Double-Network DNA Macroporous Hydrogel Enables Aptamer-Directed Cell Recruitment to Accelerate Bone Healing.
Recruiting endogenous bone marrow mesenchymal stem cells (BMSCs) in vivo to bone defect sites shows great promise in cell therapies for bone tissue engineering, which tackles the shortcomings of delivering exogenous stem cells, including limited sources, low retention, stemness loss, and immunogenicity. However, it remains challenging to efficiently recruit stem cells while simultaneously directing cell differentiation in the dynamic microenvironment and promoting neo-regenerated tissue ingrowth to achieve augmented bone regeneration. Herein, a synthetic macroporous double-network hydrogel presenting nucleic acid aptamer and nano-inducer enhances BMSCs recruitment, and osteogenic differentiation is demonstrated. An air-in-water template enables the rapid construction of highly interconnective macroporous structures, and the physical self-assembly of DNA strands and chemical cross-linking of gelatin chains synergistically generate a resilient double network. The aptamer Apt19S and black phosphorus nanosheets-specific macroporous hydrogel demonstrate highly efficient endogenous BMSCs recruitment, cell differentiation, and extracellular matrix mineralization. Notably, the enhanced calvarial bone healing with promising matrix mineralization and new bone formation is accompanied by adapting this engineered hydrogel to the bone defects. The findings suggest an appealing material approach overcoming the traditional limitations of cell-delivery therapy that can inspire the future design of next-generation hydrogel for enhanced bone tissue regeneration.


Impact of Intraoperative Ocular Lubricants on Corneal Debridement Rate During Vitreoretinal Surgery.
To compare surgical parameters among patients receiving Viscoat (sodium chondroitin sulfate 4%-sodium hyaluronate 3%) or Goniosol (hydroxypropyl methylcellulose 2.5%) as topical lubricants for retinal surgery. This was a retrospective analysis of patients undergoing retinal surgery between March 2013 and March 2018 using Goniosol or Viscoat as adjuvants. Primary outcome measures were rate of corneal debridement and operative time between groups, compared using χ 2 and t-tests, respectively. Compared to Viscoat (n=319), the Goniosol group (n=210) had more frequent intraoperative corneal debridement (21.4% vs 0, p<0.05) and longer surgical times (98 vs 78 minutes, p<0.05). Patients in the Viscoat group had higher rates of complex procedures (34.8% vs 26.7%, p<0.05), but were younger (50.7 vs 55.0 years, p<0.05) and more likely to be phakic (83.4% vs 70.5%, p<0.05). These findings suggest potential advantages of using Viscoat over Goniosol for corneal lubrication to aid visualization during vitreoretinal surgery.


Football Fitness - a new version of football? A concept for adult players in Danish football clubs.
This article explores a new Danish football-based activity for health called Football Fitness (FF). Data are from quantitative and qualitative methods, and the theoretical framework for the analysis of the organizational form of FF is the theory of path dependency (Mahoney) and first- and second-order change (Watzlawick et al.). Theories of Pestoff concerning differences between state, market, and the civil society and theories of voluntary associations in a Danish context (Kaspersen & Ottesen; Ibsen & Seippel) are applied. This article indicates how FF is a result of the changing landscape of sport and argues that it can be beneficial to target sports organizations and include the expertise of non-profit sports clubs if the goal is to raise the physical activity level of the local community and make these long lasting. But the organizations need to consider how this is to be done. FF, established by the Danish Football Association (FA) and managed by the voluntary clubs, is one example in a Danish context. Data indicate that FF is beneficial to the clubs involved in a number of ways. Among other things, it attracts new user groups and improves the club environment, including social activities and parental environment.


Radioimmunoassay of human serum serotonin.
A radioimmunoassay for extracted, N-acetylated human serum serotonin (5-hydroxytryptamine) is described. Antisera were raised in rabbits against a conjugate of bovine serum albumin with serotonin hemisuccinamide. Polyethylene glycol in combination with anti-rabbit immunoglobulins was used to separate bound and unbound 125I-Bolton Hunter-serotonin conjugate. Ethanol precipitation of serum proteins was used to extract serotonin, which was subsequently acetylated with acetic anhydride to N-acetyl serotonin. The average recovery was 66%. The minimal detectable concentration of N-acetyl serotonin was 0.012 mumol/l serum (25 fmol per tube). The intra-assay precision (CV) was 6.8% (n = 20) at a level of 0.9 +/- 0.06 mumol/l. The inter-assay CV was 10% at a level of 0.49 +/- 0.049 mumol/l, and 25% (n = 10) at a level of 2.16 +/- 0.53. Analytical recovery of serotonin, corrected for losses during extraction and acetylation, was 99 +/- 13%. The only substance cross-reacting with the antibody was endogenous N-acetyl serotonin. This was detectable when the acetylation step was omitted, and it can be removed by extraction before the acetylation. The observed range for the concentration of serotonin in serum was for 59 women 0.45 - 3.46 (mean +/- SD: 1.37 +/- 0.63 mumol/l) and for 59 men 0.19 - 2.8 (mean +/- SD: 1.18 +/- 0.56 mumol/l). All values are corrected for endogenous N-acetyl serotonin: observed range 0 - 0.18 (mean +/- SD: 0.03 +/- 0.03 mumol/l).


Early-Stage Ocular Hypertension Alters Retinal Ganglion Cell Synaptic Transmission in the Visual Thalamus.
Axonopathy is a hallmark of many neurodegenerative diseases including glaucoma, where elevated intraocular pressure (ocular hypertension, OHT) stresses retinal ganglion cell (RGC) axons as they exit the eye and form the optic nerve. OHT causes early changes in the optic nerve such as axon atrophy, transport inhibition, and gliosis. Importantly, many of these changes appear to occur prior to irreversible neuronal loss, making them promising points for early diagnosis of glaucoma. It is unknown whether OHT has similarly early effects on the function of RGC output to the brain. To test this possibility, we elevated eye pressure in mice by anterior chamber injection of polystyrene microbeads. Five weeks post-injection, bead-injected eyes showed a modest RGC loss in the peripheral retina, as evidenced by RBPMS antibody staining. Additionally, we observed reduced dendritic complexity and lower spontaneous spike rate of On-αRGCs, targeted for patch clamp recording and dye filling using a Opn4-Cre reporter mouse line. To determine the influence of OHT on retinal projections to the brain, we expressed Channelrhodopsin-2 (ChR2) in melanopsin-expressing RGCs by crossing the Opn4-Cre mouse line with a ChR2-reporter mouse line and recorded post-synaptic responses in thalamocortical relay neurons in the dorsal lateral geniculate nucleus (dLGN) of the thalamus evoked by stimulation with 460 nm light. The use of a Opn4-Cre reporter system allowed for expression of ChR2 in a narrow subset of RGCs responsible for image-forming vision in mice. Five weeks following OHT induction, paired pulse and high-frequency stimulus train experiments revealed that presynaptic vesicle release probability at retinogeniculate synapses was elevated. Additionally, miniature synaptic current frequency was slightly reduced in brain slices from OHT mice and proximal dendrites of post-synaptic dLGN relay neurons, assessed using a Sholl analysis, showed a reduced complexity. Strikingly, these changes occurred prior to major loss of RGCs labeled with the Opn4-Cre mouse, as indicated by immunofluorescence staining of ChR2-expressing retinal neurons. Thus, OHT leads to pre- and post-synaptic functional and structural changes at retinogeniculate synapses. Along with RGC dendritic remodeling and optic nerve transport changes, these retinogeniculate synaptic changes are among the earliest signs of glaucoma.


FAM222A, Part of the BET-Regulated Basal Endothelial Transcriptome, Is a Novel Determinant of Endothelial Biology and Angiogenesis.
BETs (bromodomain and extraterminal domain-containing epigenetic reader proteins), including BRD4, orchestrate transcriptional programs induced by pathogenic stimuli, as intensively studied in cardiovascular disease and elsewhere. In endothelial cells (ECs), BRD4 directs induced proinflammatory, proatherosclerotic transcriptional responses; BET inhibitors, like JQ1, repress these effects and decrease atherosclerosis. While BET effects in pathogenic conditions have prompted therapeutic BET inhibitor development, BET action under basal conditions, including ECs, has remained understudied. To understand BET action in basal endothelial transcriptional programs, we first analyzed EC RNA-Seq data in the absence versus presence of JQ1 before using BET regulation to identify novel determinants of EC biology and function. RNA-Seq datasets of human umbilical vein ECs without and with JQ1 treatment were analyzed. After identifying C12orf34, also known as FAM222A (family with sequence similarity 222 member A), as a previously unreported, basally expressed, potently JQ1-induced EC gene, FAM222A was studied in endothelial and angiogenic responses in vitro using small-interference RNA silencing and lentiviral overexpression, in vitro, ex vivo and in vivo, including aortic sprouting, matrigel plug assays, and murine neonatal oxygen-induced retinopathy. Resting EC RNA-Seq data indicate BETs direct transcriptional programs underlying core endothelial properties including migration, proliferation, and angiogenesis. BET inhibition in resting ECs also significantly induced a subset of mRNAs, including FAM222A-a unique BRD4-regulated gene with no reported EC role. Silencing endothelial FAM222A significantly decreased cellular proliferation, migration, network formation, aorta sprouting, and Matrigel plug vascularization through coordinated modulation of VEGF (vascular endothelial growth factor) and NOTCH mediator expression in vitro, ex vivo, or in vivo; lentiviral FAM222A overexpression had opposite effects. In vivo, siFAM222A significantly repressed retinal revascularization in neonatal murine oxygen-induced retinopathy through similar angiogenic signaling modulation. BET control over the basal endothelial transcriptome includes FAM222A, a novel, BRD4-regulated, key determinant of endothelial biology and angiogenesis.


