Web-Based Problem-solving Training With and Without Peer Support in Veterans With Unmet Mental Health Needs: Pilot Study of Feasibility, User Acceptability, and Participant Engagement.
eHealth tools have the potential to meet the mental health needs of individuals who experience barriers to accessing in-person treatment. However, most users have less than optimal engagement with eHealth tools. Coaching from peer specialists may increase their engagement with eHealth. This pilot study aims to test the feasibility and acceptability of a novel, completely automated web-based system to recruit, screen, enroll, assess, randomize, and then deliver an intervention to a national sample of military veterans with unmet mental health needs; investigate whether phone-based peer support increases the use of web-based problem-solving training compared with self-directed use; and generate hypotheses about potential mechanisms of action for problem-solving and peer support for future full-scale research. Veterans (N=81) with unmet mental health needs were recruited via social media advertising and enrolled and randomized to the self-directed use of a web-based problem-solving training called Moving Forward (28/81, 35%), peer-supported Moving Forward (27/81, 33%), or waitlist control (26/81, 32%). The objective use of Moving Forward was measured with the number of log-ins. Participants completed pre- and poststudy measures of mental health symptoms and problem-solving confidence. Satisfaction was also assessed post treatment. Automated recruitment, enrollment, and initial assessment methods were feasible and resulted in a diverse sample of veterans with unmet mental health needs from 38 states. Automated follow-up methods resulted in 46% (37/81) of participants completing follow-up assessments. Peer support was delivered with high fidelity and was associated with favorable participant satisfaction. Participants randomized to receive peer support had significantly more Moving Forward log-ins than those of self-directed Moving Forward participants, and those who received peer support had a greater decrease in depression. Problem-solving confidence was associated with greater Moving Forward use and improvements in mental health symptoms among participants both with and without peer support. Enrolling and assessing individuals in eHealth studies without human contact is feasible; however, different methods or designs are necessary to achieve acceptable participant engagement and follow-up rates. Peer support shows potential for increasing engagement in web-based interventions and reducing symptoms. Future research should investigate when and for whom peer support for eHealth is helpful. Problem-solving confidence should be further investigated as a mechanism of action for web-based problem-solving training. ClinicalTrials.gov NCT03555435; http://clinicaltrials.gov/ct2/show/NCT03555435.


[Clinical course and scar development in operated vesico-renal reflux in a long-term study].
62 patients (14 boys, 48 girls) representing 85 refluxive renal units (Grade 2-4) were investigated after successful operation for the development of further urinary tract infections (UTI) and renal scars (RS). The mean follow-up was 9.3 years. With the exception of one boy, none of the male patients developed any UTI or new RS. A similar result was obtained for about 45% of the girls. These two groups of patients presented with high-grade reflux before surgery. The remaining female patients (about 55%), however, presenting with lower-grade reflux before surgical treatment, developed further UTI as well as new RS despite surgical correction of their reflux. Investigations on the capacity of uroepithelial cells (UEC) to suppress bacterial growth revealed a deficient antibacterial effect of UEC in these patients. Such an UEC defect has also been shown in patients with asymptomatic bacteriuria. In conclusion, different reasons seem to be responsible for recurrent UTI and the development of RS in patients with reflux.


A Case of ADEM Mimicking Cerebral Adrenoleukodystrophy Based on Supratentorial MRI Findings.
A 9-year-old male admitted for syncope also had the complains of pain and numbness in his legs and frequent falling down. There was a history of upper respiratory tract infection 10 days before. On neurologic examination, paraparesia and fall a sleep were identified. On magnetic resonance imaging, the symetric signal increases were seen in biparieto-occipital white matter intented to corpus callosum at T2-weighted sequences and cytotoxic edema was seen at diffusion-weighted images. Heterogeneous contrast enhancement was seen on these areas. In addition, at the C7-Th5 vertebrae levels, spinal cord had diffuse increased signal intensity and contrast enhancement. Acute disseminated encephalomyelitis was thought based on clinical and radiological findings. Steroid therapy was started. Significant improvement was shown after treatment. On 2-year follow-up, there was no recurrence. In conclusion, it must be kept in mind that acute disseminated encephalomyelitis can rarely present with biparieto-occipital involvement which extends to corpus callosum and can mimic adrenoleukodystrophy. For the differential diagnosis butterfly glioma, tumefactive demyelinating lesions or multiple sclerosis should be considered.


Radiation-guided drug delivery to mouse models of lung cancer.
The purpose of this study was to achieve improved cancer-specific delivery and bioavailability of radiation-sensitizing chemotherapy using radiation-guided drug delivery. Phage display technology was used to isolate a recombinant peptide (HVGGSSV) that binds to a radiation-inducible receptor in irradiated tumors. This peptide was used to target nab-paclitaxel to irradiated tumors, achieving tumor-specificity and enhanced bioavailability of paclitaxel. Optical imaging studies showed that HVGGSSV-guided nab-paclitaxel selectively targeted irradiated tumors and showed 1.48 ± 1.66 photons/s/cm(2)/sr greater radiance compared with SGVSGHV-nab-paclitaxel, and 1.49 ± 1.36 photons/s/cm(2)/sr greater than nab-paclitaxel alone (P < 0.05). Biodistribution studies showed >5-fold increase in paclitaxel levels within irradiated tumors in HVGGSSV-nab-paclitaxel-treated groups as compared with either nab-paclitaxel or SGVSGHV-nab-paclitaxel at 72 hours. Both Lewis lung carcinoma and H460 lung carcinoma murine models showed significant tumor growth delay for HVGGSSV-nab-paclitaxel as compared with nab-paclitaxel, SGVSGHV-nab-paclitaxel,and saline controls. HVGGSSV-nab-paclitaxel treatment induced a significantly greater loss in vasculature in irradiated tumors compared with unirradiated tumors, nab-paclitaxel, SGVSGHV-nab-paclitaxel, and untreated controls. HVGGSSV-nab-paclitaxel was found to bind specifically to the tax-interacting protein-1 (TIP-1) receptor expressed in irradiated tumors, enhance bioavailability of paclitaxel, and significantly increase tumor growth delay as compared with controls in mouse models of lung cancer. Here we show that targeting nab-paclitaxel to radiation-inducible TIP-1 results in increased tumor-specific drug delivery and enhanced biological efficacy in the treatment of cancer.


Conceptualizing Care Continua: Lessons from HIV, Hepatitis C Virus, Tuberculosis and Implications for the Development of Improved Care and Prevention Continua.
To examine the application of continuum models to tuberculosis, HIV, and other conditions; to theorize the concept of continua; and to learn lessons that could inform the development of improved care and prevention continua as public health metrics. An analytic review of literature drawn from several fields of health care. The continuum construct is now part of public health evaluation systems for HIV, and is increasingly used in public health and the medical literature. Issues with the comparability and optimal design of care continuum models have been raised, and their methodologic and theoretic underpinnings and scope of focus have been under-addressed. Review of relevant publications suggests that a key limitation of current models is their lack of measures reflecting incidence and mortality. Issues relating to continua data being longitudinal or cross-sectional, definition of numerators and denominators for each step, data sources, measures of timeliness of step completion, theoretic models to facilitate inferences of causes of care continuum gaps, how measures of prevention efforts, reinfection/relapses, and interactions of continua for co-occurring comorbidities should be reflected, and how analyses of differences in retention over time, across geographic regions, and in response to interventions should be conducted are critical to the development of sound care and prevention continuum models. Lessons learned from the application of continuum models to HIV and other conditions suggest that the application of well-formulated constructs of care and prevention continua, that depict, in well defined, standardized steps, incidence and mortality, along with degrees of and time to screening, engagement in care and prevention, treatment and treatment outcomes, including relapse or reinfection, may be vital tools in evaluating intervention and program outcomes, and in improving population health and population health metrics for a wide range conditions.


Stage Shift Improves Lung Cancer Survival: Real-World Evidence.
Lung cancer is the global leading cause of cancer death. Taiwan initiated several health policies including smoking cessation, precision therapy, and low-dose computed tomography (LDCT) screening in 1997. We aimed to investigate the effect of public policies on lung cancer survival. We retrieved the nationwide cancer registry from the Ministry of Health and Welfare to evaluate the smoking prevalence and lung cancer incidence and mortality from 1994 to 2020. We also conducted a retrospective analysis of clinical characteristics and survival on 17,298 patients with lung cancer from 2006 to 2019 using the National Taiwan University Hospital database. Taiwan initiated an anti-smoking campaign in 1997, reimbursed tyrosine kinase inhibitors since 2004, and conducted an LDCT screening trial in 2015. Lung cancer incidence keeps rising but the annual percent change in mortality rate gradually decreased from 0.41% to -2.41%. The National Taiwan University Hospital data revealed that the 5-year survival substantially improved from 22.1% in 2006 to 2011 to 54.9% in 2015 to 2020. Improvement was observed in all stages, especially late stages (stage III: from 17.2% to 35.2%; stage IV: from 7.9% to 16.5%). Furthermore, a remarkable shift in cancer stage was observed (stage 0, I, and IIincreased from 19.3% to 62.8%, and stage III and IV decreased from 70.9% to 33.8%). The prominent improvement in survival was primarily driven by the stage shift from advanced to localized, potentially curable disease. This real-world evidence suggested an association between improved survival and LDCT screening and the diagnostic shift from late to early-stage of lung cancer, highlighting the importance of early detection for lung cancer control.


Whole-body fluid distribution in humans during dehydration and recovery, before and after humid-heat acclimation induced using controlled hyperthermia.
This experiment was designed to test the hypothesis that the plasma volume is not selectively defended during exercise- and heat-induced dehydration following humid-heat acclimation. Eight physically active males were heat acclimated (39.8 °C, relative humidity 59.2%) using 17 days of controlled hyperthermia (core temperature: 38.5 °C). Inter-compartmental fluid losses and movements were tracked (radioisotopes and Evans blue dye) during progressive dehydration (cycling) in these same conditions and also during a resting recovery without fluid replacement (28 °C), before (day 1), during (day 8) and after heat acclimation (day 22). On days 8 and 22, there were significant increases in total body water, interstitial fluid and plasma volume (P < 0.05), but the intracellular compartments did not change (P > 0.05). The baseline plasma volume remained expanded throughout: 43.4 [±2.6 (day 1)], 49.1 [±2.4 (day 8); P < 0.05] and 48.9 mL kg(-1) [±3.0 (day 22); P < 0.05]. During progressive dehydration, plasma reductions of 9.0% (±0.9: day 1), 12.4% (±1.6: day 8) and 13.6% (±1.2: day 22) were observed, with day 8 and 22 losses significantly exceeding day 1 (P < 0.05). During recovery, plasma volume restoration commenced, with the intracellular fluid contribution becoming more pronounced as acclimation progressed. It is concluded that the plasma volume was not defended more vigorously following humid-heat acclimation. Indeed, a greater fluid loss may well underlie the mechanisms for enhancing plasma volume recovery when heat acclimation is induced using the controlled-hyperthermia technique.


