Perspectives for integration into the local health system of community-based management of acute malnutrition in children under 5 years: a qualitative study in Bangladesh.
Acute malnutrition is a major cause of death among under-five children in low- and middle-income countries. United Nations agencies recommend the integration of community-based management of acute malnutrition (CMAM) into the local health systems for sustainability. The objective of the study was to assess the preparedness of the health system to implement CMAM targeting children under-five years in two sub-districts of Bangladesh. The assessment was performed through direct observation of 44 health centres, individual interviews of seven policy makers, three donors, four health and nutrition implementing partners, 29 health workers, and review of secondary data. Assessment themes, derived from the WHO six Building Blocks, were nutrition governance, nutrition financing, health service delivery, human resources, equipment and supply, referral, monitoring and supervision mechanism. They were subdivided into 16 criteria. Findings were compared with CMAM operational recommendations according to WHO, Valid International and Food and Nutrition Technical Assistance guidelines. The government of Bangladesh has developed inpatient and outpatient CMAM guidelines, and a policy offering free-of-charge health care for under-five children. Nutrition coordination was not under full government leadership. Most of funds (74%) dedicated to CMAM were provided by donors, for short-term interventions. Of the total 44 health centres assessed, 39 (88.6%) were active, among which 4 (10.2%) delivered inpatient services, 35 (89.8%) outpatient services, and 24 (61.5%) outreach services. These were regarded as opportunities to include CMAM activities. There were 48.9% vacant positions and the health workers were not trained for management of acute malnutrition. Equipment and supplies did not meet the operational recommendations for management of acute malnutrition. Implementing CMAM through the health centres of both sub-districts would warrant progressive strengthening of the overall health system in the light of identified barriers. A short term strategy would consist of strengthening government coordination of nutrition interventions, exploring additional funding sources, equipping and supplying functional health centres, training health workers and actively involving community health workers to cope with health facility staff shortage. A mid-term strategy would consist of securing permanent funding for CMAM, rehabilitating non-functional health centres, attracting and retaining health workers in rural areas.


Patterns of sequence polymorphism in the fleshless berry locus in cultivated and wild Vitis vinifera accessions.
Unlike in tomato, little is known about the genetic and molecular control of fleshy fruit development of perennial fruit trees like grapevine (Vitis vinifera L.). Here we present the study of the sequence polymorphism in a 1 Mb grapevine genome region at the top of chromosome 18 carrying the fleshless berry mutation (flb) in order, first to identify SNP markers closely linked to the gene and second to search for possible signatures of domestication. In total, 62 regions (17 SSR, 3 SNP, 1 CAPS and 41 re-sequenced gene fragments) were scanned for polymorphism along a 3.4 Mb interval (85,127-3,506,060 bp) at the top of the chromosome 18, in both V. vinifera cv. Chardonnay and a genotype carrying the flb mutation, V. vinifera cv. Ugni Blanc mutant. A nearly complete homozygosity in Ugni Blanc (wild and mutant forms) and an expected high level of heterozygosity in Chardonnay were revealed. Experiments using qPCR and BAC FISH confirmed the observed homozygosity. Under the assumption that flb could be one of the genes involved into the domestication syndrome of grapevine, we sequenced 69 gene fragments, spread over the flb region, representing 48,874 bp in a highly diverse set of cultivated and wild V. vinifera genotypes, to identify possible signatures of domestication in the cultivated V. vinifera compartment. We identified eight gene fragments presenting a significant deviation from neutrality of the Tajima's D parameter in the cultivated pool. One of these also showed higher nucleotide diversity in the wild compartments than in the cultivated compartments. In addition, SNPs significantly associated to berry weight variation were identified in the flb region. We observed the occurrence of a large homozygous region in a non-repetitive region of the grapevine otherwise highly-heterozygous genome and propose a hypothesis for its formation. We demonstrated the feasibility to apply BAC FISH on the very small grapevine chromosomes and provided a specific probe for the identification of chromosome 18 on a cytogenetic map. We evidenced genes showing putative signatures of selection and SNPs significantly associated with berry weight variation in the flb region. In addition, we provided to the community 554 SNPs at the top of chromosome 18 for the development of a genotyping chip for future fine mapping of the flb gene in a F2 population when available.


Calcium and sodium channels in spontaneously contracting vascular muscle cells.
Electrophysiological recordings of inward currents from whole cells showed that vascular muscle cells have one type of sodium channel and two types of calcium channels. One of the calcium channels, the transient calcium channel, was activated by small depolarizations but then rapidly inactivated. It was equally permeable to calcium and barium and was blocked by cadmium, but not by tetrodotoxin. The other type, the sustained calcium channel, was activated by larger depolarizations, but inactivated very little; it was more permeable to barium than calcium. The sustained calcium channel was more sensitive to block by cadmium than the transient channel, but also was not blocked by tetrodotoxin. The sodium channel inactivated 15 times more rapidly than the transient calcium channel and at more negative voltages. This sodium channel, which is unusual because it is only blocked by a very high (60 microM) tetrodotoxin concentration but not by cadmium, is the first to be characterized in vascular muscle, and together with the two calcium channels, provides a basis for different patterns of excitation in vascular muscles.


Origin of co-expression patterns in E. coli and S. cerevisiae emerging from reverse engineering algorithms.
The concept of reverse engineering a gene network, i.e., of inferring a genome-wide graph of putative gene-gene interactions from compendia of high throughput microarray data has been extensively used in the last few years to deduce/integrate/validate various types of "physical" networks of interactions among genes or gene products. This paper gives a comprehensive overview of which of these networks emerge significantly when reverse engineering large collections of gene expression data for two model organisms, E. coli and S. cerevisiae, without any prior information. For the first organism the pattern of co-expression is shown to reflect in fine detail both the operonal structure of the DNA and the regulatory effects exerted by the gene products when co-participating in a protein complex. For the second organism we find that direct transcriptional control (e.g., transcription factor-binding site interactions) has little statistical significance in comparison to the other regulatory mechanisms (such as co-sharing a protein complex, co-localization on a metabolic pathway or compartment), which are however resolved at a lower level of detail than in E. coli. The gene co-expression patterns deduced from compendia of profiling experiments tend to unveil functional categories that are mainly associated to stable bindings rather than transient interactions. The inference power of this systematic analysis is substantially reduced when passing from E. coli to S. cerevisiae. This extensive analysis provides a way to describe the different complexity between the two organisms and discusses the critical limitations affecting this type of methodologies.


[Ichthyofauna from wetlands of San Pedro, Balancán, Tabasco, México].
San Pedro River's wetlands sustain trophic nets in the fluvial system, due to the high habitat availability, and space and temporal variations. In order to describe the relationship between environmental parameters and ichthyofauna, this study evaluated fish assemblages composition, distribution, abundance, density, biomass, richness species, diversity and equitability in the wetlands. Sampling considered three different sites and climatic seasons (dry, rainy and cold fronts). The physical and chemical parameters considered were dissolved oxygen, temperature, pH, water transparency and the depth. Fishes were caught with a shrimp net, after six minutes towings and were identified afterwards. A total of 1 049 organisms of 25 fish species were caught, two of which were exotic species: Oreochromis niloticus and Parachromis managuense. A total of 23 species were found at site I (with the highest density 0.23 ind./m2), 17 at site II (0.23 ind./m2) and 14 at site III (0.12 ind./m2). The dry season had the highest species number with 21 species, followed by the rainy season with 17 species, and the cold season with five species. Similarly, the highest biomass (8.30 g/m2) was found in dry season, followed by the rainy (2.16 g/m2) and the cold seasons (0.03 g/m2). Considering seasons, highest density was found during the dry (0.436 ind./m2), followed by the rainy (0.213 ind./m2) and the cold (0.023 ind./m2) seasons. The dominant density species during the study period, according to the quadrants graphic of Olmstead-Tukey were: Petenia splendida, Vieja heterospila, Vieja synspila, Dorosoma petenense and Astyanax aeneus. There were significant differences in the species richness among sites. Temperature, depth and transparency showed differences among the seasons. The canonical correspondence analysis indicated that fish distribution was governed by environmental parameters during all seasons. In terms of fish abundance and composition, environmental parameters play an important role showing spatial and temporal differences in the ecosystem, this could be explained with the fact that most of young fishes have a movement behavior to the wetlands, searching refuge and feed during the dry season. Considering the diversity indexes variation, it may be concluded that San Pedro River's wetlands correspond to a system where the ichthyofauna composition fluctuates spatial and seasonally.


SU-E-J-85: Anthropomorphic Development for Intermodality Deformation Algorithms Validation.
Radiation therapy is often based on a single treatment plan calculated on patient's anatomy at the time of the simulation scan. Deformation algorithms offer the possibility to register initial treatment plan on a daily CBCT. This way, the planning can be adapted to the evolution of patient anatomy. Validation of deformable image registration algorithms (DRA) ideally requires the use of phantoms offering some deformation possibilitiesMethods: An anthropomorphic, pelvic phantom was built to test volume variation (bladder), deformation of contours (prostate) and translation (all organs). Algorithms must be able to perform intermodality registration. Therefore, images were acquired for both CT and CBCT. The phantom has been created in a way to allow total control of the deformation amplitude. Each of the three types of deformations studied were realized independently and scanned in a manner to have the same initial and deformed images set for each modality. Two algorithm systems were use to compare their efficiency; an open-source software, a toolbox for registration that offers parameter adjustment and a commercial system with limited control for user. The phantom provides us usable images for DRA validation. For a 2 cm mass center organ translation, the first one reduced 98% of the distance while the other only performed 60%. For a 100 ml volume variation, we get 88% and 62%. Comparison of each intermodal deformation registration performed by the two algorithm systems show how control on parameters improves registration quality. DRA allow the initial planning adaptation on different deformations which occur in human body.