Changes in geochemical and isotopic contents in groundwater before seismic events in Ischia Island (Italy).
We analysed the hydrogeochemical and isotopic contents in groundwater for the period 2002-2020, in the Ischia Island, a volcanic island in southern Italy, and compared them with seismic events that occurred in the same period. The study is based on a large hydrochemical database, which includes chemical (major and minor compounds, metals and trace elements) and isotopic analyses (δ18O and δ2H). For each of the 34 seismic events occurred in the studied period, we considered coordinates, date, time, depth, and magnitude. To exclude the influence of meteorological variability on the hydrochemistry, we examined rainfall time series measured in four stations located in the island. Results show hydrogeochemical anomalies for some chemical elements observed months before the seismic events. Arsenic, electrical conductivity, chromium and vanadium have been identified as potentially affected by hydrogeochemical anomalies related to the earthquakes. The variations in stable isotopes (δ2H and δ18O) in groundwater also seem associated with the earthquakes. This study aims to contribute to the individuation of components in groundwater prone to register sudden changes related to seismic events and it highlights the need of a continuous and long-term hydrogeochemical monitoring in seismic areas. Indeed, the conclusions of this study must be further confirmed by a future continuous monitoring of major compounds and trace elements and isotopes in groundwater to evaluate the effective temporal coincidence/lag with the seismic events.


Factors associated with wife beating in Egypt: analysis of two surveys (1995 and 2005).
Wife beating is an important public health problem in many developing countries. We assessed the rates of wife beating and examined factors associated with wife beating in 1995 and 2005 in Egypt. We used data from two Demographic and Health Surveys (DHS) conducted in Egypt in 1995 and 2005 using multistage household sampling. Data related to wife beating included information from 7122 women in 1995 and 5612 women in 2005. Logistic regression was used to analyze factors independently associated with wife beating. Special weights were used to obtain nationally representative estimates. In 1995 17.5% of married women in Egypt experienced wife beating in the last 12 months, in 2005--18.9% or 16.0%, using different measures. The association between socio-demographic differentials and wife beating was weaker in the newer survey. The 12-month prevalence of wife beating was lower only when both partners were educated, but the differences across education levels were less pronounced in 2005. Based on the information available in the 2005 survey, more educated women experienced less severe forms of wife beating than less educated women. Different measures used in both surveys make a direct comparison difficult. The observed patterns indicate that the changes in prevalence may be masked by two opposite processes occurring in the society: a decrease in (severe forms of) wife beating and an increase in reporting of wife beating. Improving the access to education for women and raising education levels in the whole society may help reducing wife beating.


Intimate partner violence among women with mental health-related activity limitations: a Canadian population based study.
There is strong evidence that women with serious or chronic mental illness experience higher rates of violence than women in the general population. Our objective was to examine the risk of intimate partner violence (IPV), a form of violence that is often recurrent and linked to negative physical and psychological consequences, among a representative sample of non-institutionalized women with activity limitations (ALs) due to a mental health condition. Data from the 2009 General Social Survey were used, a national, population-based, cross-sectional survey. The sample included 6851 women reporting contact with a current or former partner in the previous five years, of whom 322 (4.7%) reported a mental health-related AL always/often or sometimes. The prevalence of any type of IPV was highest among women with mental health-related ALs always/often (54.4%), followed by women reporting ALs sometimes (49.9%), and those reporting no ALs (18.3%, p < 0.0001). The same pattern was observed for emotional (51.1%, 45.5%, 16.3%, p < 0.0001) and financial IPV (18.1%, 9.5%, 4.0%, p < 0.0001). For physical/sexual violence, rates were similar among women reporting mental health-related ALs always/often and sometimes, but were lower among those reporting no ALs (20.2%, 20.9%, 5.9%, p < 0.0001). In a logistic regression analysis the odds of having experienced any IPV remained greater for women reporting ALs always/often (OR = 3.65; 95% CI: 2.10, 6.32) and sometimes (OR = 3.20; 95% CI: 2.15, 4.75) than those reporting no ALs. Several social capital variables, including perceptions of having experienced discrimination, a weak sense of belonging in their local community, and low trust toward family members and strangers were also significantly associated with having experienced IPV. Findings suggest that women with mental health-related ALs may be at increased risk of IPV. Health and social service providers may need, therefore, to better target prevention and intervention initiatives to this population.


Bioremediation of Cr(VI) using indigenous bacterial strains isolated from a common industrial effluent treatment plant in Vishakhapatnam.
The present study focuses on removing hexavalent chromium (Cr(VI)) using indigenous metal-resistant bacterial strains isolated from a common industrial effluent treatment plant, a contaminated site in Vishakhapatnam. Three high metal-resistant isolates were screened by growing them in nutrient agar media containing different Cr(VI) concentrations for 24 h at 35 ± 2 °C. The three strains' minimum inhibitory concentrations of Cr(VI) were examined at neutral pH and 35 ± 2 °C temperature. Morphological, biochemical, and molecular characterizations were carried out, and the strains were identified as Bacillus subtilis NITSP1, Rhizobium pusense NITSP2, and Pseudomonas aeruginosa NITSP3. Elemental composition and functional group analysis of the native and metal-loaded cells were done using energy-dispersive spectroscopy and Fourier-transform infrared spectroscopy, respectively. The operating conditions were optimized using a one-factor-at-a-time analysis. When compared with three bacterial isolates, maximum Cr(VI) removal (80.194 ± 4.0%) was observed with Bacillus subtilis NITSP1 with an initial Cr(VI) concentration of 60 mg/L, pH 7.0, an inoculum size of 2% (v/v), and an incubation period of 24 h. The logistic model was used to predict the variation of biomass growth with time. The present study can be extended to remove heavy metals from industrial wastewater in an environmental-friendly manner.


Arabidopsis Fructokinases Are Important for Seed Oil Accumulation and Vascular Development.
Sucrose (a disaccharide made of glucose and fructose) is the primary carbon source transported to sink organs in many plants. Since fructose accounts for half of the hexoses used for metabolism in sink tissues, plant fructokinases (FRKs), the main fructose-phosphorylating enzymes, are likely to play a central role in plant development. However, to date, their specific functions have been the subject of only limited study. The Arabidopsis genome contains seven genes encoding six cytosolic FRKs and a single plastidic FRK. T-DNA knockout mutants for five of the seven FRKs were identified and used in this study. Single knockouts of the FRK mutants did not exhibit any unusual phenotype. Double-mutants of AtFRK6 (plastidic) and AtFRK7 showed normal growth in soil, but yielded dark, distorted seeds. The seed distortion could be complemented by expression of the well-characterized tomato SlFRK1, confirming that a lack of FRK activity was the primary cause of the seed phenotype. Seeds of the double-mutant germinated, but failed to establish on 1/2 MS plates. Seed establishment was made possible by the addition of glucose or sucrose, indicating reduced seed storage reserves. Metabolic profiling of the double-mutant seeds revealed decreased TCA cycle metabolites and reduced fatty acid metabolism. Examination of the mutant embryo cells revealed smaller oil bodies, the primary storage reserve in Arabidopsis seeds. Quadruple and penta FRK mutants showed growth inhibition and leaf wilting. Anatomical analysis revealed smaller trachea elements and smaller xylem area, accompanied by necrosis around the cambium and the phloem. These results demonstrate overlapping and complementary roles of the plastidic AtFRK6 and the cytosolic AtFRK7 in seed storage accumulation, and the importance of AtFRKs for vascular development.


Signaling pathway switch in breast cancer.
Next generation sequencing studies have drawn the general landscape of breast cancers and identified hundreds of new, actual therapeutic targets. Two major signaling pathways seem to be altered in a vast proportion of breast cancers. The PI3 kinase/AKT pathway is activated and the JUN/MAPK pathway is repressed. Via the regulation of the cell cycle this metabolic switch impacts on the balance between self-renewal, proliferation and differentiation of the tumor-initiating cells.


Biogenic amines serotonin and dopamine regulate cholangiocyte hyperplastic and neoplastic growth.
Biogenic amines, such as serotonin and dopamine, regulate a multitude of cellular responses. A great deal of effort has been invested into understanding the effects of these molecules and their corresponding receptor systems on cholangiocyte and cholangiocarcinoma secretion, apoptosis and growth. This review summarizes the results of these efforts and highlights the importance of these regulatory molecules on the physiology and pathophysiology of cholangiocytes. Specifically we have focused on the recent findings into the effects of serotonin and dopamine on cholangiocyte hyperplasia and neoplastic growth.


[Premorbid functioning by gender and its relationship with duration of untreated psychosis in first psychotic episode].
There are two phenotypes proposed for the psychotic disorders based on premorbid functioning and probably related with the duration of untreated psychosis (DUP). The aim of this study was to compare the clinical features, premorbid functioning and its relationship with DUP by gender in a group of first episode psychosis patients. We included 77 patients in their first admission to a psychiatric facility. A clinical evaluation was performed with the PANSS, Calgary Depression Scale,Hamilton Depression Scale and Mania Rating Scale. Premorbid functioning was rated with the Premorbid Adjustment Scale. There were no clinical differences between men and women. Men had greater impairment in their premorbid functioning. Patients with short DUP (< 28 weeks) showed better premorbid functioning compared to those with long DUP (> 28 weeks). Duration of untreated psychosis is determined by premorbid functioning and it is possible that male patients, who show a higher frequency of poor premorbid functioning, have a longer delay in seeking treatment, that conditions a longer duration of untreated psychosis.


Measurement of the Intensity of Long-Lifetime Luminophores in the Presence of Background Signals Using Phase-Modulation Fluorometry.
We describe a method to correct for background fluorescence and to measure the intensity of long-lifetime probes using phase-modulation fluorometry. The theoretically predicted and simulated data were supported by two experiments. The fractional contribution of background fluorescence in the sample was determined by measurement of phase angle and/or modulation at single modulation frequency. In certain experimental situations, where the mean decay times of the background and the long lifetime probe are widely separated, determination of background signals in the sample does not require a blank sample or information about the nature of intensity decay of the background. Hence, phase-modulation fluorometry can be used to directly determine the intensity of the long-lifetime probe in the presence of an unknown short-lifetime background. We also discuss the effects of ambient light (indefinitely long lifetime) and scattered excitation light (zero lifetime) on phase-modulation measurements.


