Hirschsprung disease (HSCR), which is also called congenital megacolon or intestinal aganglionosis, is characterized by an absence of enteric (intrinsic) neurons from variable lengths of the most distal bowel. Because enteric neurons are essential for propulsive intestinal motility, infants with HSCR suffer from severe constipation and have a distended abdomen. Currently the only treatment is surgical removal of the affected bowel. HSCR has an incidence of around 1:5,000 live births, with a 4:1 male:female gender bias. Most enteric neurons arise from neural crest cells that emigrate from the caudal hindbrain and then migrate caudally along the entire gut. The absence of enteric neurons from variable lengths of the bowel in HSCR results from a failure of neural crest-derived cells to colonize the affected gut regions. HSCR is therefore regarded as a neurocristopathy. HSCR is a multigenic disorder and has become a paradigm for understanding complex factorial disorders. The major HSCR susceptibility gene is RET. The penetrance of several mutations in HSCR susceptibility genes is sex-dependent. HSCR can occur as an isolated disorder or as part of syndromes; for example, Type IV Waardenburg syndrome is characterized by deafness and pigmentation defects as well as intestinal aganglionosis. Studies using animal models have shown that HSCR genes regulate multiple processes including survival, proliferation, differentiation, and migration. Research into HSCR and the development of enteric neurons is an excellent example of the cross fertilization of ideas that can occur between human molecular geneticists and researchers using animal models. WIREs Dev Biol 2013, 2:113-129. doi: 10.1002/wdev.57 For further resources related to this article, please visit the WIREs website.

The Ccr4-Not complex is a multisubunit complex present in all eukaryotes that contributes to regulate gene expression at all steps, from production of messenger RNAs (mRNAs) in the nucleus to their degradation in the cytoplasm. In the nucleus it influences the post-translational modifications of the chromatin template that has to be remodeled for transcription, it is present at sites of transcription and associates with transcription factors as well as with the elongating polymerase, it interacts with the factors that prepare the new transcript for export to the cytoplasm and finally is important for nuclear quality control and influences mRNA export. In the cytoplasm it is present in polysomes where mRNAs are translated and in RNA granules where mRNAs will be redirected upon inhibition of translation. It influences mRNA translatability, and is needed during translation, on one hand for co-translational protein interactions and on the other hand to preserve translation that stalls. It is one of the relevant players during co-translational quality control. It also interacts with factors that will repress translation or induce mRNA decapping when recruited to the translating template. Finally, Ccr4-Not carries deadenylating enzymes and is a key player in mRNA decay, generic mRNA decay that follows normal translation termination, co-translational mRNA decay of transcripts on which the ribosomes stall durably or which carry a non-sense mutation and finally mRNA decay that is induced by external signaling for a change in genetic programming. Ccr4-Not is a master regulator of eukaryotic gene expression. WIREs RNA 2016, 7:438-454. doi: 10.1002/wrna.1332 For further resources related to this article, please visit the WIREs website.

Antagonists of the N-methyl-D-aspartate (NMDA) subtype of glutamate (Glu) receptor have become the focus of considerable attention as potential neurotherapeutic agents in view of mounting evidence implicating NMDA receptors in acute central nervous system (CNS) injury syndromes such as stroke, trauma, and status epilepticus. In addition, NMDA receptor antagonists are of potential interest for the clinical management of neuropathic pain and preventing the development of tolerance to opiate analgesics. A potentially serious obstacle to the development of NMDA antagonists as neurotherapeutic drugs is the paradoxical fact that whereas these agents do have significant neurotherapeutic potential, they also have psychotogenic and neurotoxic properties. We have been intensively investigating the mechanisms underlying these adverse properties and have discovered several methods of suppressing or preventing their expression. In addition, we have been exploring the possibility that a common mechanism may underlie the psychotogenic and neurotoxic actions of these agents and that this mechanism may have relevance to the pathogenesis of idiopathic psychotic processes such as schizophrenia. In this chapter, we will review our findings pertaining to NMDA antagonists in the dual context of their value as tools for exploring mechanisms underlying neuropsychiatric disturbances, particularly schizophrenia, and their potential promise as therapeutic agents. For additional references and a more complete elaboration of our hypothesis pertaining to NMDA receptor dysfunction and schizophrenia, please see a recent review (Olney and Farber 1995).

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief and Deputy Editor-in-Chief following an investigation into the data that were presented in several figures within the article. A number of images used in this article are believed to be duplicated images. The authors stated that they inadvertently inserted images of the wrong blots in several of the figures, resulting in the duplications; however, they did not address all of the concerns raised. Because the editors were no longer confident in the conclusions of the article based on these incorrect data, a decision was made to retract the paper. All authors have been notified of this decision. The University of Campinas (UNICAMP) in São Paulo, Brazil was contacted regarding these concerns, but to date the journal has received no response.

