Why is (SiO)(4) calculated to be tetrahedral, whereas (CO)(4) is square planar? A molecular orbital analysis.
Qualitative molecular orbital (MO) theory predicts that square-planar tetrasilacyclobutanetetraone D4h-(SiO)4 should, like D4h-(CO)4, have a triplet ground state, and the results of the (U)CCSD(T)-F12b/cc-pVTZ-F12//(U)B3LYP/6-311+G(2df) calculations, reported here, confirm this expectation. Calculations at the same level of theory find that square-planar tetrasilacyclobutanetetrathione D4h-(SiS)4 also has a triplet ground state. However, these ab initio calculations predict that (SiO)4 and (SiS)4 both have a singlet state of much lower energy, with a tetrahedral (Td) equilibrium geometry and six, electron-deficient, Si-Si bonds. In contrast, the lowest singlet state of (CO)4 and of (CS)4 is calculated to prefer a D4h to a Td geometry. An analysis, based on the second-order Jahn-Teller effect, rationalizes the influence of the electronegativity difference between A and Y in (AY)4 on the energy difference between a D4h and Td geometry. This analysis predicts that (BF)4 and (BCl)4, which are isoelectronic with, respectively, (CO)4 and (CS)4, should both prefer a Td to a D4h equilibrium geometry. These qualitative predictions have been confirmed by our calculations, and (BCl)4 is known experimentally to have a Td equilibrium geometry.


A Conserved Core Region of the Scaffold NEMO is Essential for Signal-induced Conformational Change and Liquid-liquid Phase Separation.
Scaffold proteins help mediate interactions between protein partners, often to optimize intracellular signaling. Herein, we use comparative, biochemical, biophysical, molecular, and cellular approaches to investigate how the scaffold protein NEMO contributes to signaling in the NF-κB pathway. Comparison of NEMO and the related protein optineurin from a variety of evolutionarily distant organisms revealed that a central region of NEMO, called the Intervening Domain (IVD), is conserved between NEMO and optineurin. Previous studies have shown that this central core region of the IVD is required for cytokine-induced activation of IκB kinase (IKK). We show that the analogous region of optineurin can functionally replace the core region of the NEMO IVD. We also show that an intact IVD is required for the formation of disulfide-bonded dimers of NEMO. Moreover, inactivating mutations in this core region abrogate the ability of NEMO to form ubiquitin-induced liquid-liquid phase separation droplets in vitro and signal-induced puncta in vivo. Thermal and chemical denaturation studies of truncated NEMO variants indicate that the IVD, while not intrinsically destabilizing, can reduce the stability of surrounding regions of NEMO, due to the conflicting structural demands imparted on this region by flanking upstream and downstream domains. This conformational strain in the IVD mediates allosteric communication between N- and C-terminal regions of NEMO. Overall, these results support a model in which the IVD of NEMO participates in signal-induced activation of the IKK/NF-κB pathway by acting as a mediator of conformational changes in NEMO.


Supply and demand factors in the determination of Medicare expenditures.
This article presents multivariate estimates of the effects of supply-side factors (e.g., provider reimbursement) and demand-side factors (e.g., beneficiary ability to pay) on state-level expenditures per enrollee in Medicare Part A and Part B. The results indicate that a 1 percent increase in elderly income significantly increases the propensity to use Medicare Part B services, resulting in a 0.45 percent increase in Part B expenditures per enrollee. By contrast, patients' ability to pay has a much weaker effect on Part A expenditures. Changes in provider reimbursement also exert a substantial effect on expenditures. A 1 percent rise in the Medicare Prevailing Charge Index raises Medicare Part B expenditures by 0.43 percent. Collectively, the findings of this study suggest that both limits on Medicare reimbursement to providers and increased beneficiary liability have substantial effects on Medicare costs. Whatever the merits of arguments for or against such controls, the responsiveness of Medicare expenditures to equal percentage changes in supply and demand factors appears to be of a similar order of magnitude.


[HLA-DR in rheumatoid arthritis].
The authors describe the results of HLA-DR typing of 80 patients with rheumatoid arthritis (RA). The patients showed accumulation of HIA-DR (51.25% versus 28.9% in the control), with the relative risk being 2.58. The interrelationship is demonstrated between the clinical picture of RA and HIA-DR antigens: a statistically significant accumulation of HIA-DR4 in the seropositive patterns according to the RF of RA as compared with the seronegative pattern and primary demonstration of HIA-DR3 in RA with the systemic manifestations as compared with the articular pattern.


[Chemotherapy associated hepatotoxicity in the treatment of advanced colorectal cancer (CRC)].
Modern combination chemotherapies, mainly including oxaliplatin or irinotecan, have demonstrated a significant increase in response rates. This led to the concept of down-sizing irresectable liver metastases from colorectal cancer, thereby achieving secondary resectability and possibly cure. However, these benefits of preoperative chemotherapy must be weighed against potential side effects to the surrounding normal liver tissue. In particular, in patients with pre-existing liver disease combination therapy can cause liver damage which may exceed mere steatosis of hepatocytes and lead to inflammation, cholestasis and bleeding. In correspondence to the "non-alcoholic steatohepatitis" (NASH) the term "chemotherapy associated steatohepatitis" (CASH) has been proposed in the literature. Platinum derivatives, in particular, can lead to damage of the hepatic microcirculation and the so-called sinusoidal obstruction syndrome (SOS). Few reports mention an increase in perioperative morbidity after combination chemotherapy. However, there are no comprehensive data on the individual risk of a patient for postoperative complications. If elevated liver enzymes are detected before chemotherapy and cannot readily be explained through liver involvement by the tumor, then close monitoring of enzymes should be performed and a biopsy may be considered in unclear cases. We recommend that the histological changes observed in the liver be quantified and classified by a unifying scoring system and propose, in correspondence to the hepatitis activity scores, a modified scoring system.


Freshwater neurotoxins and concerns for human, animal, and ecosystem health: A review of anatoxin-a and saxitoxin.
Toxic cyanobacteria are a concern worldwide because they can adversely affect humans, animals, and ecosystems. However, neurotoxins produced by freshwater cyanobacteria are understudied relative to microcystin. Thus, the objective of this critical review was to provide a comprehensive examination of the modes of action, production, fate, and occurrence of the freshwater neurotoxins anatoxin-a and saxitoxin as they relate to human, animal, and ecosystem health. Literature on freshwater anatoxin-a and saxitoxin was obtained and reviewed for both laboratory and field studies. Current (2020) research identifies as many as 41 anatoxin-a producing species and 15 saxitoxin-producing species of freshwater cyanobacteria. Field studies indicate that anatoxin-a and saxitoxin have widespread distribution, and examples are given from every continent except Antarctica. Human and animal health concerns can range from acute to chronic. However, few researchers studied chronic or sublethal effects of freshwater exposures to anatoxin-a or saxitoxin. Ecosystem health also is a concern, as the effects of toxicity may be far reaching and include consequences throughout the food web. Several gaps in knowledge were identified for anatoxin-a and saxitoxin, including triggers of production and release, environmental fate and degradation, primary and secondary exposure routes, diel variation, food web effects, effects of cyanotoxin mixtures, and sublethal health effects on individual organisms and populations. Despite the gaps, this critical review facilitates our current understanding of freshwater neurotoxins and thus can serve to `` guide future research on anatoxin-a, saxitoxin, and other cyanotoxins.


