Molecular and structural analysis of genetic variations in congenital cataract.
To determine the relative contributions of mutations in congenital cataract cases in an Indian population by systematic screening of genes associated with cataract. We enrolled 100 congenital cataract cases presenting at the Dr. R. P. Centre for Ophthalmic Sciences, a tertiary research and referral hospital (AIIMS, New Delhi, India). Crystallin, alpha A (CRYAA), CRYAB, CRYGs, CRYBA1, CRYBA4, CRYBB1, CRYBB2, CRYBB3, beaded filament structural protein 1 (BFSP1), gap function protein, alpha 3 (GJA3), GJA8, and heat shock transcription factor 4 gene genes were amplified. Protein structure differences analysis was performed using Discovery Studio (DS) 2.0. The mean age of the patients was 17.45±16.51 months, and the age of onset was 1.618±0.7181 months. Sequencing analysis of 14 genes identified 18 nucleotide variations. Fourteen variations were found in the crystallin genes, one in Cx-46 (GJA3), and three in BFSP1. Congenital cataract shows marked clinical and genetic heterogeneity. Five nucleotide variations (CRYBA4:p.Y67N, CRYBB1:p.D85N, CRYBB1:p.E75K, CRYBB1:p.E155K, and GJA3:p.M1V) were predicted to be pathogenic. Variants in other genes might also be involved in maintaining lens development, growth, and transparency. The study confirms that the crystallin beta cluster on chromosome 22, Cx-46, and BFSP1 plays a major role in maintaining lens transparency. This study also expands the mutation spectrum of the genes associated with congenital cataract.


Increased sulphation improves the anticoagulant activities of heparan sulphate and dermatan sulphate.
Heparan sulphate and dermatan sulphate have both antithrombotic and anticoagulant properties. These are, however, significantly weaker than those of a comparable amount of standard pig mucosal heparin. Antithrombotic and anticoagulant effects of glycosaminoglycans depend on their ability to catalyse the inhibition of thrombin and/or to inhibit the activation of prothrombin. Since heparan sulphate and dermatan sulphate are less sulphated than unfractionated heparin, we investigated whether the decreased sulphation contributes to the lower antithrombotic and anticoagulant activities compared with standard heparin. To do this, we compared the anticoagulant activities of heparan sulphate and dermatan sulphate with those of their derivatives resulphated in vitro. The ratio of sulphate to carboxylate in these resulphated heparan sulphate and dermatan sulphate derivatives was approximately twice that of the parent compounds and similar to that of standard heparin. Anticoagulant effects were assessed by determining (a) the catalytic effects of each glycosaminoglycan on the inhibition of thrombin added to plasma, and (b) the ability of each glycosaminoglycan to inhibit the activation of 125I-prothrombin in plasma. The least sulphated glycosaminoglycans were least able to catalyse the inhibition of thrombin added to plasma and to inhibit the activation of prothrombin. Furthermore, increasing the degree of sulphation improved the catalytic effects of glycosaminoglycans on the inhibition of thrombin by heparin cofactor II in plasma. The degree of sulphation therefore appears to be an important functional property that contributes significantly to the anticoagulant effects of the two glycosaminoglycans.


Adenocarcinoma of the urethra in women. A clinicopathologic study.
Twenty-two cases of adenocarcinoma of the urethra in women were studied. Nine were classified histologically as clear cell adenocarcinoma and 13 were classified as columnar/mucinous adenocarcinoma. Thirteen patients (59%) were black. The average patient age was 61 years (range, 27 to 76 years). Follow-up ranged from 6 to 194 months, (average, 40 months). At presentation, most patients (82%) had extension of tumor into adjacent structures or metastases to regional lymph nodes. Eighty-six percent received radiation therapy and 41% underwent an anterior exenteration or cystectomy. Eight of 22 patients (36%) had no evidence of disease 21 to 194 months after diagnosis (average, 83 months). Fourteen (64%) were dead of disease 6 to 23 months after diagnosis (average, 15 months). In general, the extent of tumor correlated best with survival time. Forty-four percent of patients with clear cell adenocarcinoma were dead of disease within 24 months of diagnosis, in contrast to 77% of those with columnar/mucinous adenocarcinoma, suggesting that patients with clear cell adenocarcinoma may have a better prognosis than those with columnar/mucinous adenocarcinoma. However, the difference in survival probability between the two groups was not found to be statistically significant. Recognition of the two histologic types of urethral adenocarcinoma is important to prevent misdiagnosis of such tumors as metastases (or direct extension) of nonurethral neoplasms having a similar histologic appearance. A possible predilection of the disease for black women has not been previously described.


The integrative future of taxonomy.
Taxonomy is the biological discipline that identifies, describes, classifies and names extant and extinct species and other taxa. Nowadays, species taxonomy is confronted with the challenge to fully incorporate new theory, methods and data from disciplines that study the origin, limits and evolution of species. Integrative taxonomy has been proposed as a framework to bring together these conceptual and methodological developments. Here we review perspectives for an integrative taxonomy that directly bear on what species are, how they can be discovered, and how much diversity is on Earth. We conclude that taxonomy needs to be pluralistic to improve species discovery and description, and to develop novel protocols to produce the much-needed inventory of life in a reasonable time. To cope with the large number of candidate species revealed by molecular studies of eukaryotes, we propose a classification scheme for those units that will facilitate the subsequent assembly of data sets for the formal description of new species under the Linnaean system, and will ultimately integrate the activities of taxonomists and molecular biologists.


General classification of maturation reaction-norm shape from size-based processes.
Phenotypic plasticity of size at maturation is commonly described using size-age maturation reaction norms (MRNs). MRNs for age and size at maturation are analyzed and classified into three general categories related to different size scalings of growth and mortality. The underlying model for growth and mortality is based on processes at the level of the individual, and is motivated by the energy budget of fish. MRN shape is a balance between opposing factors and depends on subtle details of size dependence of growth and mortality. MRNs with both positive and negative slopes are predicted, and for certain mortality conditions also a lower critical spawning mass. The model is applied to predict a generic fishery-induced evolutionary response and allows assessment of climate change impact on MRNs. Our work stresses the importance of using realistic size dependence of mortality and growth, since this strongly influences the predicted MRNs and sensitivity to harvest pressure.


Analysis of Platelet Count and New Cancer Diagnosis Over a 10-Year Period.
Individuals with cancer often have an elevated platelet count at the time of diagnosis. The extent to which an elevated platelet count is an indicator of cancer is unclear. To evaluate the association of an elevated platelet count with a cancer diagnosis. This nested case-control study included Ontario residents enrolled in the provincial health insurance plan who had 1 or more routine complete blood count (CBC) tests performed between January 1, 2007, and December 31, 2017, with follow-up through December 31, 2018. Case patients were individuals with a new cancer diagnosis during the observation period. Eligible control individuals were cancer free before the date of diagnosis for a case patient to whom they were matched. One case patient was matched to 3 controls based on sex, age, and health care use patterns. Data were analyzed from September 24, 2020, to July 13, 2021. Case patients and controls were assigned to 1 of 5 exposure groups based on age- and sex-specific platelet count distributions in the control population: very low (≤10th percentile), low (>10th to 25th percentile), medium (>25th to <75th percentile), high (75th to <90th percentile), and very high (≥90th percentile). Odds ratios (ORs) were estimated for specific cancer sites for each category of platelet count at intervals up to 10 years after a blood test. Of the 8 917 187 eligible Ontario residents with a routine CBC record available, 4 971 578 (55.8%) were women; the median age at the first CBC was 46.4 years (IQR, 32.5-59.5 years). Among individuals with a routine CBC record available, 495 341 (5.6%) received a diagnosis of first primary cancer during the 10-year observation period. The OR for a solid tumor diagnosis associated with a very high platelet count vs a medium platelet count in the 6-month period before the diagnosis was 2.32 (95% CI, 2.28-2.35). A very high platelet count was associated with colon (OR, 4.38; 95% CI, 4.22-4.54), lung (OR, 4.37; 95% CI, 4.22-4.53), ovarian (OR, 4.62; 95% CI, 4.19-5.09), and stomach (OR, 4.27; 95% CI, 3.91-4.66) cancers. Odds ratios attenuated with increasing time from CBC test to cancer diagnosis. In this nested case-control study, an elevated platelet count was associated with increased risk of cancer at several sites. Our findings suggest that an elevated platelet count could potentially serve as a marker for the presence of some cancer types.


Tracheomalacia in adults with cystic fibrosis: determination of prevalence and severity with dynamic cine CT.
To determine the prevalence and severity of tracheomalacia in adults with cystic fibrosis (CF) by using dynamic cine multidetector computed tomography (CT) and to correlate these findings with pulmonary function test (PFT) results and the severity of parenchymal lung disease. In this institutional review board-approved HIPAA-compliant study, 40 patients with CF (22 men, 18 women; mean age, 28 years +/- 8 [standard deviation]; age range, 18-54 years) prospectively underwent PFTs, standard thin-section CT, and two dynamic cine multidetector CT acquisitions. Ten control subjects underwent dynamic cine multidetector CT. After standard thin-section CT was completed, dynamic cine multidetector CT was performed during a forced expiratory maneuver and during coughing. Dynamic cine multidetector CT images in nine patients were excluded. Maximal inspiratory, dynamic expiratory, and end-expiratory tracheal luminal areas were compared (Student t test) and correlated (Spearman rank) with PFT results and severity of parenchymal lung disease. Mean predicted forced expiratory volume in 1 second (FEV(1)) was 70.6% +/- 20.7, and mean Bhalla CT score was 41.8% +/- 13.6. In patients with CF, dynamic cine mean tracheal cross-sectional area reduction was 51.7% +/- 18.4 (range, 9%-89%) for forced expiratory maneuvers and 68.8% +/- 11.7 (range, 18%-88%) for coughing (P = .001). Tracheomalacia was demonstrated in 24 (69%) patients and no control subjects during forced expiratory maneuvers (P = .001) and in 10 (29%) patients and one (10%) control subject during coughing. For end-expiration images, mean tracheal luminal reduction was 16.1% +/- 14.0% (range, 0.0%-53.0%), with one patient demonstrating tracheal luminal reduction of more than 50%. There was no correlation between tracheal cross-sectional luminal reduction and either predicted FEV(1) or CT Bhalla score. Tracheomalacia depicted at dynamic cine multidetector CT is a highly prevalent finding in adults with CF. http://radiology.rsnajnls.org/cgi/content/full/2522081956/DC1.


