The incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with angiotensin converting enzyme inhibitors (ACEIs) and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database.
A total of 1094 nondiabetic adults with hypertensive CKD (glomerular filtration rate [GFR], 20–65 mL/min/1.73 m2) were followed for 3.0 to 6.4 years in the AASK trial. Participants were randomly assigned to ACEI, β-blocker (BB), or dihydropyridine calcium channel blocker (CCB). The outcome variables for this analysis were a serum potassium level higher than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center initiated hyperkalemia stop point.
A total of 6497 potassium measurements were obtained, and 80 events in 51 subjects were identified (76 events driven by a central laboratory result and 4 driven by a clinical center–initiated hyperkalemia stop point). Compared with a GFR higher than 50 mL/min/1.73 m2, after multivariable adjustment, the hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/min/1.73 m2 and a GFR lower than 30 mL/min/1.73 m2 was 3.61 (95% confidence interval [CI], 1.42–9.18 [P=.007]) and 6.81 (95% CI, 2.67–17.35 [P<.001]), respectively; there was no increased risk of hyperkalemia if GFR was 41 to 50 mL/min/1.73 m2. Use of ACEIs was associated with more episodes of hyperkalemia compared with CCB use (HR, 7.00; 95% CI, 2.29–21.39 [P<.001]) and BB group (HR, 2.85; 95% CI, 1.50–5.42 [P=.001]). Diuretic use was associated with a 59% decreased risk of hyperkalemia.
In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m2. Including a diuretic in the regimen may markedly reduce risk of hyperkalemia.
The gastric sling muscle has not been investigated for possible sensory innervation, in spite of the key roles the structure plays in lower esophageal sphincter (LES) function and gastric physiology. Thus, the present experiment used tracing techniques to label vagal afferents and survey their projections in the lesser curvature.
Sprague Dawley rats received injections of dextran biotin into the nodose ganglia. Fourteen days post-injection, animals were euthanized and their stomachs were processed to visualize the vagal afferent innervation. In different cases, neurons, muscle cells, or interstitial cells of Cajal were counterstained.
The sling muscle is innervated throughout its length by vagal afferent intramuscular arrays (IMAs) associated with interstitial cells of Cajal. In addition, the distal antral attachment site of the sling muscle is innervated by a novel vagal afferent terminal specialization, an antral web ending. The muscle wall of the distal antrum is also innervated by conventional IMAs and intraganglionic laminar endings (IGLEs), the two types of mechanoreceptors found throughout stomach smooth muscle.
Conclusions & Inferences
The innervation of sling muscle by IMAs, putative stretch receptors, suggests that sling sensory feedback may generate vago-vagal or other reflexes with vagal afferent limbs. The restricted distribution of afferent web endings near the antral attachments of sling fibers suggests the possibility of specialized mechanoreceptor functions linking antral and pyloric activity to the operation of the LES. Dysfunctional sling afferents could generate LES motor disturbances, or normative compensatory sensory feedback from the muscle could compromise therapies targeting only effectors.
interstitial cells of Cajal; lower esophageal sphincter; mechanoreceptor; reflux; vagus
Interactions between macrophages and the autonomic innervation of gastrointestinal (GI) tract smooth muscle have received little experimental attention. To better understand this relationship, immunohistochemistry was performed on GI whole mounts from rats at three ages. The phenotypes, morphologies, and distributions of gut macrophages are consistent with the cells performing extensive housekeeping functions in the smooth muscle layers. Specifically, a dense population of macrophages was located throughout the muscle wall where they were distributed among the muscle fibers and along the vasculature. Macrophages were also associated with ganglia and connectives of the myenteric plexus and with the sympathetic innervation. Additionally, these cells were in tight registration with the dendrites and axons of the myenteric neurons as well as the varicosities along the length of the sympathetic axons, suggestive of a contribution by the macrophages to the homeostasis of both synapses and contacts between the various elements of the enteric circuitry. Similarly, macrophages were involved in the presumed elimination of neuropathies as indicated by their association with dystrophic neurons and neurites which are located throughout the myenteric plexus and smooth muscle wall of aged rats. Importantly, the patterns of macrophage-neuron interactions in the gut paralleled the much more extensively characterized interactions of macrophages (i.e., microglia) and neurons in the CNS. The present observations in the PNS as well as extrapolations from homologous microglia in the CNS suggest that GI macrophages play significant roles in maintaining the nervous system of the gut in the face of wear and tear, disease, and aging.
aged; alpha-synuclein; CD163; myenteric; MHCII; muscularis; resident macrophage; sympathetic
Federally Qualified Health Centers are expanding to increase access for millions of more Americans with a goal of doubling capacity to serve 40 million people. Health centers provide a lot of behavioral health services but many have difficulty accessing mental health and substance use professionals for their patients. To meet the needs of the underserved and newly insured it is important to better estimate how many behavioral health professionals are needed.