[The immobile vocal cord].
Usually dysphonia is the result of a functional disorder of the larynx. It can also result from paresis or paralysis of a hemilarynx. Four patients, men aged 57, 41, 42 and 18 years, had a neurological cause of paralysis of a hemilarynx. Processes responsible for this kind of pathology can appear at three different levels: central, nuclear and peripheral. Each of the four patients had a disorder at the peripheral level: two had a tumour, in one the vagus nerve was severed during lobectomy for squamous cell carcinoma (iatrogenic), and in the last one an upper respiratory viral infection was the probable cause. Other causes of these peripheral lesions are toxicological, traumatic or idiopathic. When dysphonia does not improve within three weeks, inspection of the larynx and palpation of the neck, including examination of the aspect and mobility of the vocal folds by an otorhinolaryngologist should be performed. If paresis of a hemilarynx is seen, an orientation examination of the cranial nerves and selective additional examination is necessary, as paresis of a hemilarynx is a symptom, not a diagnosis.


Aortic valve replacement with concomitant annular enlargement for small aortic annulus of less than 19 mm.
Three female patients with aortic stenosis associated with a severely small annulus underwent aortic valve replacement. In intraoperative measurements, a 19-mm obtulator could not pass through the aortic annulus in each case. We therefore concluded that it would be difficult to implant an appropriate-sized prosthesis in a routine fashion, so we performed an annular enlargement in a modified Nicks procedure. By using a wide teardrop-shaped patch for enlargement and slightly tilting insertion of a prosthesis, a 21 mm bileaflet mechanical prosthesis could be inserted into the enlarged annulus. Despite being a simpler method than other enlarging procedures, a two- or three-sizes larger prosthesis than the native annulus can be inserted with relative ease. Thus, the use of a 19 mm mechanical prosthesis may be avoidable in most adult cases.


Costing and perspective in published cost-effectiveness analysis.
Methods for appropriate costing in Cost-effectiveness analyses (CEAs), seemingly straightforward, have always raised questions. Questions linger about what cost components to include under a "societal" perspective, as well as how to value resources. This article discusses issues surrounding costing and "perspective" in published CEA. I examine data from the Tufts Medical Center Cost-Effectiveness (CEA) Registry to investigate the use of perspective and costing methodology in published cost-utility analyses. The CEA Registry contains over 3000 cost-utility ratios and utility weights for roughly 4000 health states from 1164 published cost-utility analyses through 2005. The Registry also provides an online-based searchable database (Available at: www.cearegistry.org). I analyze changes over time in several dimensions related to costing methodology: disclosure of study perspective; statement of time horizon; use of discounting for future costs and quality-adjusted life years (QALYs); statement of year of currency; reporting of sensitivity analysis; and use of incremental analysis. In practice, there has been a great deal of variation in costing methodology used in published CEAs, though methods have improved somewhat over time. Many CE researchers continue to claim that their studies take a societal perspective, but instead their articles only consider a health care payer perspective. Analysts conducting CEAs should be more transparent about their costing methodology and clearer in their usage of terminology regarding perspective. The field would also benefit from more attention to the question of how much different costing methods influence the results of CEAs.


Retinal cotton-wool spots as the first sign of systemic sarcoidosis.
Isolated retinal cotton-spots have not yet been reported as the sign of ocular sarcoidosis. We describe three patients with retinal cotton-wool spots of initially unknown etiology in whom systemic sarcoidosis was diagnosed 6-16 months later. The diagnosis was confirmed by conjunctival biopsy. These observations indicate that sarcoidosis should be included in the differential diagnosis of retinal cotton-wool spots and patients with these lesions should be followed for the development of this disease.


Modeling the evolution of weighted networks.
We present a general model for the growth of weighted networks in which the structural growth is coupled with the edges' weight dynamical evolution. The model is based on a simple weight-driven dynamics and a weights' reinforcement mechanism coupled to the local network growth. That coupling can be generalized in order to include the effect of additional randomness and nonlinearities which can be present in real-world networks. The model generates weighted graphs exhibiting the statistical properties observed in several real-world systems. In particular, the model yields a nontrivial time evolution of vertices' properties and scale-free behavior with exponents depending on the microscopic parameters characterizing the coupling rules. Very interestingly, the generated graphs spontaneously achieve a complex hierarchical architecture characterized by clustering and connectivity correlations varying as a function of the vertices' degree.


Objective assessment of total laparoscopic hysterectomy: Development and validation of a feasible rating scale for formative and summative feedback.
The aims of the study were to develop and gather validity evidence for a feasible rating scale for formative and summative assessment of total laparoscopic hysterectomy in the operating theatre. The study was a prospective observer-blinded cohort study. The rating scale was developed according to the generic format of Objective Structured Assessment of Technical Skills. We applied the contemporary framework of validity to examine validity evidence of the content, response process, internal structure, relationship to other variables, and consequences. Two experienced gynecologists constructed a preliminary version of the rating scale, which was reviewed by a multicentre team of experienced gynecologists in a modified Delphi process. The surgeons (beginners and experienced surgeons) were video recorded during live performance of total laparoscopic hysterectomies. Two blinded raters evaluated the performances independently using the rating scale. Internal consistency reliability and interrater reliability were calculated as measures of internal structure. The performances of the two groups were compared and a pass/fail score was set to show the consequences of the rating scale. The content of the rating scale was defined during three Delphi rounds and upon agreement comprised of 12 items. Sixteen participants including 8 beginners and 8 experienced surgeons performed total laparoscopic hysterectomies. The internal consistency reliability of the items was 0.95 (Cronbach's alpha), and the interrater reliabilities (Intraclass Correlation Coefficient, absolute agreement) were 0.996 for one rater and 0.998 for two raters (P < 0.001 for all correlations). The beginners' mean performance score was 19.2 (SD 7.1) and the experienced surgeons' score was 36.4 (SD 3.9); the groups performed statistically significantly different (P < 0.001). The pass/fail score was 29.3 with no false positives and no false negatives. With this study, a feasible rating scale for the objective assessment of total laparoscopic hysterectomy was developed with sound validity evidence. The rating scale is suitable for both formative and summative feedback in the commencement of surgical training in gynecology.


Methylthioadenosine/S-adenosylhomocysteine nucleosidase, a critical enzyme for bacterial metabolism.
The importance of methylthioadenosine/S-adenosylhomocysteine (MTA/SAH) nucleosidase in bacteria has started to be appreciated only in the past decade. A comprehensive analysis of its various roles here demonstrates that it is an integral component of the activated methyl cycle, which recycles adenine and methionine through S-adenosylmethionine (SAM)-mediated methylation reactions, and also produces the universal quorum-sensing signal, autoinducer-2 (AI-2). SAM is also essential for synthesis of polyamines, N-acylhomoserine lactone (autoinducer-1), and production of vitamins and other biomolecules formed by SAM radical reactions. MTA, SAH and 5'-deoxyadenosine (5'dADO) are product inhibitors of these reactions, and are substrates of MTA/SAH nucleosidase, underscoring its importance in a wide array of metabolic reactions. Inhibition of this enzyme by certain substrate analogues also limits synthesis of autoinducers and hence causes reduction in biofilm formation and may attenuate virulence. Interestingly, the inhibitors of MTA/SAH nucleosidase are very effective against the Lyme disease causing spirochaete, Borrelia burgdorferi, which uniquely expresses three homologous functional enzymes. These results indicate that inhibition of this enzyme can affect growth of different bacteria by affecting different mechanisms. Therefore, new inhibitors are currently being explored for development of potential novel broad-spectrum antimicrobials.