Variants of uncertain significance in BRCA1 and BRCA2 assessment of in silico analysis and a proposal for communication in genetic counselling.
Nearly 15% of BRCA1 and BRCA2 DNA tests lead to the identification of Variants of Uncertain Significance (VUS). VUS are classified in the Netherlands according to the Bell system and it is current practice that class III VUS are communicated to counsellees, but not class II or lower VUS. Our aims were to investigate the utility of in silico characteristics in the classification of VUS and whether initial VUS classifications justify differences in communication protocols during counselling. We classified 88 missense VUS in BRCA1 and BRCA2 on the basis of an in silico analysis and compared the classification of a subset of 60 VUS of which additional information including family, genetic and tumour data was available. VUS allocated to class III more frequently showed in silico indications of a deleterious effect than class II VUS. Of the 46 VUS assigned to class II by in silico analysis alone, nearly half were eventually recategorised as class I and 10% as class III when additional information was included. As in silico analysis alone is not always sufficient to unambiguously assign VUS to either class II or class III, we would argue that the prospect of obtaining additional information from a family should be given more weight during the decision process preceding the communication of a VUS test result. Research initiatives such as the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA), which strive to combine diverse sources of information, will be valuable in aiding a definitive classification of a VUS.


Nausea and vomiting of pregnancy.
Nausea and vomiting are common experiences in pregnancy, affecting 70% to 80% of all pregnant women. Various metabolic and neuromuscular factors have been implicated in the pathogenesis of nausea and vomiting of pregnancy (NVP) and hyperemesis gravidarum (HG), an entity distinct from NVP. However, their exact cause is unknown. Consequently, treatment of NVP and HG can be difficult, as neither the optimal targets for treatment nor the full effects of potential treatments on the developing fetus are known. This article reviews the epidemiology, pathology, diagnosis, outcomes, and treatment of NVP and HG.


The Clinical Efficacy and Safety of Flexible Ureteroscopic Treatment for Parapelvic Renal Cyst and Secondary Renal Stone.
To explore the efficacy and safety of flexible ureteroscopic incision and drainage and flexible ureteroscopic lithotripsy for treatment of parapelvic renal cyst combined with secondary renal stone. 28 patients with parapelvic renal cyst combined with renal stone were treated with flexible ureteroscopic incision and drainage and flexible ureteroscopic lithotripsy simultaneously from May 2010 to December 2016. The follow-up was made 1, 3, 6?12 months and 2 years after surgical treatment in our outpatient department. Ultrasonic examination and CT were used to detect the residual stone and recurrence of renal cyst. The mean age of the patients was 45.3 ± 18.6 years. The average size of the parapelvic renal cysts was 4.3 ± 1.6 cm, including 27 with Bosniak category I and 1 patient with Bosniak II renal cysts. The mean size of the renal stones was 14.3 ± 3.9 mm. The mean operative time was 53.4 ± 20.7 minutes and the mean blood loss was 10.8 ± 5.6 ml. The mean hospitalization time was 3.2 ± 0.7 days. No severe complications were encountered. The complications included transient fever ( > 38°C) in 3 patients and significant hemorrhage in 1 patient. The stone-free rates one month and three months after operation were 89.3% and 96.4%, respectively. During the 2 years follow-up, the cyst recurrence rate was 14.3% and the stone recurrence rate was 7.1%. In this study, we firstly demonstrated that it is safe and effective to treat both renal stone and parapelvic renal cyst simultaneously by flexible ureteroscopic lithotripsy and flexible ureteroscopic incision and drainage, with satisfactory stone free rate and low cyst recurrence rate.


Salient Arithmetic Data Extraction from Brain Activity via an Improved Deep Network.
Interpretation of neural activity in response to stimulations received from the surrounding environment is necessary to realize automatic brain decoding. Analyzing the brain recordings corresponding to visual stimulation helps to infer the effects of perception occurring by vision on brain activity. In this paper, the impact of arithmetic concepts on vision-related brain records has been considered and an efficient convolutional neural network-based generative adversarial network (CNN-GAN) is proposed to map the electroencephalogram (EEG) to salient parts of the image stimuli. The first part of the proposed network consists of depth-wise one-dimensional convolution layers to classify the brain signals into 10 different categories according to Modified National Institute of Standards and Technology (MNIST) image digits. The output of the CNN part is fed forward to a fine-tuned GAN in the proposed model. The performance of the proposed CNN part is evaluated via the visually provoked 14-channel MindBigData recorded by David Vivancos, corresponding to images of 10 digits. An average accuracy of 95.4% is obtained for the CNN part for classification. The performance of the proposed CNN-GAN is evaluated based on saliency metrics of SSIM and CC equal to 92.9% and 97.28%, respectively. Furthermore, the EEG-based reconstruction of MNIST digits is accomplished by transferring and tuning the improved CNN-GAN's trained weights.


miR-181c-5p Exacerbates Hypoxia/Reoxygenation-Induced Cardiomyocyte Apoptosis via Targeting PTPN4.
Activation of cell apoptosis is a major form of cell death during myocardial ischemia/reperfusion injury (I/RI). Therefore, examining ways to control cell apoptosis has important clinical significance for improving postischemic recovery. Clinical evidence demonstrated that miR-181c-5p was significantly upregulated in the early phase of myocardial infarction. However, whether or not miR-181c-5p mediates cardiac I/RI through cell apoptosis pathway is unknown. Thus, the present study is aimed at investigating the role and the possible mechanism of miR-181c-5p in apoptosis during I/R injury by using H9C2 cardiomyocytes. The rat origin H9C2 cardiomyocytes were subjected to hypoxia/reoxygenation (H/R, 6 hours hypoxia followed by 6 hours reoxygenation) to induce cell injury. The results showed that H/R significantly increased the expression of miR-181c-5p but not miR-181c-3p in H9C2 cells. In line with this, in an in vivo rat cardiac I/RI model, miR-181c-5p expression was also significantly increased. The overexpression of miR-181c-5p by its agomir transfection significantly aggravated H/R-induced cell injury (increased lactate dehydrogenase level and reduced cell viability) and exacerbated H/R-induced cell apoptosis (greater cleaved caspases 3 expression, Bax/Bcl-2 and more TUNEL-positive cells). In contrast, inhibition of miR-181c-5p in vitro had the opposite effect. By using computational prediction algorithms, protein tyrosine phosphatase nonreceptor type 4 (PTPN4) was predicted as a potential target gene of miR-181c-5p and was verified by the luciferase reporter assay. The overexpression of miR-181c-5p significantly attenuated the mRNA and protein expression of PTPN4 in H9C2 cardiomyocytes. Moreover, knockdown of PTPN4 significantly aggravated H/R-induced enhancement of LDH level, cleaved caspase 3 expression, and apoptotic cell death, which mimicked the proapoptotic effects of miR-181c-5p in H9C2 cardiomyocytes. These findings suggested that miR-181c-5p exacerbates H/R-induced cardiomyocyte injury and apoptosis via targeting PTPN4 and that miR-181c-5p/PTPN4 signaling may yield novel strategies to combat myocardial I/R injury.


Effects of Ketogenic Diet on Reproductive Hormones in Women With Polycystic Ovary Syndrome.
Ketogenic diet has recently made a comeback as a part of lifestyle and dietary modifications in patients with polycystic ovary syndrome (PCOS). Despite studies suggesting its beneficial effects in reversing hormonal imbalance in women with PCOS, evidence has been patchy and derived from small populations under varying conditions. To pool evidence from clinical trials to study the effects of ketogenic diet on reproductive hormones (LH/FSH ratio, free testosterone, serum progesterone) and observe evidence of weight change. PubMed, ScienceDirect, Scopus, and Web of Science core collection were searched for clinical trials evaluating the effects of ketogenic diet in established PCOS women consistent with the Rotterdam classification. Single- or double-arm studies that included an outcome of interest were included. Two investigators worked independently to screen potential articles and a designated investigator extracted data on study characteristics and evaluated the outcomes. Data were pooled using a random-effects model. The quality of selected studies was assessed using the Cochrane Risk of Bias Tool. Following ≥45 days of intervention with ketogenic diet among women with PCOS, significant improvement was observed in reproductive hormone levels, with reduced LH/FSH ratio (d -0.851; 95% CI -1.015, -0.686; P < .001), reduced serum free testosterone (d -0.223; 95% CI -0.328, -0.119; P < .001), and an increased in serum sex hormone binding globulin (SHBG) (d 9.086; 95% CI 3.379, 14.792; P = .002). Significant weight loss was unanimously observed in all included studies (d -11.56; 95% CI -14.97, -8.15; P < .001). Short-term ketogenic diet potentially improved hormonal imbalances commonly associated with PCOS.


[Circular RNA hsa_circ_0006834 is a potential prognostic biomarker for hepatocellular carcinoma].
To explore the differentially expressed circular RNAs (circRNAs) in hepatocellular carcinoma (HCC) and their association with clinical features and prognosis of HCC patients. RNA sequencing was performed on 56 pairs of HCC and adjacent tissues to identify the differentially expressed circRNAs in HCC, whose expressions were validated by RT-qPCR in another 15 pairs of HCC and adjacent tissues. The correlation of the selected circRNAs with the clinical features and prognosis of the patients was analyzed using Chi-square test, Cox proportional hazards regression model and Kaplan-Meier analysis. The predictive value of the identified circRNA for recurrence-free survival and overall survival of HCC patients was assessed using ROC curves. We identified 17 significantly up-regulated and 45 down-regulated circRNAs in HCC tissues using RNA sequencing (P < 0.05). Among these circRNAs, hsa_circ_0006834 was found to be significantly down-regulated in HCC tissues, and its expression level was negatively correlated with vascular invasion and Barcelona Clinic Liver Cancer (BCLC) stage and positively with recurrence-free survival and overall survival of the patients (P < 0.05). As an independent prognostic factor for HCC, hsa_circ_0006834 had an AUC of 0.750 and 0.7601 for predicting 2-year recurrence-free survival and overall survival of HCC patients, respectively. hsa_circ_0006834 is a new potential biomarker for evaluating the prognosis of HCC patients.


