Systematic review and meta-analysis of diagnostic accuracy of detection of any level of diabetic retinopathy using digital retinal imaging.
Visual impairment from diabetic retinopathy (DR) is an increasing global public health concern, which is preventable with screening and early treatment. Digital retinal imaging has become a preferred choice as it enables higher coverage of screening. The aim of this review is to evaluate how different characteristics of the DR screening (DRS) test impact on diagnostic test accuracy (DTA) and its relevance to a low-income setting. We conducted a systematic literature search to identify clinic-based studies on DRS using digital retinal imaging of people with DM (PwDM). Summary estimates of different sub-groups were calculated using DTA values weighted according to the sample size. The DTA of each screening method was derived after exclusion of ungradable images and considering the eye as the unit of analysis. The meta-analysis included studies which measured DTA of detecting any level of DR. We also examined the effect on detection from using different combinations of retinal fields, pupil status, index test graders and setting. Six thousand six hundred forty-six titles and abstracts were retrieved, and data were extracted from 122 potentially eligible full reports. Twenty-six studies were included in the review, and 21 studies, mostly from high-income settings (18/21, 85.7%), were included in the meta-analysis. The highest sensitivity was observed in the mydriatic greater than two field strategy (92%, 95% CI 90-94%). The highest specificity was observed in greater than two field methods (94%, 95% CI 93-96%) where mydriasis did not affect specificity. Overall, there was no difference in sensitivity between non-mydriatic and mydriatic methods (86%, 95% CI 85-87) after exclusion of ungradable images. The highest DTA (sensitivity 90%, 95% CI 88-91%; specificity 95%, 95% CI 94-96%) was observed when screening was delivered at secondary/tertiary level clinics. Non-mydriatic two-field strategy could be a more pragmatic approach in starting DRS programmes for facility-based PwDM in low-income settings, with dilatation of the pupils of those who have ungradable images. There was insufficient evidence in primary studies to draw firm conclusions on how graders' background influences DTA. Conducting more context-specific DRS validation studies in low-income and non-ophthalmic settings can be recommended.


Association between drinking patterns and cardiovascular risk: a population-based study in the Southern Cone of Latin America.
Using data from general adult population, this study aims to describe epidemiology of alcohol consumption patterns and their association with cardiovascular risk. CESCAS I is a population-based study from four mid-sized cities in Argentina, Chile and Uruguay. Associations between diabetes, hypertension, dyslipidemia, cardiovascular disease (CVD) risk and history of CVD and drinking patterns were assessed using crude prevalence odds ratios (ORs) and adjusted OR. A total of 37.2% of the studied population never drank and 18.3% reported to be former drinkers. Among current drinkers, moderate drinking was the most frequent pattern (24.2%). For women with light and moderate consumption, the odds of having >20% CVD risk was ~40% lower than that of never drinkers. The odds of having a history of CVD was 50% lower in those with moderate consumption. For men with heavy consumption, the odds of having >20% CVD risk was about twice as high as for never drinkers. A harmful association was observed between heavy drinking and having >20% CVD risk for men. However, for women, an apparently protective association was observed between light and moderate drinking and having >20% CVD risk and between moderate drinking and having a history of CVD.


Cerebellar contribution to higher and lower order rule learning and cognitive flexibility in mice.
Cognitive flexibility has traditionally been considered a frontal lobe function. However, converging evidence suggests involvement of a larger brain circuit which includes the cerebellum. Reciprocal pathways connecting the cerebellum to the prefrontal cortex provide a biological substrate through which the cerebellum may modulate higher cognitive functions, and it has been observed that cognitive inflexibility and cerebellar pathology co-occur in psychiatric disorders (e.g., autism, schizophrenia, addiction). However, the degree to which the cerebellum contributes to distinct forms of cognitive flexibility and rule learning is unknown. We tested lurcher↔wildtype aggregation chimeras which lose 0-100% of cerebellar Purkinje cells during development on a touchscreen-mediated attentional set-shifting task to assess the contribution of the cerebellum to higher and lower order rule learning and cognitive flexibility. Purkinje cells, the sole output of the cerebellar cortex, ranged from 0 to 108,390 in tested mice. Reversal learning and extradimensional set-shifting were impaired in mice with⩾95% Purkinje cell loss. Cognitive deficits were unrelated to motor deficits in ataxic mice. Acquisition of a simple visual discrimination and an attentional-set were unrelated to Purkinje cells. A positive relationship was observed between Purkinje cells and errors when exemplars from a novel, non-relevant dimension were introduced. Collectively, these data suggest that the cerebellum contributes to higher order cognitive flexibility, lower order cognitive flexibility, and attention to novel stimuli, but not the acquisition of higher and lower order rules. These data indicate that the cerebellar pathology observed in psychiatric disorders may underlie deficits involving cognitive flexibility and attention to novel stimuli.


A multicenter pilot evaluation of the National Institutes of Health chronic graft-versus-host disease (cGVHD) therapeutic response measures: feasibility, interrater reliability, and minimum detectable change.
The lack of standardized criteria for measuring therapeutic response is a major obstacle to the development of new therapeutic agents for chronic graft-versus-host disease (cGVHD). National Institutes of Health (NIH) consensus criteria for evaluating therapeutic response were published in 2006. We report the results of 4 consecutive pilot trials evaluating the feasibility and estimating the interrater reliability and minimum detectable change of these response criteria. Hematology-oncology clinicians with limited experience in applying the NIH cGVHD response criteria (n = 34) participated in a 2.5-hour training session on response evaluation in cGVHD. Feasibility and interrater reliability between subspecialty cGVHD experts and this panel of clinician raters were examined in a sample of 25 children and adults with cGVHD. The minimum detectable change was calculated using the standard error of measurement. Clinicians' impressions of the brief training session, the photo atlas, and the response criteria documentation tools were generally favorable. Performing and documenting the full set of response evaluations required a median of 21 minutes (range: 12-60 minutes) per rater. The Schirmer tear test required the greatest time of any single test (median: 9 minutes). Overall, interrater agreement for skin and oral manifestations was modest; however, in the third and fourth trials, the agreement between clinicians and experts for all dimensions except movable sclerosis approached satisfactory values. In the final 2 trials, the threshold for defining change exceeding measurement error was 19% to 22% body surface area (BSA) for erythema, 18% to 26% BSA for movable sclerosis, 17% to 21% BSA for nonmovable sclerosis, and 2.1 to 2.6 points on the 15-point NIH Oral cGHVD scale. Agreement between clinician-expert pairs was moderate to substantial for the measures of functional capacity and for the gastrointestinal and global cGVHD rating scales. These results suggest that the NIH response criteria are feasible for use, and these reliability estimates are encouraging, because they were observed following a single 2.5-hour training session given at multiple transplant centers, with no opportunity for iterative training and calibration. Research is needed to evaluate inter- and intrarater reliability in larger samples, and to evaluate these response criteria as predictors of outcomes in clinical trials.


[General principles of the treatment of suppurative wounds and suppurative surgical diseases].
The article discusses the results of treatment of 7,092 patients with purulent wounds and septic surgical diseases by means of a suggested method of active surgical management. The main principles of the method are as follows: preoperative examination and preparation of the patients for operation for 12-36 hours; radical excision of all purulent and nonviable tissues followed by active drainage and treatment under conditions of controlled abacterial medium or by ointments on a water-soluble base; use of auxiliary methods for the treatment of the wound surface (pulsed stream of antiseptics, ultrasonic cavitation, vacuum treatment); performance of laboratory tests (microbial dissemination per 1 g tissue, cytologic and morphologic studies, values of tissue hemostasis) as an objective criterion of the course of the wound process and for determining whether the wound surface is ready for closure; accomplishment of intensive therapy; early closure of the wound surface with sutures or by plastic operations. Analysis of the data allows the conclusions that active surgical treatment may be accepted as an optimal and universal method for the management of purulent wounds of any etiology and septic surgical diseases. With its application, the terms of treatment are shortened due to most economical mechanisms of healing by first intention, and good functional and cosmetic results are produced. Such an effect is due to the pathogenetic character of all components of the method.


Cancer stem cells: involvement in pancreatic cancer pathogenesis and perspectives on cancer therapeutics.
Pancreatic cancer is one of the most aggressive and lethal malignancies. Despite remarkable progress in understanding pancreatic carcinogenesis at the molecular level, as well as progress in new therapeutic approaches, pancreatic cancer remains a disease with a dismal prognosis. Among the mechanisms responsible for drug resistance, the most relevant are changes in individual genes or signaling pathways and the presence of highly resistant cancer stem cells (CSCs). In pancreatic cancer, CSCs represent 0.2%-0.8% of pancreatic cancer cells and are considered to be responsible for tumor growth, invasion, metastasis and recurrence. CSCs have been extensively studied as of late to identify specific surface markers to ensure reliable sorting and for signaling pathways identified to play a pivotal role in CSC self-renewal. Involvement of CSCs in pancreatic cancer pathogenesis has also highlighted these cells as the preferential targets for therapy. The present review is an update of the results in two main fields of research in pancreatic cancer, pathogenesis and therapy, focused on the narrow perspective of CSCs.


The Household Water Insecurity Experiences Scale: answer patterns and cutoffs in Mexico.
To investigate the degree in which answer patterns in the Household Water Insecurity Experiences Scale (HWISE) relate to scores aiming at identifying latent groups with different water insecurity levels in a nationwide representative sample of the Mexican population. Based on data from the 2021 National Survey on Health and Nutrition (Estudio Nacional de Salud y Nutrición 2021, Ensanut 2021), sequence data representations, and a latent class analysis (LCA), in this article we estimate the likely misclassification errors of different cutoffs proposed for the HWISE scoring system. The main results suggest that a 5-item subset of the HWISE may exhibit a more reliable and cost-effective behavior than the complete 12-item set for a 2-level partition of the sample. Our methodological approach provides new insights regarding the efficiency and likely errors in distinguishing between levels of water insecurity based on the Mexican chapter of the HWISE.