Effects of ethanol on RhoA/Rho-kinase-mediated calcium sensitization in mouse lung parenchymal tissue.
Calcium sensitization by the RhoA/Rho-kinase (ROCK) pathway contributes to the contraction in smooth muscle. Contractile stimuli can sensitize myosin to Ca(2+) by activating RhoA/Rho-kinase that inhibits myosin light chain phosphatase activity. The present study was aimed at investigating the possible involvement of RhoA/Rho-kinase pathway in contractile responses to agonist (phenylephrine) and depolarizing (KCl) of mouse lung parenchymal tissues. Also, we investigated the effect of ethanol on RhoA/Rho-kinase pathway. Phenylephrine (10(-8)-10(-4) M) and KCl (10-80 mM) induced sustained contractions in parenchymal strips. Ethanol significantly attenuated the contractions to phenylephrine and KCl. The Rho-kinase inhibitors fasudil (5×10(-5) M) and Y-27632 (5×10(-5) M) inhibited contractions to in both control and ethanol-treated parenchymal strips. In addition, the relaxations induced by fasudil (10(-4) M) and Y-27632 (5×10(-4) M) on parenchymal strips contracted by phenylephrine but not KCl was decreased in ethanol-treatment group. Also, RhoA, ROCK1 and ROCK2 expressions were detected in mouse lung parenchymal tissue. In ethanol-treated group, expression of RhoA and ROCK1 but not ROCK2 decreased compared to control. Furthermore, ethanol causes apoptotic changes in alveolar type I epithelial cells of parenchymal tissue. These results suggest that RhoA/Rho-kinase signaling pathway plays an important role in phenylephrine- and KCl-induced Ca(2)(+) sensitization in mouse lung parenchymal tissue. Also, ethanol may be decrease phenylephrine- and KCl-induced contraction due to lowering the RhoA/Rho-kinase-mediated Ca(2+)-sensitizing by inhibiting RhoA/Rho-kinase pathway in parenchymal tissue. These results may be lead to important insights into the mechanisms of lung diseases due to alcohol consumption.


The Small Molecule Nobiletin Targets the Molecular Oscillator to Enhance Circadian Rhythms and Protect against Metabolic Syndrome.
Dysregulation of circadian rhythms is associated with metabolic dysfunction, yet it is unclear whether enhancing clock function can ameliorate metabolic disorders. In an unbiased chemical screen using fibroblasts expressing PER2::Luc, we identified Nobiletin (NOB), a natural polymethoxylated flavone, as a clock amplitude-enhancing small molecule. When administered to diet-induced obese (DIO) mice, NOB strongly counteracted metabolic syndrome and augmented energy expenditure and locomotor activity in a Clock gene-dependent manner. In db/db mutant mice, the clock is also required for the mitigating effects of NOB on metabolic disorders. In DIO mouse liver, NOB enhanced clock protein levels and elicited pronounced gene expression remodeling. We identified retinoid acid receptor-related orphan receptors as direct targets of NOB, revealing a pharmacological intervention that enhances circadian rhythms to combat metabolic disease via the circadian gene network.


A matrix method for modeling electroelastic moduli of 0-3 piezo-composites.
A model is proposed to predict the electroelastic moduli of 0-3 connectivity piezo-composites from which parameters such as longitudinal wave velocity and thickness mode coupling factor can be deduced. The composite, a polymer loaded with ceramic particles, is represented by a unit cell, and a matrix manipulation is shown to be a practical way to perform a generalization of the series and parallel analysis used for 2-2 connectivity composites. The anisotropy of the ceramic phase is taken into account, and its effect on the properties of the composite is shown. The model is then used to optimize composite performance and to choose the two constituents through comparison of results obtained using several commercial polymers and ceramics.


Healthy life expectancy in the context of population health and ageing in India.
This study examines life expectancy (LE) and healthy life expectancy (HLE) in India longitudinally over the period 2007 to 2020, providing projections into the future. Specifically, the Indian Healthy Life Expectancy Projection model was developed based on epidemiological data (mortality, disability rates) obtained from the World Health Organization and the Government of India. The current model contributed to 4 key findings: decreases in mortality but not in all age and gender groups; increasing disability in the Indian population over time; increase in LE and HLE into the future in all age and gender groups; and the largest gains in LE and HLE are in the older age bands starting from the 70+ age band in women and 65+ age band in men. This study sheds some light on the population health measures needed to improve the understanding of the determinants of health for the efficient allocation of resources and to inform policy in the planning of health and social services.


Characterization of postreplication repair in mutagen-sensitive strains of Drosophila melanogaster.
Mutants of Drosophila melanogaster, with suspected repair deficiencies, were analyzed for their capacity to repair damage induced by X-rays and UV radiation. Analysis was performed on cell cultures derived from embryos of homozygous mutant shocks. Postreplication repair following UV radiation has been analyzed in mutant stocks derived from a total of ten complementation groups. Cultures were irradiated, pulse-labeled, and incubated in the dark prior to analysis by alkaline sucrose gradient centrifugation. Kinetics of the molecular weight increase in newly synthesized DNA were assayed after cells had been incubated in the presence or absence of caffeine. Two separate pathways of postreplication repair have been tentatively identified by mutants derived from four complementation groups. The proposed caffeine sensitive pathway (CAS) is defined by mutants which also disrupt meiosis. The second pathway (CIS) is caffeine insensitive and is not yet associated with meiotic functions. All mutants deficient in postreplication repair are also sensitive to nitrogen mustard. The mutants investigated display a normal capacity to repair single-strand breaks induced in DNA byX-rays, although two may possess a reduced capacity to repair damage caused by localized incorporation of high specific activity thymidine-3H. The data have been employed to construct a model for repair of UV-induced damage in Drosophila DNA. Implications of the model for DNA repair in mammals are discussed.


Adenolipoma of the thyroid gland: report of a case.
We report a case of adenolipoma of the thyroid gland, which is very unusual because thyroid adenoma rarely contains mature adipose tissue. A 55-year-old Japanese woman presented with a 1-month history of a neck mass. A blinded fine-needle aspiration biopsy showed benign follicular cells with no adipose cells, and we performed a left hemithyroidectomy. The specimen measured 7.0 x 4.4 cm and weighed 59.9 g. The cut surface of the tumor revealed a solid yellowish mass, and hematoxylin-eosin staining showed that the solid tumor was well separated from the adjacent thyroid tissue by a thin fibrous capsule. The tumor was found to be follicular adenoma composed of epithelial cells arranged in monotonous microfollicular patterns, intermingled with mature adipose tissue. No adipose tissue was found outside the tumor, and there were no signs of amyloid deposits in the tumor or adjacent thyroid tissue. The pathological diagnosis was adenolipoma of the thyroid gland. We discuss the pathogenesis of this entity and review the previously documented cases.


Evaluation of the Directigen FluA+B test for rapid diagnosis of influenza virus type A and B infections.
Directigen FluA+B (BD Diagnostic Systems, Sparks, Md.), a new rapid test for the detection of influenza virus types A and B, was evaluated with nasopharyngeal aspirate specimens collected from 250 patients in comparison with culture and direct fluorescent antigen (DFA) detection tests. The patients studied were predominantly children, 80% being </=6 years old. Specimens negative by culture but positive by the Directigen FluA+B or DFA tests were analyzed by reverse transcription-PCR to resolve the discrepant results. The resolved sensitivity, specificity, and positive and negative predictive values of the Directigen FluA+B test for influenza virus type A were 96%, 99.6%, 96%, and 99.6%, respectively, and for influenza virus type B they were 87.5%, 96.8%, 80%, and 98%, respectively. Storage of nasopharyngeal aspirates in virus transport medium at 2 to 8 degrees C for 48 h had little adverse effect on the detection of influenza virus type A, but diagnosis of influenza virus type B is best carried out with fresh specimens. The test detected a range of human and animal influenza virus A subtypes, including the H5N1 and H9N2 viruses that recently caused human disease in Hong Kong.