Mechanisms and means of detection of biocontrol activity of Pseudozyma yeasts against plant-pathogenic fungi.
Fungi belonging to Pseudozyma spp. represent a small group of yeasts that have drawn limited interest in the scientific literature. However, new research with one species of Pseudozyma, Pseudozyma flocculosa, has demonstrated the potential of this yeast as a biocontrol agent of plant-pathogenic fungi. Based on recent work, it appears that P. flocculosa, a natural inhabitant of the phyllosphere, possesses unique means of defending its ecological niche by producing unusual extracellular fatty acids that are detrimental to, among other fungi, powdery mildews, an important group of plant pathogens. Results from these studies have shown that the fatty acids naturally insert themselves into powdery mildew fungi and cause disorganization of cellular membranes and cell disintegration. Further work with insertional mutagenesis yielded mutants of P. flocculosa that represent valuable biological tools to better understand the properties of the yeast. For instance, preliminary work with mutants having lost their antagonistic properties has led to the isolation of a new metabolite with antifungal activity. Discoveries pertaining to the ecology and mode of action of P. flocculosa may lead to the study of unique metabolic or biological processes in other Pseudozyma spp. that could well release the untapped potential of these misunderstood yeasts.


CYP6B3: a second furanocoumarin-inducible cytochrome P450 expressed in Papilio polyxenes.
Cytochrome P450 monooxygenases in the larvae of Papilio polyxenes (black swallowtail) (Lepidoptera: Papilionidae) are capable of detoxifying linear and angular furanocoumarins found in their host plants. The CYP6B1 locus, which is transcriptionally induced in these larvae in response to xanthotoxin, encodes a P450 that principally metabolizes linear furanocoumarins such as xanthotoxin and bergapten. We have now cloned CYP6B3 cDNA derived from a second locus that is evolutionarily related to the CYP6B1 locus. Reverse transcription-PCR Southern analyses have demonstrated that CYP6B3 transcripts are expressed in response to a wider range of linear and angular furanocoumarins but at lower abundance than CYP6B1 transcripts. Whereas CYP6B1 transcripts are expressed at a low detectable level in uninduced control larvae and at high levels in xanthotoxin-induced larvae, CYP6B3 transcripts are nearly undetectable in control larvae and are highly induced by xanthotoxin and bergapten (linear furanocoumarins) as well as by angelicin and sphondin (angular furanocoumarins). The fact that these two CYP6B loci are differentially regulated by these four furanocoumarins indicates that P. polyxenes has adapted to the presence of the wide range of furanocoumarins in its host plants by diversifying its P450 isozyme structure and its furanocoumarin-responsive regulatory cascades.


A carboxylesterase 2 gene polymorphism as predictor of capecitabine on response and time to progression.
Capecitabine is a drug that requires the consecutive action of three enzymes: carboxylesterase 2 (CES 2), cytidine deaminase (CDD), and thymidine phosphorylase (TP) for transformation into 5-fluorouracil (5FU). The metabolism of 5FU requires the activity of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) among other enzymes. The present study prospectively examined the possible relationship between the toxicity and efficacy of capecitabine and 14 different polymorphisms in CES 2, CDD, TS and DPD. Between 2003 and 2005, a total of 136 patients with advanced breast or colorectal cancer treated with capecitabine were prospectively enrolled. The presence of two polymorphisms (CDD 943insC and CES 2 Exon3 6046 G/A) were associated with a non-statistically significant higher incidence of grade 3 hand-foot syndrome (HFS) (p=0.07) and grade 3-4 diarrhoea (p=0.09), respectively. Patients heterozygous or homozygous for the polymorphism CES 2 5'UTR 823 C/G exhibited a significantly greater response rate to capecitabine, and time to progression of disease (59%, 8.7 months) than patients with the wild type gene sequence (32%, p=0.015; 5.3 months, p=0.014). For the first time, an association between a polymorphism in the CES2 gene and the efficacy of capecitabine has been described, providing preliminary evidence of its predictive and prognostic value.


Recombinant retroviruses encoding cell surface antigens as selectable markers.
Recombinant retroviruses are frequently used in the transfer and analysis of genes. This report describes new retrovirus vectors that incorporate a cDNA copy of a cell surface antigen to function as a selectable marker. By using techniques based on quantitative cell surface immunofluorescence, these vectors allow the rapid detection and isolation of infected cells. These vectors also allow the rapid detection of packaging cell lines producing large amounts of recombinant retroviruses. Potential applications of these vectors are demonstrated.


[Biochemical semiology of the liver in ruminants].
Many different serum biochemical tests can help in the diagnosis of liver disturbances in ruminants. The best tests for hepato-cellular damage are the measurement of enzymes such as glutamate dehydrogenase, sorbitol dehydrogenase and, if available, arginase or ornithine carbamoyl transferase. Disturbances of biliary function can be investigated through the measurement of so-called "cholestasis enzyme markers" such as gammaglutamyl transferase or alkaline phosphatases; bilirubin and bile salts can also be helpful. Liver insufficiency can be approached through the measurement of serum albumin, fibrinogen and coagulation tests whereas inflammative and inductive processes are difficult to investigate. Moreover, liver clearances (bromosulfonephtalein or indocyanine green) can provide useful data about whole liver function.


Insulin Autoimmune Syndrome (Hirata Disease): A Comprehensive Review Fifty Years After Its First Description.
Insulin autoimmune syndrome (IAS), also named Hirata's disease, is a rare condition characterized by hypoglycemic episodes due to the presence of high titers of insulin autoantibodies (IAA). IAS is a form of immune-mediated hypoglycemia, which develops when a triggering factor (ie, a medication or a viral infection) acts on an underlying predisposing genetic background. IAS pathogenesis involves the formation of insulin-IAA complexes that induce glycemic alterations with a double-phase mechanism: IAA prevent insulin to bind its receptor in the postprandial phase, possibly resulting in mild hyperglycemia; thereafter, insulin is released from the complexes irrespective of blood glucose concentrations, thus inducing hypoglycemia. The diagnosis of IAS is challenging, requiring a careful workup aimed at excluding other causes of hyperinsulinemic hypoglycemia. The gold standard for the definitive diagnosis is the finding of IAA in a blood sample. Because IAS is frequently a self-remitting disease, its management mostly consists of supportive measures, such as dietary modifications, aimed at preventing the development of hypoglycemia. Pharmacological therapies may occasionally be necessary for patients presenting with severe manifestations of IAS. Available therapies may include drugs that reduce pancreatic insulin secretion (somatostatin analogues and diazoxide, for instance) and immunosuppressive agents (glucocorticoids, azathioprine and rituximab). The purpose of this review is to provide a comprehensive analysis of the disease, by describing the burden of knowledge that has been obtained in the 50 years following its first description, took in 1970, and by highlighting the points that are still unclear in its pathogenesis and management.


Long non-coding RNA, steroid receptor RNA activator (SRA), induces tumor proliferation and invasion through the NOTCH pathway in cervical cancer cell lines.
Contemporary research has focused on the function of long non-coding RNAs (lncRNAs) in carcinogenesis. However, the involvement of the lncRNA, steroid receptor RNA activator (SRA), in cervical carcinogenesis remains to be elucidated. In the present study, we investigated the bio-functional consequences of lncRNA SRA knockdown in vitro. To verify the role of lncRNA SRA in cell proliferation, migration, and invasion, lncRNA RNA interference was utilized to knock down lncRNA SRA expression in cervical cancer cell lines, resulting in our discovery that lncRNA SRA knockdown inhibited cell proliferation, cell migration and tumor invasion in the cervical cancer cell lines. Additionally, in vitro experiments using the lncRNA SRA-knockdown cervical cancer cell lines revealed that lncRNA SRA is a strong inducer and modulator of the expression of genes related to epithelial-mesenchymal transition and the NOTCH signaling pathway. In conclusion, our findings demonstrated that lncRNA SRA is highly correlated with cancer progression and cervical cancer cell proliferation and migration. Furthermore, these results indicate that lncRNA SRA may be a potential therapeutic target and prognostic marker for cervical malignancy.


Update on the Extracorporeal Life Support.
Extracorporeal life support (ECLS) is a type of cardiopulmonary bypass. It is an artificial means of supplying oxygen and removing CO2 on behalf of damaged lungs while patients are recovering from underlying diseases. Recently, the use of ECLS is rapidly increasing as this machine becomes smaller, less invasive and easier to use. In addition, the improvement of clinicians' technique and outcome is increasing their application to patients with acute respiratory distress. In this regard, the purpose of this review is to introduce the physiological principles, risk factors, and advantages of ECLS, clinical rationale for using ECLS, ventilatory strategy during ECLS, which are still causing different opinions, the weaning from ECLS, and the use of anticoagulant.


Prediction models for hospital readmissions in patients with heart disease: a systematic review and meta-analysis.
To describe the discrimination and calibration of clinical prediction models, identify characteristics that contribute to better predictions and investigate predictors that are associated with unplanned hospital readmissions. Systematic review and meta-analysis. Medline, EMBASE, ICTPR (for study protocols) and Web of Science (for conference proceedings) were searched up to 25 August 2020. Studies were eligible if they reported on (1) hospitalised adult patients with acute heart disease; (2) a clinical presentation of prediction models with c-statistic; (3) unplanned hospital readmission within 6 months. Model discrimination for unplanned hospital readmission within 6 months measured using concordance (c) statistics and model calibration. Meta-regression and subgroup analyses were performed to investigate predefined sources of heterogeneity. Outcome measures from models reported in multiple independent cohorts and similarly defined risk predictors were pooled. Sixty studies describing 81 models were included: 43 models were newly developed, and 38 were externally validated. Included populations were mainly patients with heart failure (HF) (n=29). The average age ranged between 56.5 and 84 years. The incidence of readmission ranged from 3% to 43%. Risk of bias (RoB) was high in almost all studies. The c-statistic was <0.7 in 72 models, between 0.7 and 0.8 in 16 models and >0.8 in 5 models. The study population, data source and number of predictors were significant moderators for the discrimination. Calibration was reported for 27 models. Only the GRACE (Global Registration of Acute Coronary Events) score had adequate discrimination in independent cohorts (0.78, 95% CI 0.63 to 0.86). Eighteen predictors were pooled. Some promising models require updating and validation before use in clinical practice. The lack of independent validation studies, high RoB and low consistency in measured predictors limit their applicability. CRD42020159839.


