Simple preconditioning for time-dependent density functional perturbation theory.
By far, the most common use of time-dependent density functional theory is in the linear-reponse regime, where it provides information about electronic excitations. Ideally, the linear-response equations should be solved by a method that avoids the use of the unoccupied Kohn-Sham states--such as the Sternheimer method--as this reduces the complexity and increases the precision of the calculation. However, the Sternheimer equation becomes ill-conditioned near and indefinite above the first resonant frequency, seriously hindering the use of efficient iterative solution methods. To overcome this serious limitation, and to improve the general convergence properties of the iterative techniques, we propose a simple preconditioning strategy. In our method, the Sternheimer equation is solved directly as a linear equation using an iterative Krylov subspace method, i.e., no self-consistent cycle is required. Furthermore, the preconditioner uses the information of just a few unoccupied states and requires simple and minimal modifications to existing implementations. In this way, convergence can be reached faster and in a considerably wider frequency range than the traditional approach.


Assessment of outpatient treatment of deep-vein thrombosis with low-molecular-weight heparin.
Low-molecular-weight (LMW) heparins are safe and effective for out-of-hospital treatment of acute deep-vein thrombosis (DVT) in a clinical trial setting. We examined the efficacy, safety, and feasibility of home treatment with LMW heparin of consecutive eligible patients with acute DVT in a routine care setting. In addition, we report our experience with patient compliance, acceptance, and satisfaction. We performed a prospective cohort study of consecutive patients presenting to 2 thromboembolism clinics in a large Ontario city. Eligible patients were treated with LMW heparin for a minimum of 5 days and with long-term warfarin sodium. Outcomes included the incidences of bleeding and recurrence of DVT and pulmonary embolism and patient satisfaction as determined by a questionnaire. One hundred thirteen patients with objectively confirmed DVT underwent screening; 89 patients were treated at home with LMW heparin. During the study, 1 patient died of a combination of pulmonary embolism and major bleeding, another patient required admission to the hospital for bleeding, and 5 patients with active malignant disease had recurrent DVT. Of the patients who completed the satisfaction questionnaire, 75 (91%) of 82 were pleased with home treatment; 44 (70%) of 63 felt comfortable self-injecting the LMW heparin; and 71 (92%) of 77 were satisfied with the support and instruction they received during the outpatient treatment. Outpatient treatment of DVT with LMW heparin is safe, effective, and feasible for most patients and is associated with a high degree of patient satisfaction.


Antimicrobial and Immune-Modulatory Effects of Vitamin D Provide Promising Antibiotics-Independent Approaches to Tackle Bacterial Infections - Lessons Learnt from a Literature Survey.
Antimicrobial multidrug-resistance (MDR) constitutes an emerging threat to global health and makes the effective prevention and treatment of many, particularly severe infections challenging, if not impossible. Many antibiotic classes have lost antimicrobial efficacy against a plethora of infectious agents including bacterial species due to microbial acquisition of distinct resistance genes. Hence, the development of novel anti-infectious intervention strategies including antibiotic-independent approaches is urgently needed. Vitamins such as vitamin D and vitamin D derivates might be such promising molecular candidates to combat infections caused by bacteria including MDR strains. Using the Pubmed database, we therefore performed an in-depth literature survey, searching for publications on the antimicrobial effect of vitamin D directed against bacteria including MDR strains. In vitro and clinical studies between 2009 and 2019 revealed that vitamin D does, in fact, possess antimicrobial properties against both Gram-positive and Gram-negative bacterial species, whereas conflicting results could be obtained from in vivo studies. Taken together, the potential anti-infectious effects for the antibiotic-independent application of vitamin D and/or an adjunct therapy in combination with antibiotic compounds directed against infectious diseases such as tuberculosis, H. pylori infections, or skin diseases, for instance, should be considered and further investigated in more detail.


Evaluation of serum interleukin-10 levels as a predictor of glycemic alteration in chronic periodontitis and type 2 diabetes mellitus.
Chronic periodontal disease (CPD) and type 2 diabetes mellitus (T2DM) share common pathogenic pathways. This study aimed to estimate levels of serum interleukin (IL-10), an anti-inflammatory cytokine also associated with T2DM and evaluate its association with hyperglycemia. This investigation involved sixty participants divided into four groups comprising 15 participants each: Group 1 (healthy controls), Group 2 (CPD patients), Group 3 (T2DM patients with CPD) and Group 4 (T2DM patients). Plaque index, gingival index, probing pocket depths (PPD), clinical attachment loss, bleeding on probing, random blood sugar, glycosylated hemoglobin (HbA1c), and serum IL-10 was measured. Interleukin-10 was detected in all four groups. Statistically significant (P < 0.05) differences were observed in most of the variables in all groups. IL-10 correlated significantly with PPD in Group 1 and with HbA1c in Group 4. IL-10 regressed with PPD in Group 1 and with HbA1c in Group 4. IL-10 levels were lower in Group 3 when compared with Group 4 and was lowest in Group 2. Low IL-10 levels associated with high HbA1c. Pathogenic mechanisms of CPD seem to regulate IL-10. Serum IL-10 levels may be one of the predictors of glycemia.


ATG5-Dependent Autophagy Uncouples T-cell Proliferative and Effector Functions and Separates Graft-versus-Host Disease from Graft-versus-Leukemia.
Autophagy is a vital cellular process whose role in T immune cells is poorly understood, specifically, in its regulation of allo-immunity. Stimulation of wild-type T cells in vitro and in vivo with allo-antigens enhances autophagy. To assess the relevance of autophagy to T-cell allo-immunity, we generated T-cell-specific Atg5 knock-out mice. Deficiency of ATG5-dependent autophagy reduced T-cell proliferation and increased apoptosis following in vitro and in vivo allo-stimulation. The absence of ATG5 in allo-stimulated T cells enhanced their ability to release effector cytokines and cytotoxic functions, uncoupling their proliferation and effector functions. Absence of autophagy reduced intracellular degradation of cytotoxic enzymes such as granzyme B, thus enhancing the cytotoxicity of T cells. In several in vivo models of allo-HSCT, ATG5-dependent dissociation of T-cell functions contributed to significant reduction in graft-versus-host disease (GVHD) but retained sufficient graft versus tumor (GVT) response. Our findings demonstrate that ATG5-dependent autophagy uncouples T-cell proliferation from its effector functions and offers a potential new strategy to enhance outcomes after allo-HSCT. SIGNIFICANCE: These findings demonstrate that induction of autophagy in donor T-cell promotes GVHD, while inhibition of T-cell autophagy mitigates GVHD without substantial loss of GVL responses.


Recent advances in diagnosis and treatment of microscopic colitis.
Microscopic colitis, comprising collagenous colitis and lymphocytic colitis, is a common cause of chronic diarrhea. It is characterized clinically by chronic watery diarrhea and a macroscopically normal colonic mucosa where diagnostic histopathological features are seen on microscopic examination. The annual incidence of each disorder is 4-6/100,000 inhabitants, with a peak incidence in individuals 60-70 years old and a noticeable female predominance in collagenous colitis. The etiology is unknown. Chronic diarrhea, abdominal pain, weight loss, fatigue, and fecal incontinence are common symptoms that impair the health-related quality of life of the patient. There is an association with other autoimmune disorders, such as celiac disease, thyroid disorders, diabetes mellitus, and arthritis. Budesonide is the best-documented treatment, both short-term and long-term. Recurrence of symptoms is common after withdrawal of successful budesonide therapy, and the optimal long-term treatment strategy needs further study. The long-term prognosis is good, and the risk of complications including colon cancer is low. We review the epidemiology, clinical features, diagnosis and treatment of microscopic colitis.


Evidence of Faradaic Reactions in Electrostatic Atomizers.
Any rational theory of electrostatic atomizers (EAs) would require a detailed understanding of the nature of the polarized layer near the electrode, since this is the source of the electric charge carried by the jets issued from the EAs. The polarized layer either is driven out as the electrically-driven Smoluchowski flow and/or entrained by the viscous shear imposed by the bulk flow. The standard Gouy-Chapman theory of polarized diffuse layers implies zero electric current passing across the layer, which is impossible to reconcile with the fact that there are leak currents in the EAs. Here, we show that the electric current through the EA is controlled by faradaic reactions at the electrodes. The experiments were conducted with stainless steel or brass pin-like cathodes and three different anode (the conical nozzle) materials, which were copper, stainless steel, and brass. The different electrode materials resulted in different spray, leakage, and total currents in all the cases. Accordingly, it is shown that the total electric current generated by EAs can be controlled by the cathode and anode materials, i.e., by faradaic reactions on them. This lays the foundation for a more detailed understanding and description of the operation of EAs.


Local curvature mismatch may worsen the midterm functional outcomes of osteochondral allograft transplantation.
This study aimed to determine the magnitude of local curvature matching in the sagittal plane between an implanted graft and the condylar region receiving the graft and to analyze its effect on clinical outcomes in patients undergoing osteochondral allograft transplantation (OCA). Patients who underwent knee OCA between 2016 and 2019 without circumferential step-off and were matched with a donor in accordance with the conventional matching process were included. The magnitude of donor-host local curvature matching was measured using postoperative sagittal magnetic resonance imaging data with Syngo (Siemens Medical Solutions, Forchheim, Germany) and GeoGebra (GeoGebra GmbH, Linz, AU) software. In addition to radiological evaluation, ROC analysis was performed to compare the patient-reported outcome measures (PROMs) obtained during the 2-year follow-up period among the patients in the SagA group, who had a graft match in the sagittal plane; SagB group, who had low convexity of the graft in the sagittal plane; and SagC group, who had high convexity of the graft in the sagittal plane in accordance with the determined indices. The study included 27 patients who fulfilled the inclusion criteria, and the mean clinical scores of the SagC group were not statistically significantly higher than those of the other groups at any timepoint during the follow-up. The mean Tegner, IKDC, total KOOS and SF-12 physical and mental health scores of the SagC group were lower than those of the other two groups at various follow-up time points, particularly at month 24 (p < 0.05). There were no significant differences between the SagA and SagB groups in the PROMs at any of the follow-up time points (n.s.). The significant differences observed between the SagC group and the other groups in the mean KOOS scores for function in daily living and function in sport and recreation were also observed between the SagA and SagB groups at the follow-ups (p < 0.05). During OCA, a local curvature mismatch between the donor and the host involving large graft convexity may have a negative impact on midterm clinical outcomes. A preoperative analysis of the convexity relationship between the defect site and the graft region in the hemicondylar allograft to be used may enhance donor-host matching. The local analysis method described in the current study may also facilitate graft supply by ensuring donor-host matching without condyle-side and size matching. III.


