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Focuses on the telomerase elongation, a mutation in Drosophila melanogaster that produces long telomeres. Drosophila stocks and genetic crosses; Cytological procedures; Fluorescent in situ hybridization; Immunostaining with HP1; Genomic DNA isolation.

Several letters to the editor and a reply are presented in response to the article "Penicillin to prevent recurrent leg cellulitis," by K.S. Thomas and colleagues, and about the PATCH trial to determine changes in the duration of stay in hospital or hospitalization.

Purpose: Cognitive load, specifically extraneous load (EL) reflective of distractions, may provide evidence of a lack of focus, potentially making additional work unsafe. The assessment of trainees performing inpatient consultations provides a helpful model for examining this question. The goal of this study was to provide useful information to clinical and educational leaders to optimize inpatient consultation services and rotations and mitigate potential patient safety risk., Method: In 2019, using the Consult Cognitive Load instrument, the authors obtained EL data from inpatient consultations performed by internal medicine fellows and psychiatry residents across 5 University of California hospitals. In 2023, the authors constructed a Wright map to compare the participants' EL data with the number of prior initial consultations performed during the shift., Results: Of 326 trainees contacted, 139 (43%) completed the EL survey items. The Wright map shows that trainees were estimated to agree that interruptions were already distracting at the first consultation of the shift. After 4 consultations, trainees were estimated to strongly agree that interruptions were distracting, and to agree that emotions, extraneous information, and technology were distracting., Conclusions: The authors propose a quantitative, empirically driven, mean safety limit of 4 new inpatient consultations per shift for trainees to avoid cognitive overload, thereby potentially supporting patient safety. Clinical and educational leaders can adjust this limit to fit the unique needs of their practice setting. A similar approach using cognitive load and item response theory could be used to conduct patient safety research in other domains., (Copyright © 2024 the Association of American Medical Colleges.)

Background: In patients with out-of-hospital cardiac arrest, the effectiveness of drugs such as epinephrine is highly time-dependent. An intraosseous route of drug administration may enable more rapid drug administration than an intravenous route; however, its effect on clinical outcomes is uncertain., Methods: We conducted a multicenter, open-label, randomized trial across 11 emergency medical systems in the United Kingdom that involved adults in cardiac arrest for whom vascular access for drug administration was needed. Patients were randomly assigned to receive treatment from paramedics by means of an intraosseous-first or intravenous-first vascular access strategy. The primary outcome was survival at 30 days. Key secondary outcomes included any return of spontaneous circulation and favorable neurologic function at hospital discharge (defined by a score of 3 or less on the modified Rankin scale, on which scores range from 0 to 6, with higher scores indicating greater disability). No adjustment for multiplicity was made., Results: A total of 6082 patients were assigned to a trial group: 3040 to the intraosseous group and 3042 to the intravenous group. At 30 days, 137 of 3030 patients (4.5%) in the intraosseous group and 155 of 3034 (5.1%) in the intravenous group were alive (adjusted odds ratio, 0.94; 95% confidence interval [CI], 0.68 to 1.32; P = 0.74). At the time of hospital discharge, a favorable neurologic outcome was observed in 80 of 2994 patients (2.7%) in the intraosseous group and in 85 of 2986 (2.8%) in the intravenous group (adjusted odds ratio, 0.91; 95% CI, 0.57 to 1.47); a return of spontaneous circulation at any time occurred in 1092 of 3031 patients (36.0%) and in 1186 of 3035 patients (39.1%), respectively (adjusted odds ratio, 0.86; 95% CI, 0.76 to 0.97). During the trial, one adverse event, which occurred in the intraosseous group, was reported., Conclusions: Among adults with out-of-hospital cardiac arrest requiring drug therapy, the use of an intraosseous-first vascular access strategy did not result in higher 30-day survival than an intravenous-first strategy. (Funded by the National Institute for Health and Care Research; PARAMEDIC-3 ISRCTN Registry number, ISRCTN14223494.)., (Copyright © 2024 Massachusetts Medical Society.)

