The Fear Reduction Exercised Early (FREE) approach to low back pain: study protocol for a randomised controlled trial.
Low back pain (LBP) is a major health issue associated with considerable health loss and societal costs. General practitioners (GPs) play an important role in the management of LBP; however, GP care has not been shown to be the most cost-effective approach unless exercise and behavioural counselling are added to usual care. The Fear Reduction Exercised Early (FREE) approach to LBP has been developed to assist GPs to manage LBP by empowering exploration and management of psychosocial barriers to recovery and provision of evidence-based care and information. The aim of the Low Back Pain in General Practice (LBPinGP) trial is to explore whether patients with LBP who receive care from GPs trained in the FREE approach have better outcomes than those who receive usual care. This is a cluster randomised controlled superiority trial comparing the FREE approach with usual care for LBP management with investigator-blinded assessment of outcomes. GPs will be recruited and then cluster randomised (in practice groups) to the intervention or control arm. Intervention arm GPs will receive training in the FREE approach, and control arm GPs will continue to practice as usual. Patients presenting to their GP with a primary complaint of LBP will be allocated on the basis of allocation of the GP they consult. We aim to recruit 60 GPs and 275 patients (assuming patients are recruited from 75% of GPs and an average of 5 patients per GP complete the study, accounting for 20% patient participant dropout). Patient participants and the trial statistician will be blind to group allocation throughout the study. Analyses will be undertaken on an intention-to-treat basis. The primary outcome will be back-related functional impairment 6 months post-initial LBP consultation (interim data at 2 weeks, 6 weeks and 3 months), measured with the Roland-Morris Disability Questionnaire. Secondary patient outcomes include pain, satisfaction, quality of life, days off from work and costs of care. Secondary GP outcomes include beliefs about pain and impairment, GP confidence, and actual and reported clinical behaviour. Health economic and process evaluations will be conducted. In the LBPinGP trial, we will investigate providing an intervention during the first interaction a person with back pain has with their GP. Because the FREE approach is used within a normal GP consultation, if effective, it may be a cost-effective means of improving LBP care. Australian New Zealand Clinical Trials Registry, ACTRN12616000888460 . Registered on 6 July 2016.


Analysing and reporting of observational data: a systematic review informing the EULAR points to consider when analysing and reporting comparative effectiveness research with observational data in rheumatology.
To evaluate the analysis and reporting of comparative effectiveness research with observational data in rheumatology, informing European Alliance of Associations for Rheumatology points to consider. We performed a systematic literature review searching Ovid MEDLINE for original articles comparing drug effectiveness in longitudinal observational studies, published in key rheumatology journals between 2008 and 2019. The extracted information focused on reporting and types of analyses. We evaluated if year of publication impacted results. From 9969 abstracts reviewed, 211 articles fulfilled the inclusion criteria. Ten per cent of studies did not adjust for confounding factors. Some studies did not explain how they chose covariates for adjustment (9%), used bivariate screening (21%) and/or stepwise selection procedures (18%). Only 33% studies reported the number of patients lost to follow-up and 25% acknowledged attrition (drop-out or treatment cessation). To account for attrition, studies used non-responder imputation, followed by last observation carried forward (LOCF) and complete case (CC) analyses. Most studies did not report the number of missing data on covariates (83%), and when addressed, 49% used CC and 11% LOCF. Date of publication did not influence the results. Most studies did not acknowledge missing data and attrition, and a tenth did not adjust for any confounding factors. When attempting to account for them, several studies used methods which potentially increase bias (LOCF, CC analysis, bivariate screening…). This study shows that there is no improvement over the last decade, highlighting the need for recommendations for the assessment and reporting of comparative drug effectiveness in observational data in rheumatology.


Association between environmental exposure to pesticides and neurodegenerative diseases.
Preliminary studies have shown associations between chronic pesticide exposure in occupational settings and neurological disorders. However, data on the effects of long-term non-occupational exposures are too sparse to allow any conclusions. This study examines the influence of environmental pesticide exposure on a number of neuropsychiatric conditions and discusses their underlying pathologic mechanisms. An ecological study was conducted using averaged prevalence rates of Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral degeneration, polyneuropathies, affective psychosis and suicide attempts in selected Andalusian health districts categorized into areas of high and low environmental pesticide exposure based on the number of hectares devoted to intensive agriculture and pesticide sales per capita. A total of 17,429 cases were collected from computerized hospital records (minimum dataset) between 1998 and 2005. Prevalence rates and the risk of having Alzheimer's disease, Parkinson's disease, multiple sclerosis and suicide were significantly higher in districts with greater pesticide use as compared to those with lower pesticide use. The multivariate analyses showed that the population living in areas with high pesticide use had an increased risk for Alzheimer's disease and suicide attempts and that males living in these areas had increased risks for polyneuropathies, affective disorders and suicide attempts. In conclusion, this study supports and extends previous findings and provides an indication that environmental exposure to pesticides may affect the human health by increasing the incidence of certain neurological disorders at the level of the general population.


The disparity in hesitancy toward COVID-19 vaccination between older individuals in nursing homes and those in the community in Taizhou, China.
Older individuals are priority coronavirus disease 2019 (COVID-19) vaccine recipients. Our aim was to investigate the prevalence of and factors influencing vaccine hesitancy in older individuals living in nursing homes and communities. A self-administered COVID-19 vaccine hesitancy survey was conducted from September 2021 to December 2021 among people aged ≥ 60 years in eight nursing homes (382 participants) and the community (112 participants) in Taizhou, China. The response rate was 72.1% (382/530) for older adults in nursing homes and 68.7% (112/163) for older adults in the community. We found that 58.1% of the older individuals in nursing homes and 36.6% of those in the community were hesitant to receive the COVID-19 vaccine and that there was a statistically significant difference (P < 0.001). Multiple logistic regression results indicated that the main factors influencing hesitation among the older individuals in nursing homes were being male (Odds Ratio (OR) = 1.67, 95% Confidence Interval (CI): 1.01-2.76); their cognitive level, including having a high perceived risk of COVID-19 infection (OR = 3.06, 95% CI: 1.73-5.43) or the perception of low vaccine safety (OR = 3.08, 95% CI: 1.545- 6.145); anxiety (OR = 3.43, 95% CI: 1.96-5.99); and no previous influenza vaccination (OR = 1.82, 95% CI: 1.13-2.93); whereas those for older individuals in the community were comorbid chronic diseases (OR = 3.13, 95% CI: 1.11- 8.78) and community workers not recommending the vaccine (OR = 8.223, 95% CI: 1.77-38.27). The proportion of older individuals in nursing homes who were hesitant to receive the COVID-19 vaccine was significantly higher than for older individuals in the community. Targeted measures should be implemented to reduce vaccine hesitancy and improve vaccination rates in response to the special environment of nursing homes and the characteristics of this population.


Community walking in people with Parkinson's disease.
People with Parkinson's disease often have walking difficulty, and this is likely to be exacerbated while walking in places in the community, where people are likely to face greater and more varied challenges. This study aims to understand the facilitators and the barriers to walking in the community perceived by people with Parkinson's disease. This qualitative study involved 5 focus groups (n = 34) of people with Parkinson's disease and their partners residing in metropolitan and rural regions in Queensland, Australia. Results found that people with PD reported to use internal personal strategies as facilitators to community walking, but identified primarily external factors, particularly the environmental factors as barriers. The adoption of strategies or the use of facilitators allows people with Parkinson's disease to cope so that participants often did not report disability.


Transforming growth factor β1 and Fas ligand synergistically enhance immune tolerance in dendritic cells in liver transplantation.
Long-term survival of patients following liver transplantation can be achieved by application of genetically modified, immune tolerogenic immature dendritic cells (imDCs) to overcome allograft-induced acute cellular rejection, a major cause of death. In this study, using a rat model of liver transplantation, we determined whether cotransfection of transforming growth factor β1 (TGF-β1) and Fas ligand (FasL) in imDCs synergistically enhances immune tolerance. We first determined the immune tolerogenic effects of TGF-β1 and FasL independently or together in imDCs by measuring the levels of CD86 and CD80 and by assessing T-cell proliferation using mixed lymphocyte reaction tests. Next, a rat model of liver transplantation, in which dark agouti and Lewis rats treated with DCs exogenously expressing TGF-β1 and/or FasL served as donors and recipients, respectively, was used to examine TGF-β1/FasL-induced immune tolerance. Specifically, we assessed the Banff rejection activity index (RAI), liver functions (alanine transaminase and total bilirubin levels), serum levels of interleukin (IL)-1, IL-10, and IL-12, apoptosis by TUNEL, and posttransplant survival. TGF-β1/FasL cotransfection of imDCs resulted in greater reduction of CD85 and CD80 expression and T-cell proliferation than a monotransfection. Cotransfected imDCs also showed reduced RAI scores, decreased plasma alanine transaminase and total bilirubin, altered cytokine levels, increased apoptosis, and prolonged survival than monotransfected imDCs in liver-allografted rats. By enhancing immune tolerance, reducing liver damage, and achieving long-term postsurgery survival, TGF-β1/FasL cotransfection of imDCs may prove more beneficial for patients undergoing liver transplantation.


Conformational dynamics of bacterial trigger factor in apo and ribosome-bound states.
The chaperone trigger factor (TF) binds to the ribosome exit tunnel and helps cotranslational folding of nascent chains (NC) in bacterial cells and chloroplasts. In this study, we aim to investigate the functional dynamics of fully-atomistic apo TF and its complex with 50S. As TF accomodates a high percentage of charged residues on its surface, the effect of ionic strength on TF dynamics is assessed here by performing five independent molecular dynamics (MD) simulations (total of 1.3 micro-second duration) at 29 mM and 150 mM ionic strengths. At both concentrations, TF exhibits high inter- and intra-domain flexibility related to its binding (BD), core (CD), and head (HD) domains. Even though large oscillations in gyration radius exist during each run, we do not detect the so-called 'fully collapsed' state with both HD and BD collapsed upon the core. In fact, the extended conformers with relatively open HD and BD are highly populated at the physiological concentration of 150 mM. More importantly, extended TF snapshots stand out in terms of favorable docking onto the 50S subunit. Elastic network modeling (ENM) indicates significant changes in TF's functional dynamics and domain decomposition depending on its conformation and positioning on the 50S. The most dominant slow motions are the lateral sweeping and vertical opening/closing of HD relative to 50S. Finally, our ENM-based efficient technique -ClustENM- is used to sample atomistic conformers starting with an extended TF-50S complex. Specifically, BD and CD motions are restricted near the tunnel exit, while HD is highly mobile. The atomistic conformers generated without an NC are in agreement with the cryo-EM maps available for TF-ribosome-NC complex.