Association between Helicobacter pylori virulence factors and gastroduodenal diseases in Okinawa, Japan.
The incidence of gastric cancer in Okinawa is lowest in Japan. Some previous reports using small number of strains suggested that the high prevalence of Helicobacter pylori with Western-type cagA in Okinawa compared to other areas in Japan might contribute to the low incidence of gastric cancer. It has still not been confirmed why the prevalence of Western-type cagA strains is high in Okinawa. We examined the association between the virulence factors of H. pylori and gastroduodenal diseases in Okinawa. The genotypes of cagA and vacA of 337 H. pylori strains were determined by PCR and gene sequencing. The genealogy of these Western-type cagA strains in Okinawa was analyzed by multilocus sequence typing (MLST). Overall, 86.4% of the strains possessed cagA: 70.3% were East-Asian type and 16.0% were Western type. After adjustment by age and sex, the presence of East-Asian-type cagA/vacA s1m1 genotypes was significantly associated with gastric cancer compared to gastritis (odds ratio = 6.68, 95% confidence interval = 1.73 to 25.8). The structure of Western-type CagA in Okinawa was different from that of typical Western-type CagA found in Western countries. Intriguingly, MLST analysis revealed that the majority of Western-type cagA strains formed individual clusters but not hpEurope. Overall, low prevalence of gastric cancer in Okinawa may result from the high prevalence of non-East-Asian-type cagA strains. The origin of Western-type cagA strains in Okinawa may be different from those of Western countries.


C- and N-catabolic utilization of tricarboxylic acid cycle-related amino acids by Scheffersomyces stipitis and other yeasts.
Scheffersomyces stipitis and the closely related yeast Candida shehatae assimilated the L-amino acids glutamate, aspartate and proline as both carbon and nitrogen sole sources. We also found this rarely investigated ability in ascomycetous species such as Candida glabrata, C. reukaufii, C. utilis, Debaryomyces hansenii, Kluyveromyces lactis, K. marxianus, Candida albicans, L. elongisporus, Meyerozyma guilliermondii, C. maltosa, Pichia capsulata and Yarrowia lipolytica and in basidiomycetous species such as Rhodotorula rubra and Trichosporon beigelii. Glutamate was a very efficient carbon source for Sc. stipitis, which enabled a high biomass yield/mole, although the growth rate was lower when compared to growth on glucose medium. The cells secreted waste ammonium during growth on glutamate alone. In Sc. stipitis cultures grown in glucose medium containing glutamate as the nitrogen source the biomass yield was maximal, and ethanol concentration and specific ethanol formation rate were significantly higher than in glucose medium containing ammonium as the nitrogen source. Mainly C-assimilation of glutamate but also N-assimilation in glucose-containing medium correlated with enhanced activity of the NAD-dependent glutamate dehydrogenase 2 (GDH2). A Δgdh2 disruptant was unable to utilize glutamate as either a carbon or a nitrogen source; moreover, this disruptant was also unable to utilize aspartate as a carbon source. The mutation was complemented by retransformation of the GDH2 ORF into the Δgdh2 strain. The results show that Gdh2p plays a dual role in Sc. stipitis as both C- and N-catabolic enzyme, which indicates its role as an interface between the carbon and nitrogen metabolism of this yeast.


Intramolecular triplet energy transfer in anthracene-based platinum acetylide oligomers.
Platinum acetylide oligomers that contain an anthracene moiety have been synthesized and subjected to photophysical characterization. Spectroscopic measurement and DFT calculations reveal that both the singlet and triplet energy levels of the anthracene segment are lower than those of the platinum acetylide segment. Thus, the platinum acetylide segment acts as a sensitizer to populate the triplet state of the anthrancene segment via intramolecular triplet-triplet energy transfer. The objective of this work is to understand the mechanisms of energy-transfer dynamics in these systems. Fluorescence quenching and the dominant triplet absorption that arises from the anthracene segment in the transient absorption spectrum of Pt4An give clear evidence that energy transfer adopts an indirect mechanism, which begins with singlet-triplet energy transfer from the anthracene segment to the platinum acetylide segment followed by triplet-triplet energy transfer to the anthracene segment.


Changes in emergency department access between 2001 and 2005 among general and vulnerable populations.
We analyzed how ease of geographic access to emergency departments (EDs), defined as driving time to the closest ED, changed between 2001 and 2005, and whether access deterioration was more likely to occur in vulnerable communities. We classified communities on the basis of American Hospital Association and Census data into 3 categories according to driving time to the nearest ED: no increase, less than a 10-minute increase, and a 10-minute or more increase. We estimated a multinomial logit model to examine the relative risk ratio (RRR) of various community characteristics. More than 95% of communities experienced no ED access deterioration. However, 11.4 million people experienced increased driving time to their nearest ED. Low-income communities had a higher risk of facing deteriorating access compared with high-income communities (urban: RRR = 3.67; P < .01; rural: RRR = 1.75; P < .10), and communities with higher shares of Hispanics also had higher risks of facing declines (urban: RRR = 3.41; P < .10; rural: RRR = 2.67; P < .01). Deteriorating access to EDs is more likely to occur in communities with economic hardship and high shares of Hispanic populations. The uneven access to critical services warrants increased attention from policymaking bodies.


More than Tuskegee: understanding mistrust about research participation.
This paper describes results of a qualitative study that explored barriers to research participation among African American adults. A purposive sampling strategy was used to identify African American adults with and without previous research experience. A total of 11 focus groups were conducted. Groups ranged in size from 4-10 participants (N=70). Mistrust of the health care system emerged as a primary barrier to participation in medical research among participants in our study. Mistrust stems from historical events including the Tuskegee syphilis study and is reinforced by health system issues and discriminatory events that continue to this day. Mistrust was an important barrier expressed across all groups regardless of prior research participation or socioeconomic status. This study illustrates the multifaceted nature of mistrust, and suggests that mistrust remains an important barrier to research participation. Researchers should incorporate strategies to reduce mistrust and thereby increase participation among African Americans.


Combining Inserts With Warning Labels on Cigarette Packs to Promote Smoking Cessation: A 2-Week Randomized Trial.
Cigarette pack inserts with messages on cessation benefits and advice are a promising labeling policy that may help promote smoking cessation. To assess insert effects, with and without accompanying pictorial health warning labels(HWLs), on hypothesized psychosocial and behavioral outcomes. We conducted a 2 × 2 between-subject randomized trial (inserts with efficacy messages vs. no inserts; large pictorial HWLs vs. small text HWLs), with 367 adults who smoked at least 10 cigarettes a day. Participants received a 14-day supply of their preferred cigarettes with packs modified to reflect their experimental condition. Over 2 weeks, we surveyed participants approximately 4-5 times a day during their smoking sessions, querying feelings about smoking, level of worry about harms from smoking, self-efficacy to cut down on cigarettes, self-efficacy to quit, hopefulness about quitting, and motivation to quit. Each evening, participants reported their perceived susceptibility to smoking harms and, for the last 24 hr, their frequency of thinking about smoking harms and cessation benefits, conversations about smoking cessation or harms, and foregoing or stubbing out cigarettes before they finished smoking. Mixed-effects ordinal and logistic models were estimated to evaluate differences between groups. Participants whose packs included inserts were more likely than those whose packs did not include inserts to report foregoing or stubbing out of cigarettes (OR = 2.39, 95% CI = 1.36, 4.20). Otherwise, no statistically significant associations were found between labeling conditions and outcomes. This study provides some evidence, albeit limited, that pack inserts with efficacy messages can promote behaviors that predict smoking cessation attempts.


A professional curriculum vitae will open career doors.
In today's challenging healthcare environment, it is essential for nurse practitioners to be able to describe themselves professionally on paper to compete for practice and academic opportunities. Nurse practitioners are competing with physician assistants as well as physicians for primary and acute care positions. A carefully compiled curriculum vitae will present the individual in the best light possible to help open career doors and enhance chances of success. Preparing a curriculum vitae will serve to highlight relevant professional accomplishments, whatever the setting, toward the fulfillment of professional goals. This article reviews the current professional print and electronic literature on preparing a curriculum vitae to assist the nurse practitioner in developing this vital document.


Lessons learned from a resident-led clinical trial in obstetrics.
Completion of a randomised controlled trial is one way by which the resident research requirement can be met in Canadian obstetrics and gynaecology programmes. However, little is known about the specific challenges of performing clinical trials within the specialty, let alone as a resident project. A resident-led randomised controlled trial comparing two methods of labour induction at term was halted due to insufficient patient enrolment. A structured review of the study design and recruitment process was conducted to identify factors contributing to poor recruitment. In addition to completing a literature review and internal review by the research team, we surveyed obstetricians and residents regarding recruitment efforts and barriers to participation. We solicited feedback on trial design and the expectations of clinicians with respect to participation in research studies. Eight obstetricians (67%) and 13 residents (93%) responded to the survey. All were able to identify eligible patients, though only 60% had invited one or more patients to participate during the recruitment period. Failure to consider trial participation and excessive clinical workload were the most commonly cited barriers for clinicians. Resistance to the test intervention was the major barrier to patient participation. Several residents cited a lack of personal incentive to recruit patients as a significant barrier. The research team was unable to contact patients directly, thus limiting the scope of our review to our internal methods and feedback from clinicians. Poor recruitment in a resident-led clinical trial in obstetrics resulted from multiple coexisting factors. A structured review provided valuable insight for the research team. Academic clinicians and trainees in all specialties should be encouraged to share their experiences in the hope of improving the likelihood of success in future research endeavours.


Engaging village health workers in non-communicable disease (NCD) prevention and control in Vietnam: A qualitative study.
The burden of non-communicable diseases (NCDs) continues to grow in Vietnam, and reducing the burden of NCDs is a national priority. This study explored perspective of community health workers (CHWs), known as Village Health Workers (VHWs) in Vietnam, and public health leaders towards potential of expanding VHWs' role to deliver NCDs prevention and control services, and determined barriers and facilitators. We conducted focus group discussions (FGDs) with VHWs (n = 24) and in-depth interviews (IDIs) with public health administrators (n = 13). The findings show that VHWs in Vietnam deliver multiple public health services, including several NCDs related services. Perceived barriers include lack of policy support, shortages of trained health personnel, lack of training, imbalanced workload and inadequate remuneration. Perceived barriers include lack of policy support, shortages of trained health personnel, lack of training, imbalanced workload and inadequate remuneration. Facilitators include government commitment to NCDs prevention and control, priority on capacity building, professional recognition and provision of incentives with availability of appropriate resources. While additional quantitative studies are needed to supplement the current qualitative findings, the current results inform the policy and intervention development in engaging VHWs in the delivery of community-based NCDs prevention and control initiatives in Vietnam.


