Identification of the Telomere elongation Mutation in Drosophila.

Telomeres in Drosophila melanogaster, which have inspired a large part of Sergio Pimpinelli work, are similar to those of other eukaryotes in terms of their function. Yet, their length maintenance relies on the transposition of the specialized retrotransposons Het-A, TART, and TAHRE, rather than on the activity of the enzyme telomerase as it occurs in most other eukaryotic organisms. The length of the telomeres in Drosophila thus depends on the number of copies of these transposable elements. Our previous work has led to the isolation of a dominant mutation, Tel1, that caused a several-fold elongation of telomeres. In this study, we molecularly identified the Tel1 mutation by a combination of transposon-induced, site-specific recombination and next-generation sequencing. Recombination located Tel1 to a 15 kb region in 92A. Comparison of the DNA sequence in this region with the Drosophila Genetic Reference Panel of wild-type genomic sequences delimited Tel1 to a 3 bp deletion inside intron 8 of Ino80. Furthermore, CRISPR/Cas9-induced deletions surrounding the same region exhibited the Tel1 telomere phenotype, confirming a strict requirement of this intron 8 gene sequence for a proper regulation of Drosophila telomere length.

A procalcitonin-based algorithm to guide antibiotic use in patients with acute pancreatitis (PROCAP): a single-centre, patient-blinded, randomised controlled trial.

BACKGROUND: Differentiating inflammation from bacterial infection in patients with acute pancreatitis can be difficult. Procalcitonin can distinguish infection from inflammation, and algorithms based on procalcitonin measurement can differentiate bacterial sepsis from a systemic inflammatory response. We aimed to test the hypothesis that a procalcitonin-based algorithm to guide initiation, continuation, and discontinuation of antibiotics could lead to reduced antibiotic use without an adverse effect on outcome in acute pancreatitis. METHODS: PROCAP was a single-centre, patient-blinded, randomised controlled trial done at the Manchester Royal Infirmary (Manchester, UK). Eligible participants were aged 18 years or older and had a clinical diagnosis of acute pancreatitis. Participants were randomly assigned (1:1) to procalcitonin-guided care or usual care using web-based randomisation software. The randomisation sequence was stratified by disease severity and admission pathway, using variable block sizes of 4, 6, or 8. Patients, but not clinicians, were masked to group assignment. In the procalcitonin-guided care group, procalcitonin testing was conducted on days 0, 4, 7, and weekly thereafter. Guidance was to stop or not start antibiotics following a test value of less than 1·0 ng/mL and to start or continue antibiotics following a test value of 1·0 ng/mL or more. In the intervention group, any empirical clinical decision to use antibiotics was preceded by measurement of procalcitonin. Otherwise, both groups received standard care. The primary outcome was use of antibiotics during the index admission to hospital. All analyses were done in the intention-to-treat population. This study was registered with the International Standard Randomised Controlled Trial registry, ISRCTN 50584992. FINDINGS: Between July 29, 2018, and Nov 13, 2020, 369 patients were screened, of whom 260 were enrolled and randomly assigned to a treatment group (132 to procalcitonin-guided care and 128 to usual care). 59 (45%) of patients in the procalcitonin-guided care group were prescribed antibiotics compared with 79 (63%) in the usual care group (adjusted risk difference -15·6% [95% CI -27·0 to -4·2]; p=0·0071). The odds ratio for the treatment effect was 0·49 (95% CI 0·29 to 0·83; p=0·0077). There was no significant difference between groups in terms of the number of clinical infections or hospital-acquired infections per patient. Four (3%) patients in the procalcitonin-guided care group and three (2%) patients in the usual care group died; all deaths were related to underlying severe pancreatitis. There was no difference in adverse events between the groups. INTERPRETATION: Our findings suggest that procalcitonin-guided care can reduce antibiotic use without increasing infection or harm in patients with acute pancreatitis. Procalcitonin-based algorithms to guide antibiotic use should be considered in the care of this group of patients and be incorporated into future guidelines on the management of acute pancreatitis. FUNDING: None.