Chemical constituents and bioactivities of the plants of genus Flemingia Roxb. et Ait. (Leguminosae).
The genus Flemingia Roxb. et Ait. (Leguminosae) has been used for disease prevention and therapy in China since ancient times. So the material basis of the pharmacological activity in the genus Flemingia should be clear for how to use this kind of traditional Chinese medicines more reasonably in pharmacology. Therefore, this review gives an account of the current knowledge on the chemical constituents, biological activities and pharmacological properties of the plants of the genus. Several different classes of compounds were previously isolated, which the main groups are flavones, particularly prenylated flavones, and triterpenes accompanied with sterols, anthraquinones, and others. The names and structures of the chemical constituents are given in this review. In addition, the pharmacological effects of the extracts and individual compounds (mainly for flavones) derived from the genus plants have been found, including neuroprotection, anti-inflammation, anti-oxidation, cytotoxicity, hormone-like effects, antimicrobial activities, and so on.


Donor origin of circulating endothelial progenitors after allogeneic bone marrow transplantation.
Endothelial cell precursors circulate in blood and express antigens found on hematopoietic stem cells, suggesting that such precursors might be subject to transplantation. To investigate, we obtained adherence-depleted peripheral blood mononuclear cells from 3 individuals who had received a sex-mismatched allogeneic bone marrow transplant (BMT) and cultured the cells on fibronectin-coated plates with endothelial growth factors. The phenotype of the spindle-shaped cells that emerged in culture was characterized by immunofluorescent staining, and the origin of the cells was determined using a polymerase chain reaction (PCR)-based assay for polymorphic short tandem repeats (STRs). The cells manifested a number of endothelial characteristics-such as von Wlllebrand factor, CD31, and Flk-1/KDR expression; Bandeiraea simplicifolia lectin 1 binding; and acetylated low-density lipoprotein uptake-but lacked expression of certain markers of activation or differentiation, including intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and the epitope for the anti-endothelial cell antibody P1H12. For each patient and at all time points studied (ranging from 5 to 52 months after transplantation), STR-PCR analysis showed that cultured cells and nucleated blood cells came exclusively from the bone marrow donor. These results demonstrate that circulating endothelial progenitors are both transplantable and capable of long-term repopulation of human allogeneic BMT recipients.


Alcohol consumption and the long-term incidence of cataract and cataract surgery: the Blue Mountains Eye Study.
To assess whether alcohol consumption is associated with the long-term incidence of cataract or cataract surgery. Population-based prospective cohort study. A total of 3654 persons aged 49+ years were examined at baseline and 2564 were re-examined after 5 and/or 10 years. Lens photographs were taken at each visit and assessed using the Wisconsin Cataract Grading System by masked graders. An interviewer-administered questionnaire was used to collect information on alcohol consumption. No significant associations were observed between alcohol consumption and long-term risk of nuclear, cortical, and posterior subcapsular cataract. However, after adjusting for age, gender, smoking, diabetes, myopia, socioeconomic status, and steroid use, total alcohol consumption of over 2 standard drinks per day was associated with a significantly increased likelihood of cataract surgery, when compared to total daily alcohol consumption of 1 to 2 standard drinks (adjusted odds ratio [OR] 2.10, 95% confidence interval [CI] 1.16-3.81). Abstinence from alcohol was also associated with increased likelihood of cataract surgery when compared to a total alcohol consumption of 1 to 2 standard drinks per day (adjusted OR 2.36, 95% CI 1.25-4.46). A U-shaped association of alcohol consumption with the long-term risk of cataract surgery was found in this older cohort: moderate consumption was associated with 50% lower cataract surgery incidence, compared either to abstinence or heavy alcohol consumption.


Effect of bromocriptine and pergolide on pituitary tumor size and serum prolactin.
Forty-two patients with elevated serum prolactin were treated in a randomized, open-label trial with the conventional ergot bromocriptine, or a new ergot pergolide. Before treatment, the patients underwent thorough endocrine evaluation and computed tomographic scan. All patients had prolactin levels greater than 25 ng/ml, and 27 patients had a pituitary mass. Follow-up studies performed after 6 months of treatment showed both drugs effectively reduced prolactin levels to normal, though pergolide effects were more rapid. There was no change in the contents of the pituitary fossa in the 10 patients with hyperprolactinemia but without pituitary mass. Sixty percent of patients with pituitary mass had diminution of tumor size. Pergolide appears to be an effective medical treatment for hyperprolactinemia and pituitary tumor and offers a possible alternative to bromocriptine and surgical treatment.


Multifactorial analysis of conditional reprogramming of human keratinocytes.
Co-culture of human primary epithelial cells with irradiated 3T3 fibroblast feeder cells (J2 cells) and the Rho kinase inhibitor Y-27632 (Y) allows for the unrestricted growth of cells of epithelial origin by the process termed conditional reprogramming. To better understand the nature of the signaling processes associated with conditionally reprogrammed cells, the effect of the two critical components of the co-culture conditions, J2 cells and Y, on the growth of human foreskin keratinocytes (HFKs) was evaluated by gene expression profiling, reverse-phase protein arrays and siRNA screening. J2 cells and Y acted cooperatively to down-regulate differentiation, and upregulate proliferation and cell adhesion, including increased pT308Akt and pERK, and reduced TGF-β pathway signaling. These findings establish a mechanistic basis for the unlimited growth potential of human epithelial cells that will be invaluable to assess the effect of genetic changes in pathologic tissues and their response to therapeutic agents.


Molecular mechanisms underpinning phosphorus-use efficiency in rice.
Orthophosphate (H2 PO4- , Pi) is an essential macronutrient integral to energy metabolism as well as a component of membrane lipids, nucleic acids, including ribosomal RNA, and therefore essential for protein synthesis. The Pi concentration in the solution of most soils worldwide is usually far too low for maximum growth of crops, including rice. This has prompted the massive use of inefficient, polluting, and nonrenewable phosphorus (P) fertilizers in agriculture. We urgently need alternative and more sustainable approaches to decrease agriculture's dependence on Pi fertilizers. These include manipulating crops by (a) enhancing the ability of their roots to acquire limiting Pi from the soil (i.e. increased P-acquisition efficiency) and/or (b) increasing the total biomass/yield produced per molecule of Pi acquired from the soil (i.e. increased P-use efficiency). Improved P-use efficiency may be achieved by producing high-yielding plants with lower P concentrations or by improving the remobilization of acquired P within the plant so as to maximize growth and biomass allocation to developing organs. Membrane lipid remodelling coupled with hydrolysis of RNA and smaller P-esters in senescing organs fuels P remobilization in rice, the world's most important cereal crop.


Localizing the RPGR protein along the cilium: a new method to determine efficacies to treat RPGR mutations.
Retinal dystrophies constitute a group of clinically and genetically heterogeneous diseases that cause visual impairment. As treatments are not readily available, readout assays performed in patient-derived cells can aid in the development and comparative analysis of therapeutic approaches. We describe a new method with which the localization of the retinitis pigmentosa GTPase regulator (RPGR) protein along the cilium can be used as a measure for treatment efficacy. In a patient-derived fibroblast cell line, we found that the RPGR protein is mislocalized along the ciliary axoneme. The patient carried a point mutation that leads to skipping of RPGR exon 10. We confirmed that this skipping is causative for the impaired localization of RPGR using a U7 small nuclear RNA (U7snRNA)-based antisense approach in control cells. Treatment of the patient-derived fibroblasts with therapeutic U1snRNA significantly corrected the proteins' mislocalization. In this proof of principle study, we show that detecting the RPGR protein along the cilium provides a reliable and quantifiable readout assay to evaluate the efficacy of therapies intended to correct or silence RPGR gene mutations. This method opens the possibility to compare different therapeutic agents, and thus facilitate the identification of treatment options for the clinically and molecularly complex RPGR-associated diseases.


Greater Visual Working Memory Capacity for Visually Matched Stimuli When They Are Perceived as Meaningful.
Almost all models of visual working memory-the cognitive system that holds visual information in an active state-assume it has a fixed capacity: Some models propose a limit of three to four objects, where others propose there is a fixed pool of resources for each basic visual feature. Recent findings, however, suggest that memory performance is improved for real-world objects. What supports these increases in capacity? Here, we test whether the meaningfulness of a stimulus alone influences working memory capacity while controlling for visual complexity and directly assessing the active component of working memory using EEG. Participants remembered ambiguous stimuli that could either be perceived as a face or as meaningless shapes. Participants had higher performance and increased neural delay activity when the memory display consisted of more meaningful stimuli. Critically, by asking participants whether they perceived the stimuli as a face or not, we also show that these increases in visual working memory capacity and recruitment of additional neural resources are because of the subjective perception of the stimulus and thus cannot be driven by physical properties of the stimulus. Broadly, this suggests that the capacity for active storage in visual working memory is not fixed but that more meaningful stimuli recruit additional working memory resources, allowing them to be better remembered.


Perceptual awareness and active inference.
Perceptual awareness depends upon the way in which we engage with our sensorium. This notion is central to active inference, a theoretical framework that treats perception and action as inferential processes. This variational perspective on cognition formalizes the notion of perception as hypothesis testing and treats actions as experiments that are designed (in part) to gather evidence for or against alternative hypotheses. The common treatment of perception and action affords a useful interpretation of certain perceptual phenomena whose active component is often not acknowledged. In this article, we start by considering Troxler fading - the dissipation of a peripheral percept during maintenance of fixation, and its recovery during free (saccadic) exploration. This offers an important example of the failure to maintain a percept without actively interrogating a visual scene. We argue that this may be understood in terms of the accumulation of uncertainty about a hypothesized stimulus when free exploration is disrupted by experimental instructions or pathology. Once we take this view, we can generalize the idea of using bodily (oculomotor) action to resolve uncertainty to include the use of mental (attentional) actions for the same purpose. This affords a useful way to think about binocular rivalry paradigms, in which perceptual changes need not be associated with an overt movement.