Molecular Cytogenetics of Pisum sativum L. Grown under Spaceflight-Related Stress.
The ontogenesis and reproduction of plants cultivated aboard a spacecraft occur inside the unique closed ecological system wherein plants are subjected to serious abiotic stresses. For the first time, a comparative molecular cytogenetic analysis of Pisum sativum L. (Fabaceae) grown on board the RS ISS during the Expedition-14 and Expedition-16 and also plants of their succeeding (F1 and F2) generations cultivated on Earth was performed in order to reveal possible structural chromosome changes in the pea genome. The karyotypes of these plants were studied by multicolour fluorescence in situ hybridization (FISH) with five different repeated DNA sequences (45S rDNA, 5S rDNA, PisTR-B/1, microsatellite motifs (AG)12, and (GAA)9) as probes. A chromosome aberration was revealed in one F1 plant. Significant changes in distribution of the examined repeated DNAs in karyotypes of the "space grown" pea plants as well as in F1 and F2 plants cultivated on Earth were not observed if compared with control plants. Additional oligo-(GAA)9 sites were detected on chromosomes 6 and 7 in karyotypes of F1 and F2 plants. The detected changes might be related to intraspecific genomic polymorphism or plant cell adaptive responses to spaceflight-related stress factors. Our findings suggest that, despite gradual total trace contamination of the atmosphere on board the ISS associated with the extension of the space station operating life, exposure to the space environment did not induce serious chromosome reorganizations in genomes of the "space grown" pea plants and generations of these plants cultivated on Earth.


Chlamydia pneumoniae and atherosclerosis: does the evidence support a causal or contributory role?
The intracellular bacterial pathogen Chlamydia pneumoniae causes respiratory tract infection and has been associated with atherosclerosis and coronary artery disease. Since atherosclerosis is a progressive disease and is considered to be a chronic inflammation of the artery vessel wall, the interaction of C. pneumoniae with cells of the vasculature that can result in a local inflammatory response is of paramount importance. In this essay we review the pathophysiology of atherosclerosis in the context of C. pneumoniae infection and present an integrated model that includes the involvement of C. pneumoniae in all stages of atherogenesis including initiation, inflammation, fibrous plaque formation, plaque rupture and thrombosis. We hypothesize that acute and persistent infection of professional immune cells (T-cells, monocytes and macrophages) and non-immune cells (endothelial cells and smooth muscle cells) contributes to a sustained inflammatory response mediated by extensive cellular 'crosstalk' and numerous cytokines/chemokines. This cascade of inflammatory mediators may contribute to cellular dysfunction and tissue remodelling of the arterial intima. An improved understanding of the precise mechanism(s) of C. pneumoniae involvement in atherogenesis may help resolve the question of causality however, at the present time, we interpret the data as favoring a contributory rather than a causal role. Future research directed at the discovery of chlamydial virulence factors necessary for intracellular survival and subsequent alterations in host cell gene expression including signalling pathways may be important for the design of future clinical trials.


Bovine tuberculosis breakdown duration in cattle herds: an investigation of herd, host, pathogen and wildlife risk factors.
Despite rigorous controls placed on herds which disclose ante-mortem test positive cattle to bovine tuberculosis, caused by the infection of Mycobacterium bovis, many herds in Northern Ireland (NI) experience prolonged breakdowns. These herds represent a considerable administrative and financial burden to the State and farming community. A retrospective observational study was conducted to better understand the factors associated with breakdown duration, which was modelled using both negative binomial and ordinal regression approaches. Six explanatory variables were important predictors of breakdown length in both models; herd size, the number of reactors testing positive in the initial SICCT test, the presence of a lesioned animal at routine slaughter (LRS), the count of M. bovis genotypes during the breakdown (MLVA richness), the local herd-level bTB prevalence, and the presence of herds linked via management factors (associated herds). We report that between 2008 and 2014, mean breakdown duration in NI was 226 days (approx. seven months; median: 188 days). In the same period, however, more than 6% of herds in the region remained under movement restriction for more than 420 days (13 months); almost twice as long as the mean. The MLVA richness variable was a particularly important predictor of breakdown duration. We contend that this variable primarily represents a proxy for beef fattening herds, which can operate by purchasing cattle and selling animals straight to slaughter, despite prolonged trading restrictions. For other herd types, the model supports the hypothesis that prolonged breakdowns are a function of both residual infection within the herd, and infection from the environment (e.g. infected wildlife, contiguous herds and/or a contaminated environment). The impact of badger density on breakdown duration was assessed by including data on main sett (burrow) density. Whilst a positive association was observed in the univariate analysis, confounding with other variables means that the contribution of badgers to prolonged breakdowns was not clear from our study. We do not fully reject the hypothesis that badgers are implicated in prolonging bTB breakdowns via spillback infection, but given our results, we posit that increased disease risk from badgers is unlikely to simply be a function of increasing badger density measured using sett metrics.


Tobacco companies' use of retailer incentives after a ban on point-of-sale tobacco displays in Scotland.
Incentives have been used by tobacco companies for many years to encourage retailers to sell and promote their products. However, few studies have examined the use of retailer incentives in countries with a ban on the open display of tobacco products in stores. As part of the DISPLAY(Determining the Impact of Smoking Point of Sale Legislation Among Youth) study, annual qualitative interviews were conducted with 24 small retailers in four Scottish communities. This article focuses on data collected in June to July 2015 and June to July 2016 after a ban on the open display of tobacco was fully implemented in Scotland. Retailers described being offered and benefiting from a range of financial and other incentives, typically offered via tobacco company representatives ('reps'). Most of the retailers received tobacco manufacturer support for converting their storage unit to be compliant with the new regulations, and several participated in manufacturer 'loyalty' or 'reward' schemes. Incentives were additionally offered for maintaining stock levels and availability, positioning brands in specified spaces in the public-facing storage units (even though products were covered up), increasing sales, trialling new products and participating in specific promotions, such as verbally recommending specific brands to customers. Even in a market where the open display of tobacco is prohibited, tobacco companies continue to incentivise retailers to sell and promote their brands and have developed new promotional strategies. For countries that have implemented tobacco display bans, or are considering doing so, one option to combat these practices would be to ban promotional communications between manufacturers and retailers.


Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial.
Dapagliflozin, a highly selective inhibitor of the renal sodium-glucose cotransporter-2, increases urinary excretion of glucose and lowers plasma glucose levels in an insulin-independent manner. We evaluated the efficacy and safety of dapagliflozin in treatment-naive patients with type 2 diabetes. This was a 24-week parallel-group, double-blind, placebo-controlled phase 3 trial. Patients with A1C 7.0-10% (n = 485) were randomly assigned to one of seven arms to receive once-daily placebo or 2.5, 5, or 10 mg dapagliflozin once daily in the morning (main cohort) or evening (exploratory cohort). Patients with A1C 10.1-12% (high-A1C exploratory cohort; n = 73) were randomly assigned 1:1 to receive blinded treatment with a morning dose of 5 or 10 mg/day dapagliflozin. The primary end point was change from baseline in A1C in the main cohort, statistically tested using an ANCOVA. In the main cohort, mean A1C changes from baseline at week 24 were -0.23% with placebo and -0.58, -0.77 (P = 0.0005 vs. placebo), and -0.89% (P < 0.0001 vs. placebo) with 2.5, 5, and 10 mg dapagliflozin, respectively. Signs, symptoms, and other reports suggestive of urinary tract infections and genital infection were more frequently noted in the dapagliflozin arms. There were no major episodes of hypoglycemia. Data from exploratory cohorts were consistent with these results. Dapagliflozin lowered hyperglycemia in treatment-naive patients with newly diagnosed type 2 diabetes. The near absence of hypoglycemia and an insulin-independent mechanism of action make dapagliflozin a unique addition to existing treatment options for type 2 diabetes.


Peak isovolumic pressure-volume relation of puppy left ventricle.
We studied peak isovolumic pressure-volume (PV) relation of the left ventricle in 3-mo-old mongrel puppies. A puppy heart was excised and cross circulated with an adult dog. Left ventricular pressure and volume were measured with a water-filled balloon. Peak isovolumic PV curve in control contractile state was convex upward, reaching a maximum pressure of 130 mmHg. Epinephrine (0.6 microgram/min intracoronary) shifted the curve leftward and up to a maximum pressure of 160 mmHg. Propranolol (0.8 mg intracoronary) shifted it rightward and down to a maximum pressure of 110 mmHg. These PV curves were reasonably fitted by an asymptotic equation: P = A (1 - exp[-B (V - Vd)]), where V was normalized volume for 100 g left ventricle and Vd (6 ml/100 g) was V at which peak pressure was zero. A and B are regression coefficients. A was 149, 169, and 120 mmHg, and B was 0.16, 0.19, and 0.06 ml, respectively, in control, enhanced, and depressed contractile states. These changes in A and B were statistically significant. We conclude that the puppy left ventricular peak isovolumic PV curve is convex upward and shifts sensitively with inotropic changes.


[Carbohydrate deficient transferrin: what's new 20 years later?].
The clinical diagnosis of alcohol abuse has frequently to be supported by biological data. These data help the practitioner to establish the diagnosis and to monitor the alcohol withdrawal and possible relapses. They also can help to demonstrate to the patient the existence of a denied alcohol abuse. CDT determination has been proposed for more than twenty years, but commercial kits are available since only 1990. A consensus has to be established concerning a reference method and the definition of the transferrin isoforms that should be included in the CDT. CDT is nevertheless considered in many studies as the best marker of alcohol abuse now available. Its sensitivity is at least equal to that of gamma glutamyltransferase (GGT), and its specificity remains very high even in the presence of other pathologies connected or not to the alcohol abuse. CDT is, despite the lack of standardisation and the cost of its determination, a basic marker of alcohol abuse more particularly in the circumstances of lack of efficiency of the other markers.