Attentional capture for tool images is driven by the head end of the tool, not the handle.
Tools afford specialized actions that are tied closely to object identity. Although there is mounting evidence that functional objects, such as tools, capture visuospatial attention relative to non-tool competitors, this leaves open the question of which part of a tool drives attentional capture. We used a modified version of the Posner cueing task to determine whether attention is oriented towards the head versus the handle of realistic images of common elongated tools. We compared cueing effects for tools with control stimuli that consisted of images of fruit and vegetables of comparable elongation to the tools. Critically, our displays controlled for lower-level influences on attention that can arise from global shape asymmetries in the image cues. Observers were faster to detect low-contrast targets positioned near the head end versus the handle of tools. As expected, no lateralized performance bias was observed for the control stimuli. In a follow-up experiment, we confirmed that the bias towards tool heads was not due to inhibition of return as a result of early attentional orienting towards tool handles. Finally, we confirmed that real-world exemplars of the tools in the cueing studies were associated more strongly with specific grasping patterns than the elongated fruits and vegetables. Together, our results demonstrate that affordance effects on attentional capture are driven by the head end of a tool. Prioritizing the head end of a tool is adaptive because it ensures that the most relevant region of the object takes priority in selecting an effective motor plan.


Closed Complete Genome Sequences of Two Nontypeable Haemophilus influenzae Strains Containing Novel modA Alleles from the Sputum of Patients with Chronic Obstructive Pulmonary Disease.
Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen that causes otitis media and exacerbations of chronic obstructive pulmonary disease (COPD). Here, we report the complete genome sequences of NTHi strains 10P129H1 and 84P36H1, isolated from COPD patients, which contain the phase-variable epigenetic regulators ModA15 and ModA18, respectively.


Feasibility and initial efficacy of a culturally sensitive women-centered substance use intervention in Georgia: Sex risk outcomes.
This paper reports on the feasibility and initial efficacy of a culturally sensitive, comprehensive women-centered substance use intervention for women who inject drugs in Georgia in terms of the primary and secondary sex risk outcomes. The hypothesis under examination was that, relative to case management participants, participants in a culturally sensitive, comprehensive women-specific and -centered intervention would, on average, show significant decreases in past-30-day frequency of unprotected sex, unprotected sex at the last sexual encounter, and increases in condom use and safer sex actions. The study was a two-arm randomized trial, in which 173 potentially eligible women were screened, and those 128 women determined to be eligible were assigned at random to either Reinforcement-based Treatment plus Women's Co-Op (RBT + WC) or case management (CM). RBT + WC participants received 12 sessions of a structured intervention with the goal of reducing risky sex and substance use and improving physical and mental health. CM participants received 12 sessions of case management and informational brochures that focused on the same issues on which RBT + WC focused. Participants were assessed at baseline, post-treatment, and 3 months following treatment enrollment. Analyses revealed case management having significantly overall higher Safer Sex action scores than RBT + WC, and a significant decrease over time for past 30-day number of unprotected sex acts. Unprotected sex at the last encounter and Condom Use action scores were nonsignificant. Women who inject drugs in Georgia are engaging in risky sexual practices, and are in need of an intervention that addresses these risky behaviors. Reasons for the failure to find differences between a culturally sensitive, comprehensive women-centered intervention and case management tailored to the needs of women who inject drugs in Georgia may have been the result of inadequate power to detect an effect in a sample whose drug use was not as serious as warranted by the intervention. (ClinicalTrials.gov Identifier: NCT01331460 ).


Regional distribution of type II Ca2+/calmodulin-dependent protein kinase in rat brain.
The distribution of type II Ca2+/calmodulin-dependent protein kinase has been mapped in rat brain by immunochemical and immunohistochemical methods using an antibody against its alpha-subunit. The concentration of the kinase, measured by radioimmunoassay, varies markedly in different brain regions. It is most highly concentrated in the telencephalon where it comprises approximately 2% of the total hippocampal protein, 1.3% of cortical protein, and 0.7% of striatal protein. It is less concentrated in lower brain structures, ranging from about 0.3% of hypothalamic protein to 0.1% of protein in the pons/medulla. The gradient of staining intensity observed in brain sections by immunohistochemistry corroborates this distribution. Neurons and neuropil of the hippocampus are densely stained, whereas little staining is observed in lower brain regions such as the superior colliculus. Within the diencephalon and midbrain, dense staining is observed only in thalamic nuclei and the substantia nigra. The skewed distribution of alpha-subunit appears to be due in part to the occurrence in the cerebellum and pons/medulla of forms of the kinase with a high ratio of beta- to alpha-subunits. However, most of the variation is due to the extremely high concentration of the kinase in particular neurons, especially those of the hippocampus, cortex and striatum. The unusually high expression of the kinase in these neurons is likely to confer upon them specialized responses to calcium ion that are different from those of neurons in lower brain regions.


Targeted drug delivery for cancer therapy: the other side of antibodies.
Therapeutic monoclonal antibody (TMA) based therapies for cancer have advanced significantly over the past two decades both in their molecular sophistication and clinical efficacy. Initial development efforts focused mainly on humanizing the antibody protein to overcome problems of immunogenicity and on expanding of the target antigen repertoire. In parallel to naked TMAs, antibody-drug conjugates (ADCs) have been developed for targeted delivery of potent anti-cancer drugs with the aim of bypassing the morbidity common to conventional chemotherapy. This paper first presents a review of TMAs and ADCs approved for clinical use by the FDA and those in development, focusing on hematological malignancies. Despite advances in these areas, both TMAs and ADCs still carry limitations and we highlight the more important ones including cancer cell specificity, conjugation chemistry, tumor penetration, product heterogeneity and manufacturing issues. In view of the recognized importance of targeted drug delivery strategies for cancer therapy, we discuss the advantages of alternative drug carriers and where these should be applied, focusing on peptide-drug conjugates (PDCs), particularly those discovered through combinatorial peptide libraries. By defining the advantages and disadvantages of naked TMAs, ADCs and PDCs it should be possible to develop a more rational approach to the application of targeted drug delivery strategies in different situations and ultimately, to a broader basket of more effective therapies for cancer patients.


Conformational dependence of hemoglobin reactivity under high viscosity conditions: the role of solvent slaved dynamics.
The concept of protein dynamic states is introduced. This concept is based on (i) protein dynamics being organized hierarchically with respect to solvent slaving and (ii) which tier of dynamics is operative over the time window of a given measurement. The protein dynamic state concept is used to analyze the kinetic phases derived from the recombination of carbon monoxide to sol-gel-encapsulated human adult hemoglobin (HbA) and select recombinant mutants. The temperature-dependent measurements are made under very high viscosity conditions obtained by bathing the samples in an excess of glycerol. The results are consistent with a given tier of solvent slaved dynamics becoming operative at a time delay (with respect to the onset of the measurement) that is primarily solvent- and temperature-dependent. However, the functional consequences of the dynamics are protein- and conformation-specific. The kinetic traces from both equilibrium populations and trapped allosteric intermediates show a consistent progression that exposes the role of both conformation and hydration in the control of reactivity. Iron-zinc symmetric hybrid forms of HbA are used to show the dramatic difference between the kinetic patterns for T state alpha and beta subunits. The overall results support a model for allostery in HbA in which the ligand-binding-induced transition from the deoxy T state to the high -affinity R state proceeds through a progression of T state intermediates.


UCNEbase--a database of ultraconserved non-coding elements and genomic regulatory blocks.
UCNEbase (http://ccg.vital-it.ch/UCNEbase) is a free, web-accessible information resource on the evolution and genomic organization of ultra-conserved non-coding elements (UCNEs). It currently covers 4351 such elements in 18 different species. The majority of UCNEs are supposed to be transcriptional regulators of key developmental genes. As most of them occur as clusters near potential target genes, the database is organized along two hierarchical levels: individual UCNEs and ultra-conserved genomic regulatory blocks (UGRBs). UCNEbase introduces a coherent nomenclature for UCNEs reflecting their respective associations with likely target genes. Orthologous and paralogous UCNEs share components of their names and are systematically cross-linked. Detailed synteny maps between the human and other genomes are provided for all UGRBs. UCNEbase is managed by a relational database system and can be accessed by a variety of web-based query pages. As it relies on the UCSC genome browser as visualization platform, a large part of its data content is also available as browser viewable custom track files. UCNEbase is potentially useful to any computational, experimental or evolutionary biologist interested in conserved non-coding DNA elements in vertebrates.


Vancouver Declaration II on Global Headache Patient Advocacy 2019.
In 2017, the International Headache Society convened a Global Patient Advocacy Summit (GPAS-1) to begin a collaborative effort involving patients, patient advocates, patient advocacy organizations, healthcare professionals, scientists, professional pain, neurology, and headache societies, pharmaceutical manufacturers, and regulatory agencies to advance issues of importance to patients affected by headache worldwide. In September 2019, the second Global Patient Advocacy Summit (GPAS-2) was convened to revisit issues from the inaugural meeting, assess the progress of the International Headache Society Global Patient Advocacy Coalition (IHS-GPAC) in meeting the goals set forth therein, and discuss strategies for achieving established goals and supporting future development. Short- and long-term mandates from the first Summit were realized, including publishing the Vancouver Declaration on Global Headache Patient Advocacy 2018, determining the governing and operational structures of the IHS-GPAC, and helping to facilitate the first World Federation of Neurology World Brain Day dedicated to migraine. Another short-term mandate, creating a unified advocacy strategy, was fulfilled by the Coalition's decision to focus on encouraging support from employers and implementing employee support programs for people with migraine. To help execute the strategy, the Coalition is developing an employer engagement toolkit that will educate employers and employees about the impact of migraine in the workplace, reduce stigma directed toward employees with migraine, and facilitate the care of employees with migraine to reduce the burden of illness and improve workplace productivity. Coalition members will disseminate the toolkit and encourage the adoption of migraine workplace programs by employers worldwide. The Coalition has established an alliance with two global, multinational employers to expand migraine awareness and support among policy makers and other stakeholders around the world. The IHS-GPAC met many of the goals established at GPAS-1, and it has initiated a global strategy focused on the psychosocial and economic toll of headache disorders, especially migraine, in the workplace. Ongoing and future activities will explore a range of opportunities with employers and across the full spectrum of advocacy goals.


