Abstract Purpose This multi-disciplinary, evidence-based guideline for clinically non-metastatic muscle-invasive bladder cancer focuses on the evaluation, treatment, and surveillance of ...muscle-invasive bladder cancer guided toward curative intent. Materials and Methods A systematic review utilizing research from the Agency for Healthcare Research and Quality (AHRQ) as well as additional supplementation by the authors and consultant methodologists was used to develop the guideline. Evidence-based statements were based on body of evidence strengths Grade A, B, or C and were designated as Strong, Moderate, and Conditional Recommendations with additional statements presented in the form of Clinical Principles or Expert Opinions. (Table 1) Results For the first time, for any type of malignancy, the American Urological Association (AUA), the American Society of Clinical Oncology (ASCO), the American Society for Radiation Oncology (ASTRO), and the Society of Urologic Oncology (SUO) have formulated an evidence-based guideline based on a risk-stratified clinical framework for the management of muscle-invasive urothelial bladder cancer. This document is designed to be used in conjunction with the associated treatment algorithm. Conclusions The intensity and scope of care for muscle-invasive bladder cancer should focus on the patient, disease, and treatment response characteristics. This guideline attempts to improve a clinician’s ability to evaluate and treat each patient, but higher quality evidence in future trials will be essential to improve level of care for these patients.
Summary Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment ...can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.
In a cluster-randomized trial conducted in five ICUs, a nurse-led family-support intervention did not affect surrogates’ scores for anxiety and depression 6 months after the patients’ ...hospitalization, but it improved surrogates’ ratings of the patient-centeredness of care.
Background Abelmoschus manihot , a single medicament of traditional Chinese medicine, has been widely used to treat kidney disease. This is the first randomized controlled clinical trial to assess ...its efficacy and safety in patients with primary glomerular disease. Study Design Prospective, open-label, multicenter, randomized, controlled, clinical trial. Setting & Participants From May 2010 to October 2011, a total of 417 patients with biopsy-proven primary glomerular disease from 26 hospitals participated in the study. Interventions A manihot in the form of a huangkui capsule, 2.5 g, 3 times per day; losartan potassium, 50 mg/d; or combined treatment, a huangkui capsule at 2.5 g 3 times per day, was combined with losartan potassium, 50 mg/d. The duration of intervention was 24 weeks. Outcomes & Measurements The primary outcome was change in 24-hour proteinuria from baseline after treatment. Change in estimated glomerular filtration rate (eGFR) from baseline after treatment was a secondary outcome. The 24-hour proteinuria was measured every 4 weeks and eGFR was measured at 0, 4, 12, and 24 weeks. Results Mean baseline urine protein excretion was 1,045, 1,084, and 1,073 mg/d in the A manihot , losartan, and combined groups, respectively, and mean eGFR was 108, 106, and 106 mL/min/1.73 m2 , respectively. After 24 weeks of treatment, mean changes in proteinuria were protein excretion of −508, −376, and −545 mg/d, respectively ( P = 0.003 for A manihot vs losartan and P < 0.001 for the combined treatment vs losartan). Mean eGFR did not change significantly. The incidence of adverse reactions was not different among the 3 groups ( P > 0.05), and there were no severe adverse events in any group. Limitations Results cannot be generalized to those with nephrotic syndrome or reduced eGFR. Conclusions A manihot is a promising therapy for patients with primary kidney disease (chronic kidney disease stages 1-2) with moderate proteinuria.
