A single centre 20-year retrospective cohort study: Percutaneous endoscopic colostomy.

AIM: Percutaneous endoscopic colostomy (PEC) represents an important intervention in specific patients. Limited data currently exist. We present the largest recorded study of patients undergoing PEC. METHODS: Retrospective analysis of consultant logbooks highlighted all patients from 1997 to 2020. Two independent reviewers assessed records. Parameters measured were age, sex, indication, number of sites, complications, mortality and survival. Three subgroups were identified: recurrent sigmoid volvulus (RSV), pseudo-obstruction and neurogenic. ANOVA, chi-squared and Fischer's exact tests were utilized; Kaplan-Meier curves estimated survival and the log-rank test was applied. A p value of <0.05 was considered statistically significant. RESULTS: Ninety-six PEC insertions were done on 91 patients (five reinsertions). There were 66 men (69%) and the mean age was 73.1 years (interquartile range 23). The indications were RSV n = 72, pseudo-obstruction n = 13, neurogenic n = 11. The 30-day complication rate was overall n = 27 (28%), RSV n = 23, pseudo-obstruction n = 4. Nine patients leaked (9.9%) (eight RSV, one pseudo-obstruction), of whom five died. 90-day mortality was 14.6% (14 patients), 18.5% (13/72) for RSV, 7.7% (1/13) for pseudo-obstruction. Overall recurrence following PEC was 10.4%. The median follow-up was 25 months (interquartile range 4.6-62.2 months). At 3, 5 and 10 years survival was 46%, 34% and 26% for RSV, 70%, 55% and 15% for pseudo-obstruction and 91%, 91% and 81% for neurogenic respectively. CONCLUSION: Recurrent sigmoid volvulus and pseudo-obstruction patients undergoing PEC compared to neurogenic patients have poorer outcomes with higher complication rates and shorter life expectancy. We advocate that high volume specialist units undertake PEC. The significant associated risks of PEC require careful consideration when determining patient suitability. Utilizing risk stratification scores may help guide shared decision making between patients, relatives and clinicians.

The landscape complexity relevance to farming effect assessment on small mammal occupancy in Argentinian farmlands.

The responses of organisms to organic farming depend on the taxonomic group and landscape complexity. Following the intermediate landscape complexity hypothesis, organic farming can compensate for the lack of complexity in simple landscapes. Argentinian farmlands are simple with large fields and scarce linear habitat array, and conventional agriculture is almost the only agriculture practice. We hypothesize that there is an interaction effect of landscape complexity and farming practices on occupancy and species richness of small mammals in farmland of central Argentina. We selected circular landscapes under organic farming and low- and high-intensity conventional farming and quantified heterogeneity in each landscape considering different cover types (crops, resting plots, fallow land, border habitats, grasslands and man-made structures). We used multi-species occupancy models accounting for multiple seasons with a Bayesian approach to make the estimates. Landscapes under organic farms had the highest level of landscape heterogeneity. In simple Argentinian farmlands, organic farming benefited species richness and occupancy of all small mammal species. Some management strategies used in organic farming (wide and vegetated border habitats, diversity in types of production, winter cover crops, natural or semi-natural patches) should be taken into account to increase landscape complexity in conventional farming.

Hepatocellular carcinoma in the adult Fontan patient.

In this study, we describe the case of a 36-year-old woman who was diagnosed with hepatocellular carcinoma on a background of Fontan procedure for tricuspid atresia. She had worsening heart failure in the months before presentation, and early investigations noted derangement in liver enzymes and hepatomegaly. Liver biopsy confirmed a hepatocellular carcinoma. Hepatocellular carcinoma is a rare but recognised consequence of cardiac cirrhosis in Fontan patients.

Slowed Diffusion and Excluded Volume Both Contribute to the Effects of Macromolecular Crowding on Alcohol Dehydrogenase Steady-State Kinetics.