Pathologic evaluation of canine renal biopsies: methods for identifying features that differentiate immune-mediated glomerulonephritides from other categories of glomerular diseases.
Human renal biopsies are routinely evaluated with light microscopy (LM) using a panel of histologic stains, transmission electron microscopy (TEM), and immunofluorescence (IF) microscopy to obtain a diagnosis. In contrast, the pathologic evaluation of glomerular disease in veterinary medicine has relied mostly on LM and was of limited utility. To address this problem, recently established veterinary renal diagnostic centers have adopted methods used in human nephropathology for evaluation of renal biopsies. Three broad categories of disease, which have the greatest implications for clinical management of proteinuric dogs, have been established and include amyloidosis, immune complex-mediated glomerulonephritis (ICGN), and non-ICGN. To demonstrate histopathologic, ultrastructural, and IF findings in renal biopsy specimens that experienced veterinary nephropathologists utilize to make accurate and clinically useful diagnoses in dogs with proteinuric glomerular disease and to provide guidelines for the proper evaluation of renal biopsies. Renal biopsy specimens were routinely examined by LM, IF, and TEM. Samples were reviewed by members of the World Small Animal Veterinary Association Renal Standardization Study Group to identify lesions that were diagnostic for, or suggestive of, the presence of immune complexes (IC) or amyloidosis in all modalities. Ten guidelines for renal biopsy evaluation were formulated. Each method of investigation contributed important findings that were integrated to make an accurate final morphological diagnosis. The guidelines were validated by an independent group of veterinary pathologists. Routine evaluation of renal biopsies with LM, TEM, and IF is feasible and necessary for making accurate, morphologic diagnoses that can be used to guide clinical management of dogs with glomerular disease.


The International Multiple Sclerosis Visual System Consortium: Advancing Visual System Research in Multiple Sclerosis.
The International Multiple Sclerosis Visual System Consortium (IMSVISUAL) was formed in November 2014 with the primary goal of improving research, care, and education regarding the role of the visual system in multiple sclerosis (MS) and related disorders. In this review, we describe the formation, goals, activities, and structure of IMSVISUAL, as well as the relationship of IMSVISUAL with the Americas Committee for Treatment and Research in MS (ACTRIMS). Finally, we provide an overview of the work IMSVISUAL has completed to date, as well as an outline of research projects ongoing under the auspices of IMSVISUAL. IMSVISUAL has 140 members worldwide and continues to grow. Through IMSVISUAL-related research, optical coherence tomography (OCT)-derived peripapillary retinal nerve fiber layer (pRNFL) thinning has been established as a predictor of future disability in MS. IMSVISUAL has also developed guidelines for reporting OCT studies in MS. Moreover, a systematic review performed by IMSVISUAL found that not only are pRNFL and ganglion cell + inner plexiform layer (GCIPL) thicknesses reduced in patients with MS (particularly in eyes with prior optic neuritis [ON]), but that inner nuclear layer measures may be higher among MS ON eyes, relative to healthy control eyes. Currently, there are several ongoing IMSVISUAL projects that will establish a role for visual outcomes in diagnosing MS and quantifying the effects of emerging therapies in clinical trials. The development of IMSVISUAL represents a major collaborative commitment to defining the role of visual outcomes in high-quality, large-scale studies that generate definitive and instructive findings in the field of MS. As a consortium, IMSVISUAL has completed several international collaborative projects, is actively engaged in numerous ongoing research studies, and is committed to expanding the role of vision research in MS and related disorders.


Altered amygdala connectivity within the social brain in schizophrenia.
Impairments in social cognition have been described in schizophrenia and relate to core symptoms of the disorder. Social cognition is subserved by a network of brain regions, many of which have been implicated in schizophrenia. We hypothesized that deficits in connectivity between components of this social brain network may underlie the social cognition impairments seen in the disorder. We investigated brain activation and connectivity in a group of individuals with schizophrenia making social judgments of approachability from faces (n = 20), compared with a group of matched healthy volunteers (n = 24), using functional magnetic resonance imaging. Effective connectivity from the amygdala was estimated using the psychophysiological interaction approach. While making approachability judgments, healthy participants recruited a network of social brain regions including amygdala, fusiform gyrus, cerebellum, and inferior frontal gyrus bilaterally and left medial prefrontal cortex. During the approachability task, healthy participants showed increased connectivity from the amygdala to the fusiform gyri, cerebellum, and left superior frontal cortex. In comparison to controls, individuals with schizophrenia overactivated the right middle frontal gyrus, superior frontal gyrus, and precuneus and had reduced connectivity between the amygdala and the insula cortex. We report increased activation of frontal and medial parietal regions during social judgment in patients with schizophrenia, accompanied by decreased connectivity between the amygdala and insula. We suggest that the increased activation of frontal control systems and association cortex may reflect a compensatory mechanism for impaired connectivity of the amygdala with other parts of the social brain networks in schizophrenia.


Neutrophilic Dermatoses and Their Implication in Pathophysiology of Asthma and Other Respiratory Comorbidities: A Narrative Review.
Neutrophilic dermatoses (ND) are a polymorphous group of noncontagious dermatological disorders that share the common histological feature of a sterile cutaneous infiltration of mature neutrophils. Clinical manifestations can vary from nodules, pustules, and bulla to erosions and ulcerations. The etiopathogenesis of neutrophilic dermatoses has continuously evolved. Accumulating genetic, clinical, and histological evidence point to NDs being classified in the spectrum of autoinflammatory conditions. However, unlike the monogenic autoinflammatory syndromes where a clear multiple change in the inflammasome structure/function is demonstrated, NDs display several proinflammatory abnormalities, mainly driven by IL-1, IL-17, and tumor necrosis factor-alpha (TNF-a). Additionally, because of the frequent association with extracutaneous manifestations where neutrophils seem to play a crucial role, it was plausible also to consider NDs as a cutaneous presentation of a systemic neutrophilic condition. Neutrophilic dermatoses are more frequently recognized in association with respiratory disorders than by chance alone. The combination of the two, particularly in the context of their overlapping immune responses mediated primarily by neutrophils, raises the likelihood of a common neutrophilic systemic disease or an aberrant innate immunity disorder. Associated respiratory conditions can serve as a trigger or may develop or be exacerbated secondary to the uncontrolled skin disorder. Physicians should be aware of the possible pulmonary comorbidities and apply this knowledge in the three steps of patients' management, work-up, diagnosis, and treatment. In this review, we attempt to unravel the pathophysiological mechanisms of this association and also present some evidence for the role of targeted therapy in the treatment of both conditions.


A systematic review of ayres sensory integration intervention for children with autism.
Sensory integration is one of the most highly utilized interventions in autism, however, a lack of consensus exists regarding its evidence base. An increasing number of studies are investigating the effectiveness of this approach. This study used the Council for Exceptional Children (CEC) Standards for Evidence-based Practices in Special Education to evaluate the effectiveness research from 2006 to 2017 on Ayres Sensory Integration (ASI) intervention for children with autism. A systematic review was conducted in three stages. Stage 1 involved an extensive database search for relevant studies using search terms related to sensory integration and autism, interventions suggesting a sensory integration approach, and high-quality study designs. Searches yielded 19 studies that were evaluated in Stage 2. Six of these met inclusion criteria of being peer-reviewed, written in English, description of intervention this is consistent with ASI intervention, and comparison group design or single subject method employed. Prior to analysis using CEC standards, three articles were excluded because intervention details were not consistent with the core principles of ASI, or because of major methodological flaws. In Stage 3, the remaining three studies were rated using the CEC quality indicators and standards for an evidence-based practice. Two randomized controlled trials respectively met 100% and 85% of the CEC criteria items. One additional study met more than 50% of the criteria. Based on CEC criteria, ASI can be considered an evidence-based practice for children with autism ages 4-12 years old. Autism Research 2019, 12: 6-19. © 2018 The Authors. Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Ayres Sensory Integration intervention is one of the most frequently requested and highly utilized interventions in autism. This intervention has specific requirements for therapist qualifications and the process of therapy. This systematic review of studies providing Ayres Sensory Integration therapy to children with autism indicates that it is an evidence-based practice according to the criteria of the Council for Exceptional Children.


Role of D3 dopamine receptors in modulating neuroanatomical changes in response to antipsychotic administration.
Clinical research has shown that chronic antipsychotic drug (APD) treatment further decreases cortical gray matter and hippocampus volume, and increases striatal and ventricular volume in patients with schizophrenia. D2-like receptor blockade is necessary for clinical efficacy of the drugs, and may be responsible for inducing these volume changes. However, the role of other D2-like receptors, such as D3, remains unclear. Following our previous work, we undertook a longitudinal study to examine the effects of chronic (9-week) typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs on the neuroanatomy of wild-type (WT) and dopamine D3-knockout (D3KO) mice using magnetic resonance imaging (MRI) and histological assessments in a sub-region of the anterior cingulate cortex (the prelimbic [PL] area) and striatum. D3KO mice had larger striatal volume prior to APD administration, coupled with increased glial and neuronal cell density. Chronic HAL administration increased striatal volume in both WT and D3KO mice, and reduced PL area volume in D3KO mice both at trend level. CLZ increased volume of the PL area of WT mice at trend level, but decreased D3KO PL area glial cell density. Both typical and atypical APD administration induced neuroanatomical remodeling of regions rich in D3 receptor expression, and typically altered in schizophrenia. Our findings provide novel insights on the role of D3 receptors in structural changes observed following APD administration in clinical populations.


Expression of Pseudomonas aeruginosa virulence genes requires cell-to-cell communication.
Pseudomonas aeruginosa is an opportunistic human pathogen that causes a variety of infections in immunocompromised hosts and individuals with cystic fibrosis. Expression of elastase, one of the virulence factors produced by this organism, requires the transcriptional activator LasR. Experiments with gene fusions show that gene lasl is essential for high expression of elastase. The lasl gene is involved in the synthesis of a diffusible molecule termed Pseudomonas autoinducer (PAI). PAI provides P. aeruginosa with a means of cell-to-cell communication that is required for the expression of virulence genes and may provide a target for therapeutic approaches.