The American Diabetes Association (ADA) "Standards of Medical Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, a multidisciplinary expert committee (https://doi.org/10.2337/dc20-SPPC), are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations, please refer to the Standards of Care Introduction (https://doi.org/10.2337/dc20-SINT). Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.

BACKGROUND

Most patients with cancer prefer to die at home or in a hospice, but hospitals remain the most common place of death (PoD).This study aims to explore the changing time trends of PoD and the associated factors, which are essential for end-of-life care improvement.

RESULTS

The study analysed all cancer deaths in England collected by the Office for National Statistics during 1993-2010 (n = 2,281,223). Time trends of age- and gender-standardised proportion of deaths in individual PoDs were evaluated using weighted piecewise linear regression. Variables associated with PoD (home or hospice versus hospital) were determined using proportion ratio (PR) derived from the log-binomial regression, adjusting for clustering effects. Hospital remained the most common PoD throughout the study period (48.0%; 95% CI 47.9%-48.0%), followed by home (24.5%; 95% CI 24.4%-24.5%), and hospice (16.4%; 95% CI 16.3%-16.4%). Home and hospice deaths increased since 2005 (0.87%; 95% CI 0.74%-0.99%/year, 0.24%; 95% CI 0.17%-0.32%/year, respectively, p<0.001), while hospital deaths declined (-1.20%; 95% CI -1.41 to -0.99/year, p<0.001). Patients who died from haematological cancer (PRs 0.46-0.52), who were single, widowed, or divorced (PRs 0.75-0.88), and aged over 75 (PRs 0.81-0.84 for 75-84; 0.66-0.72 for 85+) were less likely to die in home or hospice (p<0.001; reference groups: colorectal cancer, married, age 25-54). There was little improvement in patients with lung cancer of dying in home or hospice (PRs 0.87-0.88). Marital status became the second most important factor associated with PoD, after cancer type. Patients from less deprived areas (higher quintile of the deprivation index) were more likely to die at home or in a hospice than those from more deprived areas (lower quintile of the deprivation index; PRs 1.02-1.12). The analysis is limited by a lack of data on individual patients' preferences for PoD or a clinical indication of the most appropriate PoD.

CONCLUSIONS

More efforts are needed to reduce hospital deaths. Health care facilities should be improved and enhanced to support the increased home and hospice deaths. People who are single, widowed, or divorced should be a focus for end-of-life care improvement, along with known at risk groups such as haematological cancer, lung cancer, older age, and deprivation. Please see later in the article for the Editors' Summary.

BACKGROUND

Advancing the search, publication and integration of bioinformatics tools and resources demands consistent machine-understandable descriptions. A comprehensive ontology allowing such descriptions is therefore required.

RESULTS

EDAM is an ontology of bioinformatics operations (tool or workflow functions), types of data and identifiers, application domains and data formats. EDAM supports semantic annotation of diverse entities such as Web services, databases, programmatic libraries, standalone tools, interactive applications, data schemas, datasets and publications within bioinformatics. EDAM applies to organizing and finding suitable tools and data and to automating their integration into complex applications or workflows. It includes over 2200 defined concepts and has successfully been used for annotations and implementations.

BACKGROUND

The latest stable version of EDAM is available in OWL format from http://edamontology.org/EDAM.owl and in OBO format from http://edamontology.org/EDAM.obo. It can be viewed online at the NCBO BioPortal and the EBI Ontology Lookup Service. For documentation and license please refer to http://edamontology.org. This article describes version 1.2 available at http://edamontology.org/EDAM_1.2.owl.

BACKGROUND

jison@ebi.ac.uk.

BACKGROUND

Phosphorylation is the most prevalent post-translational modification on eukaryotic proteins. Multisite phosphorylation enables a specific combination of phosphosites to determine the speed, specificity and duration of biological response. Until recent years, the lack of high quality data limited the possibility for analyzing the properties of phosphorylation at the proteome scale and in the context of a wide range of conditions. Thanks to advances of mass spectrometry technologies, thousands of phosphosites from in-vivo experiments were identified and archived in the public domain. Such resource is appropriate to derive an unbiased view on the phosphosites properties in eukaryotes and on their functional relevance.

RESULTS

We present statistically rigorous tests on the spatial and functional properties of a collection of approximately 70,000 reported phosphosites. We show that the distribution of phosphosites positioning along the protein tends to occur as dense clusters of Serine/Threonines (pS/pT) and between Serine/Threonines and Tyrosines, but generally not as much between Tyrosines (pY) only. This phenomenon is more ubiquitous than anticipated and is pertinent for most eukaryotic proteins: for proteins with>> or = 2 phosphosites, 54% of all pS/pT sites are within 4 amino acids of another site. We found a strong tendency for clustered pS/pT to be activated by the same kinase. Large-scale analyses of phosphopeptides are thus consistent with a cooperative function within the cluster.