Patient-reported outcomes in women with breast cancer enrolled in a dual-center, double-blind, randomized controlled trial assessing the effect of acupuncture in reducing aromatase inhibitor-induced musculoskeletal symptoms.
Aromatase inhibitors (AIs) have been associated with decrements in patient-reported outcomes (PROs). The objective of this study was to assess whether real acupuncture (RA), compared with sham acupuncture (SA), improves PROs in patients with breast cancer who are receiving an adjuvant AI. Postmenopausal women with a stage 0 through III breast cancer who received an AI and had treatment-associated musculoskeletal symptoms were randomized to receive 8 weekly RA versus SA in a dual-center, randomized controlled trial. The National Surgical Adjuvant Breast and Bowel Project (NSABP) menopausal symptoms questionnaire, the Center for Epidemiological Studies Depression (CESD) scale, the Hospital Anxiety and Depression Scale (HADS), the Pittsburgh Sleep Quality Index (PSQI), the hot flash daily diary, the Hot Flash-Related Daily Interference Scale (HFRDI), and the European quality-of-life survey (EuroQol) were used to assess PROs at baseline and at 4weeks, 8 weeks, and 12 weeks. The intention-to-treat analysis included 23 patients in the RA arm and 24 patients in the SA arm. There were no significant differences in baseline characteristics between the 2 groups. Compared with baseline, scores in the RA arm improved significantly at week 8 on the CESD (P = .022), hot flash severity (P = .006), hot flash frequency (P = .011), the HFRDI (P = .014), and NSABP menopausal symptoms (P = .022); scores in the SA arm improved significantly on the EuroQol (P = .022),the HFRDI (P = .043), and NSABP menopausal symptoms (P = .005). Post-hoc analysis indicated that African American patients (n = 9) benefited more from RA than SA compared with non-African American patients (n = 38) in reducing hot flash severity (P < .001) and frequency (P < .001) scores. Both RA and SA were associated with improvement in PROs among patients with breast cancer who were receiving AIs, and no significant difference was detected between arms. Racial differences in response to acupuncture warrant further study.


Strategies and policies deteriorate occupational health situation in India: A review based on social determinant framework.
Overwhelming evidence shows that hazardous work, working conditions, and environment fail to maintain homeostasis results in death or severe disability. Up to the 1980s, governments did not pay major attention to occupational health in developing countries, including India. The Bhopal Gas Tragedy, in 1984, was the turning point in the history of health and safety in India. It was time for the government to think deeply and review the existing legislative measures, for the upliftment of the occupational health situation in India. However, all the services remain grossly underutilized because of inadequate strategies, policies, and the lack of a proper monitoring mechanism, for occupational workers. The present study reviews the fact that Inaction or Destruction of Demands, Use of Power, Appeal to the existing bias of the system, and Exportation and Flexibility of the workers are some of the main reasons for the alarming situation of the Occupational Health Policy (OHP) in India. The existing and traditional condition of the laborers before and after independence is also highlighted in this article. Finally the threats are identified and options are provided to improve the health conditions of the workers.


Designing Fluorescent Peptide Sensors with Dual Specificity for the Detection of HIV-1 Protease.
HIV-1 protease is a key enzyme in the life cycle of HIV/AIDS, as it is responsible for the formation of the mature virus particle. We demonstrate here that phage-display peptides raised against this enzyme can be used as peptide sensors for the detection of HIV-1 protease in a simple, one-pot assay. The presence of the enzyme is detected through an energy transfer between two peptide sensors when simultaneously complexed with the target protein. The multivalent nature of this assay increases the specificity of the detection by requiring all molecules to be interacting in order for there to be a FRET signal. We also perform molecular dynamics simulations to explore the interaction between the protease and the peptides in order to guide the design of these peptide sensors and to understand the mechanisms which cause these simultaneous binding events. This approach aims to facilitate the development of new assays for enzymes that are not dependent on the cleavage of a substrate and do not require multiple washing steps.


Drivers of successful implementation of integrated care for multi-morbidity: Mechanisms identified in 17 case studies from 8 European countries.
This paper provides a deeper understanding of the mechanisms underlying implementation strategies for integrated care. As part of the SELFIE project, 17 integrated care programmes addressing multi-morbidity from eight European countries were selected and studied. Data was extracted from 'thick descriptions' of the 17 programmes and analysed both inductively and deductively using implementation theory. The following ten mechanisms for successful implementation of integrated care were identified. With regards to service delivery, successful implementers (1) commonly adopted an incremental growth model rather than a disruptive innovation approach, and found (2) a balance between flexibility and formal structures of integration. For leadership & governance, they (3) applied collaborative governance by engaging all stakeholders, and (4) distributed leadership throughout all levels of the system. For the workforce, these implementers (5) were able to build a multidisciplinary team culture with mutual recognition of each other's roles, and (6) stimulated the development of new roles and competencies for integrated care. With respect to financing, (7) secured long-term funding and innovative payments were applied as means to overcome fragmented financing of health and social care. Implementers emphasised (8) the implementation of ICT that was specifically developed to support collaboration and communication rather than administrative procedures (technology & medical devices), and (9) created feedback loops and a continuous monitoring system (information & research). The overarching mechanism was that implementers (10) engaged in alignment work across the different components and levels of the health and social care system. These evidence-based mechanisms for implementation are applicable in different local, regional and national contexts.


Functional characterization of two naturally occurring mutations in the human sodium-phosphate cotransporter type IIa.
Mutations in the gene encoding the human sodium-phosphate cotransporter (NPT2), causing reduced phosphate affinity and dominant-negative behavior, were described. We found no evidence of altered kinetics or dominant-negative effects. Thus, the mutations cannot account for the clinical phenotype. Mutations in NPT22a, the gene encoding the sodium-phosphate cotransporter NaPi-IIa, were for the first time linked to human disease by Priè and colleagues. Two patients are described with renal phosphate wasting who were heterozygous for either the A48F or V147M mutation. Expressed in Xenopus oocytes, both mutants showed reduced phosphate affinity. Furthermore, coexpression of mutants with wildtype (WT) NaPi-IIa resulted in reduced cotransport function, explaining the mutants' dominant-negative effect in the patients. Intrigued by the implications of these findings on transporter kinetics, we decided to examine the transport characteristics of the two mutants in more detail. We recreated the two mutants, expressed them in Xenopus oocytes, and analyzed their kinetic behavior by two-electrode voltage clamp. We also performed coexpression experiments where we injected mRNA for WT and mutants containing an additional S462C mutation, enabling complete inhibition of cotransport function with cysteine-modifying reagents. Finally, we expressed WT and mutant NaPi-IIa as C-terminal fusions to green fluorescent protein (GFP) in opossum kidney (OK) cells. We found in our oocyte expression experiments that P(i)-induced currents were reduced in both mutants, whereas P(i) and Na affinities and other transport characteristics were not affected. The amount of cotransport activity remaining after cysteine modification, corresponding to WT activity, was not affected by coexpression of either mutant. Finally, GFP-tagged WT and mutants were expressed at the apical membrane in OK cells, showing that both mutants are correctly targeted in a mammalian cell. In conclusion, our data from oocyte and OK cell expression studies suggest that the heterozygous A48F and V 147M mutations cannot explain the pathological phenotype observed by Priè and colleagues.


Autoreactive T cells in mercury-induced autoimmunity. Ability to induce the autoimmune disease.
It has been previously shown that autoreactive T cells appear during mercury-induced autoimmunity in Brown-Norway (BN) rats. In the present work, it is shown that: 1) T cells and T helper cells from HgCl2-injected BN rats are able to actively transfer autoimmunity in normal BN rats; the disease transferred is exacerbated when recipients are treated with the antisuppressor/cytotoxic T cell monoclonal antibody (OX8); 2) normal T cells preincubated with HgCl2 are also able to transfer the disease in OX8-treated but not in T cell-depleted rats; and 3) T cells from HgCl2-injected BN rats also transferred the disease in both normal and T cell depleted rats. It is concluded that: 1) autoreactive T cells, and presumably anti-Ia T cells are involved in the pathogenesis of mercury-induced autoimmunity; 2) these autoreactive T cells induce suppressor/cytotoxic T cells to proliferate in normal syngeneic recipients; the fact that this T cell subset did not proliferate in HgCl2-injected BN rats suggests that HgCl2 also affects T suppressor cells; and 3) mercury-induced autoimmunity could result from the additive effect of the emergence of autoreactive T cells and of a defect at the T suppressor level.


SU-D-BRA-04: Improvement of Diaphragm Motion Reproducibility in MRI Using Audiovisual Biofeedback for Lung Cancer Radiotherapy.
Previous studies have investigated the effect of AV biofeedback on the external respiratory signal reproducibility. This is the first study investigating the effect of AV biofeedback to improve the motion reproducibility of the internal anatomy. The aim of the project is to test the hypothesis that AV biofeedback improves the diaphragm motion reproducibility. An AV biofeedback system has been employed with MRI acquisitions. The AV biofeedback system utilized (1) the external marker position on the abdomen using an RPM system (Real-time Position Management, Varian) to audio-visually guide a human subject for regular breathing and (2) a fast Gradient-Recalled-Echo (fGRE) MR pulse sequence of 3 Tesla GE MRI (GE Healthcare) to monitor the diaphragm motion (200ms). The improvement in the diaphragm motion reproducibility using the AV biofeedback system combined with MRI has been assessed in 26 studies with 13 healthy human subjects. Each subject underwent two studies for assessment of the diaphragm motion reproducibility both with AV biofeedback and without (free breathing). The second study features a reversed order of breathing conditions. The total MRI acquisitions across the 26 studies are 202 measurements including sagittal and coronal planes. Average RMSE (root mean square error) of diaphragm displacement obtained from MRI analysis has been reduced from 2.7mm of free breathing to 1.6mm of AV biofeedback breathing (p-value < 0.05). Additionally, the average RMSE of diaphragm motion period was reduced from 1.84s with free breathing to 0.34s with AV biofeedback breathing (p- value < 0.05). 22% of average displacement error was reduced using AV biofeedback in the first study, and 47% reduction in the second study. The study demonstrated the improvement in the diaphragm motion reproducibility using AV biofeedback. This system can provide clinically applicable motion management of the internal anatomy in MRI and for Image Guided Radiotherapy (IGRT).


