study was conducted after laparoscopic mesh fixation detailed pelvic dissection was performed following a standardized protocol. In addition, 64-row multidetector computed tomography was conducted to further define lumbosacral anatomy and tack positioning. PATIENTS: Eighteen fresh cadavers (10 female, 8 male) were included in this study. MAIN OUTCOME MEASURES: True tack position and vascular and neuronal involvement served as outcome measures. RESULTS: A total of 52 tacks were deployed (median 3, range 2-3 tacks). Median tack distance to the midsacral promontory was 16.1 mm (0.0-54.2). Only a total of 22 tacks (42.3%) were found on the right surface of the S1 vertebra, correlating with the planned deployment area. In 7 cadavers (38.8%), all tacks were deployed on the planned deployment area. The median distance to the major vessels was 10.5 mm (0.0-35.0), which was the internal iliac artery in half of the cases. Median distance of tacks to the right ureter was 32.1 mm (7.5-46.1). Neither major vessels nor the ureter was injured. Dissection of the hypogastric plexus was undertaken in 14 cadavers, and in each cadaver, tacks affected the hypogastric nerve plexus. LIMITATIONS: This study was limited by the moderate number of cadavers. CONCLUSIONS: Tack placement showed significant variation in our specimen, emphasising the need for reliable anatomic landmarks and sufficient exposure during ventral mesh rectopexy. Hypogastric nerve plexus involvement is common, thus detailed functional assessment after surgery is required. It also points out the importance of cadaver studies before implementing new surgical techniques into clinical practice. See Video Abstract at http://links.lww.com/DCR/B827. FIJACIN LAPAROSCPICA DE MALLA SACRA PARA RECTOPEXIA VENTRAL IMPLICACIONES CLNICAS DE UN ESTUDIO SOBRE CADAVERS: ANTECEDENTES:La colocación correcta de la tachuela en el promontorio sacro para la fijación de la malla en la rectopexia con malla ventral es crucial para evitar hemorragias, disfunción nerviosa y espondilodiscitis.OBJETIVO:El presente estudio en cadáveres fue diseñado para evaluar la verdadera ubicación de las tachuelas después de la fijación de la malla durante la rectopexia laparoscópica con malla ventral en relación con las estructuras vasculares y nerviosas y los puntos de referencia óseos.DISEÑO:Estudio intervencionista de cadáveres.AJUSTE:Después de la fijación laparoscópica de la malla, se realizó una disección pélvica detallada siguiendo un protocolo estandarizado. Además, se realizó una tomografía computarizada multidetector de 64 cortes para definir mejor la anatomía lumbosacra y la posición de la tachuela.PACIENTES:Se incluyeron en este estudio dieciocho cadáveres frescos (10 mujeres, 8 hombres).PRINCIPALES MEDIDAS DE RESULTADO:Posición real de tachuela y compromiso vascular y neuronal.RESULTADOS:Se utilizaron un total de 52 tachuelas (mediana 3, 2-3 tachuelas). La distancia media de tachuela al promontorio sacro medio fue de 16,1 mm (0,0-54,2). Solo se encontraron un total de 22 tachuelas (42,3%) en la superficie derecha de la vértebra S1, correlacionándose con el área planificada. En siete cadáveres (38,8%) todas las tachuelas se utilizaron en el área de planificada. La distancia media a los vasos principales fue de 10,5 mm (0,0-35,0), que era la arteria ilíaca interna en la mitad de los casos. La distancia media de las tachuelas al uréter derecho fue de 32,1 mm (7,5-46,1). No se lesionó ni los grandes vasos ni el uréter. La disección del plexo hipogástrico se realizó en 14 cadáveres y en cada cadáver, las tachuelas afectaron el plexo nervioso hipogástrico.LIMITACIONES:Número moderado de cadáveres incluidos en el estudio.CONCLUSIONES:La colocación de tachuelas mostró una variación significativa en nuestra muestra, enfatizando la necesidad de puntos de referencia anatómicos confiables y una exposición suficiente durante la rectopexia con malla ventral. La afectación del plexo nervioso hipogástrico es común, por lo que se requiere una evaluación funcional detallada después de la cirugía. También destaca la importancia de los estudios sobre cadáveres antes de implementar nuevas técnicas quirúrgicas en la práctica clínica. Consulte Video Resumen en http://links.lww.com/DCR/B827. (Traducción-Dr Yolanda Colorado).

Conceptualising public mental health: development of a conceptual framework for public mental health.