Density functional theory study on the mechanism of the reductive cleavage of CO2 by a bis-beta-diketoiminatediiron dinitrogen complex.
Density functional theory has been used to analyze the detailed reaction mechanism for the reductive cleavage of CO(2) by a dinitrogen bridged bis-beta-diketoiminatediiron complex, L(tBu)Fe-N(2)-FeL(tBu) (I), recently reported by Holland and co-workers. A number of pathways have been investigated and the most likely mechanism correlates well with experimental evidence. A rationale has been provided for the binding of CO(2), the release of CO, and the ready formation of CO(3)(2-). Our results show that the insertion of CO(2) into the diiron complex is the rate determining step of the reductive cleavage reaction. An intramolecular reduction step from the reduced dinitrogen bridge is proposed which serves to increase the activation of CO(2). This is followed by an intersystem crossing from the septet to the nonet state which acts as a driving force for the subsequent release of CO. The overall reductive cleavage reaction is exergonic by 120 kJ/mol, and further reaction of the released CO with the starting diiron complex is also predicted to be strongly exergonic.


Differential diagnosis of localized tumors of the gingiva.
Localized tumors arising from the periodontal structures are commonly seen in the oral cavity. Although not a daily occurrence, these tumors will probably be encountered by all practitioners during their professional lives. The majority of localized tumors arising from the periodontal structures are benign, but early recognition and treatment are imperative to prevent invasion and destruction of the surrounding structures.


The Mechanical Basis of Memory - the MeshCODE Theory.
One of the major unsolved mysteries of biological science concerns the question of where and in what form information is stored in the brain. I propose that memory is stored in the brain in a mechanically encoded binary format written into the conformations of proteins found in the cell-extracellular matrix (ECM) adhesions that organise each and every synapse. The MeshCODE framework outlined here represents a unifying theory of data storage in animals, providing read-write storage of both dynamic and persistent information in a binary format. Mechanosensitive proteins that contain force-dependent switches can store information persistently, which can be written or updated using small changes in mechanical force. These mechanosensitive proteins, such as talin, scaffold each synapse, creating a meshwork of switches that together form a code, the so-called MeshCODE. Large signalling complexes assemble on these scaffolds as a function of the switch patterns and these complexes would both stabilise the patterns and coordinate synaptic regulators to dynamically tune synaptic activity. Synaptic transmission and action potential spike trains would operate the cytoskeletal machinery to write and update the synaptic MeshCODEs, thereby propagating this coding throughout the organism. Based on established biophysical principles, such a mechanical basis for memory would provide a physical location for data storage in the brain, with the binary patterns, encoded in the information-storing mechanosensitive molecules in the synaptic scaffolds, and the complexes that form on them, representing the physical location of engrams. Furthermore, the conversion and storage of sensory and temporal inputs into a binary format would constitute an addressable read-write memory system, supporting the view of the mind as an organic supercomputer.


System Theory and Physiological Processes.
Engineers and physiologists working together in experimental and theoretical studies predict that the application of system analysis to biological processes will increase understanding of these processes and broaden the base of system theory. Richard W. Jones, professor of electrical engineering at Northwestern University, Evanston, Illinois, and John S. Gray, professor of physiology at Northwestern's Medical School, discuss these developments. Their articles are adapted from addresses delivered in Chicago in November 1962 at the 15th Annual Conference on Engineering in Medicine and Biology.


Quadricuspid aortic valve by transthoracic echocardiography.
A 55-year-old woman seeks medical attention with palpitations, atypical chest pain and dyspnea upon exertion, lasting for 12 months. ECG showed left ventricular hypertrophy. Transthoracic Doppler echocardiogram confirmed hypertrophy of the left chambers and showed a quadricuspid aortic valve, with equal-sized cusps, in addition to a moderate regurgitant central flow. Upon echocardiography, the quadricuspid valve is identified by its characteristic "X" form during diastole and rectangular aspect during systole. Heart failure symptoms are presumably caused by valve insufficiency due to abnormal leaflet coaptation. Considering the possibility of progressive regurgitation, follow up on the patient was performed with periodic echocardiographic control. Symptoms responded to treatment.


A trypanothione-dependent glyoxalase I with a prokaryotic ancestry in Leishmania major.
Glyoxalase I forms part of the glyoxalase pathway that detoxifies reactive aldehydes such as methylglyoxal, using the spontaneously formed glutathione hemithioacetal as substrate. All known eukaryotic enzymes contain zinc as their metal cofactor, whereas the Escherichia coli glyoxalase I contains nickel. Database mining and sequence analysis identified putative glyoxalase I genes in the eukaryotic human parasites Leishmania major, Leishmania infantum, and Trypanosoma cruzi, with highest similarity to the cyanobacterial enzymes. Characterization of recombinant L. major glyoxalase I showed it to be unique among the eukaryotic enzymes in sharing the dependence of the E. coli enzyme on nickel. The parasite enzyme showed little activity with glutathione hemithioacetal substrates but was 200-fold more active with hemithioacetals formed from the unique trypanosomatid thiol trypanothione. L. major glyoxalase I also was insensitive to glutathione derivatives that are potent inhibitors of all other characterized glyoxalase I enzymes. This substrate specificity is distinct from that of the human enzyme and is reflected in the modification in the L. major sequence of a region of the human protein that interacts with the glycyl-carboxyl moiety of glutathione, a group that is conjugated to spermidine in trypanothione. This trypanothione-dependent glyoxalase I is therefore an attractive focus for additional biochemical and genetic investigation as a possible target for rational drug design.


Improvement of CVD risk assessment tools' performance through innovative patients' grouping strategies.
There are available in the clinical community several practical risk tools to assess the risk of occurrence of a cardiovascular event. Although valuable, these tools typically present some lack of performance (low sensitivity/low specificity) when applied to a general (average) patient. This flaw is addressed in this work through an innovative personalization strategy that is supported on the evidence that current risk assessment tools perform differently among different populations/groups of patients. The proposed methodology is based on two main hypotheses: i) patients are grouped through a proper dimension reduction technique complemented with an unsupervised learning algorithm, ii) for each group the most suitable risk assessment tool can be selected improving the risk prediction performance. As a result, risk personalization is simply achieved by the identification of the group that patients belong to. The validation of the strategy is carried out through the combination of three current risk assessment tools (GRACE, TIMI, PURSUIT) developed to predict the risk of an event in coronary artery disease patients. The combination of these tools is validated with a real patient testing dataset: Santa Cruz Hospital, Portugal, N=460 ACS-NSTEMI patients. Considering the obtained results with the available dataset it is possible to state that the main objective of this work was achieved.


DNA cards: determinants of DNA yield and quality in collecting genetic samples for pharmacogenetic studies.
As pharmacogenetic studies frequently require establishment of DNA banks containing large cohorts with multi-centric designs, inexpensive methods for collecting and storing high-quality DNA are needed. The aims of this study were two-fold: to compare the amount and quality of DNA obtained from two different DNA cards (IsoCode Cards or FTA Classic Cards, Whatman plc, Brentford, Middlesex, UK); and to evaluate the effects of time and storage temperature, as well as the influence of anticoagulant ethylenediaminetetraacetic acid on the DNA elution procedure. The samples were genotyped by several methods typically used in pharmacogenetic studies: multiplex PCR, PCR-restriction fragment length polymorphism, single nucleotide primer extension, and allelic discrimination assay. In addition, they were amplified by whole genome amplification to increase genomic DNA mass. Time, storage temperature and ethylenediaminetetraacetic acid had no significant effects on either DNA card. This study reveals the importance of drying blood spots prior to isolation to avoid haemoglobin interference. Moreover, our results demonstrate that re-isolation protocols could be applied to increase the amount of DNA recovered. The samples analysed were accurately genotyped with all the methods examined herein. In conclusion, our study shows that both DNA cards, IsoCode Cards and FTA Classic Cards, facilitate genetic and pharmacogenetic testing for routine clinical practice.


Association between Bethesda Categories and Ultrasound Features of Conventional Papillary Thyroid Carcinoma.
The association between categories 3, 5 and 6 of the Bethesda System for Reporting Thyroid Cytopathology and the clinical and ultrasonography (US) features of conventional papillary thyroid carcinoma (PTC) was evaluated. We included 2005 patients diagnosed with conventional PTC at surgery and Bethesda categories 3, 5 and 6 at pre-operative US-guided fine-needle aspiration. Multinomial regression analysis was performed to determine the odds ratio (ORs) of each US feature associated with category 3 or 5, with category 6 as reference. Category 3 and 5 PTCs were smaller (ORs = 0.925 and 0.937) and did not exhibit marked hypo-echogenicity (ORs = 0.341 and 0.268) compared with category 6 PTCs. Category 3 and 5 PTCs exhibited significant macrocalcification (ORs = 2.372 and 1.594) and heterogeneous parenchyma (OR = 1.265 in category 5). In conclusion, conventional PTCs pre-operatively aspirated as Bethesda category 3, 5 or 6 significantly differ in size, macrocalcification, underlying thyroid parenchymal echogenicity and final assessment of US features.


Oxystress inducing antitumor therapeutics via tumor-targeted delivery of PEG-conjugated D-amino acid oxidase.
We had developed a H(2)O(2) generating enzyme, polyethylene glycol conjugated D-amino acid oxidase (PEG-DAO), which exhibited potent antitumor activity by generating toxic reactive oxygen species, namely oxidation therapy, subsequently showed remarkable antitumor effect on murine Sarcoma 180 solid tumor, by taking advantage of the enhanced permeability and retention effect. Along this line, we report here the preparation of PEG-DAO by use of recombinant DAO and its antitumor activity by using various tumor cell lines and tumor models. Recombinant DAO (rDAO) was obtained from E. coli BL21 (DE3) carrying the porcine DAO expression vector with high yield (20 mg/l) and high enzyme activity (5.3 U/mg). Pegylated rDAO (PEG-rDAO) showed high stability against sonication, repeated freezing/thawing, lyophilization and exhibited superior in vivo pharmacokinetics. PEG-rDAO had a molecular size of 65 kDa and existed as nanoparticles in aqueous solution with mean particle diameter of 119 nm. In vitro experiments showed strong cytotoxicity of PEG-rDAO against various tumor cells, whereas less cytotoxicity was found against various normal cells. In vivo antitumor treatment was carried out using 2 mice tumor models, namely colon 38 tumor and Meth A tumor model. PEG-rDAO was administered i.v. and after an adequate lag time, D-proline (the substrate of DAO) was injected i.p. to the tumor-bearing mice. Consequently, preferential generation of H(2)O(2) in the tumor was successfully achieved, which resulted in remarkable suppression of tumor growth without any visible side effects. These findings suggest a potential of PEG-rDAO as a novel anticancer strategy toward clinical development.