Colorectal cancer and synchronous liver metastases: An individual case-based qualitative study (CoSMIC-Q).

BACKGROUND: Contemporary management of colorectal cancer with synchronous liver metastases is complex. Although there is a large body of cohort data, there is no research exploring patient and clinician perspectives. This study explores the experiences and views of patients following treatment for colorectal cancer with synchronous liver metastases and the clinicians involved in their care. METHODS: This is a qualitative study based on interviews with patients who had completed treatment for colorectal cancer with synchronous liver metastases and their treating clinicians. The interviews were recorded, transcribed and analysed using thematic analysis methods. Codes were developed both horizontally regarding each interview as a standalone hermeneutic unit and vertically by scanning across interviews for specific terms. RESULTS: Four overarching themes emerged: patients' experience of initial diagnosis, involvement in treatment, views on the order of staged resections and views about research. For patients, the first consultation is critically important. Patients generally perceived sufficient autonomy in decision-making. In treatment options there is a preference for synchronous surgery balanced by an understanding of the greater risk. Patients did not want liver-first surgery due to the perceived risk of continued seeding from an in situ primary tumour. Clinicians accepted limited evidence for decision making but felt that trials of treatment sequencing were not feasible. CONCLUSIONS: This first qualitative study explores patients' perceptions in colorectal cancer with synchronous liver metastases that are not possible to obtain from quantitative data. CoSMIC-Q demonstrates the importance of incorporating patients' views into treatment planning particularly where equipoise exists in surgical sequence.

Management of Colorectal Cancer with Synchronous Liver Metastases: An Inception Cohort Study (CoSMIC).

BACKGROUND: Approximately one-fifth of patients with colorectal cancer present with hepatic metastases. There are limited prospective data on the outcomes of synchronous combined liver and bowel surgery and liver-first or bowel-first routes where contemporary chemo(radio)therapy is integrated into management. METHODS: Between 1 April 2014 and 31 March 2017, 125 patients with colorectal cancer and synchronous liver metastases were recruited. Data are reported on pathway-specific outcomes, including perioperative complications, treatment completion, and overall and disease-free survival. The study was registered with ClinicalTrials.gov (NCT02456285). RESULTS: There was no difference in age, body mass index, or Charlson score between surgical groups. Neoadjuvant chemotherapy was used in 50 (40%) patients for a mean duration of 4.6 months (standard deviation [SD] 5.4), and mean time from completion of chemotherapy to surgery was 2.6 months (SD 1.9). Complications were similar between patients completing the synchronous and staged pathways (p = 0.66). Mean total inpatient stay was 16.5 days (SD 8.1) for staged surgery compared with 16.8 days (SD 10.3) for the synchronous group (t-test; p = 0.91). There was no difference in time to treatment completion between pathways. Thirty six (35%) patients were disease-free at 12 months, with no significant difference between groups (Chi-square, p = 0.448). Quality of life was similar in all surgical groups. CONCLUSIONS: Perioperative complications and oncological and healthcare occupancy outcomes are equivalent between patients completing staged and synchronous pathways for the management of patients with colorectal cancer and synchronous liver metastases. Future studies should focus on optimizing the criteria for pathway selection, incorporation of cancer genomics data, and patient (user) preferences.

Ceramic Bearings Are Associated With a Significantly Reduced Revision Rate in Primary Hip Arthroplasty: An Analysis From the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man.