Transgenic analysis of the atrialnatriuretic factor (ANF) promoter: Nkx2-5 and GATA-4 binding sites are required for atrial specific expression of ANF.
The atrial natriuretic factor (ANF) gene is initially expressed throughout the myocardial layer of the heart, but during subsequent development, expression becomes limited to the atrial chambers. Mouse knockout and mammalian cell culture studies have shown that the ANF gene is regulated by combinatorial interactions between Nkx2-5, GATA-4, Tbx5, and SRF; however, the molecular mechanisms leading to chamber-specific expression are currently unknown. We have isolated the Xenopus ANF promoter in order to examine the temporal and spatial regulation of the ANF gene in vivo using transgenic embryos. The mammalian and Xenopus ANF promoters show remarkable sequence similarity, including an Nkx2-5 binding site (NKE), two GATA sites, a T-box binding site (TBE), and two SRF binding sites (SREs). Our transgenic studies show that mutation of either SRE, the TBE or the distal GATA element, strongly reduces expression from the ANF promoter. However, mutations of the NKE, the proximal GATA, or both elements together, result in relatively minor reductions in transgene expression within the myocardium. Surprisingly, mutation of these elements results in ectopic ANF promoter activity in the kidneys, facial muscles, and aortic arch artery-associated muscles, and causes persistent expression in the ventricle and outflow tract of the heart. We propose that the NKE and proximal GATA elements serve as crucial binding sites for assembly of a repressor complex that is required for atrial-specific expression of the ANF gene.


Leucaena and dried poultry waste improve the performance of West African Dwarf sheep on a grass diet.
This study investigated the effects on digestibility and growth when West African Dwarf (WAD) sheep were fed a basal diet of Tripsacum laxum with Leucaena leucocephala or dried poultry waste as supplement. Fifteen WAD sheep (12 rams and 3 ewes) were randomly allocated to three dietary treatments of 5 animals each, namely T1-basal diet of chopped T. laxum (control), T2-basal diet plus dried poultry waste, and T3-basal diet plus L. leucocephala. Animals had access to drinking water and a mineral mix ad libitum. They were weighed weekly after a 2-week adaptation period, for a duration of 12 weeks. At the end of the feeding trial, three rams randomly selected from each treatment group were used for the digestibility study. Results revealed that average daily intake of L. leucocephala (350.0 ± 0.3 g/animal) was higher than that of dried poultry waste (260.0 ± 0.1 g/animal). The supplemented groups, T2 and T3, gained 21.4 and 31.0 g daily respectively, while animals of the control group (T1) lost 6.0 g daily. There was a significant difference (P<0.01) in dry matter intake between the control and supplemented groups, with T2 recording the highest intake. Organic matter intake of treatment 3 was significantly (P<0.01) higher than that of T1 and T2. The differences in crude fibre (CF) ingestion between T2 and T1 as well as T3 and T1 were significant (P<0.01), with the highest ingestion of CF occurring in T1. The dry matter digestibility of the supplemented groups was significantly higher (P<0.05) than that of the control. The organic matter digestibility of T2 and T3, as well as T1 and T3 were significantly different (P<0.05), being highest in T3 (77.0 ± 2.1 %) and lowest in T2 (58.1 ± 1.0 %) It was concluded from the study that T. laxum can be better utilized in West African Dwarf sheep when supplemented with dried poultry waste or L. leucocephala.


Violence against female sex workers in Karnataka state, south India: impact on health, and reductions in violence following an intervention program.
Violence against female sex workers (FSWs) can impede HIV prevention efforts and contravenes their human rights. We developed a multi-layered violence intervention targeting policy makers, secondary stakeholders (police, lawyers, media), and primary stakeholders (FSWs), as part of wider HIV prevention programming involving >60,000 FSWs in Karnataka state. This study examined if violence against FSWs is associated with reduced condom use and increased STI/HIV risk, and if addressing violence against FSWs within a large-scale HIV prevention program can reduce levels of violence against them. FSWs were randomly selected to participate in polling booth surveys (PBS 2006-2008; short behavioural questionnaires administered anonymously) and integrated behavioural-biological assessments (IBBAs 2005-2009; administered face-to-face). 3,852 FSWs participated in the IBBAs and 7,638 FSWs participated in the PBS. Overall, 11.0% of FSWs in the IBBAs and 26.4% of FSWs in the PBS reported being beaten or raped in the past year. FSWs who reported violence in the past year were significantly less likely to report condom use with clients (zero unprotected sex acts in previous month, 55.4% vs. 75.5%, adjusted odds ratio (AOR) 0.4, 95% confidence interval (CI) 0.3 to 0.5, p < 0.001); to have accessed the HIV intervention program (ever contacted by peer educator, 84.9% vs. 89.6%, AOR 0.7, 95% CI 0.4 to 1.0, p = 0.04); or to have ever visited the project sexual health clinic (59.0% vs. 68.1%, AOR 0.7, 95% CI 0.6 to 1.0, p = 0.02); and were significantly more likely to be infected with gonorrhea (5.0% vs. 2.6%, AOR 1.9, 95% CI 1.1 to 3.3, p = 0.02). By the follow-up surveys, significant reductions were seen in the proportions of FSWs reporting violence compared with baseline (IBBA 13.0% vs. 9.0%, AOR 0.7, 95% CI 0.5 to 0.9 p = 0.01; PBS 27.3% vs. 18.9%, crude OR 0.5, 95% CI 0.4 to 0.5, p < 0.001). This program demonstrates that a structural approach to addressing violence can be effectively delivered at scale. Addressing violence against FSWs is important for the success of HIV prevention programs, and for protecting their basic human rights.


Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation.
Studies employing nonselective serotonin 5-HT(2C) receptor agonists and antagonists have implicated this receptor subtype in many of the actions of serotonin. To further examine the function of this receptor, 5-HT(2C) receptor mutant mice were generated; studies of these animals reveal pleiotropic neurobehavioural effects of the mutation. Three examples are described: (1) Mutants exhibit chronically elevated food intake and the development of an obesity syndrome during the 'middle-age' portion of their lifespan. Their potential utility as a model of human obesity is further indicated by their enhanced sensitivity to high-fat feeding, leading to the development of type 2 diabetes. (2) 5-HT(2C) receptor mutants also display infrequent and sporadic spontaneous seizures. Further studies suggested the presence of globally enhanced neuronal network excitability in these mice. These findings raise the possibility that 5-HT(2C) receptors mediate a role for serotonin in the suppression of seizure activity. (3) Behavioural analysis of mutant mice revealed abnormal performance in a spatial learning task and altered exploratory behaviour, associated with perturbed long-term potentiation restricted to the dentate gyrus perforant path synapse. Taken together, the above findings implicate 5-HT(2C) receptors in the serotonergic regulation of feeding, neuronal network excitability, and hippocampal function.


Quantitative salivary proteomic differences in oral chronic graft-versus-host disease.
Chronic graft-versus-host disease (cGVHD) is a severe immunological complication that occurs after allogeneic hematopoietic stem cell transplantation (HSCT). Although oral cGVHD occurs in >25% of cGVHD patients and leads to decreased quality of life, its etiology is poorly understood. The present retrospective cross-sectional analysis of oral cGVHD patients sought to (1) test the feasibility of liquid chromatography tandem mass spectrometry (LC-MS/MS) to identify protein biomarkers of oral cGVHD and (2) to gain a clearer understanding of salivary proteins impacted by oral cGVHD. Using unstimulated whole saliva, we compared pooled saliva from five patients with a diagnosis of moderate or severe oral cGVHD, with a gender-and age- matched pool of five cGVHD patients with no oral mucosal findings. LC-MS/MS was used to identify salivary proteins, followed by Ingenuity Pathway Analysis (IPA). Selected mass spectrometric findings, including lactotransferrin, lactoperoxidase, and albumin, were confirmed by targeted label-free quantification. LC-MS/MS led to confident identification of 180 proteins. Of these proteins, 102 changed in abundance at least 2 fold, including 12 proteins identified only in the No oral cGVHD group. Downregulation of ~0.4 fold was confirmed for both lactotransferrin and lactoperoxidase in Oral cGVHD saliva using targeted label-free quantification. IPA analysis implicated pathways involved in cellular metabolism and immunoregulation. Reduction of salivary lactoperoxidase, lactotransferrin, and several cysteine proteinase inhibitor family proteins suggests impaired oral antimicrobial host immunity in cGVHD patients. This shotgun proteomic analysis of oral cGVHD saliva using targeted label-free quantification of select proteins supports the use of mass spectrometry for future validation in a large patient population as noninvasive tests for screening, early detection, and monitoring of cGVHD.


Hydroboration and reductive amination of ketones and aldehydes with HBpin by a bench stable Pd(II)-catalyst.
A palladium(II) complex [(κ4-{1,2-C6H4(NCH-C6H4O)2}Pd] (1) supported by a dianionic salen ligand [1,2-C6H4(NCH-C6H4O)2]2- (L) was synthesised and used as a molecular pre-catalyst in the hydroboration of aldehydes and ketones. The molecular structure of Pd(II) complex 1 was established by single-crystal X-ray diffraction analysis. Complex 1 was tested as a competent pre-catalyst in the hydroboration of aldehydes and ketones with pinacolborane (HBpin) to produce corresponding boronate esters in excellent yields at ambient temperature under solvent-free conditions. Further, the complex 1 proved to be a competent catalyst in the reductive amination of aldehydes with HBpin and primary amines under mild and solvent-free conditions to afford a high yield (up to 97%) of corresponding secondary amines. Both protocols provided high conversion, superior selectivity and broad substrate scope, from electron-withdrawing to electron-donating and heterocyclic substitutions. A computational study based on density functional theory (DFT) revealed a reaction mechanism for Pd-catalysed hydroboration of carbonyl species in the presence of HBpin. The protocols also uncovered the dual role of HBpin in achieving the hydroboration reaction.


Neuropsychological deficits in probands from multiply-affected schizophrenic families.
This study was designed to determine if schizophrenics from families with more than one psychotic relative show more severe neuropsychological deficits than schizophrenics with only one psychotic relative, non-familial schizophrenics, and a group of matched normal controls. Eighty-one schizophrenic-spectrum patients were divided into three groups on the basis of the presence of psychotic disorder among first- and second-degree relatives. The three groups of schizophrenics and the normal controls were compared for differences on a brief neuropsychological testing battery. The four groups showed significant multivariate differences. Patients from multiply-affected families showed significantly greater neuropsychological dysfunction on measures of abstract concept formation, visuomotor-coordination, and attention than patients from families that had only one psychotic relative. Schizophrenics from low-density families showed more severe deficits in fine motor-control than non-familial schizophrenics. These data suggest that abnormalities in those frontal systems that are likely to mediate fine motor control and abstract concept formation may be related to the degree of familial loading for psychotic disorder.


