Defining the timing and causes of death amongst patients undergoing colorectal resection in England.

AIM: Historically, postoperative deaths have been reported up to 30 days following surgery. There is, however, emerging evidence that deaths attributable to surgery continue to occur much later than this time frame. This aim of this study was to analyse the timing and causes of mortality following colorectal resection. METHOD: Data were obtained from the Hospital Episode Statistics database with linkage to mortality data from the Office for National Statistics. Patients who underwent colorectal resection between April 2001 and February 2007 were included. Causes of death were classified into colorectal cancer (CRC), other malignancy, cardiac, respiratory, gastrointestinal, neurological and other. RESULTS: During the study period 171 791 patients underwent a colorectal resection. Thirty-day mortality rates for elective procedures were 1.3, 3.5, 7.0 and 12.1% for the ≤ 65, 66-75, 76-85 and > 85 year age groups, respectively, compared with 2.2, 5.4, 9.8 and 16.7% at 90 days. For elective operations, at 30 days, 38.6% of patients who died had CRC recorded as the primary cause of death, whilst 25.4% died of cardiac causes. In the younger population undergoing a resection, deaths due to cardiac causes were significantly higher than the national average for the same age group even beyond 30 days (13.5% at 30 days, 11.1% at 90 days and 5.7% at 1 year). CONCLUSION: This study shows that deaths attributable to colorectal surgery occur beyond the conventionally utilized 30-day period. Information presented to patients on the basis of 30-day mortality estimates is likely to underestimate the true risk of surgical intervention.

Initiation of adjuvant chemotherapy within 8 weeks of elective colorectal resection improves overall survival regardless of reoperation.

AIM: Reoperation after elective colorectal resection may delay the start of adjuvant chemotherapy (AC). The study investigated the dual impact of a reoperation and AC delay on overall survival (OS). METHOD: The Hospital Episode Statistics database was analysed between 1997 and 2012. Patients were divided into colon and rectal cancer cohorts and data were analysed based on whether there was delay in receiving AC beyond 8 weeks and whether a patient suffered reoperation within 30 days. Multivariate regression analysis was undertaken to investigate the relationship between delay in giving AC and reoperation and their combined effect on OS. RESULTS: Logistic regression showed reoperation, amongst other things, to be an independent predictor of AC delay, in both colon and rectal cancer (colon, odds ratio 2.31, P < 0.001; rectal, odds ratio 2.19, P < 0.001). There was no significant difference in OS between patients who had no AC delay but suffered a reoperation and patients who had no AC delay and no reoperation. Patients who had AC delay but no reoperation, however, had significantly worse OS compared to those who had no AC delay and no reoperation [colon, hazard ratio (HR) 1.16, P < 0.001; rectal, HR 1.17, P < 0.001]. Individuals who had both AC delay and a reoperation also had worse OS compared with patients who had neither (colon, HR 1.33, P = 0.037; rectal, HR 1.38, P < 0.001). CONCLUSION: Delayed receipt of AC beyond 8 weeks after surgery is associated with significantly reduced OS regardless of reoperation status in both colon and rectal cancer patients.

Structural determinants of specificity and catalytic mechanism in mammalian 25-kDa thiamine triphosphatase.

BACKGROUND: Thiamine triphosphate (ThTP) is present in most organisms and might be involved in intracellular signaling. In mammalian cells, the cytosolic ThTP level is controlled by a specific thiamine triphosphatase (ThTPase), belonging to the CYTH superfamily of proteins. CYTH proteins are present in all superkingdoms of life and act on various triphosphorylated substrates. METHODS: Using crystallography, mass spectrometry and mutational analysis, we identified the key structural determinants of the high specificity and catalytic efficiency of mammalian ThTPase. RESULTS: Triphosphate binding requires three conserved arginines while the catalytic mechanism relies on an unusual lysine-tyrosine dyad. By docking of the ThTP molecule in the active site, we found that Trp-53 should interact with the thiazole part of the substrate molecule, thus playing a key role in substrate recognition and specificity. Sea anemone and zebrafish CYTH proteins, which retain the corresponding Trp residue, are also specific ThTPases. Surprisingly, the whole chromosome region containing the ThTPase gene is lost in birds. CONCLUSIONS: The specificity for ThTP is linked to a stacking interaction between the thiazole heterocycle of thiamine and a tryptophan residue. The latter likely plays a key role in the secondary acquisition of ThTPase activity in early metazoan CYTH enzymes, in the lineage leading from cnidarians to mammals. GENERAL SIGNIFICANCE: We show that ThTPase activity is not restricted to mammals as previously thought but is an acquisition of early metazoans. This, and the identification of critically important residues, allows us to draw an evolutionary perspective of the CYTH family of proteins.

