Acute complicated diverticulitis managed by laparoscopic lavage.
The classic surgical treatment of acute complicated sigmoid diverticulitis with peritonitis is often a two-stage operation with colon resection and a temporary stoma. This approach is associated with high mortality and morbidity and the reversal of the stoma is in many cases not performed because of concurrent diseases and age. Recently, several studies have experimented with laparoscopic lavage as a treatment of acute complicated diverticulitis. The aim of this review was to give an overview of the literature for this new approach and to determine the safety compared with Hartmann's procedure for patients with acute complicated sigmoid diverticulitis. A PubMed search was performed for publications between 1990 and May 2008. The terms acute, perforated, diverticulitis, lavage, drainage, and laparoscopy were used in combination. The EMBASE and Cochrane databases were also searched. Eight studies met the inclusion criteria and reported 213 patients with acute complicated diverticulitis managed by laparoscopic lavage. None of these studies were randomized. The patients' mean age was 59 years and most patients had Hinchey Grade 3 disease. All patients were treated with antibiotics and laparoscopic lavage. Conversion to laparotomy was made in six (3%) patients and the mean hospital stay was nine days. Ten percent of the patients had complications. During the mean follow-up of 38 months, 38% of the patients underwent elective sigmoid resection with primary anastomosis. Primary laparoscopic lavage for complicated diverticulitis may be a promising alternative to more radical surgery in selected patients. Larger studies have to be made before clinical recommendations can be given.


Intriguing balancing selection on the intron 5 region of LMBR1 in human population.
The intron 5 of gene LMBR1 is the cis-acting regulatory module for the sonic hedgehog (SHH) gene. Mutation in this non-coding region is associated with preaxial polydactyly, and may play crucial roles in the evolution of limb and skeletal system. We sequenced a region of the LMBR1 gene intron 5 in East Asian human population, and found a significant deviation of Tajima's D statistics from neutrality taking human population growth into account. Data from HapMap also demonstrated extended linkage disequilibrium in the region in East Asian and European population, and significantly low degree of genetic differentiation among human populations. We proposed that the intron 5 of LMBR1 was presumably subject to balancing selection during the evolution of modern human.


Backdoor opening mechanism in acetylcholinesterase based on X-ray crystallography and molecular dynamics simulations.
The transient opening of a backdoor in the active-site wall of acetylcholinesterase, one of nature's most rapid enzymes, has been suggested to contribute to the efficient traffic of substrates and products. A crystal structure of Torpedo californica acetylcholinesterase in complex with the peripheral-site inhibitor aflatoxin is now presented, in which a tyrosine at the bottom of the active-site gorge rotates to create a 3.4-Å wide exit channel. Molecular dynamics simulations show that the opening can be further enlarged by movement of Trp84. The crystallographic and molecular dynamics simulation data thus point to the interface between Tyr442 and Trp84 as the key element of a backdoor, whose opening permits rapid clearance of catalysis products from the active site. Furthermore, the crystal structure presented provides a novel template for rational design of inhibitors and reactivators, including anti-Alzheimer drugs and antidotes against organophosphate poisoning.


Ethical issues associated with HIV phylogenetics in HIV transmission dynamics research: A review of the literature using the Emanuel Framework.
The reduced costs of DNA sequencing and the use of such data for HIV-1 clinical management and phylogenetic analysis have led to a massive increase of HIV-1 sequences in the last few years. Phylogenetic analysis has shed light on the origin, spread and characteristics of HIV-1 epidemics and outbreaks. Phylogenetic analysis is now also being used to advance our knowledge of the drivers of HIV-1 transmission in order to design effective interventions. However, HIV phylogenetic analysis presents unique ethical challenges, which have not been fully explored. This review presents an analysis of what appear to be key ethical issues in HIV phylogenetics in the hope of stimulating further conceptual and empirical work in this rapidly emerging area. We structure the review using the Emanuel Framework, a systematic, holistic framework, which has been adapted for use in developing countries, which bear the brunt of the HIV-1 pandemic.


Cryo-EM structure of the nucleosome containing the ALB1 enhancer DNA sequence.
Pioneer transcription factors specifically target their recognition DNA sequences within nucleosomes. FoxA is the pioneer transcription factor that binds to the ALB1 gene enhancer in liver precursor cells, and is required for liver differentiation in embryos. The ALB1 enhancer DNA sequence is reportedly incorporated into nucleosomes in cells, although the nucleosome structure containing the targeting sites for FoxA has not been clarified yet. In this study, we determined the nucleosome structure containing the ALB1 enhancer (N1) sequence, by cryogenic electron microscopy at 4.0 Å resolution. The nucleosome structure with the ALB1 enhancer DNA is not significantly different from the previously reported nucleosome structure with the Widom 601 DNA. Interestingly, in the nucleosomes, the ALB1 enhancer DNA contains local flexible regions, as compared to the Widom 601 DNA. Consistently, DNaseI treatments revealed that, in the nucleosome, the ALB1 enhancer (N1) DNA is more accessible than the Widom 601 sequence. The histones also associated less strongly with the ALB1 enhancer (N1) DNA than the Widom 601 DNA in the nucleosome. Therefore, the local histone-DNA contacts may be responsible for the enhanced DNA accessibility in the nucleosome with the ALB1 enhancer DNA.


A mechanism for death receptor discrimination by death adaptors.
The death domain and death effector domain are two common motifs that mediate protein-protein interactions between components of cell death signaling complexes. The mechanism by which these domains engage their binding partners has been explored by extensive mutagenesis of two death adaptors, FADD and TRADD, suggesting that a death adaptor can discriminate its intended binding partners from other proteins harboring similar motifs. Death adaptors are found to utilize one of two topologically conserved surfaces for protein-protein interaction, whether that partner is another adaptor or its cognate receptor. These surfaces are topologically related to the interaction between death domains observed in the x-ray crystal structure of the Drosophila adaptor Tube bound to Pelle kinase. Comparing the topology of protein-protein interactions for FADD complexes to TRADD complexes reveals that FADD uses a Tube-like surface in each of its death motifs to engage either CD95 or TRADD. TRADD reverses these roles, employing a Pelle-like surface to interact with either receptor TNFR1 or adaptor FADD. Since death adaptors display a Tube-like or Pelle-like preference for engaging their binding partners, Tube/Pelle-like pairing provides a mechanism for death adaptor discrimination of death receptors.


Vitamin D3 Supplementation Increases Long-Chain Ceramide Levels in Overweight/Obese African Americans: A Post-Hoc Analysis of a Randomized Controlled Trial.
Sphingolipid metabolism plays a critical role in cell growth regulation, lipid regulation, neurodevelopment, type 2 diabetes, and cancer. Animal experiments suggest that vitamin D may be involved in sphingolipid metabolism regulation. In this study, we tested the hypothesis that vitamin D supplementation would alter circulating long-chain ceramides and related metabolites involved in sphingolipid metabolism in humans. We carried out a post-hoc analysis of a previously conducted randomized, placebo-controlled clinical trial in 70 overweight/obese African-Americans, who were randomly assigned into four groups of 600, 2000, 4000 IU/day of vitamin D3 supplements or placebo for 16 weeks. The metabolites were measured in 64 subjects (aged 26.0 ± 9.4 years, 17% male). Serum levels of N-stearoyl-sphingosine (d18:1/18:0) (C18Cer) and stearoyl sphingomyelin (d18:1/18:0) (C18SM) were significantly increased after vitamin D3 supplementation (ps < 0.05) in a dose-response fashion. The effects of 600, 2000, and 4000 IU/day vitamin D3 supplementation on C18Cer were 0.44 (p = 0.049), 0.52 (p = 0.016), and 0.58 (p = 0.008), respectively. The effects of three dosages on C18SM were 0.30 (p = 0.222), 0.61 (p = 0.009), and 0.68 (p = 0.004), respectively. This was accompanied by the significant correlations between serum 25-hydroxyvitamin D3 [25(OH)D] concentration and those two metabolites (ps < 0.05). Vitamin D3 supplementations increase serum levels of C18Cer and C18SM in a dose-response fashion among overweight/obese African Americans.


Treatment of intracranial and extracranial haemorrhages in a neonate with severe haemophilia B with recombinant factor IX infusion.
Intracranial (ICH) and extracranial (ECH) haemorrhages are potentially life-threatening events that may occur comorbidly in neonates with haemophilia. There is little data on the use of recombinant factor IX (rFIX; BeneFIX in the neonate. Children <15 years of age are known to require higher doses of recombinant Factor IX (FIX) than older persons, which raises specific concerns in the neonate due to the increased risk of thrombosis in this age group (Thromb Haemost 2002; 87: 431). This report describes a case in which a high rate of continuous infusion of recombinant FIX was used to treat a newborn with significant intracranial and subgaleal haemorrhages. A high rate of infusion maintained at 30-35 U kg(-1) h(-1) was necessary to maintain adequate FIX levels. Despite the high rate of continuous infusion, no adverse events were noted. Our patient had a rare genetic mutation causing severe haemophilia B. A neonate with severe haemophilia B was treated successfully with recombinant FIX through continuous infusion. A high rate of infusion was required and no complications were noted.


Persisting symptoms in schizophrenia predicted by background factors.
A social worker's Home Inquiry was conducted for 75 schizophrenic males as soon as possible after hospitalization. A standard set of items based on this inquiry was scored in terms of nine factors. These Home Inquiry factor scores were found to have modest but statistically significant correlations with specific symptom ratings conducted two years after admission. In the present sample, an interpersonally uncomfortable childhood home and low premorbid self-esteem have untoward implications for the remission of symptoms.