To understand the consequences of macromolecular crowding, studies have largely employed in vitro experiments with synthetic polymers assumed to be both pure and "inert". These polymers alter enzyme kinetics by excluding volume that would otherwise be available to the enzymes, substrates, and products. Presented here is evidence that other factors, in addition to excluded volume, must be considered in the interpretation of crowding studies with synthetic polymers. Dextran has a weaker effect on the Michaelis-Menten kinetic parameters of yeast alcohol dehydrogenase (YADH) than its small molecule counterpart, glucose. For glucose, the decreased Vmax values directly correlate with slower translational diffusion and the decreased Km values likely result from enhanced substrate binding due to YADH stabilization. Because dextran is unable to stabilize YADH to the same extent as glucose, this polymer's ability to decrease Km is potentially due to the nonideality of the solution, a crowding-induced conformational change, or both. Chronoamperometry reveals that glucose and dextran have surprisingly similar ferricyanide diffusion coefficients. Thus, the reduction in Vmax values for glucose is partially offset by an additional macromolecular crowding effect with dextran. Finally, this is the first report that supplier-dependent impurities in dextran affect the kinetic parameters of YADH. Taken together, our results reveal that caution should be used when interpreting results obtained with inert synthetic polymeric agents, as additional effects from the underlying monomer need to be considered.

Fluorinated N,N'-diarylureas as AMPK activators.

Adenosine monophosphate-activated kinase (AMPK) plays a central role in regulating energy homeostasis in eukaryotic cells. AMPK also regulates lipid synthesis by inhibiting acetyl-CoA carboxylase (ACC) and regulates mTOR signaling by activating TSC2. Due to its important roles in cell metabolism, AMPK is an attractive target for metabolic diseases, such as type II diabetes and obesity. AMPK activators, such as metformin, that are used for diabetes treatment are also effective anticancer agents. However, the efficacies of many known AMPK activators are relatively low. For example, metformin activates AMPK at millimolar levels. In this study, we identified a novel family of AMPK activators, namely fluorinated N,N'-diarylureas, that activate AMPK at 1-3µM concentrations. These novel agents strongly inhibit the proliferation of colon cancer cells. We studied the potential mechanisms of these agents, performed a structure-activity relationship (SAR) study and identified several fluorinated N,N'-diarylureas as potent AMPK activators.

Neoadjuvant immune checkpoint inhibitor therapy in resectable non-small cell lung cancer.

Only a minority of lung cancers are resectable at diagnosis, and many of these will eventually relapse. Adjuvant chemotherapy in this setting has a modest survival advantage, and there is significant need for new approaches to improve cure rates. Checkpoint inhibitor immunotherapy has transformed the prognosis for advanced lung cancer, and is increasingly being used in the neoadjuvant setting alone, or in combination with cytotoxic chemotherapy. While this has demonstrated convincing improvements in event-free survival and pathologic response, questions remain over optimal duration of therapy, predictive and prognostic biomarkers, response assessment and combination with other modalities. In addition, these results must be considered in the context of recent positive studies of adjuvant immunotherapy. Here, we summarise preclinical context and clinical trials in this space, discuss areas of controversy and pitfalls, and consider future challenges.

Amyand's Hernia: A Radiological Solution of a Surgical Dilemma.

Amyand's hernia is a rare condition whereby the appendix lies within the sac of an inguinal hernia; rarer still, the appendix can become inflamed (acute appendicitis) and is frequently misdiagnosed as a strangulated inguinal hernia. We report a case of Amyand's hernia complicated with acute appendicitis. In this case an accurate preoperative diagnosis was provided by a preoperative Computerised Tomography (CT) scan, permitting planning of treatment by a laparoscopic approach.

Targeting KRAS in Pancreatic Cancer.

Pancreatic cancer is mainly driven by mutations in the KRAS oncogene. While this cancer has shown remarkable therapy resistance, new approaches to inhibit mutated KRAS, KRAS activators and effectors show promise in breaking this therapeutic deadlock. Here, we review these innovations in therapies that target RAS signaling in pancreatic cancer from a clinical point of view. A number of promising approaches are currently in clinical trials or in clinical development. We focus on small-molecule drugs but also discuss immunotherapies and tumor vaccines.

Pemphigoid gestationis: a case report and review of the literature.