BACKGROUND: Numerous determinants have been linked to public mental health; however, they have not been brought together in a comprehensive conceptual framework. The goal of this work was to bring together academic research, practitioner expertise, and public perspectives to create a public mental health conceptual framework. METHODS: The development process proceeded in four stages. First, we identified a comprehensive list of potential determinants through a state-of-the-art academic literature review, grey literature review, and created mind maps created by peer researchers. Next, we conducted in-person workshops, consultations, and an online survey with academics, practitioners, policy makers, and members of the public to review the potential determinants, nominate additional determinants, and prioritise determinants by importance for understanding public mental health. This iterative process resulted in the final list of determinants contained in the framework. We then conducted rapid reviews to define each determinant and to identify key research, interventions, and resources. Finally, we worked with a design team to visualise the conceptual framework as an online tool and printable infographic. RESULTS: We found substantial overlap between sources reflecting a shared understanding of the key drivers of public mental health. The unique determinants that emerged from each data source highlighted the importance of using multiple sources to create a comprehensive model. 72 potential determinants were prioritised through stakeholder consultations, resulting in a final list of 55 determinants and organised into four levels: individual, family, community, and structural. CONCLUSIONS: This is the most complete conceptual framework for public mental health to date, bringing together academic research, policy and practitioner views, and lived experience perspectives. The co-production processes and tools we used provides a template for researchers looking to include multiple perspectives in their research. The conceptual framework draws together current knowledge on each determinant, but also highlights areas where further research is needed to better understand the relationship between each factor and mental health, which can inform the research agenda. This online tool and infographic can be used by practitioners to identify interventions for promoting mental health, and by the general public as a resource to increase awareness of the broad factors which shape public mental health.

Phosphaturic Mesenchymal Tumor of the Ankle: A Case Report and Review of the Literature.

We report the case of a phosphaturic mesenchymal tumor of the ankle; an extremely rare lesion that causes osteomalacia via paraneoplastic renal phosphate wasting. A 41-year-old man was referred to plastic surgery with a swelling over the anterior ankle, which had been increasing in size for 1 year. Focused ultrasound assessment was inconclusive, but excision biopsy demonstrated features in keeping with a phosphaturic mesenchymal tumor. Evidence of tumor-induced osteomalacia was subsequently identified on review of historical biochemistry. The patient was followed-up for 1 year with normalization of serum phosphate. In this case report, we present a discussion of the differential diagnosis for foot and ankle soft tissue lesions, and a review of the literature regarding the diagnosis and management of these tumors. Accurate identification of any soft tissue lesion on clinical examination alone is extremely challenging and excision biopsy should be considered in cases of diagnostic uncertainty.

Maintaining Standards in Colorectal Cancer Surgery During the Global Pandemic: A Cohort Study.

AIM: Cancer surgery in the COVID-19 pandemic presents many new challenges. For each patient, the risk of contracting COVID-19 during the perioperative period, with the potential for life-threatening sequelae (1), has to be weighed against the risk of delaying treatment. We assessed the response and short-term outcomes from elective colorectal cancer surgery during the pandemic at our institution. METHOD: We report a prospective cohort study of all elective colorectal surgery cases performed at our Trust during the 11 weeks following the national UK lockdown on 23rd March 2020, compared with the same time period in 2019. RESULTS: Eighty-five colorectal operations were performed during the 2020 (COVID) time period, and 179 performed in the 2019 (non-COVID) time period. A significantly higher proportion of cases during the COVID period were cancer-related (66% vs 26%, p < 0.00001). There was no difference in length of hospital stay, complications or readmissions. There were no mortalities in either cohort. Among the cancer patients, there were no differences in TMN staging, R1 resection rate or lymph node yields. No elective patient tested positive for COVID-19 during the perioperative period. CONCLUSION: At the height of the COVID pandemic, we maintained delivery the of high-quality elective colorectal cancer surgery, with no worsening of short-term outcomes and no compromise in the quality of cancer resections. Ongoing monitoring of this cohort is essential. The risks associated with COVID-19 will continue for some time, necessitating adaptive responses to maintain high-quality cancer services.

Knockout of the non-essential gene SUGCT creates diet-linked, age-related microbiome disbalance with a diabetes-like metabolic syndrome phenotype.

SUGCT (C7orf10) is a mitochondrial enzyme that synthesizes glutaryl-CoA from glutarate in tryptophan and lysine catabolism, but it has not been studied in vivo. Although mutations in Sugct lead to Glutaric Aciduria Type 3 disease in humans, patients remain largely asymptomatic despite high levels of glutarate in the urine. To study the disease mechanism, we generated SugctKO mice and uncovered imbalanced lipid and acylcarnitine metabolism in kidney in addition to changes in the gut microbiome. After SugctKO mice were treated with antibiotics, metabolites were comparable to WT, indicating that the microbiome affects metabolism in SugctKO mice. SUGCT loss of function contributes to gut microbiota dysbiosis, leading to age-dependent pathological changes in kidney, liver, and adipose tissue. This is associated with an obesity-related phenotype that is accompanied by lipid accumulation in kidney and liver, as well as "crown-like" structures in adipocytes. Furthermore, we show that the SugctKO kidney pathology is accelerated and exacerbated by a high-lysine diet. Our study highlights the importance of non-essential genes with no readily detectable early phenotype, but with substantial contributions to the development of age-related pathologies, which result from an interplay between genetic background, microbiome, and diet in the health of mammals.