Quantitative, video-based histochemistry to measure regional effects of anticholinesterase pesticides in rat brain.
Acetylcholinesterase histochemistry was coupled to inexpensive and widely available apparatus for video microscopy and densitometry to study enzyme activity and inhibition in different parts of the rat brain. Quantitative histochemistry, under properly defined conditions, yielded an output that increased linearly with incubation time and section thickness and was a smooth hyperbolic function of substrate concentration. The time-course of staining after in vivo exposure to eserine revealed no sign that carbamate-induced cholinesterase inhibition was readily reversed in vitro. Brains from rats treated either with a carbamate or an organophosphate anticholinesterase pesticide showed significant regional variation in cholinesterase inhibition. The histochemical data corresponded well with data from biochemical assays of acetylcholinesterase activity (overall correlation coefficient of absolute values, r = 0.95). Also, a comparison of assay types by two-way analysis of variance showed no significant main effect. These results support the conclusion that video-based histochemistry is suitable for detailed studies of developmental and toxicological influences on cholinesterases in multiple microscopic regions of the rat brain.


Navigating institutional complexity in the health sector: lessons from tobacco control in Kenya.
This research examines the institutional dynamics of tobacco control following the establishment of Kenya's 2007 landmark tobacco control legislation. Our analysis focuses specifically on coordination challenges within the health sector. We conducted semi-structured interviews with key informants (n = 17) involved in tobacco regulation and control in Kenya. We recruited participants from different offices and sectors of government and non-governmental organizations. We find that the main challenges toward successful implementation of tobacco control are a lack of coordination and clarity of mandate of the principal institutions involved in tobacco control efforts. In a related development, the passage of a new constitution in 2010 created structural changes that have affected the successful implementation of the country's tobacco control legislation. We discuss how proponents of tobacco control navigated these two overarching institutional challenges. These findings point to the institutional factors that influence policy implementation extending beyond the traditional focus on the dynamic between government and the tobacco industry. These findings specifically point to the intragovernmental challenges that bear on policy implementation. The findings suggest that for effective implementation of tobacco control legislation and regulation, there is need for increased cooperation among institutions charged with tobacco control, particularly within or involving the Ministry of Health. Decisive leadership was also widely presented as a component of successful institutional reform. This study points to the importance of coordinating policy development and implementation across levels of government and the need for leadership and clear mandates to guide cooperation within the health sector. The Kenyan experience offers useful lessons in the pitfalls of institutional incoherence, but more importantly, the value of investing in and then promoting well-functioning institutions.


A sea urchin homologue of the chordate Brachyury (T) gene is expressed in the secondary mesenchyme founder cells.
Chordates are thought to have emerged from some common ancestor of deuterostomes by organizing shared anatomical and embryological features including a notochord, a dorsal nerve cord and pharyngeal gill slits. Because the notochord is the most prominent feature of chordates and because the Brachyury (T) gene is essential for notochord formation, the T gene is a key molecular probe with which to explore the origin and evolution of chordates. We investigated whether the sea urchin (echinoderm) conserves the T gene and, if so, where the sea urchin T gene is expressed. A cDNA clone for the sea urchin T (HpTa) gene contained a long open reading frame that encodes a polypeptide of 434 amino acids. Although the overall degree of amino acid identity was not very high (52%, sea urchin/mouse), in the T domain of the N terminus the amino acid identity was 73% (sea urchin/mouse). The HpTa gene is present as a single copy per haploid genome. As with the chordate T gene, the expression of HpTa is transient, being first detected in the swimming blastula, maximally transcribed in the gastrula, decreasing at the prism larval stage and barely detectable at the pluteus larval stage. HpTa transcripts were found in the secondary mesenchyme founder cells, vegetal plate of the mesenchyme blastula, extending tip of the invaginating archenteron and, finally, the secondary mesenchyme cells at the late-gastrula stage.(ABSTRACT TRUNCATED AT 250 WORDS)


Defective interaction between Pol2p and Dpb2p, subunits of DNA polymerase epsilon, contributes to a mutator phenotype in Saccharomyces cerevisiae.
Most of the prokaryotic and eukaryotic replicative polymerases are multi-subunit complexes. There are several examples indicating that noncatalytic subunits of DNA polymerases may function as fidelity factors during replication process. In this work, we have further investigated the role of Dpb2p, a noncatalytic subunit of DNA polymerase epsilon holoenzyme from Saccharomyces cerevisiae in controlling the level of spontaneous mutagenesis. The data presented indicate that impaired interaction between catalytic Pol2p subunit and Dpb2p is responsible for the observed mutator phenotype in S. cerevisiae strains carrying different mutated alleles of the DPB2 gene. We observed a significant correlation between the decreased level of interaction between different mutated forms of Dpb2p towards a wild-type form of Pol2p and the strength of mutator phenotype that they confer. We propose that structural integrity of the Pol epsilon holoenzyme is essential for genetic stability in S. cerevisiae cells.


Severe Vitamin D Deficiency in Human Immunodeficiency Virus-Infected Pregnant Women is Associated with Preterm Birth.
Background Low maternal vitamin D has been associated with preterm birth (PTB). Human immunodeficiency virus (HIV)-infected pregnant women are at risk for PTB, but data on maternal vitamin D and PTB in this population are scarce. Methods In a cohort of Latin American HIV-infected pregnant women from the National Institute of Child Health and Human Development International Site Development Initiative protocol, we examined the association between maternal vitamin D status and PTB. Vitamin D status was defined as the following 25-hydroxyvitamin D levels: severe deficiency (< 10 ng/mL), deficiency (10-20 ng/mL), insufficiency (21-29 ng/mL), and sufficiency (≥30 ng/mL). PTB was defined as delivery at < 37 weeks' gestational age (GA). Logistic regression was used to assess the association between maternal vitamin D status and PTB. Results Of 715 HIV-infected pregnant women, 13 (1.8%) were severely vitamin D deficient, 224 (31.3%) were deficient, and 233 were (32.6%) insufficient. Overall, 23.2% (166/715) of pregnancies resulted in PTB (median GA of PTBs = 36 weeks [interquartile range: 34-36]). In multivariate analysis, severe vitamin D deficiency was associated with PTB (odds ratio = 4.7, 95% confidence interval: 1.3-16.8]). Conclusion Severe maternal vitamin D deficiency is associated with PTB in HIV-infected Latin American pregnant women. Further studies are warranted to determine if vitamin D supplementation in HIV-infected women may impact PTB.


Exosomal miR-224 contributes to hemolymph microbiota homeostasis during bacterial infection in crustacean.
It is well known that exosomes could serve as anti-microbial immune factors in animals. However, despite growing evidences have shown that the homeostasis of the hemolymph microbiota was vital for immune regulation in crustaceans, the relationship between exosomes and hemolymph microbiota homeostasis during pathogenic bacteria infection has not been addressed. Here, we reported that exosomes released from Vibrio parahaemolyticus-infected mud crabs (Scylla paramamosain) could help to maintain the homeostasis of hemolymph microbiota and have a protective effect on the mortality of the host during the infection process. We further confirmed that miR-224 was densely packaged in these exosomes, resulting in the suppression of HSP70 and disruption of the HSP70-TRAF6 complex, then the released TRAF6 further interacted with Ecsit to regulate the production of mitochondrial ROS (mROS) and the expression of Anti-lipopolysaccharide factors (ALFs) in recipient hemocytes, which eventually affected hemolymph microbiota homeostasis in response to the pathogenic bacteria infection in mud crab. To the best of our knowledge, this is the first document that reports the role of exosome in the hemolymph microbiota homeostasis modulation during pathogen infection, which reveals the crosstalk between exosomal miRNAs and innate immune response in crustaceans.


Assessment of the efficacy and safety of a Judo exercise program in improving the quality of life among elderly patients.
Objectives: Several reports have shown that Tai Chi Chuan can be an effective way to prevent falls among the elderly. However, an exercise program that can prevent injury during falls has not been reported previously. The judo technique called ukemi is used to prevent injuries. To evaluate whether a judo-based exercise program could prevent falls in the elderly, we had the participants practice ukemi as part of a therapeutic routine. The purpose of this study was to examine the clinical significance of the program and to predict its safety. Methods: From July 2016 to March 2017, we examined 53 individuals who participated in the exercise program. The individuals were divided into high (n=39) and low (n=14) movement ability groups (HMA and LMA groups, respectively), and their physical and psychological functions were evaluated using scores from the Short-Form Health Survey 36. We also collected and analyzed data from questionnaires obtained from 384 patients who participated in the program from July 2016 to July 2019. Results: The HMA group showed a significant increase in the mental component summary scores before and after the exercise program. In the LMA group, physical functioning, social functioning, and physical component summary scores were significantly improved. Of the participants surveyed, 94.8% had a high level of satisfaction, and 93.2% began accepting the exercise as a daily habit. No adverse events were observed during these exercises. Conclusion: This novel exercise program was performed safely, and positive effects were observed, especially in individuals with a low quality of life.


Competitive balance trends in elite table tennis: the Olympic Games and World Championships 1988-2016.
Competitive balance is important because it enhances outcome uncertainty and therefore it promotes spectator interest, and encourages government investment in a sport. This article analyses the distribution of gold medals, medals, medal points and top eight points amongst nations in table tennis from 1988 to 2016 at the Olympic Games and the World Championships respectively. A normalised version of the Herfindahl-Hirschman Index and a coefficient of variation are calculated for each nation's share of these performance indicators. The key findings are that China dominates both events, with successful female players being more dominant than their male counterparts. The competitive balance for gold medals has declined, whilst there is a trend towards improved competitive balance for top eight points for women, suggesting that more teams are featuring in the top eight (but not necessarily the top three) placings. This research has implications for the development of table tennis competitions. Compared to other racket sports, the issue of competitive imbalance in table tennis is particularly thorny, which threatens the long-term development of this sport. Accordingly, some measures are recommended for the International Olympic Committee and the International Table Tennis Federation to propel a more balanced development of international table tennis.