CONCLUSIONS

We present evidence supporting the notion that clusters of pS/pT but generally not pY should be considered as the elementary building blocks in phosphorylation regulation. Indeed, closely positioned sites tend to be activated by the same kinase, a signal that overrides the tendency of a protein to be activated by a single or only few kinases. Within these clusters, coordination and positional dependency is evident. We postulate that cellular regulation takes advantage of such design. Specifically, phosphosite clusters may increase the robustness of the effectiveness of phosphorylation-dependent response.

METHODS

Reviewed by Joel Bader, Frank Eisenhaber, Emmanuel Levy (nominated by Sarah Teichmann). For the full reviews, please go to the Reviewers' comments section.

BACKGROUND

Tuberculous meningitis (TBM) is difficult to diagnose promptly. The utility of the Xpert MTB/RIF test for the diagnosis of TBM remains unclear, and the effect of host- and sample-related factors on test performance is unknown. This study sought to evaluate the sensitivity and specificity of Xpert MTB/RIF for the diagnosis of TBM.

RESULTS

235 South-African patients with a meningeal-like illness were categorised as having definite (culture or Amplicor PCR positive), probable (anti-TBM treatment initiated but microbiological confirmation lacking), or non-TBM. Xpert MTB/RIF accuracy was evaluated using 1 ml of uncentrifuged and, when available, 3 ml of centrifuged cerebrospinal fluid (CSF). To evaluate the incremental value of MTB/RIF over a clinically based diagnosis, test accuracy was compared to a clinical score (CS) derived using basic clinical and laboratory information. Of 204 evaluable patients (of whom 87% were HIV-infected), 59 had definite TBM, 64 probable TBM, and 81 non-TBM. Overall sensitivity and specificity (95% CI) were 62% (48%-75%) and 95% (87%-99%), respectively. The sensitivity of Xpert MTB/RIF was significantly better than that of smear microscopy (62% versus 12%; p = 0.001) and significantly better than that of the CS (62% versus 30%; p = 0.001; C statistic 85% [79%-92%]). Xpert MTB/RIF sensitivity was higher when centrifuged versus uncentrifuged samples were used (82% [62%-94%] versus 47% [31%-61%]; p = 0.004). The combination of CS and Xpert MTB/RIF (Xpert MTB/RIF performed if CS<8) performed as well as Xpert MTB/RIF alone but with a ∼10% reduction in test usage. This overall pattern of results remained unchanged when the definite and probable TBM groups were combined. Xpert MTB/RIF was not useful in identifying TBM among HIV-uninfected individuals, although the sample was small. There was no evidence of PCR inhibition, and the limit of detection was ∼80 colony forming units per millilitre. Study limitations included a predominantly HIV-infected cohort and the limited number of culture-positive CSF samples.

CONCLUSIONS

Xpert MTB/RIF may be a good rule-in test for the diagnosis of TBM in HIV-infected individuals from a tuberculosis-endemic setting, particularly when a centrifuged CSF pellet is used. Further studies are required to confirm these findings in different settings. Please see later in the article for the Editors' Summary.

Predictive coding is a unifying framework for understanding redundancy reduction and efficient coding in the nervous system. By transmitting only the unpredicted portions of an incoming sensory signal, predictive coding allows the nervous system to reduce redundancy and make full use of the limited dynamic range of neurons. Starting with the hypothesis of efficient coding as a design principle in the sensory system, predictive coding provides a functional explanation for a range of neural responses and many aspects of brain organization. The lateral and temporal antagonism in receptive fields in the retina and lateral geniculate nucleus occur naturally as a consequence of predictive coding of natural images. In the higher visual system, predictive coding provides an explanation for oriented receptive fields and contextual effects as well as the hierarchical reciprocally connected organization of the cortex. Predictive coding has also been found to be consistent with a variety of neurophysiological and psychophysical data obtained from different areas of the brain. WIREs Cogni Sci 2011 2 580-593 DOI: 10.1002/wcs.142 For further resources related to this article, please visit the WIREs website.

BACKGROUND

Endometrial cancer incidence is continuing to rise in the wake of the current ageing and obesity epidemics. Much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Accumulating evidence suggests that the epigenome serves as the interface between the genome and the environment and that hypermethylation of stem cell polycomb group target genes is an epigenetic hallmark of cancer. The objective of this study was to determine the functional role of epigenetic factors in endometrial cancer development.