The Ambulatory Integration of the Medical and Social (AIMS) model: A retrospective evaluation.
An exploratory, retrospective evaluation of Ambulatory Integration of the Medical and Social (AIMS), a care coordination model designed to integrate medical and non-medical needs of patients and delivered exclusively by social workers was conducted to examine mean utilization of costly health care services for older adult patients. Results reveal mean utilization of 30-day hospital readmissions, emergency department (ED) visits, and hospital admissions are significantly lower for the study sample compared to the larger patient population. Comparisons with national population statistics reveal significantly lower mean utilization of 30-day admissions and ED visits for the study sample. The findings offer preliminary support regarding the value of AIMS.


Preventive effect of andrographolide against ultraviolet-B radiation-induced oxidative stress and apoptotic signaling in human dermal fibroblasts.
Ultraviolet radiation induces oxidative photoaging in the skin cells. In this study, we investigated the ability of andrographolide (ADP) to protect human dermal fibroblasts (HDFa) from UVB radiation-induced oxidative stress and apoptosis. The HDFa cells were exposed to UVB (19.8 mJ/cm2 ) radiation in the presence or absence of ADP (7 μM) and then oxidative stress and apoptotic protein expression were analyzed. UVB exposure resulted in a significant decline in the activity of antioxidant enzymes and altered mitochondrial membrane potential (MMP). Furthermore, UVB-irradiation causes increased intracellular reactive oxygen species (ROS) production, apoptotic morphological changes, and lipid peroxidation levels in the HDFa. Moreover, the pretreatment with ADP reduced the UVB-induced cytotoxicity, ROS production, and increased antioxidant enzymes activity. Further, the ADP pretreatment prevents the UVB-induced loss of MMP and apoptotic signaling in HDFa cells. Therefore, the present results suggest that ADP protects HDFa cells from UVB-induced oxidative stress and apoptotic damage.


Effects of BMI on SI Joint Fusion Outcomes: Examining the Evidence to Improve Insurance Guidelines.
Obesity is increasing. Previous studies have demonstrated an association between obesity and adverse events after lumbar fusion. There is limited evidence on the effect of obesity on minimally invasive SI joint fusion outcomes. The purpose of this study was to investigate the impact of obesity on patient-reported outcomes in patients undergoing SI joint fusion surgery using triangular titanium implants (TTI). Retrospective cohort study based on 4 prospective clinical trials (INSITE [NCT01681004], SIFI [NCT01640353], iMIA [NCT01741025], and SALLY [NCT03122899]) PATIENT SAMPLE: Adult patients ≥ 18 years of age who underwent MIS SIJ fusion between 2012 and 2021. Visual Analog Scale (VAS Pain), Oswestry Disability Index (ODI). Participants were classified using the National Institutes of Health body mass index (BMI). Patients with a BMI of 30 to 39 with no significant comorbidity are considered obese, patients with a BMI of 35 to 39 with a significant comorbidity or a BMI of 40 or greater are considered morbidly obese. All subjects underwent either minimally invasive SIJ fusion with TTI or non-surgical management (INSITE and iMIA studies only). All subjects completed SIJ pain scale scores (measured with a 100-point visual analog scale, VAS) and disability scores (measured with Oswestry Disability Index, ODI) at baseline and at scheduled visits to 24 months. Repeated measures analysis of variance was used to examine the impact of BMI category on score changes. In the SIJF group, mean SIJ pain improved at 24 months by 53.3 points (p<.0001). Over the 24-month follow-up period, BMI category did not impact mean improvement in SIJ pain scale score (repeated measures ANOVA p=.44). In the SIJF group, mean ODI at 24 months improved by 25.8 points (p<.0001). BMI category did not impact mean improvement in ODI (ANOVA p=.60). In the NSM group, mean improvements in SIJ pain scale and ODI were clinically small (8.7 and 5.2 points, respectively) and not affected by BMI category (ANOVA p=.49 and .40). This study demonstrates similar benefits and risks of minimally invasive SIJ fusion with TTI across all BMI categories. This analysis suggests that obese patients benefit from minimally invasive SIJ fusion and should not be denied this procedure based solely on elevated BMI.


Molecular screening of cancer: the future is here.
The remarkable growth in our knowledge of the biology of cancer is leading to the identification of previously elusive pathways and networks involved in cancer causation. The development of technologies has played a pivotal role in furthering this understanding and appreciation of the complexity of tumorigenesis, and is advancing efforts to fully grasp the biology and exploit the knowledge for improvements in cancer detection, prevention, and therapy. The future of molecular screening, i.e. detection of risk or cancer via molecular determinants, has never been so close to a reality. Molecular assays employed in cancer detection and therapy are likely to revolutionize cancer treatment through individual-based diagnosis and treatment, i.e. personalized medicine. A number of detection techniques, such as the detection of aberrant DNA and RNA, the presence of auto-antibodies in serum or plasma, and protein profiling, are already in limited use for patient stratification for clinical trials and for predicting drug response.


Extension for Community Health Outcomes-hepatitis C: Small steps carve big footprints in the allocation of scarce resources for hepatitis C virus treatment to remote developing areas.
Hepatitis C virus (HCV) infection is still a major health problem throughout the world. HCV patients living in rural areas are less fortunate than their counterparts residing in populous urbanized regions. The lack of medical resources and properly trained medical personnel in rural regions make it especially burdensome for HCV patients seeking treatment. Dr. Sanjeev Arora at the University of New Mexico Health Sciences Center took initiative to resolve the issue at hand by developing a model named Project Extension for Community Health Outcomes (ECHO). ECHO connects primary care providers (PCPs), usually family medicine physicians, in local communities with specialists. ECHO providers test the efficacy of treatment given using the ECHO model vs that at academic medical centers. The ECHO model has produced promising results such that the sustained virologic response rates for both types of sites were near-equivalent. Show Me ECHO was adapted from Project ECHO to train PCPs in Missouri and equip them with the tools and skills to properly treat and diagnose HCV in a timely manner. This healthcare model can be implemented for treating other common infections and chronic diseases. Telemedicine is the direction healthcare is headed for the next several decades. It has potential to be applied in developing countries to alleviate agony and despair resulting from limited resources and lack of access to expert medical care.


Estimating baseline kidney function in hospitalized patients with impaired kidney function.
Inaccurate determination of baseline kidney function can misclassify acute kidney injury (AKI) and affect the study of AKI-related outcomes. No consensus exists on how to optimally determine baseline kidney function when multiple preadmission creatinine measurements are available. The accuracy of commonly used methods for estimating baseline serum creatinine was compared with that of a reference standard adjudicated by a panel of board-certified nephrologists in 379 patients with AKI or CKD admitted to a tertiary referral center. Agreement between estimating methods and the reference standard was highest when using creatinine values measured 7-365 days before admission. During this interval, the intraclass correlation coefficient (ICC) for the mean outpatient serum creatinine level (0.91 [95% confidence interval (CI), 0.88-0.92]) was higher than the most recent outpatient (ICC, 0.84 [95% CI, 0.80-0.88]; P<0.001) and the nadir outpatient (ICC, 0.83 [95% CI, 0.76-0.87; P<0.001) serum creatinine. Using the final creatinine value from a prior inpatient admission increased the ICC of the most recent outpatient creatinine method (0.88 [95% CI, 0.85-0.91]). Performance of all methods declined or was unchanged when the time interval was broadened to 2 years or included serum creatinine measured within a week of admission. The mean outpatient serum creatinine measured within a year of hospitalization most closely approximates nephrologist-adjudicated serum creatinine values.


Eye health and safety among Latino farmworkers.
Farmworkers face a variety of risk factors for eye injuries. Measures of eye protection use and of eye safety knowledge and beliefs are based on a survey of 300 Latino farmworkers in North Carolina. Few farmworkers report using eye protection (8.3%); most (92.3%) report that employers do not provide eye protection. Approximately 70% report that they are not trained in preventing eye injuries; 81% believe that their chances of getting an eye injury are low. Many farmworkers choose to take risks in order to save time. Interventions are needed that target farmworker knowledge and beliefs about eye safety.


Association of atherosclerosis-related markers and its relationship to n-3 polyunsaturated fatty acids levels with a prevalence of coronary artery disease in an urban area in Japan.
Higher intakes of fish and n-3 polyunsaturated fatty acids (n-3PUFAs: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are associated with a reduced risk of coronary artery disease (CAD). We investigated the relationships between fish-derived n-3PUFAs and prevalence of CAD, and to assess the association of n-3PUFAs with atherosclerosis-related markers in an urban area. This study was designed as a hospital-based cross-sectional study on 649 consecutive outpatients who had undergone regular examinations between April 2009 and October 2009. After adjustments for the coronary risk factors in a multilogistic regression analysis of variables for which a significant difference was identified between the group of patients with a prevalence of CAD and the group with no prevalence of CAD, the multivariable odds ratio (95 % confidence interval) was 0.394 (0.205/0.760; P = 0.005) for the highest (92.4-373.5 μg/ml) versus lowest (6.2-40.0 μg/ml) quartile of serum EPA values and 0.433 (0.228/0.824; P = 0.011) for the highest (160.7-451.8 μg/ml) versus lowest (35.7-100.7 μg/ml) quartile of serum DHA values. Multivariate regression analyses after adjustment for risk factors showed that higher serum EPA and DHA levels were independent variables of a higher level of serum apolipoprotein A-1, a major compound of high-density lipoprotein. However, the results suggested that there might be conflicting effects of EPA and DHA in regard of the serum levels of other lipid markers. This cross-sectional study suggests that higher serum levels of n-3PUFAs were associated with a lower prevalence of CAD and an increase in serum apolipoprotein A-1 level, even in an urban area.


