Association between a genetic index for digital dermatitis resistance and the presence of digital dermatitis, heel horn erosion and interdigital hyperplasia in Holstein cows.

Digital dermatitis (DD) is a polybacterial disease endemic to most UK dairy farms. It poses a major financial and welfare threat and is characterized by high incidence and recurrence rates. We aimed to investigate the association between the UK estimated breeding value for resistance to digital dermatitis, the Digital Dermatitis Index (DDI) and the frequency of DD, heel horn erosion (HHE), and interdigital hyperplasia (IH) in a population of Holstein dairy cows. We enrolled and genotyped 2,352 cows from 4 farms in a prospective cohort study. Foot lesion records were recorded by veterinary surgeons for each animal at 4 time points during a production cycle, starting at approximately 2 mo before calving and ending in late lactation. Importantly, these records were not used in the calculation of the DDI. Lesion records were matched to the animal's own DDI (n = 2,101) and their sire's DDI (n = 1,812). Digital Dermatitis Index values in our study population ranged from -1.41 to +1.2 and were transformed to represent distance from the mean expressed in standard deviations. The relationship between the DDI and the presence of DD was investigated using a logistic regression model, with farm, parity, and a farm-parity interaction fitted as covariates. A multivariable logistic regression model was fitted to evaluate the relationship between HHE and DDI with farm fitted as a covariate. Finally, a univariable logistic regression model with DDI as explanatory variable was used to investigate the relationship between IH and DDI. The odds ratio of an animal being affected by DD was 0.69 for one standard deviation (SD) increase in the animal's DDI (95% confidence interval (CI) = 0.63-0.76). The odds of HHE and IH were 0.69 (95%CI = 0.62-0.76) and 0.58 (95%CI = 0.49-0.68) respectively for one SD increase in DDI. The adjusted probability of DD was 32% (95% CI = 27-36%) for cows with mean DDI value of 0 while it was 24% (95% CI = 20-29%) in cows with a DDI value of +1. Sire DDI breeding values were standardized in the same way and then binned into terciles creating an ordinal variable representing bulls of high, medium, and low genetic merit for DD resistance. The daughters of low genetic merit bulls were at 2.05 (95% CI = 1.60-2.64), 1.96 (95% CI = 1.53-2.50), and 2.85 (95% CI = 1.64-5.16) times greater odds of being affected by DD, HHE, and IH respectively compared with the daughters of high genetic merit bulls. The results of this study highlight the potential of digital dermatitis genetic indexes to aid herd management of DD, and suggest that breeding for resistance to DD, alongside environmental and management control practices, could reduce the prevalence of the disease.

Development and validation of a fully automated 2-dimensional imaging system generating body condition scores for dairy cows using machine learning.

Monitoring body condition score (BCS) is a useful management tool to estimate the energy reserves of an individual cow or a group of cows. The aim of this study was to develop and evaluate the performance of a fully automated 2-dimensional imaging system using a machine learning algorithm to generate real-time BCS for dairy cows. Two separate datasets were used for training and testing. The training dataset included 34,150 manual BCS (MAN_BCS) assigned by 5 experienced veterinarians during 35 visits at 7 dairy farms. Ordinal regression methods and deep learning architecture were used when developing the algorithm. Subsequently, the testing dataset was used to evaluate the developed BCS prediction algorithm on 4 of the participating farms. An experienced human assessor (HA1) visited these farms and performed 8 whole-milking-herd BCS sessions. Each farm was visited twice, allowing for 30 d (±2 d) to pass between visits. The MAN_BCS assigned by HA1 were considered the ground truth data. At the end of the validation study, MAN_BCS were merged with the stored automated BCS (AI_BCS), resulting in a testing dataset of 9,657 single BCS. A total of 3,817 cows in the testing dataset were scored twice 30 d (±2 d) apart, and the change in their BCS (ΔBCS) was calculated. A subset of cows at one farm were scored twice on consecutive days to evaluate the within-observer agreement of both the human assessor and the system. The manual BCS of 2 more assessors (HA2 and HA3) were used to assess the interobserver agreement between humans. Finally, we also collected ultrasound measurements of backfat thickness (BFT) from 111 randomly selected cows with available MAN_BCS and AI_BCS. Using the testing dataset, intra- and interobserver agreement for single BCS and ΔBCS were estimated by calculating the simple percentage agreement (PA) at 3 error levels and the weighted kappa (κw) for the exact agreement. A Bland-Altman plot was constructed to visualize the systematic and proportional bias. The association between MAN_BCS and AI_BCS and the BFT was assessed with Passing-Bablok regressions. The system had an almost perfect repeatability with a κw of 0.99. The agreement between MAN_BCS and AI_BCS was substantial, with an overall κw of 0.69. The overall PA at the exact, ± 0.25-unit, and ± 0.50-unit BCS error range between MAN_BCS and AI_BCS was 44.4%, 84.6%, and 94.8%, respectively, and greater than the PA obtained between HA1 and HA3. The Bland-Altman plot revealed a minimal systematic bias of -0.09 with a proportional bias at the extreme scores. Furthermore, despite the low κw of 0.20, the overall PA at the exact and ± 0.25-unit of BCS error range between MAN_BCS and AI_BCS regarding the ΔBCS was 45.7 and 88.2%, respectively. A strong linear relationship was observed between BFT and AI_BCS (ρ = 0.75), although weaker than that between BFT and MAN_BCS (ρ = 0.91). The system was able to predict single BCS and ΔBCS with satisfactory accuracy, comparable to that obtained between trained human scorers.