Improving GRADE evidence tables part 3: detailed guidance for explanatory footnotes supports creating and understanding GRADE certainty in the evidence judgments.
The Grading of Recommendations Assessment, Development and Evaluation (GRADE) is widely used and reliable and accurate for assessing the certainty in the body of health evidence. The GRADE working group has provided detailed guidance for assessing the certainty in the body of evidence in systematic reviews and health technology assessments (HTAs) and how to grade the strength of health recommendations. However, there is limited advice regarding how to maximize transparency of these judgments, in particular through explanatory footnotes or explanations in Summary of Findings tables and Evidence Profiles (GRADE evidence tables). We conducted this study to define the essential attributes of useful explanations and to develop specific guidance for explanations associated with GRADE evidence tables. We used a sample of explanations according to their complexity, type of judgment involved, and appropriateness from a database of published GRADE evidence tables in Cochrane reviews and World Health Organization guidelines. We used an iterative process and group consensus to determine the attributes and develop guidance. Explanations in GRADE evidence tables should be concise, informative, relevant, easy to understand, and accurate. We provide general and domain-specific guidance to assist authors with achieving these desirable attributes in their explanations associated with GRADE evidence tables. Adhering to the general and GRADE domain-specific guidance should improve the quality of explanations associated with GRADE evidence tables, assist authors of systematic reviews, HTA reports, or guidelines with information that they can use in other parts of their evidence synthesis. This guidance will also support editorial evaluation of evidence syntheses using GRADE and provide a minimum quality standard of judgments across tables.


In search of flavour-nutrient learning. A study of the Samburu pastoralists of North-Central Kenya.
Much of our dietary behaviour is learned. In particular, one suggestion is that 'flavour-nutrient learning' (F-NL) influences both choice and intake of food. F-NL occurs when an association forms between the orosensory properties of a food and its postingestive effects. Unfortunately, this process has been difficult to evaluate because F-NL is rarely observed in controlled studies of adult humans. One possibility is that we are disposed to F-NL. However, learning is compromised by exposure to a complex Western diet that includes a wide range of energy-dense foods. To test this idea we explored evidence for F-NL in a sample of semi-nomadic pastoralists who eat a very limited diet, and who are lean and food stressed. Our Samburu participants (N = 68) consumed a sensory-matched portion (400 g) of either a novel low (0.72 kcal/g) or higher (1.57 kcal/g) energy-dense semi-solid food on two training days, and an intermediate version on day 3. Before and after each meal we measured appetite and assessed expected satiation and liking for the test food. We found no evidence of F-NL. Nevertheless, self-reported measures were very consistent and, as anticipated, expected satiation increased as the test food became familiar (expected-satiation drift). Surprisingly, we observed insensitivity to the effects of test-meal energy density on measures of post-meal appetite. To explore this further we repeated a single training day using participants (N = 52) from the UK. Unlike in the Samburu, the higher energy-dense meal caused greater suppression of appetite. These observations expose interesting cross-cultural differences in sensitivity to the energy content of food. More generally, our work illustrates how measures can be translated to assess different populations, highlighting the potential for further comparisons of this kind.


A structure filter for the Eukaryotic Linear Motif Resource.
Many proteins are highly modular, being assembled from globular domains and segments of natively disordered polypeptides. Linear motifs, short sequence modules functioning independently of protein tertiary structure, are most abundant in natively disordered polypeptides but are also found in accessible parts of globular domains, such as exposed loops. The prediction of novel occurrences of known linear motifs attempts the difficult task of distinguishing functional matches from stochastically occurring non-functional matches. Although functionality can only be confirmed experimentally, confidence in a putative motif is increased if a motif exhibits attributes associated with functional instances such as occurrence in the correct taxonomic range, cellular compartment, conservation in homologues and accessibility to interacting partners. Several tools now use these attributes to classify putative motifs based on confidence of functionality. Current methods assessing motif accessibility do not consider much of the information available, either predicting accessibility from primary sequence or regarding any motif occurring in a globular region as low confidence. We present a method considering accessibility and secondary structural context derived from experimentally solved protein structures to rectify this situation. Putatively functional motif occurrences are mapped onto a representative domain, given that a high quality reference SCOP domain structure is available for the protein itself or a close relative. Candidate motifs can then be scored for solvent-accessibility and secondary structure context. The scores are calibrated on a benchmark set of experimentally verified motif instances compared with a set of random matches. A combined score yields 3-fold enrichment for functional motifs assigned to high confidence classifications and 2.5-fold enrichment for random motifs assigned to low confidence classifications. The structure filter is implemented as a pipeline with both a graphical interface via the ELM resource http://elm.eu.org/ and through a Web Service protocol. New occurrences of known linear motifs require experimental validation as the bioinformatics tools currently have limited reliability. The ELM structure filter will aid users assessing candidate motifs presenting in globular structural regions. Most importantly, it will help users to decide whether to expend their valuable time and resources on experimental testing of interesting motif candidates.


COVID-19 and pregnancy - where are we now? A review.
The new acute respiratory disease severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is highly contagious. It has caused many deaths, despite a relatively low general case fatality rate (CFR). The most common early manifestations of infection are fever, cough, fatigue and myalgia. The diagnosis is based on the exposure history, clinical manifestation, laboratory test results, chest computed tomography (CT) findings and a positive reverse transcription-polymerase chain reaction (RT-PCR) result for coronavirus disease 2019 (COVID-19). The effect of SARS-CoV-2 on pregnancy is not already clear. There is no evidence that pregnant women are more susceptible than the general population. In the third trimester, COVID-19 can cause premature rupture of membranes, premature labour and fetal distress. There are no data on complications of SARS-CoV-2 infection before the third trimester. COVID-19 infection is an indication for delivery if necessary to improve maternal oxygenation. Decision on delivery mode should be individualised. Vertical transmission of coronavirus from the pregnant woman to the fetus has not been proven. As the virus is absent in breast milk, the experts encourage breastfeeding for neonatal acquisition of protective antibodies.


Left and right heart haemodynamics during spontaneous angina pectoris. Comparison between angina with ST segment depression and angina with ST segment elevation.
The function of both right and left sides of the heart was studied during spontaneous attacks of angina pectoris at rest in 7 patients showing ST depression (type I) and 4 showing ST elevation (type II) during the attack. In none of the 44 type I attacks and 29 type II attacks which were recorded did circulatory changes; the latter were different in the two groups. Type I attacks showed: a) a brief fall in arterial pressure, accompanied by b) a rise of right atrial and pulmonary wedge pressures and c) a decrease of cardiac output, right and left stroke work, the mean rate of systolic ejection, and indirect left ventricular pre-ejection dP/dt. In the course of the attack a hypertensive phase followed, which was paralleled by an increase of heart rate, cardiac output, left and right stroke work, and mean systolic ejection rate, left dP/dt; right atrial pressure and wedge pressure remained raised. All of the circulatory functions started to revert towards the pre-attack levels coincident with the waning phase of the electrocardiographic alteration, the latter occurring either spontaneously or after nitroglycerin. Type II attacks for the entire duration of the electrocardiographic changes showed: a) a reduction of arterial pressure, cardiac output, right and left stroke work, mean systolic ejection rate, and left dP/dt, b) a rise of right atrial and wedge pressures, and c) quite small changes of heart rate. When the electrocardiogram started to revert to the pre-attack aspect, the cardiac function rapidly improved and, after a supernormal phase, returned to the basal levels in about 2 minutes. It is concluded: 1) that no circulatory factor interfering with the mechanical effort of the heart is responsible for eliciting spontaneous angina: 2) that in type I attacks right and left ventricular impairment occurs which recovers rapidly, possibly through a sympathetic compensation; 3) that in type II attachs dysfunction of both sides of the heart occurs and persists throughout the episode of electrocardiographic alteration; 4) that the dynamic impairment is probably more severe in type I than in type II angina.


A review of dental treatment of head and neck cancer patients, before, during and after radiotherapy: part 1.
The incidence of head and neck cancer is on the rise. Most head and neck cancers are treated with surgery, radiotherapy, chemotherapy or a combination of these modalities. Patients undergoing radiotherapy can experience several unwanted oral side effects, which have both short and long term implications. Dental general practitioners should be aware of these implications and should liaise closely with the restorative consultants and the oncology team to establish the best oral care pathway. This two-part series is a review of the oral changes that occur during and after radiotherapy and the oral management of head and neck oncology before, during and after radiotherapy. This article deals with both immediate sequelae such as cellulitis, mucositis, dysphagia, dysguesia and weight loss as well as long term sequelae such as rampant caries, trismus, xerostomia and osteoradionecrosis. It also encompasses the importance and need for pre-radiotherapy assessment.


Tumor necrosis factor receptor expression and signaling in renal cell carcinoma.
Clear cell renal cell carcinoma (ccRCC), a tubular epithelial cell (TEC) malignancy, frequently secretes tumor necrosis factor (TNF). TNF signals via two distinct receptors (TNFRs). TNFR1, expressed in normal kidney primarily on endothelial cells, activates apoptotic signaling kinase 1 and nuclear factor-kappaB (NF-kappaB) and induces cell death, whereas TNFR2, inducibly expressed on endothelial cells and on TECs by injury, activates endothelial/epithelial tyrosine kinase (Etk), which trans-activates vascular endothelial growth factor receptor 2 (VEGFR2) to promote cell proliferation. We investigated TNFR expression in clinical samples and function in short-term organ cultures of ccRCC tissue treated with wild-type TNF or specific muteins selective for TNFR1 (R1-TNF) or TNFR2 (R2-TNF). There is a significant increase in TNFR2 but not TNFR1 expression on malignant TECs that correlates with increasing malignant grade. In ccRCC organ cultures, R1-TNF increases TNFR1, activates apoptotic signaling kinase and NF-kappaB, and promotes apoptosis in malignant TECs. R2-TNF increases TNFR2, activates NF-kappaB, Etk, and VEGFR2 and increases entry into the cell cycle. Wild-type TNF induces both sets of responses. R2-TNF actions are blocked by pretreatment with a VEGFR2 kinase inhibitor. We conclude that TNF, acting through TNFR2, is an autocrine growth factor for ccRCC acting via Etk-VEGFR2 cross-talk, insights that may provide a more effective therapeutic approach to this disease.