Abstract Background Experimental and epidemiologic data suggest that among non-pregnant adults, sleep duration may be an important risk factor for chronic disease. Although pregnant women commonly ...complain of poor sleep, few studies have objectively evaluated the quality of sleep in pregnancy or have explored the relationship between sleep disturbances and maternal and perinatal outcomes. Objectives Our objective was to examine the relationship between objectively assessed sleep duration, timing and continuity (measured via wrist actigraphy) and maternal cardiovascular and metabolic morbidity specific to pregnancy. Study Design This was a prospective cohort study of nulliparous women. Women were recruited between 16 0/7 and 21 6/7 weeks’ gestation. They were asked to wear a wrist actigraphy monitor and to complete a daily sleep log for a seven consecutive-day period. The primary sleep exposure variables were the averages of the following over the total valid nights (minimum 5, maximum 7 nights): short sleep duration during the primary sleep period (< 7 hours/night), late sleep midpoint (midpoint between sleep onset and sleep offset > 5 AM), and top quartile of minutes of wake time after sleep onset (WASO) and sleep fragmentation index. The primary outcomes of interest were a composite of hypertensive disorders of pregnancy (mild, severe, or superimposed preeclampsia; eclampsia; or antepartum gestational hypertension) and gestational diabetes (GDM). Chi-square tests were used to assess associations between sleep variables and categorical baseline characteristics. Crude odds ratios and 95% confidence intervals were estimated from univariate logistic regression models to characterize the magnitude of the relationship between sleep characteristics and hypertensive disorders of pregnancy and GDM. For associations that were significant in univariate analysis, multiple logistic regression was used to explore further the association of sleep characteristics with pregnancy outcomes. Results Nine-hundred and one eligible women consented to participate. Of these women 782 submitted valid actigraphy studies. Short sleep duration and a later sleep midpoint were associated with an increased risk of GDM (OR 2.24, 95% CI 1.11, 4.53; OR 2.58, 95% CI 1.24, 5.36, respectively) but not of hypertensive disorders. A model with both sleep duration and sleep midpoint as well as their interaction term revealed that while there was no significant interaction between these exposures, the main effects of both short sleep duration and later sleep midpoint with GDM remained significant (aOR 2.06, 95% CI 1.01, 4.19; aOR 2.37, 95% CI 1.13, 4.97, respectively). Additionally, after adjusting separately for age, BMI and race/ethnicity, both short sleep duration and later sleep midpoint remained associated with GDM. No associations were demonstrated between the sleep quality measures (WASO, sleep fragmentation) and hypertensive disorders or GDM. Conclusions Our results demonstrate a relationship between short sleep duration and later sleep midpoint with GDM. Our data suggest independent contributions of these two sleep characteristics to the risk for GDM in nulliparous women.
Resveratrol, a phytochemical found in various plants and Chinese herbs, is associated with multiple tumor-suppressing activities, has been tested in clinical trials. However, the molecular mechanisms ...involved in resveratrol-mediated tumor suppressing activities are not yet completely defined. Here, we showed that treatment with resveratrol inhibited cell mobility through induction of the mesenchymal-epithelial transition (MET) in lung cancer cells. We also found that downregulation of FOXC2 (forkhead box C2) is critical for resveratrol-mediated suppression of tumor metastasis in an in vitro and in vivo models. We also identified a signal cascade, namely, resveratrol-∣miRNA-520h-∣PP2A/C-∣Akt → NF-κB → FOXC2, in which resveratrol inhibited the expression of FOXC2 through regulation of miRNA-520h-mediated signal cascade. This study identified a new miRNA-520h-related signal cascade involved in resveratrol-mediated tumor suppression activity and provide the clinical significances of miR-520h, PP2A/C and FOXC2 in lung cancer patients. Our results indicated a functional link between resveratrol-mediated miRNA-520h regulation and tumor suppressing ability, and provide a new insight into the role of resveratrol-induced molecular and epigenetic regulations in tumor suppression.
Summary Background Whether concomitant therapy is superior to bismuth quadruple therapy or 14-day triple therapy for the first-line treatment of Helicobacter pylori infection remains poorly ...understood. We aimed to compare the efficacy and safety of 10-day concomitant therapy, 10-day bismuth quadruple therapy, and 14-day triple therapy in the first-line treatment of H pylori. Methods In this multicentre, open-label, randomised trial, we recruited adult patients (aged >20 years) with H pylori infection from nine medical centres in Taiwan. Patients who had at least two positive tests from the rapid urease test, histology, culture, or serology or who had a single positive13 C-urea breath test for gastric cancer screening were eligible for enrolment. Patients were randomly assigned (1:1:1) to either concomitant therapy (lansoprazole 30 mg, amoxicillin 1 g, clarithromycin 500 mg, and metronidazole 500 mg, all given twice daily) for 10 days; bismuth quadruple therapy (bismuth tripotassium dicitrate 300 mg four times a day, lansoprazole 30 mg twice daily, tetracycline 500 mg four times a day, and metronidazole 500 mg three times a day) for 10 days; or triple therapy (lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg, all given twice daily) for 14 days. A computer-generated permuted block randomisation sequence with a block size of 6 was used for randomisation, and the sequence was concealed in an opaque envelope until the intervention was assigned. Investigators were masked to treatment allocation. The primary outcome was the eradication frequency of H pylori with first-line therapy assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT01906879. Findings Between July 17, 2013, and April 20, 2016, 5454 patients were screened for eligibility. Of these, 1620 patients were randomly assigned in this study. The eradication frequencies were 90·4% (488/540 95% CI 87·6–92·6) for 10-day bismuth quadruple therapy, 85·9% (464/540 82·7–88·6) for 10-day concomitant therapy, and 83·7% (452/540 80·4–86·6) for 14-day triple therapy in the intention-to-treat analysis. 10-day bismuth quadruple therapy was superior to 14-day triple therapy (difference 6·7% 95% CI 2·7–10·7, p=0·001), but not 10-day concomitant therapy. 10-day concomitant therapy was not superior to 14-day triple therapy. The frequency of adverse events was 67% (358/533) in patients treated with 10-day bismuth quadruple therapy, 58% (309/535) in patients treated with 10-day concomitant therapy, and 47% (252/535) in patients treated with 14-day triple therapy. Interpretation Bismuth quadruple therapy is preferable to 14-day triple therapy in the first-line treatment in the face of rising prevalence of clarithromycin resistance. Concomitant therapy given for 10 days might not be optimum and a longer treatment length should be considered. Funding National Taiwan University Hospital and Ministry of Science and Technology of Taiwan.