Using health center staffing data and behavioral health service patterns from the 2010 Uniform Data System and the 2010 National Survey on Drug Use and Health, we estimated the number of patients likely to need behavioral health care by insurance type, the number of visits likely needed by health center patients annually, and the number of full time equivalent providers needed to serve them.
More than 2.5 million patients, 12 or older, with mild or moderate mental illness, and more than 357,000 with substance abuse disorders, may have gone without needed behavioral health services in 2010. This level of need would have required more than 11,600 full time providers. This translates to approximately 0.9 licensed mental health provider FTE, 0.1 FTE psychiatrist, 0.4 FTE other mental health staff, and 0.3 FTE substance abuse provider per 2,500 patients. These estimates suggest that 90% of current centers could not access mental health services or provide substance abuse services to fully meet patients’ needs in 2010. If needs are similar after health center expansion, more than 27,000 full time behavioral health providers will be needed to serve 40 million medical patients, and grantees will need to increase behavioral health staff more than four-fold.
More behavioral health is seen in primary care than in any other setting, and health center clients have greater behavioral health needs than typical primary care patients. Most health centers needed additional behavioral health services in 2010, and this need will be magnified to serve 40 million patients. Further testing of these workforce models are needed, but the degree of current underservice suggests that we cannot wait to move on closing the gap.
In observational studies, the relationship between blood pressure and end-stage renal disease (ESRD) is direct and progressive. The burden of hypertension-related chronic kidney disease and ESRD is especially high among black patients. Yet few trials have tested whether intensive blood-pressure control retards the progression of chronic kidney disease among black patients.
We randomly assigned 1094 black patients with hypertensive chronic kidney disease to receive either intensive or standard blood-pressure control. After completing the trial phase, patients were invited to enroll in a cohort phase in which the blood-pressure target was less than 130/80 mm Hg. The primary clinical outcome in the cohort phase was the progression of chronic kidney disease, which was defined as a doubling of the serum creatinine level, a diagnosis of ESRD, or death. Follow-up ranged from 8.8 to 12.2 years.
During the trial phase, the mean blood pressure was 130/78 mm Hg in the intensive-control group and 141/86 mm Hg in the standard-control group. During the cohort phase, corresponding mean blood pressures were 131/78 mm Hg and 134/78 mm Hg. In both phases, there was no significant between-group difference in the risk of the primary outcome (hazard ratio in the intensive-control group, 0.91; P = 0.27). However, the effects differed according to the baseline level of proteinuria (P = 0.02 for interaction), with a potential benefit in patients with a protein-to-creatinine ratio of more than 0.22 (hazard ratio, 0.73; P = 0.01).
In overall analyses, intensive blood-pressure control had no effect on kidney disease progression. However, there may be differential effects of intensive blood-pressure control in patients with and those without baseline proteinuria. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Center on Minority Health and Health Disparities, and others.)
For digestion of starch in humans, α-amylase first hydrolyzes starch molecules to produce α-limit dextrins, followed by complete hydrolysis to glucose by the mucosal α-glucosidases in the small intestine. It is known that α-1,6 linkages in starch are hydrolyzed at a lower rate than are α-1,4 linkages. Here, to create designed slowly digestible carbohydrates, the structure of waxy corn starch (WCS) was modified using a known branching enzyme alone (BE) and an in combination with β-amylase (BA) to increase further the α-1,6 branching ratio. The digestibility of the enzymatically synthesized products was investigated using α-amylase and four recombinant mammalian mucosal α-glucosidases. Enzyme-modified products (BE-WCS and BEBA-WCS) had increased percentage of α-1,6 linkages (WCS: 5.3%, BE-WCS: 7.1%, and BEBA-WCS: 12.9%), decreased weight-average molecular weight (WCS: 1.73×108 Da, BE-WCS: 2.76×105 Da, and BEBA-WCS 1.62×105 Da), and changes in linear chain distributions (WCS: 21.6, BE-WCS: 16.9, BEBA-WCS: 12.2 DPw). Hydrolysis by human pancreatic α-amylase resulted in an increase in the amount of branched α-limit dextrin from 26.8% (WCS) to 56.8% (BEBA-WCS). The α-amylolyzed samples were hydrolyzed by the individual α-glucosidases (100 U) and glucogenesis decreased with all as the branching ratio increased. This is the first report showing that hydrolysis rate of the mammalian mucosal α-glucosidases is limited by the amount of branched α-limit dextrin. When enzyme-treated materials were gavaged to rats, the level of postprandial blood glucose at 60 min from BEBA-WCS was significantly higher than for WCS or BE-WCS. Thus, highly branched glucan structures modified by BE and BA had a comparably slow digesting property both in vitro and in vivo. Such highly branched α-glucans show promise as a food ingredient to control postprandial glucose levels and to attain extended glucose release.