What is a reasonable length of employment for health workers in Australian rural and remote primary healthcare services?
Optimising retention of rural and remote primary healthcare (PHC) workers requires workforce planners to understand what constitutes a reasonable length of employment and how this varies. Currently, knowledge of retention patterns is limited and there is an absence of PHC workforce benchmarks that take account of differences in geographic context and profession. Three broad strategies were employed for proposing benchmarks for reasonable length of stay. They comprised: a comprehensive literature review of PHC workforce-retention indicators and benchmarks; secondary analysis of existing Australian PHC workforce datasets; and a postal survey of 108 rural and remote PHC services, identifying perceived and actual workforce-retention patterns of selected professional groups. The literature review and secondary data analysis revealed little that was useful for establishing retention benchmarks. Analysis of primary data revealed differences in retention by geographic location and profession that took time to emerge and were not sustained indefinitely. Provisional benchmarks for reasonable length of employment were developed for health professional groups in both rural and remote settings. Workforce-retention benchmarks that differ according to geographic location and profession can be empirically derived, facilitating opportunities for managers to improve retention performance and reduce the high costs of staff replacement. WHAT IS KNOWN ABOUT THE TOPIC? Health services located in small rural and remote locations are likely to continue to experience workforce shortages and high costs of recruitment. Health workforce retention is therefore crucial. However, effective rural health workforce planning and use of strategies to maximise retention of existing health workers is hindered by inadequate knowledge about baseline employment-retention patterns. WHAT DOES THIS PAPER ADD? Differences in health worker retention patterns by geographic location and profession are most evident after the first 6 months through until the end of the second year of employment. Health worker-retention benchmarks that differ according to geographic location and profession are proposed. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Benchmarking workforce retention in comparable health services can enable identification of best practice and the underpinning retention strategies. Workforce planners can use this, together with knowledge of baseline retention patterns and the high cost of staff replacement, to guide the design, timing and implementation of cost-neutral retention strategies.


Risk of multiple sclerosis after head injury: record linkage study.
The possibility that head injury may influence the development of multiple sclerosis (MS) has been studied inconclusively in the past. To determine whether head injury is associated with an increased risk of MS. Analysis of database of linked hospital and death records, comparing the occurrence of MS in a cohort of people admitted to hospital with head injury and a reference cohort. The rate ratio for MS after head injury, compared with the reference cohort, was 1.1 (95% confidence interval, 0.88 to 1.36). There was no significant increase in the risk of MS at either short or long time periods after head injury. Using length of hospital stay as a proxy for severity of injury, there was no significant increase in the rate ratio for MS after head injuries with hospital stays of less than two days (rate ratio = 1.1 (0.71 to 1.57)), two or more days (rate ratio = 1.0 (0.68 to 1.45)), or seven or more days (rate ratio = 1.3 (0.64 to 2.34)). The method used, record linkage, ensures that patients' recollection of injury, or any tendency to attribute MS to injury, cannot have influenced the results. Injuries to the head were not associated with either the aetiological initiation or the clinical precipitation of onset of multiple sclerosis.


Health status measurement in exacerbations of COPD.
This article evaluates recent publications measuring health status in exacerbations of chronic obstructive pulmonary disease (COPD) and sets them in the context of existing knowledge. Limitations of the studies are discussed and the validity of health status measurement for exacerbations in light of new evidence is reviewed. Additional research is required to characterize health status measurement across exacerbation frequencies and to clarify predictive validity according to the definition of an exacerbation. There is also a need for the population composition of future studies to reflect the changing gender prevalence of COPD, investigate exacerbation-related health status in patients classified with mild COPD and incorporate unreported exacerbation events. Challenges in developing new tools for the quantification of exacerbations are outlined and their likely future contribution to health status measurement is discussed.


Evolution of multi-drug resistant hepatitis B virus during sequential therapy.
Multi-drug resistant hepatitis B virus (HBV) has been reported in hepatitis B patients who received sequential antiviral therapy. In vitro studies showed that HBV constructs with mutations resistant to lamivudine and adefovir have marked reduction in sensitivity to combination of lamivudine and adefovir, whereas constructs with mutations resistant to either drug remain sensitive to the other drug. We conducted this study to determine whether mutations conferring resistance to multiple antiviral agents co-locate on the same HBV genome in vivo and to describe the evolution of these mutations. Sera from six patients who had been found to have multi-drug resistant HBV mutations to lamivudine+adefovir, lamivudine+hepatitis B immunoglobulin (HBIG), or lamivudine+entecavir on direct sequencing were cloned after nested polymerase chain reaction (PCR). Analysis of 215 clones from 11 samples with multi-drug resistant mutations on direct sequencing showed that 183 (85%) clones had mutations to both therapies on the same genome; 31 clones had lamivudine-resistant mutants only. Clonal analysis of serial samples from three patients showed progressive evolution from all clones with lamivudine-resistant HBV mutations only to mixtures of clones that have multi-drug resistant mutations and clones that have lamivudine-resistant HBV mutations only, and ultimately all clones having multi-drug resistant HBV mutations. In conclusion, mutations conferring resistance to multiple antiviral agents co-locate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multi-drug resistant HBV. De novo combination therapy may prevent the emergence of multi-drug resistant mutants.


Ventilator function improvement in patients undergoing regular hemodialysis: relation to sex differences.
Uremic lung is different entity then oedema present in cardiovascular diseases or in adult respiratory distress syndrome as well. This state is one of the possible complications in patients with chronic renal failure (CRF) receiving regular hemodialysis (HD). There are several studies suggesting that in these patients in 30-40% cases pulmonary hypertension was developed. It is known that patients with primary pulmonary hypertension have peripheral airway obstruction The data also showed that primary as well secondary pulmonary hypertension are more often developed in females; even real reason is still unknown. The aim of the study was to estimate the ventilator function improvement in patients with CRF receiving regular HD related to sex differences. The study population consisted in 39 patients with CRF, with no cardiac and pulmonary diseases. These patients were treated by regular hemodialysis using bicarbonate or acetate mode, respectively. They were divided into two groups according to the sex. Spirometry parameters before and after onset of hemodialysis were recorded. The results were analyzed using Student t-test and presented as mean +/-SD. All p values <0,05 were considered significant. The result showed that ventilatory function in male patients is significantly improved, especially VC and FEV1, whereas in female patients improvement had not statistical significance. It can be concluded that one of the possible reasons for slight improvement of ventilator function in female patients is pulmonary hypertension.


Multimodal super-resolution optical microscopy visualizes the close connection between membrane and the cytoskeleton in liver sinusoidal endothelial cell fenestrations.
Liver sinusoidal endothelial cells (LSECs) act as a filter between blood and the hepatocytes. LSECs are highly fenestrated cells; they contain transcellular pores with diameters between 50 to 200 nm. The small sizes of the fenestrae have so far prohibited any functional analysis with standard and advanced light microscopy techniques. Only the advent of super-resolution optical fluorescence microscopy now permits the recording of such small cellular structures. Here, we demonstrate the complementary use of two different super-resolution optical microscopy modalities, 3D structured illumination microscopy (3D-SIM) and single molecule localization microscopy in a common optical platform to obtain new insights into the association between the cytoskeleton and the plasma membrane that supports the formation of fenestrations. We applied 3D-SIM to multi-color stained LSECs to acquire highly resolved overviews of large sample areas. We then further increased the spatial resolution for imaging fenestrations by single molecule localization microscopy applied to select small locations of interest in the same sample on the same microscope setup. We optimized the use of fluorescent membrane stains for these imaging conditions. The combination of these techniques offers a unique opportunity to significantly improve studies of subcellular ultrastructures such as LSEC fenestrations.


Spatio-Spectral Feature Representation for Motor Imagery Classification Using Convolutional Neural Networks.
Convolutional neural networks (CNNs) have recently been applied to electroencephalogram (EEG)-based brain-computer interfaces (BCIs). EEG is a noninvasive neuroimaging technique, which can be used to decode user intentions. Because the feature space of EEG data is highly dimensional and signal patterns are specific to the subject, appropriate methods for feature representation are required to enhance the decoding accuracy of the CNN model. Furthermore, neural changes exhibit high variability between sessions, subjects within a single session, and trials within a single subject, resulting in major issues during the modeling stage. In addition, there are many subject-dependent factors, such as frequency ranges, time intervals, and spatial locations at which the signal occurs, which prevent the derivation of a robust model that can achieve the parameterization of these factors for a wide range of subjects. However, previous studies did not attempt to preserve the multivariate structure and dependencies of the feature space. In this study, we propose a method to generate a spatiospectral feature representation that can preserve the multivariate information of EEG data. Specifically, 3-D feature maps were constructed by combining subject-optimized and subject-independent spectral filters and by stacking the filtered data into tensors. In addition, a layer-wise decomposition model was implemented using our 3-D-CNN framework to secure reliable classification results on a single-trial basis. The average accuracies of the proposed model were 87.15% (±7.31), 75.85% (±12.80), and 70.37% (±17.09) for the BCI competition data sets IV_2a, IV_2b, and OpenBMI data, respectively. These results are better than those obtained by state-of-the-art techniques, and the decomposition model obtained the relevance scores for neurophysiologically plausible electrode channels and frequency domains, confirming the validity of the proposed approach.