Specific pathway abundances in the neonatal calf faecal microbiome are associated with susceptibility to Cryptosporidium parvum infection: a metagenomic analysis.

BACKGROUND: Cryptosporidium parvum is the main cause of calf scour worldwide. With limited therapeutic options and research compared to other Apicomplexa, it is important to understand the parasites' biology and interactions with the host and microbiome in order to develop novel strategies against this infection. The age-dependent nature of symptomatic cryptosporidiosis suggests a link to the undeveloped immune response, the immature intestinal epithelium, and its associated microbiota. This led us to hypothesise that specific features of the early life microbiome could predict calf susceptibility to C. parvum infection. RESULTS: In this study, a single faecal swab sample was collected from each calf within the first week of life in a cohort of 346 animals. All 346 calves were subsequently monitored for clinical signs of cryptosporidiosis, and calves that developed diarrhoea were tested for Rotavirus, Coronavirus, E. coli F5 (K99) and C. parvum by lateral flow test (LFT). A retrospective case-control approach was taken whereby a subset of healthy calves (Control group; n = 33) and calves that went on to develop clinical signs of infectious diarrhoea and test positive for C. parvum infection via LFT (Cryptosporidium-positive group; n = 32) were selected from this cohort, five of which were excluded due to low DNA quality. A metagenomic analysis was conducted on the faecal microbiomes of the control group (n = 30) and the Cryptosporidium-positive group (n = 30) prior to infection, to determine features predictive of cryptosporidiosis. Taxonomic analysis showed no significant differences in alpha diversity, beta diversity, and taxa relative abundance between controls and Cryptosporidium-positive groups. Analysis of functional potential showed pathways related to isoprenoid precursor, haem and purine biosynthesis were significantly higher in abundance in calves that later tested positive for C. parvum (q ≤ 0.25). These pathways are either absent or streamlined in the C. parvum parasites. Though the de novo production of isoprenoid precursors, haem and purines are absent, C. parvum has been shown to encode enzymes that catalyse the downstream reactions of these pathway metabolites, indicating that C. parvum may scavenge those products from an external source. CONCLUSIONS: The host has previously been put forward as the source of essential metabolites, but our study suggests that C. parvum may also be able to harness specific metabolic pathways of the microbiota in order to survive and replicate. This finding is important as components of these microbial pathways could be exploited as potential therapeutic targets for the prevention or mitigation of cryptosporidiosis in bovine neonates.

The bovine foot skin microbiota is associated with host genotype and the development of infectious digital dermatitis lesions.