Regulation and validation of smartphone applications in plastic surgery: It's the Wild West out there.

BACKGROUND AND PURPOSE: The use of smartphone applications is ubiquitous within healthcare. Over recent years there have been multiple applications developed within the field of plastic surgery. In the UK, applications with a medical purpose should be registered with the Medicines and Healthcare products Regulatory Authority (MHRA) as a medical device. The aim of this study was to evaluate plastic surgery specific smartphone applications designed for healthcare professional usage, and determine what proportion meet the criteria of a medical device and are suitably certified. METHODS: A systematic review of the Apple and Google Play App stores was carried out using search terms relevant to plastic surgery. Data was extracted from the app store listing, developer website and the contents of each application. Each application was evaluated against the criteria given by the MHRA to determine whether it constituted a medical device. RESULTS: 215 applications for plastic surgery healthcare professionals were identified, of which 22 met the definition of a medical device. Only 14% (n = 3) of these applications were appropriately certified, 14% (n = 3) were validated in peer-reviewed literature and 45% (n = 10) had documented medical professional involvement. CONCLUSION: Most applications with a medical purpose were not certified as a medical device, had not been validated in any peer-reviewed research, and did not have any documented involvement of medical professionals. The potential consequences of such applications operating incorrectly are stark and represent a risk to patient safety. Usage of multiple applications in a single patient encounter may compound error and safety of clinical care.

Exploring UK medical school differences: the MedDifs study of selection, teaching, student and F1 perceptions, postgraduate outcomes and fitness to practise.

BACKGROUND: Medical schools differ, particularly in their teaching, but it is unclear whether such differences matter, although influential claims are often made. The Medical School Differences (MedDifs) study brings together a wide range of measures of UK medical schools, including postgraduate performance, fitness to practise issues, specialty choice, preparedness, satisfaction, teaching styles, entry criteria and institutional factors. METHOD: Aggregated data were collected for 50 measures across 29 UK medical schools. Data include institutional history (e.g. rate of production of hospital and GP specialists in the past), curricular influences (e.g. PBL schools, spend per student, staff-student ratio), selection measures (e.g. entry grades), teaching and assessment (e.g. traditional vs PBL, specialty teaching, self-regulated learning), student satisfaction, Foundation selection scores, Foundation satisfaction, postgraduate examination performance and fitness to practise (postgraduate progression, GMC sanctions). Six specialties (General Practice, Psychiatry, Anaesthetics, Obstetrics and Gynaecology, Internal Medicine, Surgery) were examined in more detail. RESULTS: Medical school differences are stable across time (median alpha = 0.835). The 50 measures were highly correlated, 395 (32.2%) of 1225 correlations being significant with p < 0.05, and 201 (16.4%) reached a Tukey-adjusted criterion of p < 0.0025. Problem-based learning (PBL) schools differ on many measures, including lower performance on postgraduate assessments. While these are in part explained by lower entry grades, a surprising finding is that schools such as PBL schools which reported greater student satisfaction with feedback also showed lower performance at postgraduate examinations. More medical school teaching of psychiatry, surgery and anaesthetics did not result in more specialist trainees. Schools that taught more general practice did have more graduates entering GP training, but those graduates performed less well in MRCGP examinations, the negative correlation resulting from numbers of GP trainees and exam outcomes being affected both by non-traditional teaching and by greater historical production of GPs. Postgraduate exam outcomes were also higher in schools with more self-regulated learning, but lower in larger medical schools. A path model for 29 measures found a complex causal nexus, most measures causing or being caused by other measures. Postgraduate exam performance was influenced by earlier attainment, at entry to Foundation and entry to medical school (the so-called academic backbone), and by self-regulated learning. Foundation measures of satisfaction, including preparedness, had no subsequent influence on outcomes. Fitness to practise issues were more frequent in schools producing more male graduates and more GPs. CONCLUSIONS: Medical schools differ in large numbers of ways that are causally interconnected. Differences between schools in postgraduate examination performance, training problems and GMC sanctions have important implications for the quality of patient care and patient safety.

The Analysis of Teaching of Medical Schools (AToMS) survey: an analysis of 47,258 timetabled teaching events in 25 UK medical schools relating to timing, duration, teaching formats, teaching content, and problem-based learning.