Through veiled mirrors: Fish fins giving insight into size regulation.
Faithful establishment and maintenance of proportion is seen across biological systems and provides a glimpse at fundamental rules of scaling that underlie development and evolution. Dysregulation of proportion is observed in a range of human diseases and growth disorders, indicating that proper scaling is an essential component of normal anatomy and physiology. However, when viewed through an evolutionary lens, shifts in the regulation of relative proportion are one of the most striking sources of morphological diversity among organisms. To date, the mechanisms via which relative proportion is specified and maintained remain unclear. Through the application of powerful experimental, genetic and molecular approaches, the teleost fin has provided an effective model to investigate the regulation of scaling, size, and relative growth in vertebrate organisms. This article is categorized under: Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Comparative Development and Evolution > Regulation of Organ Diversity.


Acute bacterial inflammation of the mouse prostate.
Prostatic inflammation is gaining increasing attention as a potential etiologic factor in prostate cancer, benign prostatic hyperplasia, lower urinary tract symptoms, and CPPS. This study was performed to address the need for a well characterized model of acute prostatic inflammation that may be used to study the effect of acute inflammation on epithelial and stromal cell proliferation, voiding behavior, and neurovascular physiology. Uropathogenic E. coli 1677 was instilled transurethrally into adult C57BL/6J male mice. Prostates were analyzed at 1, 2, 3, 5, 7, or 14 days post-instillation and compared to saline-instilled and naïve controls. Time course and severity of inflammation were characterized by the quantity and type of inflammatory infiltrate present, hemorrhage, proliferation, and reactive hyperplasia. RT-PCR was performed to characterize inflammatory mediators including IL-1α, IL-1β, IL-1RA, IL-18, IL-6, IL-10, IL-8, TNFα, and COX-2. Inflammation was evident in all lobes of the prostate with the DLP most severely affected. Infection consistently led to a significant increase in neutrophils and macrophages in the early stages of prostate infection, followed by lymphocytic inflammation at the later time points. Inflammation was accompanied by induction of several inflammatory genes, including IL-1 family members, IL-6, and COX-2, and induced a significant increase in epithelial proliferation and reactive hyperplasia in all three prostate lobes. Transurethral inoculation of uropathogenic E. coli 1677 reliably infects the mouse prostate, produces a significant inflammatory response, and induces quantifiable epithelial proliferation and reactive hyperplasia.


Universal clinical Parkinson's disease axes identify a major influence of neuroinflammation.
There is large individual variation in both clinical presentation and progression between Parkinson's disease patients. Generation of deeply and longitudinally phenotyped patient cohorts has enormous potential to identify disease subtypes for prognosis and therapeutic targeting. Replicating across three large Parkinson's cohorts (Oxford Discovery cohort (n = 842)/Tracking UK Parkinson's study (n = 1807) and Parkinson's Progression Markers Initiative (n = 472)) with clinical observational measures collected longitudinally over 5-10 years, we developed a Bayesian multiple phenotypes mixed model incorporating genetic relationships between individuals able to explain many diverse clinical measurements as a smaller number of continuous underlying factors ("phenotypic axes"). When applied to disease severity at diagnosis, the most influential of three phenotypic axes "Axis 1" was characterised by severe non-tremor motor phenotype, anxiety and depression at diagnosis, accompanied by faster progression in cognitive function measures. Axis 1 was associated with increased genetic risk of Alzheimer's disease and reduced CSF Aβ1-42 levels. As observed previously for Alzheimer's disease genetic risk, and in contrast to Parkinson's disease genetic risk, the loci influencing Axis 1 were associated with microglia-expressed genes implicating neuroinflammation. When applied to measures of disease progression for each individual, integration of Alzheimer's disease genetic loci haplotypes improved the accuracy of progression modelling, while integrating Parkinson's disease genetics did not. We identify universal axes of Parkinson's disease phenotypic variation which reveal that Parkinson's patients with high concomitant genetic risk for Alzheimer's disease are more likely to present with severe motor and non-motor features at baseline and progress more rapidly to early dementia.


Regulated protein kinases and phosphatases in cell cycle decisions.
Many aspects of cell physiology are controlled by protein kinases and phosphatases, which together determine the phosphorylation state of targeted substrates. Some of these target proteins are themselves kinases or phosphatases or other components of a regulatory network characterized by feedback and feed-forward loops. In this review we describe some common regulatory motifs involving kinases, phosphatases, and their substrates, focusing particularly on bistable switches involved in cellular decision processes. These general principles are applied to cell cycle transitions, with special emphasis on the roles of regulated phosphatases in orchestrating progression from one phase to the next of the DNA replication-division cycle.


Global DNA methylation in fetal human germ cells and germ cell tumours: association with differentiation and cisplatin resistance.
Differences in the global methylation pattern, ie hyper- as well as hypo-methylation, are observed in cancers including germ cell tumours (GCTs). Related to their precursor cells, GCT methylation status differs according to histology. We investigated the methylation pattern of normal fetal, infantile, and adult germ cells (n = 103) and GCTs (n = 251) by immunohistochemical staining for 5-(m)cytidine. The global methylation pattern of male germ cells changes from hypomethylation to hypermethylation, whereas female germ cells remain unmethylated at all stages. Undifferentiated GCTs (seminomas, intratubular germ cell neoplasia unclassified, and gonadoblastomas) are hypomethylated, whereas more differentiated GCTs (teratomas, yolk sac tumours, and choriocarcinomas) show a higher degree of methylation. Embryonal carcinomas show an intermediate pattern. Resistance to cisplatin was assessed in the seminomatous cell line TCam-2 before and after demethylation using 5-azacytidine. Exposure to 5-azacytidine resulted in decreased resistance to cisplatin. Furthermore, after demethylation, the stem cell markers NANOG and POU5F1 (OCT3/4), as well as the germ cell-specific marker VASA, showed increased expression. Following treatment with 5-azacytidine, TCam-2 cells were analysed using a high-throughput methylation screen for changes in the methylation sites of 14,000 genes. Among the genes revealing changes, interesting targets were identified: ie demethylation of KLF11, a putative tumour suppressor gene, and hypermethylation of CFLAR, a gene previously described in treatment resistance in GCTs.


Computerized tomography scan interpretation of a bone expansion technique.
Bone expansion can be defined as the manipulation of bone to form a receptor site for an implant without the removal of any bone from the patient. The way this technique is used provides a number of advantages to patients. There is a marked decrease in the need to graft ridges, even those as narrow as 1 mm. This results in less surgical time for the surgeon and much less cost to the patient. It also allows for the significant improvement of atrophic arch morphology and interarch relationships for the restorative phases. Soft tissue revisions at the time of implant placement allow for the development of keratinized tissue surrounding the implant, thus saving the patient the morbidity and cost of another surgical procedure. Cortical bone is preserved by not raising the periosteum during the manipulation of bone.


Identification of candidate substrates for the Golgi Tul1 E3 ligase using quantitative diGly proteomics in yeast.
Maintenance of protein homeostasis is essential for cellular survival. Central to this regulation are mechanisms of protein quality control in which misfolded proteins are recognized and degraded by the ubiquitin-proteasome system. One well-studied protein quality control pathway requires endoplasmic reticulum (ER)-resident, multi-subunit E3 ubiquitin ligases that function in ER-associated degradation. Using fission yeast, our lab identified the Golgi Dsc E3 ligase as required for proteolytic activation of fungal sterol regulatory element-binding protein transcription factors. The Dsc E3 ligase contains five integral membrane subunits and structurally resembles ER-associated degradation E3 ligases. Saccharomyces cerevisiae codes for homologs of Dsc E3 ligase subunits, including the Dsc1 E3 ligase homolog Tul1 that functions in Golgi protein quality control. Interestingly, S. cerevisiae lacks sterol regulatory element-binding protein homologs, indicating that novel Tul1 E3 ligase substrates exist. Here, we show that the S. cerevisiae Tul1 E3 ligase consists of Tul1, Dsc2, Dsc3, and Ubx3 and define Tul1 complex architecture. Tul1 E3 ligase function required each subunit as judged by vacuolar sorting of the artificial substrate Pep12D. Genetic studies demonstrated that Tul1 E3 ligase was required in cells lacking the multivesicular body pathway and under conditions of ubiquitin depletion. To identify candidate substrates, we performed quantitative diGly proteomics using stable isotope labeling by amino acids in cell culture to survey ubiquitylation in wild-type and tul1Δ cells. We identified 3116 non-redundant ubiquitylation sites, including 10 sites in candidate substrates. Quantitative proteomics found 4.5% of quantified proteins (53/1172) to be differentially expressed in tul1Δ cells. Correcting the diGly dataset for these differences increased the number of Tul1-dependent ubiquitylation sites. Together, our data demonstrate that the Tul1 E3 ligase functions in protein homeostasis under non-stress conditions and support a role in protein quality control. This quantitative diGly proteomics methodology will serve as a robust platform for screening for stress conditions that require Tul1 E3 ligase activity.


Auditing as part of the terminology design life cycle.
To develop and test an auditing methodology for detecting errors in medical terminologies satisfying systematic inheritance. This methodology is based on various abstraction taxonomies that provide high-level views of a terminology and highlight potentially erroneous concepts. Our auditing methodology is based on dividing concepts of a terminology into smaller, more manageable units. First, we divide the terminology's concepts into areas according to their relationships/roles. Then each multi-rooted area is further divided into partial-areas (p-areas) that are singly-rooted. Each p-area contains a set of structurally and semantically uniform concepts. Two kinds of abstraction networks, called the area taxonomy and p-area taxonomy, are derived. These taxonomies form the basis for the auditing approach. Taxonomies tend to highlight potentially erroneous concepts in areas and p-areas. Human reviewers can focus their auditing efforts on the limited number of problematic concepts following two hypotheses on the probable concentration of errors. A sample of the area taxonomy and p-area taxonomy for the Biological Process (BP) hierarchy of the National Cancer Institute Thesaurus (NCIT) was derived from the application of our methodology to its concepts. These views led to the detection of a number of different kinds of errors that are reported, and to confirmation of the hypotheses on error concentration in this hierarchy. Our auditing methodology based on area and p-area taxonomies is an efficient tool for detecting errors in terminologies satisfying systematic inheritance of roles, and thus facilitates their maintenance. This methodology concentrates a domain expert's manual review on portions of the concepts with a high likelihood of errors.