BACKGROUND: Prosthetic joint infection (PJI) is a devastating complication. Studies have suggested reduction in PJI with the use of ceramic bearings. METHODS: Adult patients who underwent total hip arthroplasty (THA) using an uncemented acetabular component with ceramic-on-ceramic (CoC), ceramic-on-polyethylene (CoP), or metal-on-polyethylene (MoP) bearing surfaces between 2002 and 2016 were extracted from the National Joint Registry for England, Wales, Northern Ireland, and the Isle of Man. A competing risk regression model to investigate predictors of each revision outcome was used. Time-to-event was determined by duration of implantation since primary surgery with competing risks being death or revision. The results were adjusted for age, gender, American Association of Anaesthesiologists grade, body mass index, surgical indication, intraoperative complications, and implant data. RESULTS: In total, 456,457 THAs (228,786 MoP, 128,403 CoC, and 99,268 CoP) were identified. Multivariable modeling showed that the risk of revision for PJI was significantly lower with CoC (risk ratio 0.748, P < .001) and CoP (risk ratio 0.775, P < .001) compared to MoP. Significant reduction in risk of aseptic and all-cause revision was also seen. The significant protective effect of ceramic bearing was predominantly seen 2 years after implantation. Aseptic revision beyond 2 years reduced by 18.1% and 24.8% for CoC and CoP (P < .001), respectively. All-cause revision rate beyond 2 years reduced by 21.6% for CoC and 27.1% for CoP (P < .001) CONCLUSION: This study demonstrates an association between the use of ceramic as part of the bearing, with lower rates of revision for all causes, revision for infection, and revision for aseptic causes, supporting ceramic bearings in THA.

PROCalcitonin-based algorithm for antibiotic use in Acute Pancreatitis (PROCAP): study protocol for a randomised controlled trial.

BACKGROUND: Differentiating infection from inflammation in acute pancreatitis is difficult, leading to overuse of antibiotics. Procalcitonin (PCT) measurement is a means of distinguishing infection from inflammation as levels rise rapidly in response to a pro-inflammatory stimulus of bacterial origin and normally fall after successful treatment. Algorithms based on PCT measurement can differentiate bacterial sepsis from a systemic inflammatory response. The PROCalcitonin-based algorithm for antibiotic use in Acute Pancreatitis (PROCAP) trial tests the hypothesis that a PCT-based algorithm to guide initiation, continuation and discontinuation of antibiotics will lead to reduced antibiotic use in patients with acute pancreatitis and without an adverse effect on outcome. METHODS: This is a single-centre, randomised, controlled, single-blind, two-arm pragmatic clinical and cost-effectiveness trial. Patients with a clinical diagnosis of acute pancreatitis will be allocated on a 1:1 basis to intervention or standard care. Intervention will involve the use of a PCT-based algorithm to guide antibiotic use. The primary outcome measure will be the binary outcome of antibiotic use during index admission. Secondary outcome measures include: safety non-inferiority endpoint all-cause mortality; days of antibiotic use; clinical infections; new isolates of multiresistant bacteria; duration of inpatient stay; episode-related mortality and cause; quality of life (EuroQol EQ-5D); and cost analysis. A 20% absolute change in antibiotic use would be a clinically important difference. A study with 80% power and 5% significance (two-sided) would require 97 patients in each arm (194 patients in total): the study will aim to recruit 200 patients. Analysis will follow intention-to-treat principles. DISCUSSION: When complete, PROCAP will be the largest randomised trial of the use of a PCT algorithm to guide initiation, continuation and cessation of antibiotics in acute pancreatitis. PROCAP is the only randomised trial to date to compare standard care of acute pancreatitis as defined by the International Association of Pancreatology/American Pancreatic Association guidelines to patients having standard care but with all antibiotic prescribing decisions based on PCT measurement. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number, ISRCTN50584992. Registered on 7 February 2018.

Colorectal cancer with Synchronous liver-limited Metastases: the protocol of an Inception Cohort study (CoSMIC).

INTRODUCTION: Colorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome. METHODS AND ANALYSIS: Colorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care. ETHICS AND DISSEMINATION: The full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences. TRIAL REGISTRATION NUMBER: NCT02456285, pre-results.

Narrow band imaging optical diagnosis of small colorectal polyps in routine clinical practice: the Detect Inspect Characterise Resect and Discard 2 (DISCARD 2) study.