BACKGROUND: Bovine Digital Dermatitis (BDD) is a prevalent infectious disease, causing painful foot skin lesions and lameness in cattle. We describe herein the bovine foot skin microbiota and its associations with BDD using 16S rRNA gene amplicon and shotgun metagenomic sequencing on samples from 259 dairy cows from three UK dairy farms. RESULTS: We show evidence of dysbiosis, and differences in taxonomy and functional profiles in the bovine foot skin microbiome of clinically healthy animals that subsequently develop BDD lesions, compared to those that do not. Our results suggest that taxonomical and functional differences together with alterations in ecological interactions between bacteria in the normal foot skin microbiome may predispose an animal to develop BDD lesions. Using genome-wide association and regional heritability mapping approaches, we provide first evidence for interactions between host genotype and certain members of the foot skin microbiota. We show the existence of significant genetic variation in the relative abundance of Treponema spp. and Peptoclostridium spp. and identify regions in the bovine genome that explain a significant proportion of this variation. CONCLUSIONS: Collectively this work shows early changes in taxonomic and functional profiles of the bovine foot-skin microbiota in clinically healthy animals which are associated with subsequent development of BDD and could be relevant to prevention of disease. The description of host genetic control of members of the foot skin microbiota, combined with the association of the latter with BDD development offer new insights into a complex relationship that can be exploited in selective breeding programmes. Video Abstract.

The impact of multidisciplinary team decision-making in locally advanced and recurrent rectal cancer.

INTRODUCTION: Appropriate patient selection within the context of a multidisciplinary team (MDT) is key to good clinical outcomes. The current evidence base for factors that guide the decision-making process in locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LRRC) is limited to anatomical factors. METHODS: A registry-based, prospective cohort study was undertaken of patients referred to our specialist MDT between 2015 and 2019. Data were collected on patients and disease characteristics including performance status, Charlson Comorbidity Index, the English Index of Multiple Deprivation quintiles and MDT treatment decision. Curative treatment was defined as neoadjuvant treatment and surgical resection that would achieve a R0 resection, and/or complete treatment of distant metastatic disease. Palliative treatment was defined as non-surgical treatment. RESULTS: In total, 325 patients were identified; 72.7% of patients with LARC and 63.6% of patients with LRRC were offered treatment with curative intent (p = 0.08). Patients with poor performance status (PS > 2; p < 0.001), severe comorbidity (p < 0.001), socio-economic deprivation (p = 0.004), a positive predictive circumferential resection margin (p = 0.005) and metastatic disease (p < 0.001) were associated with palliative treatment. Overall survival in the curative cohort was 49 months (95% confidence interval [CI] 32.4-65.5) compared with 12 months (95% CI 9.1-14.9) in the palliative cohort (p < 0.001). The presence of metastatic disease was identified as a prognostic factor for patients undergoing curative treatment (p = 0.05). The only prognostic factor identified in patients treated palliatively was performance status (p < 0.001). CONCLUSIONS: Our study identifies a number of preoperative, prognostic factors that affect MDT decision-making and overall survival.

Preoperative assessment and optimisation for pelvic exenteration in locally advanced and recurrent rectal cancer: A review.

The pre-operative phase in planning a pelvic exenteration or extended resections is critical to optimising patient outcomes. This review summarises the key components of preoperative assessment and planning in patients with locally advanced rectal cancer (LARC) and locally recurrent rectal cancer (LLRC) being considered for potential curative resection. The preoperative period can be considered in 5 key phases: 1) Multidisciplinary meeting (MDT) review and recommendation for neoadjuvant therapy and surgery, 2) Anaesthetic preoperative assessment of fitness for surgery and quantification of risk, 3) Shared decision making with the patient and the process of informed consent, 4) Prehabilitation and physiological optimisation 5) Technical aspects of surgical planning. This review will focus on patients who have been recommended for surgery by the MDT and have completed neoadjuvant therapy. Other important considerations beyond the scope of this review are the various neoadjuvant strategies employed which in this patient group include Total Neo-adjuvant Therapy and reirradiation. Critical to improving perioperative outcomes is the dual aim of achieving a negative resection margin in a patient fit enough for extended surgery. Advanced, realistic communication is required pre-operatively and should be maintained throughout recovery. Optimising patient's physiological and psychological reserve with a preoperative prehabilitation programme is important, with physiotherapy, psychological and nutritional input. From a surgical perspective, image based technical preoperative planning is important to identify risk points and ensure correct surgical strategy. Careful attention to the entire patient journey through these 5 preoperative phases can optimise outcomes with the accumulation of marginal gains at multiple timepoints.

Emergency Laparotomy Follow-Up Study (ELFUS): prospective feasibility investigation into postoperative complications and quality of life using patient-reported outcome measures up to a year after emergency laparotomy.