Trait-based prediction of extinction risk of small-bodied freshwater fishes.
Small body size is generally correlated with r-selected life-history traits, including early maturation, short-generation times, and rapid growth rates, that result in high population turnover and a reduced risk of extinction. Unlike other classes of vertebrates, however, small freshwater fishes appear to have an equal or greater risk of extinction than large fishes. We explored whether particular traits explain the International Union for Conservation of Nature (IUCN) Red List conservation status of small-bodied freshwater fishes from 4 temperate river basins: Murray-Darling, Australia; Danube, Europe; Mississippi-Missouri, North America; and the Rio Grande, North America. Twenty-three ecological and life-history traits were collated for all 171 freshwater fishes of ≤120 mm total length. We used generalized linear mixed-effects models to assess which combination of the 23 traits best explained whether a species was threatened or not threatened. We used the best models to predict the probability of 29 unclassified species being listed as threatened. With and without controlling for phylogeny at the family level, small body size-among small-bodied species-was the most influential trait correlated with threatened species listings. The k-folds cross-validation demonstrated that body size and a random effect structure that included family predicted the threat status with an accuracy of 78% (SE 0.5). We identified 10 species likely to be threatened that are not listed as such on the IUCN Red List. Small body size is not a trait that provides universal resistance to extinction, particularly for vertebrates inhabiting environments affected by extreme habitat loss and fragmentation. We hypothesize that this is because small-bodied species have smaller home ranges, lower dispersal capabilities, and heightened ecological specialization relative to larger vertebrates. Trait data and further model development are needed to predict the IUCN conservation status of the over 11,000 unclassified freshwater fishes, especially those under threat from proposed dam construction in the world's most biodiverse river basins.


Ontogenetic scaling of the human nose in a longitudinal sample: implications for genus Homo facial evolution.
Researchers have hypothesized that nasal morphology, both in archaic Homo and in recent humans, is influenced by body mass and associated oxygen consumption demands required for tissue maintenance. Similarly, recent studies of the adult human nasal region have documented key differences in nasal form between males and females that are potentially linked to sexual dimorphism in body size, composition, and energetics. To better understand this potential developmental and functional dynamic, we first assessed sexual dimorphism in the nasal cavity in recent humans to determine when during ontogeny male-female differences in nasal cavity size appear. Next, we assessed whether there are significant differences in nasal/body size scaling relationships in males and females during ontogeny. Using a mixed longitudinal sample we collected cephalometric and anthropometric measurements from n = 20 males and n = 18 females from 3.0 to 20.0+ years of age totaling n = 290 observations. We found that males and females exhibit similar nasal size values early in ontogeny and that sexual dimorphism in nasal size appears during adolescence. Moreover, when scaled to body size, males exhibit greater positive allometry in nasal size compared to females. This differs from patterns of sexual dimorphism in overall facial size, which are already present in our earliest age groups. Sexually dimorphic differences in nasal development and scaling mirror patterns of ontogenetic variation in variables associated with oxygen consumption and tissue maintenance. This underscores the importance of considering broader systemic factors in craniofacial development and may have important implications for the study of patters craniofacial evolution in the genus Homo.


Estimating resource selection with count data.
Resource selection functions (RSFs) are typically estimated by comparing covariates at a discrete set of "used" locations to those from an "available" set of locations. This RSF approach treats the response as binary and does not account for intensity of use among habitat units where locations were recorded. Advances in global positioning system (GPS) technology allow animal location data to be collected at fine spatiotemporal scales and have increased the size and correlation of data used in RSF analyses. We suggest that a more contemporary approach to analyzing such data is to model intensity of use, which can be estimated for one or more animals by relating the relative frequency of locations in a set of sampling units to the habitat characteristics of those units with count-based regression and, in particular, negative binomial (NB) regression. We demonstrate this NB RSF approach with location data collected from 10 GPS-collared Rocky Mountain elk (Cervus elaphus) in the Starkey Experimental Forest and Range enclosure. We discuss modeling assumptions and show how RSF estimation with NB regression can easily accommodate contemporary research needs, including: analysis of large GPS data sets, computational ease, accounting for among-animal variation, and interpretation of model covariates. We recommend the NB approach because of its conceptual and computational simplicity, and the fact that estimates of intensity of use are unbiased in the face of temporally correlated animal location data.


Beyond neuropathic pain: gabapentin use in cancer pain and perioperative pain.
Gabapentin (GBP), originally an antiepileptic drug, is more commonly used in the treatment of neuropathic pain. In recent years, GBP has been used as an adjunct or primary therapy in non-neuropathic pain, most commonly for the treatment of perioperative and cancer pain. The aim of this study was to conduct a clinical evidence literature review of GBP's use in perioperative pain and cancer pain. Using PUBMED and OVID Medline databases, keyword searches for surgery and cancer in reference to GBP and pain were carried out. Nonblinded studies and case reports that did not present a unique finding were excluded. Studies that focused only on neuropathic pain were also excluded. An initial 142 references focusing on GBP's use in surgical pain and cancer pain were identified. Of these, 48 studies were quality of evidence at a level of II-2 or higher. Although efficacy varies, multiple well-designed clinical trials have demonstrated reduced pain and analgesic use with otolaryngology, orthopedic, mastectomy, and abdominal/pelvic surgical perioperative use of GBP, whereas there is limited or no efficacy for cardiothoracic surgery. Cancer pain studies have had greater design variability, often nonblinded, with pain benefit being mild to moderate, and more efficacious with partial neuropathic pain quality. Overall, GBP seems to have significant benefit in neuropathic and non-neuropathic pain associated with the perioperative period and cancer. Considering its favorable side effect profile, GBP represents a beneficial pain adjunctive therapy, beyond neuropathic symptoms.


Intraoperative carcinoid syndrome during small-bowel neuroendocrine tumour surgery.
Only few descriptions of intraoperative carcinoid syndrome (ioCS) have been reported. The primary objective of this study was to describe ioCS. A second aim was to identify risk factors of ioCS. We retrospectively analysed patients operated for small-bowel neuroendocrine tumour in our institution between 2007 and 2015, and receiving our preventive local regimen of octreotide continuous administration. ioCS was defined as highly probable in case of rapid (<5 min) arterial blood pressure changes ≥40%, not explained by surgical/anaesthetic management and regressive ≥20% after octreotide bolus injection. Probable cases were ioCS which did not meet all criteria of highly-probable ioCS. Suspected ioCS were detected on the anaesthesia record by an injection of octreotide due to a manifestation which did not meet the criteria for highly-probable or probable ioCS. A total of 81 patients (liver metastases: 59, prior carcinoid syndrome: 49, carcinoid heart disease: 7) were included; 139 ioCS occurred in 45 patients: 45 highly probable, 67 probable and 27 suspected. ioCs was hypertensive (91%) and/or hypotensive (29%). There was no factor, including the use of vasopressors, significantly associated with the occurrence of an ioCS. All surgeries were completed and one patient died from cardiac failure 4 days after surgery. After preoperative octreotide continuous infusion, ioCS were mainly hypertensive. No ioCS risk factors, including vasopressor use, were identified. No intraoperative carcinoid crisis occurred, suggesting the clinical relevance of a standardized octreotide prophylaxis protocol.


Guillain-Barré syndrome with severe persistent disability: relationship to hyperacute Guillain-Barré syndrome.
Guillain-Barré syndrome (GBS) is a heterogeneous condition with a variable prognosis. We studied nine patients who were unable to walk unaided 12 months after the onset of their illness to discover whether they belonged to a more homogeneous subgroup. Sis of the nine patients had symptoms of gastroenteritis shortly before the onset of their neuropathic symptoms and a hyperacute onset of weakness so that they were bed-bound within 24 h. These patients had predominantly motor rather than sensory involvement We compared these nine poor outcome patients with 66 patients with lesser degrees of persistent disability of whom only three had both a history of prodromal gastroenteritis and a hyperacute onset (p < 0.0001). The poor and better outcome groups did not differ significantly in the severity of disability or other clinical or neurophysiological features in the acute stage. Patients with previous gastroenteritis and hyperacute onset of weakness may represent a relatively homogeneous subgroup of "hyperacute GB" in which severe axonal damage is caused by an aberrant immune response to a gastrointestinal pathogen such as Campylobacter jejuni.


Monoclonal antibody capture enzyme-linked immunosorbent assay for detection of bovine enteric coronavirus.
Monoclonal antibodies reactive with three different viral polypeptides were evaluated singly and in combination as the capture antibody(s) in an enzyme-linked immunosorbent assay system for the detection of bovine enteric coronavirus. Similar levels of sensitivity were found for all combinations tested. A sensitive, highly specific, and reproducible assay for the detection of bovine enteric coronavirus was developed, using a mixture of two of these monoclonal antibodies reactive with antigenic components either external or internal to the virion. These monoclonal antibodies were bound indirectly to 96-well plates via rabbit anti-mouse immunoglobulin. After sample application and incubation, virus was detected by using rabbit anti-coronavirus peroxidase conjugate followed by enzyme substrate and chromagen. Fecal samples from a single herd of cows were screened for the presence of coronavirus by this assay. Five percent of clinically normal cows were found to be shedding coronavirus.


Adverse Outcomes of Tacrolimus Withdrawal in Immune-Quiescent Kidney Transplant Recipients.
Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.


Predictors of Pancreatic Cancer-Associated Weight Loss and Nutritional Interventions.
Pancreatic ductal adenocarcinoma (PDAC) is often accompanied by weight loss. We sought to characterize factors associated with weight loss and observed nutritional interventions, as well as define the effect of weight loss on survival. Consecutive subjects diagnosed with PDAC (N = 123) were retrospectively evaluated. Univariate analysis was used to compare subjects with and without substantial (>5%) weight loss. Multivariate logistic regression was performed to identify factors associated with weight loss, and survival analyses were performed using Kaplan-Meier curves and Cox survival models. Substantial weight loss at diagnosis was present in 71.5% of subjects and was independently associated with higher baseline body mass index, longer symptom duration, and increased tumor size. Recommendations for nutrition consultation and pancreatic enzyme replacement therapy occurred in 27.6% and 36.9% of subjects, respectively. Weight loss (>5%) was not associated with worse survival on multivariate analysis (hazard ratio, 1.32; 95% confidence interval, 0.76-2.30), unless a higher threshold (>10%) was used (hazard ratio, 1.77; 95% confidence interval, 1.09-2.87). Despite the high prevalence of weight loss at PDAC diagnosis, there are low observed rates of nutritional interventions. Weight loss based on current criteria for cancer cachexia is not associated with poor survival in PDAC.