[Morpho-chemical characteristics of the brain of rats genetically predisposed to catalepsy].
Cell organization of the cerebral cortex and striatum has been studied by+light optics and enzymatic activity of neuromediators catabolism--histochemically. In layers III and V of the sensomotor cortex and in the nucleus caudatus the number of neurons per unit area is increased, and their size is decreased. Volume of cytoplasm and nuclei of neurons in both layers is decreased, the latter--to less extent. The total amount of the perineuronal glia in the nucleus caudatus is also decreased at the expense of astroglia. In the cerebral cortex it is equal, but the ratio between astro-++- and oligodendroglia is changed. Acetylcholinesterase activity in the layers III and V of the sensomotor cortex is lower than in the control, while monoamine oxidase activity is kept at the control level. The genetically determined anomalies++ of growth and development of the cerebral cells is supposed to be considered as a structural base of the cataleptic state.


Plenoptic layer-based modeling for image based rendering.
Image based rendering is an attractive alternative to model based rendering for generating novel views because of its lower complexity and potential for photo-realistic results. To reduce the number of images necessary for alias-free rendering, some geometric information for the 3D scene is normally necessary. In this paper, we present a fast automatic layer-based method for synthesizing an arbitrary new view of a scene from a set of existing views. Our algorithm takes advantage of the knowledge of the typical structure of multiview data to perform occlusion-aware layer extraction. In addition, the number of depth layers used to approximate the geometry of the scene is chosen based on plenoptic sampling theory with the layers placed non-uniformly to account for the scene distribution. The rendering is achieved using a probabilistic interpolation approach and by extracting the depth layer information on a small number of key images. Numerical results demonstrate that the algorithm is fast and yet is only 0.25 dB away from the ideal performance achieved with the ground-truth knowledge of the 3D geometry of the scene of interest. This indicates that there are measurable benefits from following the predictions of plenoptic theory and that they remain true when translated into a practical system for real world data.


Fast Diagnosis of Failure Mechanisms and Lifetime Prediction of Li Metal Batteries.
Lithium (Li) metal serving as an anode has the potential to double or triple stored energies in rechargeable Li batteries. However, they typically have short cycling lifetimes due to parasitic reactions between the Li metal and electrolyte. It is critically required to develop early fault-detection methods for different failure mechanisms and quick lifetime-prediction methods to ensure rapid development. Prior efforts to determine the dominant failure mechanisms have typically required destructive cell disassembly. In this study, non-destructive diagnostic method based on rest voltages and coulombic efficiency are used to easily distinguish the different failure mechanisms-from loss of Li inventory, electrolyte depletion, and increased cell impedance-which are deeply understood and well validated by experiments and modeling. Using this new diagnostic method, the maximum lifetime of a Li metal cell can be quickly predicted from tests of corresponding anode-free cells, which is important for the screenings of electrolytes, anode stabilization, optimization of operating conditions, and rational battery design.


Effects of delta 9-tetrahydrocannabinol and cannabidiol on sodium-dependent high affinity choline uptake in the rat hippocampus.
Doses of delta 9-tetrahydrocannabinol (delta 9-THC) and cannabidiol (CBD) affording the same degree of protection against seizures induced by maximal electroshock were compared for their effects on sodium-dependent high affinity choline uptake into six rat brain regions: cortex, striatum, medulla-pons, hypothalamus, midbrain and hippocampus. One hour after administration of CBD, 60 mg/kg i.p. in vitro choline uptake was not altered in any brain region. In contrast, 1 hr after administration of delta 9-THC, 10 mg/kg i.p., in vitro choline uptake in hippocampus and hypothalamus was significantly reduced. Moreover, in vivo administration of delta 9-THC was followed by a dose-related reduction in in vitro hippocampus choline uptake. Kinetic analysis of hippocampal choline uptake after administration of delta 9-THC, 10 mg/kg i.p., indicated that there was a reduction in Vmax with no change in the Km of the transport system. After direct addition to the hippocampal homogenates (in vitro) both delta 9-THC and CBD inhibited choline uptake, with IC50 values of 4.6 and 15.9 microM, respectively. Kinetic analysis revealed that the in vitro choline uptake inhibition induced by delta 9-THC was noncompetitive in nature. These results suggest that the septal-hippocampal cholinergic tract is a major site of action of delta 9-THC and may provide a neurochemical basis for the differential pharmacological properties of delta 9-THC and CBD.


Identification of immune-responsive circular RNAs in shrimp (Litopenaeus vannamei) upon yellow head virus infection.
Circular RNAs (circRNAs) are a subclass of non-coding RNAs (ncRNAs) formed through a process known as back-splicing. They play a crucial role in the genetic regulation of various biological processes. Currently, circRNAs have been identified as participants in the antiviral response within mammalian cells. However, circRNAs in shrimp infected with the yellow head virus (YHV) remain largely unexplored. Therefore, this study aims to identify circRNAs in the hemocytes of Litopenaeus vannamei during YHV infection. We discovered 358 differentially expressed circRNAs (DECs), with 177 of them being up-regulated and 181 down-regulated. Subsequently, eight DECs, including circ_alpha-1-inhibitor 3, circ_CDC42 small effector protein 2, circ_hemicentin 2, circ_integrin alpha V, circ_kazal-type proteinase inhibitor, circ_phenoloxidase 3, circ_related protein rab-8B, and circ_protein toll-like, were randomly selected for analysis of their expression patterns during YHV infection using qRT-PCR. Furthermore, the circRNAs' characteristics were confirmed through PCR, RNase R treatment, and Sanger sequencing, all of which were consistent with the features of circRNAs. These findings contribute to a better understanding of circRNAs' involvement in the antiviral response in shrimp.


Strategies to define performance specifications in laboratory medicine: 3 years on from the Milan Strategic Conference.
Measurements in clinical laboratories produce results needed in the diagnosis and monitoring of patients. These results are always characterized by some uncertainty. What quality is needed and what measurement errors can be tolerated without jeopardizing patient safety should therefore be defined and specified for each analyte having clinical use. When these specifications are defined, the total examination process will be "fit for purpose" and the laboratory professionals should then set up rules to control the measuring systems to ensure they perform within specifications. The laboratory community has used different models to set performance specifications (PS). Recently, it was felt that there was a need to revisit different models and, at the same time, to emphasize the presuppositions for using the different models. Therefore, in 2014 the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) organized a Strategic Conference in Milan. It was felt that there was a need for more detailed discussions on, for instance, PS for EQAS, which measurands should use which models to set PS and how to set PS for the extra-analytical phases. There was also a need to critically evaluate the quality of data on biological variation studies and further discussing the use of the total error (TE) concept. Consequently, EFLM established five Task Finish Groups (TFGs) to address each of these topics. The TFGs are finishing their activity on 2017 and the content of this paper includes deliverables from these groups.


General practice consultations - how well do doctors predict patient satisfaction?
While patient satisfaction with the general practice consultation has been extensively researched, there have been relatively few studies of doctors' perception of patient satisfaction. This study sought to measure how accurately doctors are able to predict patient satisfaction with consultations in general practice. Adult patients consulting about new episodes of illness in general practice completed a consultation satisfaction questionnaire. The scores from the questionnaire were compared with doctors' predictions of patient satisfaction. Nine general practitioners completed the study and returned a total of 167 pairs of questionnaires. On average, the patients gave their doctors higher scores on the general satisfaction and professional care scales than on the depth of relationship and perceived time scales of the questionnaire. On every scale, patients reported higher levels of satisfaction than their doctors predicted they would. There was poor correlation between patient and doctor scores for the perceived time scale, but moderate correlation for the other three scales. Our findings suggest that a doctor's sense that a patient was not satisfied following a consultation may be valid, but that doctors may underestimate their patients' satisfaction.


Alleviation of Metabolic Syndrome with Dietary Egg White Protein.
Abdominal fat accumulation causes metabolic syndrome, which is a cluster of metabolic abnormalities such as dyslipidemia, glucose intolerance, insulin resistance or hyperinsulinemia, and hypertension, leading to the development of diabetes and cardiovascular disease. Diets are known to contribute to the development or prevention of metabolic syndrome. Several studies have reported that the quality of dietary proteins may be an important modulator of the risk of this syndrome. We investigated the effects of consuming egg white protein (EWP) or lactic-fermented egg white (LE), an easy-to-consume form of egg white, on the development of metabolic syndrome in animal models and humans. In comparison with casein, dietary EWP decreased lymphatic lipid transport in thoracic lymph duct-cannulated rats. In an in vitro experiment, EWP pepsin hydrolysate decreased the cholesterol micellar solubility and cholesterol transfer rate from micelles to oil phase, and increased water-holding capacity, settling volume in water, and relative viscosity compared with casein pepsin hydrolysate. The daily consumption of LE for 8 weeks reduced serum total cholesterol and LDL cholesterol levels in men with mild hypercholesterolemia. Furthermore, dietary EWP reduced the body fat mass of rats by increasing the body protein mass and accelerating hepatic β-oxidation. The daily consumption of LE for 12 weeks reduced the visceral fat area and improved the ratio of the visceral to subcutaneous fat area. Taken together, these results indicated that dietary EWP and LE would be useful for preventing or alleviating metabolic syndrome.


Distinct Mechanisms of Biotic and Chemical Elicitors Enable Additive Elicitation of the Anticancer Phytoalexin Glyceollin I.
Phytoalexins are metabolites biosynthesized in plants in response to pathogen, environmental, and chemical stresses that often have potent bioactivities, rendering them promising for use as therapeutics or scaffolds for pharmaceutical development. Glyceollin I is an isoflavonoid phytoalexin from soybean that exhibits potent anticancer activities and is not economical to synthesize. Here, we tested a range of source tissues from soybean, in addition to chemical and biotic elicitors, to understand how to enhance the bioproduction of glyceollin I. Combining the inorganic chemical silver nitrate (AgNO₃) with the wall glucan elicitor (WGE) from the soybean pathogen Phytophthora sojae had an additive effect on the elicitation of soybean seeds, resulting in a yield of up to 745.1 µg gt-1 glyceollin I. The additive elicitation suggested that the biotic and chemical elicitors acted largely by separate mechanisms. WGE caused a major accumulation of phytoalexin gene transcripts, whereas AgNO₃ inhibited and enhanced the degradation of glyceollin I and 6″-O-malonyldaidzin, respectively.