BACKGROUND: Accurate optical characterisation and removal of small adenomas (<10 mm) at colonoscopy would allow hyperplastic polyps to be left in situ and surveillance intervals to be determined without the need for histopathology. Although accurate in specialist practice the performance of narrow band imaging (NBI), colonoscopy in routine clinical practice is poorly understood. METHODS: NBI-assisted optical diagnosis was compared with reference standard histopathological findings in a prospective, blinded study, which recruited adults undergoing routine colonoscopy in six general hospitals in the UK. Participating colonoscopists (N=28) were trained using the NBI International Colorectal Endoscopic (NICE) classification (relating to colour, vessel structure and surface pattern). By comparing the optical and histological findings in patients with only small polyps, test sensitivity was determined at the patient level using two thresholds: presence of adenoma and need for surveillance. Accuracy of identifying adenomatous polyps <10 mm was compared at the polyp level using hierarchical models, allowing determinants of accuracy to be explored. FINDINGS: Of 1688 patients recruited, 722 (42.8%) had polyps <10 mm with 567 (78.5%) having only polyps <10 mm. Test sensitivity (presence of adenoma, N=499 patients) by NBI optical diagnosis was 83.4% (95% CI 79.6% to 86.9%), significantly less than the 95% sensitivity (p<0.001) this study was powered to detect. Test sensitivity (need for surveillance) was 73.0% (95% CI 66.5% to 79.9%). Analysed at the polyp level, test sensitivity (presence of adenoma, N=1620 polyps) was 76.1% (95% CI 72.8% to 79.1%). In fully adjusted analyses, test sensitivity was 99.4% (95% CI 98.2% to 99.8%) if two or more NICE adenoma characteristics were identified. Neither colonoscopist expertise, confidence in diagnosis nor use of high definition colonoscopy independently improved test accuracy. INTERPRETATION: This large multicentre study demonstrates that NBI optical diagnosis cannot currently be recommended for application in routine clinical practice. Further work is required to evaluate whether variation in test accuracy is related to polyp characteristics or colonoscopist training. TRIAL REGISTRATION NUMBER: The study was registered with clinicaltrials.gov (NCT01603927).

Telomerase lost?

Telomerase and telomerase-generated telomeric DNA sequences are widespread throughout eukaryotes, yet they are not universal. Neither telomerase nor the simple DNA repeats associated with telomerase have been found in some plant and animal species. Telomerase was likely lost from Diptera before the divergence of Diptera and Siphonaptera, some 260 million years ago. Even so, Diptera is one of the most successful animal orders, making up 11% of known animal species. In addition, many species of Coleoptera and Hemiptera seem to lack canonical telomeric repeats at their chromosome ends. These and other insects that appear to lack canonical terminal repeat sequences account for another 10-15% of animal species. Conversely, the silk moth Bombyx mori maintains canonical telomeric sequences at its chromosome ends but seems to lack a functional telomerase. We speculate that a telomere-specific capping complex that recognizes the telomeric repeats and protects chromosome ends is the determining factor in maintaining canonical telomeric sequences and that telomerase is an early and efficacious mechanism for satisfying the needs of capping complex. There are alternate mechanisms for maintaining chromosome ends that do not depend on telomerase, such as recombination found in some human cancer cells and yeast mutants. These mechanisms may maintain the canonical telomeric repeats or allow the terminal sequence to evolve when specificity of the capping complex for terminal repeat sequences is weak.

The impact of body mass index on patient reported outcome measures (PROMs) and complications following primary hip arthroplasty.

Influence of BMI upon patient outcomes and complications following THA was examined across a national cohort of patients. Outcomes were compared by BMI groups (19.0-29.9kg/m(2) [reference], 30.0-34.9kg/m(2) [obese class I], 35.0kg/m(2)+ [obese class II/III]), adjusted for case-mix differences. Obese class I patients had a significantly smaller improvement in OHS (18.9 versus 20.5, P<0.001) and a greater risk of wound complications (odds ratio [OR]=1.57, P=0.006). For obese class II/III patients, there were significantly smaller improvements in OHS and EQ-5D index (P<0.001), and greater risk of wound complications (P=0.006), readmission (P=0.001) and reoperation (P=0.003). Large improvements in patient outcomes were seen irrespective of BMI, although improvements were marginally smaller and complication rates higher in obese patients.