Creation of active water-splitting photocatalysts by controlling cocatalysts using atomically precise metal nanoclusters.
With global warming and the depletion of fossil resources, our fossil-fuel-dependent society is expected to shift to one that instead uses hydrogen (H2) as clean and renewable energy. Water-splitting photocatalysts can produce H2 from water using sunlight, which are almost infinite on the earth. However, further improvements are indispensable to enable their practical application. To improve the efficiency of the photocatalytic water-splitting reaction, in addition to improving the semiconductor photocatalyst, it is extremely effective to improve the cocatalysts (loaded metal nanoclusters, NCs) that enable the reaction to proceed on the photocatalysts. We have thus attempted to strictly control metal NCs on photocatalysts by introducing the precise-control techniques of metal NCs established in the metal NC field into research on water-splitting photocatalysts. Specifically, the cocatalysts on the photocatalysts were controlled by adsorbing atomically precise metal NCs on the photocatalysts and then removing the protective ligands by calcination. This work has led to several findings on the electronic/geometrical structures of the loaded metal NCs, the correlation between the types of loaded metal NCs and the water-splitting activity, and the methods for producing high water-splitting activity. We expect that the obtained knowledge will lead to clear design guidelines for the creation of practical water-splitting photocatalysts and thereby contribute to the construction of a hydrogen-energy society.


[Significance and prospective view of microbiological examination concerning the guidelines for pneumonia management].
In Japan, the guidelines for the management of pneumonia in adults will be established in about tow years followed by Europe and the USA. The significance and prospective view of microbiological examination concerning the guidelines for pneumonia management in Japan are discussed here. Concerning the management of acute pneumonia, the differential diagnosis between bacterial pneumonia and atypical pneumonia is necessary, but the present system of microbiological examination using culture of microbials and antimicrobial susceptibility testing is time-consuming. A quick reporting system of sputum gram-staining and molecular diagnosis in microbiological laboratories will greatly contribute to the management of bacterial pneumonia and atypical pneumonia, respectively. This quick reporting system should be combined with automatic systematization of microbiological examination in laboratories in the future.


Quality of reconstruction of compressed off-axis digital holograms by frequency filtering and wavelets.
Compression of digital holograms can significantly help with the storage of objects and data in 2D and 3D form, its transmission, and its reconstruction. Compression of standard images by methods based on wavelets allows high compression ratios (up to 20-50 times) with minimum losses of quality. In the case of digital holograms, application of wavelets directly does not allow high values of compression to be obtained. However, additional preprocessing and postprocessing can afford significant compression of holograms and the acceptable quality of reconstructed images. In this paper application of wavelet transforms for compression of off-axis digital holograms are considered. The combined technique based on zero- and twin-order elimination, wavelet compression of the amplitude and phase components of the obtained Fourier spectrum, and further additional compression of wavelet coefficients by thresholding and quantization is considered. Numerical experiments on reconstruction of images from the compressed holograms are performed. The comparative analysis of applicability of various wavelets and methods of additional compression of wavelet coefficients is performed. Optimum parameters of compression of holograms by the methods can be estimated. Sizes of holographic information were decreased up to 190 times.


Specific ion effects in amphiphile hydration and interface stabilization.
Specific ion effects can influence many processes in aqueous solutions: protein folding, enzyme activity, self-assembly, and interface stabilization. Ionic amphiphiles are known to stabilize the oil/water interface, presumably by dipping their hydrophobic tails into the oil phase while sticking their hydrophilic head groups in water. However, we find that anionic and cationic amphiphiles adopt strikingly different structures at liquid hydrophobic/water interfaces, linked to the different specific interactions between water and the amphiphile head groups, both at the interface and in the bulk. Vibrational sum frequency scattering measurements show that dodecylsulfate (DS(-)) ions do not detectably perturb the oil phase while dodecyltrimethylammonium (DTA(+)) ions do. Raman solvation shell spectroscopy and second harmonic scattering (SHS) show that the respective hydration-shells and the interfacial water structure are also very different. Our work suggests that specific interactions with water play a key role in driving the anionic head group toward the water phase and the cationic head group toward the oil phase, thus also implying a quite different surface stabilization mechanism.


Using Machine Learning to Predict the Information Seeking Behavior of Clinicians Using an Electronic Medical Record System.
Poor electronic medical record (EMR) usability is detrimental to both clinicians and patients. A better EMR would provide concise, context sensitive patient data, but doing so entails the difficult task of knowing which data are relevant. To determine the relevance of patient data in different contexts, we collect and model the information seeking behavior of clinicians using a learning EMR (LEMR) system. Sufficient data were collected to train predictive models for 80 different targets (e.g., glucose level, heparin administration) and 27 of them had AUROC values of greater than 0.7. These results are encouraging considering the high variation in information seeking behavior (intraclass correlation 0.40). We plan to apply these models to a new set of patient cases and adapt the LEMR interface to highlight relevant patient data, and thus provide concise, context sensitive data.


Heparan sulfate proteoglycan isoforms of the CD44 hyaluronan receptor induced in human inflammatory macrophages can function as paracrine regulators of fibroblast growth factor action.
The CD44 glycoprotein is expressed in multiple isoforms on a variety of cell types where it functions as a receptor for hyaluronan-mediated motility. Recently, interest has centered on CD44 heparan sulfate proteoglycan (HSPG) isoforms because of their potential to sequester heparin-binding growth factors and chemokines. Expression of these isoforms on ectodermal cells has recently been shown to regulate limb morphogenesis via presentation of fibroblast growth factor (FGF) 4/FGF 8 while expression on tumor cells was shown to sequester hepatocyte growth factor and promote tumor dissemination. To date, however, CD44 HSPG expression in tissue macrophages and lymphocytes has not been adequately investigated, despite the fact these cells actively synthesize growth factors and chemokines and indirect evidence that monocyte CD44 sequesters macrophage inflammatory protein-1beta. Here we show primary human monocytes rather than lymphocytes express CD44 HSPGs, but only following in vitro differentiation to macrophages or activation with the proinflammatory cytokine interleukin-1alpha or bacterial lipopolysaccharide. Furthermore, we show these isoforms are preferentially modified with heparan rather than chondroitin sulfate, bind the macrophage-derived growth factors FGF-2, vascular endothelial growth factor, and heparin-binding epidermal growth factor with varying affinities (K(d) 25-330 nM) and in the case of FGF-2, can stimulate productive binding to the high affinity tyrosine kinase FGF receptor 1 (FGFR1). In contrast, we find no evidence for significant binding to C-C chemokines. Last, we confirm by immunofluorescent antibody staining that inflamed synovial membrane macrophages express CD44 HSPGs and that expression is greatest in cells containing high FGF-2 levels. These results suggest a paracrine role for macrophage CD44 HSPG isoforms in the regulation of growth factor action during inflammation.


Estimating the effect of calorie menu labeling on calories purchased in a large restaurant franchise in the southern United States: quasi-experimental study.
To evaluate whether calorie labeling of menus in large restaurant chains was associated with a change in mean calories purchased per transaction. Quasi-experimental longitudinal study. Large franchise of a national fast food company with three different restaurant chains located in the southern United States (Louisiana, Texas, and Mississippi) from April 2015 until April 2018. 104 restaurants with calorie information added to in-store and drive-thru menus in April 2017 and with weekly aggregated sales data during the pre-labeling (April 2015 to April 2017) and post-labeling (April 2017 to April 2018) implementation period. Primary outcome was the overall level and trend changes in mean purchased calories per transaction after implementation of calorie labeling compared with the counterfactual (ie, assumption that the pre-intervention trend would have persisted had the intervention not occurred) using interrupted time series analyses with linear mixed models. Secondary outcomes were by item category (entrees, sides, and sugar sweetened beverages). Subgroup analyses estimated the effect of calorie labeling in stratums defined by the sociodemographic characteristics of restaurant census tracts (defined region for taking census). The analytic sample comprised 14 352 restaurant weeks. Over three years and among 104 restaurants, 49 062 440 transactions took place and 242 726 953 items were purchased. After labeling implementation, a level decrease was observed of 60 calories/transaction (95% confidence interval 48 to 72; about 4%), followed by an increasing trend of 0.71 calories/transaction/week (95% confidence interval 0.51 to 0.92) independent of the baseline trend over the year after implementation. These results were generally robust to different analytic assumptions in sensitivity analyses. The level decrease and post-implementation trend change were stronger for sides than for entrees or sugar sweetened beverages. The level decrease was similar between census tracts with higher and lower median income, but the post-implementation trend in calories per transaction was higher in low income (change in calories/transaction/week 0.94, 95% confidence interval 0.67 to 1.21) than in high income census tracts (0.50, 0.19 to 0.81). A small decrease in mean calories purchased per transaction was observed after implementation of calorie labeling in a large franchise of fast food restaurants. This reduction diminished over one year of follow-up.


Preferential loss of expression of p16(INK4a) rather than p19(ARF) in breast cancer.
The tumor suppressor p16(INK4a) has been shown to be inactivated in numerous cancer lines and primary tumors. Recently, we reported loss of heterozygosity of the region in which p16(INK4a) is located in more than one-half of primary breast tumors. However, mutational analysis of these same tumors revealed mutation of p16(INK4a) to be infrequent. Other possible modes of inactivation, such as de novo methylation and homozygous deletion, have since been shown to occur in numerous neoplasias. Furthering the complexity of this locus, a transcript overlapping the p16(INK4a) coding sequence and encoding a novel peptide with growth-suppressive activity, p19(ARF), has been described. To clearly elucidate the target of aberrations affecting this subchromosomal region and approximate frequency in breast cancer, we performed a comprehensive study including p16 deletion analysis by means of interphase chromosomal fluorescence in situ hybridization, methylation analysis of the first exon encoding p16(INK4a) (exon 1alpha), mutational analysis of exon 1beta by single-strand conformational polymorphism analysis of p19(ARF) transcripts, and expression of both alpha and beta transcripts by reverse transcription PCR. Homozygous deletion of p16, as determined by interphase chromosomal fluorescence in situ hybridization, was observed in 3 of 18 (17%) tumors analyzed, whereas de novo methylation of exon 1alpha was observed in an additional 17% (4 of 23). Reduced expression of p16(INK4a) was observed in 11 tumors (48%), including all those in which homozygous deletion or complete methylation was observed. No mutations of exon 1 beta were detected, and expression of its transcript was variable, with 13% demonstrating decreased expression and 17% demonstrating overexpression. These results further support p16(INK4a) as a target of inactivation in the 9p21 region for breast cancer.