Glomerulonephritis associated with antibody to glomerular basement membrane.
Glomerulonephritis associated with antibody to glomerular basement membrane, shown by linear staining of the glomerular basement membrane with fluoresceinated anti-IgG antisera, was found in only 10 out of 400 (2.5%) renal biopsy specimens studied by immunofluorescence. Seven of these cases had rapidly progressive glomerulonephritis, five with lung haemorrhage (Goodpasture's syndrome) and two without, and three had less severe nephritis without lung haemorrhage. Circulating antibody to glomerular basement membrane, measured by a passive haemagglutination technique and by indirect immunofluorescence, was detected in the serum of all patients with rapidly progressive glomerulonephritis by both techniques but only by the passive haemagglutination method in two of the other three patients. Two patients died of their lung haemorrhage, one despite bilateral nephrectomy, and lung haemorrhage and circulating antibody to glomerular basement membrane persisted after bilateral nephrectomy in another patient.


Liquid chromatography-high resolution/ high accuracy (tandem) mass spectrometry-based identification of in vivo generated metabolites of the selective androgen receptor modulator ACP-105 for doping control purposes.
Selective androgen receptor modulators (SARMs) represent an emerging class of therapeutics which have been prohibited in sport as anabolic agents according to the regulations of the World Anti-Doping Agency (WADA) since 2008. Within the past three years, numerous adverse analytical findings with SARMs in routine doping control samples have been reported despite missing clinical approval of these substances. Hence, preventive doping research concerning the metabolism and elimination of new therapeutic entities of the class of SARMs are vital for efficient and timely sports drug testing programs as banned compounds are most efficiently screened when viable targets (for example, characteristic metabolites) are identified. In the present study, the metabolism of ACP-105, a novel SARM drug candidate, was studied in vivo in rats. Following oral administration, urine samples were collected over a period of seven days and analyzed for metabolic products by Liquid chromatography-high resolution/high accuracy (tandem) mass spectrometry. Samples were subjected to enzymatic hydrolysis prior to liquid-liquid extraction and a total of seven major phase-I metabolites were detected, three of which were attributed to monohydroxylated and four to bishydroxylated ACP-105. The hydroxylation sites were assigned by means of diagnostic product ions and respective dissociation pathways of the analytes following positive or negative ionization and collisional activation as well as selective chemical derivatization. The identified metabolites were used as target compounds to investigate their traceability in a rat elimination urine samples study and monohydroxylated and bishydroxylated species were detectable for up to four and six days post-administration, respectively.


Opportunities to improve measurement-based care practices in mental health care systems: A case example of electronic mental health screening and measurement.
Measurement-based care (MBC) involves the systematic collection of data to inform clinical decision-making and monitor treatment outcomes. In addition to benefitting patients and providers, data on MBC implementation can also be used to inform quality improvement efforts within existing health care systems. The method was retrospective chart review. We collected data on electronic mental health (MH) screens and symptom measures recorded by MH providers. Patients were 28,376 veterans who received MH services in a northeastern region. Although rates varied by MH condition and clinic type, screening for alcohol misuse, depression, and posttraumatic stress disorder appeared to occur with regularity. MH symptom measurement was less frequent than screening but included measures of alcohol and substance use, posttraumatic stress disorder, depression, and suicidal ideation. Patient demographics (e.g., age, military service era, sex, MH diagnosis) and frequency of clinic contact emerged as significant predictors of symptom measurement. In this article, we illustrate how data on MH screening and measurement can be organized, analyzed, and interpreted to identify opportunities to enhance MBC practices in MH care. We conclude with a discussion of how large data set analyses can contribute to programmatic MBC initiatives. (PsycINFO Database Record (c) 2018 APA, all rights reserved).


Technical Note: Coccygeal vein catheterization for sampling of reproductive tract-derived products from the uterine-ovarian drainage.
Blood sample collection from the caudal vena cava at the site of uterine-ovarian drainage provides a more exact evaluation of the concentration and pattern of secretion of uterine or ovarian secreted products for studies of reproductive processes in cyclic and pregnant cattle compared with samples collected from general circulation. This paper describes a thorough and updated procedure for cannulating the coccygeal vein into the caudal vena cava for the collection of serial blood samples at or near the site of uterine-ovarian drainage. Concentrations of progesterone were quantified in cows of different reproductive tract sizes with an active corpus luteum to assess the distance for proper catheter placement compared with circulating concentrations collected from the jugular vein. This procedure has a low risk for side effects, can be used effectively in pregnant animals with no major consequence to the viability of the pregnancy, and provides means for frequent collections up to 12 d.


A novel approach to simultaneously scan genes at fragile sites.
Fragile sites are regions of the genome sensitive to replication stress and to exposure to environmental carcinogens. The two most commonly expressed fragile sites FRA3B and FRA16D host the histidine triad (FHIT) and WW domain containing oxidoreductase (WWOX) genes respectively. There is growing evidence that both genes contribute to cancer development and they are frequently altered by allelic and homozygous deletions in a variety of tumors. Their status is linked to prognosis in several malignancies and they are thought to be involved in early tumorigenesis. The loci for FHIT and WWOX both span over a megabase but the genes encode for small transcripts. Thus the screening of intragenic deletion can be difficult and has relied on loss of heterozygosity LOH assays, or genomic arrays. Multiplex ligation dependent probe amplification MLPA, allows for the detection of deletions/duplications and relative quantification of up to 40 specific probes in a single assay. A FHIT/WWOX MLPA assay was designed, applied and validated in five esophageal squamous cell carcinoma ESCC, cell lines established in South Africa where this cancer is of high prevalence. Sixteen probes covered all FHIT exons and 7 probes covered WWOX. Both homozygous and hemizygous deletions were detected in FHIT, in four of the cell lines with a preferential deletion of exons 5 and 4. Chromosome 3 short arm was present in normal copy number indicating that deletions were site specific. In contrast WWOX was not altered in any cell lines. RT-PCR expression pattern paralleled the pattern of deletions. Ten primary ESCC tumor specimens were subsequently screened with this assay. FHIT exon deletions were found in four of them. This method offers an alternative to loss of heterozygosity studies. Simultaneous scanning of FHIT and WWOX exons in the context of early tumorigenesis and tumor progression, may help clarify the mechanistic events related to cancer development which are not revealed by immuno histochemistry assays. The presence of site specific deletions of FHIT in these cell lines and primary tumors support its possible role in South African ESCC and justifies a wider screening.


Research recruitment through US central cancer registries: balancing privacy and scientific issues.
Cancer registries are a valuable resource for recruiting participants for public health-oriented research, although such recruitment raises potentially competing concerns about patient privacy and participant accrual. We surveyed US central cancer registries about their policies for research contact with patients, and results showed substantial variation. The strategy used most frequently (37.5% of those that allowed patient contact), which was among the least restrictive, was for investigators to notify patients' physicians and then contact patients with an opt-out approach. The most restrictive strategy was for registry staff to obtain physician permission and contact patients with an opt-in approach. Population-based studies enhance cancer control efforts, and registry policies can affect researchers' ability to conduct such studies. Further discussion about balanced recruitment approaches that protect patient privacy and encourage beneficial research is needed.