Evidence-based comparisons of interventions can be challenging because of the diversity of outcomes in randomized controlled trials (RCTs). We aimed to describe outcomes in RCTs assessing pulp treatments for primary teeth and to develop a core set of component outcomes to be part of composite outcome defining the failure of a pulp treatment.
We systematically reviewed articles of RCTs comparing pulp treatments for primary molars published up to February 2012. We abstracted all outcomes assessed in each trial, then used a small-group consensus process to group similar outcomes, which were reduced to a composite outcome of failure of a pulp treatment by a 3-round Delphi process involving expert authors and dentists.
We included 47 reports of RCTs in the review, for 83 reported outcomes (median 11 outcomes per RCT). These outcomes were grouped into 24 overarching outcome categories. We contacted 210 experts for the Delphi process and 25% to 30% participated. The process identified the following 5 component outcomes as part of a composite outcome of failure of a pulp treatment: soft-tissue pathology, pain, pathologic mobility, pathologic radiolucency and pathologic root resorption.
RCTs of pulp treatments for primary teeth investigate diverse outcomes. Our consensus process, involving clinicians but no patient, allowed for compiling a core set of component outcomes to define the composite outcome failure of a pulp treatment for primary teeth.
To systematically summarize the randomized trial evidence regarding the relative effectiveness of cognitive behavioural therapy (CBT) in patients with depression in receipt of disability benefits in comparison to those not receiving disability benefits.
All relevant RCTs from a database of randomized controlled and comparative studies examining the effects of psychotherapy for adult depression (http://www.evidencebasedpsychotherapies.org), electronic databases (MEDLINE, EMBASE, PSYCINFO, AMED, CINAHL and CENTRAL) to June 2011, and bibliographies of all relevant articles.
Study Eligibility Criteria, Participants and Intervention
Adult patients with major depression, randomly assigned to CBT versus minimal/no treatment or care-as-usual.
Study Appraisal and Synthesis Methods
Three teams of reviewers, independently and in duplicate, completed title and abstract screening, full text review and data extraction. We performed an individual patient data meta-analysis to summarize data.
Of 92 eligible trials, 70 provided author contact information; of these 56 (80%) were successfully contacted to establish if they captured receipt of benefits as a baseline characteristic; 8 recorded benefit status, and 3 enrolled some patients in receipt of benefits, of which 2 provided individual patient data. Including both patients receiving and not receiving disability benefits, 2 trials (227 patients) suggested a possible reduction in depression with CBT, as measured by the Beck Depression Inventory, mean difference [MD] (95% confidence interval [CI]) = −2.61 (−5.28, 0.07), p = 0.06; minimally important difference of 5. The effect appeared larger, though not significantly, in those in receipt of benefits (34 patients) versus not receiving benefits (193 patients); MD (95% CI) = −4.46 (−12.21, 3.30), p = 0.26.
Our data does not support the hypothesis that CBT has smaller effects in depressed patients receiving disability benefits versus other patients. Given that the confidence interval is wide, a decreased effect is still possible, though if the difference exists, it is likely to be small.
African American and Latino young men who have sex with men (YMSM) are at the forefront of the U.S. HIV epidemic. As members of the “cellular generation,” these youth are very likely to use text messaging; yet, relatively little research has explored use of text messaging as a tool for sexual health promotion, particularly among racial ethnic minorities who are also sexual minorities. We report on the results of ten focus groups conducted among African American and Latino YMSM, aged 18–25, regarding their current texting practices and the feasibility/acceptability of text messaging as a means of conducting sexual health promotion. Our analyses revealed four main themes around their texting behaviors, texting preferences, perceived advantages/disadvantages of texting, and the “etiquette” of texting. We consider implications of these findings for the development of texting-based sexual health promotion interventions, particularly in conjunction with other existing interventions operating in a new risk environment.