Molecular cloning and characterization of endogenous feline leukemia virus sequences from a cat genomic library.
Recombinant bacteriophage lambda clones from a cat genomic library derived from placental DNA of a specific pathogen-free cat were screened to identify endogenous feline leukemia virus (FeLV) sequences. Restriction endonuclease mapping of four different clones indicates that there are a number of similarities among them, notably the presence of a 6.0- to 6.4-kilobase pair (kbp) EcoRI hybridizing fragment containing portions of sequences homologous to the gag, pol, env, and long terminal repeat-like elements of the infectious FeLV. The endogenous FeLV sequences isolated are approximately 4 kbp in length and are significantly shorter than the cloned infectious FeLV isolates, which are 8.5 to 8.7 kbp in length. The endogenous elements have 3.3- to 3.6-kbp deletions in the gag-pol region and approximately 0.7- to 1.0-kbp deletions in the env region. These deletions would render them incapable of encoding an infectious virus and may therefore be related to the non-inducibility of FeLV from uninfected cat cells and the subgenomic expression of these endogenous sequences in placental tissue. It appears that there is conservation in the ordering of restriction sites previously reported in the proviruses of the infectious FeLVs in sequences corresponding to the pol and env boundary as well as the region spanning the env gene of the endogenous clones, whereas a greater divergence occurs among restriction sites mapped to the gag and part of the pol regions of the infectious FeLV. Such deleted, FeLV-related subsets of DNA sequences could have originated either by germ-line integration of a complete ecotropic virus followed by deletion, or by integration of a preexisting, defective, deleted variant of the infectious virus.


Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity.
Mounting evidence points to individual contributions of tumour necrosis factor-alpha (TNF) and the c-Jun N-terminal kinase (JNK) pathway to the induction and maintenance of various pain states. Here we explore the role of spinal TNF and JNK in carrageenan-induced hypersensitivity. As links between TNF and JNK have been demonstrated in vitro, we investigated if TNF regulates spinal JNK activity in vivo. TNF levels in lumbar cerebrospinal fluid (CSF) were measured by enzyme-linked immunosorbent assay, spinal TNF gene expression by real-time polymerase chain reaction and TNF protein expression, JNK and c-Jun phosphorylation by western blotting. The role of spinal TNF and JNK in inflammation-induced mechanical and thermal hypersensitivity was assessed by injecting the TNF inhibitor etanercept and the JNK inhibitors SP600125 and JIP-1 intrathecally (i.t.). TNF-mediated regulation of JNK activity was examined by assessing the effect of i.t. etanercept on inflammation-induced spinal JNK activity. TNF levels were increased in CSF and spinal cord following carrageenan-induced inflammation. While JNK phosphorylation followed the same temporal pattern as TNF, c-jun was only activated at later time points. Intrathecal injection of TNF and JNK inhibitors attenuated carrageenan-induced mechanical and thermal hypersensitivity. TNF stimulation induced JNK phosphorylation in cultured spinal astrocytes and blocking the spinal actions of TNF in vivo by i.t. injection of etanercept reduced inflammation-induced spinal JNK activity. Here we show that spinal JNK activity is dependent on TNF and that both TNF and the JNK signalling pathways modulate pain-like behaviour induced by peripheral inflammation.


Zinc Binds to RRM2 Peptide of TDP-43.
Transactive response DNA and RNA binding protein 43 kDa (TDP-43) is a highly conserved heterogeneous nuclear ribonucleoprotein (hnRNP), which is involved in several steps of protein production including transcription and splicing. Its aggregates are frequently observed in motor neurons from amyotrophic lateral sclerosis patients and in the most common variant of frontotemporal lobar degeneration. Recently it was shown that TDP-43 is able to bind Zn2+ by its RRM domain. In this work, we have investigated Zn2+ binding to a short peptide 256-264 from C-terminus of RRM2 domain using isothermal titration calorimetry, electrospray ionization mass spectrometry, QM/MM simulations, and NMR spectroscopy. We have found that this peptide is able to bind zinc ions with a Ka equal to 1.6 × 105 M-1. Our findings suggest the existence of a zinc binding site in the C-terminal region of RRM2 domain. Together with the existing structure of the RRM2 domain of TDP-43 we propose a model of its complex with Zn2+ which illustrates how zinc might regulate DNA/RNA binding.


Caspase-2 deficiency protects mice from diabetes-induced marrow adiposity.
Type I (T1) diabetes is an autoimmune and metabolic disease associated with bone loss. Bone formation and density are decreased in T1-diabetic mice. Correspondingly, the number of TUNEL positive, dying osteoblasts increases in bones of T1-diabetic mice. Moreover, two known mediators of osteoblast death, TNFα and ROS, are increased in T1-diabetic bone. TNFα and oxidative stress are known to activate caspase-2, a factor involved in the extrinsic apoptotic pathway. Therefore, we investigated the requirement of caspase-2 for diabetes-induced osteoblast death and bone loss. Diabetes was induced in 16-week old C57BL/6 caspase-2 deficient mice and their wild type littermates and markers of osteoblast death, bone formation and resorption, and marrow adiposity were examined. Despite its involvement in extrinsic cell death, deficiency of caspase-2 did not prevent or reduce diabetes-induced osteoblast death as evidenced by a twofold increase in TUNEL positive osteoblasts in both mouse genotypes. Similarly, deficiency of caspase-2 did not prevent T1-diabetes induced bone loss in trabecular bone (BV/TV decreased by 30 and 50%, respectively) and cortical bone (decreased cortical thickness and area with increased marrow area). Interestingly, at this age, differences in bone parameters were not seen between genotypes. However, caspase-2 deficiency attenuated diabetes-induced bone marrow adiposity and adipocyte gene expression. Taken together, our data suggest that caspase-2 deficiency may play a role in promoting marrow adiposity under stress or disease conditions, but it is not required for T1-diabetes induced bone loss.


Reversal of P-glycoprotein-mediated multidrug resistance in human sarcoma MES-SA/Dx-5 cells by nonsteroidal anti-inflammatory drugs.
Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is one of the major reasons for the failure of cancer therapy. Several chemosensitizers are able to reverse in vitro MDR by inhibiting P-gp, although high toxicity limits their clinical application. In this study, we aimed to investigate the in vitro effectiveness of four common non-steroidal anti-inflammatory drugs (NSAIDs) such as Curcumin (Cur), Sulindac (Sul), Ibuprofen (Ibu) and NS-398 (NS) to inhibit P-gp activity at clinically achievable doses and to evaluate their potential use as sensitizers in anti-cancer chemotherapy. The human doxorubicin (doxo) resistant uterine sarcoma cells (MES-SA/Dx-5) expressing high levels of P-gp, were treated with different doxo concentrations in the presence or absence of NSAIDs. Cellular accumulation of doxo, cytotoxicity and apoptosis induction were measured in comparison with Verapamil, a specific P-gp inhibitor, used as a reference molecule. We found that Ibu, Cur and NS-398 enhanced significantly doxo retention, cytotoxicity and apoptosis on resistant MES-SA/Doxo-5 cells when compared with doxo alone. In contrast, no significant changes were found in resistant cells treated with Sul-doxo combinations. Our results demonstrate that Ibu, Cur and NS-398 below their therapeutic plasma concentrations were able to overcome P-gp-mediated MDR in MES-SA/Dx-5 cells. These findings provide the rationale for clinical studies of NSAIDs and/or derivatives as a new potential generation of chemosensitizers to improve effectiveness of the anti-cancer drugs in the treatment of human cancer.


High-dose anti-histamine use and risk factors in children with urticaria.
The drugs of choice in the treatment of urticaria in children are H1-antihistamines. The aim of the study was to evaluate children with urticaria and define risk factors for requirement of high-dose H1-antihistamines in children with urticaria. The medical data of children who were diagnosed as having urticaria admitted to our outpatient clinic between January 2014 and January 2016 were searched. The medical histories, concomitant atopic diseases, parental atopy histories, medications, treatment responses, blood eosinophil and basophil counts, and serum total IgE levels were recorded. In addition, the urticaria activity score for seven days, autoimmune antibody tests, and skin prick test results were evaluated in children with chronic urticaria. The numbers of the children with acute and chronic urticaria were 138 and 92, respectively. The age of the children with chronic urticaria was higher than that of those with acute urticaria (p<0.0001). There was no difference between the two groups in terms of blood eosinophil and basophil counts, and serum total IgE levels (p>0.05). There was a negative correlation between blood eosinophil count and the UAS7 score in children with chronic urticaria (r=-0.276, p=0.011). Chronic urticaria and requirement of high dose H1-antihistamines were significant in children aged ≥10 years (p<0.001, p=0.015). High UAS7 score (OR: 1.09; CI 95%: [1.03-1.15]) and basopenia (OR: 6.77; CI 95%: [2.01-22.75]) were associated with the requirement of high-dose H1-AH in children with chronic urticaria. The requirement of high-dose H1-antihistamines was higher with children's increasing age. Disease severity and basopenia were risk factors for the requirement of high-dose H1-antihistamines.


Anaphylaxis during general anaesthesia: one-year survey from a British allergy clinic.
Anaphylaxis during general anaesthesia is a major concern. Early recognition and management of anaphylaxis, as well as its future prevention, remain a challenge for the anaesthetists, while for the allergists, the elucidation of the causal agents may be difficult. We aimed to describe our experience in our drug allergy clinic. We retrospectively reviewed 23 consecutive adult patients who presented with anaphylaxis during anaesthesia from March 1, 2005 to February 28, 2006. Out of the 23 patients (12 females, 11 males) with mean age (+/- SD) of 53.1 +/- 15.8 years, 15 patients were found to have a positive skin test to at least one neuromuscular blocking agent (NMBA); all of them showed cross-sensitivity with one or more NMBA(s). Three patients had a positive skin test to opioids, two patients to gelofusine, two patients to penicillin, and one patient each to povidone-iodine and chlorhexidine. Two patients had negative test results to agents used during their anaesthesia. Four patients had double positive skin tests to different families of drugs/agents. 18 patients had severe reaction-grade 3, and 15 of them tested positive for NMBA(s). Serum tryptase levels were known in nine patients. We did not encounter any latex or hypnotics sensitisation. NMBA was the commonest cause of anaphylaxis during general anaesthesia, occurring in 65% in our series.


Technique and Outcome of a Modified Tibial Plateau Levelling Osteotomy for Treatment of Concurrent Medial Patellar Luxation and Cranial Cruciate Ligament Rupture in 76 Stifles.
The main aim of this article is to describe the technique and outcome of a modified tibial plateau levelling osteotomy (TPLO) that simultaneously levels the tibial plateau and realigns the quadriceps mechanism through medial translation of the proximal tibial segment in dogs less than 15 kg. A retrospective medical records search identified dogs with concurrent cranial cruciate ligament rupture (CCLR) and medial patellar luxation (MPL). A study group (76 stifles) treated with a modified TPLO was compared with a non-tibial translation group (45 stifles) corrected with traditional surgical technique. Signalment, arthroscopic findings, adjunctive surgical procedures, osteotomy healing time and complications were recorded. Tibial plateau angle, proximal tibial segment medialization, width of the tibial osteotomy, mechanical medial proximal tibial angle and mechanical medial distal tibial angle were measured and recorded on preoperative and postoperative radiographs. Overall complication rate was 18.4% in the treatment group and 28.9% in the non-tibial translation group. Reluxation occurred in 6.6% of cases in the study group and in 8.8% of cases in the non-tibial translation group. There was no statistical difference in healing time between groups. A modified TPLO can be used to treat patients with concurrent MPL and CCLR with good clinical outcome. Complication rates are comparable to traditional repairs for MPL. No major differences were appreciated between study and a non-tibial translation groups for variables compared.