Impact of Resident Participation on Operative Time and Outcomes in Otologic Surgery.
Objectives To describe the impact of resident involvement in tympanoplasty on operative time and surgical complication rates. Study Design Case series with chart review. Setting Tertiary medical center. Subjects and Methods Current Procedural Terminology codes were used to identify patients in the 2011-2014 public use files of the American College of Surgeons National Surgical Quality Improvement Program who underwent a tympanoplasty or tympanomastoidectomy. Cases were included if the database indicated whether the operating room was staffed with an attending alone or an attending with residents. Categorical and continuous variables were compared with chi-square, Fisher's exact, and Mann-Whitney U tests. Generalized linear models with a log-link and gamma distribution were used to examine the factors affecting operative time. Results Overall, 1045 cases met our study criteria (tympanoplasty, n = 797; tympanomastoidectomy, n = 248). Resident involvement increased mean operative time for tympanoplasties by 46% (107 vs 73 minutes, P < .001) and tympanomastoidectomies by 49% (175 vs 117 minutes, P < .001). While controlling for confounding factors, the variable with the largest impact on operative time was resident involvement. There were no significant differences observed in the rate of surgical complications between attending-alone and attending-resident cases. Conclusion Resident involvement in tympanoplasty and tympanomastoidectomy did not affect the surgical complication rate. Resident involvement increased operative time for tympanoplasties and tympanomastoidectomies; however, the specific reasons for the increase are not explained by the available data.


Recurrent Somatic Chromosomal Abnormalities in Relapsed Extraocular Retinoblastoma.
Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management.


Microtubule-bundling protein Spef1 enables mammalian ciliary central apparatus formation.
Cilia are cellular protrusions containing nine microtubule (MT) doublets and function to propel cell movement or extracellular liquid flow through beating or sense environmental stimuli through signal transductions. Cilia require the central pair (CP) apparatus, consisting of two CP MTs covered with projections of CP proteins, for planar strokes. How the CP MTs of such '9 + 2' cilia are constructed, however, remains unknown. Here we identify Spef1, an evolutionarily conserved microtubule-bundling protein, as a core CP MT regulator in mammalian cilia. Spef1 was selectively expressed in mammalian cells with 9 + 2 cilia and specifically localized along the CP. Its depletion in multiciliated mouse ependymal cells by RNAi completely abolished the CP MTs and markedly attenuated ciliary localizations of CP proteins such as Hydin and Spag6, resulting in rotational beat of the ependymal cilia. Spef1, which binds to MTs through its N-terminal calponin-homologous domain, formed homodimers through its C-terminal coiled coil region to bundle and stabilize MTs. Disruption of either the MT-binding or the dimerization activity abolished the ability of exogenous Spef1 to restore the structure and functions of the CP apparatus. We propose that Spef1 bundles and stabilizes central MTs to enable the assembly and functions of the CP apparatus.


Improvement of functional capacity in sacubitril-valsartan treated patients assessed by cardiopulmonary exercise test.
Neprilisin and angiotensin receptor inhibition (Sacubitril/Valsartan, i.e. ARNI) is recommended in heart failure guidelines for patients in NYHA class II-III with reduced left ventricular ejection fraction (LVEF). ARNI increase survival and quality of life; due to their hemodynamic effects, ARNI could also affect exercise tolerance. We studied the effects of ARNI on cardiopulmonary test (CPET) after six months of treatment in 35 patients [67 ± 11 years; LVEF 31 ± 6%; NT-proBNP 1822 ± 1651 pg/ml; ICD/CRT since at least 6 months in 26/35], treated with increasing doses of Sacubitril/Valsartan up to 318 ± 36 mg/die. In addition, levels of NT-proBNP, renal function, electrolytes, and echocardiocolorDoppler were assessed in the same time periods. No variations of renal function and/or potassium levels were observed; NT-proBNP decreased. Most CPET variables were improved by ARNI (p < .05): peak VO2 and O2 pulse increased (from 15.8 ± 3.4 to 17.0 ± 4.0 ml/kg/min and from 11.5 ± 2.5 to 12.6 ± 2.4 ml/beat, respectively), while VEVCO2 slope decreased from 35.2 ± 11.2 to 33.1 ± 12.3. A significant relationship (p < .05) was observed between the amount of increase in LVEF and that of O2 pulse in all patients, and between the amount of decrease in PAPs and that of VEVCO2 slope in patients showing pulmonary hypertension in baseline. In a subgroup of 22 patients who already completed A 1 year follow-up, overall CPET improvement was maintained. In conclusion, already in the short term ARNI favourably affect cardiopulmonary response to exercise in heart failure patients; such a change seems to be preserved on a longer period.


A novel strategy for preparing nanoporous biphasic calcium phosphate of controlled composition via a modified nanoparticle-assembly method.
Biphasic calcium phosphate (BCP) consisting of hydroxyapatite (HAp) and β-tricalcium phosphate is usually prepared by thermal decomposition of calcium-deficient HAp (CDHAp). However, the calcium deficiency and morphology of CDHAp are difficult to manipulate in parallel. In this study, we report a novel strategy for controlling the composition of nanoporous BCP by using only CDHAp nanoparticles with specific properties (Ca/P molar ratio, 1.61; particle size, 50 nm) as a building block and by adjusting the calcium deficiency of the nanoparticle-assembled CDHAp (Ca/P molar ratio, 1.50-1.67; pore size, 8 nm) with the addition of water-soluble Ca(NO3)2 or (NH4)2HPO4. After thermal treatment at 1000 °C, the composition of BCP could be predictably controlled by adjusting the Ca/P ratio of the nanoparticle-assembled CDHAp. Changes in the Ca/P ratio did not significantly affect the surface morphology of BCP, but the grain size (210-300 nm) and pore size (140-170 nm) tended to increase slightly as the Ca/P ratio decreased. The porosity significantly decreased upon the addition of Ca salts (porosity, 20%) or PO4 salts (porosity, 14%) compared with that of the sample without additives (porosity, 53%). In vitro tests demonstrated enhanced cell adhesion on nanoporous BCP compared with densely sintered pure HAp, and cell differentiation was promoted on the nanoporous pure HAp.


Increased amounts of the influenza virus nucleoprotein do not promote higher levels of viral genome replication.
Influenza virus genome replication requires the virus-encoded nucleoprotein (NP), partly because it is necessary to encapsidate the viral genomic RNA (vRNA) and antigenomic cRNA segments into ribonucleoproteins (RNPs). However, there is also evidence that NP actively regulates viral RNA synthesis and there is a long-standing hypothesis that increased concentrations of NP in the cell are responsible for a switch from genome transcription to replication. Here, this hypothesis is tested in a recombinant setting and in the context of virus infection. In a plasmid-based system for reconstituting active viral RNPs in cells, titration of increasing amounts of NP did not promote higher levels of genome replication relative to transcription, but in fact caused the opposite effect. An approximately fourfold reduction in the ratio of genomic and antigenomic RNAs to mRNA was seen across an 80-fold range of NP plasmid concentrations. When cells were transfected with the same amounts of NP plasmid to establish a concentration gradient of NP prior to virus superinfection, no change in the ratio of cRNA to mRNA was seen for segments 5 and 7, or for the ratio of segment 5 vRNA to mRNA. A slight reduction in the ratio of segment 7 vRNA to mRNA was seen. These findings do not support the simple hypothesis that increased intracellular concentrations of NP promote influenza virus genome replication.


fdg-pet in two cases of neurofibromatosis type 1 and atypical malignancies.
Patients with neurofibromatosis type 1 (nf1) are at increased risk for both benign and malignant tumours, and distinguishing the malignant potential of an individual tumour is a common clinical problem in these patients. Here, we review two cases of uncommon malignancies (Hodgkin lymphoma and mediastinal germ-cell tumour) in patients with nf1. Although (18)F-fluorodeoxyglucose positron-emission tomography (fdg-pet) has been used to differentiate benign neurofibromas from malignant peripheral nerve sheath tumours, fdg-pet characteristics for more rare tumours have been poorly described in children with nf1. Here, we report the role of pet imaging in clinical decision-making in each case. In nf1, fdg-pet might be useful in the clinical management of unusual tumour presentations and might help to provide information about the malignant potential of uncommon tumours.


In-treatment midwall and endocardial fractional shortening predict cardiovascular outcome in hypertensive patients with preserved baseline systolic ventricular function: the Losartan Intervention For Endpoint reduction study.
Endocardial fractional shortening (EFS) and midwall shortening (MWS) are impaired in patients with left ventricular hypertrophy. However, it remains unknown whether improvement of left ventricular systolic function during treatment reduces cardiovascular morbidity and mortality in hypertensive patients with preserved left ventricular function. Echocardiograms were performed yearly in 840 hypertensive patients with electrocardiographic left ventricular hypertrophy and baseline left ventricular ejection fraction more and equal to 50%. Baseline and annual in-treatment levels of EFS, MWS and blood pressure (BP) were related to occurrence of a composite endpoint (cardiovascular death, myocardial infarction or stroke) and the component endpoints during 3914 patient-years of follow-up. Adjusting for in-treatment BP, left ventricular mass, relative wall thickness and randomized treatments, higher in-treatment EFS was associated with lower risk of myocardial infarction (by 35% per standard deviation [4.5%], P = 0.004) and heart failure (49%, P < 0.001), but in-treatment stress-corrected EFS predicted only incident heart failure (41%, P = 0.014) but not other endpoints. Higher in-treatment MWS tended to be associated with lower risk of composite endpoints (16% per standard deviation [1.8%], P = 0.07) and was significantly associated with myocardial infarction (33%, P = 0.004) and heart failure (43%, P < 0.001). Higher in-treatment stress-corrected MWS was associated with lower rates of myocardial infarction (35%, P = 0.021) and heart failure (50%, P = 0.001). These results support a prognostic role for left ventricular myocardial function, as estimated by stress-corrected MWS, during aggressive BP lowering in hypertensive patients with preserved ejection fraction at baseline evaluation.


