Drinkable in situ-forming tough hydrogels for gastrointestinal therapeutics.

Pills are a cornerstone of medicine but can be challenging to swallow. While liquid formulations are easier to ingest, they lack the capacity to localize therapeutics with excipients nor act as controlled release devices. Here we describe drug formulations based on liquid in situ-forming tough (LIFT) hydrogels that bridge the advantages of solid and liquid dosage forms. LIFT hydrogels form directly in the stomach through sequential ingestion of a crosslinker solution of calcium and dithiol crosslinkers, followed by a drug-containing polymer solution of alginate and four-arm poly(ethylene glycol)-maleimide. We show that LIFT hydrogels robustly form in the stomachs of live rats and pigs, and are mechanically tough, biocompatible and safely cleared after 24 h. LIFT hydrogels deliver a total drug dose comparable to unencapsulated drug in a controlled manner, and protect encapsulated therapeutic enzymes and bacteria from gastric acid-mediated deactivation. Overall, LIFT hydrogels may expand access to advanced therapeutics for patients with difficulty swallowing.

Primary tumour immune response and lymph node yields in colon cancer.

BACKGROUND: The mechanism underlying improved survival in non-metastatic colon cancer with higher lymph node (LN) yield is unknown. This study aimed to identify whether molecular features in the primary tumour were predictive of LN yield. METHODS: Clinical, genomic, transcriptomic, proteomic and methylation data of non-metastatic, colon cancers studied in The Cancer Genome Atlas were interrogated for associations with LN yield. Based on maximal survival effects, patients were segregated into high (>15) and low (≤15) LN yield. Gene set enrichment analysis was performed on transcriptomic changes to identify biological processes associated with LN yield. Correlations were validated in an independent set of Stage II colon cancers. RESULTS: High LN yield was found predictive of overall and disease-free survival. There was no association of higher LN yield and increasing nodal positivity. High LN yield was strongly linked with gene expression changes associated with the adaptive and dendritic cell immune response. This association was most prominent in node-negative cancers. Analogous findings were reproduced in the validation dataset. CONCLUSION: The study shows a strong association of an activated immune response in tumours with a high LN yield. Immunogenic tumours have a better prognosis, likely explaining the survival benefit with higher LN yields.

Fine wire versus locking plate fixation of type C pilon fractures.

PURPOSE: The successful treatment of high energy pilon fractures (AO-OTA 43C) can be achieved with a fine wire circular external fixator (CEF) or locking plate construct (ORIF). There is no consensus on whether ORIF or CEF achieves superior outcomes, and both have unique complications. We report early to mid-term outcomes comparing type C pilon fractures treated with ORIF and CEF. METHODS: An 8-year retrospective review was performed on all patients who underwent ORIF or CEF for closed 43C fractures in a tertiary orthoplastic centre. Outcomes included unplanned return to theatre prior to union including superficial and deep surgical site infections (SSI), non-union and post-traumatic osteoarthritis (PTOA) needing fusion. RESULTS: 76 patients underwent ORIF and 59 patients had CEF, with a mean follow-up of 2 years. 7/76 (9.2%) patients who underwent ORIF had a superficial SSI; 2 patients (2.6%) required a formal debridement for deep SSI; none required a flap. 13/59 patients (22%) had a pin track infection following CEF. With the numbers available, there was no significant difference in rates of unplanned return to theatre before bone healing (ORIF 7/76, 9.2%, CEF 9/59, 15.2%, p = 0.7), rates of mal-union (1.7% CEF, 3.9% ORIF, p = 0.7), deep SSI (p = 0.9), time to union (ORIF: 8.1 months v CEF 10.8 months, p = 0.51), non-union (p = 0.24) and fusion for PTOA (ORIF: 6/76, CEF 2/59, p = 0.46). CONCLUSION: With correct patient selection, both ORIF and CEF offer equivalent and favourable early to mid-term outcomes with regard to deep SSI, non-union, mal-union and PTOA. Although statistically insignificant, ORIF with more than 2 plates carries a risk of superficial and deep SSI, whilst CEF is associated with a 22% pin track infection rate. These unique risks must be discussed with the patient as part of a shared decision-making process.

Ethnic disparities in the uptake of colorectal cancer screening: An analysis of the West London population.