Identification and characterization of a leptin-responsive neuroblastoma cell line.
The adipocyte-derived hormone leptin plays a critical role in a variety of physiological and pathological actions. As such the determination of leptin signal transduction pathways are important both for understanding the molecular mechanisms of leptin action and for identifying sites for possible therapeutic intervention. Since the hypothalamus is the primary site of leptin action, we sought to identify a neuronal-derived human cell line containing the long form of the leptin receptor (OBRb). To this end, we screened several neuroblastoma cell lines and isolated a sub-line of SH-SY5Y cells, which we designated as SH-OBRb, for further studies. We characterized the transduction pathways induced by leptin in SH-OBRb cells and demonstrated that OBRb mediates tyrosine phosphorylation of STAT3, phosphorylation of ERK1/2, but not SAPK/JNK and p38 MAPK, in a dose and time dependent fashion. In addition, Akt appears to be phosphorylated in the basal state and to be insensitive to further activation by leptin. In summary, we have isolated a unique cell line that can be utilized as a model for use in the study of leptin action and molecular mechanisms.


Amplification of Wound Healing by Propolis and Honey Ointment in Healthy and Diabetic Rat Models; Histopathological and Morphometric Findings.
Skin wound healing, especially in diabetic patients, has been a major medical challenge for decades. In the meantime, the use of traditional medicine has always been questioned. Propolis) resin and wax (is one of the most likely solutions to this problem. The present study aimed to establish an animal model for healing skin wounds and diabetic ulcers. To this aim, rats were randomly allocated into two healthy and diabetic groups (50 mg/kg streptozotocin resulted in diabetes with high BSL to 300 mg/dL), which were divided into four subgroups. The 7 mm full-thickness skin wounds were created on the abdomen region in 80 male Wistar rats using paunch. In the subgroups, the wounds were cleaned with normal 0.9% saline as the control subgroup and dressed with Eucerit, 1.5% honey+eucerit, and 3% propolis +1.5% honey+eucerit, once daily for 14 days in other subgroups, respectively. On days 1, 3, 5, and 7 after the intervention, wound and area contractions were calculated using digital photographs measurement. The histopathological and semi-quantitative studies were performed on days 7 and 14 after wounds creation. The microscopic findings demonstrated that the granulation tissue, fibroblasts, re-epithelization, and angiogenesis increased (P≤0.05) in the subgroups treated by propolis and honey combination in healthy and diabetic rats within 7 and 14 days post-injury. Also, less inflammation and a significant reduction in wound contraction were observed in the same subgroups on days 3, 5, and 7 compared to other subgroups (P≤0.05). The results indicated that significant healing quality and acceleration were affected by propolis and honey compared to other subgroups on days 3 and 5 (P≤0.05).


Geographic Variation in Camouflage Specialization by a Decorator Crab.
In North Carolina, the decorator crab Libinia dubia camouflages almost exclusively with the chemically noxious alga Dictyota menstrualis. By placing this alga on its carapace, the crab behaviorally sequesters the defensive chemicals of the plant and gains protection from omnivorous consumers. However, Dictyota is absent north of North Carolina, whereas Libinia occurs as far north as New England. Crabs from three northern locations where Dictyota is absent (Rhode Island, Connecticut, and New Jersey) camouflaged to match their environment, rather than selectively accumulating any one species. When D. menstrualis was offered to crabs from northern sites, they did not distinguish between it and other seaweeds for camouflage, whereas crabs from Alabama and two locations in North Carolina used D. menstrualis almost exclusively. In addition, in winter and spring, when Dictyota was seasonally absent in North Carolina, Libinia selectively camouflaged with the sun sponge Hymeniacidon heliophila, which was chemically unpalatable to local fishes. Thus, southern crabs were consistent specialists on chemically defended species for camouflage, while northern crabs were more generalized. The geographic shift in crab behavior away from specialization coincides with a reported decrease in both total predation pressure and the frequency of omnivorous consumers. These shifts in the nature and intensity of predation pressure may favor different camouflage strategies (generalist vs. specialist), contributing to the observed geographic differences in camouflage behavior.


MBS measurement tool for swallow impairment--MBSImp: establishing a standard.
The aim of this study was to test reliability, content, construct, and external validity of a new modified barium swallowing study (MBSS) tool (MBSImp) that is used to quantify swallowing impairment. Multiple regression, confirmatory factor, and correlation analyses were used to analyze 300 in- and outpatients with heterogeneous medical and surgical diagnoses who were sequentially referred for MBS exams at a university medical center and private tertiary care community hospital. Main outcome measures were the MBSImp and index scores of aspiration, health status, and quality of life. Inter- and intrarater concordance were 80% or greater for blinded scoring of MBSSs. Regression analysis revealed contributions of eight of nine swallow types to impressions of overall swallowing impairment (p < or = 0.05). Factor analysis revealed 13 significant components (loadings >/= 0.5) that formed two impairment groupings (oral and pharyngeal). Significant correlations were found between Oral and Pharyngeal Impairment scores and Penetration-Aspiration Scale scores, and indexes of intake status, nutrition, health status, and quality of life. The MBSImp demonstrated clinical practicality, favorable inter- and intrarater reliability following standardized training, content, and external validity. This study reflects potential for establishment of a new standard for quantification and comparison of oropharyngeal swallowing impairment across patient diagnoses as measured on MBSS.


Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin.
The glycosphingolipid (GSL) lysosomal storage diseases result from the inheritance of defects in the genes encoding the enzymes required for catabolism of GSLs within lysosomes. A strategy for the treatment of these diseases, based on an inhibitor of GSL biosynthesis N-butyldeoxynojirimycin, was evaluated in a mouse model of Tay-Sachs disease. When Tay-Sachs mice were treated with N-butyldeoxynojirimycin, the accumulation of GM2 in the brain was prevented, with the number of storage neurons and the quantity of ganglioside stored per cell markedly reduced. Thus, limiting the biosynthesis of the substrate (GM2) for the defective enzyme (beta-hexosaminidase A) prevents GSL accumulation and the neuropathology associated with its lysosomal storage.


First Report of Blueberry Reddening Disease in Serbia Associated with 16SrXII-A (Stolbur) Phytoplasma.
Blueberries (Vaccinium corymbosum) are among the healthiest fruits due to their high antioxidant content. The total growing area of blueberries in Serbia ranges from 80 to 90 ha. A phytoplasma-like disease was observed for the first time during July 2009 in three blueberry cultivars (Bluecrop, Duke, and Spartan) grown in central Serbia, locality Kopljare (44°20'10.9″ N, 20°38'39.3″ E). Symptoms of yellowing and reddening were observed on the upper leaves and proliferating shoots, similar to those already described on blueberries (4). There was uneven ripening of the fruits on affected plants. Incidence of affected plants within a single field was estimated to be greater than 20% in 2009 and 50% in 2010. Blueberry leaves, together with petioles, were collected during two seasons, 2009 and 2010, and six samples from diseased plants and one from symptomless plants from each cultivar, resulting in 42 samples in total. For phytoplasma detection, total DNA was extracted from the veins of symptomatic and asymptomatic leaves of V. corymbosum using the protocol of Angelini et al. (1). Universal oligonucleotide primers P1/P7 were used to amplify a 1.8-kb DNA fragment containing the 16S rRNA gene, the 16S-23S spacer region, and the 5' end of the 23S rRNA gene. Subsequently, a 1.2-kb fragment of the 16S rRNA gene was amplified by nested PCR with the R16F2n/R16R2 primers. Reactions were performed in a volume of 50 μl using Dream Taq Green master mix (Thermo Scientific, Lithuania). PCR reaction conditions were as reported (3), except for R16F2n/R2 primers set (annealing for 30 s at 58°C). PCR products were obtained only from the DNA of symptomatic plants. Fragments of 1.2 kb were further characterized by the PCR-RFLP analysis, using AluI, HpaII, HhaI, and Tru1I restriction enzymes (Thermo Scientific, Lithuania), as recommended by the manufacturer. The products of restriction enzyme digestion were separated by electrophoresis on 2.5% agarose gel. All R16F2n/R2 amplicons showed identical RFLP patterns corresponding to the profile of the Stolbur phytoplasma (subgroup 16SrXII-A). The results were confirmed by sequencing the nested PCR product from the representative strain Br1. The sequence was deposited in NCBI GenBank database under accession number KC960486. Phylogenetic analysis showed maximal similarities with SH1 isolate from Vitis vinifera, Jordan (KC835139.1), Bushehr (Iran) eggplant big bud phytoplasma (JX483703.1), BA strain isolated from insect in Italy (JQ868436.1), and also with several plants from Serbia: Arnica montana L. (JX891383.1), corn (JQ730750.1), Hypericum perforatum (JQ033928.1), tobacco (JQ730740.1), etc. In conclusion, our results demonstrate that leaf discoloration of V. corymbosum was associated with a phytoplasma belonging to the 16SrXII-A subgroup. The wild European blueberry (Vaccinium myrtillus L.) is already detected as a host plant of 16SrIII-F phytoplasma in Germany, North America, and Lithuania (4). The main vector of the Stolbur phytoplasma, Hyalesthes obsoletus Signoret, was already detected in Serbia (2). The first report of Stolbur phytoplasma occurrence on blueberry in Serbia is significant for the management of the pathogen spreading in blueberry fields. Since the cultivation of blueberry has a great economic potential in the region, it is important to identify emerging disease concerns in order to ensure sustainable production. References: (1) E. Angelini et al. Vitis 40:79, 2001. (2) J. Jović et al. Phytopathology 99:1053, 2009. (3) S. Pavlovic et al. J. Med. Plants Res. 6:906, 2012. (4) D. Valiunas et al. J. Plant Pathol. 86:135, 2004.