Reconciliation of international administrative coding systems for comparison of colorectal surgery outcome.

AIM: Significant variation in colorectal surgery outcomes exists between different countries. Better understanding of the sources of variable outcomes using administrative data requires alignment of differing clinical coding systems. We aimed to map similar diagnoses and procedures across administrative coding systems used in different countries. METHOD: Administrative data were collected in a central database as part of the Global Comparators (GC) Project. In order to unify these data, a systematic translation of diagnostic and procedural codes was undertaken. Codes for colorectal diagnoses, resections, operative complications and reoperative interventions were mapped across the respective national healthcare administrative coding systems. Discharge data from January 2006 to June 2011 for patients who had undergone colorectal surgical resections were analysed to generate risk-adjusted models for mortality, length of stay, readmissions and reoperations. RESULTS: In all, 52 544 case records were collated from 31 institutions in five countries. Mapping of all the coding systems was achieved so that diagnosis and procedures from the participant countries could be compared. Using the aligned coding systems to develop risk-adjusted models, the 30-day mortality rate for colorectal surgery was 3.95% (95% CI 0.86-7.54), the 30-day readmission rate was 11.05% (5.67-17.61), the 28-day reoperation rate was 6.13% (3.68-9.66) and the mean length of stay was 14 (7.65-46.76) days. CONCLUSION: The linkage of international hospital administrative data that we developed enabled comparison of documented surgical outcomes between countries. This methodology may facilitate international benchmarking.

Population-based cohort study comparing 30- and 90-day institutional mortality rates after colorectal surgery.

BACKGROUND: Surgical mortality results are increasingly being reported and published in the public domain as indicators of surgical quality. This study examined how mortality outlier status at 90 days after colorectal surgery compares with mortality at 30 days and subsequent intervals in the first year after surgery. METHODS: All adults undergoing elective and emergency colorectal resection between April 2001 and February 2007 in English National Health Service (NHS) Trusts were identified from administrative data. Funnel plots of postoperative case mix-adjusted institutional mortality rate against caseload were created for 30, 90, 180 and 365 days. High- or low-mortality unit status of individual Trusts was defined as breaching upper or lower third standard deviation confidence limits on the funnel plot for 90-day mortality. RESULTS: A total of 171 688 patients from 153 NHS Trusts were included. Some 14 537 (8·5 per cent) died within 30 days of surgery, 19 466 (11·3 per cent) within 90 days, 23 942 (13·9 per cent) within 180 days and 31 782 (18·5 per cent) within 365 days. Eight institutions were identified as high-mortality units, including all four units with high outlying status at 30 days. Twelve units were low-mortality units, of which six were also low outliers at 30 days. Ninety-day mortality correlated strongly with later mortality results (rs = 0·957, P < 0·001 versus 180-day mortality; rs = 0·860, P < 0·001 versus 365-day mortality). CONCLUSION: Extending mortality reporting to 90 days identifies a greater number of mortality outliers when compared with the 30-day death rate. Ninety-day mortality is proposed as the preferred indicator of perioperative outcome for local analysis and public reporting.

Hierarchical multilevel analysis of increased caseload volume and postoperative outcome after elective colorectal surgery.