Information systems for the analysis of drug prescriptions in Spain.
The Spanish National Health Service, largely represented by INSALUD, covers at present over 98% of the Spanish population. Services are free at the point of delivery with exception of prescription charges. The patients contribution towards the price of their medicines is approximately 40% of the cost of the drug for most ethical preparations. Non-prescription drugs are not reimbursed by the National Health Service. Pensioners and the disabled are exempt from prescription charges. Prescription analysis or monitoring is possible within INSALUD because of the necessity to reimburse pharmacists for the prescriptions they dispense, monthly batches of prescriptions are processed. The Drug Data Bank possesses three databases that may be used for prescription analysis, these are ESPES, ECOM and PACTIV. Information from these databases is used by external workers in: drug Monitoring Centres for Adverse Drug Reactions; the Spanish Collaborative Study on drug-induced birth effects; drug utilization research workers; INSALUD also produces reports on drug prescribing and these have a particular emphasis on expenditure; the General Directorate of Pharmacy also use these databases for their policy making on issues related to, and derived from prescribing.


Medication reconciliation in a Swiss hospital: methods, benefits and pitfalls.
To assess the feasibility and main obstacles to the implementation of a medication reconciliation (MR) process in a Swiss hospital and to develop a standardised method which can be used in similar healthcare systems. For this prospective, observational single-centre and single-ward study, a best possible medication history (BPMH) was established by a clinical pharmacist for 147 patients with heart failure based on two sources and a patient interview for each case. Identified discrepancies with medication histories established during emergency service were conveyed to the ward physician. At the end of each hospital stay, the planned discharge treatments were compared with the BPMHs to identify discrepancies and to propose modifications. After a final validation, the comparative treatment plans were distributed. MR was conducted for 120 (82%) patients and the mean time needed was 74 min/patient. At least one discrepancy was identified among 94% of the patients on admission, with 4.1 discrepancies found per patient (mainly omissions). At discharge, 83% of the patients had at least one discrepancy, with 2.3 discrepancies found per patient (mainly unintentional substitutions). The majority (86%) of pharmaceutical interventions to adjust the discharge prescriptions were accepted by the physician. A standardised method of MR which offers precise definitions of discrepancies and key tools for the process was developed. This method was applicable to most of our cohort and it effectively identified medication discrepancies. Two potential obstacles for its implementation are the time needed for MR and the questionable impact of pharmaceutical interventions on discrepancies.


Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease.
Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 microg once-daily from a dry-powder inhaler (HandiHaler, 20 patients), or ipratropium 40 microg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1-2 h postdosing and a duration of action of approximately 4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation.


Restrictive measures and substance use reporting: New evidence from the COVID-19 pandemic.
Since the beginning of the COVID-19 pandemic, several studies have been conducted on the impact of lockdown and containment measures on various aspects of individual and social behaviour, including substance use. The increasing body of literature investigating this phenomenon emphasizes the need for additional studies at the local level. We investigate changes in reported illicit drug consumption following changes in public measures limiting individual mobility in the province of Bergamo, one of the regions that faced the most severe consequences in terms of number of cases and death toll in the early stages of the pandemic. The empirical analysis is based on a unique dataset covering all people recorded by police forces as drug users between January 2019 and December 2021 in the province of Bergamo. Data relate to reports for illicit drug consumption and not criminal activities. Estimates show that, during periods when individual mobility was severely limited, the probability of reported cannabis consumption decreased by 8-9%, while that of reported cocaine use increased by 6-12%. No significant changes emerge in the reported consumption of heroin or polysubstance. Furthermore, while reported cannabis use returned to pre-pandemic levels once the restrictive measures were eased, the increased likelihood of reported cocaine use appears to have been more long-lasting. These findings are robust to alternative estimation strategies and different model specifications. Our study also reveals significant gender, age and housing status disparities in reported drug use. We provide a novel and distinctive perspective on the topic by using previously unexploited administrative data sources. We show that the relationship between restrictions and reported drug use varies by type of substance. Our methodology and findings can support the design of targeted policies for better resource allocation and improved public health outcomes.


Structural, elastic and optoelectronic properties of inorganic cubic FrBX3 (B = Ge, Sn; X = Cl, Br, I) perovskite: the density functional theory approach.
Inorganic metal-halide cubic perovskite semiconductors have become more popular in industrial applications of photovoltaic and optoelectronic devices. Among various perovskites, lead-free materials are currently most explored due to their non-toxic effect on the environment. In this study, the structural, electronic, optical, and mechanical properties of lead-free cubic perovskite materials FrBX3 (B = Ge, Sn; X = Cl, Br, I) are investigated through first-principles density-functional theory (DFT) calculations. These materials are found to exhibit semiconducting behavior with direct bandgap energy and mechanical phase stability. The observed variation in the bandgap is explained based on the substitutions of cations and anions sitting over B and X-sites of the FrBX3 compounds. The high absorption coefficient, low reflectivity, and high optical conductivity make these materials suitable for photovoltaic and other optoelectronic device applications. It is observed that the material containing Ge (germanium) in the B-site has higher optical absorption and conductivity than Sn containing materials. A systematic analysis of the electronic, optical, and mechanical properties suggests that among all the perovskite materials, FrGeI3 would be a potential candidate for optoelectronic applications. The radioactive element Fr-containing perovskite FrGeI3 may have applications in nuclear medicine and diagnosis such as X-ray imaging technology.


Overexpression of microRNAs from the Gtl2-Rian locus contributes to postnatal death in mice.
The Dlk1-Dio3 imprinted domain functions in embryonic development but the roles of noncoding RNAs expressed from this domain remain unclear. We addressed this question by generating transgenic (TG) mice harbouring a BAC carrying IG-DMR (intergenic-differentially methylated region), Gtl2-DMR, Gtl2, Rtl1/Rtl1as, and part of Rian. High postnatal lethality (>85%) of the BAC-TG pups was observed in the maternally transmitted individuals (MAT-TG), but not following paternal transmission (PAT-TG). The DNA methylation status of IG-DMR and Gtl2-DMR in the BAC-allele was paternally imprinted similar to the genomic allele. The mRNA-Seq and miRNA-Seq analysis revealed marked expression changes in the MAT-TG, with 1,500 upregulated and 2,131 downregulated genes. The long noncoding RNAs and 12 miRNAs containing the BAC locus were markedly enhanced in the MAT-TG. We identified the 24 target genes of the overexpressed miRNAs and confirmed the downregulation in the MAT-TG. Notably, overexpression of mir770, mir493, and mir665 from Gtl2 in the MAT-TG embryos led to decreased expression of the 3 target genes, Col5a1, Pcgf2, and Clip2. Our results suggest that decreased expression of the 3 target genes concomitant with overexpression of the miRNAs within Gtl2 may be involved in the postnatal death in the MAT-TG. Because this imprinted domain is well conserved between mice and humans, the results of genetic and molecular analysis in mice hold important implications for related human disorders such as Temple syndrome.


Anti-CEA Pretargeted Immuno-PET Shows Higher Sensitivity Than DOPA PET/CT in Detecting Relapsing Metastatic Medullary Thyroid Carcinoma: Post Hoc Analysis of the iPET-MTC Study.
Pretargeting parameters for the use of anti-carcinoembryonic antigen (CEA) bispecific monoclonal antibody TF2 and the 68Ga-labeled IMP288 peptide for immuno-PET have been optimized in a first-in-humans study performed on medullary thyroid carcinoma (MTC) patients (the iPET-MTC study). The aim of this post hoc analysis was to determine the sensitivity of immuno-PET in relapsing MTC patients, in comparison with conventional imaging and 18F-l-dihydroxyphenylalanine (18F-DOPA) PET/CT. Methods: Twenty-five studies were analyzed in 22 patients. All patients underwent immuno-PET 1 and 2 h after 68Ga-IMP288 injection pretargeted by TF2, in addition to neck, thoracic, abdominal, and pelvic CT; bone and liver MRI; and 18F-DOPA PET/CT. The gold standard was histology or confirmation by one other imaging method or by imaging follow-up. Results: In total, 190 lesions were confirmed by the gold standard: 89 in lymph nodes, 14 in lungs, 46 in liver, 37 in bone, and 4 in other sites (subcutaneous tissue, heart, brain, and pancreas). The number of abnormal foci detected by immuno-PET was 210. Among these, 174 (83%) were confirmed as true-positive by the gold standard. Immuno-PET showed a higher overall sensitivity (92%) than 18F-DOPA PET/CT (65%). Regarding metastatic sites, immuno-PET had a higher sensitivity than CT, 18F-DOPA PET/CT, or MRI for lymph nodes (98% vs. 83% for CT and 70% for 18F-DOPA PET/CT), liver (98% vs. 87% for CT, 65% for 18F-DOPA PET/CT, and 89% for MRI), and bone (92% vs. 64% for 18F-DOPA PET/CT and 86% for MRI), whereas sensitivity was lower for lung metastases (29% vs. 100% for CT and 14% for 18F-DOPA PET/CT). Tumor SUVmax at 60 min ranged from 1.2 to 59.0, with intra- and interpatient variability. Conclusion: This post hoc study demonstrates that anti-carcinoembryonic antigen immuno-PET is an effective procedure for detecting metastatic MTC lesions. Immuno-PET showed a higher overall sensitivity than 18F-DOPA PET/CT for disclosing metastases, except for the lung, where CT remains the most effective examination.


Aligning everyday life priorities with people's self-management support networks: an exploration of the work and implementation of a needs-led telephone support system.
Recent initiatives to target the personal, social and clinical needs of people with long-term health conditions have had limited impact within primary care. Evidence of the importance of social networks to support people with long-term conditions points to the need for self-management approaches which align personal circumstances with valued activities. The Patient-Led Assessment for Network Support (PLANS) intervention is a needs-led assessment for patients to prioritise their health and social needs and provide access to local community services and activities. Exploring the work and practices of patients and telephone workers are important for understanding and evaluating the workability and implementation of new interventions. Qualitative methods (interviews, focus group, observations) were used to explore the experience of PLANS from the perspectives of participants and the telephone support workers who delivered it (as part of an RCT) and the reasons why the intervention worked or not. Normalisation Process Theory (NPT) was used as a sensitising tool to evaluate: the relevance of PLANS to patients (coherence); the processes of engagement (cognitive participation); the work done for PLANS to happen (collective action); the perceived benefits and costs of PLANS (reflexive monitoring). 20 patients in the intervention arm of a clinical trial were interviewed and their telephone support calls were recorded and a focus group with 3 telephone support workers was conducted. Analysis of the interviews, support calls and focus group identified three themes in relation to the delivery and experience of PLANS. These are: formulation of 'health' in the context of everyday life; trajectories and tipping points: disrupting everyday routines; precarious trust in networks. The relevance of these themes are considered using NPT constructs in terms of the work that is entailed in engaging with PLANS, taking action, and who is implicated this process. PLANS gives scope to align long-term condition management to everyday life priorities and valued aspects of life. This approach can improve engagement with health-relevant practices by situating them within everyday contexts. This has potential to increase utilisation of local resources with potential cost-saving benefits for the NHS. ISRCTN45433299.