Background
This is the fourth updated Enhanced Recovery After Surgery (ERAS
®
) Society guideline presenting a consensus for optimal perioperative care in colorectal surgery and providing graded ...recommendations for each ERAS item within the ERAS
®
protocol.
Methods
A wide database search on English literature publications was performed. Studies on each item within the protocol were selected with particular attention paid to meta-analyses, randomised controlled trials and large prospective cohorts and examined, reviewed and graded according to Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system.
Results
All recommendations on ERAS
®
protocol items are based on best available evidence; good-quality trials; meta-analyses of good-quality trials; or large cohort studies. The level of evidence for the use of each item is presented accordingly.
Conclusions
The evidence base and recommendation for items within the multimodal perioperative care pathway are presented by the ERAS
®
Society in this comprehensive consensus review.
Living systems can generate an enormous range of cellular functions, from mechanical infrastructure and signalling networks to enzymatic catalysis and information storage, using a notably limited set ...of chemical functional groups. This observation is especially notable when compared to the breadth of functional groups used as the basis for similar functions in synthetically derived small molecules and materials. The relatively small cross-section between biological and synthetic reactivity space forms the foundation for the development of bioorthogonal chemistry, in which the absence of a pair of reactive functional groups within the cell allows for a selective in situ reaction
. However, biologically 'rare' functional groups, such as the fluoro
, chloro
, bromo
, phosphonate
, enediyne
, cyano
, diazo
, alkene
and alkyne
groups, continue to be discovered in natural products made by plants, fungi and microorganisms, which offers a potential route to genetically encode the endogenous biosynthesis of bioorthogonal reagents within living organisms. In particular, the terminal alkyne has found broad utility via the Cu(I)-catalysed azide-alkyne cycloaddition 'click' reaction
. Here we report the discovery and characterization of a unique pathway to produce a terminal alkyne-containing amino acid in the bacterium Streptomyces cattleya. We found that L-lysine undergoes an unexpected reaction sequence that includes halogenation, oxidative C-C bond cleavage and triple bond formation through a putative allene intermediate. This pathway offers the potential for de novo cellular production of halo-, alkene- and alkyne-labelled proteins and natural products from glucose for a variety of downstream applications.
Summary Background Whether sequential treatment can replace triple therapy as the standard treatment for Helicobacter pylori infection is unknown. We compared the efficacy of sequential treatment for ...10 days and 14 days with triple therapy for 14 days in first-line treatment. Methods For this multicentre, open-label, randomised trial, we recruited patients (≥20 years of age) with H pylori infection from six centres in Taiwan. Using a computer-generated randomisation sequence, we randomly allocated patients (1:1:1; block sizes of six) to either sequential treatment (lansoprazole 30 mg and amoxicillin 1 g for the first 7 days, followed by lansoprazole 30 mg, clarithromycin 500 mg, and metronidazole 500 mg for another 7 days; with all drugs given twice daily) for either 10 days (S-10) or 14 days (S-14), of 14 days of triple therapy (T-14; lansoprazole 30 mg, amoxicillin 1 g, and clarithromycin 500 mg for 14 days; with all drugs given twice daily). Investigators were masked to treatment allocation. Our primary outcome was the eradication rate in first-line treatment by intention-to-treat (ITT) and per-protocol (PP) analyses. This trial is registered with ClinicalTrials.gov , number NCT01042184. Findings Between Dec 28, 2009, and Sept 24, 2011, we enrolled 900 patients: 300 to each group. The eradication rate was 90·7% (95% CI 87·4–94·0; 272 of 300 patients) in the S-14 group, 87·0% (83·2–90·8; 261 of 300 patients) in the S-10 group, and 82·3% (78·0–86·6; 247 of 300 patients) in the T-14 group. Treatment efficacy was better in the S-14 group than it was in the T-14 group in both the ITT analysis (number needed to treat of 12·0 95% CI 7·2–34·5; p=0·003) and PP analyses (13·7 8·3–40, p=0·003). We recorded no significant difference in the occurrence of adverse effects or in compliance between the three groups. Interpretation Our findings lend support to the use of sequential treatment as the standard first-line treatment for H pylori infection. Funding National Taiwan University Hospital and National Science Council.
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