BACKGROUND: The study aimed to explore the impact of surgeon and institution volume on outcome following colorectal surgery in England using multilevel hierarchical analysis. METHODS: An observational study design was used. All patients undergoing primary elective colorectal resection between 2000 and 2008 were included from the Hospital Episode Statistics database. Consultant surgeons and hospitals were divided into tertiles (low, medium and high volume) according to their mean annual colorectal cancer resection caseload. Outcome measures examined were postoperative 30-day mortality, 28-day readmission and reoperation, and length of stay. Hierarchical multiple regression analysis adjusted for age, sex, co-morbidity, social deprivation, year of surgery, operation type and surgical approach. RESULTS: A total of 109 261 elective cancer colorectal resections were included. High-volume consultant surgeons and hospitals were defined as performing more than 20·7 and 103·5 elective colorectal cancer procedures per year respectively. Consultant and hospital operative volumes increased throughout the study period. In hierarchical regression models, greater surgeon and institutional volume independently predicted only shorter length of hospital stay. No statistical association was observed between higher provider volume and postoperative mortality, 28-day reoperation or readmission rates. CONCLUSION: Increasing elective colorectal cancer caseload alone may have marginal postoperative benefit.

A specific inorganic triphosphatase from Nitrosomonas europaea: structure and catalytic mechanism.

The CYTH superfamily of proteins is named after its two founding members, the CyaB adenylyl cyclase from Aeromonas hydrophila and the human 25-kDa thiamine triphosphatase. Because these proteins often form a closed ß-barrel, they are also referred to as triphosphate tunnel metalloenzymes (TTM). Functionally, they are characterized by their ability to bind triphosphorylated substrates and divalent metal ions. These proteins exist in most organisms and catalyze different reactions depending on their origin. Here we investigate structural and catalytic properties of the recombinant TTM protein from Nitrosomonas europaea (NeuTTM), a 19-kDa protein. Crystallographic data show that it crystallizes as a dimer and that, in contrast to other TTM proteins, it has an open ß-barrel structure. We demonstrate that NeuTTM is a highly specific inorganic triphosphatase, hydrolyzing tripolyphosphate (PPP(i)) with high catalytic efficiency in the presence of Mg(2+). These data are supported by native mass spectrometry analysis showing that the enzyme binds PPP(i) (and Mg-PPP(i)) with high affinity (K(d) < 1.5 µm), whereas it has a low affinity for ATP or thiamine triphosphate. In contrast to Aeromonas and Yersinia CyaB proteins, NeuTTM has no adenylyl cyclase activity, but it shares several properties with other enzymes of the CYTH superfamily, e.g. heat stability, alkaline pH optimum, and inhibition by Ca(2+) and Zn(2+) ions. We suggest a catalytic mechanism involving a catalytic dyad formed by Lys-52 and Tyr-28. The present data provide the first characterization of a new type of phosphohydrolase (unrelated to pyrophosphatases or exopolyphosphatases), able to hydrolyze inorganic triphosphate with high specificity.

Is 30-day mortality an appropriate measure of risk in elderly patients undergoing elective colorectal resection?

AIM: The study aimed to define mortality in the elderly following elective colorectal resection and to identify the most meaningful postoperative period to report mortality rates in this group of patients. METHOD: A systematic review was undertaken to identify studies that reported on mortality in the elderly following elective colorectal resection. Searches of MEDLINE, Embase and PubMed databases were carried out by two independent reviewers and the results were collated. Two reviewers conducted literature searches independently and the third reviewer acted as an arbiter in case of discordance. RESULTS: Two-hundred and thirty-six studies published in 2000 or later were identified in the search. Studies were excluded if they included emergency surgery, included patients receiving surgery before 1995, or did not comment on mortality in an elderly age group. Seventeen studies were finally included in the review. Thirty-day or postoperative mortality rates varied from 0 to 13.3%. Short-term mortality was low in elderly patients selected for minimal access surgery. National population and registry observational audits reported higher short-term mortality rates than most small case series or cohort studies. One national audit demonstrated that a significant mortality risk persists for up to 1 year after surgery. CONCLUSION: Historical case series suggest that 30-day mortality following colorectal resection in the elderly is low. The reliability of 30-day mortality measures to reflect surgical success in this cohort is, however, questionable as a significant proportion of patients die in the months following surgery.