Objective: The Trans Woman Voice Questionnaire (TWVQ) is commonly used to quantify self-perceptions of voice for trans women seeking gender-affirming voice care, but the interpretation of TWVQ scores remains challenging. The objective of this study was to use item-response theory (IRT) to evaluate the relationship between TWVQ items and persons on a common scale and identify improvements to increase the meaningfulness of TWVQ scores., Methods: A retrospective review of TWVQ scores from trans women patients between 2018-2020 was performed. Rasch-family models were used to generate item-person maps positioning respondent location and item difficulty estimates on a logit scale, which was then converted into a scaled score using linear transformations., Results: TWVQ responses from 86 patients were analyzed. Initial item-person maps demonstrated that the middle response categories ("sometimes" and "often") performed inconsistently across items (poor threshold banding); interpretability improved when these ratings were scored as one category. The models were rerun using revised scoring, which retained high reliability (0.93) and supported a unidimensional construct. Updated item-person maps revealed four scaled score zones (≤54, >54 to ≤101, >101 to ≤140, and >140) that each corresponded to an increasing pattern of item thresholds (probability of selecting one response category vs. others). These ranges can be interpreted as minimal, low, moderate, and high, respectively., Conclusions: Empiric data from Rasch analysis supports new interval scoring for the TWVQ that advances the clinical and research utility of the instrument and lays the foundation for future improvements in clinical care and outcomes assessment., Level of Evidence: NA Laryngoscope, 133:1197-1204, 2023., (© 2022 The American Laryngological, Rhinological and Otological Society, Inc.)

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., Competing Interests: Declaration of interests AKS and SJ are employees of the Manchester University NHS Foundation Trust. JMM is an employee of the University of Warwick. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2022 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Background: Torus (buckle) fractures of the wrist are the most common fractures in children involving the distal radius and/or ulna. It is unclear if children require rigid immobilisation and follow-up or would recover equally as well by being discharged without any immobilisation or a bandage. Given the large number of these injuries, identifying the optimal treatment strategy could have important effects on the child, the number of days of school absence and NHS costs., Objectives: To establish whether or not treating children with a distal radius torus fracture with the offer of a soft bandage and immediate discharge (i.e. offer of a bandage) provides the same recovery, in terms of pain, function, complications, acceptability, school absence and resource use, as treatment with rigid immobilisation and follow-up as per usual practice (i.e. rigid immobilisation)., Design: A pragmatic, multicentre, randomised controlled equivalence trial., Setting: Twenty-three UK emergency departments., Participants: A total of 965 children (aged 4-15 years) with a distal radius torus fracture were randomised from January 2019 to July 2020 using a secure, centralised, online-encrypted randomisation service. Exclusion criteria included presentation > 36 hours after injury, multiple injuries and an inability to complete follow-up., Interventions: A bandage was offered to 489 participants and applied to 458, and rigid immobilisation was carried out in 476 participants. Participants and clinicians were not blinded to the treatment allocation., Main Outcome Measures: The pain at 3 days post randomisation was measured using the Wong-Baker FACES Pain Rating Scale. Secondary outcomes were the patient-reported outcomes measurement system upper extremity limb score for children, health-related quality of life, complications, school absence, analgesia use and resource use collected up to 6 weeks post randomisation., Results: A total of 94% of participants provided primary outcome data. At 3 days, the primary outcome of pain was equivalent in both groups. With reference to the prespecified equivalence margin of 1.0, the adjusted difference in the intention-to-treat population was -0.10 (95% confidence interval -0.37 to 0.17) and the per-protocol population was -0.06 (95% confidence interval -0.34 to 0.21). There was equivalence of pain in both age subgroups (i.e. 4-7 years and 8-15 years). There was no difference in the rate of complications, with five complications (1.0%) in the offer of a bandage group and three complications (0.6%) in the rigid immobilisation group. There were no differences between treatment groups in functional recovery, quality of life or school absence at any point during the follow-up. Analgesia use was marginally higher at day 1 in the offer of a bandage group than it was in the rigid immobilisation group (83% vs. 78% of participants), but there was no difference at other time points. The offer of a bandage significantly reduced the cost of treatment and had a high probability of cost-effectiveness at a willingness-to-pay threshold of £30,000 per quality-adjusted life-year., Limitations: Families had a strong pre-existing preference for the rigid immobilisation treatment. Given this, and the inability to blind families to the treatment allocation, observer bias was a concern. However, there was clear evidence of equivalence., Conclusions: The study findings support the offer of a bandage in children with a distal radius torus fracture., Future Work: A clinical decision tool to determine which children require radiography is an important next step to prevent overtreatment of minor wrist fractures. There is also a need to rationalise interventions for other common childhood injuries (e.g. 'toddler's fractures' of the tibia)., Trial Registration: This trial is registered as ISRCTN13955395 and UKCRN Portfolio 39678., Funding: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 26, No. 33. See the NIHR Journals Library website for further project information.