Management of colorectal cancer presenting with synchronous liver metastases.

Up to a fifth of patients with colorectal cancer (CRC) present with synchronous hepatic metastases. In patients with CRC who present without intestinal obstruction or perforation and in whom comprehensive whole-body imaging confirms the absence of extrahepatic disease, evidence indicates a state of equipoise between several different management pathways, none of which has demonstrated superiority. Neoadjuvant systemic chemotherapy is advocated by current guidelines, but must be integrated with surgical management in order to remove the primary tumour and liver metastatic burden. Surgery for CRC with synchronous liver metastases can take a number of forms: the 'classic' approach, involving initial colorectal resection, interval chemotherapy and liver resection as the final step; simultaneous removal of the liver and bowel tumours with neoadjuvant or adjuvant chemotherapy; or a 'liver-first' approach (before or after systemic chemotherapy) with removal of the colorectal tumour as the final procedure. In patients with rectal primary tumours, the liver-first approach can potentially avoid rectal surgery in patients with a complete response to chemoradiotherapy. We overview the importance of precise nomenclature, the influence of clinical presentation on treatment options, and the need for accurate, up-to-date surgical terminology, staging tests and contemporary management options in CRC and synchronous hepatic metastatic disease, with an emphasis on multidisciplinary care.

Prior hysterectomy and discomfort during colonoscopy: a retrospective cohort analysis.

BACKGROUND AND STUDY AIMS: Discomfort during colonoscopy may affect acceptability of the procedure. The study aim was to determine factors, including prior hysterectomy and gender, associated with higher levels of patient discomfort during colonoscopy to help with procedural planning such as choice of instrument and sedation. METHODS: A retrospective cohort study of colonoscopies (n = 1098) performed between February 2007 and March 2012 at the Tees Bowel Cancer Screening Centre within the English Bowel Cancer Screening Programme (BCSP). Determinants of moderate/severe discomfort assessed using the Gloucester Scale were explored, using logistic regression with a range of participant and procedural variables. RESULTS: Rates of moderate/severe discomfort varied significantly among men, women without hysterectomy, and women with hysterectomy (5.8 %, 10.4 %, and 17.8 %, respectively; P < 0.001). In an unadjusted model, women with hysterectomy were significantly more likely to experience moderate/severe discomfort than those without (odds ratio [OR]1.87, 95 % confidence interval [95 %CI] 1.05 - 3.32, P = 0.005). The very strong influence of sedation on discomfort level precluded an adjusted model. In subgroup analysis of participants receiving sedation, adjusted comparison again showed increased odds for moderate/severe discomfort for women with hysterectomy, compared with women without (OR 1.70, 95 %CI 1.03 - 2.80, P = 0.036). CONCLUSIONS: Prior hysterectomy is associated with greater levels of moderate/severe discomfort in women undergoing colonoscopy. Minimizing participant discomfort is desirable in any screening or surveillance program. This should be considered in preprocedural counseling and in selecting equipment, sedation, and analgesia. Further studies should examine methods to minimize discomfort in those with prior hysterectomy.

Biodegradable stent or balloon dilatation for benign oesophageal stricture: pilot randomised controlled trial.