AIM: Colorectal cancer (CRC) screening reduces mortality but variation exists in uptake, with poorer uptake in ethnic minority groups. The aim of this work was to evaluate the relationship between ethnicity and uptake of CRC screening in West London. METHOD: Results of CRC screening from the Central London, West London, Hammersmith and Fulham, Hounslow and Ealing Clinical commissioning group collaborative between 2012 and 2017 were retrospectively analysed. These five clinical commissioning groups (CCGs) are located in West London. Compliance with screening according to ethnic group was evaluated compared with White British as the control. RESULTS: A total of 155 038 individuals were screened. White British individuals had the highest compliance (52.6%). A maximum difference in compliance of 8.2% was seen between CCGs. The odds of being less likely to participate were significant (p < 0.05) in all ethnic minorities except for Asian Chinese on univariate and multivariate analysis (adjusted OR 1.091, p = 0.88). CONCLUSION: This is the largest retrospective study focusing on the role of ethnicity in the uptake of CRC screening in England. Poor uptake of screening in all ethnic minorities in West London, with the exception of Asian Chinese individuals in particular, is a novel finding. A mandate to routinely collect ethnicity data, the use of a single more diverse census and further intervention are needed to understand this disparity and reduce health inequity.

Open Versus Laparoscopic Versus Robotic Versus Transanal Mesorectal Excision for Rectal Cancer: A Systematic Review and Network Meta-analysis.

OBJECTIVE: To compare techniques for rectal cancer resection. SUMMARY BACKGROUND DATA: Different surgical approaches exist for mesorectal excision. METHODS: Systematic literature review and Bayesian network meta-analysis performed. RESULTS: Twenty-nine randomized controlled trials included, reporting on 6237 participants, comparing: open versus laparoscopic versus robotic versus transanal mesorectal excision. No significant differences identified between treatments in intraoperative morbidity, conversion rate, grade III/IV morbidity, reoperation, anastomotic leak, nodes retrieved, involved distal margin, 5-year overall survival, and locoregional recurrence. Operative blood loss was less with laparoscopic surgery compared with open, and with robotic surgery compared with open and laparoscopic. Robotic operative time was longer compared with open, laparoscopic, and transanal. Laparoscopic operative time was longer compared with open. Laparoscopic surgery resulted in lower overall postoperative morbidity and fewer wound infections compared with open. Robotic surgery had fewer wound infections compared with open. Time to defecation was longer with open surgery compared with laparoscopic and robotic. Hospital stay was longer after open surgery compared with laparoscopic and robotic, and after laparoscopic surgery compared with robotic. Laparoscopic surgery resulted in more incomplete or nearly complete mesorectal excisions compared with open, and in more involved circumferential resection margins compared with transanal. Robotic surgery resulted in longer distal resection margins compared with open, laparoscopic, and transanal. CONCLUSIONS: The different techniques result in comparable perioperative morbidity and long-term survival. The laparoscopic and robotic approaches may improve postoperative recovery, and the open and transanal approaches may improve oncological resection. Technique selection should be based on expected benefits by individual patient.

A systematic review of the literature reporting on randomised controlled trials comparing treatments for faecal incontinence in adults.

AIM: To perform a review of the literature reporting on randomised controlled trials (RCTs) comparing treatments for faecal incontinence (FI) in adults. METHODS: A literature search of MEDLINE, Embase, Science Citation Index Expanded and Cochrane was performed in order to identify RCTs reporting on treatments for FI. RESULTS: The review included 60 RCTs reporting on 4838 patients with a mean age ranging from 36.8 to 88 years. From the included RCTs, 32 did not identify a significant difference between the treatments compared. Contradictory results were identified in RCTs comparing percutaneous posterior tibial nerve stimulation and transcutaneous tibial nerve stimulation versus sham stimulation, biofeedback-pelvic floor muscle training (BF-PFMT) versus PFMT, and between bulking agents such as PTQTM versus Durasphere®. In two separate RCTs, combination treatment of amplitude-modulated medium frequency stimulation and electromyography-biofeedback (EMG-BF), was noted to be superior to EMG-BF and low-frequency electrical stimulation alone. Combination of non-surgical treatments such as BF with sphincteroplasty significantly improved continence scores compared to sphincteroplasty alone. Surgical treatments were associated with higher rates of serious adverse events compared to non-surgical interventions. CONCLUSIONS: The current evidence has not identified significant differences between treatments for FI, and where differences were identified, the results were contradictory between RCTs.