So many, yet few: Human resources for health in India.
In many developing countries, such as India, information on human resources in the health sector is incomplete and unreliable. This prevents effective workforce planning and management. This paper aims to address this deficit by producing a more complete picture of India's health workforce. Both the Census of India and nationally representative household surveys collect data on self-reported occupations. A representative sample drawn from the 2001 census was used to estimate key workforce indicators. Nationally representative household survey data and official estimates were used to compare and supplement census results. India faces a substantial overall deficit of health workers; the density of doctors, nurses and midwifes is a quarter of the 2.3/1000 population World Health Organization benchmark. Importantly, a substantial portion of the doctors (37%), particularly in rural areas (63%) appears to be unqualified. The workforce is composed of at least as many doctors as nurses making for an inefficient skill-mix. Women comprise only one-third of the workforce. Most workers are located in urban areas and in the private sector. States with poorer health and service use outcomes have a lower health worker density. Among the important human resources challenges that India faces is increasing the presence of qualified health workers in underserved areas and a more efficient skill mix. An important first step is to ensure the availability of reliable and comprehensive workforce information through live workforce registers.


Changing the model of care for patients with acute coronary syndromes.
Acute coronary syndromes (ACS) represent a major cause of morbidity and mortality for patients with cardiovascular disease, but evidence-based therapies shown to improve outcomes for ACS are often underused in clinically eligible patients. Although clinical practice guidelines have been developed to provide standards for the diagnosis and treatment of patients with ACS and to provide physicians with a framework for clinical decision-making, multiple obstacles have hindered their implementation and questions remain about the applicability of guidelines for diverse clinical situations. Systematic reviews of quality-improvement studies have shown that multifaceted approaches using targeted educational interventions, creation of quality standards, and regular performance feedback are needed to ensure sustained improvements in care. Approaches to quality improvement thus are being redirected to focus on multidisciplinary collaborations designed to improve the entire process of care for patients with ACS. Multiple large observational registries and quality-improvement initiatives now are capturing data regarding adherence to practice guidelines and contemporary patterns of care for ACS. This comprehensive evaluation of ACS treatment will help guide efforts designed to promote evidence-based care and ultimately determine the effect of widespread implementation of practice guidelines on clinical outcomes. The shifting model of care for ACS therefore suggests that quality improvement and monitoring of adherence to practice guidelines should be considered components of optimal clinical practice.


Monitoring digoxin therapy: II. Determinants of the apparent volume of distribution.
1 In eighteen subjects receiving digoxin therapy the apparent volume of distribution (Vd) of the drug has been calculated. 2 For each subject the sensitivity of the 86Rb transport mechanism of his pre-treatment erythrocytes to in vitro inhibition by digoxin has been measured (IC50). 3 The Vd of digoxin correlates both with the age of the patients and with the IC50 of their pre-treatment erythrocytes. 4 The implications of these findings are discussed in terms of the possible determinants of the Vd of digoxin. 5 Digoxin requirements may be predictable before therapy commences if IC50 measurements are performed.


Comparison of Prostate Imaging Reporting and Data System (PI-RADS) version 1 and version 2 and combination with apparent diffusion coefficient as a predictor of biopsy outcome.
The main aim of the study was to compare the diagnostic performance of Prostate Imaging Reporting and Data System (PI-RADS) versions 1 and 2 for detection of prostate carcinoma (PCa) and clinically significant prostate carcinoma (CSPCa). The second aim was to evaluate the potential benefit of adding the apparent diffusion coefficient (ADC) and prostate specific antigen (PSA) density to the standard evaluation protocol. A total of 167 consecutive patients with elevated PSA underwent magnetic resonance imaging. The images were evaluated prospectively using both versions of the PI-RADS and the results compared with 12-core template biopsy and magnetic resonance/transrectal ultrasound fusion biopsy. Receiver-operating characteristic (ROC) curves were compared for each scoring system using DeLong\'s test. The area under the curve (AUC) was calculated for ADC and PSA density for lesions scored 4. PI-RADS V2 had high discriminative ability for PCa prediction with an AUC of 0.824 (95% CI 0.763 to 0.885), compared to an AUC of 0.724 (95% CI 0.654 to 0.794) for PI-RADS V1 (p = 0.0335). ADC demonstrated a higher discriminative ability with an AUC of 0.702 (95% CI 0.548 to 0.856) in CSPCa prediction. Using the obtained ADC threshold of 828x10^-6 mm^2/s improved specificity to 86.73% with a sensitivity of 60.38%. PI-RADS version 2 exhibited significantly higher discriminative ability for PCa and CSPCa detection compared to PI-RADS version 1. Using the ADC can improve the tumor predictability of PI-RADS version 2 in lesions scored 4.


Classical, quantum and statistical simulations of vibrationally excited HOSO(2): IVR, dissociation, and implications for OH + SO(2) kinetics at high pressures.
In this paper, we present classical and coupled coherent states quantum dynamics simulations to investigate intramolecular vibrational energy redistribution (IVR) from an excited (v = 1-10) OH stretch within the HOSO(2) complex to the other molecular bath modes. Using an analytical PES derived from electronic structure theory calculations, the results obtained from both the classical and quantum simulations are in reasonable agreement. The dynamics results suggest that statistical models overpredict HOSO(2) dissociation k(E)s, and underpredict the amount of vibrational excitation in the nascent OH formed following complex dissociation. In order to understand the dynamics results, we utilize a simple analytical model for describing energy flow from excited modes to bath modes, and show that IVR limits complex dissociation at short times. We also consider qualitative mass affects on IVR, and consider the implications of this work on previous measurements of the OH + SO(2) association k(infinity) using the proxy method.


2019 update of the European AIDS Clinical Society Guidelines for treatment of people living with HIV version 10.0.
The European AIDS Clinical Society (EACS) Guidelines cover key aspects of HIV management with major updates every two years. The 2019 Guidelines were extended with a new section focusing on drug-drug interactions and other prescribing issues in people living with HIV (PLWH). The recommendations for treatment-naïve PLWH were updated with four preferred regimens favouring unboosted integrase inhibitors. A two-drug regimen with dolutegravir and lamivudine, and a three-drug regimen including doravirine were also added to the recommended initial regimens. Lower thresholds for hypertension were expanded to all PLWH and for cardiovascular disease prevention, the 10-year predicted risk threshold for consideration of antiretroviral therapy (ART) modification was lowered from 20% to 10%. Frailty and obesity were added as new topics. It was specified to use urine albumin to creatinine ratio to screen for glomerular disease and urine protein to creatinine ratio for tubular diseases, and thresholds were streamlined with the Kidney Disease: Improving Global Outcomes (KDIGO) recommendations. Hepatitis C virus (HCV) treatment recommendations were split into preferred and alternative treatment options. The algorithm for management of recently acquired HCV infection was updated and includes recommendations for early chronic infection management. Treatment of resistant tuberculosis (TB) was streamlined with the World Health Organization (WHO) recommendations, and new tables on immune reconstitution inflammatory syndrome, on when to start ART in the presence of opportunistic infections and on TB drug dosing were included. The EACS Guidelines underwent major revisions of all sections in 2019. They are available in four different formats including a new interactive web-based version and are translated into Chinese, French, German, Japanese, Portuguese, Russian and Spanish.


What are the most appropriate return-to-play guidelines for concussed child athletes?
To examine concussion literature for specific guidelines regarding return to play (RTP) following sport-related concussion in child athletes. To make recommendations regarding the most appropriate RTP guidelines for child athletes following sport-related concussion. A literature review of concussion literature. A literature search was conducted using Medline and Embase databases from 1998 to 2008. More than 60 articles and two websites were reviewed. There is a paucity of research on sport-related concussion in child athletes, particularly younger children (age 5-12 years). In particular, there is no research on RTP guidelines for child athletes following sport-related concussion. Child athletes take longer to recover from concussions than adults. Concussion symptoms may resolve before cognitive function has completely recovered. Concussion assessment and management in children can be confounded by their growth and development, as well as the lack of trained medical personnel involved with youth sports. There are no child-specific assessment tools for concussion. RTP decisions in children should be made cautiously and should be individualised. No concussed child athlete should be allowed to RTP the same day. Physical and cognitive rest is very important to allow for the resolution of concussion symptoms. Child athletes should remain symptom free for several days before starting a medically supervised stepwise exertion protocol. Further research is needed to elucidate the effects of concussion in children and to determine the most appropriate RTP guidelines. Child-specific concussion assessment tools need to be developed to improve concussion assessment and management in children.


The capsule of the fungal pathogen Cryptococcus neoformans.
The capsule of the fungal pathogen Cryptococcus neoformans has been studied extensively in recent decades and a large body of information is now available to the scientific community. Well-known aspects of the capsule include its structure, antigenic properties and its function as a virulence factor. The capsule is composed primarily of two polysaccharides, glucuronoxylomannan (GXM) and galactoxylomannan (GalXM), in addition to a smaller proportion of mannoproteins (MPs). Most of the studies on the composition of the capsule have focused on GXM, which comprises more than 90% of the capsule's polysaccharide mass. It is GalXM, however, that is of particular scientific interest because of its immunological properties. The molecular structure of these polysaccharides is very complex and has not yet been fully elucidated. Both GXM and GalXM are high molecular mass polymers with the mass of GXM equaling roughly 10 times that of GalXM. Recent findings suggest, however, that the actual molecular weight might be different to what it has traditionally been thought to be. In addition to their structural roles in the polysaccharide capsule, these molecules have been associated with many deleterious effects on the immune response. Capsular components are therefore considered key virulence determinants in C. neoformans, which has motivated their use in vaccines and made them targets for monoclonal antibody treatments. In this review, we will provide an update on the current knowledge of the C. neoformans capsule, covering aspects related to its structure, synthesis and particularly, its role as a virulence factor.