Suicide: a Socratic revenge.
2400 years have passed since the occurrence in Athens, Greece of one of the famous suicides recorded in human history. This autobiographical essay provides a montage on the history of suicide, with snippets from the final hours of Socrates, as described by Plato. Suicide in contemporary Japanese culture is also explored briefly, with reference to the deaths of internationally acclaimed movie directors Akira Kurosawa and Juzo Itami. The author also questions why no researcher has yet been honoured for the past 99 years with a Medicine Nobel prize for his or her work on suicidology or thanatology.


What's Sex Got to Do With COVID-19? Gender-Based Differences in the Host Immune Response to Coronaviruses.
The novel severe acute respiratory syndrome coronavirus 2, the cause of the coronavirus disease 2019 (COVID-19) pandemic, has ravaged the world, with over 22 million total cases and over 770,000 deaths worldwide as of August 18, 2020. While the elderly are most severely affected, implicating an age bias, a striking factor in the demographics of this deadly disease is the gender bias, with higher numbers of cases, greater disease severity, and higher death rates among men than women across the lifespan. While pre-existing comorbidities and social, behavioral, and lifestyle factors contribute to this bias, biological factors underlying the host immune response may be crucial contributors. Women mount stronger immune responses to infections and vaccinations and outlive men. Sex-based biological factors underlying the immune response are therefore important determinants of susceptibility to infections, disease outcomes, and mortality. Despite this, gender is a profoundly understudied and often overlooked variable in research related to the immune response and infectious diseases, and it is largely ignored in drug and vaccine clinical trials. Understanding these factors will not only help better understand the pathogenesis of COVID-19, but it will also guide the design of effective therapies and vaccine strategies for gender-based personalized medicine. This review focuses on sex-based differences in genes, sex hormones, and the microbiome underlying the host immune response and their relevance to infections with a focus on coronaviruses.


Falsely high ankle-brachial index predicts major amputation in critical limb ischemia.
Falsely high ankle-brachial index (ABI) values are associated with an adverse clinical outcome in diabetes mellitus. The aim of the present study was to verify whether such an association also exists in patients with chronic critical limb ischemia (CLI) with and without diabetes. A total of 229 patients (74 +/- 11 years, 136 males, 244 limbs with CLI) were followed for 262 +/- 136 days. Incompressibility of lower limb arteries (ABI > 1.3) was found in 45 patients, and was associated with diabetes mellitus (p = 0.01) and renal insufficiency (p = 0.035). Limbs with incompressible ankle arteries had a higher rate of major amputation (p = 0.002 by log-rank). This association was confirmed by multivariate Cox regression analysis (relative risk [RR] 2.67; 95% CI 1.27-5.64, p = 0.01). The relationship between ABI > 1.3 and amputation rate persisted after subjects with diabetes and renal insufficiency had been removed from the analysis (RR 3.85; 95% CI 1.25-11.79, p = 0.018). Dividing limbs with measurable ankle pressure according to tertiles of ABI, the group in the second tertile (0.323 < or = ABI < or = 0.469) had the lowest amputation rate (4/64, 6.2%), and a U-shaped association between the occurrence of major amputation and ABI was evident. No association was found between ABI and mortality. In conclusion, this study demonstrates that falsely high ABI is an independent predictor of major amputation in patients with CLI.


Treatment failure in osteoporosis.
Guidelines concerning the definition of failure of therapies used to reduce the risk of fracture are provided. This study aims to provide guidelines concerning the definition of failure of therapies used to reduce the risk of fracture. A working group of the Committee of Scientific Advisors of the International Osteoporosis Foundation was convened to define outcome variables that may assist clinicians in decision making. In the face of limited evidence, failure of treatment may be inferred when two or more incident fractures have occurred during treatment, when serial measurements of bone remodelling markers are not suppressed by anti-resorptive therapy and where bone mineral density continues to decrease. The provision of pragmatic criteria to define failure to respond to treatment provides an unmet clinical need and may stimulate research into an important issue.


Post-hospital home health care for Medicare patients.
Medicare patients in five diagnosis-related groups (DRGs) associated with heavy use of post-hospital care discharged from 52 hospitals in 3 cities were followed up at 6 weeks, 6 months, and 1 year to determine the factors associated with their being discharged home with or without home health care and the correlates of improvement in their functional status. Models correctly predicted those discharged home from those going to institutions in a range from 54 to 82 percent of cases. The amount of the variance in the change in function for those who went home (with or without home health care) explained by the models tested ranged from 19 percent to 73 percent. Total Medicare costs for the patients who went home were considerably less in the year subsequent to the hospitalization compared with those discharged to institutional care.


Effects of a low calcium environment on luteinizing hormone biosynthesis in cultured rat anterior pituitary cells.
The purpose of this study was to investigate the effects of lowering the extracellular calcium concentration on GnRH-stimulated LH glycosylation and LH translation, as measured by the incorporation of [3H]glucosamine (3H-Gln) and [35S]methionine (35S-Met) into immunoprecipitable LH. Cultured anterior pituitary cells, previously exposed to estradiol (5 X 10(-10) M) to maximize precursor incorporation were incubated for 4 h in normal calcium (2.5 mM) or low calcium medium (less than 15 microM) containing radiolabeled precursors with or without 1 nM GnRH. In the presence of normal calcium, GnRH significantly increased 3H-Gln-labeled LH in the medium (278%) and cells (290%), as well as total (cells plus medium) 3H- Gln LH (280%) compared to the control value (no GnRH). GnRH also significantly increased the 35S-Met LH released into the medium (164%) and total 35S-Met LH (186%) over control values. Depletion of extracellular calcium completely inhibited GnRH-stimulated 3H-Gln LH and 35S-Met LH production. Total immunoreactive LH (iLH), as measured by RIA, was also increased significantly by GnRH treatment in the presence of calcium, but this response was prevented by removal of calcium from the medium. Lowering extracellular calcium had no effect on cellular uptake or incorporation of 3H-Gln or 35S-Met into total trichloroacetic acid-precipitable protein. Approximately 80% of newly synthesized LH was released into the medium in all treatment groups independent of whether calcium or GnRH was present. The specific activity (disintegrations per min/microgram iLH) of radiolabeled LH released into the medium was significantly reduced by treatment with GnRH due to the large amount of unlabeled iLH released into the medium. However, when the cells were incubated in low calcium, the SA of 3H-Gln LH and 35S-Met LH in the medium was unaltered by GnRH, whereas GnRH-stimulated iLH release was inhibited. We conclude that GnRH stimulation of LH glycosylation and LH apoprotein synthesis involves extracellular calcium-dependent events, and the release of newly synthesized LH is closely coupled to LH biosynthesis and is less dependent on extracellular calcium, whereas the GnRH-stimulated release of previously synthesized, stored LH is dependent on extracellular calcium.


People's perception of their overall coronary risk: an Italian experience.
Strategies to prevent cardiovascular diseases are still not widely applied. It is vital to involve people for effective prevention, and knowledge of their own coronary risk is a first step. Little is known about how people perceive their coronary risk. For this reason, we examined this perception in a sample of the general population and compared it with a reference risk chart. We invited the population of two small towns to come for a free check of their blood pressure and blood cholesterol levels. People were first asked to complete a self-administered questionnaire grading their perceived risk of developing a coronary event. Then, basic data were collected for calculating their risk according to a reference chart. A total of 877 individuals (382 males, 495 females, age 30-80 years) without ischemic heart disease completed the questionnaire and had their blood pressure and cholesterol checked. Many important risk factors are still not taken into account by patients, particularly male sex, older age and diabetes. One out of 4 subjects underestimates his level of coronary risk and 9 out of 10 high-risk subjects are not even aware of it. Our study shows that large numbers of persons are still unaware of their level of coronary risk and of its major determinants. Better counseling by general practitioners is needed since a realistic perception of risk is essential for reducing it.


Effectiveness of melatonin for sleep impairment post paediatric acquired brain injury: evidence from a systematic review.
To retrieve and review all the relevant literature describing the administration of melatonin to treat impaired sleep in children following acquired brain injury (ABI). A systematic search and retrieval of the literature was conducted using advanced search techniques. The retrieval identified 589 papers, seven of which were relevant. Review/outcomes criteria were developed and study quality was determined. There is paucity of high-quality evidence to support use of melatonin for sleep impairment post paediatric ABI. Variation in dosage, screening and outcome measures, data reporting and a lack of impairment delineation and treatment stratification were recurrent themes. Retrieved evidence for the effectiveness of melatonin for post paediatric ABI sleep impairment appears promising. There is a clear need for further study in this area to inform clinical and research practices. Recommendations are given.


PubChemRDF: towards the semantic annotation of PubChem compound and substance databases.
PubChem is an open repository for chemical structures, biological activities and biomedical annotations. Semantic Web technologies are emerging as an increasingly important approach to distribute and integrate scientific data. Exposing PubChem data to Semantic Web services may help enable automated data integration and management, as well as facilitate interoperable web applications. This work, one of a series covering the PubChemRDF project, describes an approach to translate PubChem Substance and Compound information into Resource Description Framework (RDF) format. Basic examples are provided to demonstrate its use. The aim of this effort is to provide two new primary benefits to researchers in a cost-effective manner. Firstly, we aim to remove the inherent limitations of using the web-based resource PubChem by allowing a researcher to use readily available semantic technologies (namely, RDF triple stores and their corresponding SPARQL query engines) to query and analyze PubChem data on local computing resources. Secondly, this work intends to help improve data sharing, analysis, and integration of PubChem data to resources external to NCBI and across scientific domains, by means of the association of PubChem data to existing ontological frameworks, including CHEMical INFormation ontology, Semanticscience Integrated Ontology, and others. With the goal of semantically describing information available in the PubChem archive, pre-existing ontological frameworks were used, rather than creating new ones. Semantic relationships between compounds and substances, chemical descriptors associated with compounds and substances, interrelationships between chemicals, as well as provenance and attribute metadata of substances are described. Graphical abstract:Schematic representation of the semantic links for PubChem compounds and substances.