Sacral nerve stimulation versus percutaneous tibial nerve stimulation for faecal incontinence: a systematic review and meta-analysis.

AIMS: Percutaneous tibial nerve stimulation (PTNS) and sacral nerve stimulation (SNS) are both second-line treatments for faecal incontinence (FI). To compare the clinical outcomes and effectiveness of SNS versus PTNS for treating FI in adults. METHOD: A literature search of MEDLINE, Embase, Science Citation Index Expanded and Cochrane was performed in order to identify studies comparing SNS and PTNS for treating FI. A risk of bias assessment was performed using The Cochrane Collaboration's risk of bias tool. A random effects model was used for the meta-analysis. RESULTS: Four studies (one randomised controlled trial and three nonrandomised prospective studies) reported on 302 patients: 109 underwent SNS and 193 underwent PTNS. All included studies noted an improvement in symptoms after treatment, without any significant difference in efficacy between SNS and PTNS. Meta-analysis demonstrated that the Wexner score improved significantly with SNS compared to PTNS (weighted mean difference 2.27; 95% confidence interval 3.42, 1.12; P < 0.01). Moreover, SNS was also associated with a significant reduction in FI episodes per week and a greater improvement in the Fecal Incontinence Quality of Life coping and depression domains, compared to PTNS on short-term follow-up. Only two studies reported on adverse events, reporting no serious adverse events with neither SNS nor PTNS. CONCLUSION: Current evidence suggests that SNS results in significantly improved functional outcomes and quality of life compared to PTNS. No serious adverse events were identified with either treatment. Further, high-quality, multi-centre randomised controlled trials with standardised outcome measures and long-term follow-up are required in this field.

Surgical audit: are we not closing the loop?

PURPOSE: A clinical audit is a key component of the clinical governance framework. The rate of audit completion in general surgery has not been investigated. The purpose of this paper is to assess the rates of audit activity and completion and explore the barriers to successful audit completion. DESIGN/METHODOLOGY/APPROACH: This was a multi-centre study evaluating current surgical audit practice. A standardised audit proforma was designed. All clinical audits in general surgery during a two-year period were identified and retrospectively reviewed. Data held by the audit departments were collated, and individual audit teams were contacted to verify the data accuracy. Audit teams failing to complete the full audit cycle with a re-audit were asked to explain the underlying reasons behind this. FINDINGS: Of the six trusts approached, two refused to participate, and one failed to initiate the project. A total of 39 audits were registered across three surgical directorates. Only 15 out of 39 audits completed at least one audit cycle, with 4 deemed of no value to re-audit. Only seven audits were completed to re-audit. Achieving a publication or a presentation was the most cited reason for not completing the audit loop. ORIGINALITY/VALUE: This study demonstrates that the poor rates of audit completion rate found in other areas of clinical medicine pervade general surgery. Improved completion of an audit is essential and strategies to achieve this are urgently needed.

Closed-loop automated drug infusion regulator: A clinically translatable, closed-loop drug delivery system for personalized drug dosing.

BACKGROUND: Dosing of chemotherapies is often calculated according to the weight and/or height of the patient or equations derived from these, such as body surface area (BSA). Such calculations fail to capture intra- and interindividual pharmacokinetic variation, which can lead to order of magnitude variations in systemic chemotherapy levels and thus under- or overdosing of patients. METHODS: We designed and developed a closed-loop drug delivery system that can dynamically adjust its infusion rate to the patient to reach and maintain the drug's target concentration, regardless of a patient's pharmacokinetics (PK). FINDINGS: We demonstrate that closed-loop automated drug infusion regulator (CLAUDIA) can control the concentration of 5-fluorouracil (5-FU) in rabbits according to a range of concentration-time profiles (which could be useful in chronomodulated chemotherapy) and over a range of PK conditions that mimic the PK variability observed clinically. In one set of experiments, BSA-based dosing resulted in a concentration 7 times above the target range, while CLAUDIA keeps the concentration of 5-FU in or near the targeted range. Further, we demonstrate that CLAUDIA is cost effective compared to BSA-based dosing. CONCLUSIONS: We anticipate that CLAUDIA could be rapidly translated to the clinic to enable physicians to control the plasma concentration of chemotherapy in their patients. FUNDING: This work was supported by MIT's Karl van Tassel (1925) Career Development Professorship and Department of Mechanical Engineering and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

Actively Triggerable Metals via Liquid Metal Embrittlement for Biomedical Applications.