Role of genetic and acquired prothrombotic risk factors in genesis of sudden sensorineural hearing loss.
The methylenetetrahydrofolate reductase C677T mutation, factor V G1691A (factor V Leiden) mutation, prothrombin G20210A mutation and 8 other laboratory values associated with increased thrombotic risk were analyzed in 40 patients with sudden sensorineural hearing loss (SSHL). The results were compared with those obtained from 120 controls not affected by SSHL. We found a statistically significant higher frequency of hyperhomocysteinemia in the SSHL group compared with controls, and that this was also associated with the presence of homozygosity for the MTHFR C677T mutation. The study results suggest that SSHL might be caused, among other factors, by a combination of these 2 variables. We suggest that this analysis of the MTHFR C677T mutation should be further investigated to establish the etiology of SSHL, and that the same analysis should be taken into account in those patients with high levels of homocysteine.


Usage of Image-Enhancement Tools When Reading Radiographs Taken During Root-Canals Treatments' Procedures.
This study aimed at exploring the usage of radiographic image-enhancement tools in Saudi dental practice when interpreting radiographs taken for root-canal-treatments' (RCTs) procedures and the influencing factors. An online survey including questions related mainly to the usage of images enhancement tools and the reasons for no or low frequently usage was constructed. The survey was sent to 550 general dentists (GDs), randomly selected from the Saudi Dental Register, and all endodontists (185) in Saudi Arabia using the Google-Drive tool. A reminder email was sent two months later to encourage none-respondents to complete the survey. Data were analyzed using the Chi-square and Linear-by-Linear Association tests at p=0.05. While the highest percentage of GDs (48.3%) never used the colour-coded tool, the highest percentage of endodontists (46.1%) used it sometimes (P<0.001). The majority (84.2%) used the contrast tool either generally (67.8%) or sometimes (16.4%) (P<0.001); with more endodontists (77.55%) than GDs (63.1%) (P=0.011). As participants experience decreased and the weekly performed cases increased, the trend of using this tool increased (P<0.05). While most GDs (67.6%) either never (46%) or few-times (21.6%) used the highlight tool, most endodontists (56.9%) either used it generally (34.4%) or sometimes (22.5%) (P<0.001). The majority (82.3%) were using the magnification tool either generally (55.1%) or sometimes (27.2%). The highest percentage (36.1%) was generally using the negative-view tool (P=0.045); with more endodontists (63.7%) than GDs (20.8%) (P<0.001). While "I don't know how to use it" was the dominant reason reported by GDs for not using most of the tools, lack of time was the dominant reason reported by endodontists (P≤0.001). The contrast and magnification were the most common used image-enhancement tools in Saudi dental practice. Endodontists reported greater preferences on using all images-enhancement tools than GDs. Unawareness and lack of time were the dominant reasons for not using the tools reported by GDs and endodontists, respectively. Further studies are required to determine the exact application for each tool and to investigate the impact of all image-enhancement tools on their diagnostic accuracy.


Esophageal dysphagia and reflux symptoms before and after oral IQoro(R) training.
To examine whether muscle training with an oral IQoro(R) screen (IQS) improves esophageal dysphagia and reflux symptoms. A total of 43 adult patients (21 women and 22 men) were consecutively referred to a swallowing center for the treatment and investigation of long-lasting nonstenotic esophageal dysphagia. Hiatal hernia was confirmed by radiologic examination in 21 patients before enrollment in the study (group A; median age 52 years, range: 19-85 years). No hiatal hernia was detected by radiologic examination in the remaining 22 patients (group B; median age 57 years, range: 22-85 years). Before and after training with an oral IQS for 6-8 mo, the patients were evaluated using a symptom questionnaire (esophageal dysphagia and acid chest symptoms; score 0-3), visual analogue scale (ability to swallow food: score 0-100), lip force test (≥ 15 N), velopharyngeal closure test (≥ 10 s), orofacial motor tests, and an oral sensory test. Another twelve patients (median age 53 years, range: 22-68 years) with hiatal hernia were evaluated using oral IQS traction maneuvers with pressure recordings of the upper esophageal sphincter and hiatus canal as assessed by high-resolution manometry. Esophageal dysphagia was present in all 43 patients at entry, and 98% of patients showed improvement after IQS training [mean score (range): 2.5 (1-3) vs 0.9 (0-2), P < 0.001]. Symptoms of reflux were reported before training in 86% of the patients who showed improvement at follow-up [1.7 (0-3) vs 0.5 (0-2), P < 0.001). The visual analogue scale scores were classified as pathologic in all 43 patients, and 100% showed improvement after IQS training [71 (30-100) vs 22 (0-50), P < 0.001]. No significant difference in symptom frequency was found between groups A and B before or after IQS training. The lip force test [31 N (12-80 N) vs 54 N (27-116), P < 0.001] and velopharyngeal closure test values [28 s (5-74 s) vs 34 s (13-80 s), P < 0.001] were significantly higher after IQS training. The oral IQS traction results showed an increase in mean pressure in the diaphragmatic hiatus region from 0 mmHg at rest (range: 0-0 mmHG) to 65 mmHg (range: 20-100 mmHg). Oral IQS training can relieve/improve esophageal dysphagia and reflux symptoms in adults, likely due to improved hiatal competence.


Ancient DNA from the first European farmers in 7500-year-old Neolithic sites.
The ancestry of modern Europeans is a subject of debate among geneticists, archaeologists, and anthropologists. A crucial question is the extent to which Europeans are descended from the first European farmers in the Neolithic Age 7500 years ago or from Paleolithic hunter-gatherers who were present in Europe since 40,000 years ago. Here we present an analysis of ancient DNA from early European farmers. We successfully extracted and sequenced intact stretches of maternally inherited mitochondrial DNA (mtDNA) from 24 out of 57 Neolithic skeletons from various locations in Germany, Austria, and Hungary. We found that 25% of the Neolithic farmers had one characteristic mtDNA type and that this type formerly was widespread among Neolithic farmers in Central Europe. Europeans today have a 150-times lower frequency (0.2%) of this mtDNA type, revealing that these first Neolithic farmers did not have a strong genetic influence on modern European female lineages. Our finding lends weight to a proposed Paleolithic ancestry for modern Europeans.


In vivo efficacy of artemether-lumefantrine and chloroquine against Plasmodium vivax: a randomized open label trial in central Ethiopia.
In vivo efficacy assessments of antimalarials are essential for ensuring effective case management. In Ethiopia, chloroquine (CQ) without primaquine is the first-line treatment for Plasmodium vivax in malarious areas, but artemether-lumefantrine (AL) is also commonly used. In 2009, we conducted a 42-day efficacy study of AL or CQ for P. vivax in Oromia Regional State, Ethiopia. Individuals with P. vivax monoinfection were enrolled. Primary endpoint was day 28 cure rate. In patients with recurrent parasitemia, drug level and genotyping using microsatellite markers were assessed. Using survival analysis, uncorrected patient cure rates at day 28 were 75.7% (95% confidence interval (CI) 66.8-82.5) for AL and 90.8% (95% CI 83.6-94.9) for CQ. During the 42 days of follow-up, 41.6% (47/113) of patients in the AL arm and 31.8% (34/107) in the CQ arm presented with recurrent P. vivax infection, with the median number of days to recurrence of 28 compared to 35 days in the AL and CQ arm, respectively. Using microsatellite markers to reclassify recurrent parasitemias with a different genotype as non-treatment failures, day 28 cure rates were genotype adjusted to 91.1% (95% CI 84.1-95.1) for AL and to 97.2% (91.6-99.1) for CQ. Three patients (2.8%) with recurrent parasitemia by day 28 in the CQ arm were noted to have drug levels above 100 ng/ml. In the short term, both AL and CQ were effective and well-tolerated for P. vivax malaria, but high rates of recurrent parasitemia were noted with both drugs. CQ provided longer post-treatment prophylaxis than AL, resulting in delayed recurrence of parasitemia. Although the current policy of species-specific treatment can be maintained for Ethiopia, the co-administration of primaquine for treatment of P. vivax malaria needs to be urgently considered to prevent relapse infections. ClinicalTrials.gov NCT01052584.


Gβ promotes pheromone receptor polarization and yeast chemotropism by inhibiting receptor phosphorylation.
Gradient-directed cell migration (chemotaxis) and growth (chemotropism) are processes that are essential to the development and life cycles of all species. Cells use surface receptors to sense the shallow chemical gradients that elicit chemotaxis and chemotropism. Slight asymmetries in receptor activation are amplified by downstream signaling systems, which ultimately induce dynamic reorganization of the cytoskeleton. During the mating response of budding yeast, a model chemotropic system, the pheromone receptors on the plasma membrane polarize to the side of the cell closest to the stimulus. Although receptor polarization occurs before and independently of actin cable-dependent delivery of vesicles to the plasma membrane (directed secretion), it requires receptor internalization. Phosphorylation of pheromone receptors by yeast casein kinase 1 or 2 (Yck1/2) stimulates their internalization. We showed that the pheromone-responsive Gβγ dimer promotes the polarization of the pheromone receptor by interacting with Yck1/2 and locally inhibiting receptor phosphorylation. We also found that receptor phosphorylation is essential for chemotropism, independently of its role in inducing receptor internalization. A mathematical model supports the idea that the interaction between Gβγ and Yck1/2 results in differential phosphorylation and internalization of the pheromone receptor and accounts for its polarization before the initiation of directed secretion.