Dietary Interventions in the Management of Fibromyalgia: A Systematic Review and Best-Evidence Synthesis.
Fibromyalgia syndrome (FMS) is characterised by chronic widespread pain alongside fatigue, poor sleep quality and numerous comorbidities. It is estimated to have a worldwide prevalence of 1.78%, with a predominance in females. Treatment interventions for fibromyalgia have limited success, leading to many patients seeking alternative forms of treatment, including modifications to their diet and lifestyle. The effectiveness of dietary changes in fibromyalgia has not been widely researched or evaluated. This systematic review identified twenty-two studies, including 18 randomised control trials (RCTs) and four cohort studies which were eligible for inclusion. In total these studies investigated 17 different nutritional interventions. Significant improvements in reported pain were observed for those following a vegan diet, as well as with the low fermentable oligo di-mono-saccharides and polyols (FODMAP) diets. Supplementation with Chlorella green algae, coenzyme Q10, acetyl-l-carnitine or a combination of vitamin C and E significantly improved measures of pain. Interpretation of these studies was limited due to the frequent poor quality of the study design, the wide heterogeneity between studies, the small sample size and a high degree of bias. Therefore, there is insufficient evidence to recommend any one particular nutritional intervention for the management of fibromyalgia and further research is needed.


The regulatory logic of m-xylene biodegradation by Pseudomonas putida mt-2 exposed by dynamic modelling of the principal node Ps/Pr of the TOL plasmid.
The structure of the extant transcriptional control network of the TOL plasmid pWW0 born by Pseudomonas putida mt-2 for biodegradation of m-xylene is far more complex than one would consider necessary from a mere engineering point of view. In order to penetrate the underlying logic of such a network, which controls a major environmental cleanup bioprocess, we have developed a dynamic model of the key regulatory node formed by the Ps/Pr promoters of pWW0, where the clustering of control elements is maximal. The model layout was validated with batch cultures estimating parameter values and its predictive capability was confirmed with independent sets of experimental data. The model revealed how regulatory outputs originated in the divergent and overlapping Ps/Pr segment, which expresses the transcription factors XylS and XylR respectively, are computed into distinct instructions to the upper and lower catabolic xyl operons for either simultaneous or stepwise consumption of m-xylene and/or succinate. In this respect, the model reveals that the architecture of the Ps/Pr is poised to discriminate the abundance of alternative and competing C sources, in particular m-xylene versus succinate. The proposed framework provides a first systemic understanding of the causality and connectivity of the regulatory elements that shape this exemplary regulatory network, facilitating the use of model analysis towards genetic circuit optimization.


What drives adoption of a computerised, multifaceted quality improvement intervention for cardiovascular disease management in primary healthcare settings? A mixed methods analysis using normalisation process theory.
A computerised, multifaceted quality improvement (QI) intervention for cardiovascular disease (CVD) management in Australian primary healthcare was evaluated in a cluster randomised controlled trial. The intervention was associated with improved CVD risk factor screening but there was no improvement in prescribing rates of guideline-recommended medicines. The aim of this study was to conduct a process evaluation to identify and explain the underlying mechanisms by which the intervention did and did not have an impact. Normalisation process theory (NPT) was used to understand factors that supported or constrained normalisation of the intervention into routine practice. A case study design was used in which six of the 30 participating intervention sites were purposively sampled to obtain a mix of size, governance, structure and performance. Multiple data sources were drawn on including trial outcome data, surveys of job satisfaction and team climate (68 staff) and in-depth interviews (19 staff). Data were primarily analysed within cases and compared with quantitative findings in other trial intervention and usual care sites. We found a complex interaction between implementation processes and several contextual factors affecting uptake of the intervention. There was no clear association between team climate, job satisfaction and intervention outcomes. There were four spheres of influence that appeared to enhance or detract from normalisation of the intervention: organisational mission and history (e.g. strategic investment to promote a QI culture enhanced cognitive participation), leadership (e.g. ability to energise or demotivate others influenced coherence), team environment (e.g. synergistic activities of team members with different skill sets influenced collective action) and technical integrity of the intervention (e.g. tools that slowed computer systems limited reflective action). Use of NPT helped explain how certain contextual factors influence the work that is done by individuals and teams when implementing a novel intervention. Although these factors do not necessarily distil into a recipe for successful uptake, they may assist system planners, intervention developers, and health professionals to better understand the trajectory that primary health care services may take when developing and engaging with QI interventions. ACTRN 12611000478910 . Registered 08 May 2011.


Anti-Inflammatory Activities of Pentaherbs Formula, Berberine, Gallic Acid and Chlorogenic Acid in Atopic Dermatitis-Like Skin Inflammation.
Atopic dermatitis (AD) is a common allergic skin disease, characterized by dryness, itchiness, thickening and inflammation of the skin. Infiltration of eosinophils into the dermal layer and presence of edema are typical characteristics in the skin biopsy of AD patients. Previous in vitro and clinical studies showed that the Pentaherbs formula (PHF) consisting of five traditional Chinese herbal medicines, Flos Lonicerae, Herba Menthae, Cortex Phellodendri, Cortex Moutan and Rhizoma Atractylodis at w/w ratio of 2:1:2:2:2 exhibited therapeutic potential in treating AD. In this study, an in vivo murine model with oxazolone (OXA)-mediated dermatitis was used to elucidate the efficacy of PHF. Active ingredients of PHF water extract were also identified and quantified, and their in vitro anti-inflammatory activities on pruritogenic cytokine IL-31- and alarmin IL-33-activated human eosinophils and dermal fibroblasts were evaluated. Ear swelling, epidermis thickening and eosinophils infiltration in epidermal and dermal layers, and the release of serum IL-12 of the murine OXA-mediated dermatitis were significantly reduced upon oral or topical treatment with PHF (all p < 0.05). Gallic acid, chlorogenic acid and berberine contents (w/w) in PHF were found to be 0.479%, 1.201% and 0.022%, respectively. Gallic acid and chlorogenic acid could suppress the release of pro-inflammatory cytokine IL-6 and chemokine CCL7 and CXCL8, respectively, in IL-31- and IL-33-treated eosinophils-dermal fibroblasts co-culture; while berberine could suppress the release of IL-6, CXCL8, CCL2 and CCL7 in the eosinophil culture and eosinophils-dermal fibroblasts co-culture (all p < 0.05). These findings suggest that PHF can ameliorate allergic inflammation and attenuate the activation of eosinophils.


A prospective, single-blind, randomized, phase III study to evaluate the safety and efficacy of Fibrin Sealant Grifols as an adjunct to hemostasis compared with manual compression in vascular surgery.
New formulations and applications of hemostatic adjuncts such as fibrin sealant (FS) to support local hemostasis and sutures continue to be developed. In a pivotal, confirmatory, controlled, prospective, single-blinded, randomized, multicenter phase III clinical trial, the efficacy and safety of FS Grifols during vascular surgeries were evaluated. Patients undergoing a nonemergency, open, peripheral vascular surgical procedure with moderate arterial bleeding were recruited. In an initial preliminary part of the study, all patients were treated with FS Grifols. In a subsequent primary part, patients were randomized (2:1) to FS Grifols or manual compression (MC). The primary efficacy end point was the proportion of the primary part patients achieving hemostasis by 4 minutes after the start of treatment. Cumulative proportion and time to hemostasis were secondary efficacy end points. Safety end points (in pooled preliminary and primary parts) included adverse events (AEs), vital signs, physical assessments, clinical laboratory tests, viral markers, and immunogenicity. The primary efficacy end point was met by 76.1% of patients (83/109) for the FS Grifols group versus 22.8% of patients (13/57) for the MC group (P < .001). The cumulative proportion of patients at 5, 7, and 10 minutes was 80.7%, 84.4%, and 88.1%, respectively, in the FS Grifols treatment group, and 28.1%, 35.1%, and 45.6% in the MC treatment group (P < .001). The median time to hemostasis was shorter in the FS Grifols group (4 minutes vs ≥10 minutes in the MC group; P < .001). The nature of AEs reported were those expected in the study patient profile. The percentage of patients experiencing treatment-emergent AEs were similar in both the FS Grifols (pooled n = 59 + 109) and MC groups (81.0% and 77.2%, respectively), most recurrent being procedural pain (34.5% and 36.8%, respectively) and pyrexia (11.3% and 10.5%, respectively). FS Grifols was superior in efficacy and similar in safety to MC as an adjunct local hemostatic agent in patients undergoing open vascular surgeries.


Effects of FAME biodiesel and HVORD on emissions from an older-technology diesel engine.
The results of laboratory evaluations were used to compare the potential of two alternative, biomass-derived fuels as a control strategy to reduce the exposure of underground miners to aerosols and gases emitted by diesel-powered equipment. The effects of fatty acid methyl ester (FAME) biodiesel and hydrotreated vegetable oil renewable diesel (HVORD) on criteria aerosol and gaseous emissions from an older-technology, naturally aspirated, mechanically controlled engine equipped with a diesel oxidation catalytic converter were compared with those of widely used petroleum-derived, ultralow-sulfur diesels (ULSDs). The emissions were characterized for four selected steady-state conditions. When fueled with FAME biodiesel and HVORD, the engine emitted less aerosols by total particulate mass, total carbon mass, elemental carbon mass and total number than when it was fueled with ULSDs. Compared with ULSDs, FAME biodiesel and HVORD produced aerosols that were characterized by single modal distributions, smaller count median diameters, and lower total and peak concentrations. For the majority of test cases, FAME biodiesel and HVORD favorably affected nitric oxide (NO) and adversely affected nitrogen dioxide (NO2) generation. Therefore, the use of these alternative fuels appears to be a viable tool for the underground mining industry to address the issues related to emissions from diesel engines, and to transition toward more universal solutions provided by advanced engines with integrated exhaust after treatment technologies.