BACKGROUND: Emergency laparotomy carries a significant risk profile around the time of surgery. This research aimed to establish the feasibility of recruitment to a study using validated scoring tools to assess complications after surgery; and patient-reported outcome measures (PROMs) to assess quality of life and quality of recovery up to a year following emergency laparotomy (EL). METHODS: We used our local National Emergency Laparotomy Audit (NELA) register to identify potential participants at a single NHS centre in England. Complications were assessed at 5, 10 and 30 days after EL. Patient-reported outcome measures were collected at 1, 3, 6 and 12 months after surgery using EQ5D and WHODAS 2.0 questionnaires. RESULTS: Seventy of 129 consecutive patients (54%) agreed to take part in the study. Post-operative morbidity survey data was recorded from 63 and 37 patients at postoperative day 5 and day 10. Accordion Complication Severity Grading data was obtained from 70 patients. Patient-reported outcome measures were obtained from patients at baseline and 1, 3, 6 and 12 months after surgery from 70, 59, 51, 48, to 42 patients (100%, 87%, 77%, 75% and 69% of survivors), respectively. CONCLUSIONS: This study affirms the feasibility of collecting PROMs and morbidity data successfully at various time points following emergency laparotomy, and is the first longitudinal study to describe quality of life up to a year after surgery. This finding is important in the design of a larger observational study into quality of life and recovery after EL.

A study on the use of thermal imaging as a diagnostic tool for the detection of digital dermatitis in dairy cattle.

Our aims were to (1) determine how interdigital skin temperature (IST), measured using infrared thermography, was associated with different stages of digital dermatitis (DD) lesions and (2) develop and validate models that can use IST measurements to identify cows with an active DD lesion. Between March 2019 and March 2020, infrared thermographic images of hind feet were taken from 2,334 Holstein cows across 4 farms. We recorded the maximum temperature reading from infrared thermographic images of the interdigital skin between the heel bulbs on the hind feet. Pregnant animals were enrolled approximately 1 to 2 mo precalving, reassessed 1 wk after calving, and again at approximately 50 to 100 d postpartum. At these time points, IST and the clinical stage of DD (M-stage scoring system: M1-M4.1) were recorded in addition to other data such as the ambient environmental temperature, height, body condition score, parity, and the presence of other foot lesions. A mixed effect linear regression model with IST as the dependent variable was fitted. Interdigital skin temperature was associated with DD lesions; compared to healthy feet, IST was highest in feet with M2 lesions, followed by M1 and M4.1 lesions. Subsequently, the capacity of IST measurements to detect the presence or absence of an active DD lesion (M1, M2, or M4.1) was explored by fitting logistic regression models, which were tested using 10-fold validation. A mixed effect logistic regression model with the presence of active DD as the dependent variable was fitted first. The average area under the curve for this model was 0.80 when its ability to detect presence of active DD was tested on 10% of the data that were not used for the model's training; an average sensitivity of 0.77 and an average specificity of 0.67 was achieved. This model was then restricted so that only explanatory variables that could be practically recorded in a nonresearch, external setting were included. Validation of this model demonstrated an average area under the curve of 0.78, a sensitivity of 0.88, and a specificity of 0.66 for 1 of the time points (precalving). Lower sensitivity and specificity were achieved for the other 2 time points. Our study adds further evidence to the relationship between DD and foot skin temperature using a large data set with multiple measurements per animal. Additionally, we highlight the potential for infrared thermography to be used for routine on-farm diagnosis of active DD lesions.

A systematic review of outcome reporting in incisional hernia surgery.