RESULTS

Epigenome-wide methylation analysis of >27,000 CpG sites in endometrial cancer tissue samples (n = 64) and control samples (n = 23) revealed that HAND2 (a gene encoding a transcription factor expressed in the endometrial stroma) is one of the most commonly hypermethylated and silenced genes in endometrial cancer. A novel integrative epigenome-transcriptome-interactome analysis further revealed that HAND2 is the hub of the most highly ranked differential methylation hotspot in endometrial cancer. These findings were validated using candidate gene methylation analysis in multiple clinical sample sets of tissue samples from a total of 272 additional women. Increased HAND2 methylation was a feature of premalignant endometrial lesions and was seen to parallel a decrease in RNA and protein levels. Furthermore, women with high endometrial HAND2 methylation in their premalignant lesions were less likely to respond to progesterone treatment. HAND2 methylation analysis of endometrial secretions collected using high vaginal swabs taken from women with postmenopausal bleeding specifically identified those patients with early stage endometrial cancer with both high sensitivity and high specificity (receiver operating characteristics area under the curve = 0.91 for stage 1A and 0.97 for higher than stage 1A). Finally, mice harbouring a Hand2 knock-out specifically in their endometrium were shown to develop precancerous endometrial lesions with increasing age, and these lesions also demonstrated a lack of PTEN expression.

CONCLUSIONS

HAND2 methylation is a common and crucial molecular alteration in endometrial cancer that could potentially be employed as a biomarker for early detection of endometrial cancer and as a predictor of treatment response. The true clinical utility of HAND2 DNA methylation, however, requires further validation in prospective studies. Please see later in the article for the Editors' Summary.

Despite repeated calls to emphasize the humanistic dimensions of care during medical education, these are few known techniques for effective teaching of humanism. We describe the barriers that inhibit humanistic teaching and suggest pragmatic teaching methods to overcome such barriers and teach humanistic care in clinical settings. We began by asking participants at a conference on patient-physician communications sponsored by the American Academy on Physician and Patient in June 1998, "What can we do in the patient's presence to improve and teach the human dimensions of care? Please provide one or more examples of approaches you found to be effective." We augmented this information with suggestions from a number of colleagues in other settings. In a series of iterations, we analyzed all their suggestions to identify key teaching methods. We found that barriers to teaching humanism largely consist of elements of the informal and hidden curricula in medical schools. We then defined methods to help teachers overcome these barriers. Specific methods fall into the 3 categories of taking advantage of seminal events, role modeling, and using active learning skills. We believe that formal courses and other well-motivated endeavors that take place away from patients fail to foster humanistic care. In contrast, we present pragmatic teaching methods that can be used in the fast-paced setting of the clinical environment.

BACKGROUND

Long- and short-term exposures to air pollution, especially fine particulate matter (PM(2.5)), have been linked to cardiovascular morbidity and mortality. One hypothesized mechanism for these associations involves microvascular effects. Retinal photography provides a novel, in vivo approach to examine the association of air pollution with changes in the human microvasculature.

RESULTS

Chronic and acute associations between residential air pollution concentrations and retinal vessel diameters, expressed as central retinal arteriolar equivalents (CRAE) and central retinal venular equivalents (CRVE), were examined using digital retinal images taken in Multi-Ethnic Study of Atherosclerosis (MESA) participants between 2002 and 2003. Study participants (46 to 87 years of age) were without clinical cardiovascular disease at the baseline examination (2000-2002). Long-term outdoor concentrations of PM(2.5) were estimated at each participant's home for the 2 years preceding the clinical exam using a spatio-temporal model. Short-term concentrations were assigned using outdoor measurements on the day preceding the clinical exam. Residential proximity to roadways was also used as an indicator of long-term traffic exposures. All associations were examined using linear regression models adjusted for subject-specific age, sex, race/ethnicity, education, income, smoking status, alcohol use, physical activity, body mass index, family history of cardiovascular disease, diabetes status, serum cholesterol, glucose, blood pressure, emphysema, C-reactive protein, medication use, and fellow vessel diameter. Short-term associations were further controlled for weather and seasonality. Among the 4,607 participants with complete data, CRAE were found to be narrower among persons residing in regions with increased long- and short-term levels of PM(2.5). These relationships were observed in a joint exposure model with -0.8 µm (95% confidence interval [CI] -1.1 to -0.5) and -0.4 µm (95% CI -0.8 to 0.1) decreases in CRAE per interquartile increases in long- (3 µg/m(3)) and short-term (9 µg/m(3)) PM(2.5) levels, respectively. These reductions in CRAE are equivalent to 7- and 3-year increases in age in the same cohort. Similarly, living near a major road was also associated with a -0.7 µm decrease (95% CI -1.4 to 0.1) in CRAE. Although the chronic association with CRAE was largely influenced by differences in exposure between cities, this relationship was generally robust to control for city-level covariates and no significant differences were observed between cities. Wider CRVE were associated with living in areas of higher PM(2.5) concentrations, but these findings were less robust and not supported by the presence of consistent acute associations with PM(2.5).