Detection of lytA, pspC, and rrgA genes in Streptococcus pneumoniae isolated from healthy children.
Many surface proteins are implicated in nasopharyngeal colonization and pathogenesis of Streptococcus pneumoniae. Some of these factors are candidate antigens for protein based vaccines. New vaccine designs focus on the surface proteins (e. g., pspA and pspC) and also cytolysin, and pneumolysin. In this study, 3 key virulence genes, lytA, pspC, and rrgA, which encoded surface proteins, were detected among S. pneumoniae isolates. A total of 260 nasopharyngeal swabs were collected from healthy children under 6 years old attending day care centers in Mashhad, Iran. Isolates of S. pneumoniae were confirmed by optochin susceptibility and colony appearance and also by PCR for cpsA gene. The presence of lytA, pspC, and rrgA genes were also detected by PCR. A total of 59 isolates were confirmed as S. pneumoniae. Among these isolates, 50 (84.74%), 19 (32.20%), and 2 (3.38%) were positive for lytA, rrgA, and pspC genes respectively. The presence of these genes among S.pneumoniae isolates were as follows: 1) rrgA, lytA, pspC (1 isolate), 2) rrgA, lytA(17isolates), 3) pspC (2 isolate), 4) lytA (50 isolates). cpsA gene was specific for detection of S. pneumoniae isolates which were colonized in nasopharynx. The lytA gene was the most frequent gene among the S. pneumoniae isolates, and combination of rrgA, lytA was the most observed pattern. Thus, it is important for future monitoring of vaccine formulation in our country.


Multivariate genetic analysis of chronic pelvic pain and associated phenotypes.
Chronic pelvic pain (CPP) is a common condition in women that is difficult to diagnose. Although heritability estimates have been published for some conditions potentially underlying pelvic pain, the heritability of CPP itself has never been investigated. Using data from 623 MZ and 377 DZ female twin pairs aged 29-50 from an Australian twin cohort, we found an increased CPP concordance among MZs compared to DZs, with tetrachoric correlations of 0.43 (95% CI: 0.26-0.58) and 0.11 (95% CI: -0.16-0.38), respectively. This corresponded to a heritability of 0.41 (95% CI: 0.25-0.56). Lack of correlations with environmental indicators suggested that violation of the equal environments assumption was not responsible for this effect. Multivariate Cholesky decomposition models incorporating CPP and significantly correlated phenotypes showed that the entire CPP heritability could be explained by genetic variance underlying endometriosis (38%), dysmenorrhoea (23%), fibroids (24%), and somatic distress (15%), the latter a possible indicator of increased nociception. CPP itself is unlikely to be a useful independent phenotype to conduct genetic aetiological studies; contributing conditions such as endometriosis and variation in nociception are likely to provide more useful phenotypes.


Guidelines for standardization of radiostereometry (RSA) of implants.
There is a need for standardization of radiostereometric (RSA) investigations to facilitate comparison of outcome reported from different research groups. In this document, 6 research centers have agreed upon standards for terminology, description and use of RSA arrangement including radiographic set-up and techniques. Consensus regarding minimum requirements for marker stability and scatter, choice of coordinate systems, and preferred way of describing prosthetic micromotion is of special interest. Some notes on data interpretation are also presented. Validation of RSA should be standardized by preparation of protocols for assessment of accuracy and precision. Practical issues related to loading of the joint by weight bearing or other conditions, follow-up intervals, length of follow-up, radiation dose, and the exclusion of patients due to technical errors are considered. Finally, we present a checklist of standardized output that should be included in any clinical RSA paper.This document will form the basis of a detailed standardization protocol under supervision of ISO and the European Standards Working Group on Joint Replacement Implants (CEN/TC 285/WG4). This protocol will facilitate inclusion of RSA in a standard protocol for implant testing before it is released for general use. Such a protocol-also including other recognized clinical outcome parameters-will reduce the risk of implanting potentially inferior prostheses on a large scale.


Gelatinase expression and proteolytic activity in giant-cell arteritis.
Gelatinases (MMP2 and MMP9) are expressed in giant-cell arteritis (GCA) and are thought to play a role in vessel disruption. However, their activation status and enzymatic activity have not been evaluated. Our aim was to investigate the distribution and proteolytic activity of gelatinases in GCA lesions at different stages. Expression of MMP2, MMP9, MMP2-activator MMP14 and their natural inhibitors TIMP1 and TIMP2 was determined by real-time PCR and immunohistochemistry in temporal artery sections from 46 patients and 12 controls. MMP activation status and enzymatic activity were assessed by gelatin and film in situ zymography. Vascular smooth muscle cells from normal specimens constitutively expressed pro-MMP2 and its inhibitor TIMP2 with no resulting proteolytic activity. In GCA MMP2, MMP9 and MMP14 were strongly expressed in their active form by infiltrating leucocytes. Inflamed arteries also expressed TIMP1 and TIMP2. However, the MMP9/TIMP1 and MMP2/TIMP2 ratios were higher in patients compared with controls, indicating an increased proteolytic balance in GCA which was confirmed by in situ zymography. Maximal gelatinase expression and activity occurred at the granulomatous areas surrounding the internal elastic lamina (IEL). Myointimal cells also expressed MMPs and exhibited proteolytic activity, suggesting a role for gelatinases in vascular remodelling and repair. GCA lesions show intense expression of gelatinases. Activators and inhibitors are regulated to yield enhanced gelatinase activation and proteolytic activity. Distribution of expression and proteolytic activity suggests that gelatinases have a major role not only in the progression of inflammatory infiltrates and vessel destruction but also in vessel repair.


Excipient Nanoemulsions for Improving Oral Bioavailability of Bioactives.
The oral bioavailability of many hydrophobic bioactive compounds found in natural food products (such as vitamins and nutraceuticals in fruits and vegetables) is relatively low due to their low bioaccessibility, chemical instability, or poor absorption. Most previous research has therefore focused on the design of delivery systems to incorporate isolated bioactive compounds into food products. However, a more sustainable and cost-effect approach to enhancing the functionality of bioactive compounds is to leave them within their natural environment, but specifically design excipient foods that enhance their bioavailability. Excipient foods typically do not have functionality themselves but they have the capacity to enhance the functionality of nutrients present in natural foods by altering their bioaccessibility, absorption, and/or chemical transformation. In this review article we present the use of excipient nanoemulsions for increasing the bioavailability of bioactive components from fruits and vegetables. Nanoemulsions present several advantages over other food systems for this application, such as the ability to incorporate hydrophilic, amphiphilic, and lipophilic excipient ingredients, high physical stability, and rapid gastrointestinal digestibility. The design, fabrication, and application of nanoemulsions as excipient foods will therefore be described in this article.


The Biobanking Analysis Resource Catalogue (BARCdb): a new research tool for the analysis of biobank samples.
We report the development of a new database of technology services and products for analysis of biobank samples in biomedical research. BARCdb, the Biobanking Analysis Resource Catalogue, is a freely available web resource, listing expertise and molecular resource capabilities of research centres and biotechnology companies. The database is designed for researchers who require information on how to make best use of valuable biospecimens from biobanks and other sample collections, focusing on the choice of analytical techniques and the demands they make on the type of samples, pre-analytical sample preparation and amounts needed. BARCdb has been developed as part of the Swedish biobanking infrastructure (BBMRI.se), but now welcomes submissions from service providers throughout Europe. BARCdb can help match resource providers with potential users, stimulating transnational collaborations and ensuring compatibility of results from different labs. It can promote a more optimal use of European resources in general, both with respect to standard and more experimental technologies, as well as for valuable biobank samples. This article describes how information on service and reagent providers of relevant technologies is made available on BARCdb, and how this resource may contribute to strengthening biomedical research in academia and in the biotechnology and pharmaceutical industries.


Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway.
Death receptor 4 (DR4) is a recently described receptor for the cytotoxic ligand TRAIL that reportedly uses a FADD-independent pathway to induce apoptosis and does not activate the NF-kappaB pathway. We have isolated a new member of the tumor necrosis factor receptor (TNFR) family, designated DR5, which bears a high degree of sequence homology to DR4. However, contrary to the previous reports, both DR4- and DR5-induced apoptosis can be blocked by dominant-negative FADD, and both receptors can activate NF-kappaB using a TRADD-dependent pathway. Finally, both receptors can interact with FADD, TRADD, and RIP. Thus, both DR5 and DR4 use FADD, TRADD, and RIP in their signal transduction pathways, and FADD is the common mediator of apoptosis by all known death domain-containing receptors.


Immune-based mutation classification enables neoantigen prioritization and immune feature discovery in cancer immunotherapy.
Genetic mutations lead to the production of mutated proteins from which peptides are presented to T cells as cancer neoantigens. Evidence suggests that T cells that target neoantigens are the main mediators of effective cancer immunotherapies. Although algorithms have been used to predict neoantigens, only a minority are immunogenic. The factors that influence neoantigen immunogenicity are not completely understood. Here, we classified human neoantigen/neopeptide data into three categories based on their TCR-pMHC binding events. We observed a conservative mutant orientation of the anchor residue from immunogenic neoantigens which we termed the "NP" rule. By integrating this rule with an existing prediction algorithm, we found improved performance in neoantigen prioritization. To better understand this rule, we solved several neoantigen/MHC structures. These structures showed that neoantigens that follow this rule not only increase peptide-MHC binding affinity but also create new TCR-binding features. These molecular insights highlight the value of immune-based classification in neoantigen studies and may enable the design of more effective cancer immunotherapies.


Salivary polypeptide/hyaluronic acid multilayer coatings act as "fungal repellents" and prevent biofilm formation on biomaterials.
Candida-associated denture stomatitis (CADS) is a common, recurring clinical complication in denture wearers that can lead to serious oral and systemic health problems. Current management strategies are not satisfactory due to their short-acting and ineffective therapeutic effects. Here, we describe a new fungal biofilm controlling strategy using the polyelectrolyte layer-by-layer (LBL) self-assembly technology on denture materials. Conventional poly(methyl methacrylate) (PMMA) denture material discs were functionalized with negatively charged poly(methacrylic acid) (PMAA) via plasma-initiated surface grafting, followed by repetitive alternating coating with the salivary antimicrobial polypeptide histatin 5 (H-5; cationic polymer) and hyaluronic acid (HA; anionic polymer). On the other hand, the H-5/HA LBL coatings (i.e., the outermost layer was H-5) inhibited fungal attachment/adhesion, significantly reduced fungal biofilm formation, and showed synergistic effects with the antifungal drug miconazole. LBL surface hydrophilicity was not the key mechanism in controlling Candida biofilm formation. The current approach demonstrates the utility of a new design principle for fabricating anticandidal denture materials, as well as potentially other related medical devices, for controlling fungal biofilm formation and combating insidious infections.