Actively triggerable materials, which break down upon introduction of an exogenous stimulus, enable precise control over the lifetime of biomedical technologies, as well as adaptation to unforeseen circumstances, such as changes to an established treatment plan. Yet, most actively triggerable materials are low-strength polymers and hydrogels with limited long-term durability. By contrast, metals possess advantageous functional properties, including high mechanical strength and conductivity, that are desirable across several applications within biomedicine. To realize actively triggerable metals, a mechanism called liquid metal embrittlement is leveraged, in which certain liquid metals penetrate the grain boundaries of certain solid metals and cause them to dramatically weaken or disintegrate. In this work, it is demonstrated that eutectic gallium indium (EGaIn), a biocompatible alloy of gallium, can be formulated to reproducibly trigger the breakdown of aluminum within different physiologically relevant environments. The breakdown behavior of aluminum after triggering can further be readily controlled by manipulating its grain structure. Finally, three possible use cases of biomedical devices constructed from actively triggerable metals are demonstrated.

A systematic review and meta-analysis assessing the impact of body mass index on long-term survival outcomes after surgery for colorectal cancer.

BACKGROUND: The impact of body mass index (BMI) on long-term survival outcomes after colorectal cancer surgery is debated. DESIGN: A systematic literature review and meta-analysis was performed to compare long-term survival outcomes of patients of different BMI categories after colorectal cancer surgery. RESULTS: Of the 2588 articles screened, 56 articles met the inclusion criteria, reporting on 72,582 participants. Patients with BMI <18.5 had significantly worse overall survival [hazard ratio (HR) 1.91; P < 0.0001], cancer-specific survival (HR = 1.91; P < 0.0001), disease-free survival (HR = 1.50; P < 0.0001) and recurrence-free survival (HR = 1.13; P = 0.007) compared to patients with a BMI of 18.5-25. There was no significant difference between those with BMI 25-30 and 18.5-25 in overall survival, cancer-specific survival, disease-free survival and recurrence-free survival, except for the subgroup of patients with colon cancer where patients with BMI 25-30 had significantly improved overall survival (HR = 0.90; P = 0.05) and disease-free survival (HR = 0.90; P = 0.04). Patients with BMI >30 had significantly worse disease-free survival (HR = 1.05; P = 0.03) compared to patients with a BMI of 18.5-25, but no significant difference in overall survival, cancer-specific survival and recurrence-free survival. Patients with BMI >35 compared to 18.5-25 had significantly worse overall survival (HR = 1.24; P = 0.02), cancer-specific survival (HR = 1.36; P = 0.01), disease-free survival (HR = 1.15; P = 0.03) and recurrence-free survival for colon (HR = 1.11; P = 0.04) and rectal (HR = 4.10; P = 0.04) cancer. CONCLUSIONS: Being underweight (BMI < 18.5) or class II/III obese (BMI > 35) at the time of colorectal cancer surgery may result in worse long-term survival outcomes, whereas being overweight (BMI 25-30) may improve survival in a subgroup of patients with colon cancer. Optimising BMI may preoperatively improve long-term survival after surgery for colorectal cancer.

The impact of socioeconomic deprivation on the uptake of colorectal cancer screening in London.