Healthcare utilization at the end of life in people dying from amyotrophic lateral sclerosis: A retrospective cohort study using linked administrative data.
ALS is an incurable neurodegenerative disorder, with the recommendation that symptom management and palliative care start immediately or soon after diagnosis. However, little is known about healthcare utilization at the end of life in this patient group. To describe healthcare utilization at the end of life in patients who died from ALS. We performed a retrospective cohort study using population-level administrative databases. The description of healthcare utilization was based on (1) validated quality indicators for end-of-life care, and (2) the European Federation of Neurological Societies guidelines on the clinical management of ALS. We included all people who died from ALS in Belgium between 2010 and 2015 (using ICD-10 code G12.2). 1636 people died from ALS in Belgium between 2010 and 2015. The mean age at death was 71 years (SD11.3), and 56% were men. Specialized palliative care was used by 44% at some point in the last two years of life. In the last month of life, 13% received tube feeding, 48% received diagnostic testing, 41% were admitted to a hospital, and 25% were admitted to an emergency department. Medications were used mainly to treat pain (43%), insomnia and fatigue (33%) and thrombosis (32%); 39% used riluzole. Non-invasive ventilation was used by 18%. 39% died at home. Administrative data provide a valuable source to describe healthcare utilization in small populations such as ALS, but more clinical evidence is needed on the advantages and disadvantages initiating or terminating treatments at the end of life.


[Isolation of rat hepatocytes by a nonenzymatic method: detoxifying and respiratory activity].
A procedure for isolation of rat hepatocytes involving perfusion by EDTA, mechanical disaggregation of the liver and separation of intact cells from damaged ones by low-velocity centrifugation in isotonic sucrose media is described. A layer of a darker colour formed after separation contains hepatocytes with native plasma membrane characterized by respiratory activity and rate of biotransformation being close to the values obtained with cells isolated with the application of collagenase.


Interventions for smoking cessation in patients admitted with Acute Coronary Syndrome: a review.
Tobacco smoking contributes to about six million deaths per year and is predicted to increase in the future. Several pharmacological interventions are used for smoking cessation. Trials using nicotine replacement therapy (NRT) in acute coronary syndrome (ACS) showed inconclusive results. Furthermore, three trials using bupropion in patients admitted with ACS failed to show improvement in smoking cessation compared with placebo. Interestingly, only one trial using varenicline was successful in achieving smoking abstinence in the acute setting. With regard to behavioural interventions, a meta-analysis found that telephone counselling was successful in both the acute and stable settings, with greater effect in the acute setting. The best results for smoking cessation were found in trials that used a combination of pharmacological and behavioural interventions. The objective of this report is to review the results of studies on interventions used for smoking cessation after an ACS.


Troponin T levels and risk of 30-day outcomes in patients with the acute coronary syndrome: prospective verification in the GUSTO-IV trial.
A third-generation troponin T assay with improved precision and a lower detection limit has been developed. However, the appropriate cutoff for identifying patients with the acute coronary syndrome who are at low risk of subsequent mortality has not been established. A retrospective evaluation of data from the Fragmin and fast Revascularization during InStability in Coronary artery disease II (FRISC-II) trial suggested that a cutoff below 0.1 microg/L for troponin T levels might be more useful in risk stratification. A prospective validation of two cutoff levels (0.03 microg/L and 0.01 microg/L) was performed in 7115 patients with non-ST-elevation acute coronary syndrome from the Global Utilization of Strategies To open Occluded arteries IV (GUSTO-IV) trial. Patients with troponin T levels >0.1 microg/L had greater 30-day mortality (5.5% [201/3679]) than did those with levels <or=0.1 microg/L (2.2% [75/3436], P <0.001). A cutoff value of 0.03 microg/L provided better discrimination between high and low risk: 5.1% (234/4552) versus 1.6% (42/2563). However, a cutoff value at the lower limit of detection, 0.01 microg/L, provided the best discrimination: 5.0% (254/5123) versus 1.1% (22/1992) (P<0.001). This cutoff level had the highest negative predictive value; it also discriminated best for the combined endpoint of death and myocardial infarction. Using a cutoff of <or=0.01 microg/L for the third-generation troponin T assay, the detection level of the assay, is useful for identifying patients with the acute coronary syndrome who are at low risk of subsequent mortality.


Emergence of a novel lineage containing a prophage in emm/M3 group A Streptococcus associated with upsurge in invasive disease in the UK.
A sudden increase in invasive Group A Streptococcus (iGAS) infections associated with emm/M3 isolates during the winter of 2008/09 prompted the initiation of enhanced surveillance in England. In order to characterise the population of emm/M3 GAS within the UK and determine bacterial factors that might be responsible for this upsurge, 442 emm/M3 isolates from cases of invasive and non-invasive infections during the period 2001-2013 were subjected to whole genome sequencing. MLST analysis differentiated emm/M3 isolates into three sequence types (STs): ST15, ST315 and ST406. Analysis of the whole genome SNP-based phylogeny showed that the majority of isolates from the 2008-2009 upsurge period belonged to a distinct lineage characterized by the presence of a prophage carrying the speC exotoxin and spd1 DNAase genes but loss of two other prophages considered typical of the emm/M3 lineage. This lineage was significantly associated with the upsurge in iGAS cases and we postulate that the upsurge could be attributed in part to expansion of this novel prophage-containing lineage within the population. The study underlines the importance of prompt genomic analysis of changes in the GAS population, providing an advanced public health warning system for newly emergent, pathogenic strains.


Plasma near-infrared spectroscopy for diagnosis of idiopathic Parkinson's disease: the SPIN-PD study.
There are no established chemical biomarkers of idiopathic Parkinson's disease (PD). The results of a prior metabolomics-based biomarker study suggested that near-infrared spectroscopy of blood plasma samples may distinguish idiopathic PD from neurologically normal controls. Near-infrared spectroscopy was used to detect and quantify substrate modifications in blood plasma samples derived from 71 PD subjects enrolled in the PostCEPT observational study and 68 normal control subjects. Near-infrared spectra values were significantly higher in the PD group compared with the control group when adjusted for age and gender (PD: adjusted mean 0.49 [95% CI: 0.45-0.53]; control: adjusted mean 0.40 [95% CI: 0.36-0.44]; p = 0.004, multiple regression). Near-infrared spectra of blood plasma in early-stage idiopathic PD differ from those of non-neurological control subjects. However, the degree of overlap between the groups limits the use of this technique in its present form as a PD biomarker for routine clinical practice.


Epileptic and developmental disorders of the speech cortex: ligand/receptor interaction of wild-type and mutant SRPX2 with the plasminogen activator receptor uPAR.
Mutations in SRPX2 (Sushi-Repeat Protein, X-linked 2) cause rolandic epilepsy with speech impairment (RESDX syndrome) or with altered development of the speech cortex (bilateral perisylvian polymicrogyria). The physiological roles of SRPX2 remain unknown to date. One way to infer the function of SRPX2 relies on the identification of the as yet unknown SRPX2 protein partners. Using a combination of interactome approaches including yeast two-hybrid screening, co-immunoprecipitation experiments, cell surface binding and surface plasmon resonance (SPR), we show that SRPX2 is a ligand for uPAR, the urokinase-type plasminogen activator (uPA) receptor. Previous studies have shown that uPAR(-/-) knock-out mice exhibited enhanced susceptibility to epileptic seizures and had brain cortical anomalies consistent with altered neuronal migration and maturation, all features that are reminiscent to the phenotypes caused by SRPX2 mutations. SPR analysis indicated that the p.Y72S mutation associated with rolandic epilepsy and perisylvian polymicrogyria, led to a 5.8-fold gain-of-affinity of SRPX2 with uPAR. uPAR is a crucial component of the extracellular plasminogen proteolysis system; two more SRPX2 partners identified here, the cysteine protease cathepsin B (CTSB) and the metalloproteinase ADAMTS4, are also components of the extracellular proteolysis machinery and CTSB is a well-known activator of uPA. The identification of functionally related SRPX2 partners provides the first and exciting insights into the possible role of SRPX2 in the brain, and suggests that a network of SRPX2-interacting proteins classically involved in the proteolytic remodeling of the extracellular matrix and including uPAR participates in the functioning, in the development and in disorders of the speech cortex.


CPG15 regulates synapse stability in the developing and adult brain.
Use-dependent selection of optimal connections is a key feature of neural circuit development and, in the mature brain, underlies functional adaptation, such as is required for learning and memory. Activity patterns guide circuit refinement through selective stabilization or elimination of specific neuronal branches and synapses. The molecular signals that mediate activity-dependent synapse and arbor stabilization and maintenance remain elusive. We report that knockout of the activity-regulated gene cpg15 in mice delays developmental maturation of axonal and dendritic arbors visualized by anterograde tracing and diolistic labeling, respectively. Electrophysiology shows that synaptic maturation is also delayed, and electron microscopy confirms that many dendritic spines initially lack functional synaptic contacts. While circuits eventually develop, in vivo imaging reveals that spine maintenance is compromised in the adult, leading to a gradual attrition in spine numbers. Loss of cpg15 also results in poor learning. cpg15 knockout mice require more trails to learn, but once they learn, memories are retained. Our findings suggest that CPG15 acts to stabilize active synapses on dendritic spines, resulting in selective spine and arbor stabilization and synaptic maturation, and that synapse stabilization mediated by CPG15 is critical for efficient learning.