Pemphigoid gestationis (PG) is an uncommon autoimmune bullous disease that almost exclusively presents during pregnancy. Patients typically present with a diffuse blistering and intensely pruritic eruption that begins periumbilically and spreads to involve the rest of the body. Direct immunofluorescence demonstrating C3 in a linear pattern along the dermoepidermal junction confirms the diagnosis of PG. Corticosteroids remain the choice of therapy and early intervention is essential because of possible adverse effects of PG on the fetus. We report a case of PG and review the literature.

Systematic review of Meckel's diverticulum in pregnancy.

INTRODUCTION: Meckel's diverticulum (MD) is the most common congenital malformation in the gastrointestinal tract. Limited up-to-date evidence is available regarding MD in pregnancy. We aim to review the available pertinent literature to help support clinical decision making and patient management in the future. MATERIALS AND METHODS: The search term 'Meckel's diverticulum' was combined with 'pregnant' or 'pregnancy'. Database searches of EMBASE, Medline and PubMed were conducted. All papers published in English from 01/01/1990 to 01/01/2021 were included. Simple statistical analysis (t-test) was performed. RESULTS: Twenty-seven cases were included. Average age = 26.9 years. Average gestation = 25.1 weeks. Occurrence: first trimester = 3.7%; second trimester = 48.1% and third trimester = 48.1%. Presenting symptoms: abdominal pain 88.9%; nausea/vomiting 59.3%; fever 18.5%; abdominal distension 18.5%; haematochezia 11.1%; constipation 11.1%; haematemesis 3.7%, diarrhoea 3.7% and asymptomatic 3.7%. Mean duration of preceding symptoms = 3.4 days. Diagnostic imaging modalities utilised: ultrasound = 40.7%; CT = 25.9%; MRI = 14.8%; abdominal X-ray = 11.1% and endoscopy = 7.4%. All cases required definite surgical management: laparotomy = 65.4%; laparoscopy = 15.4%; C-section = 19.2% and unreported = 3.8%. Main intra-operative findings: perforated MD = 40.7%; intussusception with MD as a lead point = 11.1%; bleeding MD = 11.1%, inflamed MD = 11.1%; small bowel obstruction = 11.1%; gangrenous MD = 3.7%; volvulus = 3.7% and unspecified = 7.4%. Mean length from ileocolic junction = 51.7 cm. Average length of stay was 7.1 days. T-test (p-value = 0.12) when comparing management strategy. Three maternal complications and two foetal mortalities. CONCLUSION: MD and associated pathology are difficult to diagnose in the pregnant cohort. Current imaging demonstrates low diagnostic accuracy and a deviation away from recognised nuclear medicine investigations. Surgery appears the definitive management with both open and laparoscopic approaches utilised. Significant maternal morbidity and foetal mortality are associated with this condition.

Emerging RAS-directed therapies for cancer.

RAS oncogenes are the most commonly mutated oncogenes in human cancer, and RAS-mutant cancers represent a major burden of human disease. Though these oncogenes were discovered decades ago, recent years have seen major advances in understanding of their structure and function, including the therapeutic and prognostic significance of diverse isoforms. Targeting of these mutations has proven difficult, despite some successes with inhibition of RAS effector signalling. More recently, direct RAS inhibition has been achieved in a trial setting. While this has yet to be translated to everyday clinical practice, this development carries much promise. This review summarizes the diverse approaches that have been taken to RAS inhibition and then focuses on the most recent developments in direct inhibition of KRAS(G12C).

Risk prediction score and appendicectomy in the elderly: a single centre 5-year retrospective cohort study.