OBJECTIVE: Screening programmes based on the faecal occult blood test (FOBT) can reduce mortality from colorectal cancer (CRC). However, a significant variation exists in uptake of the test within the UK. Disproportionate uptake risks increasing inequity during staging at diagnosis and survival from CRC. This study aims to evaluate the impact of socioeconomic deprivation on the uptake of CRC screening (FOBT) in London. METHODS: A retrospective review of the "Vanguard RM Informatics" database was performed to identify eligible individuals for CRC screening across all general practices across London over 30 months (2014-2017). The postcodes of the general practices were used to obtain the deprivation data via the "Indices of Deprivation" database. A Spearman's rho correlation was performed to quantify the impact of the deprivation variables on FOBT uptake. RESULTS: Overall, 697,402 individuals were eligible for screening across 1359 London general practices, within 5 Clinical Commissioning Groups (CCGs); 48.4% (range: 13%-74%) participated in CRC screening with the lowest participation rates in North West (46%) and North East (47%) London CCGs. All indices of deprivation had a significant correlation with the uptake of FOBT (p < 0.01). CONCLUSION: This is the largest study across London to date demonstrating a significant positive correlation between deprivation indices and FOBT uptake, highlighting areas of particular risk. Further studies are imperative to quantify the impact of deprivation on CRC morbidity and mortality, together with focused strategies to reduce socioeconomic inequalities in screening in these high risk areas.

A systematic review and network meta-analysis comparing treatments for faecal incontinence.

BACKGROUND: Although numerous treatments exist for fecal incontinence (FI), no consensus exists on the best treatment strategy. The aim was to review the literature and to compare the clinical outcomes and effectiveness of treatments available for FI. MATERIALS AND METHOD: A systematic literature review was performed, from inception to May 2018, of the following databases: MEDLINE, EMBASE, Science Citation Index Expanded, Cochrane Library. The search terms used were "faecal incontinence" and "treatment". Only randomized controlled trials (RCTs) comparing treatments for FI were considered. A Bayesian network meta-analysis was performed using the Markov chain Monte Carlo method. RESULT: Forty-seven RCTs were included comparing 37 treatments and reporting on 3748 participants. No treatment ranked best or worst with high probability for any outcome of interest. No significant difference was identified between treatments for frequency of FI per week, or in changing the resting pressure, maximum resting pressure, squeeze pressure, and maximum squeeze pressure. Radiofrequency resulted in more adverse events compared to placebo. Sacral nerve stimulation (SNS) and zinc-aluminium improved the fecal incontinence quality of life questionnaire (FIQL) lifestyle, coping, and embarrassment domains compared to placebo. Transcutaneous posterior tibial nerve stimulation (TPTNS) improved the FIQL embarrassment domain compared to placebo. Autologous myoblasts and zinc-aluminium improved the FIQL depression domain compared to placebo. SNS, artificial bowel sphincter (ABS), and zinc-aluminium significantly improved incontinence scores compared to placebo. Injection of non-animal stabilized hyaluronic acid/dextranomer (NASHA/Dx) resulted in more patients with ≥50% reduction in FI episodes compared to placebo. CONCLUSION: SNS, ABS, TPTNS, NASHA/Dx, zinc-aluminium, and autologous myoblasts resulted in isolated improvements in specific outcomes of interest. No difference was identified in incontinence episodes, no treatment ranked best persistently or persistently improved outcomes, and many included treatments did not significantly benefit patients compared to placebo. Large multicentre RCTs with long-term follow-up and standardized inclusion criteria and outcome measures are needed.

Gastric Electrical Stimulation with the Enterra System: A Systematic Review.

Background. Gastric electrical stimulation (GES) is a surgically implanted treatment option for refractory gastroparesis. Aim. To systematically appraise the current evidence for the use of gastric electrical stimulation and suggest a method of standardisation of assessment and follow-up in these patients. Methods. A systematic review of PubMed, Web of Science, DISCOVER, and Cochrane Library was conducted using the keywords including gastric electrical stimulation, gastroparesis, nausea, and vomiting and neuromodulation, stomach, central nervous system, gastric pacing, electrical stimulation, and gastrointestinal. Results. 1139 potentially relevant articles were identified, of which 21 met the inclusion criteria and were included. The quality of studies was variable. There was a variation in outcome measures and follow-up methodology. Included studies suggested significant reductions in symptom severity reporting over the study period, but improvements in gastric emptying time were variable and rarely correlated with symptom improvement. Conclusion. The evidence in support of gastric electrical stimulation is limited and heterogeneous in quality. While current evidence has shown a degree of efficacy in these patients, high-quality, large clinical trials are needed to establish the efficacy of this therapy and to identify the patients for whom this therapy is inappropriate. A consensus view on essential preoperative assessment and postoperative measurement is needed.