Molecular Rhodium Complexes Supported on the Metal-Oxide-Like Nodes of Metal Organic Frameworks and on Zeolite HY: Catalysts for Ethylene Hydrogenation and Dimerization.
Metal-organic frameworks (MOFs) with nodes consisting of zirconium oxide clusters (Zr6) offer new opportunities as supports for catalysts with well-defined, essentially molecular, structures. We used the precursor Rh(C2H4)2(acac) (acac is acetylacetonate) to anchor Rh(I) complexes to the nodes of the MOF UiO-67 and, for comparison, to the zeolite dealuminated HY (DAY). These were characterized experimentally by measurement of catalytic activities and selectivities for ethylene hydrogenation and dimerization in a once-through flow reactor at 298 K and 1 bar. The catalyst performance data are complemented with structural information determined by infrared and extended X-ray absorption fine structure spectroscopies and by calculations at the level of density functional theory, the latter carried out also to extend the investigation to a related MOF, NU-1000. The agreement between the experimental and calculated structural metrics is good, and the calculations have led to predictions of reaction mechanisms and associated energetics. The data demonstrate a correlation between the catalytic activity and selectivity and the electron-donor tendency of the supported rhodium (as measured by the frequencies of CO ligands bonded as probes to the Rh(I) centers), which is itself a measure of the electron-donor tendency of the support.


MTG16 contributes to colonic epithelial integrity in experimental colitis.
The myeloid translocation genes (MTGs) are transcriptional corepressors with both Mtg8(-/-) and Mtgr1(-/-) mice showing developmental and/or differentiation defects in the intestine. We sought to determine the role of MTG16 in intestinal integrity. Baseline and stress induced colonic phenotypes were examined in Mtg16(-/-) mice. To unmask phenotypes, we treated Mtg16(-/-) mice with dextran sodium sulphate (DSS) or infected them with Citrobacter rodentium and the colons were examined for ulceration and for changes in proliferation, apoptosis and inflammation. Mtg16(-/-) mice have altered immune subsets, suggesting priming towards Th1 responses. Mtg16(-/-) mice developed increased weight loss, diarrhoea, mortality and histological colitis and there were increased innate (Gr1(+), F4/80(+), CD11c(+) and MHCII(+); CD11c(+)) and Th1 adaptive (CD4) immune cells in Mtg16(-/-) colons after DSS treatment. Additionally, there was increased apoptosis and a compensatory increased proliferation in Mtg16(-/-) colons. Compared with wild-type mice, Mtg16(-/-) mice exhibited increased colonic CD4;IFN-γ cells in vehicle-treated and DSS-treated mice. Adoptive transfer of wild-type marrow into Mtg16(-/-) recipients did not rescue the Mtg16(-/-) injury phenotype. Isolated colonic epithelial cells from DSS-treated Mtg16(-/-) mice exhibited increased KC (Cxcl1) mRNA expression when compared with wild-type mice. Mtg16(-/-) mice infected with C rodentium had more severe colitis and greater bacterial colonisation. Last, MTG16 mRNA levels were reduced in human ulcerative colitis versus normal colon tissues. These observations indicate that MTG16 is critical for colonocyte survival and regeneration in response to intestinal injury and provide evidence that this transcriptional corepressor regulates inflammatory recruitment in response to injury.


Surgical considerations in cochlear implantation in children and adults: a review of 342 cases in Vienna.
Our data represent the experience of the largest cochlear implant program in Austria. In conclusion, cochlear implantation is a safe procedure, associated with a low rate of intra- and postoperative complications. Nevertheless, patients should be informed about possible problems and especially about the risk of a reoperation due to device failure. To evaluate the cause of deafness, the intraoperative findings and the complication rate for all cochlear implant operations performed consecutively between 1994 and 2003 at Vienna General Hospital. Including all surgeries for bilateral implantation and revision, a series of 342 operations performed on 164 adults (age range 14.5-81 years; mean age 50.79 years) and 128 children (age range 0.75-14 years; mean age 5.00 years) was retrospectively analyzed. The etiology of deafness was predominantly congenital or progressive (66.89%). The routine mastoidectomy approach was chosen in 300 patients (87.72%) and the suprameatal approach in 42 (12.28%). Intraoperatively, 4 children (2.53%) had a cerebrospinal fluid fistula and 35 patients (10.23%) showed cochlear ossification. Three adults (1.63%) and two children (1.27%) had facial nerves with an aberrant course. The overall complication rate was 12.2%, the rate of major complications was 4.97% and the rate of minor complications was 4.09%. There were no cases of either postoperative meningitis or facial nerve palsy. Both flap necrosis and electrode dislocation occurred in one adult patient (0.54%), but in none of the children. Formation of cholesteatoma was found in one adult (0.54%) and one child (0.63%). The rate of device failure was 7.07% for adults and 13.92% for children.


Effect of heparin on the in vivo release and clearance of human platelet factor 4.
Intravenous injection of heparin (100 U/kg) into normal volunteers resulted in an increase of platelet factor 4 (PF4) level in platelet-poor plasma from a mean value of 18.1 +/- 6.6 ng/ml before the injection to 257.9 +/- 68.3 ng/ml at 5 min after injection. PF4 antigen isolated from "postheparin plasma" by adsorption on heparin-agarose and elution with 2.0 M NaCl and "authentic PF4" isolated from human platelets showed identical patterns of migration as determined by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Material released by washed human platelets was injected intravenously into rats. The clearance of PF4 followed a biphasic exponential pattern. The half-lives (T1/2) for the fast and slow components for control rats were 1.2 and 17.1 min. Heparin significantly extended the half-life of human PF4 in rat circulation. The clearance of PF4 injected together with heparin followed a single component model with a half-life of 27.6 min. Administration of heparin to rats that had been previously injected with human platelet releasate resulted in a 30-fold increase of plasma PF4 level in their circulation. The clearance of PF4 from the circulation of these rats (T1/2 = 45 min) fitted a single component model. We propose that PF4 is originally secreted by platelets into circulation and subsequently bound reversibly to vascular sites from which it can be released back into the circulation by heparin. The fast component of PF4 clearance that is abolished by heparin may reflect binding of this protein to the endothelial cells.


RELATIONSHIP BETWEEN SELECTED TRADITIONAL & NOVEL ANTHROPOMETRIC PARAMETERS AND BLOOD PRESSURE AMONG YOUNG PEOPLE.
Many anthropometric measures have been developed in the last two decades to evaluate cardiovascular health and disease. However, the relationship between these measures and blood pressure is not commonly explored among young population. This study sought to explore the relationship between selected traditional and novel anthropometric metrics and blood pressure among young people as part of ThE profile of anthRopometRy And psyChosocial issuEs on campus (TERRACE) study. A total of 375 participants were included in the study. Basic demographic details, standard methods were used to measure blood pressure, and anthropometric measures Height, weight, waist circumference, hip circumference, and neck circumference were measured. Derived waist and hip indices included the waist-hip ratio, waist-to-height ratio, weight-adjusted waist index, abdominal volume index, neck-to-height ratio, and conicity index. The linear relationships between the anthropometric parameters and systolic blood pressure, diastolic blood pressure, and pulse pressure were explored. Those that were strongly correlated, moderately correlated, weakly correlated, and effectively uncorrelated were graded 0.50-1.0, 0.30-0.49, 0.10-0.29, and less than 0.10, respectively. The analysis was done using SPSS version 23. A p-value <0.05 was considered significant. The mean age ±standard deviation(SD) and proportion of females were 21.1±3.5 years and 245 (65.3%), respectively. The mean ±SD systolic blood pressure, diastolic blood pressure, and pulse pressure were 109.2 11.2 mmHg, 67.5±8.8 mmHg, and 41.6±11.1 mmHg, respectively. Most of the variables have a statistically significant relationship with the blood pressure parameters; however, all are neither moderately nor strongly correlated. Most of the anthropometric indicators, including the novel ones, are correlated with BP parameters in this young population. However, further research is needed to unravel newer one with better correlations in this population.


Further evidence of an inverse genetic relationship between innate differences in alcohol preference and alcohol withdrawal magnitude in multiple selectively bred rat lines.
We have previously shown that a genetic association exists between low alcohol drinking and high alcohol withdrawal magnitude after acute alcohol exposure in alcohol-naïve rats. However, the behavioral rating scale used in this prior study was not optimal for assessing the magnitude of mild alcohol withdrawal. The present study examined whether a genetic relationship is again found between alcohol preference and alcohol withdrawal magnitude when a sensitive measure is used to index mild alcohol withdrawal in rats. Alcohol-naïve, male rats selectively bred for alcohol preference (P, HAD1, HAD2) or nonpreference (NP, LAD1, LAD2) received a single intragastric infusion of alcohol (4.0 g/20.3 ml/kg body weight; 25% v/v) or water followed by acoustic startle testing. Startle probability and magnitude was greater in water-treated P than in water-treated NP rats. During alcohol withdrawal, startle probability and magnitude was suppressed in P rats and elevated in NP rats relative to water-treated controls. Startle probability and magnitude was greater in water-treated LAD1 rats than in water-treated HAD1 rats. During alcohol withdrawal, startle probability and magnitude was suppressed in HAD1 and elevated in LAD1 rats relative to water-treated controls at 20 hr after acute alcohol exposure. Startle probability and magnitude did not differ between water-treated HAD2 and water-treated LAD2 rats. During alcohol withdrawal, there was a trend toward decreased startle probability and magnitude in HAD2 rats compared with water-treated controls. The acoustic startle response to a tone stimulus is a sensitive measure of mild alcohol withdrawal in rats. Rats selectively bred for low alcohol intake showed greater alcohol withdrawal magnitude than did rats selectively bred for high alcohol intake. These results provide further evidence that an inverse genetic association exists between alcohol withdrawal magnitude and propensity toward alcohol drinking in rats.