CONCLUSIONS

Residing in regions with higher air pollution concentrations and experiencing daily increases in air pollution were each associated with narrower retinal arteriolar diameters in older individuals. These findings support the hypothesis that important vascular phenomena are associated with small increases in short-term or long-term air pollution exposures, even at current exposure levels, and further corroborate reported associations between air pollution and the development and exacerbation of clinical cardiovascular disease. Please see later in the article for the Editors' Summary.

BACKGROUND

There is a growing recognition that the provision of surgical services in low-income countries is inadequate to the need. While constrained health budgets and health worker shortages have been blamed for the low rates of surgery, there has been little empirical data on the providers of surgery and cost of surgical services in Africa. This study described the range of providers of surgical care and anesthesia and estimated the resources dedicated to surgery at district hospitals in three African countries.

RESULTS

We conducted a retrospective cross-sectional survey of data from eight district hospitals in Mozambique, Tanzania, and Uganda. There were no specialist surgeons or anesthetists in any of the hospitals. Most of the health workers were nurses (77.5%), followed by mid-level providers (MLPs) not trained to provide surgical care (7.8%), and MLPs trained to perform surgical procedures (3.8%). There were one to six medical doctors per hospital (4.2% of clinical staff). Most major surgical procedures were performed by doctors (54.6%), however over one-third (35.9%) were done by MLPs. Anesthesia was mainly provided by nurses (39.4%). Most of the hospital expenditure was related to staffing. Of the total operating costs, only 7% to 14% was allocated to surgical care, the majority of which was for obstetric surgery. These costs represent a per capita expenditure on surgery ranging from US$0.05 to US$0.14 between the eight hospitals.

CONCLUSIONS

African countries have adopted different policies to ensure the provision of surgical care in their respective district hospitals. Overall, the surgical output per capita was very low, reflecting low staffing ratios and limited expenditures for surgery. We found that most surgical and anesthesia services in the three countries in the study were provided by generalist doctors, MLPs, and nurses. Although more information is needed to estimate unmet need for surgery, increasing the funds allocated to surgery, and, in the absence of trained doctors and surgeons, formalizing the training of MLPs appears to be a pragmatic and cost-effective way to make basic surgical services available in underserved areas. Please see later in the article for the Editors' Summary.

BACKGROUND

Depression is a significant cause of morbidity. Many patients have communicated an interest in non-pharmacological therapies to their general practitioners. Systematic reviews of acupuncture and counselling for depression in primary care have identified limited evidence. The aim of this study was to evaluate acupuncture versus usual care and counselling versus usual care for patients who continue to experience depression in primary care.

RESULTS

In a randomised controlled trial, 755 patients with depression (Beck Depression Inventory BDI-II score ≥ 20) were recruited from 27 primary care practices in the North of England. Patients were randomised to one of three arms using a ratio of 2.2.1 to acupuncture (302), counselling (302), and usual care alone (151). The primary outcome was the difference in mean Patient Health Questionnaire (PHQ-9) scores at 3 months with secondary analyses over 12 months follow-up. Analysis was by intention-to-treat. PHQ-9 data were available for 614 patients at 3 months and 572 patients at 12 months. Patients attended a mean of ten sessions for acupuncture and nine sessions for counselling. Compared to usual care, there was a statistically significant reduction in mean PHQ-9 depression scores at 3 months for acupuncture (-2.46, 95% CI -3.72 to -1.21) and counselling (-1.73, 95% CI -3.00 to -0.45), and over 12 months for acupuncture (-1.55, 95% CI -2.41 to -0.70) and counselling (-1.50, 95% CI -2.43 to -0.58). Differences between acupuncture and counselling were not significant. In terms of limitations, the trial was not designed to separate out specific from non-specific effects. No serious treatment-related adverse events were reported.

CONCLUSIONS

In this randomised controlled trial of acupuncture and counselling for patients presenting with depression, after having consulted their general practitioner in primary care, both interventions were associated with significantly reduced depression at 3 months when compared to usual care alone.

BACKGROUND

Controlled-Trials.com ISRCTN63787732 Please see later in the article for the Editors' Summary.

BACKGROUND

It has been suggested that outcomes of antidepressant treatment for major depressive disorder could be significantly improved if treatment choice is informed by genetic data. This study aims to test the hypothesis that common genetic variants can predict response to antidepressants in a clinically meaningful way.