BACKGROUND: The incidence of incisional hernia is up to 20 per cent after abdominal surgery. The management of patients with incisional hernia can be complex with an array of techniques and meshes available. Ensuring consistency in reporting outcomes across studies on incisional hernia is important and will enable appropriate interpretation, comparison and data synthesis across a range of clinical and operative treatment strategies. METHODS: Literature searches were performed in MEDLINE and EMBASE (from 1 January 2010 to 31 December 2019) and the Cochrane Central Register of Controlled Trials. All studies documenting clinical and patient-reported outcomes for incisional hernia were included. RESULTS: In total, 1340 studies were screened, of which 92 were included, reporting outcomes on 12 292 patients undergoing incisional hernia repair. Eight broad-based outcome domains were identified, including patient and clinical demographics, hernia-related symptoms, hernia morphology, recurrent incisional hernia, operative variables, postoperative variables, follow-up and patient-reported outcomes. Clinical outcomes such as hernia recurrence rates were reported in 80 studies (87 per cent). A total of nine different definitions for detecting hernia recurrence were identified. Patient-reported outcomes were reported in 31 studies (34 per cent), with 18 different assessment measures used. CONCLUSIONS: This review demonstrates the significant heterogeneity in outcome reporting in incisional hernia studies, with significant variation in outcome assessment and definitions. This is coupled with significant under-reporting of patient-reported outcomes.

Evaluating the time interval from diagnosis to fibrinolysis at centres in the drainage area of Tygerberg Hospital, Cape Town, South Africa.

BACKGROUND: ST-segment elevation myocardial infarction (STEMI) is one of the main contributors to morbidity and mortality in South Africa (SA). Timeous intervention by means of percutaneous coronary intervention (PCI) or fibrinolysis can significantly improve the outcome of STEMI. OBJECTIVES: To determine the median time interval between diagnosis and fibrinolysis in patients presenting to centres within the drainage area of Tygerberg Hospital, Cape Town, SA, and compare it with the European Society of Cardiology (ESC) recommendation of 10 minutes. METHODS: A retrospective medical record review of patients presenting to the abovementioned centres between 1 March 2017 and 28 February 2018 was performed. The primary presenting centre, time between diagnosis and fibrinolysis and discharge medication were recorded, in addition to other relevant demographic information. RESULTS: A total of 492 patients were identified, of whom 447 were included in the study. Three hundred and eighteen patients received fibrinolysis, of whom 18 (5.7%) were treated within 10 minutes of diagnosis. The median time interval between diagnosis and fibrinolysis was 67 (interquartile range (IQR) 32.5 -122.5) minutes. CONCLUSIONS: Most patients received fibrinolysis >10 minutes after diagnosis, which indicates suboptimal therapy when compared with the ESC guidelines. Future studies should investigate the factors prolonging this therapeutic delay.

Laparoscopic versus open colorectal surgery in the acute setting (LaCeS trial): a multicentre randomized feasibility trial.

BACKGROUND: Approximately 30 000 people undergo major emergency abdominal gastrointestinal surgery annually, and 36 per cent of these procedures (around 10 800) are carried out for emergency colorectal pathology. Some 14 per cent of all patients requiring emergency surgery have a laparoscopic procedure. The aims of the LaCeS (laparoscopic versus open colorectal surgery in the acute setting) feasibility trial were to assess the feasibility, safety and acceptability of performing a large-scale definitive phase III RCT, with a comparison of emergency laparoscopic versus open surgery for acute colorectal pathology. METHODS: LaCeS was designed as a prospective, multicentre, single-blind, parallel-group, pragmatic feasibility RCT with an integrated qualitative study. Randomization was undertaken centrally, with patients randomized on a 1 : 1 basis between laparoscopic or open surgery. RESULTS: A total of 64 patients were recruited across five centres. The overall mean steady-state recruitment rate was 1·2 patients per month per site. Baseline compliance for clinical and health-related quality-of-life data was 99·8 and 93·8 per cent respectively. The conversion rate from laparoscopic to open surgery was 39 (95 per cent c.i. 23 to 58) per cent. The 30-day postoperative complication rate was 27 (13 to 46) per cent in the laparoscopic arm and 42 (25 to 61) per cent in the open arm. CONCLUSION: Laparoscopic emergency colorectal surgery may have an acceptable safety profile. Registration number: ISRCTN15681041 ( http://www.controlled-trials.com).