RB116: an RB1+ retinoblastoma cell line expressing primitive markers.
Retinoblastoma (RB), an intraocular tumor of childhood, is commonly associated with mutations in the RB1 gene. RB116 is a novel, early passage RB cell line that has not been previously characterized. In this study, we examined RB116 for the expression of RB1 and tested the hypothesis that RB116 cells would express stem cell markers as well as retinal progenitor cell markers. We compared RB116 cells with other well known RB cell lines, including Y79 and WERI-RB27. We evaluated expression of RB1 in RB116 cells by sequencing, multiplex ligation-dependent probe amplification, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), western immunoblot, and immunocytochemistry. Next, RB116 cells, along with Y79 and WERI-RB27 cells, were examined for expression of stem cell markers (ABCG2, Nanog, Oct3/4, ALDH1A1) and retinal progenitor markers (PAX6, CHX10) by quantitative immunocytochemistry. Immunocytochemical findings were accompanied by PCR analysis. RB116 cells expressed RB1 at the mRNA and protein levels, with no mutations detected by either sequencing analysis, or gene dosage abnormalities detected by multiplex ligation-dependent probe amplification. The RB1 protein was immunoreactive in RB116 cells with an atypical perinuclear localization. RB116 cells also expressed stem cell markers, with 3%-5% of cells immunopositive for ABCG2, Oct3/4 and ALDH1A1, with at least 18% of cells immunoreactive to Nanog. These findings were confirmed by RT-PCR. Small percentages of RB116 cells also exhibited immunoreactivity to retinal progenitor markers PAX6 (9.8%) and CHX10 (1.2%). Expression of mRNAs for these markers was confirmed by qRT-PCR. RB116 cells demonstrate RB1 expression accompanied by atypical perinuclear localization. RB116 cells also express primitive stem cell and retinal progenitor cell markers. Further studies on the phenotypes of both RB1-positive and RB1-negative human RB cells may be important in assessing differentiation potential of these cells, as well as designing targeted differentiation therapies.


Biohybrid polymer-antimicrobial peptide medium against Enterococcus faecalis.
Antimicrobial peptides (AMPs) are conserved evolutionary components of the innate immune system that are being tested as alternatives to antibiotics. Slow release of AMPs using biodegradable polymers can be advantageous in maintaining high peptide levels for topical treatment, especially in the oral environment in which dosage retention is challenged by drug dilution with saliva flow and by drug inactivation by salivary enzymatic activity. Enterococcus faecalis is a multidrug resistant nosocomial pathogen and a persistent pathogen in root canal infections. In this study, four ultra-short lipopeptides (C16-KGGK, C16-KLLK, C16-KAAK and C16-KKK) and an amphipathic α-helical antimicrobial peptide (Amp-1D) were tested against E. faecalis. The antibacterial effect was determined against planktonic bacteria and bacteria grown in biofilm. Of the five tested AMPs, C16-KGGK was the most effective. Next C16-KGGK was formulated with one of two polymers poly (lactic acid co castor oil) (DLLA) or ricinoleic acid-based poly (ester-anhydride) P(SA-RA). Peptide-synthetic polymer conjugates, also referred to as biohybrid mediums were tested for antibacterial activity against E. faecalis grown in suspension and in biofilms. The new formulations exhibited strong and improved anti-E. faecalis activity.


Optimization and Characterization of Novel ALCAM-Targeting Antibody Fragments for Transepithelial Delivery.
Activated leukocyte cell adhesion molecule (ALCAM) is a cell adhesion molecule that supports T cell activation, leukocyte migration, and (lymph)angiogenesis and has been shown to contribute to the pathology of various immune-mediated disorders, including asthma and corneal graft rejection. In contrast to monoclonal antibodies (mAbs) targeting ALCAM's T cell expressed binding partner CD6, no ALCAM-targeting mAbs have thus far entered clinical development. This is likely linked with the broad expression of ALCAM on many different cell types, which increases the risk of eliciting unwanted treatment-induced side effects upon systemic mAb application. Targeting ALCAM in surface-exposed tissues, such as the lungs or the cornea, by a topical application could circumvent this issue. Here, we report the development of various stability- and affinity-improved anti-ALCAM mAb fragments with cross-species reactivity towards mouse, rat, monkey, and human ALCAM. Fragments generated in either mono- or bivalent formats potently blocked ALCAM-CD6 interactions in a competition ELISA, but only bivalent fragments efficiently inhibited ALCAM-ALCAM interactions in a leukocyte transmigration assay. The different fragments displayed a clear size-dependence in their ability to penetrate the human corneal epithelium. Furthermore, intranasal delivery of anti-ALCAM fragments reduced leukocyte infiltration in a mouse model of asthma, confirming ALCAM as a target for topical application in the lungs.


Trends in diabetes prevalence, incidence, and mortality in Ontario, Canada 1995-2005: a population-based study.
The prevalence of diabetes has been increasing greatly, but WHO's predicted 39% rise in the global rate of diabetes from 2000 to 2030 might be an underestimate. We aimed to assess diabetes trends in Ontario, Canada. Using population-based data, including a validated diabetes database from the province of Ontario, Canada, we examined trends in diabetes prevalence and mortality from 1995 to 2005, and incidence from 1997 to 2003, in adults aged 20 years or older. Age-adjusted and sex-adjusted diabetes prevalence increased by 69%, from 5.2% in a population of 7,908,562 in 1995 to 8.8% of 9,276,945 in 2005. Prevalence increased by 27% from 6.9% in a population of 8,457,720 in 2000 to 8.8% of 9,276,945 in 2005. Although prevalence rates have remained higher in people aged 50 years or older (7.1% of 3,675,554) than in those aged 20-49 years (3.5% of 5 601 391), rates increased to a greater extent in the younger population (94%vs 63%, p<0.0001). A 31% increase occurred in yearly incidence over 6 years, from 6.6 per 1000 in 1997 to 8.2 per 1000 in 2003. The adjusted mortality rate in people with diabetes fell by 25% from 1995 to 2005. The prevalence of diabetes in Ontario, Canada increased substantially during the past 10 years, and by 2005 already exceeded the global rate that was predicted for 2030. This increase in prevalence is attributable to both rising incidence and declining mortality. Effective public-health interventions aimed at diabetes prevention are needed, as well as improved resources to manage the greater number of people living longer with the disease.


Personality and Social Framing in Privacy Decision-Making: A Study on Cookie Acceptance.
Despite their best intentions, people struggle with the realities of privacy protection and will often sacrifice privacy for convenience in their online activities. Individuals show systematic, personality dependent differences in their privacy decision making, which makes it interesting for those who seek to design 'nudges' designed to manipulate privacy behaviors. We explore such effects in a cookie decision task. Two hundred and ninety participants were given an incidental website review task that masked the true aim of the study. At the task outset, they were asked whether they wanted to accept a cookie in a message that either contained a social framing 'nudge' (they were told that either a majority or a minority of users like themselves had accepted the cookie) or contained no information about social norms (control). At the end of the task, participants were asked to complete a range of personality assessments (impulsivity, risk-taking, willingness to self-disclose and sociability). We found social framing to be an effective behavioral nudge, reducing cookie acceptance in the minority social norm condition. Further, we found personality effects in that those scoring highly on risk-taking and impulsivity were significantly more likely to accept the cookie. Finally, we found that the application of a social nudge could attenuate the personality effects of impulsivity and risk-taking. We explore the implications for those working in the privacy-by-design space.


Vitamin D Receptor Gene Expression and Function in a South African Population: Ethnicity, Vitamin D and FokI.
Polymorphisms of the vitamin D receptor gene (VDR) have been associated inconsistently with various diseases, across populations of diverse origin. The T(f) allele of the functional SNP FokI, in exon 2 of VDR, results in a longer vitamin D receptor protein (VDR) isoform, proposed to be less active. Genetic association of VDR with disease is likely confounded by ethnicity and environmental factors such as plasma 25(OH)D3 status. We hypothesized that VDR expression, VDR level and transactivation of target genes, CAMP and CYP24A1, depend on vitamin D, ethnicity and FokI genotype. Healthy volunteers participated in the study (African, n = 40 and White, n = 20). Plasma 25(OH)D3 levels were quantified by LC-MS and monocytes cultured, with or without 1,25(OH)2D3. Gene expression and protein level was quantified using qRT-PCR and flow cytometry, respectively. Mean plasma 25(OH)D3 status was normal and not significantly different between ethnicities. Neither 25(OH)D3 status nor 1,25(OH)2D3 supplementation significantly influenced expression or level of VDR. Africans had significantly higher mean VDR protein levels (P<0.050), nonetheless transactivated less CAMP expression than Whites. Genotyping the FokI polymorphism by pyrosequencing together with HapMap data, showed a significantly higher (P<0.050) frequency of the CC genotype in Africans than in Whites. FokI genotype, however, did not influence VDR expression or VDR level, but influenced overall transactivation of CAMP and 1,25(OH)2D3-elicited CYP24A1 induction; the latter, interacting with ethnicity. In conclusion, differential VDR expression relates to ethnicity, rather than 25(OH)D3 status and FokI genotype. Instead, VDR transactivation of CAMP is influenced by FokI genotype and, together with ethnicity, influence 1,25(OH)2D3-elicited CYP24A1 expression. Thus, the expression and role of VDR to transactivate target genes is determined not only by genetics, but also by ethnicity and environment involving complex interactions which may confound disease association.


Mortality due to non-AIDS-defining cancers among people living with HIV in Spain over 18 years of follow-up.
Our aim was to describe non-AIDS-defining cancer (NADC) mortality among people living with HIV (PLWH), to compare it with that of the general population, and to assess potential risk factors. We included antiretroviral-naive PLWH from the multicentre CoRIS cohort (2004-2021). We estimated mortality rates and standardised mortality ratios (SMRs). We used cause-specific Cox models to identify risk factors. Among 17,978 PLWH, NADC caused 21% of all deaths observed during the follow-up. Mortality rate due to NADC was 1.58 (95%CI 1.36, 1.83) × 1000 person-years and lung and liver were the most frequent cancer-related causes of death. PLWH had 79% excess NADC mortality risk compared to the general population with the highest SMR found for Hodgkin lymphoma, anal and liver cancers. The SMRs decreased with age and were the highest in age groups under 50 years. The most important prognostic factor was low CD4 count, followed by smoking, viral hepatitis and HIV transmission through heterosexual contact or injection drug use. Non-AIDS cancers are an important cause of death among PLWH. The excess mortality related to certain malignancies and the association with immunodeficiency, smoking, and coinfections highlights the need for early detection and treatment of cancer in this population.