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., (© 2021. Society of Surgical Oncology.)

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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Introduction: Patient eczema severity time (PEST) is a new atopic dermatitis (AD) scoring system based on patients' own perception of their disease. Conventional scales such as SCORing of atopic dermatitis (SCORAD) reflect the clinician's observations during the clinic visit. Instead, the PEST score captures eczema severity, relapse and recovery as experienced by the patient or caregiver on a daily basis, promoting patient engagement, compliance with treatment and improved outcomes. This study aims to determine the correlation between carer-assessed PEST and clinician-assessed SCORAD in paediatric AD patients after 12 weeks of treatment using a ceramide-dominant therapeutic moisturizer., Methods: Prospective, open-label, observational, multi-centre study in which children with AD aged 6 months to 6 years were treated with a ceramide dominant therapeutic moisturizer twice daily for 12 weeks; 58 children with mild-to-moderate AD were included. Correlation between the 7-day averaged PEST and SCORAD scores for assessment of AD severity was measured within a general linear model. PEST and SCORAD were compared in week 4 and week 12., Results: At week 12, a moderate correlation was found between the SCORAD and PEST scores (r = 0.51). The mean change in SCORAD and PEST scores from baseline to week 12 was -11.46 [95% confidence interval (CI) -14.99 to -7.92, p < 0.0001] and -1.33 (95% CI -0.71 to -0.10, p < 0.0001) respectively. PEST demonstrated greater responsiveness to change (33.3% of scale) compared to SCORAD (13.8% of scale)., Conclusion: The PEST score correlates well with the SCORAD score and may have improved sensitivity when detecting changes in the severity of AD. The ceramide-dominant therapeutic moisturizer used was safe and effective in the management of AD in young children., Funding: Hyphens Pharma Pte Ltd., Trial Registration: clinicaltrials.gov identifier, NCT02073591.

Background: Pyoderma gangrenosum (PG) is an uncommon dermatosis with a limited evidence base for treatment., Objective: We sought to estimate the effectiveness of topical therapies in the treatment of patients with PG., Methods: This was a prospective cohort study of UK secondary care patients with a clinical diagnosis of PG that was suitable for topical treatment (recruited between July 2009 and June 2012). Participants received topical therapy after normal clinical practice (primarily topical corticosteroids [classes I-III] and tacrolimus 0.03% or 0.1%). The primary outcome was speed of healing at 6 weeks. Secondary outcomes included the following: proportion healed by 6 months; time to healing; global assessment; inflammation; pain; quality of life; treatment failure; and recurrence., Results: Sixty-six patients (22-85 years of age) were enrolled. Clobetasol propionate 0.05% was the most commonly prescribed therapy. Overall, 28 of 66 (43.8%) ulcers healed by 6 months. The median time to healing was 145 days (95% confidence interval, 96 days to ∞). Initial ulcer size was a significant predictor of time to healing (hazard ratio, 0.94 [95% confidence interval, 0.88-1.00); P = .043). Four patients (15%) had a recurrence., Limitations: Our study did not include a randomized comparator., Conclusion: Topical therapy is potentially an effective first-line treatment for PG that avoids the possible side effects associated with systemic therapy. It remains unclear whether more severe disease will respond adequately to topical therapy alone., (Crown Copyright © 2016. Published by Elsevier Inc. All rights reserved.)

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.