Intronic motif pairs cooperate across exons to promote pre-mRNA splicing.
A very early step in splice site recognition is exon definition, a process that is as yet poorly understood. Communication between the two ends of an exon is thought to be required for this step. We report genome-wide evidence for exons being defined through the combinatorial activity of motifs located in flanking intronic regions. Strongly co-occurring motifs were found to specifically reside in four intronic regions surrounding a large number of human exons. These paired motifs occur around constitutive and alternative exons but not pseudo exons. Most co-occurring motifs are limited to intronic regions within 100 nucleotides of the exon. They are preferentially associated with weaker exons. Their pairing is conserved in evolution and they exhibit a lower frequency of single nucleotide polymorphism when paired. Paired motifs display specificity with respect to distance from the exon borders and in constitutive versus alternative splicing. Many resemble binding sites for heterogeneous nuclear ribonucleoproteins. Specific pairs are associated with tissue-specific genes, the higher expression of which coincides with that of the pertinent RNA binding proteins. Tested pairs acted synergistically to enhance exon inclusion, and this enhancement was found to be exon-specific. The exon-flanking sequence pairs identified here by genomic analysis promote exon inclusion and may play a role in the exon definition step in pre-mRNA splicing. We propose a model in which multiple concerted interactions are required between exonic sequences and flanking intronic sequences to effect exon definition.


A prospective, randomized comparison of skin adhesive and subcuticular suture for closure of pediatric hernia incisions: cost and cosmetic considerations.
In this study, we compared the skin adhesive 2-octylcyanoacrylate to subcuticular suture for closure of pediatric inguinal hernia incisions to determine if skin adhesive improves wound cosmesis, shortens skin closure time, and lowers operative costs. We prospectively randomized 134 children undergoing inguinal herniorrhaphy at our institution to have skin closure with either skin adhesive (n = 64) or subcuticular closure (n = 70). Data collected included age, sex, weight, type of operation, total operative time, and skin closure time. Digital photographs of healing incisions were taken at the 6-week postoperative visit. The operating surgeon assessed cosmetic outcome of incisions using a previously validated visual analog scale, as well as an ordinate scale. A blinded assessment of cosmetic outcome was then performed by an independent surgeon comparing these photographs to the visual analog scale. Operating room time and resource use (ie, costs) relative to the skin closure were assessed. Comparisons between groups were done using Student's t tests and chi(2) tests. Children enrolled in the study had a mean +/- SE age of 3.7 +/- 0.3 years and weighed 16 +/- 0.8 kg. Patients were predominantly male (82%). Patients underwent 1 of 3 types of open hernia repair as follows: unilateral herniorrhaphy without peritoneoscopy (n = 41; 31%), unilateral herniorrhaphy with peritoneoscopy (n = 55; 41%), and bilateral herniorrhaphy (n = 38; 28%). Skin closure time was significantly shorter in the skin adhesive group (adhesive = 1.4 +/- 0.8 minutes vs suture = 2.4 +/- 1.1 minutes; P = .001). Mean wound cosmesis scores based on the visual analog scale were similar between groups (adhesive = 78 +/- 21; suture=78 +/- 18; P = .50). Material costs related to herniorrhaphy were higher for skin adhesive (adhesive = $22.63 vs suture = $11.70; P < .001), whereas operating room time costs for adhesive skin closure were lower (adhesive = $9.33 +/- 5.33 vs suture = $16.00 +/- 7.33; P < .001). Except for a 7% incidence of erythema in both groups, there were no complications encountered. There is no difference in cosmetic outcome between skin adhesive and suture closure in pediatric inguinal herniorrhaphy. Material costs are increased because of the high cost of adhesive relative to suture. This is partially offset, however, by the cost savings from reduction in operating room time.


Discrete roles for secreted and transmembrane semaphorins in neuronal growth cone guidance in vivo.
From the initial stages of axon outgrowth to the formation of a functioning synapse, neuronal growth cones continuously integrate and respond to multiple guidance cues. To investigate the role of semaphorins in the establishment of appropriate axon trajectories, we have characterized a novel secreted semaphorin in grasshopper, gSema 2a. Sema 2a is expressed in a gradient in the developing limb bud epithelium during Ti pioneer axon outgrowth. We demonstrate that Sema 2a acts as chemorepulsive guidance molecule critical for axon fasciculation and for determining both the initial direction and subsequent pathfinding events of the Ti axon projection. Interestingly, simultaneous perturbation of both secreted Sema 2a and transmembrane Sema I results in a broader range and increased incidence of abnormal Ti pioneer axon phenotypes, indicating that different semaphorin family members can provide functionally distinct guidance information to the same growth cone in vivo.


Topical antiangiogenic SRPK1 inhibitors reduce choroidal neovascularization in rodent models of exudative AMD.
Exudative AMD (wet AMD) is treated by monthly injection into the eye of anti-VEGF proteins. VEGF is alternatively spliced to produce numerous isoforms that differ in angiogenic activity. Serine-rich protein kinase-1 (SRPK1) has been identified as a regulator of pro-angiogenic VEGF splicing by phosphorylating serine-rich splicing factor-1 (SRSF1), which binds to VEGF pre-mRNA. We tested the hypothesis that topical (eye drop) SRPK1-selective inhibitors could be generated that reduce pro-angiogenic isoforms, and prevent choroidal neovascularization in vivo. Novel inhibitors were tested for SRPK inhibition in vitro, pro-angiogenic VEGF production in RPE cells by PCR and ELISA, and for inhibition of choroidal neovascularisation in mice and rats. A novel disubstituted furan inhibitor was selective for the SRPK family of kinases and reduced expression of pro-angiogenic but not antiangiogenic VEGF isoforms. This inhibitor and previously identified SRPK inhibitors significantly reduced choroidal neovascularisation in vivo. Topical administration of SRPK inhibitors dose-dependently blocked CNV with an EC50 of 9 μM. These results indicate that novel SRPK1 selective inhibitors could be a potentially novel topical (eye drop) therapeutic for wet AMD.


Clinicians' Perspectives on the Duty to Inform Patients About Medical Aid-in-Dying.
Background: As of 2019, ten jurisdictions in the United States have authorized physicians to prescribe a lethal dose of medication to a terminally ill patient for the purpose of hastening death. Relatively little bioethics scholarship has addressed the question of whether physicians have an obligation to inform qualifying patients about aid-in-dying (AID) in permissive jurisdictions and little is known about providers' actual communication practices with respect to this issue. Methods: One hundred and forty-four in-depth, semi-structured interviews were conducted and analyzed using an inductive analytic approach as part of the Vermont Study on Aid-in-Dying. Results: Seventeen respondents, 14 physicians and 3 nurse practitioners, met the inclusion criteria for this sub-study. Eleven respondents indicated that they at least sometimes inform patients about AID. Respondents described multiple factors that influence whether or not they might initiate discussions of AID, including the importance of informing patients of their options for end-of-life care, worries about undue influence, and worries about the potential effects on the patient-provider relationship. For those providers who do initiate discussion of AID at least some of the time, attention to the particulars of each individual patient's situation and the context of the discussion appear to play a role in shaping communication about AID. Conclusions: While initiating a clinical discussion of AID is undoubtedly challenging, our study provides compelling descriptive evidence that some medical providers who support AID do not unilaterally follow the conventional bioethics wisdom holding that they ought to wait for patients to introduce the topic of AID. Future research should investigate how to approach these discussions so as to minimize ethical worries about undue influence or potential negative consequences.


The 2-week wait and other initiatives to improve cancer diagnosis: Has it altered survival? The answer is unclear-the evidence is too weak.
The UK is one of the lowest ranked high-income countries for cancer survival. Later stage at diagnosis is a significant contributor to reduced survival. Several strategies have been introduced to reduce delays in an effort to diagnose cancer earlier. This commentary summarises the evidence and impact of these initiatives.


Metabolomics strategy reveals therapeutical assessment of limonin on nonbacterial prostatitis.
Limonin has been found to possess significant anti-inflammatory properties in animal tests and with, human cells, however, its precise metabolism mechanism has not been well explored. The aim of this study was to investigate the anti-inflammatory effects of limonin in a nonbacterial prostatitis (NBP) animal model. Global metabolite profiling was performed by ultra-high-performance liquid chromatography combined with time-of-flight mass spectrometry (UPLC/ESI-TOFMS) and in conjunction with multivariate data analysis and pathway analysis which were integrated to explore differentiating metabolites and clarify the mechanism of limonin against capsaicin-induced NBP. Limonin has a potential protective function revealed by the metabolic profiling of limonin-treated rats located closer to the normal group. Twenty potential biomarker candidates and several key metabolic pathways contributing to the treatment of NBP were discovered and identified. Among the pathways, the related glycine, serine and threonine metabolism, glycerophospholipid metabolism were acutely perturbed. The changes in metabolites were restored to their base-line levels after limonin treatment, which might be through regulating the perturbed pathways to the normal state. The results indicate that changed biomarkers and pathways may provide evidence and insight into limonin action mechanisms and enable us to increase research productivity toward metabolomics in therapeutical assessment and drug discovery.