RESULTS

The NEWMEDS consortium, an academia-industry partnership, assembled a database of over 2,000 European-ancestry individuals with major depressive disorder, prospectively measured treatment outcomes with serotonin reuptake inhibiting or noradrenaline reuptake inhibiting antidepressants and available genetic samples from five studies (three randomized controlled trials, one part-randomized controlled trial, and one treatment cohort study). After quality control, a dataset of 1,790 individuals with high-quality genome-wide genotyping provided adequate power to test the hypotheses that antidepressant response or a clinically significant differential response to the two classes of antidepressants could be predicted from a single common genetic polymorphism. None of the more than half million genetic markers significantly predicted response to antidepressants overall, serotonin reuptake inhibitors, or noradrenaline reuptake inhibitors, or differential response to the two types of antidepressants (genome-wide significance p<5×10(-8)). No biological pathways were significantly overrepresented in the results. No significant associations (genome-wide significance p<5×10(-8)) were detected in a meta-analysis of NEWMEDS and another large sample (STAR*D), with 2,897 individuals in total. Polygenic scoring found no convergence among multiple associations in NEWMEDS and STAR*D.

CONCLUSIONS

No single common genetic variant was associated with antidepressant response at a clinically relevant level in a European-ancestry cohort. Effects specific to particular antidepressant drugs could not be investigated in the current study. Please see later in the article for the Editors' Summary.

The introduction of proton pump inhibitors (PPIs) into clinical practice has revolutionized the management of acid-related diseases. Studies in primary care and emergency settings suggest that PPIs are frequently prescribed for inappropriate indications or for indications where their use offers little benefit. Inappropriate PPI use is a matter of great concern, especially in the elderly, who are often affected by multiple comorbidities and are taking multiple medications, and are thus at an increased risk of long-term PPI-related adverse outcomes as well as drug-to-drug interactions. Herein, we aim to review the current literature on PPI use and develop a position paper addressing the benefits and potential harms of acid suppression with the purpose of providing evidence-based guidelines on the appropriate use of these medications.

The topics, identified by a Scientific Committee, were assigned to experts selected by three Italian Scientific Societies, who independently performed a systematic search of the relevant literature using Medline/PubMed, Embase, and the Cochrane databases. Search outputs were distilled, paying more attention to systematic reviews and meta-analyses (where available) representing the best evidence. The draft prepared on each topic was circulated amongst all the members of the Scientific Committee. Each expert then provided her/his input to the writing, suggesting changes and the inclusion of new material and/or additional relevant references. The global recommendations were then thoroughly discussed in a specific meeting, refined with regard to both content and wording, and approved to obtain a summary of current evidence.

Twenty-five years after their introduction into clinical practice, PPIs remain the mainstay of the treatment of acid-related diseases, where their use in gastroesophageal reflux disease, eosinophilic esophagitis, Helicobacter pylori infection, peptic ulcer disease and bleeding as well as, and Zollinger-Ellison syndrome is appropriate. Prevention of gastroduodenal mucosal lesions (and symptoms) in patients taking non-steroidal anti-inflammatory drugs (NSAIDs) or antiplatelet therapies and carrying gastrointestinal risk factors also represents an appropriate indication. On the contrary, steroid use does not need any gastroprotection, unless combined with NSAID therapy. In dyspeptic patients with persisting symptoms, despite successful H. pylori eradication, short-term PPI treatment could be attempted. Finally, addition of PPIs to pancreatic enzyme replacement therapy in patients with refractory steatorrhea may be worthwhile.

Overall, PPIs are irreplaceable drugs in the management of acid-related diseases. However, PPI treatment, as any kind of drug therapy, is not without risk of adverse effects. The overall benefits of therapy and improvement in quality of life significantly outweigh potential harms in most patients, but those without clear clinical indication are only exposed to the risks of PPI prescription. Adhering with evidence-based guidelines represents the only rational approach to effective and safe PPI therapy. Please see related Commentary: doi: 10.1186/s12916-016-0724-1 .

BACKGROUND

Genetic and epidemiological evidence suggests an inverse association between B-type natriuretic peptide (BNP) levels in blood and risk of type 2 diabetes (T2D), but the prospective association of BNP with T2D is uncertain, and it is unclear whether the association is confounded.

RESULTS

We analysed the association between levels of the N-terminal fragment of pro-BNP (NT-pro-BNP) in blood and risk of incident T2D in a prospective case-cohort study and genotyped the variant rs198389 within the BNP locus in three T2D case-control studies. We combined our results with existing data in a meta-analysis of 11 case-control studies. Using a Mendelian randomization approach, we compared the observed association between rs198389 and T2D to that expected from the NT-pro-BNP level to T2D association and the NT-pro-BNP difference per C allele of rs198389. In participants of our case-cohort study who were free of T2D and cardiovascular disease at baseline, we observed a 21% (95% CI 3%-36%) decreased risk of incident T2D per one standard deviation (SD) higher log-transformed NT-pro-BNP levels in analysis adjusted for age, sex, body mass index, systolic blood pressure, smoking, family history of T2D, history of hypertension, and levels of triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol. The association between rs198389 and T2D observed in case-control studies (odds ratio = 0.94 per C allele, 95% CI 0.91-0.97) was similar to that expected (0.96, 0.93-0.98) based on the pooled estimate for the log-NT-pro-BNP level to T2D association derived from a meta-analysis of our study and published data (hazard ratio = 0.82 per SD, 0.74-0.90) and the difference in NT-pro-BNP levels (0.22 SD, 0.15-0.29) per C allele of rs198389. No significant associations were observed between the rs198389 genotype and potential confounders.