Objective: Patients with severe acute pancreatitis were excluded from major trials of human recombinant activated protein C (Xigris) because of concern about pancreatic haemorrhage although these individuals have an intense systemic inflammatory response that may benefit from treatment. The object of this study was to provide initial safety data evaluating Xigris in severe acute pancreatitis., Design: Prospective clinical trial recruiting between November 2009 and October 2011. Patients received human recombinant activated protein C (Xigris) for 24 h by intravenous infusion (24 μg/kg/h) in addition to standard clinical care. A matched historical control group treated within the same hospital unit were used to compare outcomes. Of 166 consecutive admitted patients, 43 met the screening criteria for severe acute pancreatitis and 19 were recruited, all contributing to the analyses., Results: Compared to historical controls, there were fewer bleeding events in the Xigris group although the finding did not reach significance (Xigris 0% vs. Control 21%, p = 0.13), similarly further intervention appeared less frequent (11% vs. 47%, p = 0.07) in the treatment group. Length of stay was shorter for patients receiving Xigris (19 vs. 41 days, p = 0.03) as was inotrope use (5% vs. 32%, p = 0.02); mortality and incidence of infections in both groups were similar. Biomarker protein C increased while IL-6 decreased following infusion., Conclusions: A 24-hr infusion of Xigris appears safe when used in patients with severe acute pancreatitis., Trial Registration: Eudract Number 2007-003635-23., (Copyright © 2015 IAP and EPC. Published by Elsevier India Pvt Ltd. All rights reserved.)

Objective: To determine whether ciclosporin is superior to prednisolone for the treatment of pyoderma gangrenosum, a painful, ulcerating skin disease with a poor evidence base for management., Design: Multicentre, parallel group, observer blind, randomised controlled trial., Setting: 39 UK hospitals, recruiting from June 2009 to November 2012., Participants: 121 patients (73 women, mean age 54 years) with clinician diagnosed pyoderma gangrenosum. Clinical diagnosis was revised in nine participants after randomisation, leaving 112 participants in the analysis set (59 ciclosporin; 53 prednisolone)., Intervention: Oral prednisolone 0.75 mg/kg/day compared with ciclosporin 4 mg/kg/day, to a maximum dose of 75 and 400 mg/day, respectively., Main Outcome Measures: The primary outcome was speed of healing over six weeks, captured using digital images and assessed by blinded investigators. Secondary outcomes were time to healing, global treatment response, resolution of inflammation, self reported pain, quality of life, number of treatment failures, adverse reactions, and time to recurrence. Outcomes were assessed at baseline and six weeks and when the ulcer had healed (to a maximum of six months)., Results: Of the 112 participants, 108 had complete primary outcome data at baseline and six weeks (57 ciclosporin; 51 prednisolone). Groups were balanced at baseline. The mean (SD) speed of healing at six weeks was -0.21 (1.00) cm(2)/day in the ciclosporin group compared with -0.14 (0.42) cm(2)/day in the prednisolone group. The adjusted mean difference showed no between group difference (0.003 cm(2)/day, 95% confidence interval -0.20 to 0.21; P=0.97). By six months, ulcers had healed in 28/59 (47%) participants in the ciclosporin group compared with 25/53 (47%) in the prednisolone group. In those with healed ulcers, eight (30%) receiving ciclosporin and seven (28%) receiving prednisolone had a recurrence. Adverse reactions were similar for the two groups (68% ciclosporin and 66% prednisolone), but serious adverse reactions, especially infections, were more common in the prednisolone group., Conclusion: Prednisolone and ciclosporin did not differ across a range of objective and patient reported outcomes. Treatment decisions for individual patients may be guided by the different side effect profiles of the two drugs and patient preference. Trial registration Current Controlled Trials ISRCTN35898459., (© Ormerod et al 2015.)

Background: Tranexamic acid (TXA) has been successfully used to reduce bleeding in joint replacement. Recently local TXA has been advocated to reduce blood loss in total knee or hip replacement; however, this raised concerns about potential adverse effects of TXA upon the artificial joint replacement., Materials and Methods: In this biomechanical study we compared the effects of TXA and saline upon the following biomechanical properties of artificial joint materials-(1) tensile properties (ultimate strength, stiffness and Young's modulus), (2) the wear rate using a multi-directional pin-on-plate machine, and (3) the surface topography of pins and plates before and after wear rate testing., Results: There were no significant differences in tensile strength, wear rates or surface topography of either ultra-high-molecular-weight polyethylene pins or cobalt chromium molybdenum metal plates between specimens soaked in TXA and specimens soaked in saline., Conclusion: Biomechanical testing shows that there are no biomechanical adverse affects on the properties of common artificial joint materials from using topical TXA., Level of Evidence: V.