The kynurenine pathway is the major route for tryptophan catabolism in animals and some fungi and bacteria. The procaryotic enzyme preferentially reacts with L-kynurenine, while eucaryotic kynureninases exhibit higher activity with 3-hydroxy-L-kynurenine. Crystallography of kynureninases from Pseudomonas fluorescens (PfKyn) and Homo sapiens (HsKyn) shows that the active sites are nearly identical, except that His-102, Asn-333, and Ser-332 in HsKyn are replaced by Trp-64, Thr-282 and Gly-281 in PfKyn. Site-directed mutagenesis of HsKyn shows that these residues are, at least in part, responsible for the differences in substrate specificity, since the H102W/S332G/N333T triple mutant shows activity with kynurenine but not 3-hydroxykynurenine. PfKyn is strongly inhibited by analogues of a proposed gem-diolate intermediate, dihydrokynurenine and S-(2-aminophenyl)-L-cysteine S,S-dioxide, with Ki values in the low nM range. Stopped-flow kinetic experiments show that a transient quinonoid intermediate is formed on mixing, which decays to a ketimine at 740 s−1. Quench experiments show that anthranilate, the first product, is formed in a stoichiometric burst at 50 s−1, and thus the rate-determining step in the steady state is the release of the second product, L-Ala. β-Benzoylalanine is also a good substrate for PfKyn, but does not show a burst of benzoate formation, indicating that the rate-determining step for this substrate is benzoate release. A Hammett plot of rate constants for substituted β-benzoylalanines is non-linear, suggesting that carbonyl hydration is rate-determining for electron-donating groups, but Cβ-Cγ cleavage is rate-determining for electron-withdrawing groups.
Pyridoxal-5′-phosphate; tryptophan; reaction mechanism; crystallography; mutagenesis
Intramuscular arrays (IMAs), vagal mechanoreceptors that innervate gastrointestinal smooth muscle, have not been completely described structurally or functionally. To delineate more fully the architecture of IMAs and to consider the structure-function implications of the observations, the present experiment examined the organization of the IMA terminal arbors and the accessory tissue elements of those arbors. IMA terminal fields, labeled by injection of biotinylated dextran into the nodose ganglia, were examined in whole mounts of rat gastric smooth muscle double-labeled with immunohistochemistry for interstitial cells of Cajal (ICCs; c-Kit) and/or inputs of different neuronal efferent transmitter (markers: TH, VChAT, and NOS) or afferent neuropeptidergic (CGRP) phenotypes. IMAs make extensive varicose and lamellar contacts with ICCs. In addition, axons of the multiple efferent and afferent phenotypes examined converge and articulate with IMA terminal arbors innervating ICCs. This architecture is consistent with the hypothesis that IMAs, or the multiply innervated IMA-ICC complexes they form, can function as stretch receptors. The tissue organization is also consonant with the proposal that those units can operate as functional analogues of muscle spindle organs. For electrophysiological assessments of IMA functions, experiments will need protocols that preserve both the complex architecture and the dynamic operations of IMA-ICC complexes.
mechanosensitive afferents; mechanoreceptors; smooth muscle; stomach; stretch receptors; vagus nerve
Complementary and alternative medicine (CAM) is commonly used by children, but estimates of that use vary widely partly due to the range of questionnaires used to assess CAM use. However, no studies have attempted to appraise measurement properties of these questionnaires. The aim of this systematic review was to critically appraise and summarize measurement properties of questionnaires of CAM use in pediatrics.
A search strategy was implemented in major electronic databases in March 2011 and conference websites, scientific journals and experts were consulted. Studies were included if they mentioned a questionnaire assessing the prevalence of CAM use in pediatrics. Members of the team independently rated the methodological quality of the studies (using the COSMIN checklist) and measurement properties of the questionnaires (using the Terwee and Cohen criteria).
A total of 96 CAM questionnaires were found in 104 publications. The COSMIN checklist showed that no studies reported adequate methodological quality. The Terwee criteria showed that all included CAM questionnaires had indeterminate measurement properties. According to the Cohen score, none were considered to be a well-established assessment, two approached the level of a well-established assessment, seven were promising assessments and the remainder (n = 87) did not reach the score’s minimum standards.
None of the identified CAM questionnaires have been thoroughly validated. This systematic review highlights the need for proper validation of CAM questionnaires in pediatrics, which may in turn lead to improved research and knowledge translation about CAM in clinical practice.
The aim of this meta-analysis is to evaluate the impact of transthoracic resection on long-term survival of patients with GEJ cancer and to compare the postoperative morbidity and mortality of patients undergoing transthoracic resection with those of patients who were not undergoing transthoracic resection.
Searches of electronic databases identifying studies from Medline, Cochrane Library trials register, and WHO Trial Registration etc were performed. Outcome measures were survival, postoperative morbidity and mortality, and operation related events.