ANTECEDENTES: Aproximadamente 30.000 personas se someten cada año una operación de cirugía mayor urgente gastrointestinal de las cuales el 36% (~ 10.800) se realizan por patología colorrectal urgente. Aproximadamente el 14% de todos los pacientes que requieren cirugía urgente son operados mediante abordaje laparoscópico. Los objetivos del ensayo de factibilidad LaCeS (Laparoscopic versus Open Colorectal Surgery in the Acute Setting; Cirugía Colorrectal Laparoscópica versus Abierta en Urgencias) fueron evaluar la factibilidad, seguridad y aceptabilidad de realizar un ensayo clínico aleatorizado definitivo a gran escala de fase III comparando la cirugía colorrectal urgente por vía laparoscópica con el abordaje abierto. MÉTODOS: LaCeS se diseñó como un ensayo clínico prospectivo, multicéntrico, simple ciego, de grupos paralelos, pragmático, aleatorizado (factibilidad) con un estudio cualitativo integrado. La asignación al azar se realizó de forma centralizada y los pacientes se asignaron al azar en proporción 1:1 a cirugía laparoscópica o abierta. RESULTADOS: Un total de 64 pacientes fueron reclutados en 5 centros. La tasa media global estable de reclutamiento fue de 1,2 pacientes/mes. El cumplimiento inicial de los datos clínicos y de calidad de vida (HRQoL) fue del 99,8% y del 93,8%, respectivamente. La tasa de conversión de la cirugía laparoscópica a cirugía abierta fue del 39,4% (i.c. del 95%: 22,9% a 57,9%). La tasa de complicaciones postoperatorias a los 30 días fue del 27,3% (i.c. del 95%: 13,3-45,5) para la cirugía laparoscópica y del 41,9% (i.c. del 95%: 24,6-60,9) para la cirugía abierta. CONCLUSIÓN: La cirugía colorrectal urgente por vía laparoscópica puede tener un perfil de seguridad aceptable.

A multicentre, prospective, observational cohort study of variation in practice in perioperative analgesia strategies in elective laparoscopic colorectal surgery (the LapCoGesic study).

INTRODUCTION: Enhanced recovery programmes are established as an essential part of laparoscopic colorectal surgery. Optimal pain management is central to the success of an enhanced recovery programme and is acknowledged to be an important patient reported outcome measure. A variety of analgesia strategies are employed in elective laparoscopic colorectal surgery ranging from patient-controlled analgesia to local anaesthetic wound infiltration catheters. However, there is little evidence regarding the optimal analgesia strategy in this cohort of patients. The LapCoGesic study aimed to explore differences in analgesia strategies employed for patients undergoing elective laparoscopic colorectal surgery and to assess whether this variation in practice has an impact on patient-reported and clinical outcomes. MATERIALS AND METHODS: A prospective, multicentre, observational cohort study of consecutive patients undergoing elective laparoscopic colorectal resection was undertaken over a two-month period. The primary outcome measure was postoperative pain scores at 24 hours. Data analysis was conducted using SPSS version 22. RESULTS: A total of 103 patients undergoing elective laparoscopic colorectal surgery were included in the study. Thoracic epidural was used in 4 (3.9%) patients, spinal diamorphine in 56 (54.4%) patients and patient-controlled analgesia in 77 (74.8%) patients. The use of thoracic epidural and spinal diamorphine were associated with lower pain scores on day 1 postoperatively (P < 0.05). The use of patient-controlled analgesia was associated with significantly higher postoperative pain scores and pain severity. DISCUSSION: Postoperative pain is managed in a variable manner in patients undergoing elective colorectal surgery, which has an impact on patient reported outcomes of pain scores and pain severity.

16S rRNA amplicon sequencing reveals a polymicrobial nature of complicated claw horn disruption lesions and interdigital phlegmon in dairy cattle.

Lameness represents an intractable problem for the dairy industry. Complicated claw horn disruption lesions, interdigital hyperplasia, and interdigital phlegmon are important lameness causing foot lesions. Their aetiology is multifactorial, but infectious processes are likely implicated in disease pathogenesis. Our aim was to investigate the bacterial profiles of these lesions using 16S rRNA gene sequencing of samples obtained from 51 cattle across ten farms in the UK. In this study, interdigital hyperplasia, interdigital hyperplasia with signs of interdigital dermatitis, interdigital phlegmon, complicated sole ulcers, complicated toe ulcers lesions, and complicated white line lesions were investigated; corresponding healthy skin control samples were also analysed. All diseased tissues displayed reduced microbial richness and diversity (as described by Chao1, Shannon, and Simpson alpha-diversity indices) compared to their healthy skin control samples. Our results confirm the association of Treponema spp with some of these disorders. Other anaerobic bacteria including Fusobacterium spp., Fastidiosipila spp. and Porphyromonas spp. were implicated in the aetiology of all these lesions with the exception of interdigital hyperplasia. Complicated claw horn disruption lesions, and interdigital phlegmon were found to have similar bacterial profiles. Such sharing of bacterial genera suggests many of the infectious agents detected in these foot lesions are acting opportunistically; this finding could contribute towards future treatment and control strategies.