Hemolytic uremic syndrome.
Hemolytic uremic syndrome (HUS) is a thrombotic microangiopathy defined by thrombocytopenia, nonimmune microangiopathic hemolytic anemia, and acute renal failure. The most frequent form is associated with infections by Shiga-like toxin-producing bacteria (STEC-HUS). Rarer cases are triggered by neuraminidase-producing Streptococcus pneumoniae (pneumococcal-HUS). The designation of aHUS is used to refer to those cases in which an infection by Shiga-like toxin-producing bacteria or S. pneumoniae can be excluded. Studies performed in the last two decades have documented that hyperactivation of the complement system is the pathogenetic effector mechanism leading to the endothelial damage and the microvascular thrombosis in aHUS. Recent data suggested the involvement of the complement system in the pathogenesis of STEC-HUS and pneumococcal-HUS as well. Clinical signs and symptoms may overlap among the different forms of HUS; however, pneumococcal-HUS and aHUS have a worse prognosis compared with STEC-HUS. Early diagnosis and identification of underlying pathogenetic mechanism allows instating specific support measures and therapies. In clinical trials in patients with aHUS, complement inhibition by eculizumab administration leads to a rapid and sustained normalization of hematological parameters with improvement in long-term renal function. This review summarizes current concepts about the epidemiological findings, the pathological and clinical aspects of STEC-HUS, pneumococcal-HUS, and aHUS, and their diagnosis and management.


Identification of prognostic immune-related genes in the tumor microenvironment of endometrial cancer.
Endometrial cancer (EC) is one of the most common gynecologic malignancies. To identify potential prognostic biomarkers for EC, we analyzed the relationship between the EC tumor microenvironment and gene expression profiles. Using the ESTIMATE R tool, we found that immune and stromal scores correlated with clinical data and the prognosis of EC patients. Based on the immune and stromal scores, 387 intersection differentially expressed genes were identified. Eight immune-related genes were then identified using two machine learning algorithms. Functional enrichment analysis revealed that these genes were mainly associated with T cell activation and response. Kaplan-Meier survival analysis showed that expression of TMEM150B, CACNA2D2, TRPM5, NOL4, CTSW, and SIGLEC1 significantly correlated with overall survival times of EC patients. In addition, using the TIMER algorithm, we found that expression of TMEM150B, SIGLEC1, and CTSW correlated positively with the tumor infiltration levels of B cells, CD8+ T cells, CD4+ T cells, macrophages, and dendritic cells. These findings indicate that the composition of the tumor microenvironment affects the clinical outcomes of EC patients, and suggests that it may provide a basis for development of novel prognostic biomarkers and immunotherapies for EC patients.


Population pharmacokinetics of S-ketamine and norketamine in healthy volunteers after intravenous and oral dosing.
Low-dose ketamine is a lucrative therapeutic approach in cancer pain, perioperative treatment of pain, and management of treatment-resistant depression. The analgesic potency of its main metabolite norketamine is thought to be one third that of ketamine. However, few studies exist on the pharmacokinetics of orally administered S-ketamine. In our study, 11 healthy volunteers received S-ketamine 0.25 mg/kg orally and 0.125 mg/kg intravenously. S-ketamine and norketamine concentrations were measured up to 23.5 h post-dose. A population pharmacokinetic model was built to describe S-ketamine and norketamine pharmacokinetics. A three-compartment model for both S-ketamine and norketamine best described the data. To accommodate for the extensive formation of norketamine after oral S-ketamine, a separate presystemic absorption-phase component was included in addition to its systemic formation. The oral bioavailability of S-ketamine was low, 8% (11% interindividual variability), and its clearance was high, 95 L/h/70 kg (13% interindividual variability). Simulations suggested that after oral dosing, norketamine AUC at steady state is 16.5 times higher than that of S-ketamine. Given that the analgesic effect of S-ketamine is due to both S-ketamine and norketamine, relatively small oral doses of S-ketamine can be assumed to be a feasible alternative to repeated intravenous dosing, for example in the setting of chronic pain.


Ensemble modeling highlights importance of understanding parasite-host behavior in preclinical antimalarial drug development.
Emerging drug resistance and high-attrition rates in early and late stage drug development necessitate accelerated development of antimalarial compounds. However, systematic and meaningful translation of drug efficacy and host-parasite dynamics between preclinical testing stages is missing. We developed an ensemble of mathematical within-host parasite growth and antimalarial action models, fitted to extensive data from four antimalarials with different modes of action, to assess host-parasite interactions in two preclinical drug testing systems of murine parasite P. berghei in mice, and human parasite P. falciparum in immune-deficient mice. We find properties of the host-parasite system, namely resource availability, parasite maturation and virulence, drive P. berghei dynamics and drug efficacy, whereas experimental constraints primarily influence P. falciparum infection and drug efficacy. Furthermore, uninvestigated parasite behavior such as dormancy influences parasite recrudescence following non-curative treatment and requires further investigation. Taken together, host-parasite interactions should be considered for meaningful translation of pharmacodynamic properties between murine systems and for predicting human efficacious treatment.


Clonal heterogeneity of small-cell anaplastic carcinoma of the lung demonstrated by flow-cytometric DNA analysis.
Flow-cytometric DNA analysis yields information on ploidy and proliferative characteristics of a cell population. The analysis was implemented on small-cell anaplastic carcinoma of the lung using a rapid detergent technique for the preparation of fine-needle aspirates for DNA determination and a newly developed procedure for storing aspirates at -80 degrees. Thirty-eight different metastases in 30 consecutive patients with small-cell anaplastic carcinoma of the lung were examined with a total of 273 fine-needle aspirations. The results on ploidy are reported in this paper. The degree of contamination of the aspirates with normal cells was determined by differential counts. The ratio of the peak channel numbers for the G1 phase of the tumor cells to that of the diploid standard (DNA index) was calculated and used for ploidy identification. Twenty-nine patients were evaluable with respect to DNA index determination. The coefficient of variation of the DNA index determinations was estimated as 0.039. In 23 (79%) patients, only one cell line could be detected. Evidence of the presence of 2 tumor cell clones with different ploidy was obtained in the remaining 6 (21%) patients. Of the 35 malignant clones thus demonstrated, 26 (74%) were significantly different from diploid (p less than or equal to 0.01). Four (11%) were hypodiploid, 3 (9%) were hypotriploid, and 19 (54%) were hypo- or near-tetraploid. Clonal heterogeneity in the tumors of 21% of the patients is a conservative estimate. Assessment of the detection limit set by the methodology used and the restricted number of samples studied in each patient indicate that the true occurrence of clonal heterogeneity in small-cell carcinoma of the lung may be much higher.


Conjugation of haloperidol to PEG allows peripheral localisation of haloperidol and eliminates CNS extrapyramidal effects.
We have previously reported the synthesis of a poly(ethylene glycol)-haloperidol (PEG-haloperidol) conjugate that retained affinity for its target D2 receptor and was stable in simulated physiological conditions. We hypothesised that this polymer-drug conjugate would localise haloperidol's activity either centrally or peripherally, dependent on the location of administration, due to the polymer preventing penetration through the blood-brain barrier (BBB). Herein, we validate this hypothesis using in vitro and in vivo studies. We first demonstrate, via a [35S]GTPγS-binding assay, that drug activity is retained after conjugation to the polymer, supportive of retention of effective therapeutic ability. Specifically, the PEG-haloperidol conjugate (at 10 and 100 nM) was able to significantly inhibit dopamine-induced G-protein activation via D2 receptors, albeit with a loss of potency compared to the free haloperidol (~18-fold at 10 nM). This loss of potency was further probed and rationalised using molecular docking experiments, which indicated that conjugated haloperidol can still bind to the D2 receptors, albeit with a flipped orientation in the binding pocket within the receptor, which may explain the reduced activity. Finally, rat catalepsy studies confirmed the restricted permeation of the conjugate through the BBB in vivo. Rats treated intravenously with free haloperidol became cataleptic, whereas normal behaviour was observed in rats that received the PEG-haloperidol conjugate, suggesting that conjugation can effectively prevent unwanted central effects. Taken together these results demonstrate that conjugating small molecules to polymers is effective at prohibiting penetration of the drug through the BBB and is a valid targeting strategy for drugs to facilitate peripheral (or central) effects without inducing side effects in other compartments.


Human natural killer cells express VLA-4 and VLA-5, which mediate their adhesion to fibronectin.
Very late Ag (VLA)-3, VLA-4, and VLA-5, belonging to the beta-1 subfamily of integrins, have been recently identified as receptors for different binding regions of fibronectin (FN). We have detected VLA-4 and VLA-5, but not VLA-3, on fresh CD3-, CD16+, CD56+ human NK cells by flow cytometry and immunochemical analyses using mAb directed against beta-1, alpha-3, alpha-4, and alpha-5 subunits. Binding assays, performed on FN-coated plates, showed that NK cells specifically adhere to FN and their binding capacity is increased by MgCl2 but not by CaCl2. Using as inhibitory probes a polyclonal antibody against the beta-1 chain of the human FN receptor, the synthetic peptide GRGDSP, which is able to inhibit cellular adhesion mediated by VLA-5, the CS1 fragment, which contains the principal adhesion site in the IIICS domain recognized by VLA-4, and functional mAb directed against alpha-4 or alpha-5 subunits, we show that both VLA-4 and VLA-5 mediate the adhesion of human NK cells to FN. The expression of these integrin receptors may be relevant for NK interaction with extracellular matrix components and other cell types.


Transfer Learning with CNN Models for Brain-Machine Interfaces to command lower-limb exoskeletons: A Solution for Limited Data.
This study evaluates the performance of two convolutional neural networks (CNNs) in a brain-machine interface (BMI) based on motor imagery (MI) by using a small dataset collected from five participants wearing a lower-limb exoskeleton. To address the issue of limited data availability, transfer learning was employed by training models on EEG signals from other subjects and subsequently fine-tuning them to specific users. A combination of common spatial patterns (CSP) and linear discriminant analysis (LDA) was used as a benchmark for comparison. The study's primary aim is to examine the potential of CNNs and transfer learning in the development of an automatic neural classification system for a BMI based on MI to command a lower-limb exoskeleton that can be used by individuals without specialized training.Clinical Relevance- BMI can be used in rehabilitation for patients with motor impairment by using mental simulation of movement to activate robotic exoskeletons. This can promote neural plasticity and aid in recovery.