Systematic review of discharge coding accuracy.

INTRODUCTION: Routinely collected data sets are increasingly used for research, financial reimbursement and health service planning. High quality data are necessary for reliable analysis. This study aims to assess the published accuracy of routinely collected data sets in Great Britain. METHODS: Systematic searches of the EMBASE, PUBMED, OVID and Cochrane databases were performed from 1989 to present using defined search terms. Included studies were those that compared routinely collected data sets with case or operative note review and those that compared routinely collected data with clinical registries. RESULTS: Thirty-two studies were included. Twenty-five studies compared routinely collected data with case or operation notes. Seven studies compared routinely collected data with clinical registries. The overall median accuracy (routinely collected data sets versus case notes) was 83.2% (IQR: 67.3-92.1%). The median diagnostic accuracy was 80.3% (IQR: 63.3-94.1%) with a median procedure accuracy of 84.2% (IQR: 68.7-88.7%). There was considerable variation in accuracy rates between studies (50.5-97.8%). Since the 2002 introduction of Payment by Results, accuracy has improved in some respects, for example primary diagnoses accuracy has improved from 73.8% (IQR: 59.3-92.1%) to 96.0% (IQR: 89.3-96.3), P= 0.020. CONCLUSION: Accuracy rates are improving. Current levels of reported accuracy suggest that routinely collected data are sufficiently robust to support their use for research and managerial decision-making.

Alzheimer's disease as an autoimmune disorder of innate immunity endogenously modulated by tryptophan metabolites.

Introduction: Alzheimer's disease (AD) is characterized by neurotoxic immuno-inflammation concomitant with cytotoxic oligomerization of amyloid beta (Aß) and tau, culminating in concurrent, interdependent immunopathic and proteopathic pathogeneses. Methods: We performed a comprehensive series of in silico, in vitro, and in vivo studies explicitly evaluating the atomistic-molecular mechanisms of cytokine-mediated and Aß-mediated neurotoxicities in AD.  Next, 471 new chemical entities were designed and synthesized to probe the pathways identified by these molecular mechanism studies and to provide prototypic starting points in the development of small-molecule therapeutics for AD. Results: In response to various stimuli (e.g., infection, trauma, ischemia, air pollution, depression), Aß is released as an early responder immunopeptide triggering an innate immunity cascade in which Aß exhibits both immunomodulatory and antimicrobial properties (whether bacteria are present, or not), resulting in a misdirected attack upon "self" neurons, arising from analogous electronegative surface topologies between neurons and bacteria, and rendering them similarly susceptible to membrane-penetrating attack by antimicrobial peptides (AMPs) such as Aß. After this self-attack, the resulting necrotic (but not apoptotic) neuronal breakdown products diffuse to adjacent neurons eliciting further release of Aß, leading to a chronic self-perpetuating autoimmune cycle.  AD thus emerges as a brain-centric autoimmune disorder of innate immunity. Based upon the hypothesis that autoimmune processes are susceptible to endogenous regulatory processes, a subsequent comprehensive screening program of 1137 small molecules normally present in human brain identified tryptophan metabolism as a regulator of brain innate immunity and a source of potential endogenous anti-AD molecules capable of chemical modification into multi-site therapeutic modulators targeting AD's complex immunopathic-proteopathic pathogenesis. Discussion:  Conceptualizing AD as an autoimmune disease, identifying endogenous regulators of this autoimmunity, and designing small molecule drug-like analogues of these endogenous regulators represents a novel therapeutic approach for AD.

Value of failure to rescue as a marker of the standard of care following reoperation for complications after colorectal resection.