Spectral analysis of arterial blood pressure and cerebral blood flow velocity during supine rest and orthostasis.
This study evaluates the effect of orthostasis on the low frequency (LF, 0.04 to 0.15 Hz) fluctuations in the blood flow velocity of the middle cerebral artery (MCAFV) in relation to its arterial blood pressure (ABP) equivalent to further define and quantify this relationship in cerebrovascular regulation. Spectral analysis was performed on 22 healthy subjects during supine rest and head-up tilt. The power in the LF range can be used to quantify the LF fluctuations, and four types of LF power data could be obtained for each individual: LF power of supine MCAFV, LF power of supine ABP, LF power of tilt MCAFV, and LF power of tilt ABP. By comparing LF power of MCAFV with LF power of ABP, two power ratios could be generated to describe the flow-pressure relationship during supine rest and head-up tilt, respectively, supine power ratio (LF power of supine MCAFV/ LF power of supine ABP) and tilt power ratio (LF power of tilt MCAFV/ LF power of tilt ABP). In addition, an index for dynamic autoregulation in response to orthostasis can be calculated from these two power ratios (tilt power ratio/supine power ratio). The authors found that this index was dependent on the extent of orthostatic MCAFV changes, and the dependency could be mathematically expressed (r = 0.61, P = .0001), suggesting its involvement in cerebrovascular regulation. Moreover, these data further support the previous observation that the LF fluctuations of MCAFV might result from modulation of its ABP equivalent, and the modulation effect could be quantified as the power ratio (LF power of MCAFV/ LF power of ABP). These observations could be an important step toward further insight into cerebrovascular regulation, which warrants more research in the future.


[On the mechanism of noopept action: decrease in activity of stress-induced kinases and increase in expression of neutrophines].
The influence of noopept (N-phenylacetyl-L-prolylglycine ethyl ester, GVS-111)--a drug combining the nootrope and neuroprotector properties--on the activity of mitogen-activated protein kinases (MAPKs) and the level of NGF and BDNF gene and protein expression in the frontal cortex, hippocampus, and hypothalamus has been studied in rats. Under conditions of chronic administration (28 days, 0.5 mg/day, i.p.), noopept decreased the activity of stress-induced kinases (SAPK/JNK 46/54 and pERK1/2) in rat hippocampus and increases the level of mRNA of the BDNF gene in both hypothalamus and hippocampus. The content of BDNF protein in the hypothalamus was also somewhat increased. In the context of notions about the activation of stress-induced kinases, as an important factor of amyloidogenesis and tau-protein deposition in brain tissue, and the role of deficiency of the neurotrophic factors in the development of neurodegenerative processes, the observed decrease in the activity of stress-activated MAPKs and increased expression of BDNF as a result of noopept administration suggest thatthis drug hasaspecific activity withrespect to some pathogenetic mechanisms involved in the Alzheimer disease.


Experience Corps: design of an intergenerational program to boost social capital and promote the health of an aging society.
Population aging portends a crisis of resources and values. Desired solutions could include intergenerational strategies to harness the untapped potential of older adults to address societal needs and to generate health improvements for older adults. Despite the desire of many older adults to remain socially engaged and productive, the creation of productive roles has lagged. This report describes the conceptual framework and major design features of a new model of health promotion for older adults called Experience Corps. Experience Corps operates at, and leads to benefits across, multiple levels, including individuals, schools, and the larger community. At the individual level, we propose a model based on Erikson's concept of generativity to explain how and why Experience Corps works. At the level of schools, we propose a parallel model based on social capital. Experience Corps is a volunteer service program designed to improve the lives of urban children and to yield health improvement for older persons. It illustrates how population aging creates new opportunities to address difficult social problems. This article explores how the linkage of concepts at multiple levels motivates a potentially cost-effective, feasible, and high-impact program.


Oral nicotine in treatment of primary sclerosing cholangitis: a pilot study.
Currently, no accepted medical therapy for patients with primary sclerosing cholangitis (PSC) is available. Case-control studies have shown an inverse association between PSC and smoking behavior, suggesting that nicotine might have a beneficial effect in PSC. The aim of this study was to evaluate the safety and estimate the efficacy of oral nicotine in the treatment of PSC. Eight PSC patients who had never smoked received oral nicotine at a maximum dose of 6 mg four times a day for up to one year. Liver biochemistries and plasma cotinine levels were determined at entry and at three-month intervals during the study duration. Five patients completed one year of treatment, but three of them had to temporarily reduce the dose due to side effects. One patient completed only four months of treatment due to dizziness and heart palpitations. Two patients completed only one month of treatment due to reactivation of colitis requiring corticosteroid therapy. No significant changes in liver biochemistries were noted during the treatment period despite a significant increase in plasma cotinine levels. In conclusion, oral nicotine seems to have no beneficial effects in the treatment of PSC, and it is frequently associated with side effects necessitating permanent drug cessation.


SET8 prevents excessive DNA methylation by methylation-mediated degradation of UHRF1 and DNMT1.
Faithful inheritance of DNA methylation across cell division requires DNMT1 and its accessory factor UHRF1. However, how this axis is regulated to ensure DNA methylation homeostasis remains poorly understood. Here we show that SET8, a cell-cycle-regulated protein methyltransferase, controls protein stability of both UHRF1 and DNMT1 through methylation-mediated, ubiquitin-dependent degradation and consequently prevents excessive DNA methylation. SET8 methylates UHRF1 at lysine 385 and this modification leads to ubiquitination and degradation of UHRF1. In contrast, LSD1 stabilizes both UHRF1 and DNMT1 by demethylation. Importantly, SET8 and LSD1 oppositely regulate global DNA methylation and do so most likely through regulating the level of UHRF1 than DNMT1. Finally, we show that UHRF1 downregulation in G2/M by SET8 has a role in suppressing DNMT1-mediated methylation on post-replicated DNA. Altogether, our study reveals a novel role of SET8 in promoting DNA methylation homeostasis and identifies UHRF1 as the hub for tuning DNA methylation through dynamic protein methylation.


Association of e-Cigarette Use and Postpartum Depression: Pregnancy Risk Assessment Monitoring System 2016-2019.
Background: Postpartum depression (PPD) is a prevalent public health concern. Combustible cigarette use is associated with increased risk of PPD. While electronic cigarette (e-cigarette) use during pregnancy is linked to increased risk of depressive symptoms during pregnancy, the relationship between e-cigarette use and PPD is not well understood. We sought to examine the association of e-cigarette use with PPD. Materials and Methods: Using Pregnancy Risk Assessment Monitoring System 2016-2019 data, unadjusted and adjusted logistic regression analyses for PPD were conducted via three analyses where e-cigarette use (any vs. none) was retrospectively self-reported (1) in past 2-year, (2) prepregnancy (i.e., 3 months before pregnancy), and (3) during pregnancy (i.e., last 3 months of pregnancy). We conducted an additional past 2-year e-cigarette use analysis excluding those who used combustible cigarette and/or hookah. Covariates included age, race, ethnicity, combustible cigarette, and/or hookah use, prenatal care during the last trimester, health insurance coverage during pregnancy, physical abuse during pregnancy, income, and survey type. Results: Only unadjusted odds ratios from past 2-year e-cigarette use (1.63, 95% confidence interval [CI]: 1.42-1.87) and past 2-year e-cigarette use excluding individuals with cigarette and/or hookah use (1.78, 95% CI: 1.30-2.38) were statistically associated with PPD. No adjusted analyses were statistically significant. Conclusion: Any e-cigarette use, as compared to no use, does not appear to be an independent risk factor of PPD, though it may be a useful clinical marker of increased risk of PPD. Future studies are warranted to advance our knowledge of impact of e-cigarette use on PPD.


Reduced expression of the G209A alpha-synuclein allele in familial Parkinsonism.
Missense mutations at the alpha-synuclein gene have been associated with familial parkinsonism. We report that the phenotype of a kindred (Family H) with autosomal dominant, levodopa-responsive parkinsonism maps to chromosomal region 4q21-23 and that affected members of this kindred harbor a previously reported mutation (G209A) in exon 4 of the alpha-synuclein gene. We assessed the expression of the G209A allele in lymphoblastoid cell lines established from 12 individuals heterozygous for the G209A allele. The expression of this allele is either absent or significantly reduced in 7 affected heterozygotes and in 3 asymptomatic heterozygotes who are older than the mean age at disease diagnosis for their generation. In contrast, it is expressed in 1 affected and 1 unaffected heterozygote. The unaffected heterozygote is younger than the mean age at disease diagnosis for their generation. The lack of or significantly reduced expression of the G209A allele in affected heterozygotes suggests that the timing of reduced expression may be critical for disease onset. If so, the parkinsonian phenotype may arise from haploinsufficiency at the alpha-synuclein gene at a time point before symptom onset. In conclusion, reduced alpha-synuclein gene expression may be important in the pathogenesis of parkinsonism.


Developing Behavioral Theory With the Systematic Integration of Community Social Capital Concepts.
Health behavior theories state that social environments influence health behaviors, but theories of how this occurs are relatively underdeveloped. This article systematically surveys community social capital concepts in health behavior literature and proposes a conceptual framework that integrates these concepts into existing behavioral theory. Fifty-three studies tested associations between community social capital concepts and physical activity (38 studies), smoking (19 studies), and diet (2 studies). Trustworthiness of community members was consistently associated with more health-promoting and less disease-promoting behaviors in 19 studies. Neighborly reciprocity showed mixed results in 10 studies. Reporting a good sense of community was associated with more physical activity in only 5 of 16 studies. Neighborhood collective efficacy, which includes social cohesion and informal social control, was inconsistently associated with behaviors in 22 studies. Behavioral social norms were associated with smoking and physical activity in 2 of 6 studies, and neighborhood modeling of physical activity was associated with increased activity in 12 of 17 studies, with 1 opposing result. This review identifies several community social capital-related concepts that are, at times, associated with both health-promoting and disease-promoting behaviors and often have no associations. Theory explains these findings by describing the relationships and interactions among these concepts. Using these findings, this article proposes a conceptual framework that integrates community social capital concepts into existing behavioral theory. Iterative empirically based theory development is needed to address these concepts, which affect behaviors. These results can also inform theoretically based community-based and socially tailored interventions.


Review. Indole-3-carbinol as a chemoprotective agent in breast and prostate cancer.
Assessment of the oral use of indole-3-carbinol (I3C) as a chemoprotective compound has not sufficiently considered the chemical instability of I3C. This review addresses the question of whether I3C is directly active in its own right or only serves as a precursor, with all of the biological responses coming from reaction products arising in culture media and in the presence of stomach acid. Because of the rapid conversion of I3C into its dimer. diindolylmethane (DIM), and trimers very little circulating I3C is present following oral use to effect a biological response. Reports of toxicity associated with oral use of I3C relate to unfavorable enzyme induction, which can be attributed to non-DIM reaction products. Because DIM provides a predictable, safer response than the mélange of compounds derived from I3C DIM should be regarded as the chemoprotective compound of choice.