CONCLUSIONS

Our results provide evidence for a potential causal role of the BNP system in the aetiology of T2D. Further studies are needed to investigate the mechanisms underlying this association and possibilities for preventive interventions. Please see later in the article for the Editors' Summary.

BACKGROUND

Abundant evidence on Xpert MTB/RIF accuracy for diagnosing tuberculosis (TB) and rifampicin resistance has been produced, yet there are few data on the population benefit of its programmatic use. We assessed whether the implementation of Xpert MTB/RIF in routine conditions would (1) increase the notification rate of laboratory-confirmed pulmonary TB to the national notification system and (2) reduce the time to TB treatment initiation (primary endpoints).

RESULTS

We conducted a stepped-wedge cluster-randomized trial from 4 February to 4 October 2012 in 14 primary care laboratories in two Brazilian cities. Diagnostic specimens were included for 11,705 baseline (smear microscopy) and 12,522 intervention (Xpert MTB/RIF) patients presumed to have TB. Single-sputum-sample Xpert MTB/RIF replaced two-sputum-sample smear microscopy for routine diagnosis of pulmonary TB. In total, 1,137 (9.7%) tests in the baseline arm and 1,777 (14.2%) in the intervention arm were positive (p<0.001), resulting in an increased bacteriologically confirmed notification rate of 59% (95% CI = 31%, 88%). However, the overall notification rate did not increase (15%, 95% CI = -6%, 37%), and we observed no change in the notification rate for those without a test result (-3%, 95% CI = -37%, 30%). Median time to treatment decreased from 11.4 d (interquartile range [IQR] = 8.5-14.5) to 8.1 d (IQR = 5.4-9.3) (p = 0.04), although not among confirmed cases (median 7.5 [IQR = 4.9-10.0] versus 7.3 [IQR = 3.4-9.0], p = 0.51). Prevalence of rifampicin resistance detected by Xpert was 3.3% (95% CI = 2.4%, 4.3%) among new patients and 7.4% (95% CI = 4.3%, 11.7%) among retreatment patients, with a 98% (95% CI = 87%, 99%) positive predictive value compared to phenotypic drug susceptibility testing. Missing data in the information systems may have biased our primary endpoints. However, sensitivity analyses assessing the effects of missing data did not affect our results.

CONCLUSIONS

Replacing smear microscopy with Xpert MTB/RIF in Brazil increased confirmation of pulmonary TB. An additional benefit was the accurate detection of rifampicin resistance. However, no increase on overall notification rates was observed, possibly because of high rates of empirical TB treatment.

BACKGROUND

ClinicalTrials.gov NCT01363765. Please see later in the article for the Editors' Summary.

BACKGROUND

Growth/differentiation factor-5 (GDF-5) has been shown to be essential for normal appendicular skeletal and joint development in humans and mice. In brachypod, a Gdf-5 gene mouse mutant, the defect is first apparent during early chondrogenesis, with the cartilage blastema already reduced in size by E12.5. This defect is associated with changes in the expression of cell surface molecules.

METHODS

To understand further how GDF-5 controls cartilage formation, we first mapped the expression of the Gdf-5 gene during skeletal development (please note that the abbreviation for the gene is given in italics and the abbreviation for the protein expressed by the gene is given in capital letters). Subsequently, we over-expressed GDF-5 in the developing chick embryo using a replication competent retrovirus, RCAS(BP). We determined its effects on skeletal development by histological examination and its effects on early growth by autoradiography of proliferating cells. In addition, we examined the effect of GDF-5 on chondrogenic differentiation using micromass and single cell suspension cultures of limb mesenchymal cells,

RESULTS

These studies show that the Gdf-5 gene is expressed in the early cartilage condensation, the perichondrium, and the joint interzone. Over-expresSion of GDF-5 in chick limb buds, during the condensation stage or later when the skeletal elements have formed, increased the size of the affected elements. In both cases, the increase in size was associated with an increase in cell number and, at later stages, this was correlated with an increase in S-phase cells. In vitro studies showed that GDF-5 could increase cell adhesiveness, and this may be a mechanism through which GDF-5 initiates condensation formation.