Activation of IL-6R/JAK1/STAT3 signaling induces de novo resistance to irreversible EGFR inhibitors in non-small cell lung cancer with T790M resistance mutation.
The secondary T790M mutation in epidermal growth factor receptor (EGFR) is the major mechanism of acquired resistance to EGFR tyrosine kinase inhibitors (TKI) in non-small cell lung cancer (NSCLC). Although irreversible EGFR TKIs, such as afatinib or dacomitinib, have been introduced to overcome the acquired resistance, they showed a limited efficacy in NSCLC with T790M. Herein, we identified the novel de novo resistance mechanism to irreversible EGFR TKIs in H1975 and PC9-GR cells, which are NSCLC cells with EGFR T790M. Afatinib activated interleukin-6 receptor (IL-6R)/JAK1/STAT3 signaling via autocrine IL-6 secretion in both cells. Inhibition of IL-6R/JAK1/STAT3 signaling pathway increased the sensitivity to afatinib. Cancer cells showed stronger STAT3 activation and enhanced resistance to afatinib in the presence of MRC5 lung fibroblasts. Blockade of IL-6R/JAK1 significantly increased the sensitivity to afatinib through inhibition of afatinib-induced STAT3 activation augmented by the interaction with fibroblasts, suggesting a critical role of paracrine IL-6R/JAK1/STAT3 loop between fibroblasts and cancer cells in the development of drug resistance. The enhancement of afatinib sensitivity by inhibition of IL-6R/JAK1/STAT3 signaling was confirmed in in vivo PC9-GR xenograft model. Similar to afatinib, de novo resistance to dacomitinib in H1975 and PC9-GR cells was also mediated by dacomitinib-induced JAK1/STAT3 activation. Taken together, these findings suggest that IL-6R/JAK1/STAT3 signaling can be a potential therapeutic target to enhance the efficacy of irreversible EGFR TKIs in patients with EGFR T790M.


Involvement of MicroRNAs in hydrogen peroxide-mediated gene regulation and cellular injury response in vascular smooth muscle cells.
MicroRNAs (miRNAs) comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate approximately 30% of genes in a cell via degradation or translational inhibition of their target mRNAs. However, the effects of reactive oxygen species (ROS) on miRNA expression and the roles of miRNAs in ROS-mediated gene regulation and biological functions of vascular cells are unclear. Using microarray analysis, we demonstrated that miRNAs are aberrantly expressed in vascular smooth muscle cells (VSMCs) after treatment with hydrogen peroxide (H(2)O(2)). H(2)O(2)-mediated up-regulation of microRNA-21 (miR-21) was further confirmed by quantitative real-time PCR. To determine the potential roles of miRNAs in H(2)O(2)-mediated gene regulation and cellular effects, miR-21 expression was down-regulated by miR-21 inhibitor and up-regulated by pre-miR-21. H(2)O(2)-induced VSMC apoptosis and death were increased by miR-21 inhibitor and decreased by pre-miR-21. Programmed cell death 4(PDCD4) was a direct target of miR-21 that was involved in miR-21-mediated effects on VSMCs. Pre-miR-21-mediated protective effect on VSMC apoptosis and death was blocked via adenovirus-mediated overexpression of PDCD4 without the miR-21 binding site. Moreover, activator protein 1 was a downstream signaling molecule of PDCD4 in miR-21-modulated VSMCs. The results suggest that miRNAs in VSMCs are sensitive to H(2)O(2) stimulation. miRN-21 participates in H(2)O(2)-mediated gene regulation and cellular injury response through PDCD4 and the activator protein 1 pathway. miRNAs might play a role in vascular diseases related to ROS.


Insulin BBB pharmacokinetics in young apoE male and female transgenic mice.
In addition to age, apolipoprotein E4 (E4), female sex, or a combination of both synergistically increase the risk for the development of Alzheimer's disease (AD). Why these risk factors predispose an individual to developing AD later in life is the target of the current investigation. Central nervous system (CNS) insulin resistance is associated with cognitive impairment and AD. CNS insulin is acquired primarily from the circulation and therefore must negotiate the blood-brain barrier (BBB). Thus, changes in BBB transport of insulin could lead to alterations in CNS insulin signaling and resistance, which would then lead to changes in cognition. There has been recent evidence suggesting the relationship between CNS insulin; E4, a risk factor to develop AD as compared to E3; and the female sex in aged individuals and in pre-clinical models. However, this relationship has been largely unexplored at a younger age, in which some of these risk factors could predispose an individual to dysregulation of CNS insulin later in life. Here, we present the first findings of BBB insulin pharmacokinetics in young E3 and E4 male and female targeted replacement (TR) mice. We found that levels of insulin binding the vasculature at the BBB are different due to genotype and sex which could impact the function of the brain endothelial cell. These early alterations could contribute to or fully explain the age-related cognitive changes observed due to CNS insulin signaling in E4 and/or female individuals.


Lensless reflective point diffraction interferometer.
A lensless reflective point diffraction interferometer (LRPDI) is proposed for dynamic wavefront measurement. The point diffraction interferometer is integrated on a small substrate with properly designed thin film, which is used for generating the interferogram with high carrier frequency at a CCD target. By lensless imaging, the complex amplitude at the CCD target can be propagated to the conjugated plane of the exit pupil of an incident wavefront, which not only avoids the edge diffraction in the interferogram, but also eliminates systematic error. The accuracy of LRPDI is demonstrated by simulation and experiment, and a precision better than 1/150 wavelength is achieved. The new design with lensless imaging processing is suitable for dynamic wavefront measurement.


Site of primary tumor has a prognostic role in operable breast cancer: the international breast cancer study group experience.
Cancer presenting at the medial site of the breast may have a worse prognosis compared with tumors located in external quadrants. For medial tumors, axillary lymph node staging may not accurately reflect the metastatic potential of the disease. Eight-thousand four-hundred twenty-two patients randomly assigned to International Breast Cancer Study Group clinical trials between 1978 and 1999 were classified as medial site (1,622; 19%) or lateral, central, and other sites (6,800; 81%). Median follow-up was 11 years. A statistically significant difference was observed for patients with medial tumors versus those with nonmedial tumors in disease-free survival (DFS; 10-year DFS, 46% v 48%; HR, 1.10; 95% CI, 1.02 to 1.18; P = .01) and overall survival (10-year OS 59% v 61%; HR, 1.09; 1.01 to 1.19; P = .04). This difference increased after adjustment for other prognostic factors (HR, 1.22; 95% CI, 1.13 to 1.32 for DFS; and HR, 1.24; 95% CI, 1.14 to 1.35 for OS; both P = .0001). The risk of relapse for patients with medial presentation was largest for the node-negative cohort and for patients with tumors larger than 2 cm. In the subgroup of 2,931 patients with negative axillary lymph nodes, 10-year DFS was 61% v 67%, and OS was 73% v 80% for medial versus nonmedial sites, respectively (HR 1.33; 95% CI, 1.15 to 1.54; P = .0001 for DFS; and HR 1.40; 95% CI, 1.17 to 1.67; P = .0003 for OS). Tumor site has a significant prognostic utility, especially for axillary lymph node-negative disease, that should be considered in therapeutic algorithms. New staging procedures such as biopsy of the sentinel internal mammary nodes or novel imaging methods should be further studied in patients with medial tumors.


Time Since Migration and HIV Risk Behaviors Among Puerto Ricans Who Inject Drugs in New York City.
Among people who inject drugs (PWID) in the United States, those who initiated drug injection in Puerto Rico (immigrant Puerto Rican PWID) engage in more injection and sexual risk behaviors, and have higher HIV incidence than non-Hispanic whites. Understand the persistence of these HIV behaviors. In a cross-sectional study conducted in New York City (NYC) in 2012 (National HIV Behavioral Surveillance), PWID aged ≥18 years were recruited using Respondent-Driven Sampling, interviewed, and tested for HIV. Participants were categorized into 5 different groups: (1) US-born non-Hispanic PWID, (2) US-born Puerto Rican PWID, (3) recent immigrant Puerto Rican PWID (≤3 years in NYC), (4) medium-term immigrant Puerto Rican PWID (>3 and ≤10 years in NYC), and (5) long-term immigrant Puerto Rican PWID (>10 years in NYC). We examined the relationship between time since migrating on sexual and injection risk behaviors among immigrant Puerto Rican PWID, compared with U.S.-born Puerto Rican PWID and US-born non-Hispanic PWID. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were estimated using logistic regression. A total of 481 PWID were recruited. In adjusted analyses using US-born non-Hispanic PWID as the comparison group, syringe sharing was significantly more likely among medium-term immigrants; and unprotected sex with casual partners was more likely among recent and long-term immigrants. The risk-acculturation process for immigrant Puerto Rican PWID may be nonlinear and may not necessarily lead to risk reduction over time. Research is needed to better understand this process.


Ancient voyaging and Polynesian origins.
The "Polynesian motif" defines a lineage of human mtDNA that is restricted to Austronesian-speaking populations and is almost fixed in Polynesians. It is widely thought to support a rapid dispersal of maternal lineages from Taiwan ~4000 years ago (4 ka), but the chronological resolution of existing control-region data is poor, and an East Indonesian origin has also been proposed. By analyzing 157 complete mtDNA genomes, we show that the motif itself most likely originated >6 ka in the vicinity of the Bismarck Archipelago, and its immediate ancestor is >8 ka old and virtually restricted to Near Oceania. This indicates that Polynesian maternal lineages from Island Southeast Asia gained a foothold in Near Oceania much earlier than dispersal from either Taiwan or Indonesia 3-4 ka would predict. However, we find evidence in minor lineages for more recent two-way maternal gene flow between Island Southeast Asia and Near Oceania, likely reflecting movements along a "voyaging corridor" between them, as previously proposed on archaeological grounds. Small-scale mid-Holocene movements from Island Southeast Asia likely transmitted Austronesian languages to the long-established Southeast Asian colonies in the Bismarcks carrying the Polynesian motif, perhaps also providing the impetus for the expansion into Polynesia.


Paramedic experiences of providing care in wales (UK) during the 2020 COVID-19 pandemic (PECC-19): a qualitative study using evolved grounded theory.
To explore paramedic experiences of providing care during the 2020 COVID-19 pandemic and develop theory in order to inform future policy and practice. Qualitative study using constructivist evolved grounded theory (EGT) methodology. One-to-one semistructured interviews were conducted using a general interview guide. Voice over Internet Protocol was used through Skype. Conducted between March 2020 and November 2020 in the Welsh Ambulance Services National Health Services Trust UK which serves a population of three million. Paramedics were recruited through a poster circulated by email and social media. Following purposive sampling, 20 Paramedics were enrolled and interviewed. Emergent categories included: Protect me to protect you, Rapid disruption and adaptation, Trust in communication and information and United in hardship. The Basic Social Process was recognised to involve Tragic Choices, conceptualised through an EGT including Tragic personal and professional choices including concerns over personnel protective equipment (PPE), protecting themselves and their families, impact on mental health and difficult clinical decisions, Tragic organisational choices including decision making support, communication, mental health and well-being and Tragic societal choices involving public shows of support, utilisation and resourcing of health services. Rich insights were revealed into paramedic care during the COVID-19 pandemic consistent with other research. This care was provided in the context of competing and conflicting decisions and resources, where Tragic Choices have to be made which may challenge life's pricelessness. Well-being support, clinical decision making, appropriate PPE and healthcare resourcing are all influenced by choices made before and during the pandemic, and will continue as we recover and plan for future pandemics. The impact of COVID-19 may persist, especially if we fail to learn, if not we risk losing more lives in this and future pandemics and threatening the overwhelming collective effort which united society in hardship when responding to the COVID-19 Pandemic. IRAS ID: 282 623.