Probabilistic sensitivity analysis methods for general decision models.
Probabilistic sensitivity analysis has previously been described for the special case of dichotomous decision trees. We now generalize these techniques for a wider range of decision problems. These methods of sensitivity analysis allow the analyst to evaluate the impact of the multivariate uncertainty in the data used in the decision model and to gain insight into the probabilistic contribution of each of the variables to the decision outcome. The techniques are illustrated using Monte Carlo simulation on a trichotomous decision tree. Application of these powerful tools permits the decision analyst to investigate the structure and limitations of more complex decision problems with inherent uncertainties in the data upon which the decisions are based. Probabilistic sensitivity measures can provide guidance into the allocation of resources to resolve uncertainty about critical components of medical decisions.


Promoter architectures in the yeast ribosomal expression program.
Ribosome biogenesis begins with the orchestrated expression of hundreds of genes, including the three large classes of ribosomal protein, ribosome biogenesis and snoRNA genes. Current knowledge about the corresponding promoters suggests the existence of novel class-specific transcriptional strategies and crosstalk between telomere length and cell growth control.


Robo2 acts in trans to inhibit Slit-Robo1 repulsion in pre-crossing commissural axons.
During nervous system development, commissural axons cross the midline despite the presence of repellant ligands. In Drosophila, commissural axons avoid premature responsiveness to the midline repellant Slit by expressing the endosomal sorting receptor Commissureless, which reduces surface expression of the Slit receptor Roundabout1 (Robo1). In this study, we describe a distinct mechanism to inhibit Robo1 repulsion and promote midline crossing, in which Roundabout2 (Robo2) binds to and prevents Robo1 signaling. Unexpectedly, we find that Robo2 is expressed in midline cells during the early stages of commissural axon guidance, and that over-expression of Robo2 can rescue robo2-dependent midline crossing defects non-cell autonomously. We show that the extracellular domains required for binding to Robo1 are also required for Robo2's ability to promote midline crossing, in both gain-of-function and rescue assays. These findings indicate that at least two independent mechanisms to overcome Slit-Robo1 repulsion in pre-crossing commissural axons have evolved in Drosophila.


Functional mechanism of the abscisic acid agonist pyrabactin.
Pyrabactin is a synthetic abscisic acid (ABA) agonist that selectively inhibits seed germination. The use of pyrabactin was pivotal in the identification of the PYR1/PYL/RCAR family (PYL) of proteins as the ABA receptor. Although they both act through PYL proteins, pyrabactin and ABA share no apparent chemical or structural similarity. It remains unclear how pyrabactin functions as an ABA agonist. Here, we report the crystal structure of pyrabactin in complex with PYL1 at 2.4 A resolution. Structural and biochemical analyses revealed that recognition of pyrabactin by the pocket residues precedes the closure of switch loop CL2. Structural comparison between pyrabactin- and ABA-bound PYL1 reveals a general principle in the arrangements of function groups of the two distinct ligands. The study provides a framework for the development of novel ABA agonists that may have applicable potentials in agriculture.


Undecylprodigiosin conjugated monodisperse gold nanoparticles efficiently cause apoptosis in colon cancer cells in vitro.
Bacterial pigment undecylprodigiosin (UP) was produced using Streptomyces sp. JS520 and conjugated to monodisperse gold nanoparticles (UP-Au). Both UP and UP-Au showed cytocidal activity towards melanoma (A375), lung carcinoma (A549), breast cancer (MCF-7) and colon cancer (HCT-116) cells, inducing apoptosis with IC50 values ranging from 0.4 to 4 μg ml-1. Unconjugated UP had a tendency to lose its activity over time and to change biophysical characteristics over pH. The loss of the pigment potency was overcome by conjugation with gold nanoparticles. UP-Au exhibited high stability over pH 3.8 to 7.4 and its activity remained unaffected in time. Nano-packing changed the mechanism of UP toxicity by converting the intracellular signals from a mitochondrial dependent to a mitochondrial independent apoptotic process. The availability of nonpyrogenic UP in high amounts, together with specific anticancer activity and improved stability in the complex with gold nanoparticles, presents a novel platform for further development of UP-Au complexes as an anticancer drug suitable for clinical applications.


Determination of spinosad at trace levels in bee pollen and beeswax with solid-liquid extraction and LC-ESI-MS.
This paper reports the use of a new LC method with a fused-core analytical column coupled to ESI-MS to determine residues of the biopesticide spinosad in bee pollen and beeswax. The method analyzes the active ingredients, spinosyns A and D, with a simple and efficient sample treatment (recovery between 90 and 105%) consisting of a solid-liquid extraction with acetone (bee pollen) or acetonitrile (beeswax). The method was validated in terms of selectivity, LOD, LOQ, linearity, and precision. The LOD and LOQ values ranged between 0.1-0.2 and 0.4-0.7 μg/kg, respectively. Moreover, the precision obtained within the linear concentration range (LOQ 500 μg/kg) was satisfactory (RSD lower than 5%). Finally, the proposed method was applied to analyze bee pollen and beeswax samples collected from apiaries located close to fruit orchards in two Spanish regions.


Comprehensive molecular characterization of clear cell renal cell carcinoma.
Genetic changes underlying clear cell renal cell carcinoma (ccRCC) include alterations in genes controlling cellular oxygen sensing (for example, VHL) and the maintenance of chromatin states (for example, PBRM1). We surveyed more than 400 tumours using different genomic platforms and identified 19 significantly mutated genes. The PI(3)K/AKT pathway was recurrently mutated, suggesting this pathway as a potential therapeutic target. Widespread DNA hypomethylation was associated with mutation of the H3K36 methyltransferase SETD2, and integrative analysis suggested that mutations involving the SWI/SNF chromatin remodelling complex (PBRM1, ARID1A, SMARCA4) could have far-reaching effects on other pathways. Aggressive cancers demonstrated evidence of a metabolic shift, involving downregulation of genes involved in the TCA cycle, decreased AMPK and PTEN protein levels, upregulation of the pentose phosphate pathway and the glutamine transporter genes, increased acetyl-CoA carboxylase protein, and altered promoter methylation of miR-21 (also known as MIR21) and GRB10. Remodelling cellular metabolism thus constitutes a recurrent pattern in ccRCC that correlates with tumour stage and severity and offers new views on the opportunities for disease treatment.


Circulating IgG Levels in SARS-CoV-2 Convalescent Individuals in Cyprus.
Long-term persistence and the heterogeneity of humoral response to SARS-CoV-2 have not yet been thoroughly investigated. The aim of this work is to study the production of circulating immunoglobulin class G (IgG) antibodies against SARS-CoV-2 in individuals with past infection in Cyprus. Individuals of the general population, with or without previous SARS-CoV-2 infection, were invited to visit the Biobank at the Center of Excellence in Biobanking and Biomedical Research of the University of Cyprus. Serum IgG antibodies were measured using the SARS-CoV-2 IgG and the SARS-CoV-2 IgG II Quant assays of Abbott Laboratories. Antibody responses to SARS-CoV-2 were also evaluated against participants' demographic and clinical data. All statistical analyses were conducted in Stata 16. The median levels of receptor binding domain (RBD)-specific IgG in 969 unvaccinated individuals, who were reportedly infected between November 2020 and September 2021, were 432.1 arbitrary units (AI)/mL (interquartile range-IQR: 182.4-1147.3). Higher antibody levels were observed in older participants, males, and those who reportedly developed symptoms or were hospitalized. The RBD-specific IgG levels peaked at three months post symptom onset and subsequently decreased up to month six, with a slower decay thereafter. IgG response to the RBD of SARS-CoV-2 is bi-phasic with considerable titer variability. Levels of IgG are significantly associated with several parameters, including age, gender, and severity of symptoms.


Role of Stem-Cell Transplantation in Leukemia Treatment.
Stem cells (SCs) play a major role in advanced fields of regenerative medicine and other research areas. They are involved in the regeneration of damaged tissue or cells, due to their self-renewal characteristics. Tissue or cells can be damaged through a variety of diseases, including hematologic and nonhematologic malignancies. In regard to this, stem-cell transplantation is a cellular therapeutic approach to restore those impaired cells, tissue, or organs. SCs have a therapeutic potential in the application of stem-cell transplantation. Research has been focused mainly on the application of hematopoietic SCs for transplantation. Cord blood cells and human leukocyte antigen-haploidentical donors are considered optional sources of hematopoietic stem-cell transplantation. On the other hand, pluripotent embryonic SCs and induced pluripotent SCs hold promise for advancement of stem-cell transplantation. In addition, nonhematopoietic mesenchymal SCs play their own significant role as a functional bone-marrow niche and in the management of graft-vs-host disease effects during the posttransplantation process. In this review, the role of different types of SCs is presented with regard to their application in SC transplantation. In addition to this, the therapeutic value of autologous and allogeneic hematopoietic stem-cell transplantation is assessed with respect to different types of leukemia. Highly advanced and progressive scientific research has focused on the application of stem-cell transplantation on specific leukemia types. We evaluated and compared the therapeutic potential of SC transplantation with various forms of leukemia. This review aimed to focus on the application of SCs in the treatment of leukemia.


CT appearance of unfused ossicles in the lumbar spine.
The computed tomographic (CT) appearance of unfused ossicles in the lumbar spine has had little attention. Unfused ossicles result from accessory ossification centers near the tip of the vertebral processes. Their main importance lies in distinguishing them from fractures. The CT appearance of unfused ossicles in the lumbar spine was correlated with that of the corresponding surface anatomy from a cadaver specimen. Thereafter, 100 consecutive CT studies were reviewed and two cases of presumedly unfused ossicles were found. The CT appearance of unfused ossicles and their differential diagnosis is discussed.