Twelve studies (including 5 RCTs and 7 non-RCTs) comprising 1105 patients were included in this meta-analysis, with 591 patients assigned treatment with transthoracic resection. Transthoracic resection did not increase the 5-y overall survival rate for RCTs and non-RCTs (HR = 1.01, 95% CI 0.80- 1.29 and HR = 0.89, 95% CI 0.70- 1.14, respectively). Stratified by the Siewert classification, our result showed no obvious differences were observed between the group with transthoracic resection and group without transthoracic resection (P>0.05). The postoperative morbidity (RR = 0.69, 95% CI 0.48- 1.00 and OR = 0.55, 95% CI 0.25- 1.22) and mortality (RD = −0.03, 95% CI −0.06- 0.00 and RD = 0.00, 95% CI −0.05- 0.05) of RCTs and non-RCTs did not suggest any significant differences between the two groups. Hospital stay was long with thransthoracic resection (WMD = −5.80, 95% CI −10.38- −1.23) but did not seem to differ in number of harvested lymph nodes, operation time, blood loss, numbers of patients needing transfusion, and reoperation rate. The results of sensitivity analyses were similar to the primary analyses.
There were no significant differences of survival rate and postoperative morbidity and mortality between transthoracic resection group and non-transthoracic resection group. Both surgical approaches are acceptable, and that one offers no clear advantage over the other. However, the results should be interpreted cautiously since the qualities of included studies were suboptimal.
Febrile neutropenia is a common and potentially life-threatening complication of treatment for childhood cancer, which has increasingly been subject to targeted treatment based on clinical risk stratification. Our previous meta-analysis demonstrated 16 rules had been described and 2 of them subject to validation in more than one study. We aimed to advance our knowledge of evidence on the discriminatory ability and predictive accuracy of such risk stratification clinical decision rules (CDR) for children and young people with cancer by updating our systematic review.
The review was conducted in accordance with Centre for Reviews and Dissemination methods, searching multiple electronic databases, using two independent reviewers, formal critical appraisal with QUADAS and meta-analysis with random effects models where appropriate. It was registered with PROSPERO: CRD42011001685.
We found 9 new publications describing a further 7 new CDR, and validations of 7 rules. Six CDR have now been subject to testing across more than two data sets. Most validations demonstrated the rule to be less efficient than when initially proposed; geographical differences appeared to be one explanation for this.
The use of clinical decision rules will require local validation before widespread use. Considerable uncertainty remains over the most effective rule to use in each population, and an ongoing individual-patient-data meta-analysis should develop and test a more reliable CDR to improve stratification and optimise therapy. Despite current challenges, we believe it will be possible to define an internationally effective CDR to harmonise the treatment of children with febrile neutropenia.
Background. The pulmonary artery catheter (PAC) is an accepted clinical method of measuring cardiac output (CO) despite no prior validation. The ultrasonic cardiac output monitor (USCOM) is a noninvasive alternative to PAC using Doppler ultrasound (CW). We compared PAC and USCOM CO measurements against a gold standard, the aortic flow probe (FP), in sheep at varying outputs. Methods. Ten conscious sheep, with implanted FPs, had measurements of CO by FP, USCOM, and PAC, at rest and during intervention with inotropes and vasopressors. Results. CO measurements by FP, PAC, and USCOM were 4.0 ± 1.2 L/min, 4.8 ± 1.5 L/min, and 4.0 ± 1.4 L/min, respectively, (n = 280, range 1.9 L/min to 11.7 L/min). Percentage bias and precision between FP and PAC, and FP and USCOM was −17 and 47%, and 1 and 36%, respectively. PAC under-measured Dobutamine-induced CO changes by 20% (relative 66%) compared with FP, while USCOM measures varied from FP by 3% (relative 10%). PAC reliably detected −30% but not +40% CO changes, as measured by receiver operating characteristic area under the curve (AUC), while USCOM reliably detected ±5% changes in CO (AUC > 0.70). Conclusions. PAC demonstrated poor accuracy and sensitivity as a measure of CO. USCOM provided equivalent measurements to FP across a sixfold range of outputs, reliably detecting ±5% changes.