[Use of alternative therapies by nursing teachers].
The necessity of the health professionals to understand the health illness process in a different paradigm of the valid bio-medical model is more and more present. The objective of this work was verify what are the alternatives practices utilised for Nursing teachers for themselves and/or in their respective family relatives and if these teachers have been utilised the practices and if they talk about this subject with their students. The population of this study were 59 Nursing graduate teachers from São Paulo City placed in four different teaching institutions that answered a questionnaire. The people that answered the questionnaire were chosen at random and the data were collected in October, 1996. Among the results, we verified that 39 (66.1%) of them referred that they used the APH, in fact, the more usual alternative practice is the homeopathy (24 times), floral (21) and the eastern massage (13). The people did not use the APH are for its use in specific situations; 56 (94.9%) teachers were for its teaching, but only 31 (52.5%) talk about APH to their students.


Diosmin prevents left ventricular hypertrophy, adenosine triphosphatases dysfunction and electrolyte imbalance in experimentally induced myocardial infarcted rats.
Currently, there has been an increased interest globally to identify natural compounds that are pharmacologically potent and have low or no adverse effects for use in preventive medicine. Myocardial infarction is a vital pathological feature resulting in high levels of mortality and morbidity. Left ventricular hypertrophy (LVH), adenosine triphosphatases (ATPases) dysfunction and electrolyte imbalance play a vital role in the pathogenesis of myocardial infarction. This study aims to evaluate the preventive effects of diosmin on LVH, ATPases dysfunction and electrolyte imbalance in isoproterenol induced myocardial infarcted rats. Male albino Wistar rats were pretreated orally with diosmin (10mg/kg body weight) daily for a period of 10 days. After pretreatment, isoproterenol (100mg/kg body weight) was injected subcutaneously into the rats twice at an interval of 24h to induce myocardial infarction. Isoproterenol induced myocardial infarcted rats showed increased LVH, altered levels/ concentrations of serum cardiac troponin-T, heart ATPases, heart sodium ion, calcium ion and potassium ion, and increased myocardial infarct size. Pretreatment with diosmin revealed preventive effects on LVH, and all the above mentioned biochemical parameters evaluated in isoproterenol induced myocardial infarcted rats. The 2, 3, 5-triphenyl tetrazolium chloride staining on myocardial infarct size confirmed the prevention of myocardial infarction. Further, the 1, 1 diphenyl-2- picryl-hydrazyl (DPPH) radical in vitro study revealed a potent DPPH free radical scavenging action of diosmin. Thus, the observed effects of diosmin are due to its antihypertrophic and free radical scavenging activities in isoproterenol induced myocardial infarcted rats.


Machine learning methods predict locomotor response to MK-801 in mouse models of down syndrome.
Down syndrome (DS), caused by trisomy of human chromosome 21 (HSA21), is a common genetic cause of cognitive impairment. This disorder results from the overexpression of HSA21 genes and the resulting perturbations in many molecular pathways and cellular processes. Knowledge-based identification of targets for pharmacotherapies will require defining the most critical protein abnormalities among these many perturbations. Here the authors show that using the Ts65Dn and Ts1Cje mouse models of DS, which are trisomic for 88 and 69 reference protein coding genes, respectively, a simple linear Naïve Bayes classifier successfully predicts behavioral outcome (level of locomotor activity) in response to treatment with the N-methyl-d-aspartate (NMDA) receptor antagonist MK-801. Input to the Naïve Bayes method were simple protein profiles generated from cortex and output was locomotor activity binned into three levels: low, medium, and high. When Feature Selection was used with the Naïve Bayes method, levels of three HSA21 and two non-HSA21 protein features were identified as making the most significant contributions to activity level. Using these five features, accuracies of up to 88% in prediction of locomotor activity were achieved. These predictions depend not only on genotype-specific differences but also on within-genotype individual variation in levels of molecular and behavioral parameters. With judicious choice of pathways and components, a similar approach may be useful in analysis of more complex behaviors, including those associated with learning and memory, and may facilitate identification of novel targets for pharmacotherapeutics.


Work-life balance amongst dental professionals during the COVID-19 pandemic-A structural equation modelling approach.
The Coronavirus disease (COVID-19) outbreak in 2019, has shocked the entire world. As an effort to control the disease spread, the Indian government declared a nationwide lockdown on March 25th, 2020. As dental treatment was considered high risk in the spread of COVID-19, dentistry became one of the most vulnerable professions during this time. Dental professionals had to face job layoffs, salary cuts in professional colleges, closure of private clinics resulting in huge psychological, moral, and financial crises. Studies during the previous and present pandemics have shown mental issues among health care workers necessitating institutional reforms, along with early care and support. A balance in the work-life amongst professionals is the key to better efficiency and, was majorly affected during the COVID-19 pandemic lockdown due to sudden unexpected changes. Hence this study was conducted to understand the changes they underwent both at home and professional front with a hypothesis that physical and mental health, activities, relationship status, and workplace influence the work-life balance. A pre-validated questionnaire survey was done on dentists across India. Structural Equation Modelling and path analysis were applied to the data collected. The results of the study supported the hypothesis that factors like physical and mental health, activities, relationship status, and workplace influenced the work-life balance directly. A significant imbalance was seen amongst the female dentists. The present study proved the unpreparedness among dental professionals. Hence an evolutionary phase in every field with better working protocols, robust mental health support, and a focus on strategies to face future such emergencies is required.


Variability of human hepatic UDP-glucuronosyltransferase activity.
The availability of a unique series of liver samples from human subjects, both control patients (9) and those with liver disease (6; biliary atresia (2), retransplant, chronic tyrosinemia type I, tyrosinemia, Wilson's disease) allowed us to characterize human hepatic UDP-glucuronosyltransferases using photoaffinity labeling, immunoblotting and enzymatic assays. There was wide inter-individual variation in photoincorporation of the photoaffinity analogs, [32P]5-azido-UDP-glucuronic acid and [32P]5-azido-UDP-glucose and enzymatic glucuronidation of substrates specific to the two subfamilies of UDP-glucuronosyltransferases. However, the largest differences were between subjects with liver disease. Glucuronidation activities toward one substrate from each of the UDP-glucuronosyltransferases subfamilies, 1A and 2B, for control and liver disease, respectively, were 1.7-4.5 vs 0.4-4.7 nmol/mg x min for hyodeoxycholic acid (2B substrate) and 9.2-27.9 vs 8.1-75 nmol/mg x min for pchloro-m-xylenol (1A substrate). Microsomes from a patient with chronic tyrosinemia (HL32) photoincorporated [32P]5-azido-UDP-glucuronic acid at a level 1.5 times higher than the other samples, was intensely photolabeled by [32P]5-azido-UDP-glucose and had significantly higher enzymatic activity toward p-chloro-m-xylenol. Immunoblot analysis using anti-UDP-glucuronosyltransferase antibodies demonstrated wide inter-individual variations in UDP-glucuronosyltransferase protein with increased UDP-glucuronosyltransferase protein in HL32 microsomes, corresponding to one of the bands photolabeled by both probes. Detailed investigation of substrate specificity, using substrates representative of both the 1A (bilirubin, 4-nitrophenol) and 2B (androsterone, testosterone) families was carried out with HL32, HL38 (age and sex matched control) and HL18 (older control). Strikingly increased (5-8-fold) glucuronidation activity was seen in comparison to HL18 only with the phenolic substrates. The results indicate that one or more phenol-specific UDP-glucuronosyltransferase 1A isoforms are expressed at above normal levels in this tyrosinemic subject.


Infusing High Value Care Education Directly into Patient Care on the Medicine Wards.
This article was migrated. The article was marked as recommended. Background: Multiple national initiatives have been implemented to promote cost-conscious care. Yet, there remains a deficiency of formal high value care (HVC) curricula among internal medicine residency programs.We aimedto develop a curriculum that teaches HVC material that can be utilized at the point of care and to assess the curriculum's impact on the participants' attitudes, knowledge, and practice patterns pertaining to HVC. Methods: We conducted our study on the inpatient internal medicine service over two-week rotations at Johns Hopkins Bayview Medical Center. Internal medicine residentsparticipated in two collaborative educational sessions that incorporated an introduction of important concepts in HVC, Bayesian thinking, clinical cases, and a review of a hospital bill of one of the patients under the team's care. Participants were also encouraged to reflect on their practice patterns and incorporate the HVC principles taught into their daily clinical work. We administered pre- and post-curriculum surveys to assess change in reported HVC-related practice behaviors, knowledge, and attitudes. Results: Forty-seven residents participated in the study. We included the twenty participants who completed both a pre- and post-curriculum survey in the data analysis. After participation in the curriculum, there was a significant increase in the use of pre-test probabilities in clinical decision making ( p=0.005). There was also a trend toward improvement in HVC knowledge and practice patterns after the rotation. Conclusion: We implemented a curriculum that may have improved high-value practice patterns through point-of-care education on the inpatient medicine wards.


Immunogenicity and safety of a DTaP-IPV//PRP approximately T combination vaccine given with hepatitis B vaccine: a randomized open-label trial.
To determine seroprotection and vaccine response rates produced by a diphtheria-tetanus-acellular pertussis-inactivated poliovirus-Haemophilus influenzae type-b conjugate (DTaP-IPV//PRP approximately T) vaccine containing a polyribosyl-ribitol-phosphate (PRP)-tetanus toxoid conjugate (Pentaxim) and given with a hepatitis B vaccine. In this multicentre open-label trial, 424 infants who received DTaP-IPV//PRP approximately T at 6, 10 and 14 weeks of age were also randomized to receive hepatitis B vaccine at either 6, 10 and 14 weeks or 0, 6 and 14 weeks of age. Antibody levels were determined at 6 and 18 weeks of age, and reactogenicity was monitored using parental reports. Immunogenicity was high for all vaccine antigens and was similar to that in a historical control study. After primary vaccination, 98.7% of all infants had an anti-PRP antibody titre > 0.15 microg/ml. Seroprotection against poliovirus type-1, -2 and -3 and tetanus was obtained in all infants, and against diphtheria, in 97.1%. Pertussis seroconversion, defined as a > fourfold increase in antibody titre, occurred in 95.3% for anti-pertussis toxoid antibody and in 89.0% for anti-filamentous haemagglutinin antibody. The hepatitis B seroprotection rate was 99.5% with administration at 0, 6 and 14 weeks, and 97.8%, at 6, 10 and 14 weeks. However, the antibody titre was higher with the 0, 6 and 14-week schedule (601 mIU/ml versus 207 mIU/ml). The reactogenicity of both vaccines was low. The DTaP-IPV//PRP approximately T vaccine was highly immunogenic. The anti-hepatitis B antibody response was seroprotective with both schedules, though the antibody titre was higher with the 0, 6 and 14-week schedule.