How to manage hypertension in pregnancy effectively.
The hypertensive disorders of pregnancy (HDP) are a leading cause of maternal mortality and morbidity in both well and under-resourced settings. Maternal, fetal, and neonatal complications of the HDP are concentrated among, but not limited to, women with pre-eclampsia. Pre-eclampsia is a systemic disorder of endothelial cell dysfunction and as such, blood pressure (BP) treatment is but one aspect of its management. The most appropriate BP threshold and goal of antihypertensive treatment are controversial. Variation between international guidelines has more to do with differences in opinion rather than differences in published data. For women with severe hypertension [defined as a sustained systolic BP (sBP) of ≥160 mmHg and/or a diastolic BP (dBP) of ≥110 mmHg], there is consensus that antihypertensive therapy should be given to lower the maternal risk of central nervous system complications. The bulk of the evidence relates to parenteral hydralazine and labetalol, or to oral calcium channel blockers such as nifedipine capsules. There is, however, no consensus regarding management of non-severe hypertension (defined as a sBP of 140-159 mmHg or a dBP of 90-109 mmHg), because the relevant randomized trials have been underpowered to define the maternal and perinatal benefits and risks. Although antihypertensive therapy may decrease the occurrence of BP values of 160-170/100-110 mmHg, therapy may also impair fetal growth. The potential benefits and risks do not seem to be associated with any particular drug or drug class. Oral labetalol and methyldopa are used most commonly, but many different β-adrenoceptor blockers and calcium channel blockers have been studied in clinical trials.


Parkinson disease: handedness predicts asymmetry.
To determine the proportion of individuals in a clinic-based setting that present with asymmetric Parkinson disease (PD) and identify predictive factors associated with asymmetric symptoms. The authors examined right vs left difference scores on the Unified Parkinson Disease Rating Scale motor subscale in a consecutive clinical series of 1,277 individuals diagnosed with PD. Predictors of asymmetry included sex, symptomatic disease duration, age at onset, initial motor symptom laterality, handedness, and medical history variables (e.g., family history of PD). Nearly half the sample (46%) met criteria for asymmetric disease based on a right vs left difference score of > or =5 points, and 12% of the sample had a difference score of > or =10 (difference score: mean = 4, SD = 3.4). All three cardinal features of PD showed characteristics of asymmetric disease presentation. Multiple regression analyses showed that an increased discrepancy between right- and left-sided symptoms was significantly associated with a shorter disease duration, younger age at symptomatic onset, asymmetric initial symptom onset, hand dominance, and a positive self-reported family history of "other" neurodegenerative disorder. Hand dominance was related to the side of asymmetric disease such that left-handed individuals tended to have more severe disease on the left side of the body. Asymmetric presentation of Parkinson disease features was a common occurrence in the clinical cohort. Asymmetry was reliably predicted by several clinical characteristics, although the moderate level of explained variance (i.e., between 16 and 23%) highlighted the need for additional research examining predictive models of asymmetric disease. Recommendations for the classification and measurement of asymmetric disease are discussed.


Occupational Therapy Interventions to Improve Reading Performance of Older Adults With Low Vision: A Systematic Review.
Low vision affects many older adults and is expected to significantly increase over the next several decades. It has a significant impact on all aspects of daily life, including the reading required for participation in occupations. To determine the effectiveness of interventions within the scope of occupational therapy to improve reading required for the performance of occupations by older adults with low vision. We conducted a systematic review of literature published in the Cochrane Database of Systematic Reviews, MEDLINE, PsycINFO, CINAHL, and OTseeker databases from 2010 through 2016. The references of retrieved articles were also hand searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to abstract and assess data quality and validity. This review followed the established methodology of the American Occupational Therapy Association Evidence-Based Practice Project. Sixteen articles met the inclusion criteria and were categorized into three themes: (1) technology, (2) visual skills training, and (3) multicomponent interventions. Moderate evidence supports stand-based electronic magnification and eccentric viewing training to improve reading outcomes. Strong evidence supports multicomponent interventions. Occupational therapy practitioners working with older adults with low vision are strongly encouraged to integrate stand-based electronic magnification, eccentric viewing training, and comprehensive low vision services into routine care. Further research with larger sample sizes and functional reading outcome measures is needed. This review provides additional support for the use of select occupational therapy interventions (stand-based electronic magnification, eccentric viewing training, and comprehensive low vision services) to support the reading required for occupational performance for older adults with low vision. The findings provide guidance to occupational therapy practitioners for selection and implementation of evidence-based interventions for reading.


GraphGPT: A Graph Enhanced Generative Pretrained Transformer for Conditioned Molecular Generation.
Condition-based molecular generation can generate a large number of molecules with particular properties, expanding the virtual drug screening library, and accelerating the process of drug discovery. In this study, we combined a molecular graph structure and sequential representations using a generative pretrained transformer (GPT) architecture for generating molecules conditionally. The incorporation of graph structure information facilitated a better comprehension of molecular topological features, and the augmentation of a sequential contextual understanding of GPT architecture facilitated molecular generation. The experiments indicate that our model efficiently produces molecules with the desired properties, with valid and unique metrics that are close to 100%. Faced with the typical task of generating molecules based on a scaffold in drug discovery, our model is able to preserve scaffold information and generate molecules with low similarity and specified properties.


Beta adrenergic receptors in lymphocyte subpopulations.
To further evaluate the potential utility of lymphocyte beta adrenergic receptor assays in the study of receptor alterations in human disease, we studied highly purified populations of B and T lymphocytes in peripheral blood to see if differences existed in the concentration or affinity of beta adrenergic receptors and catecholamine-responsive cAMP levels. The mean number of receptors present in particulate fractions of B cells did not differ significantly from the number found in T cells. Similarly, no significant difference in the dissociation constant for (-)[3H]dihydroalprenolol was found. Cyclic adenosine monophosphate (cAMP) accumulation in whole lymphocytes as measured by radioimmunoassay was comparable, although a tendency toward lower basal and stimulated levels in the T cells was evident. The data suggest that differences observed in concentrations of beta adrenergic receptors or catecholamine-responsive cAMP accumulation in lymphocytes from patients with varying illnesses are not likely to be due to differences in the proportions of circulating B and T lymphocytes.


Assessment of the expression and role of the α1-nAChR subunit in efferent cholinergic function during the development of the mammalian cochlea.
Hair cell (HC) activity in the mammalian cochlea is modulated by cholinergic efferent inputs from the brainstem. These inhibitory inputs are mediated by calcium-permeable nicotinic acetylcholine receptors (nAChRs) containing α9- and α10-subunits and by subsequent activation of calcium-dependent potassium channels. Intriguingly, mRNAs of α1- and γ-nAChRs, subunits of the "muscle-type" nAChR have also been found in developing HCs (Cai T, Jen HI, Kang H, Klisch TJ, Zoghbi HY, Groves AK. J Neurosci 35: 5870-5883, 2015; Scheffer D, Sage C, Plazas PV, Huang M, Wedemeyer C, Zhang DS, Chen ZY, Elgoyhen AB, Corey DP, Pingault V. J Neurochem 103: 2651-2664, 2007; Sinkkonen ST, Chai R, Jan TA, Hartman BH, Laske RD, Gahlen F, Sinkkonen W, Cheng AG, Oshima K, Heller S. Sci Rep 1: 26, 2011) prompting proposals that another type of nAChR is present and may be critical during early synaptic development. Mouse genetics, histochemistry, pharmacology, and whole cell recording approaches were combined to test the role of α1-nAChR subunit in HC efferent synapse formation and cholinergic function. The onset of α1-mRNA expression in mouse HCs was found to coincide with the onset of the ACh response and efferent synaptic function. However, in mouse inner hair cells (IHCs) no response to the muscle-type nAChR agonists (±)-anatoxin A, (±)-epibatidine, (-)-nicotine, or 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP) was detected, arguing against the presence of an independent functional α1-containing muscle-type nAChR in IHCs. In α1-deficient mice, no obvious change of IHC efferent innervation was detected at embryonic day 18, contrary to the hyperinnervation observed at the neuromuscular junction. Additionally, ACh response and efferent synaptic activity were detectable in α1-deficient IHCs, suggesting that α1 is not necessary for assembly and membrane targeting of nAChRs or for efferent synapse formation in IHCs.


General practitioners' perceptions of best practice care at the end of life: a qualitative study.
GPs can play a central role in palliative care delivery. However, little is known about their views on what constitutes best practice care at the end of life. To explore, in a sample of Australian GPs, their perceptions of best practice palliative care and their ideal role in its delivery. A qualitative interview study of 25 GPs practising in metropolitan and non-metropolitan locations in New South Wales, Australia. Semi-structured telephone interviews were conducted. Data were analysed using qualitative content analysis. Participants had a mean age of 51 years, and had practised between 3 and 38 years (mean 19 years). Best practice palliative care was perceived to be proactive and responsive to a wide range of patient and family needs. Many participants indicated a need for relational continuity, which involves GPs establishing a care pathway from diagnosis to palliation, coordinating care across the pathway, and collaborating with other healthcare providers. A number of participants perceived palliative care as a natural extension of primary care and indicated that best practice palliative care mainly requires experiential knowledge and good communication skills, rather than specialised medical knowledge. Participants listed a number of communication strategies to offer patients and their families choice and ongoing negotiation about the recommended treatments. This study provides novel in-depth insights into GPs' perceptions of best practice palliative care. Future research should further investigate the identified features of care, and whether they can maximise the outcomes of patients and their families.


Maximum entropy constrained balance randomization for clinical trials.
A specialization of the biased coin clinical trial randomization schemes of Pocock and Simon (1975) and Efron (1971) is proposed which gives guidelines for the coin biasing probabilities of assignment to treatment. The scheme parameterizes the often conflicting goals of random treatment assignment and allocation for stratum balance in terms of a single trade-off parameter specifying a desired degree of determinism. Treatment radomization probabilities are obtained iteratively in an exponential form which maximizes randomization entropy subject to a specified balance constraint.