Pyrrolnitrin is a commonly used and clinically effective treatment for fungal infections and provides the structural basis for the more widely used fludioxinil. The pyrrolnitrin biosynthetic pathway consists of four chemical steps, the second of which is the rearrangement of 7-chloro-tryptophan by the enzyme PrnB, a reaction that is so far unprecedented in biochemistry. When expressed in Pseudomonas fluorescens, PrnB is red in color due to the fact that it contains 1 mole of heme b per mole of protein. The crystal structure unexpectedly establishes PrnB as a member of the heme-dependent dioxygenase superfamily with significant structural but not sequence homology to the two-domain indoleamine 2,3-dioxygenase enzyme (IDO). The heme-binding domain is also structurally similar to that of tryptophan 2,3-dioxygenase (TDO). Here we report the binary complex structures of PrnB with D- and L-tryptophan and D- and L-chloro-tryptophan. The structures identify a common hydrophobic pocket for the indole ring but exhibit unusual heme ligation and substrate binding when compared with that observed in the TDO crystal structures. Our solution studies support the heme ligation observed in the crystal structures. Purification of the hexahistidine-tagged PrnB yields homogeneous protein that only displays in vitro activity with 7-chloro-L-tryptophan after reactivation with crude extract from the host strain, suggesting that an as yet unknown cofactor is required for activity. Mutation of the proximal heme ligand results, not surprisingly, in inactive enzyme. Redox titrations show that PrnB displays a significantly different reduction potential to that of IDO or TDO, indicating possible differences in the PrnB catalytic cycle. This is confirmed by the absence of tryptophan dioxygenase activity in PrnB, although a stable oxyferrous adduct (which is the first intermediate in the TDO/IDO catalytic cycle) can be generated. We propose that PrnB shares a key catalytic step with TDO and IDO, generation of a tryptophan hydroperoxide intermediate, although this species suffers a different fate in PrnB, leading to the eventual formation of the product, monodechloroaminopyrrolnitrin.
Primary biliary cirrhosis (PBC) is a chronic liver disease characterized by intrahepatic bile-duct destruction, cholestasis, and fibrosis. It can lead to cirrhosis and eventually liver failure. PBC also shows some regional differences with respect to incidence and prevalence that are becoming more pronounced each year. Recently, researchers have paid more attention to PBC. To evaluate the development of PBC research during the past 11 years, we determined the quantity and quality of articles on this subject. We also compared the contributions of scientists from the US, UK, Japan, Italy, Germany, and China.
The English-language papers covering PBC published in journals from 2000 through 2010 were retrieved from the PubMed database. We recorded the number of papers published each year, analyzed the publication type, and calculated the accumulated, average impact factors (IFs) and citations from every country. The quantity and quality of articles on PBC were compared by country. We also contrasted the level of PBC research in China and other countries.
The total number of articles did not significantly increase during the past 11 years. The number of articles from the US exceeded those from any other country; the publications from the US also had the highest IFs and the most citations. Four other countries showed complex trends with respect to the quantity and quality of articles about PBC.
The researchers from the US have contributed the most to the development of PBC research. They currently represent the highest level of research. Some high-level studies, such as RCTs, meta-analyses, and in-depth basic studies should be launched. The gap between China and the advanced level is still enormous. Chinese investigators still have a long way to go.
The long time to diagnosis of medulloblastoma, one of the most frequent brain tumors in children, is the source of painful remorse and sometimes lawsuits. We analyzed its consequences for tumor stage, survival, and sequelae.
Patients and Methods
This retrospective population-based cohort study included all cases of pediatric medulloblastoma from a region of France between 1990 and 2005. We collected the demographic, clinical, and tumor data and analyzed the relations between the interval from symptom onset until diagnosis, initial disease stage, survival, and neuropsychological and neurological outcome.
The median interval from symptom onset until diagnosis for the 166 cases was 65 days (interquartile range 31–121, range 3–457). A long interval (defined as longer than the median) was associated with a lower frequency of metastasis in the univariate and multivariate analyses and with a larger tumor volume, desmoplastic histology, and longer survival in the univariate analysis, but not after adjustment for confounding factors. The time to diagnosis was significantly associated with IQ score among survivors. No significant relation was found between the time to diagnosis and neurological disability. In the 62 patients with metastases, a long prediagnosis interval was associated with a higher T stage, infiltration of the fourth ventricle floor, and incomplete surgical resection; it nonetheless did not influence survival significantly in this subgroup.
We found complex and often inverse relations between time to diagnosis of medulloblastoma in children and initial severity factors, survival, and neuropsychological and neurological outcome. This interval appears due more to the nature of the tumor and its progression than to parental or medical factors. These conclusions should be taken into account in the information provided to parents and in expert assessments produced for malpractice claims.
Seeking ethics committee approval for research can be challenging even for relatively simple studies occurring in single settings. Complicating factors such as multicentre studies and/or contentious research issues can challenge review processes, and conducting such studies internationally adds a further layer of complexity. This paper draws on the experiences of the LINNAEUS Collaboration, an international group of primary care researchers, in obtaining ethics approval to conduct an international study investigating medical error in general practice in six countries. It describes the ethics review processes applied to exactly the same research protocol for a study run in Australia, Canada, England, the Netherlands, New Zealand, and the US. Wide variation in ethics review responses to the research proposal occurred, from no approval being deemed necessary to the study plan narrowly avoiding rejection. The authors' experiences demonstrated that ethics committees operate in their own historical and cultural context, which can lead to radically different subjective interpretations of commonly-held ethical principles, and raised further issues such as ‘what is research?’. This first LINNAEUS study started when patient safety was a particularly sensitive subject. Although it is now a respectable area of inquiry, patient safety is still a topic that can excite emotions and prejudices. The LINNAEUS Collaboration now extends to more countries and continues to pursue an international research agenda, so reflection on the influences of history, social context, and structure of each country's ethical review processes is timely.