Social media use in German visceral surgeons: a cross-sectional study of a national cohort.

AIM: Engagement in social media is increasing. Medical professionals have been adapting LinkedIn, a professional networking site, and Twitter, a microblogging service, for a number of uses. This development has been described for a number of medical specialties, but there remains a paucity of European data. A study was undertaken to measure the engagement and activity of German visceral surgeons on social media platforms. METHOD: Visceral surgeons were identified from 15 regional Associations of Statutory Health Insurance Physicians (Kassenärztliche Vereinigungen) opt-in registers. A manual search was subsequently performed across key professional social media platforms. The presence of a profile and key markers of use were recorded. RESULTS: In total, 575 visceral surgeons were identified. 523 (93%) were men. 183 (31%) surgeons engaged in professional social media. 22 (3.8%) used Twitter, producing a mean of 16.43 tweets with a mean of 7.57 followers. 137 (24%) surgeons had a profile on LinkedIn with a mean of 46.36 connections. Female surgeons were less connected on LinkedIn (P < 0.005). 60 (10%) used Xing, with a mean of 27.95 connections. There were no significant differences in use of social media between surgeons from Eastern and Western Germany (P = 0.262) or male and female surgeons (P = 0.399). CONCLUSIONS: German visceral surgeons are less engaged and less active on social media than previously examined cohorts. Loco-regional, cultural, demographic and regulatory matters may have a significant influence on uptake. If this surgical cohort wishes to have a wider international presence then education on the potential benefits of these tools may be needed.

Final results of a European, multicentre, prospective, observational study of Permacol™ collagen paste injection for the treatment of anal fistula.

AIM: Permacol™ collagen paste (Permacol™ paste) is an acellular cross-linked porcine dermal collagen matrix suspension for use in soft-tissue repair. The use of Permacol™ paste in the filling of anorectal fistula tract is a new sphincter-preserving method for fistula repair. The MASERATI100 study was a prospective, observational clinical study with the objective to assess the efficacy of Permacol™ collagen paste for anal fistula repair in 100 patients. METHOD: Patients (n = 100) with anal fistula were treated, at 10 European surgical sites, with a sphincter-preserving technique using Permacol™ paste. Fistula healing was assessed at 1, 3, 6 and 12 months post-treatment, with the primary end-point being healing at 6 months. Faecal continence and patient satisfaction were surveyed at each follow-up; adverse events (AEs) were monitored throughout the follow-up. RESULTS: At 6 months postsurgery, 56.7% of patients were healed and the percentage healed was largely maintained, with 53.5% healed at 12 months. Regarding AEs, 29.0% of patients had at least one AE, and 16.0% of patients had one or more procedure-related AE. Most AEs reported were minor and similar to those commonly observed after fistula treatment, and the incidence of serious adverse events was low (4.0% of patients). Regardless of treatment outcome, 73.0% of patients were satisfied or very satisfied with the procedure. CONCLUSION: Permacol™ paste is a promising sphincter-preserving treatment for anal fistulae and has minimal adverse side-effects.

Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines.

Tricyclic indolines are common in both natural products and synthetic chemical probes. In this study we demonstrated that enantiomerically pure tricyclic indolines can be prepared from an inexpensive commercially available chiral starting material, pyroglutamic acid. The synthesis features a highly diastereoselective gold-catalyzed cyclization of alkyne-tethered indoles and subsequent diastereoselective reductive ring-opening reaction. Using this approach, we synthesized analogs of our previously discovered tricyclic indoline probes that possess antibacterial and resistance-modifying activity. The biological activity against methicillin-resistant Staphylococcus aureus (MRSA) of these analogues was evaluated and reported. The synthetic approach reported may be leveraged in the future to prepare diastereopure chemical probes for the determination of biological targets for drug discovery.

6-Phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 is essential for p53-null cancer cells.

The bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-4 (PFKFB4) controls metabolic flux through allosteric regulation of glycolysis. Here we show that p53 regulates the expression of PFKFB4 and that p53-deficient cancer cells are highly dependent on the function of this enzyme. We found that p53 downregulates PFKFB4 expression by binding to its promoter and mediating transcriptional repression via histone deacetylases. Depletion of PFKFB4 from p53-deficient cancer cells increased levels of the allosteric regulator fructose-2,6-bisphosphate, leading to increased glycolytic activity but decreased routing of metabolites through the oxidative arm of the pentose-phosphate pathway. PFKFB4 was also required to support the synthesis and regeneration of nicotinamide adenine dinucleotide phosphate (NADPH) in p53-deficient cancer cells. Moreover, depletion of PFKFB4-attenuated cellular biosynthetic activity and resulted in the accumulation of reactive oxygen species and cell death in the absence of p53. Finally, silencing of PFKFB4-induced apoptosis in p53-deficient cancer cells in vivo and interfered with tumour growth. These results demonstrate that PFKFB4 is essential to support anabolic metabolism in p53-deficient cancer cells and suggest that inhibition of PFKFB4 could be an effective strategy for cancer treatment.

Systematic review of health-related quality of life in patients undergoing pelvic exenteration.

BACKGROUND: Pelvic exenteration is a radical operative treatment reserved for the management of a number of advanced primary and recurrent pelvic malignancies, including, rectal, gynaecological and urological. The advances in radiological staging, surgical techniques and greater use of chemotherapeutic agents haves translated clinically into improvements in the overall survival of this cohort of patients, irrespective of underlying disease pathology. Consequently, a greater proportion of the surviving population will present to healthcare professionals with a range of physical and psychological issues, therefore the profiling and understanding of the health-related quality of life (HrQoL) is integral to the long term management of this cohort of patients. The aim of this systematic review is to identify HrQoL themes from the current literature relevant to patients undergoing a pelvic exenteration. METHODS: Literature searches were performed in three databases: MEDLINE (1975-November 2015), EMBASE and CINAHL. Each study was evaluated with regards to its design and statistical methodology. Data quality was reviewed in accordance with the Newcastle-Ottowa score and Critical Appraisal Skills Programme Checklist (CAPS) for quantitative and qualitative data accordingly. A narrative synthesis of all identified HrQoL issues was undertaken using the principles of content analysis. RESULTS: A total of 24 studies were identified; 20 quantitative and 4 qualitative with 976 patients assessed in total. HrQoL was assessed as the main primary endpoint in 15 studies. The majority of studies were retrospective. Baseline data prior to the initiation of treatments were available in 6 studies alone. Nine themes were identified across the literature, which included body image, social impact, sexual function, treatment expectations, symptoms, communication, psychological impact, relationships and work and finance. CONCLUSIONS: Pelvic exenteration has a wide ranging impact on patients HrQoL affecting a range of physical and psychological domains.

A prospective multicentre observational study of Permacol collagen paste for anorectal fistula: preliminary results.

AIM: Permacol collagen paste (Permacol paste) is a new option for the treatment of anorectal fistula. It functions by filling the fistula tract with an acellular crosslinked porcine dermal collagen matrix suspension. The MASERATI 100 study group was set up to evaluate the clinical outcome of Permacol paste in the treatment of anorectal fistula. This paper reports the results from the initial 30 patients enrolled in the MASERATI 100 prospective, observational clinical trial. METHOD: Patients (N = 30) with anal fistula presenting to 10 European academic surgical units were treated with a sphincter-preserving technique using Permacol paste. Fistula healing was assessed at 1, 3, 6 and 12 months after treatment, with the primary end-point of fistula healing at 6 months post-surgery. Faecal continence and patient satisfaction were recorded at each follow-up visit and adverse events were monitored throughout the follow-up. RESULTS: Of the 28 patients with data at 6 months post-surgery, 15 (54%) were healed, and the healing rate was maintained at 12 months. Healing after treatment with Permacol paste was similar for intersphincteric to transsphincteric fistulae and primary or recurrent fistulae. Only one patient exhibited an adverse event (perianal abscess) that was possibly related to the treatment. At the last outpatient visit, over 60% of patients were satisfied or very satisfied with the operation. CONCLUSION: Permacol paste is shown to be effective in treating primary and recurrent cryptoglandular anorectal fistula with minimal unwanted side effects.