Probing fatty acid metabolism in bacteria, cyanobacteria, green microalgae and diatoms with natural and unnatural fatty acids.
In both eukaryotes and prokaryotes, fatty acid synthases are responsible for the biosynthesis of fatty acids in an iterative process, extending the fatty acid by two carbon units every cycle. Thus, odd numbered fatty acids are rarely found in nature. We tested whether representatives of diverse microbial phyla have the ability to incorporate odd-chain fatty acids as substrates for their fatty acid synthases and their downstream enzymes. We fed various odd and short chain fatty acids to the bacterium Escherichia coli, cyanobacterium Synechocystis sp. PCC 6803, green microalga Chlamydomonas reinhardtii and diatom Thalassiosira pseudonana. Major differences were observed, specifically in the ability among species to incorporate and elongate short chain fatty acids. We demonstrate that E. coli, C. reinhardtii, and T. pseudonana can produce longer fatty acid products from short chain precursors (C3 and C5), while Synechocystis sp. PCC 6803 lacks this ability. However, Synechocystis can incorporate and elongate longer chain fatty acids due to acyl-acyl carrier protein synthetase (AasS) activity, and knockout of this protein eliminates the ability to incorporate these fatty acids. In addition, expression of a characterized AasS from Vibrio harveyii confers a similar capability to E. coli. The ability to desaturate exogenously added fatty acids was only observed in Synechocystis and C. reinhardtii. We further probed fatty acid metabolism of these organisms by feeding desaturase inhibitors to test the specificity of long-chain fatty acid desaturases. In particular, supplementation with thia fatty acids can alter fatty acid profiles based on the location of the sulfur in the chain. We show that coupling sensitive gas chromatography mass spectrometry to supplementation of unnatural fatty acids can reveal major differences between fatty acid metabolism in various organisms. Often unnatural fatty acids have antibacterial or even therapeutic properties. Feeding of short precursors now gives us easy access to these extended molecules.


Adult polycystic liver disease.
Characteristics of 14 patients above 12 years of age with congenital polycystic liver disease attending liver clinic at KNH were analysed. The diagnosis was mainly based on ultrasonographic findings. The disease was found predominantly among the Kikuyu ethnic group with a female/male ratio of 6:1 and the peak age at presentation was in the 5th decade. The liver function tests were essentially normal in all cases with no complication directly relating to liver disease. Hypertension was found in 78.6% of cases and chronic renal failure in 35.7% of cases. There was an associated polycystic disease in at least one other abdominal organ in all cases.


Annual rhythms that underlie phenology: biological time-keeping meets environmental change.
Seasonal recurrence of biological processes (phenology) and its relationship to environmental change is recognized as being of key scientific and public concern, but its current study largely overlooks the extent to which phenology is based on biological time-keeping mechanisms. We highlight the relevance of physiological and neurobiological regulation for organisms' responsiveness to environmental conditions. Focusing on avian and mammalian examples, we describe circannual rhythmicity of reproduction, migration and hibernation, and address responses of animals to photic and thermal conditions. Climate change and urbanization are used as urgent examples of anthropogenic influences that put biological timing systems under pressure. We furthermore propose that consideration of Homo sapiens as principally a 'seasonal animal' can inspire new perspectives for understanding medical and psychological problems.


Sirtuin1 and autophagy protect cells from fluoride-induced cell stress.
Sirtuin1 (SIRT1) is a nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase functioning in the regulation of metabolism, cell survival and organismal lifespan. Active SIRT1 regulates autophagy during cell stress, including calorie restriction, endoplasmic reticulum (ER) stress and oxidative stress. Previously, we reported that fluoride induces ER-stress in ameloblasts responsible for enamel formation, suggesting that ER-stress plays a role in dental fluorosis. However, the molecular mechanism of how cells respond to fluoride-induced cell stress is unclear. Here, we demonstrate that fluoride activates SIRT1 and initiates autophagy to protect cells from fluoride exposure. Fluoride treatment of ameloblast-derived cells (LS8) significantly increased Sirt1 expression and induced SIRT1 phosphorylation resulting in the augmentation of SIRT1 deacetylase activity. To demonstrate that fluoride exposure initiates autophagy, we characterized the expression of autophagy related genes (Atg); Atg5, Atg7 and Atg8/LC3 and showed that both their transcript and protein levels were significantly increased following fluoride treatment. To confirm that SIRT1 plays a protective role in fluoride toxicity, we used resveratrol (RES) to augment SIRT1 activity in fluoride treated LS8 cells. RES increased autophagy, inhibited apoptosis, and decreased fluoride cytotoxicity. Rats treated with fluoride (0, 50, 100 and 125ppm) in drinking water for 6weeks had significantly elevated expression levels of Sirt1, Atg5, Atg7 and Atg8/LC3 in their maturation stage enamel organs. Increased protein levels of p-SIRT1, ATG5 and ATG8/LC3 were present in fluoride-treated rat maturation stage ameloblasts. Therefore, the SIRT1/autophagy pathway may play a critical role as a protective response to help prevent dental fluorosis.


SNP in human ARHGEF3 promoter is associated with DNase hypersensitivity, transcript level and platelet function, and Arhgef3 KO mice have increased mean platelet volume.
Genome-wide association studies have identified a genetic variant at 3p14.3 (SNP rs1354034) that strongly associates with platelet number and mean platelet volume in humans. While originally proposed to be intronic, analysis of mRNA expression in primary human hematopoietic subpopulations reveals that this SNP is located directly upstream of the predominantly expressed ARHGEF3 isoform in megakaryocytes (MK). We found that ARHGEF3, which encodes a Rho guanine exchange factor, is dramatically upregulated during both human and murine MK maturation. We show that the SNP (rs1354034) is located in a DNase I hypersensitive region in human MKs and is an expression quantitative locus (eQTL) associated with ARHGEF3 expression level in human platelets, suggesting that it may be the causal SNP that accounts for the variations observed in human platelet traits and ARHGEF3 expression. In vitro human platelet activation assays revealed that rs1354034 is highly correlated with human platelet activation by ADP. In order to test whether ARHGEF3 plays a role in MK development and/or platelet function, we developed an Arhgef3 KO/LacZ reporter mouse model. Reflecting changes in gene expression, LacZ expression increases during MK maturation in these mice. Although Arhgef3 KO mice have significantly larger platelets, loss of Arhgef3 does not affect baseline MK or platelets nor does it affect platelet function or platelet recovery in response to antibody-mediated platelet depletion compared to littermate controls. In summary, our data suggest that modulation of ARHGEF3 gene expression in humans with a promoter-localized SNP plays a role in human MKs and human platelet function-a finding resulting from the biological follow-up of human genetic studies. Arhgef3 KO mice partially recapitulate the human phenotype.


MPV17 Loss Causes Deoxynucleotide Insufficiency and Slow DNA Replication in Mitochondria.
MPV17 is a mitochondrial inner membrane protein whose dysfunction causes mitochondrial DNA abnormalities and disease by an unknown mechanism. Perturbations of deoxynucleoside triphosphate (dNTP) pools are a recognized cause of mitochondrial genomic instability; therefore, we determined DNA copy number and dNTP levels in mitochondria of two models of MPV17 deficiency. In Mpv17 ablated mice, liver mitochondria showed substantial decreases in the levels of dGTP and dTTP and severe mitochondrial DNA depletion, whereas the dNTP pool was not significantly altered in kidney and brain mitochondria that had near normal levels of DNA. The shortage of mitochondrial dNTPs in Mpv17-/- liver slows the DNA replication in the organelle, as evidenced by the elevated level of replication intermediates. Quiescent fibroblasts of MPV17-mutant patients recapitulate key features of the primary affected tissue of the Mpv17-/- mice, displaying virtual absence of the protein, decreased dNTP levels and mitochondrial DNA depletion. Notably, the mitochondrial DNA loss in the patients' quiescent fibroblasts was prevented and rescued by deoxynucleoside supplementation. Thus, our study establishes dNTP insufficiency in the mitochondria as the cause of mitochondrial DNA depletion in MPV17 deficiency, and identifies deoxynucleoside supplementation as a potential therapeutic strategy for MPV17-related disease. Moreover, changes in the expression of factors involved in mitochondrial deoxynucleotide homeostasis indicate a remodeling of nucleotide metabolism in MPV17 disease models, which suggests mitochondria lacking functional MPV17 have a restricted purine mitochondrial salvage pathway.


Criteria used by nurses to evaluate practice-related information on the World Wide Web.
Existing criteria used to evaluate information on the World Wide Web often are not related to nursing, especially in relation to clinical and evidence-based practice. Published criteria have been found orientated to the health-consumer, medicine, or general information. In this study, the process by which nurses evaluate practice-related information and the associated evaluative nursing criteria were investigated using a grounded theory approach. In the first stage of this ongoing investigation, semistructured interviews were used to collect data from UK postregistration nursing students. The findings from this initial study provided indications of the process and the criteria for evaluating information on the World Wide Web. Participating students identified intuition as part of the evaluative process. They identified some criteria similar to existing standards, but critically, with additional criteria that are nursing practice related. Because these new criteria are significant for evaluating nursing information, further refinement of these findings is being undertaken through the next stage of the research program.


Trends in cardiovascular risk factors among patients with coronary heart disease: results from the EUROASPIRE I, II, and III surveys in the Münster region.
Target values for cardiovascular risk factors in patients with coronary heart disease (CHD) are stated in guidelines for the prevention of cardiovascular disease. We studied secular trends in risk factors over a 12-year period among CHD patients in the region of Münster, Germany. The cross-sectional EUROASPIRE I, II and III surveys were performed in multiple centers across Europe. For all three, the Münster region was the participating German region. In the three periods 1995/96, 1999/2000, and 2006/07, the surveys included (respectively) 392, 402 and 457 ≤ 70-year-old patients with CHD in Münster who had sustained a coronary event at least 6 months earlier. The prevalence of smoking remained unchanged, with 16.8% in EUROASPIRE I and II and 18.4% in EUROASPIRE III (p=0.898). On the other hand, high blood pressure and high cholesterol both became less common across the three EUROASPIRE studies (60.7% to 69.4% to 55.3%, and 94.3% to 83.4% to 48.1%, respectively; p<0.001 for both). Obesity became more common (23.0% to 30.6% to 43.1%, p<0.001), as did treatment with antihypertensive and lipid-lowering drugs (80.4% to 88.6% to 94.3%, and 35.0% to 67.4% to 87.0%, respectively; p<0.001 for both). The observed trends in cardiovascular risk factors under-score the vital need for better preventive strategies in patients with CHD.