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.

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.

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.

Telomere length in Drosophila is maintained by targeted transposition of three non-LTR retrotransposons: HeT-A, TART and TAHRE (HTT), but understanding the regulation of this process is hindered by our poor knowledge of HTT associated proteins. We have identified new protein components of the HTT array: Chromator (Chro), the TRF2/DREF complex and the sumoylation machinery. Chro was localized on telomeric HTT arrays by immunostaining, where it may interact with Prod directly, as indicated by yeast two-hybrid interaction, co-IP, and colocalization on polytene chromosomes. The TRF2/DREF complex may promote the open structure of HTT chromatin. The protein interactions controlling HTT chromatin structure and telomere length may be modulated by sumoylation.

Telomeric regions in Drosophila are composed of three subdomains. A chromosome cap distinguishes the chromosome end from a DNA double-strand break; an array of retrotransposons, HeT-A, TART, and TAHRE (HTT), maintains telomere length by targeted transposition to chromosome ends; and telomere-associated sequence (TAS), which consists of a mosaic of complex repeated sequences, has been identified as a source of gene silencing. Heterochromatin protein 1 (HP1) and HP1-ORC-associated protein (HOAP) are major protein components of the telomere cap in Drosophila and are required for telomere stability. Besides the chromosome cap, HP1 is also localized along the HTT array and in TAS. Mutants for Su(var)205, the gene encoding HP1, have decreased the HP1 level in the HTT array and increased transcription of individual HeT-A elements. This suggests that HP1 levels directly affect HeT-A activity along the HTT array, although they have little or no effect on transcription of a white reporter gene in the HTT. Chromatin immunoprecipitation to identify other heterochromatic proteins indicates that TAS and the HTT array may be distinct from either heterochromatin or euchromatin.

Background: Lifestyle interventions are often recommended as initial treatment for mild hypertension, but the efficacy of relaxation therapies is unclear., Objectives: To evaluate the effects of relaxation therapies on cardiovascular outcomes and blood pressure in people with elevated blood pressure., Search Strategy: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review., Inclusion Criteria: RCTs of a parallel design comparing relaxation therapies with no active treatment, or sham therapy; follow-up >/=8 weeks; participants over 18 years, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg); SBP and DBP reported at end of follow-up., Exclusion Criteria: participants were pregnant; participants received antihypertensive medication which changed during the trial., Data Collection and Analysis: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted., Main Results: 29 RCTs, with eight weeks to five years follow-up, met our inclusion criteria; four were excluded from the primary meta-analysis because of inadequate outcome data. The remaining 25 trials assessed 1,198 participants, but adequate randomisation was confirmed in only seven trials and concealment of allocation in only one. Only one trial reported deaths, heart attacks and strokes (one of each). Meta-analysis indicated that relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mmHg, 95% CI: -8.2 to -2.8, I2 =72%) and DBP (mean difference: -3.5 mmHg, 95% CI: -5.3 to -1.6, I2 =75%) compared to control. The substantial heterogeneity between trials was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The nine trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mmHg, 95% CI: -7.7 to 1.4, I(2) =69%) associated with relaxation. The 15 trials comparing relaxation with sham therapy likewise found a non-significant reduction in blood pressure (SBP mean difference: -3.5 mmHg, 95% CI: -7.1 to 0.2, I(2) =63%)., Authors' Conclusions: In view of the poor quality of included trials and unexplained variation between trials, the evidence in favour of causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.