BACKGROUND: Complication management appears to be of vital importance to differences in survival following surgery between surgical units. Failure-to-rescue (FTR) rates have not yet distinguished surgical from general medical complications. The aim of this study was to assess whether variability exists in FTR rates after reoperation for serious surgical complications following colorectal cancer resections in England. METHODS: The Hospital Episode Statistics (HES) database was used to identify patients undergoing primary resection for colorectal cancer between 2000 and 2008 in English National Health Service (NHS) trusts. Units were ranked into quintiles according to overall risk-adjusted mortality. Highest and lowest mortality quintiles were compared with respect to reoperation rates and FTR-surgical (FTR-S) rates. FTR-S was defined as the proportion of patients with an unplanned reoperation who died within the same admission. RESULTS: Some 144 542 patients undergoing resection for colorectal cancer in 150 English NHS trusts were included. On ranking according to risk-adjusted mortality, rates varied significantly between lowest and highest mortality quintiles (5·4 and 9·3 per cent respectively; P = 0·029). Lowest and highest mortality quintiles had equivalent adjusted reoperation rates (both 4·8 per cent; P = 0·211). FTR-S rates were significantly higher at units within the worst mortality quintile (16·8 versus 11·1 per cent; P = 0·002). CONCLUSION: FTR-S rates differed significantly between English colorectal units, highlighting variability in ability to prevent death in this high-risk group. This variability may represent differences in serious surgical complication management. FTR-S represents a readily collectable marker of surgical complication management that is likely to be applicable to other surgical specialties.

Outcomes from chemoradiotherapy for patients with esophageal cancer.

Chemoradiotherapy is a widely used alternative treatment to surgical resection in certain patient groups with early esophageal cancer. The aim of this study was to retrospectively assess toxicity and outcome of patients treated with definitive chemoradiotherapy for early esophageal cancer at one institution. A retrospective analysis of all patients treated with chemoradiotherapy between February 2000 and December 2008 at a single tertiary center was performed with documentation of treatment given, toxicities recorded, and follow-up and outcome data. Sixty-two patients received chemoradiotherapy for esophageal cancer. There were 20 males and 42 female patients with an average age of 68 years. Histology revealed adenocarcinoma in 28 patients and squamous cell carcinoma in 34 patients. All patients were staged with a computerized tomography scan, endoscopic ultrasound and positron emission tomography scan. Selection criteria for chemoradiotherapy were unfit for surgery, upper esophageal squamous carcinoma, unresectable primary tumor, or patient choice. The majority of the patients received a combination of cisplatin and 5-fluorouracil chemotherapy with 55 Gy in 25 fractions of radiotherapy. Grade 3 toxicities were recorded in 11% of the patients. Eleven patients suffered from local recurrence and a stent was required in nine patients. Radiation strictures occurred in 10 patients requiring dilation in four. Five patients required a radiologically inserted feeding gastrostomy. The median overall survival was 21 months. Patients with adenocarcinomas and those with squamous cell carcinoma had a similar median survival. Overall survival was 70% at 1 year, 48% at 2 years, and 26% at 3 years. This case series of patients treated with chemoradiation for localized esophageal cancer suggest a generally well-tolerated treatment with survival rates after chemoradiotherapy comparable with those seen with surgery.

Safety and feasibility of resuming bariatric surgery under the cloud of COVID-19.

INTRODUCTION: Because of the COVID-19 pandemic, numerous bariatric surgical units globally have halted weight loss surgery. Obesity itself has been shown to be a predictor of poor outcome in people infected with the virus. The aim of this study was to report our experience as a high-volume bariatric institution resuming elective weight loss surgery safely amidst emergency admissions of COVID-19-positive patients. METHODS: A standard operating procedure based on national guidance and altered to accommodate local considerations was initiated across the hospital. Data were collected prospectively for 50 consecutive patients undergoing bariatric surgery following recommencement of elective surgery after the first national lockdown in the UK. RESULTS: Between 28 June and 5 August 2020, a total of 50 patients underwent bariatric surgery of whom 94% were female. Median age was 41 years and median body mass index was 43.8 (interquartile range 40.0-48.8)kg/m2. Half of the patients (n = 25/50) underwent laparoscopic sleeve gastrectomy and half underwent Roux-en-Y gastric bypass (RYGB). Of these 50 patients, 9 (18%) had revisional bariatric surgery. Overall median length of hospital stay was 1 day, with 96% of the study population being discharged within 24h of surgery. The overall rate of readmission was 6% and one patient (2%) returned to theatre with an obstruction proximal to jejuno-jejunal anastomosis. None of the patients exhibited symptoms or tested positive for COVID-19. CONCLUSION: With appropriately implemented measures and precautions, resumption of bariatric surgery during the COVID-19 pandemic appears feasible and safe with no increased risk to patients.