Treating patients with metastatic renal carcinoma: an escape from Phase III.
The wide availability of drugs for the treatment of advanced renal cell carcinoma has recently provided many alternatives for patients historically treated with immunotherapy alone. The six drugs currently available for the treatment of metastatic renal cell carcinoma became available to physicians after the approval processes performed by regulatory agencies, based mainly on the results of Phase III studies. Owing to the stringent entry criteria of the studies, patients are not representative of the entire population. Results of Phase III studies are extrapolated to all renal cell carcinoma populations without taking into account patients with different comorbidities. The purpose of this review is to analyze and weigh the safety data available for the drugs approved for metastatic renal cell carcinoma and to suggest the best therapy in terms of both efficacy and safety based on the multiplicity of features of each patient in relation to the main characteristics of each agent.


Cannabidiol tempers alcohol intake and neuroendocrine and behavioural correlates in alcohol binge drinking adolescent rats. Focus on calcitonin gene-related peptide's brain levels.
Alcohol binge drinking is common among adolescents and may challenge the signalling systems that process affective stimuli, including calcitonin gene-related peptide (CGRP) signalling. Here, we employed a rat model of adolescent binge drinking to evaluate reward-, social- and aversion-related behaviour, glucocorticoid output and CGRP levels in affect-related brain regions. As a potential rescue, the effect of the phytocannabinoid cannabidiol was explored. Adolescent male rats underwent the intermittent 20% alcohol two-bottle choice paradigm; at the binge day (BD) and the 24 h withdrawal day (WD), we assessed CGRP expression in medial prefrontal cortex (mPFC), nucleus accumbens (NAc), amygdala, hypothalamus and brainstem; in addition, we evaluated sucrose preference, social motivation and drive, nociceptive response, and serum corticosterone levels. Cannabidiol (40 mg/kg, i.p.) was administered before each drinking session, and its effect was measured on the above-mentioned readouts. At BD and WD, rats displayed decreased CGRP expression in mPFC, NAc and amygdala; increased CGRP levels in the brainstem; increased response to rewarding- and nociceptive stimuli and decreased social drive; reduced serum corticosterone levels. Cannabidiol reduced alcohol consumption and preference; normalised the abnormal corticolimbic CGRP expression, and the reward and aversion-related hyper-responsivity, as well as glucocorticoid levels in alcohol binge-like drinking rats. Overall, CGRP can represent both a mediator and a target of alcohol binge-like drinking and provides a further piece in the intricate puzzle of alcohol-induced behavioural and neuroendocrine sequelae. CBD shows promising effects in limiting adolescent alcohol binge drinking and rebalancing the bio-behavioural abnormalities.


Model-based evaluation of alternative reactive class closure strategies against COVID-19.
There are contrasting results concerning the effect of reactive school closure on SARS-CoV-2 transmission. To shed light on this controversy, we developed a data-driven computational model of SARS-CoV-2 transmission. We found that by reactively closing classes based on syndromic surveillance, SARS-CoV-2 infections are reduced by no more than 17.3% (95%CI: 8.0-26.8%), due to the low probability of timely identification of infections in the young population. We thus investigated an alternative triggering mechanism based on repeated screening of students using antigen tests. Depending on the contribution of schools to transmission, this strategy can greatly reduce COVID-19 burden even when school contribution to transmission and immunity in the population is low. Moving forward, the adoption of antigen-based screenings in schools could be instrumental to limit COVID-19 burden while vaccines continue to be rolled out.


Persistent immune imprinting after XBB.1.5 COVID vaccination in humans.
Immune imprinting - also known as 'original antigenic sin' - describes how the first exposure to a virus shapes the immunological outcome of subsequent exposures to antigenically related strains. SARS-CoV-2 Omicron breakthrough infections and bivalent COVID-19 vaccination were shown to primarily recall cross-reactive memory B cells and antibodies induced by prior mRNA vaccination with the Wuhan-Hu-1 spike rather than priming naive B cells that recognize Omicron-specific epitopes. These findings underscored a strong immune imprinting resulting from repeated Wuhan-Hu-1 spike exposures. To understand if immune imprinting can be overcome, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID mRNA vaccine booster. Our data show that the XBB.1.5 booster elicits neutralizing antibody responses against current variants that are dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. These results indicate that immune imprinting persists even after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 spike booster mRNA vaccination, which will need to be considered to guide the design of future vaccine boosters.


Activity of terbinafine against serious fungal pathogens.
Although primarily indicated for dermatophyte infections, the allylamine terbinafine is active in vitro against a broad spectrum of filamentous and dimorphic fungi, in most cases with a primary fungicidal action. Using the standard NCCLS M27-A assay, recent studies confirmed the high activity of terbinafine against dematiaceous fungi and other medically important moulds such as Aspergillus and Penicillium marneffei. Terbinafine displayed a geometric mean MIC of 1.4 μg/ml against Candida albicans (n = 259) and has significant in vitro activity against other species of Candida, Cryptococcus, Trichosporon and Blastoschizomyces. As an approach to treatment of refractory infections, interactions of terbinafine with azoles and other agents are being investigated. Terbinafine was synergistic with azoles (and in some cases amphotericin B) against Candida species, Trichosporon beigelii, Aspergillus species, Pseudallescheria boydii and Scopulariopsis brevicaulis, some of which were unresponsive to any drug used singly. Terbinafine combined with fluconazole showed potent synergy against fluconazole- and multidrug-resistant C. albicans isolates. In conclusion, recent in vitro data suggest that terbinafine, either alone or in combination with other antifungal drugs, has potential in the therapy of a range of more severe fungal infections, in addition to its current widespread use against dermatomycoses.


Afterdrop of body temperature during rewarming: an alternative explanation.
Afterdrop, the continued fall of deep body temperatures during rewarming after hypothermia, is thought to endanger the heart by further cooling from cold blood presumed to be returning from the periphery. However, afterdrop is not always observed, depending on the circumstances. To explore this phenomenon, mild hypothermia was induced quantitatively with a suit calorimeter, using several patterns of cooling and rewarming. When cooling was rapid and followed immediately by rewarming, there were typical afterdrops in the temperatures measured in the rectum, auditory canal, and esophagus. However, when rewarming was delayed, or when cooling had been slow and prolonged, afterdrop was not seen. Afterdrops were then observed in two physical models that had no circulation: a bag of gelatin and a leg of beef. Central layers continued to give up heat as long as the surrounding layer was cooler. These results, together with recent findings by others that peripheral blood flow is low until afterdrop is complete, make this circulatory explanation of afterdrop improbable. Alternatively, afterdrop can be explained by the way heat moves through a mass of tissue.


Prevalence and extent of atherosclerotic coronary artery disease and related outcome based on coronary computed tomographic angiography in asymptomatic elderly patients: retrospective cohort study.
There is little data regarding coronary artery disease (CAD) and/or atherosclerotic plaques on coronary computed tomographic angiography (CCTA) among the elderly and its outcome, especially in asymptomatic patients. Using CCTA, we evaluated the prevalence and extent of CAD and/or atherosclerosis and related outcomes in asymptomatic elderly patients as compared with symptomatic elderly patients. The study included 1,196 consecutive patients aged 70 years or older who underwent CCTA over a 2-year period. Data were retrospectively evaluated for clinical cardiovascular risk factors with co-morbidities, and CCTA findings, including calcium scores, atherosclerotic plaques (number, plaque-segment score, plaque-extent score, and plaque-significant score) and presence of significant CAD. Follow-up data for active management and all-cause mortality after CCTA were collected for 2 years. Two-sided Student's t test for independent samples, Chi square contingency tables, and Kaplan-Meier survival curves were used for statistical analysis. Data for 454 asymptomatic and 742 symptomatic elderly patients were analyzed. The prevalence of significant CAD and the extent of atherosclerotic plaques did not differ between the two groups (all P > 0.05). Asymptomatic patients with significant CAD on CCTA, were less likely to receive active management (P < 0.001), which may be related to the higher death rate in this group (P = 0.012) than in the symptomatic patients with significant CAD. Overall, symptoms were not related to the presence of significant CAD or to the extent of atherosclerosis in these elderly patients. However, all-cause mortality was higher in the asymptomatic patients with significant CAD than in the symptomatic ones.


Delayed contrast-enhanced computed tomography in patients with known or suspected cardiac sarcoidosis: A feasibility study.
To evaluate the diagnostic value of delayed contrast-enhanced computed tomography (DE-CT) for cardiac sarcoidosis (CS) in patients with or without implantable devices, including a quantitative comparison with late gadolinium enhancement cardiac magnetic resonance (LGE-CMR). Twenty-four patients (mean age, 64 ± 9 years; 17 women) with known or suspected CS underwent retrospective electrocardiogram-gated DE-CT at 80 kV with knowledge-based iterative model reconstruction. Fourteen patients without implantable devices also underwent LGE-CMR, while ten with pacemakers or implantable cardioverter-defibrillators did not. The presence of hyperenhanced myocardium was assessed visually and quantitatively using a 5-standard deviation threshold above the mean of remote myocardium. Inter-observer agreement for visual detection of hyperenhanced segments on DE-CT was excellent in patients with implantable devices and in those without (κ = 0.91 and κ = 0.94, respectively). Comparisons of the percent area of hyperenhanced myocardium between DE-CT and LGE-CMR on both per-patient and per-segment analyses showed good correlations (r = 0.96 and r = 0.83, respectively; p < 0.001). The sensitivity and specificity of DE-CT for the diagnosis of CS were 94% and 33%. The extent of hyperenhanced lesion with DE-CT showed good agreement with LGE-CMR results. DE-CT showed high sensitivity for detecting CS and may be useful particularly in patients with contraindications to CMR. • Delayed contrast-enhanced CT (DE-CT) can be applied to patients with implantable devices. • DE-CT can detect cardiac sarcoidosis (CS) lesions similarly to cardiac MRI. • DE-CT shows high sensitivity for detecting CS. • DE-CT may be useful particularly in patients with contraindications to cardiac MRI.