Molecular epidemiology of isolates with multiple mcr plasmids from a pig farm in Great Britain: the effects of colistin withdrawal in the short and long term.
The environment, including farms, might act as a reservoir for mobile colistin resistance (mcr) genes, which has led to calls for reduction of usage in livestock of colistin, an antibiotic of last resort for humans. To establish the molecular epidemiology of mcr Enterobacteriaceae from faeces of two cohorts of pigs, where one group had initially been treated with colistin and the other not, over a 5 month period following stoppage of colistin usage on a farm in Great Britain; faecal samples were also taken at ∼20 months. mcr-1 Enterobacteriaceae were isolated from positive faeces and was WGS performed; conjugation was performed on selected Escherichia coli and colistin MICs were determined. E. coli of diverse ST harbouring mcr-1 and multiple resistance genes were isolated over 5 months from both cohorts. Two STs, from treated cohorts, contained both mcr-1 and mcr-3 plasmids, with some isolates also harbouring multiple copies of mcr-1 on different plasmids. The mcr-1 plasmids grouped into four Inc types (X4, pO111, I2 and HI2), with mcr-3 found in IncP. Multiple copies of mcr plasmids did not have a noticeable effect on colistin MIC, but they could be transferred simultaneously to a Salmonella host in vitro. Neither mcr-1 nor mcr-3 was detected in samples collected ∼20 months after colistin cessation. We report for the first known time on the presence in Great Britain of mcr-3 from MDR Enterobacteriaceae, which might concurrently harbour multiple copies of mcr-1 on different plasmids. However, control measures, including stoppage of colistin, can successfully mitigate long-term on-farm persistence.


Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department.
Amino-terminal pro-brain natriuretic peptide (NT-proBNP) is useful for diagnosis and triage of patients with dyspnea, but its role for predicting outcomes in such patients remains undefined. A total of 599 breathless patients treated in the emergency department were prospectively enrolled, and a sample of blood was obtained for NT-proBNP measurements. After 1 year, the vital status of each patient was ascertained, and the association between NT-proBNP values at presentation and mortality was assessed. At 1 year, 91 patients (15.2%) had died. Median NT-proBNP concentrations at presentation among decedents were significantly higher than those of survivors (3277 vs 299 pg/mL; P<.001). The optimal NT-proBNP cut point for predicting 1-year mortality was 986 pg/mL. In a multivariable model, an NT-proBNP concentration greater than 986 pg/mL at presentation was the single strongest predictor of death at 1 year (hazard ratio [HR], 2.88; 95% confidence interval, 1.64-5.06; P<.001), independent of a diagnosis of heart failure. Other factors associated with death included age (by decade; HR, 1.20), heart rate (by decile; HR, 1.13), urea nitrogen level (by decile; HR, 1.20), systolic blood pressure less than 100 mm Hg (HR, 1.94), heart murmur (HR, 1.92), and New York Heart Association classification (HR, 1.38 for each increase in class). The NT-proBNP concentration alone had an area under the receiver operating characteristic curve (AUC) of 0.76 for predicting mortality; the other significant covariates combined had an AUC of 0.80. The final model for predicting death, combining NT-proBNP with other covariates associated with mortality, had a superior AUC of 0.82. In addition to assisting in emergency department diagnosis and triage, NT-proBNP concentrations at presentation are strongly predictive of 1-year mortality in dyspneic patients.


Impact of alemtuzumab on HIV persistence in an HIV-infected individual on antiretroviral therapy with Sezary syndrome.
To study the effects of alemtuzumab on HIV persistence in an HIV-infected individual on antiretroviral therapy (ART) with Sezary syndrome, a rare malignancy of CD4 T cells. Case report. Blood was collected 30 and 18 months prior to presentation with Sezary syndrome, at the time of presentation and during alemtuzumab. T-cell subsets in malignant (CD7-CD26-TCR-VBeta2+) and nonmalignant cells were quantified by flow cytometry. HIV-DNA in total CD4 T cells, in sorted malignant and nonmalignant CD4 T cells, was quantified by PCR and clonal expansion of HIV-DNA assessed by full-length next-generation sequencing. HIV-hepatitis B virus coinfection was diagnosed and antiretroviral therapy initiated 4 years prior to presentation with Sezary syndrome and primary cutaneous anaplastic large cell lymphoma. The patient received alemtuzumab 10 mg three times per week for 4 weeks but died 6 weeks post alemtuzumab. HIV-DNA was detected in nonmalignant but not in malignant CD4 T cells, consistent with expansion of a noninfected CD4 T-cell clone. Full-length HIV-DNA sequencing demonstrated multiple defective viruses but no identical or expanded sequences. Alemtuzumab extensively depleted T cells, including more than 1 log reduction in total T cells and more than 3 log reduction in CD4 T cells. Finally, alemtuzumab decreased HIV-DNA in CD4 T cells by 57% but HIV-DNA remained detectable at low levels even after depletion of nearly all CD4 T cells. Alemtuzumab extensively depleted multiple T-cell subsets and decreased the frequency of but did not eliminate HIV-infected CD4 T cells. Studying the effects on HIV persistence following immune recovery in HIV-infected individuals who require alemtuzumab for malignancy or in animal studies may provide further insights into novel cure strategies.


Stratospheric solar geoengineering without ozone loss.
Injecting sulfate aerosol into the stratosphere, the most frequently analyzed proposal for solar geoengineering, may reduce some climate risks, but it would also entail new risks, including ozone loss and heating of the lower tropical stratosphere, which, in turn, would increase water vapor concentration causing additional ozone loss and surface warming. We propose a method for stratospheric aerosol climate modification that uses a solid aerosol composed of alkaline metal salts that will convert hydrogen halides and nitric and sulfuric acids into stable salts to enable stratospheric geoengineering while reducing or reversing ozone depletion. Rather than minimizing reactive effects by reducing surface area using high refractive index materials, this method tailors the chemical reactivity. Specifically, we calculate that injection of calcite (CaCO3) aerosol particles might reduce net radiative forcing while simultaneously increasing column ozone toward its preanthropogenic baseline. A radiative forcing of -1 W⋅m-2, for example, might be achieved with a simultaneous 3.8% increase in column ozone using 2.1 Tg⋅y-1 of 275-nm radius calcite aerosol. Moreover, the radiative heating of the lower stratosphere would be roughly 10-fold less than if that same radiative forcing had been produced using sulfate aerosol. Although solar geoengineering cannot substitute for emissions cuts, it may supplement them by reducing some of the risks of climate change. Further research on this and similar methods could lead to reductions in risks and improved efficacy of solar geoengineering methods.


Essential O2-responsive genes of Pseudomonas aeruginosa and their network revealed by integrating dynamic data from inverted conditions.
Identification of the gene network through which Pseudomonas aeruginosa PAO1 (PA) adapts to altered oxygen-availability environments is essential for a better understanding of stress responses and pathogenicity of PA. We performed high-time-resolution (HTR) transcriptome analyses of PA in a continuous cultivation system during the transition from high oxygen tension to low oxygen tension (HLOT) and the reversed transition from low to high oxygen tension (LHOT). From those genes responsive to both transient conditions, we identified 85 essential oxygen-availability responsive genes (EORGs), including the expected ones (arcDABC) encoding enzymes for arginine fermentation. We then constructed the regulatory network for the EORGs of PA by integrating information from binding motif searching, literature and HTR data. Notably, our results show that only the sub-networks controlled by the well-known oxygen-responsive transcription factors show a very high consistency between the inferred network and literature knowledge, e.g. 87.5% and 83.3% of the obtained sub-network controlled by the anaerobic regulator (ANR) and a quorum sensing regulator RhIR, respectively. These results not only reveal stringent EORGs of PA and their transcription regulatory network, but also highlight that achieving a high accuracy of the inferred regulatory network might be feasible only for the apparently affected regulators under the given conditions but not for all the expressed regulators on a genome scale.


Dancing to Metallica and Dora: Case Study of a 19-Month-Old.
Rhythmic movement to music, whether deliberate (e.g., dancing) or inadvertent (e.g., foot-tapping), is ubiquitous. Although parents commonly report that infants move rhythmically to music, especially to familiar music in familiar environments, there has been little systematic study of this behavior. As a preliminary exploration of infants' movement to music in their home environment, we studied V, an infant who began moving rhythmically to music at 6 months of age. Our primary goal was to generate testable hypotheses about movement to music in infancy. Across nine sessions, beginning when V was almost 19 months of age and ending 8 weeks later, she was video-recorded by her mother during the presentation of 60-s excerpts from two familiar and two unfamiliar songs presented at three tempos-the original song tempo as well as faster and slower versions. V exhibited a number of repeated dance movements such as head-bobbing, arm-pumping, torso twists, and bouncing. She danced most to Metallica's Now that We're Dead, a recording that her father played daily in V's presence, often dancing with her while it played. Its high pulse clarity, in conjunction with familiarity, may have increased V's propensity to dance, as reflected in lesser dancing to familiar music with low pulse clarity and to unfamiliar music with high pulse clarity. V moved faster to faster music but only for unfamiliar music, perhaps because arousal drove her movement to familiar music. Her movement to music was positively correlated with smiling, highlighting the pleasurable nature of the experience. Rhythmic movement to music may have enhanced her pleasure, and the joy of listening may have promoted her movement. On the basis of behavior observed in this case study, we propose a scaled-up study to obtain definitive evidence about the effects of song familiarity and specific musical features on infant rhythmic movement, the developmental trajectory of dance skills, and the typical range of variation in such skills.


State of corals and coral reefs of the Galápagos Islands (Ecuador): Past, present and future.
Coral populations and structural coral reefs have undergone severe reductions and losses respectively over large parts of the Galápagos Islands during and following the 1982-83 El Niño event. Coral tissue loss amounted to 95% across the Archipelago. Also at that time, all coral reefs in the central and southern islands disappeared following severe degradation and eventual collapse due primarily to intense bioerosion and low recruitment. Six sites in the southern islands have demonstrated low to moderate coral community (scattered colonies, but no carbonate framework) recovery. The iconic pocilloporid reef at Devil's Crown (Floreana Island) experienced recovery to 2007, then severe mortality during a La Niña cooling event, and is again (as of 2017) undergoing rapid recovery. Notable recovery has occurred at the central (Marchena) and northern islands (Darwin and Wolf). Of the 17 structural reefs first observed in the mid-1970s, the single surviving reef (Wellington Reef) at Darwin Island remains in a positive growth mode. The remainder either degraded to a coral community or was lost. Retrospective analyses of the age structure of corals killed in 1983, and isotopic signatures of the skeletal growth record of massive corals suggest the occurrence of robust coral populations during at least a 500-year period before 1983. The greatest potential threats to the recovery and persistence of coral reefs include: ocean warming and acidification, bioerosion, coral diseases, human population growth (increasing numbers of residents and tourists), overfishing, invasive species, pollution, and habitat destruction. Such a diverse spectrum of disturbances, acting alone or in combination, are expected to continue to cause local and archipelago-wide mortality and degradation of the coral reef ecosystem.