Aspirin-resistant thromboxane biosynthesis and the risk of myocardial infarction, stroke, or cardiovascular death in patients at high risk for cardiovascular events.
We studied whether aspirin resistance, defined as failure of suppression of thromboxane generation, increases the risk of cardiovascular events in a high-risk population. Baseline urine samples were obtained from 5529 Canadian patients enrolled in the Heart Outcomes Prevention Evaluation (HOPE) Study. Using a nested case-control design, we measured urinary 11-dehydro thromboxane B2 levels, a marker of in vivo thromboxane generation, in 488 cases treated with aspirin who had myocardial infarction, stroke, or cardiovascular death during 5 years of follow-up and in 488 sex- and age-matched control subjects also receiving aspirin who did not have an event. After adjustment for baseline differences, the odds for the composite outcome of myocardial infarction, stroke, or cardiovascular death increased with each increasing quartile of 11-dehydro thromboxane B2, with patients in the upper quartile having a 1.8-times-higher risk than those in the lower quartile (OR, 1.8; 95% CI, 1.2 to 2.7; P=0.009). Those in the upper quartile had a 2-times-higher risk of myocardial infarction (OR, 2.0; 95% CI, 1.2 to 3.4; P=0.006) and a 3.5-times-higher risk of cardiovascular death (OR, 3.5; 95% CI, 1.7 to 7.4; P<0.001) than those in the lower quartile. In aspirin-treated patients, urinary concentrations of 11-dehydro thromboxane B2 predict the future risk of myocardial infarction or cardiovascular death. These findings raise the possibility that elevated urinary 11-dehydro thromboxane B2 levels identify patients who are relatively resistant to aspirin and who may benefit from additional antiplatelet therapies or treatments that more effectively block in vivo thromboxane production or activity.


Biomechanical properties of the thoracic aneurysmal wall: differences between bicuspid aortic valve and tricuspid aortic valve patients.
The prevalence for thoracic aortic aneurysms (TAAs) is significantly increased in patients with a bicuspid aortic valve (BAV) compared with patients who have a normal tricuspid aortic valve (TAV). TAA rupture is a life-threatening event, and biomechanics-based simulations of the aorta may help to disentangle the molecular mechanism behind its development and progression. The present study used polarized microscopy and macroscopic in vitro tensile testing to explore collagen organization and mechanical properties of TAA wall specimens from BAV and TAV patients. Circumferential sections of aneurysmal aortic tissue from BAV and TAV patients were obtained during elective operations. The distribution of collagen orientation was captured by a Bingham distribution, and finite element models were used to estimate constitutive model parameters from experimental load-displacement curves. Collagen orientation was almost identical in BAV and TAV patients, with a highest probability of alignment along the circumferential direction. The strength was almost two times higher in BAV samples (0.834 MPa) than in TAV samples (0.443 MPa; p<0.001). The collagen-related stiffness (Cf) was significantly increased in BAV compared with TAV patients (Cf=7.45 MPa vs 3.40 MPa; p=0.003), whereas the elastin-related stiffness was similar in both groups. A trend toward a decreased wall thickness was seen in BAV patients (p=0.058). The aneurysmal aortas of BAV patients show a higher macroscopic strength, mainly due to an increased collagen-related stiffness, compared with TAV patients. The increased wall stiffness in BAV patients may contribute to the higher prevalence for TAAs in this group.


Suppression of cyclobutane and mean value of 6-4 dipyrimidines formation in triple-stranded H-DNA.
We have determined the effect of H-DNA formation on the distributions of two ultraviolet (UV) light induced photoproducts--cyclobutane dipyrimidines and mean value of 6-4 dipyrimidines. A region of DNA containing the sequence (dT-dC)18.(dA-dG)18 was treated under conditions that specifically yield the triple-stranded H-y3 or H-y5 DNA structure and then irradiated with UV. The positions of cyclobutane dipyrimidines and mean value of 6-4 dipyrimidines were determined by T4 endonuclease V cleavage and by hot piperidine cleavage, respectively. Formation of H-DNA structures greatly decreased the photoproduct yield in the (dT-dC)18.(dA-dG)18 region but not elsewhere in the DNA. Suppression of photoproduct formation is greater in half of the repeat, reflecting whether the DNA is in the H-y3 or H-y5 conformation. Within the repeat, the suppression was less in the middle and toward the ends. Models for the suppression of photoproduct formation in H-DNA and the possible utility of our findings are discussed.


The Precision of Propex Pixi with Different Instruments and Coronal Preflaring Procedures.
This study aimed to evaluate the influence of the instrument regarding the apical fit and type of the alloy and coronal preflaring procedures in the accuracy of Propex Pixi. A total of 40 extracted human single-rooted permanent teeth with apical diameters of 200 µm were selected. A #10 K-file was inserted in the root canal until its end could be observed by a dental microscope to obtain the actual working length (WL). Electronic measurements were performed using Propex Pixi to the root apex ("0.0"). Different file alloys (stainless steel [SS] and nickel titanium [NiTi]) and sizes (#10, #15, and #20) were used before and after coronal flaring. Statistical analysis was performed by a factorial analysis of variance (P≤0.05). Results showed that the measurements of electronic length (EL) were closer to the actual working length (WL) after coronal flaring (P<0.05). A significant intraclass correlation was observed between EL and WL. In addition, results showed no significant differences between files with different sizes or alloys. Under the conditions of this study, Propex Pixi demonstrated adequate precision. Its accuracy was enhanced by coronal preflaring procedures regardless of the instrument type used (SS or NiTi) and the apical fit.


Effects of habitat quality and size on extinction in experimental populations.
Stochastic population theory makes clear predictions about the effects of reproductive potential and carrying capacity on characteristic time-scales of extinction. At the same time, the effects of habitat size and quality on reproduction and regulation have been hotly debated. To trace the causal relationships among these factors, we looked at the effects of habitat size and quality on extinction time in experimental populations of Daphnia magna. Replicate model systems representative of a broad-spectrum consumer foraging on a continuously supplied resource were established under crossed treatments of habitat size (two levels) and habitat quality (three levels) and monitored until eventual extinction of all populations. Using statistically derived estimates of key parameters, we related experimental treatments to persistence time through their effect on carrying capacity and the population growth rate. We found that carrying capacity and the intrinsic rate of increase were each influenced similarly by habitat size and quality, and that carrying capacity and the intrinsic rate of increase were in turn both correlated with time to population extinction. We expected habitat quality to have a greater influence on extinction. However, owing to an unexpected effect of habitat size on reproductive potential, habitat size and quality were similarly important for population persistence. These results support the idea that improving the population growth rate or carrying capacity will reduce extinction risk and demonstrate that both are possible by improving habitat quality or increasing habitat size.


Evidence for Continuing Professional Development and Recency of Practice Standards for Regulated Health Professionals in Australia: Protocol for a Systematic Review.
Continuing professional development (CPD) and recency of practice (ROP) standards are components of health practitioner regulation in Australia. The CPD and ROP standards are currently under review, and an evidence base to assist the development of consistent standards is required. Preliminary searching was unable to find a recent systematic review of the literature to provide an evidence base to underpin the standards review. This paper presents the protocol for a systematic review that aims to develop a current evidence base that will support the National Boards to develop more consistent, evidence-based, effective standards that are clear and easy to understand and operationalize. Research questions were developed to support the planned review of CPD and ROP registration standards. Major databases and relevant journals were searched for articles published in English between 2015 and 2021, using key search terms based on previous unpublished reviews of the CPD and ROP registration standards. The quality of the articles retrieved will be assessed using an instrument suitable for use in the development of public policy. The findings will be published in a peer-reviewed journal. In September 2021, our search strategy identified 18,002 studies for the CPD-related research questions after removal of duplicates. Of these, 509 records were screened based on their title, and 66 full-text articles were assessed for eligibility based on their abstract, of which 31 met the inclusion criteria. A further 291 articles were identified as relevant to the ROP research questions. Of these, 87 records were screened based on their title, and 46 full-text articles were assessed for eligibility based on their abstract, of which 8 studies met our inclusion criteria. This protocol outlines the scope and methodology that will be used to conduct a systematic review of evidence for CPD and ROP and inform a review of the standards for regulated health professionals in Australia. Previous research has shown that while CPD improves practitioner knowledge, the link to public safety is unclear. While there has been a greater focus on maintenance of certification and other quality assurance activities over the past 10 years, there remains great variability in CPD requirements across both professions and jurisdictions. ROP was found to be a poorly researched area with most research concentrating on medical practitioners, nurses, and midwives and no clear consensus about the optimal time period after which retraining or an assessment of competence should be introduced. As the CPD and ROP standards are currently under review, it is timely that a review of current evidence be undertaken. DERR1-10.2196/28625.


Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth.
Glycine, proline, and hydroxyproline (Hyp) contribute to 57% of total amino acids (AAs) in collagen, which accounts for one-third of proteins in animals. As the most abundant protein in the body, collagen is essential to maintain the normal structure and strength of connective tissue, such as bones, skin, cartilage, and blood vessels. Mammals, birds, and fish can synthesize: (1) glycine from threonine, serine, choline, and Hyp; (2) proline from arginine; and (3) Hyp from proline residues in collagen, in a cell- and tissue-specific manner. In addition, livestock (e.g., pigs, cattle, and sheep) produces proline from glutamine and glutamate in the small intestine, but this pathway is absent from birds and possibly most fish species. Results of the recent studies indicate that endogenous synthesis of glycine, proline, and Hyp is inadequate for maximal growth, collagen production, or feed efficiency in pigs, chickens, and fish. Although glycine, proline and Hyp, and gelatin can be used as feed additives in animal diets, these ingredients except for glycine are relatively expensive, which precludes their inclusion in practical rations. Alternatively, hydrolyzed feather meal (HFM), which contains 9% glycine, 5% Hyp, and 12% proline, holds great promise as a low cost but abundant dietary source of glycine, Hyp, and proline for ruminants and nonruminants. Because HFM is deficient in most AAs, future research efforts should be directed at improving the bioavailability of its AAs and the balance of AAs in HFM-supplemented diets. Finally, HFM may be used as a feed additive to prevent or ameliorate connective tissue disorders in domestic and aquatic animals.