Signaling by the human serotonin(1A) receptor is impaired in cellular model of Smith-Lemli-Opitz Syndrome.

The Smith-Lemli-Opitz Syndrome (SLOS) is a congenital and developmental malformation syndrome associated with defective cholesterol biosynthesis. SLOS is clinically diagnosed by reduced plasma levels of cholesterol along with elevated levels of 7-dehydrocholesterol (and its positional isomer 8-dehydrocholesterol) and the ratio of their concentrations to that of cholesterol. Since SLOS is associated with neurological deformities and malfunction, exploring the function of neuronal receptors and their interaction with membrane cholesterol under these conditions assumes significance. We have earlier shown the requirement of membrane cholesterol for the ligand binding function of an important neurotransmitter G-protein coupled receptor, the serotonin(1A) receptor. In the present work, we have generated a cellular model of SLOS using CHO cells stably expressing the human serotonin(1A) receptor. This was achieved by metabolically inhibiting the biosynthesis of cholesterol, utilizing a specific inhibitor (AY 9944) of the enzyme required in the final step of cholesterol biosynthesis. We utilized this cellular model to monitor the function of the human serotonin(1A) receptor under SLOS-like condition. Our results show that ligand binding activity, G-protein coupling and downstream signaling of serotonin(1A) receptors are impaired in SLOS-like condition, although the membrane receptor level does not exhibit any reduction. Importantly, metabolic replenishment of cholesterol using serum partially restored the ligand binding activity of the serotonin(1A) receptor. These results are potentially useful in developing strategies for the future treatment of the disease since intake of dietary cholesterol is the only feasible treatment for SLOS patients.

The impact of adjuvant chemotherapy timing on overall survival following colorectal cancer resection.

BACKGROUND: Several studies including two meta-analyses have showed that delay between surgery and adjuvant chemotherapy adversely impacts colorectal cancer survival. This study investigated this impact at a population level over a fifteen year period in England. METHODS: The Hospital Episode Statistics database was analysed between 1997 and 2012. Colonic cancer and rectal cancer patients were collated and multivariate Cox regression analyses were undertaken to ascertain the relationship between chemotherapy delay and overall survival. RESULTS: A total of 181 984 patients underwent resection without any reoperation (106 477 (58.5%) having colonic cancer and 75 507 (41.5%) having rectal cancer). In total, 30 836 (16.9%) received adjuvant chemotherapy. 9019 (49.3%), 4573 (25.0%), 2587 (14.1%), 1323 (7.2%) and 804 (4.4%) of 18 306 colonic cancer patients received within 8 weeks, 8-10 weeks, 10-12 weeks, 12-14 weeks and 14-16 weeks, respectively. Sequentially worse overall survival was observed: <8 weeks: Ref; 8-10 wks: Hazard Ratio (HR) 1.09; 10-12 wks: HR 1.13; 12-14 wks HR 1.32 and 14-16 wks: HR 1.32, p < 0.001. 5625 (44.9%), 3087 (24.6%), 1940 (15.5%), 1162 (9.3%) and 716 (5.7%) of 12 530 rectal cancer patients received within 8 weeks, 8-10 weeks, 10-12 weeks, 12-14 weeks and 14-16 weeks, respectively. Sequentially worse overall survival was observed: <8 weeks: Ref; 8-10 wks: HR 1.09; 10-12 wks: HR 1.22; 12-14 wks HR 1.23 and 14-16 wks: HR 1.31, p < 0.001. CONCLUSION: Adjuvant chemotherapy delay adversely impacts colonic and rectal cancer survival. Efforts to prevent complications such as reoperation and to improve access to chemotherapy services, will improve survival in this patient cohort.