Behavioural activation for the treatment of depression in military personnel.
INTRODUCTION: Depression is a common mental health problem in both civilian and military populations. Access to evidence based psychological therapies for treating common mental health problems such as depression may not be adequate at present. Behavioural Activation (BA) represents a National Institute for Clinical Excellence recommended, evidence-based treatment for depression. The aim of this review was to review the literature to determine how BA could work as a therapeutic approach for military personnel with depression. METHOD: Five specialty-specific electronic databases were searched using the key words 'behavioural activation', 'activity scheduling' and 'depression'. Emerging themes were drawn out of the literature using a long table approach to thematic analysis. RESULTS: Seven themes were identified: Clinical Effectiveness, Cultural Competence, Co-morbidity, Cost Effectiveness, Alternatives to Face-to-Face Therapy, Training and Patient Experience. CONCLUSIONS: Group based BA is a cost effective option that may build upon service personnel's cultural affinity to teamwork and peer support. Brief training workshops and supervision could be provided to military mental health nurses to deliver group based BA. However service delivery may also be enhanced by enabling some nurses to specialise as Cognitive Behavioural Psychotherapists. More research is needed to understand whether this pragmatic, two pronged approach to training would result in the sustained dissemination of evidence based practice.


How useful are malaria risk maps at the country level? Perceptions of decision-makers in Kenya, Malawi and the Democratic Republic of Congo.
Declining malaria prevalence and pressure on external funding have increased the need for efficiency in malaria control in sub-Saharan Africa (SSA). Modelled Plasmodium falciparum parasite rate (PfPR) maps are increasingly becoming available and provide information on the epidemiological situation of countries. However, how these maps are understood or used for national malaria planning is rarely explored. In this study, the practices and perceptions of national decision-makers on the utility of malaria risk maps, showing prevalence of parasitaemia or incidence of illness, was investigated. A document review of recent National Malaria Strategic Plans was combined with 64 in-depth interviews with stakeholders in Kenya, Malawi and the Democratic Republic of Congo (DRC). The document review focused on the type of epidemiological maps included and their use in prioritising and targeting interventions. Interviews (14 Kenya, 17 Malawi, 27 DRC, 6 global level) explored drivers of stakeholder perceptions of the utility, value and limitations of malaria risk maps. Three different types of maps were used to show malaria epidemiological strata: malaria prevalence using a PfPR modelled map (Kenya); malaria incidence using routine health system data (Malawi); and malaria prevalence using data from the most recent Demographic and Health Survey (DRC). In Kenya the map was used to target preventative interventions, including long-lasting insecticide-treated nets (LLINs) and intermittent preventive treatment in pregnancy (IPTp), whilst in Malawi and DRC the maps were used to target in-door residual spraying (IRS) and LLINs distributions in schools. Maps were also used for operational planning, supply quantification, financial justification and advocacy. Findings from the interviews suggested that decision-makers lacked trust in the modelled PfPR maps when based on only a few empirical data points (Malawi and DRC). Maps were generally used to identify areas with high prevalence in order to implement specific interventions. Despite the availability of national level modelled PfPR maps in all three countries, they were only used in one country. Perceived utility of malaria risk maps was associated with the epidemiological structure of the country and use was driven by perceived need, understanding (quality and relevance), ownership and trust in the data used to develop the maps.


SVDD-based pattern denoising.
The support vector data description (SVDD) is one of the best-known one-class support vector learning methods, in which one tries the strategy of using balls defined on the feature space in order to distinguish a set of normal data from all other possible abnormal objects. The major concern of this letter is to extend the main idea of SVDD to pattern denoising. Combining the geodesic projection to the spherical decision boundary resulting from the SVDD, together with solving the preimage problem, we propose a new method for pattern denoising. We first solve SVDD for the training data and then for each noisy test pattern, obtain its denoised feature by moving its feature vector along the geodesic on the manifold to the nearest decision boundary of the SVDD ball. Finally we find the location of the denoised pattern by obtaining the pre-image of the denoised feature. The applicability of the proposed method is illustrated by a number of toy and real-world data sets.


Antipsychotic treatment strategies for acute phase and treatment resistance in schizophrenia: A systematic review of the guidelines and algorithms.
To summarize the current state of knowledge on antipsychotic treatment strategies for the acute phase and treatment resistance in schizophrenia, we conducted a systematic review of guidelines and algorithms. We conducted a systematic literature search to identify clinical guidelines and algorithms on this topic using MEDLINE and Embase. We extracted information on recommendations for antipsychotic treatment strategies, including those for non-response (i.e., increasing antipsychotic dose and switching to another antipsychotic) and treatment resistance. We identified a total of 17 guidelines/algorithms in various countries that were published after 2011. With respect to antipsychotic dose, most of the guidelines (N = 10/11) agreed starting with a low dose or the lowest licensed/effective dose and then titrating the dose upwards. Regarding antipsychotic treatment strategies for non-response, all of the guidelines (N = 9/9) recommended increasing antipsychotic dose towards the upper end of its approved dose range. Five guidelines suggested for increasing beyond the therapeutic dose range in exceptional cases, while overall 10 guidelines including them were negative about such strategy. The vast majority of guidelines (N = 16/17) recommended switching to another antipsychotic for non-response; however, some guidelines mentioned the lack of evidence for these strategies other than the use of clozapine. All the guidelines (N = 17/17) endorsed initiating clozapine after failure to respond to 2 different antipsychotics. Four guidelines endorsed an early use of clozapine, yet as the third antipsychotic. The currently available guidelines and algorithms recommended increasing antipsychotic dose and switching to another antipsychotic, particularly clozapine for treatment-resistant schizophrenia, during the acute phase of schizophrenia for non-response.


Pharmacogenetic testing to predict antipsychotic-induced weight gain: a systematic review.
Weight gain is an important side effect of antipsychotic drugs. Since the high interindividual difference in weight gain suggests that genetic factors play a role in this weight gain, studies have tried to identify these factors. Most of these studies were carried out in the past few years and focussed largely on receptor polymorphisms, although some tried to explain the variation in weight gain by differences in pharmacokinetics. Unfortunately, the results of these association studies are often conflicting, which makes it hard to apply this genetic knowledge in daily clinical practice. This article summarizes the findings of these association studies and focuses on differences in study methodology in an attempt to explain why study results could have been conflicting. Furthermore, the feasibility of genetic testing in today's clinical practice is discussed, using a model that consists of four components; analytical validity, clinical validity, clinical utility and ethical, legal and social issues.


Ritanserin attenuates anorectic, endocrine and thermic responses to d-fenfluramine in human volunteers.
This study investigated the role of the 5-HT2/1C receptor antagonist ritanserin on d-fenfluramine (d-FF) induced changes in food intake, prolactin (PRL) secretion and oral temperature in 12 healthy male volunteers. The study was double blind and placebo controlled. Food intake was measured using an automated food dispenser. d-FF (30 mg) significantly reduced fat intake. While ritanserin (5 mg) had no effect when given alone it abolished the d-FF induced reduction in fat intake. In addition, ritanserin abolished the d-FF induced rise in PRL and oral temperature. The results suggest that 5-HT2 or 5-HT1C receptors mediate the effects of d-fenfluramine on appetite, prolactin secretion and temperature in humans.


Retrieval practice produces more learning than elaborative studying with concept mapping.
Educators rely heavily on learning activities that encourage elaborative studying, whereas activities that require students to practice retrieving and reconstructing knowledge are used less frequently. Here, we show that practicing retrieval produces greater gains in meaningful learning than elaborative studying with concept mapping. The advantage of retrieval practice generalized across texts identical to those commonly found in science education. The advantage of retrieval practice was observed with test questions that assessed comprehension and required students to make inferences. The advantage of retrieval practice occurred even when the criterial test involved creating concept maps. Our findings support the theory that retrieval practice enhances learning by retrieval-specific mechanisms rather than by elaborative study processes. Retrieval practice is an effective tool to promote conceptual learning about science.


Salinispora arenicola gen. nov., sp. nov. and Salinispora tropica sp. nov., obligate marine actinomycetes belonging to the family Micromonosporaceae.
A taxonomic study was carried out to clarify the taxonomy of representatives of a group of marine actinomycetes previously designated MAR 1 and considered to belong to the family Micromonosporaceae. The organisms had phenotypic properties consistent with their assignment to this taxon. The strains formed a distinct taxon in the 16S rRNA Micromonosporaceae gene tree and shared a range of phenotypic properties that distinguished them from members of all of the genera with validly published names classified in this family. The name proposed for this novel taxon is Salinispora gen. nov. The genus contains two species recognized using a range of genotypic and phenotypic criteria, including comparative 16S-23S rRNA gene spacer region and DNA-DNA relatedness data. The names proposed for these taxa are Salinispora arenicola sp. nov., the type species, and Salinispora tropica sp. nov.; the type strains of these novel species have been deposited in service culture collections as strain CNH-643(T) (=ATCC BAA-917(T)=DSM 44819(T)) and strain CNB-440(T) (=ATCC BAA-916(T)=DSM 44818(T)), respectively.


SARS-CoV-2 vaccines in development.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in late 2019 in China and is the causative agent of the coronavirus disease 2019 (COVID-19) pandemic. To mitigate the effects of the virus on public health, the economy and society, a vaccine is urgently needed. Here I review the development of vaccines against SARS-CoV-2. Development was initiated when the genetic sequence of the virus became available in early January 2020, and has moved at an unprecedented speed: a phase I trial started in March 2020 and there are currently more than 180 vaccines at various stages of development. Data from phase I and phase II trials are already available for several vaccine candidates, and many have moved into phase III trials. The data available so far suggest that effective and safe vaccines might become available within months, rather than years.