AIM: To undertake a randomised pilot study comparing biodegradable stents and endoscopic dilatation in patients with strictures. METHODS: This British multi-site study recruited seventeen symptomatic adult patients with refractory strictures. Patients were randomised using a multicentre, blinded assessor design, comparing a biodegradable stent (BS) with endoscopic dilatation (ED). The primary endpoint was the average dysphagia score during the first 6 mo. Secondary endpoints included repeat endoscopic procedures, quality of life, and adverse events. Secondary analysis included follow-up to 12 mo. Sensitivity analyses explored alternative estimation methods for dysphagia and multiple imputation of missing values. Nonparametric tests were used. RESULTS: Although both groups improved, the average dysphagia scores for patients receiving stents were higher after 6 mo: BS-ED 1.17 (95%CI: 0.63-1.78) P = 0.029. The finding was robust under different estimation methods. Use of additional endoscopic procedures and quality of life (QALY) estimates were similar for BS and ED patients at 6 and 12 mo. Concomitant use of gastrointestinal prescribed medication was greater in the stent group (BS 5.1, ED 2.0 prescriptions; P < 0.001), as were related adverse events (BS 1.4, ED 0.0 events; P = 0.024). Groups were comparable at baseline and findings were statistically significant but numbers were small due to under-recruitment. The oesophageal tract has somatic sensitivity and the process of the stent dissolving, possibly unevenly, might promote discomfort or reflux. CONCLUSION: Stenting was associated with greater dysphagia, co-medication and adverse events. Rigorously conducted and adequately powered trials are needed before widespread adoption of this technology.

Spaces for smoking in a psychiatric hospital: social capital, resistance to control, and significance for 'therapeutic landscapes'.

This paper reports on research framed by theories of therapeutic landscapes and the ways that the social, physical and symbolic dimensions of landscapes relate to wellbeing and healing. We focus especially on the question of how attributes of therapeutic landscapes are constructed in different ways according to the variable perspectives of individuals and groups. Through an ethnographic case study in a psychiatric hospital in the North of England we explore the perceived significance for wellbeing of 'smoking spaces' (where tobacco smoking is practiced in ways that may, or may not be officially sanctioned). We interpret our findings in light of literature on how smoking spaces are linked to the socio-geographical power relations that determine how smoking is organised within the hospital and how this is understood by different groups using the hospital building. We draw on qualitative research findings from discussion groups, observations, and interviews with patients, carers and staff. These focused on their views about the building design and setting of the new psychiatric hospital in relation to their wellbeing, and issues relating to smoking spaces emerged as important for many participants. Creating and managing smoking spaces as a public health measure in psychiatric hospitals is shown to be a controversial issue involving conflicting aims for health and wellbeing of patients and staff. Our findings indicate that although from a physical health perspective, smoking is detrimental, the spaces in which patients and staff smoke have social and psychological significance, providing a forum for the creation of social capital and resistance to institutional control. While the findings relate to one case study setting, the paper illustrates issues of wider relevance and contributes to an international literature concerning the tensions between perceived psychological and psychosocial benefits of smoking vs. physical harm that smoking is likely to cause. We consider the implications for hospital design and the model of care.

Phosphorylation at serines 216 and 221 is important for Drosophila HeT-A Gag protein stability.

Telomeres from Drosophila appear to be very different from those of other organisms - in size and the mechanism of their maintenance. In the absence of the enzyme telomerase, Drosophila telomeres are maintained by retrotransposition of three elements, HeT-A, TART, and TAHRE, but details of their transposition mechanisms are not known. Here we characterized some biochemical characteristics of the HeT-A Gag protein encoded by the HeT-A element to understand this mechanism. The HeT-A Gag protein when overexpressed in S2 cells was localized to the nucleus but was resistant to high salt, detergents and nuclease extraction treatments. Analysis of the HeT-A Gag protein by tandem mass spectrophotometry revealed that serines 216 and 221 are phosphorylated. Substituting these serines with alanine or aspartic acid by site-directed mutagenesis did not result in any changes in HeT-A Gag translocation across the nucleus, suggesting that phosphorylation of these sites is not associated with HeT-A Gag translocation, but time course experiments showed that these phosphorylation sites are important for Gag-protein stability.

The liver-first approach to the management of colorectal cancer with synchronous hepatic metastases: a systematic review.