Overall survival in advanced breast cancer: relevance of progesterone receptor expression and DNA ploidy in fine-needle aspirates of 392 patients.
Fine-needle aspiration cytology (FNAC) is essential for making a diagnosis in advanced breast cancer. The determination of hormone receptors in the material obtained is useful for predicting patient response to endocrine therapy, but the prognostic value of hormone receptor expression as well as the clinical utility of DNA flow cytometry are controversial. The aim of this prospective study with long-term follow-up (median: 81 months) was to evaluate these biomarkers in relation to overall survival in a series of 392 patients with advanced breast cancer (stage IIB, n=106; IIIA, n=66; IIIB, n=174; and IV, n=46) using FNAC. Estrogen and progesterone receptor expression was found in 65.1% and 46.1% of the tumors, respectively. Hormone receptors were not found to be associated with clinical staging. DNA aneuploidy was present in 70.9% of the cases and the median S-phase fraction (SPF) was 9.4%. There was a significant correlation of aneuploidy and high SPF with lack of hormone receptors. In univariate analysis, advanced disease stage, absence of hormone receptors, DNA aneuploidy and high SPF showed a statistically significant correlation with poor clinical outcome. In multivariate analysis, disease stage, progesterone receptors and DNA ploidy retained independent prognostic significance in relation to overall survival. These data indicate that progesterone receptor expression and DNA ploidy are independent prognostic factors in advanced breast cancer.


Gut microbiota in obesity and related complications: Unveiling the complex interplay.
In recent years, the obesity epidemic has escalated into a serious public health catastrophe that is only getting worse. However, research into the pathophysiological pathways behind the obesity development and the illnesses that it is associated with is ongoing. In the last decades, it is now clear that the gut microbiota plays a significant role in the genesis and progression of obesity and obesity-related illnesses, particularly changes in its metabolites and composition as obesity progresses. Here, we provide a summary of the processes by which variations in gut metabolite levels and the composition of gut microbiota affect obesity and associated disorders. The bacteria residing in the gut release several chemicals that influence the appetite control, metabolism, and other systems. Since it can either encourage or restrict the deposition of fat in several different ways, the gut microbiota's role in obesity is debatable. Additionally, we go over potential therapeutic approaches that could be utilized to alter gut microbiota composition and focus on the important metabolic pathways associated with obesity and metabolic disorders linked to obesity.


[Clinical value of telethermography in the diagnosis of puerperal mastitis].
The study in 209 mothers with lactational mastitis has employed an AGA-780M thermovisor. Thermograms underwent a qualitative and quantitative isotherm-based evaluation. Diagnostic sensitivity of telethermography in mastitis was 97.1%. It could not differentiate types of mastitis in most cases and thus had a low specificity. Telethermography allows early identification of mastitis, control of therapy and reduction of the incidence of suppurative mastitis. The opportunity of telethermographic differentiation of milk stasis and initial mastitis has important practical implications since it allows one to avoid inappropriate use of antibiotics.


Surface morphology, tribological properties and in vitro biocompatibility of nanostructured zirconia thin films.
Deposition of nanostructured and low-wear zirconia (ZrO2) thin films on the metallic component of a total joint implant is envisaged to reduce wear of the soft ultra-high molecular weight polyethylene (UHMWPE) counterpart. In this work, morphological surface features, wear resistance and in vitro-biocompatibility of zirconia thin films deposited by the novel Pulsed Plasma Deposition (PPD) method have been investigated. Film thickness, roughness and wettability were found to be strongly dependent on deposition gas pressure. Interestingly, wear rate of UHMWPE disks coupled to zirconia-coated titanium spheres was only poorly correlated to the contact angle values, while film roughness and thickness seemed not to affect it. Furthermore, wear of UHMWPE, when coupled with zirconia coated-titanium spheres, significantly decreased with respect to uncoated spheres under dry or NaCl-lubricated conditions; besides, when using bovine serum, similar results were obtained for coated and uncoated spheres. Finally, suitable mesenchymal stem and osteoblast cells adhesion, proliferation and viability were observed, suggesting good biocompatibility of the nanostructured zirconia films. Taken together, the results shown in this work indicate that zirconia thin films deposited by the PPD method deserve further investigations as low-wear materials for biomedical applications such as total joint replacement.


A Tat/Rev Induced Limiting Dilution Assay to Measure Viral Reservoirs in Non-Human Primate Models of HIV Infection.
The establishment of latent infection and poorly characterized viral reservoirs in tissues represent major obstacles to a definitive cure for HIV. Non-human primate (NHP) models of HIV infection are critical to elucidate pathogenic processes and an essential tool to test novel therapeutic strategies. Thus, the availability of novel assays to measure residual viral replication and reservoirs in NHP models may increase their utility in the search for an HIV cure. We developed a tat/rev induced limiting dilution assay to measure the frequency of CD4+ T cells that express multiply-spliced(ms)_SIV RNA in presence and absence of stimulation. We validated the assay using cell lines and cells from blood and lymph nodes of SIV infected macaques. In vitro, SIV/SHIV TILDA detects only cells expressing viral proteins. In SIV/SHIV-infected macaques, CD4+ T cells that express msSIV/SHIV RNA (TILDA data) were detected also in the setting of very low/undetectable viremia. TILDA data were significantly higher after stimulation and correlated with plasma viral load (pVL). Interestingly, TILDA data from early cART initiation correlated with peak and AUC pVL post-cART interruption. In summary, we developed an assay that may be useful in characterizing viral reservoirs and determining the effect of HIV interventions in NHP models.


[Long-term hemodynamic results of bifocal pacemaker stimulation].
Before and during the half year after implantation of a bifocal cardiac pacemaker haemodynamic investigations were done in 16 patients using various stimulations. Compared with ventricular stimulation bifocal pacemaker treatment resulted in an increase of cardiac ejection by 31%, the optimal AV-time being between 150 and 200 ms. Maximum benefit was obtained in patients with primary decreased cardiac index (less than 2.50 l/min X m2). In these patients the increase of cardiac index during atrial stimulation compared to ventricular stimulation was 43%. In pre-existing sinus bradycardia left-ventricular ejection fraction was significantly increased despite lowering of enddiastolic filling pressure both at rest and during bicycle ergometry. These positive haemodynamic changes were demonstrable unaltered 6 months after pacemaker implantation.


Administration of recombinant human granulocyte colony-stimulating factor (rhG-CSF) for the intracranial hemorrhage in two dogs: a case report.
Two dogs with generalized seizures were evaluated. The dogs were diagnosed with traumatic intracranial hemorrhages based on the history, neurological examinations, and magnetic resonance imaging (MRI) of the brain. Treatment was started with oxygen, prednisolone and anticonvulsant agents. No further seizure activity was observed after treatment in both dogs, however cushing reflex was detected in case 1 and a left-sided hemi-paresis was detected in case 2. Further supportive treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF) was attempted. No abnormal signs were noted in either of the dogs and no recurrence was noted 16 and 14 months later, in case 1 and 2, respectively. These cases indicate that a combination of rhG-CSF treatment with previous therapy could be used in dogs with traumatic brain injury.


MeCP2 deficiency in Rett syndrome causes epigenetic aberrations at the PWS/AS imprinting center that affects UBE3A expression.
Rett syndrome (RS) is a severe and progressive neurodevelopmental disorder caused by heterozygous mutations in the X-linked methyl CpG binding protein 2 (MeCP2) gene. MeCP2 is a nuclear protein that binds specifically to methylated DNA and functions as a general transcription repressor in the context of chromatin remodeling complexes. RS shares clinical features with those of Angelman syndrome (AS), an imprinting neurodevelopmental disorder. In AS patients, the maternally expressed copy of UBE3A that codes for the ubiquitin protein ligase 3A (E6-AP) is repressed. The similar phenotype of these two syndromes led us to hypothesize that part of the RS phenotype is due to MeCP2-associated silencing of UBE3A. Indeed, UBE3A mRNA and protein are shown here to be significantly reduced in human and mouse MECP2 deficient brains. This reduced UBE3A level was associated with biallelic production of the UBE3A antisense RNA. In addition, MeCP2 deficiency resulted in elevated histone H3 acetylation and H3(K4) methylation and reduced H3(K9) methylation at the PWS/AS imprinting center, with no effect on DNA methylation or SNRPN expression. We conclude, therefore, that MeCP2 deficiency causes epigenetic aberrations at the PWS imprinting center. These changes in histone modifications result in loss of imprinting of the UBE3A antisense gene in the brain, increase in UBE3A antisense RNA level and, consequently reduction in UBE3A production.