BACKGROUND: Appendicitis is a common surgical emergency that can be a challenging entity to manage. In the elderly, it is associated with significant morbidity and mortality. Risk prediction is not routinely performed prior to surgery. METHODS: All patients aged >65 years undergoing appendicectomy over 5 years from one NHS Trust were included. Age, American Society of Anesthesiologists physical status classification system (ASA grade), Rockwood score, type of surgery, length of stay, morbidity and 90-day mortality were recorded. ACS NSQIP was retrospectively calculated. Spearman's Rank correlation coefficient and linear regression analysis were conducted, assessing correlation between ASA, Age, Rockwood Score and ACS NSQIP with length of stay and post-operative complications. RESULTS: A total of 225 patient cases were reviewed. A complication rate of 29.3% was recorded, with a 6.7% serious complication rate. Two mortalities occurred. ASA, Age, Rockwood and NSQIP scoring systems all showed low degree positive correlation with length of stay (+0.16-+0.34). As predictors of length of stay, ASA was superior. Rockwood and age showed low degree positive correlation (+0.25-+0.33) with post-operative complications. NSQIP and ASA demonstrated a greater degree of correlation (+0.38-+0.40). CONCLUSION: Both ASA and ACS NSQIP appear superior indicators for outcomes compared to age and Rockwood score. However, caution is warranted when interpreting the superiority of ASA over validated risk stratification tools. Therefore, we advocate the use of pre-operative risk stratification for elderly patients undergoing low-risk surgery such as appendicectomy. Validated tools are not routinely applied in many centres currently. Utilisation of scores such as ACS NSQIP may help improve consent, patient selection, outcomes and expectations.

TGFß drives NK cell metabolic dysfunction in human metastatic breast cancer.

BACKGROUND: Natural killer (NK) cells provide important immune protection from cancer and are a key requirement for particular immunotherapies. There is accumulating evidence that NK cells become dysfunctional during cancer. Overcoming NK cell exhaustion would be an important step to allow them to function optimally in a range of NK cell therapies, including those that depend on autologos circulating NK cells. We have previously demonstrated that NK cells undergo a normal metabolic reprogramming in response to cytokine activation and that this is required for optimal function. The objective of this work was to investigate if cellular metabolism of circulating NK cells is dysregulated in patients with metastatic breast cancer and if so, to gain insights into potential mechanisms underpinning this. Such discoveries would provide important insights into how to unleash the full activity of NK cells for maximum immunotherapy output. METHODS: Single-cell analysis, metabolic flux and confocal analysis of NK cells from patients with metastatic breast cancer and healthy controls RESULTS: In addition to reduced interferon-γ production and cytotoxicity, peripheral blood NK cells from patients had clear metabolic deficits including reduced glycolysis and oxidative phosphorylation. There were also distinct morphologically alterations in the mitochondria with increased mitochondrial fragmentation observed. Transforminggrowth factor-ß (TGFß) was identified as a key driver of this phenotype as blocking its activity reversed many metabolic and functional readouts. Expression of glycoprotein-A repetitions predominant (GARP) and latency associated peptide (LAP), which are involved with a novel TGFß processing pathway, was increased on NK cells from some patients. Blocking the GARP-TGFß axis recapitulated the effects of TGFß neutralization, highlighting GARP as a novel NK cell immunotherapy target for the first time. CONCLUSIONS: TGFß contributes to metabolic dysfunction of circulating NK cells in patients with metastatic breast cancer. Blocking TGFß and/or GARP can restore NK cell metabolism and function and is an important target for improving NK cell-based immunotherapies.

Increase in blood-brain barrier permeability, oxidative stress, and activated microglia in a rat model of blast-induced traumatic brain injury.

Traumatic brain injury (TBI) as a consequence of exposure to blast is increasingly prevalent in military populations, with the underlying pathophysiological mechanisms mostly unknown. In the present study, we utilized an air-driven shock tube to investigate the effects of blast exposure (120 kPa) on rat brains. Immediately following exposure to blast, neurological function was reduced. BBB permeability was measured using IgG antibody and evaluating its immunoreactivity in the brain. At 3 and 24 hr postexposure, there was a transient significant increase in IgG staining in the cortex. At 3 days postexposure, IgG immunoreactivity returned to control levels. Quantitative immunostaining was employed to determine the temporal course of brain oxidative stress following exposure to blast. Levels of 4-hydroxynonenal (4-HNE) and 3-nitrotyrosine (3-NT) were significantly increased at 3 hr postexposure and returned to control levels at 24 hr postexposure. The response of microglia to blast exposure was determined by autoradiographic localization of (3) H-PK11195 binding. At 5 days postexposure, increased binding was observed in the contralateral and ipsilateral dentate gyrus. These regions also displayed increased binding at 10 days postexposure; in addition to these regions there was increased binding in the contralateral ventral hippocampus and substantia nigra at this time point. By using antibodies against CD11b/c, microglia morphology characteristic of activated microglia was observed in the hippocampus and substantia nigra of animals exposed to blast. These results indicate that BBB breakdown, oxidative stress, and microglia activation likely play a role in the neuropathology associated with TBI as a result of blast exposure.