Development of a general model for direct laser interference patterning of polymers.
This study investigates the general mechanism of Direct Laser Interference Patterning (DLIP) involved in the structuring process of polymer materials. An empirical model is developed taking into account experimental observations of DLIP-treated pigmented and transparent polycarbonate substrates with UV (263 nm) and IR (1053 nm) laser radiation. Depending on the used laser processing conditions, the type of material as well as the spatial period of the interference pattern, four different structuring mechanisms can be identified. The treated surfaces are investigated using confocal microscopy, scanning electron microscopy and focus ion beam and as a result from the experimental data analysis, the developed model predicts the material surface topography after the patterning process, by means of a set of material-dependent coefficients.


Neuraminidase inhibitors for the treatment of influenza infection in people with cystic fibrosis.
Cystic fibrosis is the most common, life-threatening, recessively inherited disease of Caucasian populations. It is a multisystem disorder caused by a mutation in the gene encoding the cystic fibrosis transmembrane conductance regulator protein which is important in producing sweat, digestive juices and mucus.The impaired or absent function of this protein results in the production of viscous mucus within the lungs and an environment that is susceptible to chronic airway obstruction and pulmonary colonization by a range of pathogenic bacteria. Morbidity and mortality of cystic fibrosis is related to chronic pulmonary sepsis and its complications by these bacteria.Influenza can worsen the course of the disease in cystic fibrosis by increasing the risk of pneumonia and secondary respiratory complications. Antiviral agents form an important part of influenza management and include the neuraminidase inhibitors zanamivir and oseltamivir. These inhibitors can limit the infection and prevent the spread of the virus. To assess the effects of neuraminidase inhibitors for the treatment of influenza infection in people with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and handsearches of relevant journals and abstract books of conference proceedings.Most recent search: 02 November 2015. Randomised controlled trials and quasi-randomised controlled trials comparing neuraminidase inhibitors with placebo or other antiviral drugs. Two review authors had planned to independently screen studies, extract data and assess risk of bias using standard Cochrane methodologies. No studies were identified for inclusion. No relevant studies were retrieved after a comprehensive search of the literature. We were unable to identify any randomised controlled studies or quasi-randomised controlled studies on the efficacy of neuraminidase inhibitors for the treatment of influenza infection in people with cystic fibrosis. The absence of high level evidence for the effectiveness of these interventions emphasises the need for well-designed, adequately powered, randomised controlled clinical studies.


Prebiotics and synbiotics in clinical medicine.
Pharmaceutical medicine has thus far been unable to stop the increasing global morbidity and mortality both in acute and chronic diseases. Typically, medical practice has focused on reducing the aggressor with treatments such as antibiotics; little interest has been given to efforts to increase the individual's resistance to disease. The increased morbidity has occurred in parallel to a deviation from a large consumption of fresh fruits, vegetables, and tubers rich in live lactic acid bacteria (LAB), plant fibers, and natural antioxidants to an industry-produced diet rich in fat and refined sugar but containing little fiber, antioxidants, and LAB. Plant fiber/prebiotics, plant-derived antioxidants, and LAB/probiotics are known to have the potential to reinforce the immune system of the body and increase resistance to disease. However, this depends on the type of fiber, antioxidant, and strain or combination of strain used. At this stage, only about 10% of the LAB studied have proven strong immunosupportive effects. Similarly, only a few plants contain what has been called superantioxidants, antioxidants 10 or more times stronger than vitamin C and E. Increasing evidence suggests that combining several probiotic bacteria into multistrain probiotics will achieve stronger effects than single-strain probiotics. And combining probiotics and prebiotics into "synbiotics" will further enhance the immunosupportive effects. There is little evidence that a single-strain-based "superprobiotic"/magic LAB will ever be found. Instead, combining several specific and defined probiotics and several key plant fibers into multistrain/multifiber synbiotics appears to be the most promising alternative. Some edge-cutting effects from using multistrain and multifiber compositions are reported both from animal and controlled clinical studies.


Alterations in Blood Monocyte Functions in Parkinson's Disease.
PD is a multisystem disease where both central and peripheral nervous systems are affected. This systemic involvement also includes the immune response in PD, which implicates not only microglia in the brain, but also peripheral immune cells, such as monocytes; however, this aspect has been understudied. The purpose of this study was to investigate the PD-related changes in peripheral immune cells, their responsiveness to stimulation, and their ability to release immunomodulatory molecules that might have consequences for the disease progression. Using flow cytometry, we investigated the monocytic population in peripheral blood mononuclear cells from PD patients and healthy individuals. We also evaluated the in vitro response to inflammogen lipopolysaccharides and to fibrillar α-synuclein by measuring the expression of CD14, CD163, and HLA-DR and by analysis of soluble immune-related molecules in the supernatant. Peripheral blood immune cells from PD patients had lower survival in culture, but showed a higher monocytic proliferative ability than control cells, which was correlated with shorter disease duration and late disease onset. In addition, PD patients' cells were less responsive to stimulation, as shown by the lack of changes in CD163 and CD14 expression, and by the absence of significant upregulation of anti-inflammatory cytokines in culture. Moreover, PD peripheral immune cells shed lower in vitro levels of soluble CD163, which suggests a less responsive monocytic population and/or an activation status different from control cells. Interestingly, some of the results were sex associated, supporting a differential immune response in females versus males. Our data suggest that PD involves monocytic changes in blood. These cells show reduced viability and are unresponsive to specific stimuli, which might have a relevant consequence for disease progression. © 2019 International Parkinson and Movement Disorder Society.


Increased incidence of co-infection in critically ill patients with influenza.
Co-infection is frequently seen in critically ill patients with influenza, although the exact rate is unknown. We determined the rate of co-infection, the risk factors and the outcomes associated with co-infection in critically ill patients with influenza over a 7-year period in 148 Spanish intensive care units (ICUs). This was a prospective, observational, multicentre study. Influenza was diagnosed using the polymerase chain reaction. Co-infection had to be confirmed using standard bacteriological tests. The primary endpoint of this analysis was the presence of community-acquired co-infection, with secondary endpoints including ICU, 28-day and hospital mortality. Of 2901 ICU patients diagnosed with influenza, 482 (16.6 %) had a co-infection. The proportion of cases of co-infection increased from 11.4 % (110/968) in 2009 to 23.4 % (80/342) in 2015 (P < 0.001). Compared with patients without co-infection, patients with co-infection were older [adjusted odds ratio (aOR) 1.1, 95 % confidence interval 1.1-1.2; P < 0.001] and were more frequently immunosuppressed due to existing HIV infection (aOR 2.6 [1.5-4.5]; P < 0.001) or preceding medication (aOR 1.4 [1.1-1.9]; P = 0.03). Co-infection was an independent risk factor for ICU mortality (aOR 1.4 [1.1-1.8]; P < 0.02), 28-day mortality (aOR 1.3 [1.1-1.7]; P = 0.04) and hospital mortality (aOR 1.9 [1.5-2.5]; P < 0.001). Co-infection in critically ill patients with influenza has increased in recent years. In this Spanish cohort, age and immunosuppression were risk factors for co-infection, and co-infection was an independent risk factor for ICU, 28-day and hospital mortality.


Measuring Outcomes of Mohs Defect Reconstruction Using Eye-Tracking Technology.
Objectively measuring how Mohs defect reconstruction changes casual observer attention has important implications for patients and facial plastic surgeons. To use eye-tracking technology to objectively measure the ability of Mohs facial defect reconstruction to normalize facial attention. This observational outcomes study was conducted at an academic tertiary referral center from January to June 2016. An eye-tracking system was used to record how 82 casual observers directed attention to photographs of 32 patients with Mohs facial defects of varying sizes and locations before and after reconstruction as well as 16 control faces with no facial defects. Statistical analysis was performed from November 2018 to January 2019. First, the attentional distraction caused by facial defects was quantified in milliseconds of gaze time using eye tracking. Second, the eye-tracking data were analyzed using mixed-effects linear regression to assess the association of facial defect reconstruction with normalized facial attention. The 82 casual observers (63 women and 19 men; mean [SD] age, 34 [12] years) viewed control faces in a similar and consistent fashion, with most attention (65%; 95% CI, 62%-69%) directed at the central triangle, which includes the eyes, nose, and mouth. The eyes were the most visually important feature, capturing a mean of 60% (95% CI, 57%-64%) of fixation time within the central triangle and 39% (95% CI, 36%-43%) of total observer attention. The presence of Mohs defects was associated with statistically significant alterations in this pattern of normal facial attention. The larger the defect and the more centrally a defect was located, the more attentional distraction was observed, as measured by increased attention on the defect and decreased attention on the eyes, ranging from 729 (95% CI, 526-931) milliseconds for small peripheral defects to 3693 (95% CI, 3490-3896) milliseconds for large central defects. Reconstructive surgery was associated with improved gaze deviations for all faces and with normalized attention directed to the eyes for all faces except for those with large central defects. Mohs defects are associated with altered facial perception, diverting attention from valuable features such as the eyes. Reconstructive surgery was associated with normalized attentional distraction for many patients with cutaneous Mohs defects. These data are important to patients who want to know how reconstructive surgery could change the way people look at their face. The data also point to the possibility of outcomes prediction based on facial defect size and location before reconstruction. Eye tracking is a valuable research tool for outcomes assessment that lays the foundation for understanding how reconstructive surgery may change perception and normalize facial deformity.