Conditional overdispersed models: Application to count area data.
This paper proposes alternative models for the analysis of count data featuring a given spatial structure, which corresponds to geographical areas. We assume that the overdispersion data structure partially results from the existing and well justified spatial correlation between geographical adjacent regions, so an extension of existing overdispersion models that include spatial neighborhood structures within a Bayesian framework is proposed. These models allow practitioners to quantify the association explained by the considered neighborhood structures and the one modelled by additional factors. Finally, using the information provided by the Colombian National Demographic and Health Survey, the usefulness of the proposed models is illustrated by fitting them to infant mortality rates and to data including the proportion of mothers who, after giving birth to their last child, underwent a postnatal screening period in Colombia.


Feasibility of newly developed endoscopic ultrasound with zone sonography technology for diagnosis of pancreatic diseases.
To confirm the feasibility of using newly developed endoscopic ultrasound (EUS) with Zone sonography™ technology (ZST; Fujifilm Corp.). Seventy-five patients with pancreatic disorders were enrolled: 45 with intraductal papillary mucinous neoplasm; 15 with ductal carcinoma; five with neuroendocrine tumors; three with serous cystic neoplasms; and seven with simple cysts. The endoscopes used were EG-530UR2 and EG-530UT2 (Fujifilm Corp.). Two items were evaluated: visualization depth among four frequencies and image quality after automatic adjustment of sound speed (AASS), assessed using a 5-scale Likert scale by two endosonographers blinded to disease status. Because sound speed could be manually controlled, besides AASS, image quality at sound speeds of 1,440 and 1,600 m/sec were also assessed. In all cases, sufficient images were obtained in the range of 3 cm from the EUS probe. Judgments of image quality before AASS were 3.49±0.50, 3.65±0.48, respectively. After AASS, A and B scored 4.36±0.48 and 4.40±0.49 (p<0.0001). There were significant differences in the data before and after AASS and plus 60 m/sec, but no significant difference between the datasets were seen after AASS and at sound speeds manually set for minus 100 m/sec. EUS with ZST was shown to be feasible in this preliminary experiment. Further evaluation of this novel technology is necessary and awaited.


Effect of left ventricular--to--aortic bypass on infarct size and infarct microcirculation in baboons.
A major diagonal branch of the left anterior descending coronary artery (LAD) was acutely occluded in 17 baboons. Complete left ventricular (LV) decompression was achieved with a left heart bypass (LHB) system in six baboons while 11 baboons served as untreated controls. In the treated group, LHB was initiated after 30 minutes of coronary occlusion. For a period of 6 hours after occlusion, aortic pressure, LV pressure, left atrial pressure, and cardiac output were monitored. During the same monitoring period, electrograms were recorded from a high resolution matrix of fixed epicardial electrodes. Regional myocardial blood flow was determined prior to and at intervals following the initiation of LHB with radioactive microspheres. Infarct size was assessed histologically from serial cross sections of the left ventricle. The degree of salvage achieved by LHB was assessed by comparing the epicardial area of infarction 6 hours after occlusion (AI) to the area of epicardial St-segment elevation (STE) 30 minutes after occlusion (maxAST). In the LHB-treated group, 40.0% +/- 8.1% (SEM) of maxAST showed subsequent infarction; in the control group, 79.8% +/- 2.7% of maxAST showed eventual infarction (p less than 0.01). STE overlying the region of ischemia in the LHB-treated group did not undergo the spontaneous decline observed in the control group, which is normally associated with the progression of necrosis. Regional myocardial blood flow did not change significantly in the ischemic region during the period of occlusion following LHB. LHB. The results suggest that LHB is capable of substantial salvage of acutely ischemic myocardium by reducing myocardial work and thus reducing myocardial oxygen requirements.


Is There any Additional Benefit of Multiple Doses of Tocilizumab in COVID-19 Patients?
Many patients with coronavirus disease 2019 (COVID-19) have a hyperactive immune response (cytokine storm) which has been incriminated in multiorgan dysfunction (MOD). Interleukin-6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are the key cytokines involved in mediating systemic inflammation and triggering endothelial dysfunction. To limit these effects, IL-6 receptor inhibitors (IL6ri) have been used in COVID-19 patients. The best approach regarding the total number of doses in COVID-19 patients is still unclear. In this single-center retrospective study, we investigated if multiple doses of tocilizumab (TCZ) prevented deterioration of COVID-19 patients. Patients were divided into two cohorts based on the number of TCZ doses; cohort 1 (received one dose) and cohort 2 (received ≥ two doses). In both cohorts, all-cause-mortality was the primary outcome. Of 270 hospitalized patients with COVID-19, 81 patients received TCZ. Fifty patients received one dose of TCZ and 31 received ≥ two doses. All-cause-mortality in cohort 2 remained higher (41.9%) suggesting that there was no additional benefit of multiple doses of TCZ to prevent the primary outcome. In addition, multiple doses of TCZ did not change any other secondary outcome [(ICU admission, acute kidney injury (AKI), acute respiratory distress syndrome (ARDS), acute cardiac injury (ACI), thrombotic events, septic shock, and total hospital stay].


Establishment of a course for Focused Assessment Sonography for Trauma.
Focused Assessment Sonography for Trauma (FAST) is not widely practiced by Trauma Surgeons in the Middle East despite its international acceptance. A FAST course was established by the Trauma Group at the Faculty of Medicine and Health Sciences at United Arab Emirates (UAE) University aiming to introduce doctors who have limited experience of ultrasound to the basics of FAST. This article summarizes the content of the course; the evaluation of the participants and their recommendations. An 8 hour FAST course was offered to 18 participants in May 2004 in the Faculty of Medicine and Health Sciences, UAE University, Al-Ain, UAE. Lectures with syllabus material were used to cover the following topics: basic ultrasound physics, knobology and sonographic orientation, the FAST scan, chest and cardiac trauma sonographic evaluation, training and credentialing issues. Each participant received 3 hours of hands-on ultrasound instruction. On completion of the course participants responded anonymously to an evaluation questionnaire. All participants responded to the questionnaire (100% response rate). Delegates found the course well organized, relevant, met their needs and encourages them to use FAST in their own practice. The course objectives were met. Participants suggested that including actual patients and the use of animal models improve the practical sessions. Organizing a FAST course is an important step towards recognizing and implementing it in practice. Nevertheless, there is a need for appropriate quality assurance and credentialing guidelines before commencing.


Selection of hprt mutant T cells as surrogates for dividing cells reveals a restricted T cell receptor BV repertoire in insulin-dependent diabetes mellitus.
T cells with somatically acquired mutations in the hypoxanthine-guanine phosphoribosyltransferase (hprt) gene were isolated from patients with insulin-dependent diabetes mellitus (IDDM) as representatives of populations potentially enriched for in vivo activated T cells. TCRB gene V region usage among mutant isolates from individual IDDM patients, but not from normal controls, showed a pronounced preference for BV14 and, to a lesser extent, BV6. Wild-type (nonmutant) isolates did not show such preferences. Extensive in vivo clonal expansions of the BV14 expressing mutant T cells from IDDM patients were revealed by sequence identity of TCRB chain junctional regions. These data support restricted TCRB gene usage in T cell populations enriched for in vivo activated clones in patients with IDDM.


Herpes simplex virus-induced changes of the keratin type intermediate filament in rat epithelial cells.
Herpes simplex virus type 1 (HSV-1) infection of human fibroblast cells grown in culture induces reorganization of the cytoskeleton fibrillar structures. Normal transport and insertion of HSV glycoproteins into the plasma membrane of the cells depend on the integrity of the microtubules. The natural host cells for HSV are epithelial cells, and an epithelial cell line established from rat palate was used in the present study. The effect of virus on the structure of the intermediate filaments and especially on the keratin proteins was studied. Two-dimensional gel electrophoresis of total cell extracts identified in uninfected cells two major acidic keratin proteins with apparent molecular weights of 44,000 (44K) and 48K (pI 5.45 to 5.30, 5.50 to 5.35). A new keratin protein of 46K (pI 5.40 to 5.25) appeared in infected cells between 8 h and 12 h post-infection. Pulse-chase experiments identified the 46K protein as a processed form of the 48K keratin component, which was also cleaved in uninfected cells grown in the presence of cycloheximide. Partial proteolysis of the 46K and 48K keratins with Staphylococcus aureus V8 protease showed that the 48K and the 46K proteins differed in only one oligopeptide. The significance of the changed keratin composition of HSV-infected cells is discussed.


Fine Needle Biopsy of Metastases at Retrograde Pyelography, Directed by Fluoroscopy.
Percutaneous fine needle aspiration biopsy was performed at retrograde pyelography in order to differentiate between metastatic and scarry involvement of a strictured ureter in a patient earlier operated upon because of malignant teratoma. The method is recommended in patients with malignant diseases where the differential diagnosis is impossible to establish at retrograde pyelography or urography.


Prion protein misfolding, strains, and neurotoxicity: an update from studies on Mammalian prions.
Prion diseases, also known as transmissible spongiform encephalopathies (TSEs), are a group of fatal neurodegenerative disorders affecting humans and other mammalian species. The central event in TSE pathogenesis is the conformational conversion of the cellular prion protein, PrP(C), into the aggregate, β -sheet rich, amyloidogenic form, PrP(Sc). Increasing evidence indicates that distinct PrP(Sc) conformers, forming distinct ordered aggregates, can encipher the phenotypic TSE variants related to prion strains. Prion strains are TSE isolates that, after inoculation into syngenic hosts, cause disease with distinct characteristics, such as incubation period, pattern of PrP(Sc) distribution, and regional severity of histopathological changes in the brain. In analogy with other amyloid forming proteins, PrP(Sc) toxicity is thought to derive from the existence of various intermediate structures prior to the amyloid fiber formation and/or their specific interaction with membranes. The latter appears particularly relevant for the pathogenesis of TSEs associated with GPI-anchored PrP(Sc), which involves major cellular membrane distortions in neurons. In this review, we update the current knowledge on the molecular mechanisms underlying three fundamental aspects of the basic biology of prions such as the putative mechanism of prion protein conversion to the pathogenic form PrP(Sc) and its propagation, the molecular basis of prion strains, and the mechanism of induced neurotoxicity by PrP(Sc) aggregates.