Magnetosomes Extracted from Magnetospirillum gryphiswaldense as Theranostic Agents in an Experimental Model of Glioblastoma.
Magnetic fluid hyperthermia (MFH) with chemically synthesized nanoparticles is currently used in clinical trials as it destroys tumor cells with an extremely localized deposition of thermal energy. In this paper, we investigated an MFH protocol based on magnetic nanoparticles naturally produced by magnetotactic bacteria: magnetosomes. The efficacy of such protocol is tested in a xenograft model of glioblastoma. Mice receive a single intratumoral injection of magnetosomes, and they are exposed three times in a week to an alternating magnetic field with concurrent temperature measurements. MRI is used to visualize the nanoparticles and to monitor tumor size before and after the treatment. Statistically significant inhibition of the tumor growth is detected in subjects exposed to the alternating magnetic field compared to control groups. Moreover, thanks to magnetosomes high transversal relaxivity, their effective delivery to the tumor tissue is monitored by MRI. It is apparent that the efficacy of this protocol is limited by inhomogeneous delivery of magnetosomes to tumor tissue. These results suggest that naturally synthesized magnetosomes could be effectively considered as theranostic agent candidates for hyperthermia based on iron oxide nanoparticles.


The anticancer application of half-sandwich iridium(III) ferrocene-thiosemicarbazide Schiff base complexes.
Ferrocenyl derivatives and organometallic iridium(III) complexes have been prospective substitutes for platinum-based anticancer drugs. Eight half-sandwich iridium(III) ferrocene-thiosemicarbazide (Fc-TSC) Schiff base anticancer complexes were prepared in this study. These complexes displayed a dimeric structure and exhibited a particular fluorescence due to the "enol" orientation of the TSC pro-ligand. An energy-dependent pathway of the uptake mechanism was ascertained, which ended in the lysosome and led to lysosome damage and apoptosis. Flow cytometry confirmed that the complexes could block the cell cycle (G1 phase) and improve the levels of intracellular reactive oxygen species, indicating an anticancer mechanism of oxidation. Then, a lysosomal-mitochondrial anticancer pathway was verified through western blotting. In vivo toxicity assays confirmed that these complexes showed better anti-migration ability and less toxicity in comparison to cisplatin. Thus, these complexes provide a new strategy for the design of non-platinum organometallic anticancer drugs.


Volatile Sedation in Reversible Cerebral Vasoconstriction Syndrome: A Case Report.
Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by reversible multifocal narrowing of cerebral arteries heralded by sudden (thunderclap) headaches with or without neurological deficits, resolving within 3 months. It often occurs in the peripartum period. To date, the ideal treatment remains unclear. Here, we report the case of a 31-year-old primigravida who presented with intracranial hemorrhage and went on to develop RCVS and acute respiratory distress syndrome over the course of her illness. Her condition was further complicated by uterine atony and septic shock.We describe for the first time the use of short-acting volatile sedation for prone positioning in acute respiratory distress syndrome during RCVS.


Combining psychodynamic and behavioral treatment approaches in the treatment of hospitalized adolescents.
This article describes a treatment approach for hospitalized adolescents which attempts to address the "response generalization" problem encountered with behaviorally based treatment milieus. The program is described and preliminary data is given to support its techniques. The treatment program attempts to combine behavioral/objective techniques that are so effective in program management, with subjective/clinical strategies.


Higher Education and Religious Liberalization among Young Adults.
Going to college has long been assumed to liberalize students' religious beliefs. Using longitudinal data from the National Survey of Youth and Religion, we compare change in the content of religious beliefs of those who do and do not attend college. We find that, in general, college students are no more likely to develop liberal religious beliefs than nonstudents. In some cases, collegians actually appear more likely to retain their initial beliefs. Change in religious beliefs appears instead to be more strongly associated with network effects. These findings indicate that college's effect on students' religious beliefs is both weak and fragmented, and suggest that the multiplicity of social worlds on college campuses may help to sustain religious beliefs as well as religious practice and commitment.


Resting state and personality component (BIS/BAS) predict the brain activity (EEG and fNIRS measure) in response to emotional cues.
The present study explored the role of resting state and personality component (BIS/BAS measure) on prefrontal cortical responsiveness to emotional cues. Indeed, we supposed that lateralized resting activity (right vs. left) and approach (BAS) versus avoidance (BIS) attitude may explain the successive emotional processing within the prefrontal cortex (PFC) based on the stimulus valence (positive and negative emotional cues). Hemodynamic (functional near-infrared spectroscopy, fNIRS) and electroencephalographic (EEG) measures were considered. The resting and experimental brain activity were registered when subjects (N = 21) viewed emotional positive versus negative stimuli (International Affective Picture System, IAPS). LIR eeg and LIR nirs (lateralized Index Response) during resting state, and LI eeg and LI nirs during emotional processing were acquired. A set of regression analyses was applied to the multiple measures. The predictive effect of resting activity and approach/avoidance dichotomy were elucidated. Indeed, more left/right resting activity (for both LIR eeg and LIR nirs) predicted the successive more brain left/right response (LI eeg and LI nirs) to emotional cues. Second, significant effects were revealed as a function of valence (increased right response to negative stimuli; increased left response to positive stimuli) during emotion processing. Third, higher BAS values explained an increased left cortical activity in resting state and in experimental condition for positive cues. In contrast, higher BIS values marked an increased right activity in resting state and in experimental condition in response to negative cues. The significance of trait component for both resting and emotional cue processing was discussed at light of the present results.


[Phospholipid metabolism in the organs of gamma-irradiated rats].
The phospholipid content and incorporation of L-3H-serine and 2-14C-glycerol into phospholipids of the liver, intestine and spleen were studied 48 hr after irradiation of rats with a dose of 8 Gy. The changes in the phospholipid content of the irradiated rat organs were induced by those in the individual phospholipids in the exposed body tissues. This is assumed to be a result of the adaptive reactions of the organism to the damaging effect of ionizing radiation.


Relation of cognitive appraisal to cardiovascular reactivity, affect, and task engagement.
The relation of primary cognitive appraisals to cardiovascular reactivity, affect, task engagement, and perceived stress was examined in 56 men (ages 18-29). Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate, preejection period, stroke index, cardiac index, and total peripheral resistance were assessed at rest and during performance of a computerized mental arithmetic task. Extending on prior investigations, threat and challenge appraisals were assessed independently from one another and from secondary appraisals. Positive and negative affect, task engagement, and levels of perceived stress were also assessed. Results indicated that threat (R2 =.08, p =.01), challenge (R2 =.14, p =.003), and their interaction (R2 =.11, p =.006) independently predicted DBP reactivity; DBP responses were greatest among participants with a high threat/low challenge pattern of appraisal. Threat appraisals predicted greater negative affect (R2 =.32) and perceived stress (R2 =.48), whereas challenge appraisals were related to greater positive affect (R2 =.44) and task engagement (R2 =.40, ps <.0001). Greater positive affect was correlated with increased SBP and DBP reactivity, and greater levels of task engagement with increased DBP response (ps < or = .002). Results suggest that primary cognitive appraisals are more potent predictors of affect and task engagement than cardiovascular reactivity.


Neural signatures of data-driven psychopathology dimensions at the transition to adolescence.
One of the challenges in human neuroscience is to uncover associations between brain organization and psychopathology in order to better understand the biological underpinnings of mental disorders. Here, we aimed to characterize the neural correlates of psychopathology dimensions obtained using two conceptually different data-driven approaches. Dimensions of psychopathology that were either maximally dissociable or correlated were respectively extracted by independent component analysis (ICA) and exploratory factor analysis (EFA) applied to the Childhood Behavior Checklist items from 9- to 10-year-olds (n = 9983; 47.8% female, 50.8% white) participating in the Adolescent Brain Cognitive Development study. The patterns of brain morphometry, white matter integrity and resting-state connectivity associated with each dimension were identified using kernel-based regularized least squares and compared between dimensions using Spearman's correlation coefficient. ICA identified three psychopathology dimensions, representing opposition-disinhibition, cognitive dyscontrol, and negative affect, with distinct brain correlates. Opposition-disinhibition was negatively associated with cortical surface area, cognitive dyscontrol was negatively associated with anatomical and functional dysconnectivity while negative affect did not show discernable associations with any neuroimaging measure. EFA identified three dimensions representing broad externalizing, neurodevelopmental, and broad Internalizing problems with partially overlapping brain correlates. All EFA-derived dimensions were negatively associated with cortical surface area, whereas measures of functional and structural connectivity were associated only with the neurodevelopmental dimension. This study highlights the importance of cortical surface area and global connectivity for psychopathology in preadolescents and provides evidence for dissociable psychopathology dimensions with distinct brain correlates.


Iron deficiency and anemia control for infants and young children in malaria-endemic areas: a call to action and consensus among the research community.
WHO recommendations on iron supplementation for infants and young children in malaria-endemic areas changed dramatically from universal to targeted supplementation for iron-deficient children only, after a trial in a high malaria transmission area showed an increased risk of hospital admission and mortality among iron-replete children following iron and folic acid supplementation. Since this time, there has been much debate and little agreement among the nutrition research community on how to move forward, and country policy and program decision makers have been left with incomplete guidance on how to address young child iron deficiency and anemia in their countries. The focus of a recent symposium during the American Society for Nutrition annual meeting, held in Washington, DC, in April 2011, was on exploring options for addressing iron deficiency and anemia among infants and young children in malaria-endemic areas, now, with safe, effective, and feasible interventions that provide iron. Papers based on the invited presentations are included in this supplement. The first paper is a review of the relationship between iron and malaria. The second is an analysis of theoretical and practical considerations regarding the targeted approach of providing iron and includes results from field testing noninvasive screening devices. This is followed by a review of the safety of universal provision of iron through home-fortification products in malaria-endemic areas. The final papers provide a call to action by highlighting pending research issues (fourth paper) and feasible strategies to move programs forward (fifth paper).


Changes in femoral artery blood flow during thermoneutral, cold, and contrast-water therapy.
The purpose of this study was to examine the changes in femoral artery blood flow during cold water immersion (CWI), contrast water therapy (CWT) and thermoneutral water immersion (TWI). Ten athletes came to the laboratory three times, to complete a 20-min procedure in upright position: 4 min in air (baseline), then 16-min full leg TWI (~35 °C), CWI (~12 °C) or CWT (2:2 ~12 °C to ~35 °C) min ratio, in a random order. Blood flow was measured every 2 min: baseline (i.e. min 3 and 1) and throughout water immersion (i.e. min 1, 3, 5, 7, 9, 11, 13 and 15), using Doppler ultrasound in the superficial femoral artery, distal to the common bifurcation (~3 cm), above the water and stocking. Compared with baseline, blood flow was significantly higher throughout TWI (min 1 to 15: P<0.001; +74.6%), significantly lower during CWI (from min 7 to 15: P<0.05; -16.2%) and did not change during CWT (min 1 to 15). No changes in blood flow occurred between the hot and cold transitions of CWT. This study shows that external hydrostatic pressure (TWI ~35 °C) significantly increases femoral artery blood flow. We also show that associating hydrostatic pressure with cooling (CWI ~12 °C) decreases femoral artery blood flow after a sufficient duration, whereas associating hydrostatic pressure with alternating brief exposures to contrasted temperatures does not change femoral artery blood flow under resting conditions.