Cytotoxic Effect and TLC Bioautography-Guided Approach to Detect Health Properties of Amazonian Hedyosmum sprucei Essential Oil.
Bioautography has been used as rapid and easy strategy to detect and identify bioactive fractions/molecules in the never before investigated Hedyosmum sprucei Solms (Chloranthaceae) essential oil (EO). The antioxidant activity, performed through DPPH bioautographic assay and spectrophotometric evaluations (IC50 = 230 ± 10 µg/mL), seemed to be mainly due to α-cadinol and α-muurolol. (HP)TLC bioautography, focused on antimicrobial capacities, pointed out α-cadinol, α-muurolol, τ-muurolol, caryophyllene oxide, and methyleugenol as the most effective compounds against Staphylococcus aureus, considered as testing strain. Moreover, the microdilution method, assessed among a wide panel of microorganisms, revealed Listeria grayi and Staphylococcus aureus as the most sensitive among human tested strains and Clavibacter michiganensis among phytopathogens. GC-MS chemical profile showed that bioactive molecules represented only a small quantity of the whole EO: germacrene D (23.16%), β-caryophyllene (15.53%), δ-cadinene (5.50%), α-copaene (5.08%), and α-phellandrene (3.48%) were the main compounds, highlighting an uncommon composition among the genus Hedyosmum. Finally, H. sprucei EO was checked for cytotoxic potential against A549 (lung cancer) and MCF-7 (breast cancer) cell lines showing promising cytotoxic effects against both cell lines after 48 h (IC50 A549 = 44.05 ± 2.35 µg/mL; IC50 MCF-7 = 32.76 ± 4.92 µg/mL) and 72 h (IC50 A549 = 43.55 ± 2.80 µg/mL; IC50 MCF-7 = 33.64 ± 0.43 µg/mL).


Genetic basis of continuous variation in the levels and modular inheritance of pigmentation in cichlid fishes.
Variation in pigmentation type and levels is a hallmark of myriad evolutionary radiations, and biologists have long been fascinated by the factors that promote and maintain variation in coloration across populations. Here, we provide insights into the genetic basis of complex and continuous patterns of colour variation in cichlid fishes, which offer a vast diversity of pigmentation patterns that have evolved in response to both natural and sexual selection. Specifically, we crossed two divergent cichlid species to generate an F2 mapping population that exhibited extensive variation in pigmentation levels and patterns. Our experimental design is robust in that it combines traditional quantitative trait locus (QTL) analysis with population genomics, which has allowed us to move efficiently from QTL interval to candidate gene. In total, we detected 41 QTL and 13 epistatic interactions that underlie melanocyte- and xanthophore-based coloration across the fins and flanks of these fishes. We also identified 2 QTL and 1 interaction for variation in the magnitude of integration among these colour traits. This finding in particular is notable as there are marked differences both within and between species with respect to the complexity of pigmentation patterns. While certain individuals are characterized by more uniform 'integrated' colour patterns, others exhibit many more degrees of freedom with respect to the distribution of colour 'modules' across the fins and flank. Our data reveal, for the first time, a genetic basis for this difference. Finally, we implicate pax3a as a mediator of continuous variation in the levels of xanthophore-based colour along the cichlid flank.


SUMO-1 overexpression increases RbAp46 protein stability and suppresses cell growth.
The retinoblastoma suppressor (Rb)-associated protein 46 (RbAp46) is a nuclear protein of 46 kDa and contains four repeats that end with Trp-Asp (WD) residues. In this study, we reveal that the RbAp46 protein level upon SUMO-1 expression was increased. The increasing level of RbAp46 protein by SUMO-1 was not regulated at the transcriptional level. SUMO-1 does not affect the degradation of RbAp46. Co-localization of RbAp46 and SUMO-1 in the nuclei of stable NIH/3T3 cells harboring the inducible Ha-ras(Val12) oncogene (pSVlacOras) designated as 7-4, and protein-protein interaction between RbAp46 and SUMO-1 was also detected by co-immunoprecipitation in these cells. However, SUMO-l-related sumoylation was not involved in the modification of RbAp46. It is possibly that SUMO-1 acts through formation of complex with RbAp46 to stabilize RbAp46 protein. Overexpression of RbAp46 protein suppressed the NIH/3T3 cell growth induced by Ha-Ras(V12). SUMO-1 further enhances the suppression of cell growth through stabilization of RbAp46 protein. This is the first report to demonstrate that SUMO-1 can suppress Ras-related cell proliferation through stabilization of RbAp46 protein.


Molecular basis of the polydispersity of mucins: implications for the generation of saccharide diversity.
Secreted epithelial mucins are large macromolecules which exhibit extreme polydispersity, the molecular basis of which is not fully understood. We have obtained partial sequences of two genes (BSM1 and BSM2) coding for two distinct molecules. This is the first time that such closely-related genes have been identified for any mucin from an animal. We propose that a combination of multiple homologous genes, alternative splicing, differential glycosylation, and additional post-translational processing all contribute to the extreme polydispersity of mucins. The multiple domain structure and non-identical tandem repeats are also very important for the generation of the saccharide diversities of mucins.


Implantable Microfluidic Device: An Epoch of Technology.
Implantable microfluidic devices are milestones in developing devices that can measure parameters like ocular pressure and blood glucose level or deliver various components for therapeutic needs or behavioral modification. Researchers are currently focusing on the miniaturization of almost all its tools for a better healthcare platform. Implantable microfluidic devices are a combination of various systems including, but not limited to, microfluidic platforms, reservoirs, sensors, and actuators, implanted inside the body of a living entity (in vivo) with the purpose of directly or indirectly helping the entity. It is a multidisciplinary approach with immense potential in the area of the biomedical field. Significant resources are utilized for the research and development of these devices for various applications. The induction of an implantable microfluidic device into an animal would enable us to measure the responses without any repeated invasive procedures. Such data would help in the development of a better drug delivery profile. Implantable microfluidic devices with reservoirs deliver specific chemical or biological products to treat situations like cancers and diabetes. They can also deliver fluorophores for specific imaging inside the body. Implantable microfluidic devices help provide a microenvironment for various cell differentiation procedures. These devices know no boundaries, and this article reviews these devices based on their design and applications.


[Factors associated with blood loss during precipitate labor].
Precipitate labour is related to the appearance of postpartum haemorrhage due to posterior uterine atony. However, preventive measures that may be effective in reducing blood loss in this type of delivery are still unknown. Therefore, the objective of this study was to determine the risk factors associated with blood loss produced in precipitate labour. This was an observational, analytical retrospective cohort study based on a total sample of 742 women with vaginal delivery whose duration was less than 180 minutes, during the period 2010-2014. Dead foetus antepartum gestations, twin gestations and labour induction were excluded from the analysis. The main outcome variable was intrapartum blood loss. By making use of multivariate analysis, the risk factors independently associated with higher blood loss (g/dL) during precipitate labour were nulliparity (0.38; p<0.001), higher antepartum haemoglobin levels (0.23; p<0.001), higher gestational age (0.06; p<0.001), manual removal of the placenta (0.92; p=0.004) and the use of episiotomy (0.34; p<0.001). Performing active management emerges as a protective factor against increased blood loss (-0.23; p<0.001). The average loss of haemoglobin was 1.0 g/dL (standard deviation =0.92). The restriction in the practice of episiotomy and the use of active management can therefore be established as key measures that professionals can modify in order to reduce blood loss during precipitate labour and to improve these mothers' postpartum period. Key words. Haemoglobin. Precipitate labour.


Amoebic colitis presenting as ileocaecal intussusception - a rare case.
Ileocaecal intussusception is a common cause of acute intestinal obstruction presenting as a surgical emergency. We report a case of amoebic colitis in a 62 years old man complaining of acute colicky pain in the right iliac fossa, associated with a three-day history of constipation but no other gastrointestinal tract symptoms. There was rebound tenderness on palpation of the right iliac fossa. Ultrasound scans revealed free fluid and a loop within a loop image in this area. At laparotomy, we discovered an Ileocaecal intussusception associated with a gangrenous caecum. A right hemicolectomy was performed with satisfactory outcome. The final diagnosis of amoebic colitis was obtained post-operatively using serology and pathology. This rare aetiology must be considered in patients with acute pain in the right iliac fossa in the tropical regions. Tropical surgeons must be aware of this scenario before they label a case of intussusception as idiopathic. The identification and treatment of invasive amoebic infection may reduce the recurrence of idiopathic intussusception.


Predictors of gambling behaviors in Filipino Americans living in Honolulu or San Francisco.
This study compared the prevalence and predictors of gambling behaviors between Filipino Americans who live in San Francisco (S.F.) or Honolulu. Data from the 1998-1999 Filipino American Community Epidemiological Survey were used to answer two research questions: (1) What are the prevalence and types of gambling behaviors among Filipino Americans and (2) What are the protective/risk factors of heavy gambling for Filipino Americans in S.F. and Honolulu? Overall, S.F. Filipino Americans had a higher level of participation in gambling, and the odds of gambling increased among older age groups, males, those who were US-born, and those with more health problems. Multinomial logistic regression analyses revealed that factors associated with infrequent and regular gambling participation were different between the S.F. group (older, male, higher education) and Honolulu group (male, US-born, more health concerns). Differential gambling environments, i.e., wide open gambling in S.F. and the restrictive gambling in Honolulu, may contribute to gambling participation and predictors of risk gambling Filipino Americans living in Honolulu and S.F. Policy makers and health professionals need to be aware of these differences to serve this population more effectively.


Experiences of health and social professionals using care technologies with older adults during the COVID-19 pandemic: A qualitative study.
To investigate the perceptions and experiences of health and social care professionals concerning the use of technology for the care of older adults during the COVID-19 pandemic. A phenomenological qualitative, exploratory, and descriptive design using semi-structured interviews. Twenty Spanish health and social care workers in six Spanish cities between February and July 2021, during the COVID-19 pandemic. During the COVID-19 pandemic care workers have become more familiar with technology devices, but they also recognize certain barriers for the implementation of technology, mainly in nursing homes and homecare, related to concerns of lack of humanization and difficulties in accessing and using these devices. Politicians and social and healthcare managers should be aware of the benefits of techno-care, reducing the difficulties in implementing it and making more funding and further training available to care providers.