How to use machine learning and fuzzy cognitive maps to test hypothetical scenarios in health behavior change interventions: a case study on fruit intake.
Intervention planners use logic models to design evidence-based health behavior interventions. Logic models that capture the complexity of health behavior necessitate additional computational techniques to inform decisions with respect to the design of interventions. Using empirical data from a real intervention, the present paper demonstrates how machine learning can be used together with fuzzy cognitive maps to assist in designing health behavior change interventions. A modified Real Coded Genetic algorithm was applied on longitudinal data from a real intervention study. The dataset contained information about 15 determinants of fruit intake among 257 adults in the Netherlands. Fuzzy cognitive maps were used to analyze the effect of two hypothetical intervention scenarios designed by domain experts. Simulations showed that the specified hypothetical interventions would have small impact on fruit intake. The results are consistent with the empirical evidence used in this paper. Machine learning together with fuzzy cognitive maps can assist in building health behavior interventions with complex logic models. The testing of hypothetical scenarios may help interventionists finetune the intervention components thus increasing their potential effectiveness.


Captopril ameliorates myocarditis in acute experimental Chagas disease.
Captopril, an angiotensin-converting enzyme inhibitor, is commonly prescribed to patients with Chagas heart disease (CHD). There are few human studies and no animal studies on the effects of captopril in CHD. We investigated the effects of captopril on myocarditis and the host immune response to Trypanosoma cruzi in an experimental model of acute CHD. A/J mice infected with Brazil strain of T cruzi developed acute myocarditis by day 21 after infection, consisting of severe focal inflammation, necrosis, fibrosis, and T cruzi pseudocysts. Administration of captopril (5 mg/L in the water) significantly reduced necrosis and fibrosis in infected mice. Increasing the captopril dose also led to a decrease in inflammation. Captopril did not affect overall mortality but did delay death while having no effect on parasitemia or cardiac parasite load. Treatment did not affect humoral immunity against T cruzi or cardiac myosin (autoimmunity) but did decrease delayed-type hypersensitivity responses against both antigens. Interestingly, increasing the dose of captopril induced mortality in infected mice in a dose-dependent manner. Mortality was apparently not due to T cruzi because neither parasitemia nor cardiac parasitosis was affected. The combination of captopril and infection may have impaired renal function because these mice had increased water consumption, decreased body mass, and increased serum BUN/creatinine ratio. Captopril ameliorates the myocarditis associated with acute T cruzi infection.


Use of Functional Foods and Oral Supplements as Adjuvants in Cancer Treatment.
In cancer patients treated with radiotherapy to the abdominopelvic region, dietary modifications and the use of functional foods (fortified food with added ingredients to provide specific health improving benefits, such as antioxidants, omega-3 fatty acids, and glutamine), may contribute to the improvement of the toxic effects of treatment, including nausea, diarrhea, and constipation, among others. With the aim of analyzing which coadjuvant foods benefit these patients, scientific evidence was gathered by a group of experts. For these patients, the authors recommend a diet that includes sufficient foods rich in antioxidants and polyphenols instead of supplements. Docosahexaenoic and eicosapentaenoic acids have proven useful for the management of anorexia/cachexia in pancreatic cancer patients. Probiotics composed of Lactobacillus spp. and Bifidobacterium spp. are regarded as safe even in patients with neutropenia and have been proven to decrease gastrointestinal symptoms. Several factors should be considered before probiotic supplementation, these include the stage of the disease, radiation dose, and symptomatology of each patient. There is no demonstrated clear benefit to the use of glutamine, so it is not recommended due to its high cost.


To each according to need: a community-based approach to allocating health care resources.
To develop a method of allocating publicly funded health care resources among communities according to their relative levels of need for health care independent of their current patterns of use. For each health care program population mean levels of resource allocation were calculated and were adjusted for age and sex to produce a national age- and sex-adjusted share of program resources. Indices of relative need for health care (for most programs the standardized mortality ratio) were derived from existing data on aspects of illness and death and were then used to weight the age- and sex-adjusted shares for between-community differences in health risks and health care needs. The populations of the 49 counties in Ontario were used as the communities among which resources were allocated. Health care expenditures in 1988-89 by the Ontario Ministry of Health were used as the "budget." Age- and sex-adjusted resource allocations weighted for between-community differences in health care needs differed from allocations based on population size, in certain cases by up to 100%. Existing data can be used to propose allocations of health care resources that relate to relative levels of need for care across communities.


Arterial stiffness and SBP variability in children and adolescents.
The aim of this study was to explore the impact of ambulatory blood pressure (ABP) parameters on arterial stiffness measured by carotid-femoral pulse wave velocity (cf-PWV) in children and adolescents. The study population consisted of 138 consecutive young patients (age range 4-20 years) referred to our hypertension center. Office blood pressure (BP), 24-h ABP monitoring and cf-PWV measurements were performed in all patients. Family history and smoking habits were also recorded. Among the study population, 10.6% had cf-PWV values equal to or higher than the 95th percentile of the study population. cf-PWV was higher in the hypertensive compared to the normotensive patients, classified by ABP levels even after adjustment for age and sex. Significant correlations were found between cf-PWV and age, weight, height, estimated central pulse pressure (PP), office SBP and DBP, and ABP parameters including 24-h SBP and DBP, weighted 24-h SBP variability, 24-h SBP and DBP load, 24-h mean arterial pressure (MAP), daytime and night-time SBP, daytime and night-time SBP variability, but not with office and 24-h heart rate, 24-h heart rate variability, 24-h daytime and night-time PP, DBP variability, ambulatory arterial stiffeness index and BMI z-score. In analysis of covariance, only weighted 24-h SBP variability (β = 0.28, P < 0.05) and daytime SBP variability (β = 0.15, P < 0.05) were the independent determinants of cf-PWV in children and adolescents. These data may suggest that increased SBP variability is closely associated with arterial stiffness in children and adolescents.


[Standard structures in protein molecules. I. Alpha-beta hairpins].
Structures formed by consecutive alpha-helices and beta-strands which are packed approximately antiparallel into alpha-beta-hairpins are considered. It is shown that there is a limited number of standard conformations for the alpha-beta-hairpins having not more than six peptide units in connecting regions. The features of the amino acid sequences encoding the alpha-beta-hairpins are analyzed. It is shown that each standard alpha-beta-hairpin has a strictly definite order of hydrophobic, hydrophilic and glycine residues in the sequence.


The structure, function and metabolism of high-density lipoproteins: A status report.
Case-control and prospective epidemiologic studies have found a striking, consistently negative association between high-density lipoprotein (HDL) levels and coronary vascular events. As a result, the genetic and environmental determinants of HDL levels are being studied intensively. These investigations and their potential clinical applications require a fundamental understanding of the structure, function and metabolism of HDL and its components. Of special interest are the means by which HDL exerts its apparently protective effect. In this report we characterize the structure of HDL and describe its components, particularly the protein component. We discuss HDL metabolism in light of the relationship of HDL to the other lipoprotein classes, and relate what little is known of the functions of HDL. We also review the biochemical mechanisms by which HDL may protect against cardiovascular disease and discuss further biochemical research that will be necessary for a better understanding of HDL.


Correlation Between Clinical Signs and High-resolution Manometry Data in Children.
High-resolution manometry (HRM) is the gold standard for diagnosis of esophageal motility disorders. However, clinical signs associated with these disorders are nonspecific, and it is difficult to correlate clinical signs with HRM data. The main objective of our study was to assess the positive predictive value (PPV) and negative predictive value (NPV) of each clinical sign, as well as their sensitivity and specificity in the diagnosis of esophageal motility disorders. This is a bicentric retrospective cohort study based on HRM data collected between May 2012 and May 2016. The studied symptoms were weight loss, feeding difficulties, swallowing disorders, dysphagia, food blockages, vomiting, gastroesophageal reflux disease (GERD), belching, and respiratory symptoms. HRM data were analyzed according to the Chicago Classification (3.0). In total, 271 HRM data were analyzed, of which 90.4% showed abnormal results. HRM was well tolerated in 91% of the cases. The most common esophageal motility disorder was ineffective esophageal motility (38%). Weight loss was significantly associated (P = 0.003) with an abnormal HRM with a 96% PPV. With nonspecific clinical signs suggesting an esophageal motility disorder, weight loss was a predictive sign of abnormal HRM results. HRM was well tolerated in pediatric patients, and ineffective esophageal motility appears to be the most frequent motility disorder in our cohort, as already observed in adult patient studies.


ErbB4 affects Th1/Th17 cell differentiation and promotes psoriasis progression.
Psoriasis seriously harms people's physical and mental health. More and more people pay attention to improving the psoriasis process by immune cells. Our study alters the course of psoriasis by discovering the effect of ErbB4 on the ratio of Th1/Th17 cells. We detected the expression of ErbB4 in CD4-positive T cells in peripheral blood of clinical patients and clinical samples by qPCR and detected the expression of ErbB4 in mouse samples of the model group. ErbB4 siRNA was designed and transfected into cells. The effect of ErbB4 siRNA on Th1/Th17 cell ratio was observed by flow cytometry. ErbB4 siRNA was transfected into mice by lentivirus infection to observe its effect on psoriasis. Finally, the mechanism of ErbB4 affecting psoriasis was observed by Western Blot. According to the results, ErbB4 is highly expressed in clinical samples of psoriasis and CD4-positive T cells of patients with psoriasis. Inhibition of ErbB4 expression can reduce the proportion of Th1/Th17 cells, improve the pathogenesis of psoriasis and have therapeutic effect on psoriasis. Western Blot results showed that ErbB4 affected psoriasis through the IL23/IL17A signal axis. Our study demonstrates that ErbB4 could be a potential immune target for the treatment of psoriasis.