Cytokine synthesis in human peripheral blood mononuclear cells after oral administration of polyenzyme preparations.
Pharmaceutical preparations containing mixtures of various proteolytic and nonproteolytic enzymes have been suggested for use in the treatment of malignant diseases. However, the mode of action of such preparations was not clear. We have shown before that intact bromelain, papain or amylase, which are components of a commercial polyenzyme preparation, induce cytokine production in peripheral blood mononuclear cells in vitro. IFN-alpha and IFN-gamma which had no effect alone, synergistically increased TNF production when applied together with the enzymes. Here we show that trypsin alone had only a small inducing effect. The tryptic but not the autolytic fragments of papain and bromelain have a higher (10- to 40-fold) inducing capacity for TNF production than the untreated enzyme. Additionally we demonstrate that after ingestion of milligram doses of the polyenzyme preparation (as recommended for clinical use), PBMNC of healthy donors acquire the ability to produce TNF-alpha, IL-1 beta and IL-6 when incubated ex vivo with IFN-gamma. Our results indicate that the biological effects observed after oral administration of polyenzyme preparations are related to their ability to induce cytokine production. This may explain the antitumor effects of such enzymes. Our results also suggest that polyenzyme preparations may have a stronger immunomodulary effect when used in combination with IFN-gamma.


Cognitive load and emotional processing in psoriasis: a thermal imaging study.
Psoriasis is a chronic dermatologic disease which is frequently associated with psychological distress. Although studies suggest a relationship between this condition and difficulties in emotion regulation, behavioral and physiological evidence about this link is scarce. We measured implicit emotion regulation abilities of psoriasis patients and a healthy control group by examining the impact of distracting emotional (positive, negative or neutral) images on a working memory task ("Emotional N-Back") which could present high (2-back) or low (1-back) cognitive workload. Moreover, we used Functional Infrared Thermal Imaging to record participants' facial temperature and obtain a measure of the activation of the autonomic system. Rising of temperature over the peri-orbital areas and the nose tip are believed to reflect the activation and the de-activation of the sympathetic system, respectively. Patients scored higher than controls on the "Lack of emotional clarity" sub-scale of the Difficulties in Emotion Regulation Scale. Compared to controls, who performed much better in the low vs. high cognitive load condition, patients showed a smaller accuracy difference between the two conditions. Moreover, patients showed less sympathetic (lower peri-orbital and higher nasal tip temperature) activity (especially in the negative and neutral blocks) during the high vs. low cognitive load condition, suggesting that the former condition might be less emotionally demanding for them. Patients benefit more than controls from the load-dependent interference effect when dealing with emotional information; thus, therapeutic techniques aiming at teaching how to use cognitive strategies to downregulate emotions might be particularly appropriated for them.


Is motivational interviewing effective at reducing alcohol misuse in young adults? A critical review of Foxcroft et al. (2014).
Foxcroft, Coombes, Wood, Allen, and Almeida Santimano (2014) recently conducted a meta-analysis evaluating the effectiveness of motivational interviewing (MI) in reducing alcohol misuse for youth up to Age 25. They concluded that the overall effect sizes of MI in this population were too small to be clinically meaningful. The present article critically reviews the Foxcroft et al. meta-analysis, highlighting weaknesses such as problems with search strategies, flawed screening and reviews of full-text articles, incorrect data abstraction and coding, and, accordingly, improper effect size estimation. In addition, between-study heterogeneity and complex data structures were not thoughtfully considered or handled using best practices for meta-analysis. These limitations undermine the reported estimates and broad conclusion made by Foxcroft et al. about the lack of MI effectiveness for youth. We call for new evidence on this question from better-executed studies by independent researchers. Meta-analysis has many important utilities for translational research. When implemented well, the overall effectiveness, as well as different effectiveness for different populations, can be examined via meta-analysis. Emerging methods utilizing individual participant-level data, such as integrative data analysis, may be particularly helpful for identifying the sources of clinical and methodological heterogeneity that matter. The need to better understand the mechanisms of alcohol interventions has never been louder in the addiction field. Through more concerted efforts throughout all phases of generating evidence, we may achieve large-scale evidence that is efficient and robust and provides critical answers for the field.


A Retrospective Observational Study of Domiciliary Oxygen Usage in a Subset of Veterans.
Long-term oxygen therapy (LTOT) delivered continuously is known to decrease mortality in patients with COPD and who are hypoxemic; however, supportive data for LTOT use in patients without COPD is lacking. In addition, many patients may be prescribed LTOT without a definitive etiology for hypoxemia. First, we investigated the diagnoses for which oxygen was prescribed to a sample of veterans and whether each diagnosis was supported by confirmatory testing. Second, we looked at the proportion of subjects who were prescribed non-continuous therapy. We retrospectively studied subjects prescribed domiciliary oxygen at the Veterans Administration Western New York Healthcare System. The subjects who met inclusion criteria were identified by using a computerized patient record system; data were collected on subject characteristics, oxygen prescription information, diagnosis for hypoxia, and diagnostic workup. Descriptive data were presented as mean ± SD and median (range). Statistical analysis was performed by using the chi-square test and an unpaired t test. A total of 494 subjects were included: 96.8% men, mean ± SD ages 74.2 ± 10.8 y. Most of the subjects were prescribed oxygen as out-patients (68.5%). A total of 335 (67.8%) were prescribed oxygen for continuous therapy, 72 (14.1%) for nocturnal therapy, 50 (10.1%) for exertion, and 30 (6.1%) for both exertion and nocturnal use. At 3 months, 19.6% of the initial cohort had oxygen discontinued. In those subjects with oxygen continued at 3 months, COPD was the most common diagnosis (63.6%), of which 76.1% had pulmonary function tests (PFTs), with 85.7% showing obstruction on spirometry. Results of our study showed a 99.4% adherence to Medicare criteria for domiciliary oxygen prescription. Also, 30.3% of the subjects were prescribed LTOT for exertional or nocturnal desaturation or both. Repeated testing at 3 months identified subjects who no longer required oxygen. COPD was the most common etiology for domiciliary oxygen. A small proportion of the subjects (6.9%) were prescribed oxygen without underlying etiology for hypoxia. Exertional and/or nocturnal oxygen prescription was common, and further research to elucidate its utility is clearly warranted.


YY1 regulates the neural crest-associated slug gene in Xenopus laevis.
slug gene expression is associated with the specification and migration of neural crest cells in the African clawed frog Xenopus laevis. We provide evidence that the protein Ying-Yang 1 (YY1) regulates the slug gene expression both indirectly and directly, via a YY1 cis-element in the slug promoter, during Xenopus development. The ability of the YY1 to bind this YY1 cis-element was confirmed by electromobility shift assays and reporter assays. YY1 was detected in the nuclei of ectodermal cells contemporaneously with the process of neural crest specification. The injection of anti-YY1 morpholino, which targeted both YY1alpha and YY1beta gene products, depleted YY1 expression below 20% and was lethal at gastrulation. Sublethal depletion of YY1 reduced the length of the anterior-posterior axis and severely inhibited the expression of the neural marker Nrp1 and of the slug gene. Overexpression of YY1 or mutation of the YY1 cis-element reduced the restricted spatial expression of the slug reporter gene in the neural ectoderm border and provoked its expression in the nonneural ectoderm. Chromatin immunoprecipitation indicated that endogenous YY1 interacts directly with the YY1 cis-element of the endogenous slug gene and with the slug gene reporter sequence injected into embryos. The results suggest that YY1 is essential for Xenopus development; is necessary for neural ectoderm differentiation, a prerequisite for neural crest specification; and restricts which cells can form neural crest mesenchyme through directly blocking slug gene activity.


Co-occurring medical conditions in adults with Down syndrome: A systematic review toward the development of health care guidelines. Part II.
Adults with Down syndrome (DS) represent a unique population who are in need of clinical guidelines to address their medical care. Many of these conditions are of public health importance with the potential to develop screening recommendations to improve clinical care for this population. Our workgroup previously identified and prioritized co-occurring medical conditions in adults with DS. In this study, we again performed detailed literature searches on an additional six medical conditions of clinical importance. A series of key questions (KQ) were formulated a priori to guide the literature search strategy. Our KQs focused on disease prevalence, severity, risk-factors, methodologies for screening/evaluation, impact on morbidity, and potential costs/benefits. The available evidence was extracted, evaluated and graded on quality. The number of participants and the design of clinical studies varied by condition and were often inadequate for answering most of the KQ. Based upon our review, we provide a summary of the findings on hip dysplasia, menopause, acquired cardiac valve disease, type 2 diabetes mellitus, hematologic disorders, and dysphagia. Minimal evidence demonstrates significant gaps in our clinical knowledge that compromises clinical decision-making and management of these medically complex individuals. The creation of evidence-based clinical guidance for this population will not be possible until these gaps are addressed.


Topographic representation of the human body in the occipitotemporal cortex.
Large-scale topographic representations of the body have long been established in the somatosensory and motor cortices. Using functional imaging, we identified a topographically organized body part map within the occipitotemporal cortex (OTC), with distinct clusters of voxels showing clear preference for different visually presented body parts. This representation was consistent both across hemispheres and participants. Using converging methods, the preference for specific body parts was demonstrated to be robust and did not merely reflect shape differences between the categories. Finally, execution of (unseen) movements with different body parts resulted in a limited topographic representation of the limbs and trunk, which partially overlapped with the visual body part map. This motor-driven activation in the OTC could not be explained solely by visual or motor imagery of the body parts. This suggests that visual and motor-related information converge within the OTC in a body part specific manner.