CONCLUSIONS

These studies show that GDF-5 acts at two stages of skeletal development and by two distinct mechanisms. First, GDF-5 promotes the initial stages of chondrogenesis by promoting cell adhesion, which is consistent with the expression of Gdf-5 in the cartilage condensation. Second, GDF-5 can increase the size of the skeletal elements by increasing proliferation within the epiphyseal cartilage adjacent to its expression within the joint interzone.

Once considered a uniquely human attribute, brain asymmetry has been proved to be ubiquitous among non-human animals. A synthetic review of evidence of animal lateralization in the motor, sensory, cognitive, and affective domains is provided, together with a discussion of its development and possible biological functions. It is argued that investigation of brain asymmetry in a comparative perspective may favor the link between classical neuropsychological studies and modern developmental and evolutionary biology approaches. WIREs Cogni Sci 2011 2 146-157 DOI: 10.1002/wcs.100 For further resources related to this article, please visit the WIREs website.

OBJECTIVE

This Guideline is intended to provide a clinical framework for the surgical management of patients with kidney and/or ureteral stones. The summary presented herein represents Part II of the two-part series dedicated to Surgical Management of Stones: American Urological Association/Endourological Society Guideline. Please refer to Part I for introductory information and a discussion of pre-operative imaging and special cases.

METHODS

A systematic review of the literature (search dates 1/1/1985 to 5/31/2015) was conducted to identify peer-reviewed studies relevant to the surgical management of stones. The review yielded an evidence base of 1,911 articles after application of inclusion/exclusion criteria. These publications were used to create the Guideline statements. Evidence-based statements of Strong, Moderate, or Conditional Recommendation were developed based on benefits and risks/burdens to patients. Additional directives are provided as Clinical Principles and Expert Opinions when insufficient evidence existed.

RESULTS

The Panel identified 12 adult Index Patients to represent the most common cases seen in clinical practice. Three additional Index Patients were also created to describe the more commonly encountered special cases, including pediatric and pregnant patients. With these patients in mind, Guideline statements were developed to aid the clinician in identifying optimal management.

CONCLUSIONS

Proper treatment selection, which is directed by patient- and stone-specific factors, remains the greatest predictor of successful treatment outcomes. This Guideline is intended for use in conjunction with the individual patient's treatment goals. In all cases, patient preferences and personal goals should be considered when choosing a management strategy.

BACKGROUND

Chemoprevention offers a promising strategy for prevention of malaria in African children. However, the optimal chemoprevention drug and dosing strategy is unclear in areas of year-round transmission and resistance to many antimalarial drugs. To compare three available regimens, we conducted an open-label randomized controlled trial of chemoprevention in Ugandan children.

RESULTS

This study was conducted between June 28, 2010, and September 25, 2013. 400 infants were enrolled and 393 randomized at 6 mo of age to no chemoprevention, monthly sulfadoxine-pyrimethamine (SP), daily trimethoprim-sulfamethoxazole (TS), or monthly dihydroartemisinin-piperaquine (DP). Study drugs were administered at home without supervision. Piperaquine (PQ) levels were used as a measure of compliance in the DP arm. Participants were given insecticide-treated bednets, and caregivers were encouraged to bring their child to a study clinic whenever they were ill. Chemoprevention was stopped at 24 mo of age, and participants followed-up an additional year. Primary outcome was the incidence of malaria during the intervention period. During the intervention, the incidence of malaria in the no chemoprevention arm was 6.95 episodes per person-year at risk. Protective efficacy was 58% (95% CI, 45%-67%, p<0.001) for DP, 28% (95% CI, 7%-44%, p = 0.01) for TS, and 7% for SP (95% CI, -19% to 28%, p = 0.57). PQ levels were below the detection limit 52% of the time when malaria was diagnosed in the DP arm, suggesting non-adherence. There were no differences between the study arms in the incidence of serious adverse events during the intervention and the incidence of malaria during the 1-y period after the intervention was stopped.

CONCLUSIONS

For preventing malaria in children living in an area of high transmission intensity, monthly DP was the most efficacious and safe, although adherence may pose a problem. Monthly SP and daily TS may not be appropriate in areas with high transmission intensity and frequent resistance to antifolates.

BACKGROUND

www.ClinicalTrials.gov NCT00948896 Please see later in the article for the Editors' Summary.

We have developed a wholemount immunofluorescence protocol for the simultaneous detection of up to three proteins in mouse and chicken embryos. Combined with Murray's clearing reagent (BABB) and microscope objectives with long working ranges and high numerical apertures mounted on a confocal microscope, cellular resolution can be obtained in depths offering the possibility of examining expression patterns in entire organs or embryos. Three-dimensional projections of the optical confocal sections can be computed with computer software allowing rotation around any axis. The protocol is robust and we find that most antibodies working on tissue sections also work with this protocol. This manuscript contains online supplemental material at http://www.jhc.org. Please visit this article online to view these materials.