Evidence for trafficking of PfEMP1 to the surface of P. falciparum-infected erythrocytes via a complex membrane network.
The human malarial parasite Plasmodium falciparum exports virulence determinants, such as the P. falciparum erythrocyte membrane protein 1 (PfEMP1), beyond its own periplasmatic boundaries to the surface of its host erythrocyte. This is remarkable given that erythrocytes lack a secretory pathway. Here we present evidence for a continuous membrane network of parasite origin in the erythrocyte cytoplasm. Co-localizations with antibodies against PfEMP1, PfExp-1, Pf332 and PfSbpl at the light and electron microscopical level indicate that this membrane network is composed of structures that have been previously described as tubovesicular membrane network (TVM), Maurer's clefts and membrane whorls. This membrane network could also be visualized in vivo by vital staining of infected erythrocytes with the fluorescent dye LysoSensor Green DND-153. At sites where the membrane network abuts the erythrocyte plasma membrane we observed small vesicles of 15-25 nm in size, which seem to bud from and/or fuse with the membrane network and the erythrocyte plasma membrane, respectively. On the basis of our data we hypothesize that this membrane network of parasite origin represents a novel secretory organelle that is involved in the trafficking of PfEMP1 across the erythrocyte cytoplasm.


Epitope Mapping by NMR of a Novel Anti-Aβ Antibody (STAB-MAb).
Alzheimer´s Disease (AD) is one of the most common neurodegenerative disorders worldwide. Excess of β-amyloid (Aβ), a peptide with a high propensity to misfold and self-aggregate, is believed to be the major contributor to the observed neuronal degeneration and cognitive decline in AD. Here, we characterize the epitope of a novel anti-Aβ monoclonal antibody, the STAB-MAb, which has previously demonstrated picomolar affinities for both monomers (KD = 80 pM) and fibrils (KD = 130 pM) of Aβ(1-42) and has shown therapeutic efficacy in preclinical mouse models of AD. Our findings reveal a widespread epitope that embraces several key Aβ residues that have been previously described as important in the Aβ fibrillation process. Of note, STAB-MAb exhibits a stronger affinity for the N-terminus of Aβ and stabilizes an α-helix conformation in the central to N-terminal region of the peptide, in addition to disrupting a characteristic salt-bridge of a hairpin structure present in fibrils. The NMR derived epitope supports the observed results from ThT-monitored fluorescence and electron microscopy experiments, in which STAB-MAb was shown to inhibit the formation of aggregates and promote disruption of pre-formed fibrils. In combination with the published in vitro and in vivo assays, our study highlights STAB-MAb as a rare and versatile antibody with analytical, diagnostic and therapeutic efficacy.


Dietary and clinical impacts of nausea and vomiting during pregnancy.
Nutrition during pregnancy is important for the health of both mother and infant. Nausea and vomiting in pregnancy (NVP) may alter food intake but the dietary and clinical consequences of NVP are poorly understood. The present study aimed to identify the differences in dietary intakes and clinical characteristics of women with NVP compared with those without. Women with (n = 134) or without (n = 53) NVP were studied in each trimester of pregnancy. The babies were studied at birth, and at 1 and 6 months. The presence of nausea and vomiting was established by interviews using standard questions. Daily intakes of foods and nutrients were assessed from 3-day food diaries. Weight gain during pregnancy and weights and lengths of the infants at birth and at 1 and 6 months of age were recorded. In the first trimester, intake of meat products and thus protein in women with NVP was lower both quantitatively (P = 0.007) and as a proportion of energy (16.4E% [interquartile range (IQR) 14.9-18.4]) compared to non-NVP [18.3E% (IQR 16.3-19.8), P = 0.003]. The proportional intakes of carbohydrates were higher in NVP subjects [50.1E% (IQR 46.7-53.6)] than in non-NVP [46.8E% (IQR 43.6-51.9), P = 0.008]. Dietary and total intakes of vitamin B(12), total intake of magnesium and dietary intake of zinc were lower in women with NVP. Changes in diet remained throughout pregnancy. Women with NVP had shorter pregnancies [39.9 (95% CI 39.6-40.1)] compared with those without [40.4 (95% CI 40.1-40.8) weeks, P = 0.018], but neither pregnancy weight gain nor infants' weight and length differed. Nausea and vomiting in pregnancy modified dietary intake and has potential clinical impacts as suggested by the altered pregnancy duration. In view of the programming effect of early nutrition, these alterations may carry long-term health consequences.


Mimiviridae: An Expanding Family of Highly Diverse Large dsDNA Viruses Infecting a Wide Phylogenetic Range of Aquatic Eukaryotes.
Since 1998, when Jim van Etten's team initiated its characterization, Paramecium bursaria Chlorella virus 1 (PBCV-1) had been the largest known DNA virus, both in terms of particle size and genome complexity. In 2003, the Acanthamoeba-infecting Mimivirus unexpectedly superseded PBCV-1, opening the era of giant viruses, i.e., with virions large enough to be visible by light microscopy and genomes encoding more proteins than many bacteria. During the following 15 years, the isolation of many Mimivirus relatives has made Mimiviridae one of the largest and most diverse families of eukaryotic viruses, most of which have been isolated from aquatic environments. Metagenomic studies of various ecosystems (including soils) suggest that many more remain to be isolated. As Mimiviridae members are found to infect an increasing range of phytoplankton species, their taxonomic position compared to the traditional Phycodnaviridae (i.e., etymologically "algal viruses") became a source of confusion in the literature. Following a quick historical review of the key discoveries that established the Mimiviridae family, we describe its current taxonomic structure and propose a set of operational criteria to help in the classification of future isolates.


Can a Strategic Pipeline Initiative Increase the Number of Women and Underrepresented Minorities in Orthopaedic Surgery?
Women and minorities remain underrepresented in orthopaedic surgery. In an attempt to increase the diversity of those entering the physician workforce, Nth Dimensions implemented a targeted pipeline curriculum that includes the Orthopaedic Summer Internship Program. The program exposes medical students to the specialty of orthopaedic surgery and equips students to be competitive applicants to orthopaedic surgery residency programs. The effect of this program on women and underrepresented minority applicants to orthopaedic residencies is highlighted in this article. (1) For women we asked: is completing the Orthopaedic Summer Internship Program associated with higher odds of applying to orthopaedic surgery residency? (2) For underrepresented minorities, is completing the Orthopaedic Summer Internship Program associated with higher odds of applying to orthopaedic residency? Between 2005 and 2012, 118 students completed the Nth Dimensions/American Academy of Orthopaedic Surgeons Orthopaedic Summer Internship Program. The summer internship consisted of an 8-week clinical and research program between the first and second years of medical school and included a series of musculoskeletal lectures, hands-on, practical workshops, presentation of a completed research project, ongoing mentoring, professional development, and counselling through each participant's subsequent years of medical school. In correlation with available national application data, residency application data were obtained for those Orthopaedic Summer Internship Program participants who applied to the match between 2011 through 2014. For these 4 cohort years, we evaluated whether this program was associated with increased odds of applying to orthopaedic surgery residency compared with national controls. For the same four cohorts, we evaluated whether underrepresented minority students who completed the program had increased odds of applying to an orthopaedic surgery residency compared with national controls. Fifty Orthopaedic Summer Internship scholars applied for an orthopaedic residency position. For women, completion of the Orthopaedic Summer Internship was associated with increased odds of applying to orthopaedic surgery residency (after summer internship: nine of 17 [35%]; national controls: 800 of 78,316 [1%]; odds ratio [OR], 51.3; 95% confidence interval [CI], 21.1-122.0; p < 0.001). Similarly, for underrepresented minorities, Orthopaedic Summer Internship completion was also associated with increased odds of orthopaedic applications from 2011 to 2014 (after Orthopaedic Summer Internship: 15 of 48 [31%]; non-Orthopaedic Summer Internship applicants nationally: 782 of 25,676 [3%]; OR, 14.5 [7.3-27.5]; p < 0.001). Completion of the Nth Dimensions Orthopaedic Summer Internship Program has a positive impact on increasing the odds of each student participant applying to an orthopaedic surgery residency program. This program may be a key factor in contributing to the pipeline of women and underrepresented minorities into orthopaedic surgery. Level III, therapeutic study.


Prenatal exposure to tobacco smoke sex dependently influences methylation and mRNA levels of the Igf axis in lungs of mouse offspring.
Prenatal smoke exposure is a risk factor for abnormal lung development and increased sex-dependent susceptibility for asthma and chronic obstructive pulmonary disease (COPD). Birth cohort studies show genome-wide DNA methylation changes in children from smoking mothers, but evidence for sex-dependent smoke-induced effects is limited. The insulin-like growth factor (IGF) system plays an important role in lung development. We hypothesized that prenatal exposure to smoke induces lasting changes in promoter methylation patterns of Igf1 and Igf1r, thus influencing transcriptional activity and contributing to abnormal lung development. We measured and compared mRNA levels along with promoter methylation of Igf1 and Igf1r and their protein concentrations in lung tissue of 30-day-old mice that had been prenatally exposed to cigarette smoke (PSE) or filtered air (control). Body weight at 30 days after birth was measured as global indicator of normal development. Female PSE mice showed lower mRNA levels of Igf1 and its receptor (Igf1: P = 0.05; Igf1r: P = 0.03). Furthermore, CpG-site-specific methylation changes were detected in Igf1r in a sex-dependent manner and the body weight of female offspring was reduced after prenatal exposure to smoke, while protein concentrations were unaffected. Prenatal exposure to smoke induces a CpG-site-specific loss of Igf1r promoter methylation, which can be associated with body weight. These findings highlight the sex-dependent and potentially detrimental effects of in utero smoke exposure on DNA methylation and Igf1 and Igf1r mRNA levels. The observations support a role for Igf1 and Igf1r in abnormal development.