Impact of Cyanine Conformational Restraint in the Near-Infrared Range.
Appending conformationally restraining ring systems to the cyanine chromophore creates exceptionally bright fluorophores in the visible range. Here, we report the application of this strategy in the near-infrared range through the preparation of the first restrained heptamethine indocyanine. Time-resolved absorption spectroscopy and fluorescence correlation spectroscopy verify that, unlike the corresponding parent unrestrained variant, the restrained molecule is not subject to photoisomerization. Notably, however, the room-temperature emission efficiency and the fluorescence lifetime of the restrained cyanine are not extended relative to the parent cyanine, even in viscous solvents. Thus, in contrast to prior reports, the photoisomerization of heptamethine cyanines does not contribute significantly to the excited-state chemistry of these molecules. We also find that the fluorescence lifetime of the restrained heptamethine cyanine is temperature-insensitive and significantly extended at moderately elevated temperatures relative to the parent cyanine. Finally, computational studies have been used to evaluate the impact of the conformational restraint on atomic and orbital structure across the cyanine series. These studies clarify the role of photoisomerization in the heptamethine cyanine scaffold and demonstrate the dramatic effect of restraint on the temperature sensitivity of these dyes.


SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.
Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.


Is the IDS glass half empty or half full?
When the concept of integrated delivery began gaining popularity throughout the healthare field, some healthcare executies saw it as the solution for organizations struggling to contain rapidly rising costs. Others hoped that joining integrated delivery systems would help preserve smaller organizations that could not otherwise compete with larger providers in the same area. And many in healthcare thought that it had the potential to dramatically enhance quality of care and promote wellness. As integration becomes increasingly common, the practice is coming under heavy criticism from those who say it has not lived up to expectatations. At the same time, however, systems that are seeing success with integrated delivery are singing its praises. "The jury is still out on the effectiveness of integrated delivery systems," says Austin Ross, FACHE, a professor at the University of Washington's School of Public Health, Seattle. "So far, they have a spotty record. There have been some serious failures, but some positive things are taking place, too." Some experts say that integrated delivery systems are doomed; others believe there are good reasons to be optimistic. So is the glass half empty or half full?


Senescent fibroblasts in melanoma initiation and progression: an integrated theoretical, experimental, and clinical approach.
We present an integrated study to understand the key role of senescent fibroblasts in driving melanoma progression. Based on the hybrid cellular automata paradigm, we developed an in silico model of normal skin. The model focuses on key cellular and microenvironmental variables that regulate interactions among keratinocytes, melanocytes, and fibroblasts, key components of the skin. The model recapitulates normal skin structure and is robust enough to withstand physical as well as biochemical perturbations. Furthermore, the model predicted the important role of the skin microenvironment in melanoma initiation and progression. Our in vitro experiments showed that dermal fibroblasts, which are an important source of growth factors in the skin, adopt a secretory phenotype that facilitates cancer cell growth and invasion when they become senescent. Our coculture experiments showed that the senescent fibroblasts promoted the growth of nontumorigenic melanoma cells and enhanced the invasion of advanced melanoma cells. Motivated by these experimental results, we incorporated senescent fibroblasts into our model and showed that senescent fibroblasts transform the skin microenvironment and subsequently change the skin architecture by enhancing the growth and invasion of normal melanocytes. The interaction between senescent fibroblasts and the early-stage melanoma cells leads to melanoma initiation and progression. Of microenvironmental factors that senescent fibroblasts produce, proteases are shown to be one of the key contributing factors that promoted melanoma development from our simulations. Although not a direct validation, we also observed increased proteolytic activity in stromal fields adjacent to melanoma lesions in human histology. This leads us to the conclusion that senescent fibroblasts may create a prooncogenic skin microenvironment that cooperates with mutant melanocytes to drive melanoma initiation and progression and should therefore be considered as a potential future therapeutic target. Interestingly, our simulations to test the effects of a stroma-targeting therapy that negates the influence of proteolytic activity showed that the treatment could be effective in delaying melanoma initiation and progression.


Flanking the fenestration: circumferential limb-to-limb stent-assisted coiling of a basilar artery fenestration aneurysm.
A man aged 61 years with a history of a ruptured basilar fenestration aneurysm underwent unassisted coiling in 1997 and repeat intervention for a recurrence at the aneurysm mouth in 2011. At repeat intervention, the decision was made to intentionally leave some filling at the base to preserve the parent vessels. Stent-assisted coil embolization, although technically feasible, was not pursued given the relative risks of the procedure. In 2017, the patient returned for repeat surveillance and further coil compaction was found at the aneurysm base. With the advent of more compliant woven stents deliverable through 0.017 microcatheters, stent-assisted coiling was possible. This case demonstrates hereto unseen agility afforded by novel low-profile stents allowing a circumferential approach to a basilar artery fenestration aneurysm and resultant limb-to-limb stent-assisted coiling. Techniques described here may be extended to more common anatomic variants that require stent-assisted coiling.


Beta-blockers and atrial natriuretic peptide (ANP) in hypertension.
Several studies (including ours) in patients with moderate hypertension indicate that beta-adrenergic blockers exert their antihypertensive action in part by increasing ANP secretion. There is also strong evidence that (beta 1- adrenergic receptors are mainly involved in this action. In this article we provide an overview on some of these studies.


Mechanisms of antibody-mediated insulin-like growth factor I receptor (IGF-IR) down-regulation in MCF-7 breast cancer cells.
The insulin-like growth factor I receptor (IGF-IR) plays a critical role in cell proliferation and survival. We previously reported that a recombinant anti-IGF-IR antibody, scFv-Fc, consisting of 1H7 monoclonal antibody (mAb)-derived single chain antibody (scFv) and human IgG1 Fc, significantly suppressed breast tumor growth, and we proposed IGFIR down-regulation as a mechanism for tumor growth inhibition (Horm Metab Res. 2003; 35:836, Cancer Res. 2003; 63:627). This study used MCF-7 breast cancer cells to investigate the effects of anti-IGF-IR mAbs with various epitope specificities on IGF-IR downregulation and signaling pathways. Despite their differing effects on IGF-IR signaling, all five mAbs used down-regulated IGF-IR. Inhibitor experiments indicated that anti-IGF-IR mAbs induced internalization of IGF-IR from clathrin coated-pits. Pretreatment of MCF-7 cells with methylamine substantially reduced the antibody-mediated IGF-IR down-regulation while MG115 did not. Ubiquitination of IGF-IR did not occur in MCF-7 cells after mAb treatment. These results suggest that anti-IGF-IR antibodies with different epitope-specificities can cause internalization of IGF-IR from clathrin-coated pits and down-regulation via a lysosome-dependent pathway in an IGF-IR activation-independent manner.


Off target: a critical review of setting goals for reducing health inequalities in the United Kingdom.
Health policy in the United Kingdom is devolved to the four home countries. Nevertheless, England, Northern Ireland, Scotland, and Wales share a common commitment to reducing health inequalities and have set explicit targets in areas such as life expectancy, cancer mortality, long-standing illness, and smoking prevalence. However, many of the targets leave much to be desired in terms of their limited conceptual scope and their selection of methods and approaches. At one level this might be regarded as relatively unimportant. The mere fact of having health inequalities targets is laudable. But because the United Kingdom has been in the vanguard of research and policy development to reduce health inequalities, a critical appraisal of the strengths and weaknesses of the approaches adopted in the four home countries is timely. Following a description of the health inequalities targets, the article focuses on experiences in England and Scotland as examples of contrasting approaches to target setting and describes progress toward meeting targets in each country. The authors then outline key emerging issues in relation to developing targets and measuring progress, including conceptual dilemmas, biased reporting, implementation failure, and statistical fallacy.


Genomic Features of the Damselfly Calopteryx splendens Representing a Sister Clade to Most Insect Orders.
Insects comprise the most diverse and successful animal group with over one million described species that are found in almost every terrestrial and limnic habitat, with many being used as important models in genetics, ecology, and evolutionary research. Genome sequencing projects have greatly expanded the sampling of species from many insect orders, but genomic resources for species of certain insect lineages have remained relatively limited to date. To address this paucity, we sequenced the genome of the banded demoiselle, Calopteryx splendens, a damselfly (Odonata: Zygoptera) belonging to Palaeoptera, the clade containing the first winged insects. The 1.6 Gbp C. splendens draft genome assembly is one of the largest insect genomes sequenced to date and encodes a predicted set of 22,523 protein-coding genes. Comparative genomic analyses with other sequenced insects identified a relatively small repertoire of C. splendens detoxification genes, which could explain its previously noted sensitivity to habitat pollution. Intriguingly, this repertoire includes a cytochrome P450 gene not previously described in any insect genome. The C. splendens immune gene repertoire appears relatively complete and features several genes encoding novel multi-domain peptidoglycan recognition proteins. Analysis of chemosensory genes revealed the presence of both gustatory and ionotropic receptors, as well as the insect odorant receptor coreceptor gene (OrCo) and at least four partner odorant receptors (ORs). This represents the oldest known instance of a complete OrCo/OR system in insects, and provides the molecular underpinning for odonate olfaction. The C. splendens genome improves the sampling of insect lineages that diverged before the radiation of Holometabola and offers new opportunities for molecular-level evolutionary, ecological, and behavioral studies.


Calcium antagonists and cardiovascular disorders.
All calcium antagonists have the ability to decrease the symptoms and signs in some patients with ischemic heart disease and help lower the blood pressure in hypertensive persons, but in clinical doses nifedipine does not exhibit antiarrhythmic properties, although these are an important part of the action of verapamil, diltiazem and some substances with a similar chemical structure. In certain disorders beta-adrenergic blocking drugs are useful adjuncts, and under some circumstances, particularly variant angina and supraventricular arrhythmias, specific calcium antagonists are the drugs of choice. More data are needed to define the role of calcium antagonists during cardiopulmonary bypass, in the protection of the ischemic myocardium, in the management of hypertrophic cardiomyopathy and in specific cases of primary pulmonary hypertension. When used with an appropriate sense of perspective and careful observation, calcium antagonists provide useful additional means of helping selected patients suffering from particular cardiovascular diseases.