Is the Increased Septal Perfusion the Signal of Asymmetrical Septal Hypertrophy?
In this study, we have compared scintigraphic and echocardiographic data in order to investigate whether increased septal perfusion represents asymmetrical septal hypertrophy (ASH), which is a symptom followed in the scintigraphy of myocardial perfusion. The study consists of a total of 186 patients (120 females and 66 males with an average age of 59.45 ± 11.54 years) who had normal myocardial perfusion scintigraphy and echocardiography examinations. Statistical comparison of septal wall thickness measurements obtained from echocardiography and septal-to-lateral wall ratios (S/L ratio) was performed scintigraphically. Left ventricular mass values were obtained as both scintigraphic and echocardiographic data and their correlations were evaluated in order to assess the presence of left ventricular hypertrophy (LVH). In statistical analyses, the values of interventricular septal thickness in diastole (IVSd), left ventricle posterior wall thickness in diastole (LVPWd), left ventricle mass (LVM), and left ventricle mass index (LVMI) were found to be significantly higher in group 2 (S/L ratio >1) compared to group 1 (S/L ratio <1). In addition, S/L ratio is significantly correlated with echocardiographic IVSd, LVPWd, LVM, LVMI, and scintigraphic LVM (rest) values. Furthermore, echocardiographic LVM and LVMI values were significantly correlated with LVM and LVMI values obtained from scintigraphy. It should be known that increased S/L ratio that can be monitored during scintigraphic studies can be an indicator of septal hypertrophy and/or LVH, however, further examination and close follow-ups should be performed in necessary cases.


Ascorbic acid and the behavioral response to haloperidol: implications for the action of antipsychotic drugs.
Haloperidol, a widely used antipsychotic drug, was tested for its ability to block the behavioral response to amphetamine and to elicit catalepsy in rats treated with saline or ascorbic acid (1000 milligrams per kilogram of body weight). By itself, ascorbic acid failed to exert significant behavioral effects, but it enhanced the antiamphetamine and cataleptogenic effects of haloperidol (0.1 or 0.5 milligrams per kilogram). These results, combined with a growing body of biochemical evidence, suggest that ascorbic acid plays an important role in modulating the behavioral effects of haloperidol and related antipsychotic drugs.


The challenge of universal literacy.
Universal literacy has always been a goal of the United States. But literacy has been a moving target: criteria have risen as technology advanced. Comprehension skills well beyond simple decoding are now required. Research by educators and psychologists has laid a scientific foundation on which new pedagogic methods can be based. But even with better teaching, the hope that all adults can attain the highest levels of literacy skills may be unrealistic.


Novel SNPs in the exon region of bovine DKK4 gene and their association with body measurement traits in Qinchuan cattle.
The aim of this study was to determine whether single nucleotide polymorphisms (SNPs) of bovine Dickkopf homolog 4 (DKK4) are associated with body measurement traits in Qinchuan cattle. By using PCR-SSCP technology and DNA sequencing, we discovered 5 DKK4 SNPs in Qingchuan cattle, including -65G>A and -77G>T in the 5'-untranslated region, 1532C>G and 1533T>C in exon 2, and 2088C>T in exon 3. The sequencing map showed that 1532C>G and 1533T>C were in close linkage disequilibrium and were treated as 1532C>G-1533T>C in this study. Allele frequencies were calculated and analyzed by the chi-square test, which showed that -65G>A and 1532C>G-1533T>C were in Hardy-Weinberg equilibrium (P > 0.05), whereas -77G>T and 2088C>T were not in all 633 tested Qinchuan cattle individuals (P < 0.01). Gene heterozygosity (HE), effective allele number (NE), and polymorphism information content (PIC) were 0.407, 1.686, and 0.324 at -65G>A; 0.472, 1.894, and 0.361 at -77G>T; 0.476, 1.908, and 0.363 at 1532C>G-1533T>C; and 0.218, 1.279, and 0.195 at 2088C>T. We also evaluated the potential association of these SNPs with body measurement traits in all 633 individuals; the results suggest that several SNPs in Qinchuan cattle DKK4 were significantly associated with body length, hip height, rump length, hip width, heart girth, and pin bone width (P < 0.05 and P < 0.01). These results suggest that bovine DKK4 could be used as candidate gene for Qinchuan cattle breeding.


Patients Who Undergo Early Aseptic Revision TKA Within 90 Days of Surgery Have a High Risk of Re-revision and Infection at 2 Years: A Large-database Study.
Early aseptic revision within 90 days after primary TKA is a devastating complication. The causes, complications, and rerevision risks of aseptic revision TKA performed during this period are poorly described. (1) What is the likelihood of re-revision within 2 years after early aseptic TKA revision within 90 days compared with that of a control group of patients undergoing primary TKA? (2) What are the indications for early aseptic TKA revision within 90 days? (3) What are the differences in revision risk between different indications for early aseptic revision TKA? Patients who underwent unilateral aseptic revision TKA within 90 days of the index procedure were identified in a national insurance claims database (PearlDiver Technologies) using administrative codes. The exclusion criteria comprised revision for infection, history of bilateral TKA, and age younger than 18 years. The PearlDiver database was selected for its large and geographically diverse patient base and the availability of outpatient follow-up data that are unavailable in other databases focused on inpatient care. A total of 481 patients met criteria for early aseptic revision TKA, with 14% (67) loss to follow-up at 2 years. This final cohort of 414 patients was compared with a control group of patients who underwent primary TKA without revision within 90 days. For the control group, 137,661 patients underwent primary TKA without early revision, with 13% (18,138) loss to follow-up at 2 years. Among these patients, 414 controls were matched using a one-to-one propensity score method; no differences in age, gender, and Charlson comorbidity index score were observed between the groups. Indications for initial revision and 2-year re-revision were recorded. The Kaplan-Meier method was used to assess survival between the early revision and control groups. Two-year survivorship free from additional revision surgery was lower in the early aseptic revision cohort compared with the control (78% [95% confidence interval 77% to 79%] versus 98% [95% CI 96% to 99%]; p < 0.001). Among early revisions, 10% (43 of 414) of the patients underwent re-revision for periprosthetic infection with an antibiotic spacer within 2 years. The reasons for early aseptic revision TKA were instability/dislocation (37% [153 of 414]), periprosthetic fracture (23% [96 of 414]), aseptic loosening (23% [95 of 414]), pain (11% [45 of 414]), and arthrofibrosis (6% [25 of 414]). Early revision for pain was associated with higher odds of re-revision than early revisions performed for other all other reasons (44% [20 of 45] versus 29% [100 of 344]; odds ratio 2.0 [95% CI 1.0 to 3.7]; p = 0.04). Acute early aseptic revision TKA carries a high risk of re-revision at 2 years and a high risk of subsequent periprosthetic joint infection. Patients who undergo an early revision should be carefully counseled regarding the very high risk of repeat revision and discouraged from having early revision unless the indications are absolutely clear and compelling. Early aseptic revision for pain alone carries an unacceptably high risk of repeat revision and should not be performed. Adjunctive measures for infection prophylaxis should be strongly considered. Specific interventions to reduce surgical complications in this subset of patients have not been adequately studied; additional investigation of strategies to minimize the risk of reoperation or infection is warranted. Level III, therapeutic study.


Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect.
Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human-induced pluripotent stem cells (iPSCs) from a family cohort with ASD. Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro, thus presenting a promising approach for disease modelling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4T280M) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4T280M) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4T280M-mutant iPSCs (iPSC-G4T280M-CMs) and ESCs (ESC-G4T280M-CMs), while the impaired proliferation ability of iPSC-G4T280M-CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4T280M and ASD was demonstrated in a human iPSC model for the first time. In summary, our study revealed the molecular mechanism of the GATA4T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.


Excitation energies in density functional theory: an evaluation and a diagnostic test.
Electronic excitation energies are determined using the CAM-B3LYP Coulomb-attenuated functional [T. Yanai et al. Chem. Phys. Lett. 393, 51 (2004)], together with a standard generalized gradient approximation (GGA) and hybrid functional. The degree of spatial overlap between the occupied and virtual orbitals involved in an excitation is measured using a quantity Lambda, and the extent to which excitation energy errors correlate with Lambda is quantified. For a set of 59 excitations of local, Rydberg, and intramolecular charge-transfer character in 18 theoretically challenging main-group molecules, CAM-B3LYP provides by far the best overall performance; no correlation is observed between excitation energy errors and Lambda, reflecting the good quality, balanced description of all three categories of excitation. By contrast, a clear correlation is observed for the GGA and, to a lesser extent, the hybrid functional, allowing a simple diagnostic test to be proposed for judging the reliability of a general excitation from these functionals--when Lambda falls below a prescribed threshold, excitations are likely to be in very significant error. The study highlights the ambiguous nature of the term "charge transfer," providing insight into the observation that while many charge-transfer excitations are poorly described by GGA and hybrid functionals, others are accurately reproduced.


Preventing fragility hip fracture in high risk groups: an opportunity missed.
The national guideline recommends selective case finding as the main strategy by identification of high risk people. This study assessed whether high risk patients were identified before their presentation with fragility fracture. A prospective study for 3.5 consecutive months on patients with low energy hip fractures to Brighton and Sussex University Hospital NHS Trusts, which serves a population of 460,000. Data were collected by interview using standardised form, medical record review, and communication with family physicians. Definition of high risk: (1) untreated hypogonadism (2) corticosteroid users (3) disorders with increased bone loss (4) previous fragility fractures. 98 patients were admitted with hip fracture. Thirty nine (40%) had at least one high risk factor. High risk patients (7 of 39, 18%) were no more likely to receive prophylaxis compared with patients without high risk factor (5 of 59, 8%) (p = 0.21). Previous fragility fracture (23) was the commonest risk factor followed by disorders with increased bone loss (10), premature menopause (10), and corticosteroid users (5). Fifteen patients (15%) had susceptibility to frequent falls and two had maternal history of osteoporosis. The proportion of treated patients were 20% (2 of 10) in premature menopause, 10% (1 of 10) in diseases with secondary osteoporosis, 13% (3 of 23) in previous fragility fracture, and 80% (4 of 5) in corticosteroid users (p = 0.01) Prevention of hip fracture is still inadequate in high risk patients. Discrepancy seemed to exist in treatment frequency among different high risk groups suggesting that emphasis on prevention of osteoporosis has not been reinforced in all people at risk.


[Various aspects of applied biochemical studies in aviation medicine].
This paper presents a review of Soviet and foreign publications (1955-1985) containing biochemical data obtained during real and simulated aircraft flights. The paper discusses the results accumulated before and after flights of varying duration, when performing tasks of different complexity and by pilots with different professional skills. Special attention is given to the studies in which biochemical parameters have been used as a measure of recovery and professional adequacy. Biochemical results are also presented which may help detect young people susceptible to hypertensive disease and ischemic heart disease as well as prevent and modify these pathologies and fatigue.


Effect of penile-extender device in increasing penile size in men with shortened penis: preliminary results.
It has been suggested that the application of penile-extender devices increases penile length and circumference. However, there are a few scientific studies in this field. The aim of this study was to assess the efficacy of a penile-extender (Golden Erect(®) , Ronas Tajhiz Teb, Tehran, Iran) in increasing penile size. This prospective study was performed on subjects complaining about "short penis" who were presented to our clinic between September 15, 2008 and December 15, 2008. After measuring the penile length in flaccid and stretched forms and penile circumference, patients were instructed to wear Golden Erect(®) , 4-6 hours per day during the first 2 weeks and then 9 hours per day until the end of the third month. The subjects were also trained how to increase the force of the device during determined intervals. The patients were visited at the end of the first and third months, and penile length and circumference were measured and compared with baseline. The primary end point of the study was changes in flaccid and stretched penile lengths compared with the baseline size during the 3 months follow-up. Twenty-three cases with a mean age of 26.5 ± 8.1 years entered the study. The mean flaccid penile length increased from 8.8 ± 1.2 cm to 10.1 ± 1.2 cm and 10.5 ± 1.2 cm, respectively, in the first and third months of follow-up, which was statistically significant (P < 0.05). Mean stretched penile length also significantly increased from 11.5 ± 1.0 cm to, respectively, 12.4 ± 1.3 cm and 13.2 ± 1.4 cm during the first and second follow-up (P < 0.05). No significant difference was found regarding proximal penile girth. However, it was not the same regarding the circumference of the glans penis (9.3 ± 0.86 cm vs. 8.8 ± 0.66 cm, P < 0.05). Our findings supported the efficacy of the device in increasing penile length. Our result also suggested the possibility of glans penis girth enhancement using penile extender. Performing more studies is recommended.


Polychlorinated biphenyls disrupt cell division and tip growth in two species of fucoid algae.
Environmental contaminants, including poly-chlorinated biphenyls (PCBs), are enriched in coastal sediments, and despite a 1977 moratorium by the United States Environmental Protection Agency on the production of PCBs, levels remain high, more so near former industrial plants. The effects of these contaminants on sessile species in the intertidal zone, particularly nonanimal species such as the ubiquitous fucoid brown algae, are not well known. We investigated the developmental effects of chronic PCB treatment beginning at fertilization on two species of marine rockweed, Fucus vesiculosus Linnaeus and Silvetia compressa (J.Agardh) E.Serrão, T.O.Cho, S.M.Boo & Brawley. A mixture of the most widely used PCB congeners, Aroclors 1221, 1242, and 1254, was delivered at concentrations well below levels found in contaminated sediments, and resulted in severely delayed mitosis and cytokinesis in both species. In F. vesiculosus, this delay was accompanied by abnormal spindle morphology. PCB treatment also dramatically slowed or arrested rhizoid growth after 2-4 d, and by 7 d F. vesiculosus embryos were dead; in contrast, polar secretion of adhesive, germination, and photopolar germination were not affected. The dramatic delay in the first cell division and reduction in tip growth within the first week of development are likely to compromise S. compressa's ability to reproduce and establish new generations. Thus, the data presented here suggest that PCBs still present in coastal sediments may be inhibiting recruitment in these species. Moreover, as sediment dredging causes temporary spikes in PCB concentrations, these kinds of bioremediation steps may exacerbate the disruption of fucoid development.