BACKGROUND: What subjects UK medical schools teach, what ways they teach subjects, and how much they teach those subjects is unclear. Whether teaching differences matter is a separate, important question. This study provides a detailed picture of timetabled undergraduate teaching activity at 25 UK medical schools, particularly in relation to problem-based learning (PBL). METHOD: The Analysis of Teaching of Medical Schools (AToMS) survey used detailed timetables provided by 25 schools with standard 5-year courses. Timetabled teaching events were coded in terms of course year, duration, teaching format, and teaching content. Ten schools used PBL. Teaching times from timetables were validated against two other studies that had assessed GP teaching and lecture, seminar, and tutorial times. RESULTS: A total of 47,258 timetabled teaching events in the academic year 2014/2015 were analysed, including SSCs (student-selected components) and elective studies. A typical UK medical student receives 3960 timetabled hours of teaching during their 5-year course. There was a clear difference between the initial 2 years which mostly contained basic medical science content and the later 3 years which mostly consisted of clinical teaching, although some clinical teaching occurs in the first 2 years. Medical schools differed in duration, format, and content of teaching. Two main factors underlay most of the variation between schools, Traditional vs PBL teaching and Structured vs Unstructured teaching. A curriculum map comparing medical schools was constructed using those factors. PBL schools differed on a number of measures, having more PBL teaching time, fewer lectures, more GP teaching, less surgery, less formal teaching of basic science, and more sessions with unspecified content. DISCUSSION: UK medical schools differ in both format and content of teaching. PBL and non-PBL schools clearly differ, albeit with substantial variation within groups, and overlap in the middle. The important question of whether differences in teaching matter in terms of outcomes is analysed in a companion study (MedDifs) which examines how teaching differences relate to university infrastructure, entry requirements, student perceptions, and outcomes in Foundation Programme and postgraduate training.

Defining a national reference level for intraoperative radiation exposure in urological procedures: FLASH, a retrospective multicentre UK study.

OBJECTIVES: To define reference levels for intraoperative radiation during stent insertion, ureteroscopy (URS), and percutaneous nephrolithotomy (PCNL); to identify variation in radiation exposure between individual hospitals across the UK, between low- and high-volume PCNL centres, and between grade of lead surgeon. PATIENTS/SUBJECTS AND METHODS: In all, 3651 patients were identified retrospectively across 12 UK hospitals over a 1-year period. Radiation exposure was defined in terms of total fluoroscopy time (FT) and dose area product (DAP). The 75th percentiles of median values for each hospital were used to define reference levels for each procedure. RESULTS: Reference levels: ureteric stent insertion/replacement (DAP, 2.3 Gy/cm2 ; FT, 49 s); URS (DAP, 2.8 Gy/cm2 ; FT, 57 s); PCNL (DAP, 24.1 Gy/cm2 ; FT, 431 s). Significant variations in the median DAP and FT were identified between individual centres for all procedures (P < 0.001). For PCNL, there was a statistically significant difference between DAP for low- (<50 cases/annum) and high-volume centres (>50 cases/annum), at a median DAP of 15.0 Gy/cm2 vs 4.2 Gy/cm2 (P < 0.001). For stent procedures, the median DAP and FT differed significantly between grade of lead surgeon: Consultant (DAP, 2.17 Gy/cm2 ; FT, 41 s) vs Registrar (DAP, 1.38 Gy/cm2 ; FT, 26 s; P < 0.001). CONCLUSION: This multicentre study is the largest of its kind. It provides the first national reference level to guide fluoroscopy use in urological procedures, thereby adding a quantitative and objective value to complement the principles of keeping radiation exposure 'as low as reasonably achievable'. This snapshot of real-time data shows significant variation around the country, as well as significant differences between low- and high-volume centres for PCNL, and grade of lead surgeon for stent procedures.

Vitamin C measurement in critical illness: challenges, methodologies and quality improvements.

Background There is renewed interest in high-dose vitamin C interventions in clinical medicine due to its antioxidant properties, safe use and cost-effectiveness. Yet, randomised control trials (RCTs) employing these interventions are failing to include robust analytical methodology and proper sample handling and processing techniques. Consequently, comparisons between studies becomes impossible as there is no metrological traceability and results may be prone to pre-analytical errors. Content Through published vitamin C stability studies, method comparison papers and data from vitamin C external quality assurance programs, an assessment was made on the functionality of current methods for critically ill patient samples. Summary Data was obtained from two external quality assurance programs, two papers assessing sample stability and interlaboratory agreement and a publication on vitamin C method comparisons. A shift from spectrophotometric and enzymatic methodologies to high performance liquid chromatography (HPLC) greatly improved the variability and interlaboratory agreement. Therefore, the current analytical performance of vitamin C HPLC methodologies are acceptable for the requirements of a high-dose vitamin C RCTs. Outlook Recommendations across the total testing process of vitamin C have been provided to improve the quality of the results. The harmonisation of sample handling and processing procedures will further improve the reliability of current analytical methodologies.