PARP-1 Val762Ala polymorphism, CagA+ H. pylori infection and risk for gastric cancer in Han Chinese population.
PARP-1 plays important role in the BER (base excision repair) and maintenance of genomic integrity. Previous study found the Val762Ala genetic variant in the PARP-1 gene contributed to susceptibility of some cancers and decreased PARP-1 enzyme activity in response to oxidative damage. Helicobacter pylori (H. pylori) infection was thought to be one of the major causes of gastric cancer. In this study, we investigated the association between the PARP-1 Val762Ala polymorphism, CagA(+) H. pylori infection, and the risk for gastric cancer. This hospital-based, case-control study was performed involving 556 individuals (236 cases with gastric cancer and 320 controls without evidence of neoplasm and gastrointestinal disease) using a PCR-RFLP method. Chi-square test and logistic regression analysis were used to count OR and 95% CI. 762Ala/Ala genotype was overrepresented in the cases (16.9%) compared with controls (10.3%), (OR, 1.942; 95% CI, 1.157-3.257, P = 0.011). Multivariate analysis showed that two factors were significantly associated with risk of gastric cancer, including CagA(+) H. pylori infection (OR, 2.562; 95% CI, 1.174-5.240, P = 0.037), PARP-1 762AA genotype (OR, 1.772; 95% CI, 1.065-3.867; P = 0.042). Stratification analysis indicated that among Cag(+) H. pylori positive subjects, 762Ala/Ala carriers had higher risk for developing gastric cancer compared with 762Val/Val carrier (OR, 2.337; 95% CI, 1.148-4.758; P = 0.017). PARP-1 762Ala/Ala could be a risk factor for gastric cancer in Han Chinese population; PARP-1 762Val/Ala polymorphism and Cag(+) H. pylori infection jointly contribute to higher risk for gastric cancer.


Cognitive reappraisal increases neuroendocrine reactivity to acute social stress and physical pain.
Cognitive reappraisal can foster emotion regulation, yet less is known about whether cognitive reappraisal alters neuroendocrine stress reactivity. Some initial evidence suggests that although long-term training in cognitive behavioral therapy techniques (which include reappraisal as a primary training component) can reduce cortisol reactivity to stress, some studies also suggest that reappraisal is associated with heightened cortisol stress reactivity. To address this mixed evidence, the present report describes two experimental studies that randomly assigned young adult volunteers to use cognitive reappraisal while undergoing laboratory stressors. Relative to the control condition, participants in the reappraisal conditions showed greater peak cortisol reactivity in response to a socially evaluative speech task (Experiment 1, N=90) and to a physical pain cold pressor task (Experiment 2, N=94). Participants in the cognitive reappraisal group also reported enhanced anticipatory psychological appraisals of self-efficacy and control in Experiment 2 and greater post-stressor self-efficacy. There were no effects of the reappraisal manipulation on positive and negative subjective affect, pain, or heart rate in either experiment. These findings suggest that although cognitive reappraisal fosters psychological perceptions of self-efficacy and control under stress, this effortful emotion regulation strategy in the short-term may increase cortisol reactivity. Discussion focuses on promising psychological mechanisms for these cognitive reappraisal effects.


Topography of N-CAM structural and functional determinants. I. Classification of monoclonal antibody epitopes.
12 distinct neural cell adhesion molecule (N-CAM) epitopes, each recognized by a different monoclonal antibody (mAb), have been characterized in terms of the major structural and functional features of the molecule. Seven antibodies, each recognizing the amino-terminal region of the molecule, altered the rate of N-CAM-mediated adhesion. Four of these were inhibitors, two of which also recognized a heparin-binding N-CAM fragment. The other three antibodies specifically enhanced the rate of N-CAM-mediated adhesion. Three epitopes, one polypeptide- and two carbohydrate-dependent, were associated with the sialic acid-rich central portion of the molecule. The remaining two antibodies were found to react with intracellular determinants, and are specific for the largest of the three major N-CAM polypeptide forms. Studies on the ability of one antibody to hinder recognition of native N-CAM by another antibody suggested that the epitopes associated with N-CAM binding functions are in close proximity compared with the other determinants. The classification of these mAb epitopes has allowed the topographical placement of key N-CAM features, as described in the following paper, and provides valuable probes for analysis of both the structure and function of N-CAM.


1,2,3,4,6-Penta-O-galloylglucose within Galla Chinensis Inhibits Human LDH-A and Attenuates Cell Proliferation in MDA-MB-231 Breast Cancer Cells.
A characteristic feature of aggressive malignancy is the overexpression of lactic acid dehydrogenase- (LDH-) A, concomitant to pericellular accumulation of lactate. In a recent high-throughput screening, we identified Rhus chinensis (Mill.) gallnut (RCG) (also known as Galla Chinensis) extract as a potent (IC50 < 1 µg/mL) inhibitor of human LDH-A (hLDH-A). In this study, through bioactivity guided fractionation of the crude extract, the data demonstrate that penta-1,2,3,4,6-O-galloyl-β-D-glucose (PGG) was a primary constituent responsible for hLDH-A inhibition, present at ~9.95 ± 0.34% dry weight. Theoretical molecular docking studies of hLDH-A indicate that PGG acts through competitive binding at the NADH cofactor site, effects confirmed by functional enzyme studies where the IC50 = 27.32 nM was reversed with increasing concentration of NADH. Moreover, we confirm protein expression of hLDH-A in MDA-231 human breast carcinoma cells and show that PGG was toxic (LC50 = 94.18 µM), parallel to attenuated lactic acid production (IC50 = 97.81 µM). In a 72-hour cell proliferation assay, PGG was found to be a potent cytostatic agent with ability to halt cell division (IC50 = 1.2 µM) relative to paclitaxel (IC50 < 100 nM). In summary, these findings demonstrate that PGG is a potent hLDH-A inhibitor with significant capacity to halt proliferation of human breast cancer cells.


T-cells and B-cells in systemic sclerosis.
Systemic sclerosis (SSc) is characterized by activation of fibroblasts with extensive deposition of collagen, by small vessel vasculopathy with fibrointimal proliferation, and activation of the immune system, with hyper-γ- globulinaemia and autoantibodies. Twin studies have shown that genetic factors play a minor role in SSc development. Serum autoantibodies and skin lymphocytic infiltrates and small vessel damage occur very early before the appearance of skin fibrosis. T cells can cause fibrosis and vasculopathy through cell-cell contact and cytokines. They produce TH2 cytokines (IL-4, IL13) and TH17 cytokines (IL-17), which are profibrotic. TH2 cells in experimental models also induce pulmonary arterial hypertension. Genetically engineered TGFβ expression in pig arteries causes fibrointimal proliferation. T cells in skin lesions exhibit oligoclonality that persists over time, which indicates an antigen-driven T cell activation, but the antigen(s) responsible are not known. There are known environmental factors that can elicit an immune response and cause a SSc-like disease. T cells also provide help for B cells. B cells can contribute to fibrosis and vasculopathy through cytokines and autoantibodies. Autoantibodies can activate endothelial cells and fibroblasts to a profibrotic phenotype. Finally, treatments directed against T cells and B cells show promising effects in SSc.


Non-viral nanosystems for gene and small interfering RNA delivery to the central nervous system: formulating the solution.
The application of gene and RNAi-based therapies to the central nervous system (CNS), for neurological and neurodegenerative disease, offers immense potential. The issue of delivery to the target site remains the single greatest barrier to achieving this. There are challenges to gene and siRNA (small interfering RNA) delivery which are specific to the CNS, including the post-mitotic nature of neurons, their resistance to transfection and the blood-brain barrier. Viral vectors are highly efficient and have been used extensively in pre-clinical studies for CNS diseases. However, non-viral delivery offers an exciting alternative. In this review, we will discuss the extracellular and intracellular barriers to gene and siRNA delivery in the CNS. Our focus will be directed towards various non-viral strategies used to overcome these barriers. In this regard, we describe selected non-viral vectors and categorise them according to the barriers that they overcome by their formulation and targeting strategies. Some of the difficulties associated with non-viral vectors such as toxicity, large-scale manufacture and route of administration are discussed. We provide examples of optimised formulation approaches and discuss regulatory hurdles to clinical validation. Finally, we outline the components of an "ideal" formulation, based on a critical analysis of the approaches highlighted throughout the review.


Meta-Analysis of Local Invasive Breast Cancer Recurrence After Electron Intraoperative Radiotherapy.
Electron intraoperative radiotherapy (IORT) can be used during breast conserving surgery to treat early-stage invasive breast cancer. Using data from current clinical and observational studies, this study aimed to assess the impact of single-fraction electron IORT on local recurrence rates. Studies on single-fraction electron IORT during breast conserving surgery were identified through a search of PubMed and Google Scholar, as well as through secondary referencing. Local recurrence rate was the main outcome of interest. A meta-analysis of proportions using a binomial distribution to model the within-study variability and a random effects model was conducted to estimate a pooled local recurrence rate. To estimate a 5-year recurrence rate, a single-sample Poisson-normal model was applied to model the probability of events occurring during a fixed period (60 months). The study identified 13 publications. The analysis demonstrated a pooled monthly local recurrence rate of 0.02% per person-month (95% confidence interval CI 0.00-0.06%) for the studies with a follow-up period shorter than 5 years, 0.03% per person-month (95% CI 0.02-0.06%) for studies with a follow-up period of 5 years or longer, and 0.02% per person-month (95% CI 0.01-0.04%) overall. Based on this model, the predicted 5-year local recurrence rate was 2.7% (range 1.9-3.7%). According to the published literature, the rate of breast cancer local recurrence after electron IORT was 0.02% per person-month, with an adjusted 5-year recurrence rate of 2.7%. These findings support the recent guidelines from the American Society for Radiation Oncology (ASTRO) supporting the use of electron IORT for low-risk patients.


The Effect of Testicular Torsion Duration on Testicular Steroidogenesis in the Rat Model.
Testicular torsion is an emergency condition in which spermatogenesis may be irreversibly damaged. There have been controversial results about the effect of testicular torsion on steroidogenesis. We aimed at investigating the effect of testicular torsion on steroidogenesis. A total of 40 adult male rats were divided into 4 groups. Left testicles were removed in all groups. Right testicles were torsioned and remained in the torsion position for 1, 3 and 5 h in study groups, whereas no torsion was performed in control. Serum luteinizing hormone (LH) and total testosterone (TT) levels were measured on the 3rd and 30th days of surgery and orchiectomy was performed on the 30th day of testicular torsion for histopathological evaluation. TT levels of study groups were significantly lower than that of the control group on the 3rd day of torsion. LH of study groups was higher than that of the control group, but the difference was significant only in the 5 h-torsion group. The total number of Leydig cells increased in 1- and 3-h groups, whereas it decreased in the 5-hour group. Testosterone production and Leydig cell functions significantly decreased after 5 h torsion in the rat model. The duration of torsion less than 5 h yielded partial dysfunction on steroidogenesis.