ethics; patient safety; primary care; regulation
The effectiveness of skills laboratory training is widely recognized. Yet, the transfer of procedural skills acquired in skills laboratories into clinical practice has rarely been investigated. We conducted a prospective, randomised, double-blind, controlled trial to evaluate, if students having trained intravenous (IV) cannulation in a skills laboratory are rated as more professional regarding technical and communication skills compared to students who underwent bedside teaching when assessed objectively by independent video assessors and subjectively by patients.
Methodology and Principal Findings
84 volunteer first-year medical students were randomly assigned to one of two groups. Three drop-outs occurred. The intervention group (IG; n = 41) trained IV cannulation in a skills laboratory receiving instruction after Peyton's ‘Four-Step Approach’. The control group (CG; n = 40) received a bedside teaching session with volunteer students acting as patients. Afterwards, performance of IV cannulation of both groups in a clinical setting with students acting as patients was video-recorded. Two independent, blinded video assessors scored students' performance using binary checklists (BC) and the Integrated Procedural Protocol Instrument (IPPI). Patients assessed students' performance with the Communication Assessment Tool (CAT) and a modified IPPI. IG required significantly shorter time needed for the performance on a patient (IG: 595.4 SD(188.1)s; CG: 692.7 SD(247.8)s; 95%CI 23.5 s to 45.1 s; p = 0.049) and completed significantly more single steps of the procedure correctly (IG: 64% SD(14) for BC items; CG: 53% SD(18); 95%CI 10.25% to 11.75%; p = 0.004). IG also scored significantly better on IPPI ratings (median: IG: 3.1; CG: 3.6; p = 0.015;). Rated by patients, students' performance and patient-physician communication did not significantly differ between groups.
Transfer of IV cannulation-related skills acquired in a skills laboratory is superior to bedside teaching when rated by independent video raters by means of IPPI and BC. It enables students to perform IV cannulation more professionally on volunteer students acting as patients.
A number of published randomized controlled trials have been conducted to evaluate visual performance of blue light-filtering intraocular lenses (IOL) and UV light-filtering intraocular lenses (IOL) after cataract phacoemulsification surgery. However, results have not always been consistent. Therefore, we carried out a meta-analysis to compare the effectiveness of blue light-filtering IOLs versus UV light-filtering IOLs in cataract surgery.
Methods and Findings
Comprehensive searches of PubMed, Embase, Cochrane Library and the Chinese BioMedical literature databases were performed using web-based search engines. Fifteen trials (1690 eyes) were included for systematic review, and 11 of 15 studies were included in this meta-analysis. The results showed that there were no significant differences in postoperative mean best corrected visual acuity, contrast sensitivity, overall color vision, or in the blue light spectrum under photopic light conditions between blue light-filtering IOLs and UV light-filtering IOLs [WMD = −0.01, 95%CI (−0.03, 0.01), P = 0.46; WMD = 0.07, 95%CI (−0.04, 0.19), P = 0.20; SMD = 0.14, 95%CI (−0.33, 0.60), P = 0.566; SMD = 0.20, 95%CI (−0.04, 0.43), P = 0.099]. However, color vision with blue light-filtering IOLs was significantly reduced in the blue light spectrum under mesopic light conditions [SMD = 0.74, 95%CI (0.29, 1.18), P = 0.001].
This meta-analysis demonstrates that postoperative visual performance with blue light-filtering IOLs is approximately equal to that of UV light-filtering IOLs after cataract surgery, but color vision with blue light-filtering IOLs demonstrated some compromise in the blue light spectrum under mesopic light conditions.
A common and potentially life-threatening complication of the treatment of childhood cancer is infection, which frequently presents as fever with neutropenia. The standard management of such episodes is the extensive use of intravenous antibiotics, and though it produces excellent survival rates of over 95%, it greatly inconveniences the three-fourths of patients who do not require such aggressive treatment. There have been a number of studies which have aimed to develop risk prediction models to stratify treatment. Individual participant data (IPD) meta-analysis in therapeutic studies has been developed to improve the precision and reliability of answers to questions of treatment effect and recently have been suggested to be used to answer questions regarding prognosis and diagnosis to gain greater power from the frequently small individual studies.