Challenging removal of a knotted nasogastric tube following insertion under general anaesthetic.

A 74-year-old man presented with acute small bowel obstruction secondary to recurrence of a caecal tumour. The patient underwent laparotomy and formation of loop ileostomy and had a nasogastric tube (NGT) inserted in the theatre. A decision was made to remove the patient's NGT postoperatively, which was found to be stuck. High-quality imaging demonstrated a knot in the tube within the nasopharynx; so, subsequent removal via the oral route necessitated sedation. This case highlights the importance of considering rare or unusual complications of NGT insertion when a patient describes more pain or discomfort than would otherwise be expected. The clarity of imaging highlights clearly the underlying findings when compared with the few other documented cases. We offer a number of learning points specific to this complication.

Patient characteristics associated with a poor response to non-surgical multidisciplinary management of knee osteoarthritis: a multisite prospective longitudinal study in an advanced practice physiotherapist-led tertiary service.

OBJECTIVES: To explore patient characteristics recorded at the initial consultation associated with a poor response to non-surgical multidisciplinary management of knee osteoarthritis (KOA) in tertiary care. DESIGN: Prospective multisite longitudinal study. SETTING: Advanced practice physiotherapist-led multidisciplinary orthopaedic service within eight tertiary hospitals. PARTICIPANTS: 238 patients with KOA. PRIMARY AND SECONDARY OUTCOME MEASURES: Standardised measures were recorded in all patients prior to them receiving non-surgical multidisciplinary management in a tertiary hospital service across multiple sites. These measures were examined for their relationship with a poor response to management 6 months after the initial consultation using a 15-point Global Rating of Change measure (poor response (scores -7 to +1)/positive response (scores+2 to+7)). Generalised linear models with binomial family and logit link were used to examine which patient characteristics yielded the strongest relationship with a poor response to management as estimated by the OR (95% CI). RESULTS: Overall, 114 out of 238 (47.9%) participants recorded a poor response. The odds of a poor response decreased with higher patient expectations of benefit (OR 0.74 (0.63 to 0.87) per 1/10 point score increase) and higher self-reported knee function (OR 0.67 (0.51 to 0.89) per 10/100 point score increase) (p<0.01). The odds of a poor response increased with a greater degree of varus frontal knee alignment (OR 1.35 (1.03 to 1.78) per 5° increase in varus angle) and a severe (compared with mild) radiological rating of medial compartment degenerative change (OR 3.11 (1.04 to 9.3)) (p<0.05). CONCLUSIONS: These characteristics may need to be considered in patients presenting for non-surgical multidisciplinary management of KOA in tertiary care. Measurement of these patient characteristics may potentially better inform patient-centred management and flag the need for judicious monitoring of outcome for some patients to avoid unproductive care.

Mortality and long-term dialysis requirement among elderly continuous renal replacement therapy patients in a tertiary referral intensive care unit.

BACKGROUND: Elderly patients are frequently considered poor candidates for continuous renal replacement therapy in intensive care units, but with little evidence base. METHODS: We gathered data regarding patients requiring continuous renal replacement therapy at our institution's intensive care unit during 2012-2014, and compared outcomes between patients of 75 years or older, and younger patients. RESULTS: Older patients had similar intensive care unit mortality to younger patients (41.5% vs. 36.1%, p = 0.21), but higher hospital mortality (54.2% vs. 44.0%, p = 0.02), and one-year mortality (63.6% vs. 50.6%, p = 0.005). There were no significant differences in dialysis-dependence rates between older and younger patients at intensive care unit discharge (31.9% vs. 35.8%, p = 0.50), and hospital discharge (18.5% vs. 24.2%, 0.32). Rates of new dialysis-dependence between older and younger patients at time of hospital discharge were similar (10.2% vs. 6.0%, p = 0.20). CONCLUSIONS: Intensivists should not withhold continuous renal replacement therapy based on age alone. Other factors should be considered in triage of patients for intensive care unit and continuous renal replacement therapy.