The frequency of lysosomal storage diseases in The Netherlands.
We have calculated the relative frequency and the birth prevalence of lysosomal storage diseases (LSDs) in The Netherlands based on all 963 enzymatically confirmed cases diagnosed during the period 1970-1996. The combined birth prevalence for all LSDs is 14 per 100,000 live births. Glycogenosis type II is the most frequent LSD with a birth prevalence of 2.0 per 100,000 live births, representing 17% of all diagnosed cases. Within the group of lipidoses, metachromatic leukodystrophy (MLD) is the most frequent LSD. MLD was diagnosed in 24% of lipidoses and the calculated birth prevalence was 1.42 per 100,000 for all types combined. Krabbe disease, diagnosed in 17% of cases, also belongs to the more frequent lipid storage diseases in The Netherlands with a birth prevalence of 1.35 per 100,000. The birth prevalence of Gaucher disease, commonly regarded as the most frequent lipid storage disease is 1.16 per 100,000 for all types combined. The combined birth prevalence for all lipid storage diseases is 6.2 per 100,000 live births. Within the group of mucopolysaccharidoses (MPSs), MPS I has the highest calculated birth prevalence of 1.19 per 100,000 (25% of all cases of MPS diagnosed), which is slightly more frequent than MPS IIIA with an estimated birth prevalence of 1.16 per 100,000. As a group, MPS III comprises 47% of all MPS cases diagnosed and the combined birth prevalence is 1.89 per 100,000 live births. The birth prevalence of MPS II is 0.67 per 100,000 (1.30 per 100,000 male live births). All other MPSs are rare. The combined birth prevalence for all MPSs is 4.5 per 100,000 live births. Mucolipidoses and oligosaccharidoses are very rare with birth prevalences between 0.04 and 0.20 for individual diseases. Only 49 cases were diagnosed between 1970 and 1996. Their combined birth prevalence is 1.0 per 100,000 live births.


Marked Underreporting of Pertussis Requiring Hospitalization in Infants as Estimated by Capture-Recapture Methodology, Germany, 2013-2015.
In Germany, pertussis became notifiable in eastern federal states in 2002 and nationwide in March 2013. Infants are at greatest risk for severe disease, with a high proportion requiring hospitalization. We implemented enhanced hospital-based surveillance to estimate the incidence of pertussis requiring hospitalization among infants in Germany and to determine the proportion of infants hospitalized with pertussis too young to have been vaccinated. Enhanced surveillance was implemented within a nationwide hospital surveillance network (ESPED). We defined cases as children less than 1 year of age hospitalized due to laboratory-confirmed pertussis with disease onset from 01/07/2013-30/06/2015. We matched cases to those ascertained in the national statutory notification system, and estimated incidence using capture-recapture methodology. The estimated annual incidence of pertussis requiring hospitalization in infants was 52/100,000 infants (95% confidence interval [CI] 48-57/100,000), with 39% under-reporting to the national notification system. During the two epidemiologic years under-reporting decreased from 46% to 32% and was lower in eastern than western federal states (21% vs. 40%). Within ESPED, 154 of 240 infants (64%) were younger than or still at the age recommended for the first vaccine dose; 55 (23%) could have received one or more vaccine doses. Median length of hospitalization was 9 days (IQR 5-13 days) and 18% required intensive care treatment. Our study revealed a high burden of pertussis in infants with marked under-reporting, especially in western federal states where notification was only recently established. Strategies for the prevention of severe pertussis.


Neuropsychological outcome and diffusion tensor imaging in complicated versus uncomplicated mild traumatic brain injury.
This study examined whether intracranial neuroimaging abnormalities in those with mild traumatic brain injury (MTBI) (i.e., "complicated" MTBIs) are associated with worse subacute outcomes as measured by cognitive testing, symptom ratings, and/or diffusion tensor imaging (DTI). We hypothesized that (i) as a group, participants with complicated MTBIs would report greater symptoms and have worse neurocognitive outcomes than those with uncomplicated MTBI, and (ii) as a group, participants with complicated MTBIs would show more Diffusion Tensor Imaging (DTI) abnormalities. Participants were 62 adults with MTBIs (31 complicated and 31 uncomplicated) who completed neurocognitive testing, symptom ratings, and DTI on a 3T MRI scanner approximately 6-8 weeks post injury. There were no statistically significant differences between groups on symptom ratings or on a broad range of neuropsychological tests. When comparing the groups using tract-based spatial statistics for DTI, no significant difference was found for axial diffusivity or mean diffusivity. However, several brain regions demonstrated increased radial diffusivity (purported to measure myelin integrity), and decreased fractional anisotropy in the complicated group compared with the uncomplicated group. Finally, when we extended the DTI analysis, using a multivariate atlas based approach, to 32 orthopedic trauma controls (TC), the findings did not reveal significantly more areas of abnormal DTI signal in the complicated vs. uncomplicated groups, although both MTBI groups had a greater number of areas with increased radial diffusivity compared with the trauma controls. This study illustrates that macrostructural neuroimaging changes following MTBI are associated with measurable changes in DTI signal. Of note, however, the division of MTBI into complicated and uncomplicated subtypes did not predict worse clinical outcome at 6-8 weeks post injury.


Metabolism site prediction based on xenobiotic structural formulas and PASS prediction algorithm.
A new ligand-based method for the prediction of sites of metabolism (SOMs) for xenobiotics has been developed on the basis of the LMNA (labeled multilevel neighborhoods of atom) descriptors and the PASS (prediction of activity spectra for substances) algorithm and applied to predict the SOMs of the 1A2, 2C9, 2C19, 2D6, and 3A4 isoforms of cytochrome P450. An average IAP (invariant accuracy of prediction) of SOMs calculated by the leave-one-out cross-validation procedure was 0.89 for the developed method. The external validation was made with evaluation sets containing data on biotransformations for 57 cardiovascular drugs. An average IAP of regioselectivity for evaluation sets was 0.83. It was shown that the proposed method exceeds accuracy of SOM prediction by RS-Predictor for CYP 1A2, 2D6, 2C9, 2C19, and 3A4 and is comparable to or better than SMARTCyp for CYP 2C9 and 2D6.


Space or physics? Children use physical reasoning to solve the trap problem from 2.5 years of age.
By 3 years of age, children can solve tasks involving physical principles such as locating a ball that rolled down a ramp behind an occluder by the position of a partially visible solid wall (Berthier, DeBlois, Poirer, Novak, & Clifton, 2000; Hood, Carey, & Prasada, 2000). However, the extent to which children use physical information (the properties of the wall) remains unclear because spatial information would suffice (the location of the wall in relation to the ball). We confronted 2- to 6-year-old children with a ball resting on a shelf inside a clear plastic-fronted box. To retrieve the ball, children had to roll it away from a trap or barrier using their fingers. Crucially, a single object acted as a barrier or supporting surface in different conditions, thus requiring a flexible response. Preschoolers solved the task and the critical transfers from 2.5 years of age (Study 1). Interestingly, 2.5-year-olds required to use a tool to displace the ball performed significantly worse than those who could use their fingers (Study 2). In contrast, 2.5- to 4.5-year-olds failed a covered trap box that provided only 2-dimensional predictive cues without any visible physical information, and even 6.5-year-olds performed significantly worse on the covered task compared to the uncovered one (Studies 3 and 4). Our results suggest that children from around 2.5 years of age integrate spatial and physical information when solving problems like the trap box task, rather than simply exploit spatial relationships between features.


Ion association of imidazolium ionic liquids in acetonitrile.
Molar conductivities, Λ, of dilute solutions of the ionic liquids (ILs) 1-ethyl-3-methylimidazolium tetrafluoroborate ([emim][BF4]), 1-butyl-3-methylimidazolium tetrafluoroborate ([bmim][BF4]), 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF6]), 1-hexyl-3-methylimidazolium tetrafluoroborate ([hmim][BF4]), and 1-hexyl-3-methylimidazolium bis-(trifluoromethanesulfonyl)amide ([hmim][NTf2]) in acetonitrile (AN) were determined as a function of temperature in the range 273.15-313.15 K. The data were analyzed with Barthel's lcCM model to obtain limiting molar conductivities, Λ(∞)(T), and association constants, K(A)°(T) of these electrolytes. The temperature dependence of these parameters, as well as the extracted limiting cation conductivities, λ(i)(∞), were discussed. Additionally, dielectric spectra for [hmim][NTf2] + AN were analyzed in terms of ion association and ion solvation and compared with the inference from conductivity. It appears that in dilute solutions the imidazolium ring of the cations is solvated by ∼6 AN molecules that are slowed by a factor of ∼8-10 compared to the bulk-solvent dynamics. Ion association of imidazolium ILs to contact ion pairs is only moderate, similar to common 1:1 electrolytes in this solvent.


Patients with stage IV epithelial ovarian cancer: understanding the determinants of survival.
The most appropriate management for patients with stage IV ovarian cancer remains unclear. Our objective was to understand the main determinants associated with survival and to discuss best surgical management. Data of 1038 patients with confirmed ovarian cancer treated between 1996 and 2016 were extracted from maintained databases of 7 French referral gynecologic oncology institutions. Patients with stage IV diseases were selected for further analysis. The Kaplan-Meier method was used to estimate the survival distribution. A Cox proportional hazards model including all the parameters statistically significant in univariable analysis, was used to account for the influence of multiple variables. Two hundred and eight patients met our inclusion criteria: 65 (31.3%) never underwent debulking surgery, 52 (25%) underwent primary debulking surgery (PDS) and 91 (43.8%) neoadjuvant chemotherapy and interval debulking surgery (NACT-IDS). Patients not operated had a significantly worse overall survival than patients that underwent PDS or NACT-IDS (p < 0.001). In multivariable analysis, three factors were independent predictors of survival: upfront surgery (HR 0.32 95% CI 0.14-0.71, p = 0.005), postoperative residual disease = 0 (HR 0.37 95% CI 0.18-0.75, p = 0.006) and association of Carboplatin and Paclitaxel regimen (HR 0.45 95% CI 0.25-0.80, p = 0.007). Presence of distant metastases should not refrain surgeons from performing radical procedures, whenever the patient is able to tolerate. Maximal surgical efforts should be done to minimize residual disease as it is the main determinant of survival.