Concomitant pulmonary tuberculosis and tuberculous appendicitis in a recipient of a renal transplant: a case report.
Tuberculosis is still a serious infection among recipients of renal transplants. Although the ileocecal region is the most affected part in intestinal tuberculosis, acute tuberculous appendicitis is quite a rare entity. We report a case of concomitant pulmonary tuberculosis and tuberculous appendicitis in a recipient of a renal transplant. A 27-year-old Iranian woman, who had been the recipient of a renal transplant five years earlier, presented with a two-week history of coughing, fever and weight loss. The cause of her end-stage renal disease was chronic pyelonephritis. There were fine crackles noted during a chest examination, and a plain chest radiography showed fine miliary nodules throughout her entire lung fields. Sputum and bronchial aspirate examination was positive for acid-fast bacilli, suggestive of Mycobacterium tuberculosis infection. A chest computed tomography scan revealed widespread miliary nodules, compatible with miliary tuberculosis. She developed severe abdominal pain and abdominal surgery disclosed a perforated appendicitis. Histopathological examination of the resected appendix revealed widespread caseating epithelioid granulomas, suggestive of tuberculosis. Our case report highlights a rare presentation of tuberculosis in a patient who has undergone renal transplant. Such unusual presentation of tuberculosis, particularly among patients receiving potent immunosuppressive protocols, should be considered by clinicians.


Echogenicity changes in the fetal brain, a 6-year follow-up study.
To asses the relation between echogenicity changes in the fetal brain and neurodevelopmental outcome until 6 years of age. Fetuses (n = 124) from pregnancies affected by hypertensive disorders (n = 64) or preterm labor (n = 60) at risk for preterm birth (26-34 weeks gestation) were studied. Moderate echogenicity changes (periventricular grade IB, II; intraventricular grade II-III; local basal ganglia/thalami) in the fetal and neonatal brain were related to neurological outcome and Griffiths mental developmental scales quotients at 1, 2 and 6 years. Multiple regression analysis tested the influence of moderate echogenicity changes and perinatal clinical characteristics on composite outcome (death or abnormal neurodevelopment). Moderate echogenicity changes were present in 37/124 (30%) fetuses. Median gestational age and weight at birth were respectively 31 weeks (range 26-43), 1314 g (range 550-4330), mortality was 19%, follow-up loss 10%. Composite outcome was abnormal in 47/124 (38%). Fetal and neonatal moderate intraventricular echodensities were related to cerebral palsy at 6 years (p < 0.04). In the multiple regression analysis only gestational age was related to composite outcome (p = 0.005). Moderate intraventricular echodensities in the fetal brain related to cerebral palsy at 6 years of age. Gestational age at birth was the main predictor of abnormal composite outcome.


Parametric modeling of wideband piezoelectric polymer sensors: Design for optoacoustic applications.
In this work, we present a three-dimensional model for the design of wideband piezoelectric polymer sensors which includes the geometry and the properties of the transducer materials. The model uses FFT and numerical integration techniques in an explicit, semi-analytical approach. To validate the model, we made electrical and mechanical measurements on homemade sensors for optoacoustic applications. Each device was implemented using a polyvinylidene fluoride thin film piezoelectric polymer with a thickness of 25 μm. The sensors had detection areas in the range between 0.5 mm2 and 35 mm2 and were excited by acoustic pressure pulses of 5 ns (FWHM) from a source with a diameter around 10 μm. The experimental data obtained from the measurements agree well with the model results. We discuss the relative importance of the sensor design parameters for optoacoustic applications and we provide guidelines for the optimization of devices.


[Application of interrupted normobaric hypoxia stimulation on healthy people].
The INHS application with the practically healthy (sane) people gained the extraordinary widening. This method was theoretically grounded by M.M. Sirotinin's and his followers' works. It is used by physiologists, therapeutists surgeons and sports' doctors in many countries of the world. Up to now a days more than 350 hundreds of people feel the positive influence of the INHS. There are the contemporary literature review, the INHS application for the sports results and olympic achievements augmentation, the illnesses prevention, the population health scale increase regarded. The advantages and disadvantages of different variants of INH, their influence on the breathing parameters, the hemopoiesis and the regeneration processes are examined. The INH usage in order to decrease the biological age and to increase the human being life quality is rather perspective.


Two-dimensional high-resolution NMR spectra in matched B(0) and B(1) field gradients.
In a recent publication we presented a method to obtain highly resolved NMR spectra in the presence of an inhomogeneous B(0) field with the help of a matched RF gradient. If RF gradient pulses are combined with "ideal" 90 degrees pulses to form inhomogeneous z rotation pulses, the line broadening caused by the B(0) gradient can be refocused, while the full chemical shift information is maintained. This approach is of potential use for NMR spectroscopy in an inhomogeneous magnetic field produced by an "ex-situ" surface spectrometer. In this contribution, we extend this method toward two-dimensional spectroscopy with high resolution in one or both dimensions. Line narrowing in the indirect dimension can be achieved by two types of nutation echoes, thus leading to depth-sensitive NMR spectra with full chemical shift information. If the nutation echo in the indirect dimension is combined with a stroboscopic acquisition using inhomogeneous z-rotation pulses, highly resolved two-dimensional correlation spectra can be obtained in matched field gradients. Finally, we demonstrate that an INEPT coherence transfer from proton to carbon spins is possible in inhomogeneous B(0) fields. Thus, it is possible to obtain one-dimensional (13)C NMR spectra with increased sensitivity and two-dimensional HETCOR spectra in the presence of B(0) gradients of 0.4 mT/cm. These schemes may be of some value for ex-situ NMR analysis of materials and biological systems.


Assessing the permeability of landscape features to animal movement: using genetic structure to infer functional connectivity.
Human-altered environments often challenge native species with a complex spatial distribution of resources. Hostile landscape features can inhibit animal movement (i.e., genetic exchange), while other landscape attributes facilitate gene flow. The genetic attributes of organisms inhabiting such complex environments can reveal the legacy of their movements through the landscape. Thus, by evaluating landscape attributes within the context of genetic connectivity of organisms within the landscape, we can elucidate how a species has coped with the enhanced complexity of human altered environments. In this research, we utilized genetic data from eastern chipmunks (Tamias striatus) in conjunction with spatially explicit habitat attribute data to evaluate the realized permeability of various landscape elements in a fragmented agricultural ecosystem. To accomplish this we 1) used logistic regression to evaluate whether land cover attributes were most often associated with the matrix between or habitat within genetically identified populations across the landscape, and 2) utilized spatially explicit habitat attribute data to predict genetically-derived Bayesian probabilities of population membership of individual chipmunks in an agricultural ecosystem. Consistency between the results of the two approaches with regard to facilitators and inhibitors of gene flow in the landscape indicate that this is a promising new way to utilize both landscape and genetic data to gain a deeper understanding of human-altered ecosystems.


Clinical management for hospital-treated deliberate self-poisoning: comparisons between patients with major depression and borderline personality disorder.
To compare the initial clinical management of hospital-treated deliberate self-poisoning patients with major depressive disorder (MDD) or borderline personality disorder (BPD) after controlling for demographic factors and level of suicide ideation. This study compared sequential hospital treated deliberate self-poisoning patients (n = 570) with either MDD or BPD (but no major comorbid psychopathology) on four outcomes modelled using logistic regression: (i) length of stay in the general hospital; (ii) discharge to a psychiatric hospital; (iii) psychiatric follow-up; and (iv) general practitioner (GP) follow-up. BPD and MDD patients were discharged to psychiatric inpatient care at very similar rates (33%-35%) and almost all subjects with high levels of suicidal ideation were discharged to psychiatric hospital. However, for mild to moderate levels of suicidal ideation BPD patients were more likely to be discharged to psychiatric hospital than MDD patients. After controlling for demographics and suicidal ideation, BPD patients were more likely to be referred for psychiatric hospitalization on discharge (adjusted OR = 1.79, 95% CI = 1.01-3.18) and less likely to be referred to GPs if discharged to home (adjusted OR = 0.44, 95% CI = 0.24-0.81). There were no differences in general hospital length of stay or arrangements made for psychiatric follow-up for those discharged to home. This suggests that for mild to moderate suicidal ideation levels clinicians are more likely to choose to send BPD patients, after deliberate self-poisoning, to inpatient psychiatric care than MDD patients. Clinicians are also apparently more likely to choose to manage MDD patients in primary care settings, for those patients discharged to home. This has implications for service planning and clinical guidelines.


Incidence of seizures in the acute phase of stroke: a population-based study.
The incidence of seizures within 24 h of acute stroke has not been studied extensively. We aimed to establish the incidence of acute poststroke seizures in a biracial cohort and to determine whether acute seizure occurrence differs by race/ethnicity, stroke subtype, and/or stroke localization. We identified all stroke cases between July 1993 and June 1994 and in 1999 within the population of the Greater Cincinnati metropolitan region. Patients with a prior history of seizures/epilepsy were excluded from analysis. A total of 6044 strokes without a history of seizure(s) were identified; 190 (3.1%) had seizures within the first 24 h of stroke onset. Of ICH/SAH patients, 8.4% had a seizure within the first 24 h of stroke onset (p <or= 0.0001 vs. all other stroke subtype). Of the patients with ischemic stroke, we observed higher incidence of seizures in cardioembolic versus small or large vessel ischemic (p = 0.02) strokes. Patients with seizures experienced higher mortality than patients without seizures (p < 0.001) but seizures were not an independent risk factor of mortality at 30 days after stroke. Independent risk factors for seizure development included hemorrhagic stroke, younger age, and prestroke Rankin score of >or=1. Race/ethnicity or localization of the ischemic stroke did not influence the risk for seizure development in the studied population. The overall incidence of acute seizures after stroke was 3.1%, with a higher incidence seen in hemorrhagic stroke, younger patients, and those presenting with higher prestroke Rankin scores. Acute seizures were associated with a higher mortality at 30 days after stroke.