Randomized, double-blind, placebo-controlled study of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis: a categorical disability trend analysis.
The treatment effects of recent immunomodulatory therapies on disease progression in relapsing-remitting multiple sclerosis (MS) have been mostly established from 'confirmed progression' endpoints. However, the reliability of this outcome measure is poor and a significant proportion of patients may be erroneously classified. We previously proposed the area under disability/time curves to quantify in-trial disability changes, but although these have advantages, they lack information on the direction of change. We have therefore performed disease trend analyses and categorical classifications using serial Expanded Disability Status Scale (EDSS) scores from the 533 complete datasets in a double-blind, randomized, placebo-controlled, phase III trial of subcutaneous interferon beta-1a (IFNbeta-1a) (PRISMS study). We found significant treatment benefits for IFNbeta-1a on in-trial disability course (P=0.002). Therapeutic advantages remained when relapse-related assessments were excluded (P=0.018). Post hoc analyses demonstrated that IFNbeta-1a was mainly effective in both increasing the proportion of patients with a 'stable' course and reducing those with prolonged, disabling deteriorations. Baseline disease duration and EDSS levels, but not MRI lesion load, predicted the subsequent disability trends. Mean 'numbers needed to treat' (NNTs) to obtain preferred disability courses were reduced in patients with shorter disease duration. These results have important implications for the targeting of immunomodulatory therapies in MS.


[Stomach cancer in patients with systemic non-differentiated connective tissue dysplasia].
The study was designed as a comparative analysis of clinical and anamnestic data and results of morphological studies of surgically obtained tissues from 61 patients with stomach cancer (SC) aged 29-78 yr with (group 1) and without (group 2) signs of connective tissue dysplasia (CTD). The groups had an identical structure of SC hystological types, but in group 1 the tumours were localized mainly in the stomach body (60.6%, p < 0.05) and in group 2 in the cardia (32.1%, p < 0.05). In group 1, SC was more frequently associated with chronic (sometimes multiple) ulcers outside the tumor (18.2 compared with 7.1% in group 2). Comparative analysis revealed the following features of SC in patients with CTD: predominance of stigmatization signs in the urogenital system (57.6%) and gastrointestinal tract (42.4%), cyst formation in different organs (75.8%) especially in kidneys (48.5%), high frequency of gastric problems in medical history (chronic gastritis, ulcer disease) (72.7 and 35.7% in groups 1 and 2 respectively, p < 0.05) and concomitant pathology of urogenital system (42.4%, p < 0.05). These peculiarities may be used as the marker for the inclusion of patients in the risk group for SC. Taking into account plastic, morphogenetic, and protective functions of connective tissue under physiological conditions, the above epithelial-stromal relationships and peculiarities of reparative processes in gastric mucosa one can not exclude effect of CTD on gastric cancerogenesis. This implies the necessity of further studies.


Highly scalable, uniform, and sensitive biosensors based on top-down indium oxide nanoribbons and electronic enzyme-linked immunosorbent assay.
Nanostructure field-effect transistor (FET) biosensors have shown great promise for ultra sensitive biomolecular detection. Top-down assembly of these sensors increases scalability and device uniformity but faces fabrication challenges in achieving the small dimensions needed for sensitivity. We report top-down fabricated indium oxide (In2O3) nanoribbon FET biosensors using highly scalable radio frequency (RF) sputtering to create uniform channel thicknesses ranging from 50 to 10 nm. We combine this scalable sensing platform with amplification from electronic enzyme-linked immunosorbent assay (ELISA) to achieve high sensitivity to target analytes such as streptavidin and human immunodeficiency virus type 1 (HIV-1) p24 proteins. Our approach circumvents Debye screening in ionic solutions and detects p24 protein at 20 fg/mL (about 250 viruses/mL or about 3 orders of magnitude lower than commercial ELISA) with a 35% conduction change in human serum. The In2O3 nanoribbon biosensors have 100% device yield and use a simple 2 mask photolithography process. The electrical properties of 50 In2O3 nanoribbon FETs showed good uniformity in on-state current, on/off current ratio, mobility, and threshold voltage. In addition, the sensors show excellent pH sensitivity over a broad range (pH 4 to 9) as well as over the physiological-related pH range (pH 6.8 to 8.2). With the demonstrated sensitivity, scalability, and uniformity, the In2O3 nanoribbon sensor platform makes great progress toward clinical testing, such as for early diagnosis of acquired immunodeficiency syndrome (AIDS).


Multi-compartment neuron-glia co-culture platform for localized CNS axon-glia interaction study.
Formation of myelin sheaths by oligodendrocytes (OLs) in the central nervous system (CNS) is essential for rapid nerve impulse conduction. Reciprocal signaling between axons and OLs orchestrates myelinogenesis but remains largely elusive. In this study, we present a multi-compartment CNS neuron-glia microfluidic co-culture platform. The platform is capable of conducting parallel localized drug and biomolecule treatments while carrying out multiple co-culture conditions in a single device for studying axon-glia interactions at a higher throughput. The "micro-macro hybrid soft-lithography master fabrication" (MMHSM) technique enables a large number of precisely replicated PDMS devices incorporating both millimeter and micrometer scale structures to be rapidly fabricated without any manual reservoir punching processes. Axons grown from the neuronal somata were physically and fluidically isolated inside the six satellite axon/glia compartments for localized treatments. Astrocytes, when seeded and co-cultured after the establishment of the isolated axons in the satellite axon/glia compartments, were found to physically damage the established axonal layer, as they tend to grow underneath the axons. In contrast, oligodendrocyte progenitor cells (OPCs) could be co-cultured successfully with the isolated axons and differentiated into mature myelin basic protein-expressing OLs with processes aligning to neighboring axons. OPCs inside the six axon/glia compartments were treated with a high concentration of ceramide (150 μM) to confirm the fluidic isolation among the satellite compartments. In addition, isolated axons were treated with varying concentrations of chondroitin sulfate proteoglycan (CSPG, 0-25 μg ml(-1)) within a single device to demonstrate the parallel localized biomolecular treatment capability of the device. These results indicate that the proposed platform can be used as a powerful tool to study CNS axonal biology and axon-glia interactions with the capacity for localized biomolecular treatments.


Anesthesia or sedation for gastroenterologic endoscopies.
Because propofol is the sedative preferred by gastroenterologists, we focus this review on gastroenterologist-directed propofol sedation, provide simulations of the respiratory depressant effect of different dosing protocols and give a perspective on future developments in computer-assisted sedation techniques. Propofol use by nonanesthesiologists remains a contraindication in the package insert of propofol in most countries. Sedation guidelines produced by the American Society of Gastroenterology partially contradict those produced by the American Society of Anesthesiologists for sedation by nonanesthesiologists, whereas the German guidelines were developed with anesthesiologists involved. The use of fospropofol, recently approved by the US Food and Drug Administration for sedation, is considered an alternative to propofol by some gastroenterologists. Methodological errors in earlier pharmacological studies have to be solved before widespread use of fospropofol is justified, however. Our simulations show that dosing protocols with small boluses administered at reasonable intervals induce less respiratory depression than large boluses. Interindividual variability of propofol-induced respiratory depression is illustrated by different pharmacokinetic and dynamic parameter sets used in the simulation. Two computer-assisted propofol infusion systems are currently being investigated. They not only incorporate the target effect but also the side effects, which may limit respiratory depression. Propofol use by gastroenterologists may be well tolerated if appropriate patient selection, staff training, monitoring and low-dose sedation protocols are applied.


Guided Protocol for Fecal Microbial Characterization by 16S rRNA-Amplicon Sequencing.
The human intestinal microbiome plays a central role in protecting cells from injury, in processing energy and nutrients, and in promoting immunity. Deviations from what is considered a healthy microbiota composition (dysbiosis) may impair vital functions leading to pathologic conditions. Recent and ongoing research efforts have been directed toward the characterization of associations between microbial composition and human health and disease. Advances in high-throughput sequencing technologies enable characterization of the gut microbial composition. These methods include 16S rRNA-amplicon sequencing and shotgun sequencing. 16S rRNA-amplicon sequencing is used to profile taxonomical composition, while shotgun sequencing provides additional information about gene predictions and functional annotation. An advantage in using a targeted sequencing method of the 16S rRNA gene variable region is its substantially lower cost compared to shotgun sequencing. Sequence differences in the 16S rRNA gene are used as a microbial fingerprint to identify and quantify different taxa within an individual sample. Major international efforts have enlisted standards for 16S rRNA-amplicon sequencing. However, several studies report a common source of variation caused by batch effect. To minimize this effect, uniformed protocols for sample collection, processing, and sequencing must be implemented. This protocol proposes the integration of broadly used protocols starting from fecal sample collection to data analyses. This protocol includes a column-free, direct-PCR approach that enables simultaneous handling and DNA extraction of large numbers of fecal samples, along with PCR amplification of the V4 region. In addition, the protocol describes the analysis pipeline and provides a script using the latest version of QIIME (QIIME 2 version 2017.7.0 and DADA2). This step-by-step protocol is aimed to guide those interested in initiating the use of 16S rRNA-amplicon sequencing in a robust, reproductive, easy to use, detailed way.


Coping with technological disaster: an application of the conservation of resources model to the Exxon Valdez oil spill.
One hundred twenty-five commercial fishers in Cordova, Alaska, completed a mailed survey regarding current mental health functioning 6 years after the Exxon Valdez oil spill. Economic and social impacts of the oil spill and coping and psychological functioning (modified Coping Strategies Scales, Symptom Checklist 90-R) were measured. Multiple regression was used to test the utility of the Conservation of Resources stress model for explaining observed psychological symptoms. Current symptoms of depression, anxiety, and Posttraumatic Stress Disorder were associated with conditions resource loss and avoidant coping strategies. The Conservation of Resources model provided a framework for explaining psychological impacts of the oil spill. Future research is needed to identify factors related to recovery.


Collision-energy-resolved penning ionization electron spectroscopy of HCOOH, CH3COOH, and HCOOCH3 by collision with He*(2(3)S) metastable atoms.
Penning ionization of formic acid (HCOOH), acetic acid (CH3COOH), and methyl formate (HCOOCH3) upon collision with metastable He*(2(3)S) atoms was studied by collision-energy/electron-energy-resolved two-dimensional Penning ionization electron spectroscopy (2D-PIES). Anisotropy of interaction between the target molecule and He*(2(3)S) was investigated based on the collision energy dependence of partial ionization cross sections (CEDPICS) obtained from 2D-PIES as well as ab initio molecular orbital calculations for the access of a metastable atom to the target molecule. For the interaction potential calculations, a Li atom was used in place of He*(2(3)S) metastable atom because of its well-known similarity in interaction with targets. The results indicate that in the studied collision energy range the attractive potential localizes around the oxygen atoms and that the potential well at the carbonyl oxygen atom is at least twice as much as that at the hydroxyl oxygen. Moreover we can notice that attractive potential is highly anisotropic. Repulsive interactions can be found around carbon atoms and the methyl group.