IMPORTANCE: To our knowledge, this is the first systematic review of the liver-first approach to the management of patients with colorectal cancer with synchronous liver metastases. OBJECTIVE: To review current evidence for the liver-first approach to the management of patients with colorectal cancer with synchronous liver metastases. EVIDENCE REVIEW: PubMed, EMBASE, the Science Citation Index, the Social Sciences Citation Index, Conference Proceedings Citation Index, and the Derwent Innovations Index were searched for the period from January 2000 to May 2012 using terms describing colorectal cancer, liver metastases, and surgery. A predefined protocol for data extraction was used to retrieve data on the design of each study including demographic profile, distribution of primary and hepatic metastatic disease, management of chemotherapy, surgery, the sequence of intervention, disease progression, the numbers completing treatment algorithm, and outcome and survival. FINDINGS: The literature search identified 417 articles, of which 4 cohort study reports described the liver-first approach and reported survival data. There was good agreement between studies on the sequence of treatment using the liver-first approach. The preferred algorithm was systemic chemotherapy, followed by liver resection, then chemoradiotherapy for those patients with rectal lesions, and colorectal resection as the last operative step. Two protocols provided further adjuvant chemotherapy after colorectal resection. Of 121 patients starting treatment, 90 (74%) completed the specified treatment protocol. Disease progression during the protocol period occurred in 23 patients (19%). There was wide variation in survival despite apparently similar protocols. CONCLUSIONS AND RELEVANCE: The liver-first approach for patients with colorectal cancer with synchronous liver metastases is possible but is associated with a wide range of survival outcomes, despite protocol similarities between studies. There is a need for a well-designed clinical trial comparing this liver-first approach with the classic (bowel-first) approach.

Factors influencing revision risk following 15 740 single-brand hybrid hip arthroplasties: a cohort study from a National Joint Registry.

This retrospective cohort study of a National Joint Registry data examines survival time to revision following the commonest brand of primary hybrid THA, exploring risk factors independently associated with failure. Overall 5-year revision was 1.56%. In the final adjusted model, revision risk was significantly higher with standard polyethylene (PE) liners (metal-on-PE: hazard ratio [HR]=2.52, P=0.005, ceramic-on-PE: HR=2.99, P=0.025) when compared to metal-on-highly-cross-linked (XL) PE. Risk of revision with ceramic-on-ceramic bearings was borderline significant (HR=1.86, P=0.061). A significant interaction between age and acetabular shell type (solid or multi-hole) was found (P=0.022), suggesting that solid shells performed significantly better in younger patients. In summary, we found that there were significant differences in implant failure between different bearing surfaces and shell types after adjusting for a range of covariates.

High prevalence of undetected heart failure in long-term care residents: findings from the Heart Failure in Care Homes (HFinCH) study.

AIMS: Diagnosis of heart failure in older people in long-term care is challenging because of co-morbidities, cognitive deficit, polypharmacy, immobility, and poor access to services. This study aimed to ascertain heart failure prevalence and clinical management in this population. METHODS AND RESULTS: A total of 405 residents, aged 65-100 years, in 33 UK care facilities were prospectively enrolled between April 2009 and June 2010. The presence of heart failure was determined using European Society of Cardiology guidelines, modified where necessary for immobility. Evaluation of symptoms and signs, functional capacity, and quality of life, portable on-site echocardiography, and medical record review were completed in 399 cases. The point prevalence of heart failure was 22.8% [n = 91, 95% confidence interval (CI) 18.8-27.2%]; of these, 62.7% (n = 57, 95% CI 59.6-66.5%) had heart failure with preserved ejection fraction and 37.3% had left ventricular systolic dysfunction (n = 34, 95% CI 34.8-40.5%). A total of 76% (n = 61) of previous diagnoses of heart failure were not confirmed, and up to 90% (n = 82) of study cases were new. No symptoms or signs were reliable predictors of heart failure. CONCLUSION: Heart failure was diagnosed in almost a quarter of residents: the prevalence was substantially higher than in other populations. The majority of heart failure cases were undiagnosed, while three-quarters of previously recorded cases were misdiagnosed. Common symptoms and signs appear to have little clinical utility in this population. Early, accurate differential diagnosis is key to the effective management of heart failure; this may be failing in long-term care facilities.