Drosophila telomeres comprise DNA sequences that differ dramatically from those of other eukaryotes. Telomere functions, however, are similar to those found in telomerase-based telomeres, even though the underlying mechanisms may differ. Drosophila telomeres use arrays of retrotransposons to maintain chromosome length, while nearly all other eukaryotes rely on telomerase-generated short repeats. Regardless of the DNA sequence, several end-binding proteins are evolutionarily conserved. Away from the end, the Drosophila telomeric and subtelomeric DNA sequences are complexed with unique combinations of proteins that also modulate chromatin structure elsewhere in the genome. Maintaining and regulating the transcriptional activity of the telomeric retrotransposons in Drosophila requires specific chromatin structures and, while telomeric silencing spreads from the terminal repeats in yeast, the source of telomeric silencing in Drosophila is the subterminal arrays. However, the subterminal arrays in both species may be involved in telomere-telomere associations and/or communication., ((c) 2007 Wiley Periodicals, Inc.)

Background: Based on equivocal clinical data, intravenous antioxidant therapy has been used for the treatment of severe acute pancreatitis. To date there is no randomised comparison of this therapy in severe acute pancreatitis., Methods: We conducted a randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. Forty-three patients were enrolled from three hospitals in the Manchester (UK) area over the period June 2001 to November 2004. Randomisation stratified for APACHE-II score and hospital site, and delivered groups that were similar at baseline., Results: Relative serum levels of antioxidants rose while markers of oxidative stress fell in the active treatment group during the course of the trial. However, at 7 days, there was no statistically significant difference in the primary end point, organ dysfunction (antioxidant vs placebo: 32% vs 17%, p = 0.33) or any secondary end point of organ dysfunction or patient outcome., Conclusions: This study provides no evidence to justify continued use of n-acetylcysteine, selenium, vitamin C based antioxidant therapy in severe acute pancreatitis. In the context of any future trial design, careful consideration must be given to the risks raised by the greater trend towards adverse outcome in patients in the treatment arm of this study.

Chromosome length in Drosophila is maintained by targeted transposition of three non-long terminal repeat retrotransposons, HeT-A, TART, and TAHRE, to the chromosome ends. The length and composition of these retrotransposon arrays can vary significantly between chromosome tips and between fly stocks, but the significance and consequences of these length differences are not understood. A dominant genetic factor, Tel, has been described, which causes a severalfold elongation of the retrotransposon arrays at all telomeres. We used this strain to assess possible affects of extended telomeres on the organism. While we found no effect on life span of the adults, we could demonstrate a correlation between long telomeres and reduced fertility and fecundity in individual females, which is also reflected in abnormal oocyte development.

Developing from a previous review, this article revisits the generalisability theme to summarise recent advances in methodology and provide an update of challenges faced by producers and users of pharmacoeconomic data. Our original evaluative criteria encompassed technical issues, applicability and transferability. The technical elements of best practice are comparatively uncontroversial: choosing relevant alternatives; transparent reporting of methods and findings; accessing and applying the best-quality evidence; using best methods to synthesise data; and using deterministic sensitivity analysis to explore potential systematic bias whilst employing probabilistic sensitivity analysis to explore the influence of random error at the whole model level. The applicability of economic findings within their original policy context (e.g. national analyses based on generalisable within-country data) can be determined, provided that best practice guidelines for economic modelling are adhered to. The transferability of economic findings (from one policy setting to another, e.g. country, region, clinical setting or patient population) requires careful exploration of changes in resource implications, unit prices and outcomes, a process facilitated again by transparent reporting of methods, adjustment for baseline risk and potentially by recent statistical developments intended to deal with hierarchically structured data. Although there is considerable consensus in the published literature about these key issues, limitations remain for economic analysis as implemented because of its opaqueness of method, failure to reflect the opportunity cost of decisions and lack of societal mandate. If the primary purpose of health economic evaluation is to help society to obtain the best value from limited resources, then, at a time when most technologically advanced societies need to engage with the realities of limited healthcare funding, technocratic solutions alone appear insufficient. Making health economic findings accessible to patients, clinicians and society, in the form of relevant narratives, will help this essential debate and expose assumptions underpinning economic analysis to broader critical inspection.