In the IPD protocol, we will collect and synthesise IPD from multiple studies and examine the outcomes of episodes of febrile neutropenia as a consequence of their treatment for malignant disease. We will develop and evaluate a risk stratification model using hierarchical regression models to stratify patients by their risk of experiencing adverse outcomes during an episode. We will also explore specific practical and methodological issues regarding adaptation of established techniques of IPD meta-analysis of interventions for use in synthesising evidence derived from IPD from multiple studies for use in predictive modelling contexts.
Our aim in using this model is to define a group of individuals at low risk for febrile neutropenia who might be treated with reduced intensity or duration of antibiotic therapy and so reduce the inconvenience and cost of these episodes, as well as to define a group of patients at very high risk of complications who could be subject to more intensive therapies. The project will also help develop methods of IPD predictive modelling for use in future studies of risk prediction.
individual participant data meta-analysis; predictive modelling; paediatric oncology; febrile neutropenia; collaborative studies
Febrile neutropenia is a frequently occurring and occasionally life-threatening complication of treatment for childhood cancer. Many biomarkers have been proposed as predictors of adverse events. We aimed to undertake a systematic review and meta-analysis to summarize evidence on the discriminatory ability of initial serum biomarkers of febrile neutropenic episodes in children and young people.
This review was conducted in accordance with the Center for Reviews and Dissemination Methods, using three random effects models to undertake meta-analysis. It was registered with the HTA Registry of systematic reviews, CRD32009100485.
We found that 25 studies exploring 14 different biomarkers were assessed in 3,585 episodes of febrile neutropenia. C-reactive protein (CRP), pro-calcitonin (PCT), and interleukin-6 (IL6) were subject to quantitative meta-analysis, and revealed huge inconsistencies and heterogeneity in the studies included in this review. Only CRP has been evaluated in assessing its value over the predictive value of simple clinical decision rules.
The limited data available describing the predictive value of biomarkers in the setting of pediatric febrile neutropenia mean firm conclusions cannot yet be reached, although the use of IL6, IL8 and procalcitonin warrant further study.
The PRISMA (Preferred Reporting Items of Systematic reviews and Meta-Analyses) Statement was published to help authors improve how they report systematic reviews. It is unknown how many journals mention PRISMA in their instructions to authors, or whether stronger journal language regarding use of PRISMA improves author compliance.
An Internet-based investigation examined the extent to which 146 leading medical journals have incorporated the PRISMA Statement into their instructions to authors. Results were analyzed using descriptive statistics. Also, systematic reviews published in the leading anesthesiology journals and the QUOROM (QUality Of Reporting Of Meta-analyses) Statement were used to explore the hypothesis that indicating compliance with the QUOROM Statement in the manuscript is associated with improved compliance with the reporting guideline. In a sample of 146 journals publishing systematic reviews, the PRISMA Statement was referred to in the instructions to authors for 27% (40/146) of journals; more often in general and internal medicine journals (7/14; 50%) than in specialty medicine journals (33/132; 25%). In the second part of the study, 13 systematic reviews published in the leading anesthesiology journals in 2008 were included for appraisal. Mention of the QUOROM Statement in the manuscript was associated with higher compliance with the QUOROM checklist (P = 0.022).
Most of the leading medical journals used ambiguous language regarding what was expected of authors. Further improvement on quality of reporting of systematic reviews may entail journals clearly informing authors of their requirements. Stronger directions, such as requiring an indication of adherence to a research quality of reporting statement in the manuscript, may improve reporting and utility of systematic reviews.
Recent progress in understanding visceral afferents, some of it reviewed in the present issue, serves to underscore how little is known about the aging of the visceral afferents in the gastrointestinal (GI) tract. In spite of the clinical importance of the issue--with age, GI function often becomes severely compromised--only a few initial observations on age-related structural changes of visceral afferents are available. Primary afferent cell bodies in both the nodose ganglia and dorsal root ganglia lose Nissl material and accumulate lipofucsin, inclusions, aggregates, and tangles. Additionally, in changes that we focus on in the present review, vagal visceral afferent terminals in both the muscle wall and the mucosa of the GI tract exhibit age-related structural changes. In aged animals, both of the vagal terminal types examined, namely intraganglionic laminar endings and villus afferents, exhibit dystrophic or regressive morphological changes. These neuropathies are associated with age-related changes in the structural integrity of the target organs of the affected afferents, suggesting that local changes in trophic environment may give rise to the aging of GI innervation. Given the clinical relevance of GI tract aging, a more complete understanding both of how aging alters the innervation of the gut and of how such changes might be mitigated should be made research priorities.
aging; intestines; intraganglionic laminar endings; intramuscular arrays; myenteric; senescence; stomach; trophic factors; vagus; villus afferents