Comparison of partial malolactic enzyme gene sequences for phylogenetic analysis of some lactic acid bacteria species and relationships with the malic enzyme.
DNA sequences covering 36% of the mle gene that encodes the malolactic enzyme were determined for 13 strains of lactic acid bacteria, representing Pediococcus, Leuconostoc, Lactobacillus and Oenococcus genera. The sequences were aligned with the corresponding region of mleS in Lactococcus lactis. The phylogenetic distance matrix tree of all mle sequences was compared with the 16S rRNA phylogenetic tree. The analysis showed that the mle fragment evolved more rapidly than the 16S gene and differently. Pediococcus and Lactobacillus species were intermixed in the 16S rRNA tree whereas they were separated in the mle tree. Leuconostoc mesenteroides and Oenococcus oeni were distinct from other species in the 16S rRNA tree, whereas they were intermixed with Lactobacillus species and Lactococcus lactis in the mle tree. The amino acid sequences deduced from partial mle genes were aligned with 22 malic enzyme sequences and the corresponding phylogenetic tree was constructed. Malic and malolactic enzymes were distinct at the phylogenetic level, except for malic enzymes of yeast and Escherichia coli which were nearer the malolactic enzymes than the other malic enzymes. The analysis of conserved sites showed several interesting amino acids specific to either malic enzyme or malolactic enzyme.


Realignment of temporal simultaneity between vision and touch.
Adaptation to temporal asynchrony between senses (audiovisual and audiotactile) affects the subsequent simultaneity or temporal order judgment. Here, we investigated the effects of adaptation to temporal asynchrony between vision and touch. Participants experienced deformation of virtual objects with a fixed temporal lag between vision and touch. In subsequent trials, the visual and haptic stimuli were deformed with variable temporal lags, and the participants judged whether the stimuli became deformed simultaneously. The point of subjective simultaneity was shifted toward the adapted lag. No intermanual transfer of the adaptation effect was, however, found. These results indicate that the perceptual simultaneity between vision and touch is adaptive, and is determined separately for each hand.


The everolimus eluting Synergy MegatronTM drug-eluting stent platform: Early outcomes from the European Synergy MegatronTM Implanters' Registry.
The Synergy MegatronTM is an everolimus-drug eluting stent that may offer advantages in the treatment of aorto-ostial disease and large proximal vessels. To report the short- to medium-term clinical outcomes from the European Synergy MegatronTM Implanters' Registry. This registry was an investigator-initiated study conducted at 14 European centers. The primary outcome was target lesion failure (TLF), defined as the composite of cardiovascular death, target vessel myocardial infarction (MI), and target lesion revascularisation. Five hundred seventy-five patients underwent PCI with MegatronTM between 2019 and 2021. Patients were 69 ± 12 years old, 26% had diabetes mellitus, 24% had moderate-severe left ventricular impairment and 59% presented with an acute coronary syndrome. 15% were deemed prohibitively high risk for surgical revascularisation. The target vessel involved the left main stem in 55%, the ostium of the RCA in 13% and was a true bifurcation (Medina 1,1,1) in 50%. At 1 year, TLF was observed in 40 patients, with 26 (65%) occurring within the first 30 days. The cumulative incidence of TLF was 4.5% at 30 days and 8.6% (95% CI 6.3-11.7) at 1 year. The incidence of stent thrombosis was 0.5% with no late stent thromboses. By multivariate analysis, the strongest independent predictors of TLF were severe left ventricular impairment (HR 3.43, 95% CI: 1.67-6.76, p < 0.001) and a target vessel involving the left main (HR 4.00 95% CI 1.81-10.15 p = 0.001). Use of the Synergy MegatronTM everolimus eluting stent in a 'real-world' setting shows favorable outcomes at 30 days and 1 year.


Ocular oxygen consumption: estimates using vitreoperfusion in the cat.
Little is known about the ocular oxygen consumption rate (QO2) in human diseases. Alterations in QO2 must occur in many conditions, such as retinal ischemia. We present a method of estimating QO2 that eventually could be used in patients during vitrectomy surgery. We performed vitreoperfusion (i.e., perfusion of the vitreous cavity after vitrectomy) in 14 cat eyes with no ocular blood flow. The solution contained nutrients at a high partial pressure of oxygen (PO2). In eight eyes, the retinas were undisturbed (Group 1), and in six eyes, we excised the retinas (Group 2). We estimated QO2 in both groups on the basis of the temporal decline of PO2 in the vitreoperfusion solution according to a pharmacokinetic model. The mean and standard deviation of QO2 was 3.2 +/- 0.8 microL/min in Group 1 and 0.4+/- 0.7 microL/min in Group 2, with the difference being the retinal contribution, 88%. In Group 1, metabolism, bulk flow, and diffusion accounted for 82, 13, and 5%, respectively, of the oxygen loss from the vitreoperfusion solution. We estimated ocular oxygen consumption by means of vitreoperfusion. Eventually, the pathophysiology of human diseases may be clarified by similar measurements during vitrectomy.


Insights into the structure and assembly of the bacteriophage 29 double-stranded DNA packaging motor.
The tailed double-stranded DNA (dsDNA) bacteriophage 29 packages its 19.3-kbp genome into a preassembled procapsid structure by using a transiently assembled phage-encoded molecular motor. This process is remarkable considering that compaction of DNA to near-crystalline densities within the confined space of the capsid requires that the packaging motor work against significant entropic, enthalpic, and DNA-bending energies. The motor consists of three phage-encoded components: the dodecameric connector protein gp10, an oligomeric RNA molecule known as the prohead RNA (pRNA), and the homomeric ring ATPase gp16. Although atomic resolution structures of the connector and different pRNA subdomains have been determined, the mechanism of self-assembly and the resulting stoichiometry of the various motor components on the phage capsid have been the subject of considerable controversy. Here a subnanometer asymmetric cryoelectron microscopy (cryo-EM) reconstruction of a connector-pRNA complex at a unique vertex of the procapsid conclusively demonstrates the pentameric symmetry of the pRNA and illuminates the relative arrangement of the connector and the pRNA. Additionally, a combination of biochemical and cryo-EM analyses of motor assembly intermediates suggests a sequence of molecular events that constitute the pathway by which the motor assembles on the head, thereby reconciling conflicting data regarding pRNA assembly and stoichiometry. Taken together, these data provide new insight into the assembly, structure, and mechanism of a complex molecular machine. Viruses consist of a protein shell, or capsid, that protects and surrounds their genetic material. Thus, genome encapsidation is a fundamental and essential step in the life cycle of any virus. In dsDNA viruses, powerful molecular motors essentially pump the viral DNA into a preformed protein shell. This article describes how a viral dsDNA packaging motor self-assembles on the viral capsid and provides insight into its mechanism of action.


Resection of the internal carotid artery in selected patients affected by cancer of the skull base.
Invasion of the internal carotid artery (ICA) has been historically considered a criterion of non-resectability of skull base cancer (SBC). Patients affected by SBC who underwent surgery including resection of ICA at two tertiary institutions were included. Demographics, oncologic, and surgical information, complications, and survival outcomes were retrospectively reviewed. Survival outcomes were calculated. Ten patients were included. Three surgical approaches (transnasal endoscopic, transorbital, and transpetrosal) were employed to resect the invaded/abutted tract(s) of the ICA. All patients underwent ICA temporary balloon occlusion test. In two patients, an extracranial-to-intracranial arterial bypass was harvested. Major neuromorbidity was observed in two patients. Perioperative mortality of the series was 10.0%. Mean overall survival was 27.2 months, with 2-year overall and progression-free survival rate of 88.9%. ICA resection is feasible as part of the ablation performed for very advanced SBCs. Survival outcomes are acceptable in adequately selected patients.


Topological solitons in three-band superconductors with broken time reversal symmetry.
We show that three-band superconductors with broken time reversal symmetry allow magnetic flux-carrying stable topological solitons. They can be induced by fluctuations or quenching the system through a phase transition. It can provide an experimental signature of the time reversal symmetry breakdown.


Allergies, antibiotics use, and multiple sclerosis.
The associations between allergies, antibiotics use, and multiple sclerosis (MS) remain controversial and their mediating or moderating effects have not yet been examined. We aimed to assess the direct and indirect influences of allergies and antibiotics use on MS development, and their interactions. A 1:3 matched case-control study was performed using the National Ambulatory Medical Care Survey database from 2006 to 2013 in the USA. Multiple sclerosis was identified based on the ICD-9 code (340.0) in any position. Cases were matched to their controls based on survey year, age, gender, race, payer type, region, and tobacco use. Allergy diseases and antibiotics prescriptions were extracted by ICD-9 code and drug classification code, respectively. Both generalized structural equation model and MacArthur approach were used to examine their intrinsic relationships. The weighted prevalence of MS was 133.7 per 100,000 visits. A total of 829 MS patients and 2441 controls were matched. Both respiratory tract allergies (OR = 0.29, 95% CI: 0.18, 0.49) and other allergies (OR = 0.38, 95% CI: 0.19, 0.77) were associated with a reduction of the risk of MS. Patients with respiratory tract allergies were more likely to use penicillin (OR = 8.73, 95% CI: 4.12, 18.53) and other antibiotics (OR = 3.77, 95% CI: 2.72, 5.21), and those with other allergies had a higher likelihood of penicillin use (OR = 4.15, 95% CI: 1.27, 13.54); however, the link between antibiotics use and MS was not confirmed although penicillin use might mediate the relationship between allergies and MS. The findings supported allergy as a protective factor for MS development. We also suggest antibiotics use might not be a suitable indicator of bacterial infection to investigate the cause of MS.


Role of microorganisms in the evolution of animals and plants: the hologenome theory of evolution.
We present here the hologenome theory of evolution, which considers the holobiont (the animal or plant with all of its associated microorganisms) as a unit of selection in evolution. The hologenome is defined as the sum of the genetic information of the host and its microbiota. The theory is based on four generalizations: (1) All animals and plants establish symbiotic relationships with microorganisms. (2) Symbiotic microorganisms are transmitted between generations. (3) The association between host and symbionts affects the fitness of the holobiont within its environment. (4) Variation in the hologenome can be brought about by changes in either the host or the microbiota genomes; under environmental stress, the symbiotic microbial community can change rapidly. These points taken together suggest that the genetic wealth of diverse microbial symbionts can play an important role both in adaptation and in evolution of higher organisms. During periods of rapid changes in the environment, the diverse microbial symbiont community can aid the holobiont in surviving, multiplying and buying the time necessary for the host genome to evolve. The distinguishing feature of the hologenome theory is that it considers all of the diverse microbiota associated with the animal or the plant as part of the evolving holobiont. Thus, the hologenome theory fits within the framework of the 'superorganism' proposed by Wilson and Sober.