The treatment of diabetic wounds is a formidable clinical challenge. In this study, lentiviral vectors carrying the human platelet-derived growth factor B (PDGF-B) gene were used to treated diabetic mouse wounds. Full-thickness 2.0-cm x 2.0-cm excisional wounds were created on the dorsa of genetically diabetic C57BL/KsJ-m+/+Lepr(db) mice. Lentiviral vectors containing the PDGF-B gene were injected into the wound margins and base. Mice were killed at 14-, 21-, and 35-day intervals. Measurement of the residual epithelial gap showed a trend towards increased healing in lentiviral PDGF-treated wounds compared with untreated and saline-treated wounds at all time points. At 21 days, there was significantly increased healing in lentiviral PDGF-treated wounds (0.98+/-0.17 cm) compared with saline-treated wounds (1.22+/-0.30 cm; P<0.05). Immunohistochemistry for CD31 revealed significantly increased neovascularization in lentiviral PDGF-treated wounds compared with untreated and saline-treated wounds at 14 and 21 days (P<0.01). Picrosirius red staining demonstrated thicker and more highly organized collagen fibers in treated wounds compared with untreated and saline-treated wounds. Quantitative analysis of collagen content showed a 3.5-fold and 2.3-fold increase in lentiviral PDGF-treated wounds versus untreated and saline-treated wounds, respectively (P<0.01). Lentiviral gene therapy with PDGF-B can sustain diabetic wound healing over time and may possess promising potential in the clinical setting.

Heterochromatin is a specialized chromatin structure in chromosomal regions associated with repeated DNA sequences and low concentrations of genes. Formation of heterochromatin is determined in large part by enzymes that modify histones and structural proteins that bind to these modified histones in a cooperative fashion. In Drosophila, mutations in genes that encode heterochromatic proteins are often dominant and increase expression of genes placed into heterochromatic positions. To find components of telomeric heterochromatin in Drosophila, we screened a collection of autosomal deficiencies for dominant suppressors of silencing of a transgene at the telomere of chromosome 2L. While many deficiency chromosomes are associated with dominant suppressors, in the cases tested on chromosome 2 the suppressor mapped to the 2L telomere, rather than the deficiency. We infer that background effects may hamper the search for genes that play a role in telomeric heterochromatin formation and that either very few genes participate in this pathway or mutations in these genes are not dominant suppressors of telomeric position effect. The data also suggest that the 2L telomere region plays a major role in telomeric silencing.

The terminal DNA arrays on chromosomes of Drosophila melanogaster are composed of two families of non-LTR retrotransposons, HeT-A and TART. Available evidence suggests that chromosome length in this species and its close relatives is maintained by targeted transposition of these elements, with attachment of the elements to the chromosome end by their 3' oligo(A) tails. However, the regulation of transposition of these elements and the control of telomere length are poorly understood. Here we present the hypothesis that the forces involved in telomere length regulation in Drosophila are the underlying forces that manifest themselves as telomeric position effect (TPE). Based on recent studies of TPE, which found that expression of a reporter gene is influenced by telomere structure in cis and trans, we propose that the subtelomeric satellite (TAS) in D. melanogaster plays an important role in controlling telomere elongation. Transcription of a HeT-A element is probably initiated at a promoter in the 3' UTR of an upstream element, and TAS may repress this transcriptional activity in cis and trans. A region of HeT-A not at the extreme 3' end of the element may act as a transcriptional enhancer that may be modulated by TAS.

One model of telomeric position effect (TPE) in Drosophila melanogaster proposes that reporter genes in the vicinity of telomeres are repressed by subterminal telomere-associated sequences (TAS) and that variegation of these genes is the result of competition between the repressive effects of TAS and the stimulating effects of promoters in the terminal HeT-A transposon array. The data presented here support this model, but also suggest that TPE is more complex. Activity of a telomeric white reporter gene increases in response to deletion of some or all of the TAS on the homolog. Only transgenes next to fairly long HeT-A arrays respond to this trans-interaction. HeT-A arrays of 6-18 kb respond by increasing the number of dark spots on the eye, while longer arrays increase the background eye color or increase the number of spots sufficiently to cause them to merge. Thus, expression of a subtelomeric reporter gene is influenced by the telomere structure in cis and trans. We propose that the forces involved in telomere length regulation in Drosophila are the underlying forces that manifest themselves as TPE. In the wild-type telomere TAS may play an important role in controlling telomere elongation by repressing HeT-A promoter activity. Modulation of this repression by the homolog may thus regulate telomere elongation.