Trellis thrombectomy system for the treatment of iliofemoral deep venous thrombosis.
To describe the use of a new percutaneous mechanical thrombectomy device to clear thrombus from the iliofemoral vein. A 52-year-old woman with non-Hodgkin's lymphoma presented to the emergency room with a posterior tibial vein deep vein thrombosis and a greater saphenous vein thrombosis. Heparin therapy caused the clot to propagate into the iliofemoral vein. Catheter-directed thrombolysis for 36 hours with 24 units of reteplase failed to clear the clot. The Trellis Thrombectomy System, a new percutaneous mechanical thrombectomy device, was used to deliver a low dose of reteplase into the clot. Complete clot lysis was achieved in 45 minutes using only 5 units of reteplase. The patient's symptoms resolved completely, and she continues to be asymptomatic at 6 months with no evidence of residual clot on duplex scans. The Trellis device may be used to rapidly clear thrombus from the iliofemoral vein with a low dose of thrombolytic agent.


Myogenic oscillatory mechanism for opossum esophageal smooth muscle contractions.
We evaluated the control of phasic contractions in opossum esophageal circular smooth muscle by determining the contractile response in vitro to agents that cause membrane depolarization and excitation by different mechanisms. Transverse muscle strips taken from different sites along the length of the smooth muscle esophagus were exposed to progressively increasing concentrations of tetraethylammonium (1-30 mM), K+ (4.6-30 mM), or bethanechol (10(-6) to 10(-2) M). In normally inactive esophageal circular smooth muscle, tetraethylammonium and high K+ concentration elicited phasic contractions that were not blocked by atropine and tetrodotoxin. Bethanechol, an M2 muscarinic receptor agonist that acts selectively on smooth muscle, elicited phasic contractions that were not blocked by tetrodotoxin. We conclude that a latent myogenic oscillatory mechanism for control of phasic contractions exists in esophageal circular smooth muscle and that it may be activated by nonspecific excitation of the smooth muscle membrane. We suggest that this myogenic oscillatory mechanism is likely excited and modulated by nerves.


Epicutaneous Immunotherapy for Aeroallergen and Food Allergy.
IgE-mediated allergies today affect up to 30 % of the population in industrialized countries. Allergen immunotherapy is the only disease-modifying treatment option with a long-term effect. However, very few patients (<5 %) choose immunotherapy, due to the long treatment duration (between 3-5 years) and possible local and systemic allergic side effects of the allergen administrations. The latter occur when an allergen accidentally reaches the blood circulation. Therefore, the ideal application route for allergen immunotherapy should be characterized by two hallmarks: firstly, by a high number of potent antigen-presenting cells, which enhance efficacy and thus shorten treatment duration. Secondly, the allergen administration site is ideally non-vascularized, so that inadvertent systemic distribution of the allergen and consequent systemic allergic side effects are minimized. The epidermis contains high numbers of potent antigen-presenting Langerhans cells and, as an epithelium, is non-vascularized. Therefore, the epidermis represents an interesting administration route. Historical evidence for the clinical efficacy of epicutaneous allergy immunotherapy (EPIT) has now been strengthened by a number of recent double-blinded placebo-controlled clinical trials performed by independent groups. We review the immunological rationale, history and clinical experience with epicutaneous allergy immunotherapy.


Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies.
Angiotensin II type 1 (AT1) receptor blockers decrease ischemia by mechanisms dependent on and independent of arterial blood pressure in hypertensive rats and AT1-R knockout mice, respectively. However, the detailed mechanisms underlying the effects of AT1 receptor blockers remain unclear. To elucidate the systemic and focal effects of AT1 receptor blockers against cerebral ischemia in in-vivo and in-vitro studies. Normotensive Wistar rats were treated for 2 weeks with 0.5 or 1 mg/kg candesartan cilexetil and then subjected to 2-h middle cerebral artery occlusion-reperfusion. Human umbilical endothelial cells were stimulated with the active form of candesartan and angiotensin II in the absence and presence of an angiotensin II type 2 (AT2) receptor antagonist. In candesartan-pretreated hypotensive and nonhypotensive rats, blood pressure was moderately increased during middle cerebral artery occlusion and fell gradually to the baseline after the reperfusion; it remained elevated in the control even after the reperfusion occlusion. Candesartan treatment resulted in a decrease in the cortical infarct volume and oxidative damage, the hypoxic status was improved, and the expression of repair-associated and growth-associated proteins in the cortical penumbra was augmented. Candesartan also increased the eNOS mRNA level and the lumen size of the middle cerebral artery. In human umbilical endothelial cells, candesartan increased the eNOS protein level AT2-R dependently, inhibited the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and angiotensin II-induced intracellular reactive oxygen species and nitric oxide, and promoted the extracellular release of nitric oxide, suggesting that it augmented the bioavailability of nitric oxide. Among the mechanisms candesartan exerts in its protection against cerebral ischemia, restoration of endothelial function may represent an attractive therapeutic goal to address cerebral ischemia.


Sex differences in treatment strategy and adverse outcomes among patients 75 and older with atrial fibrillation in the MarketScan database.
Women with atrial fibrillation (AF) experience greater symptomatology, worse quality of life, and have a higher risk of stroke as compared to men, but are less likely to receive rhythm control treatment. Whether these differences exist in elderly patients with AF, and whether sex modifies the effectiveness of rhythm versus rate control therapy has not been assessed. We studied 135,850 men and 139,767 women aged ≥ 75 years diagnosed with AF in the MarketScan Medicare database between 2007 and 2015. Anticoagulant use was defined as use of warfarin or a direct oral anticoagulant. Rate control was defined as use of rate control medication or atrioventricular node ablation. Rhythm control was defined by use of anti-arrhythmic medication, catheter ablation or cardioversion. We used multivariable Poisson and Cox regression models to estimate the association of sex with treatment strategy and to determine whether the association of treatment strategy with adverse outcomes (bleeding, heart failure and stroke) differed by sex. At the time of AF, women were on average (SD) 83.8 (5.6) years old and men 82.5 (5.2) years, respectively. Compared to men, women were less likely to receive an anticoagulant or rhythm control treatment. Rhythm control (vs. rate) was associated with a greater risk for heart failure with a significantly stronger association in women (HR women = 1.41, 95% CI 1.34-1.49; HR men = 1.21, 95% CI 1.15-1.28, p < 0.0001 for interaction). No sex differences were observed for the association of treatment strategy with the risk of bleeding or stroke. Sex differences exist in the treatment of AF among patients aged 75 years and older. Women are less likely to receive an anticoagulant and rhythm control treatment. Women were also at a greater risk of experiencing heart failure as compared to men, when treated with rhythm control strategies for AF. Efforts are needed to enhance use AF therapies among women. Future studies will need to delve into the mechanisms underlying these differences.


[Morphogenesis of the heart lesion in experimental infection with streptococcal L forms].
Histological, histochemical, and immunofluorescent methods were used to study alterations in the hearts of 250 randombred white mice inoculated once intraperitoneally with a stable culture of L-forms of beta-hemolytic group A streptococcus in a dose of 2 x 10(6) CFU and sacrificed at intervals of 1 day to 1 year after inoculation. The development of chronic progressive pathological process (inflammatory, dystrophic, and sclerotic) involving all the membranes of the heart and running against an increasing allergic background was demonstrated. In connective tissue formations of the heart, the antigen of streptococcus L-forms could be detected by immunofluorescence throughout the duration of the experiment. The observed pathogenicity of streptococcus L-forms indicates the necessity of elucidating their role in human infectious pathology.


Biomarkers of Autoimmune Chronic Spontaneous Urticaria.
Chronic spontaneous urticaria and chronic inducible urticaria (CSU/CindU) are caused by mast cell and basophil activation leading to degranulation and the release of histamine and several other mediators. Three kinds of factors can trigger mast cells in CSU: (1) activation of stimulating receptor(s) on the mast cell membrane, (2) upregulation of certain receptor(s), and (3) intracellular dysregulation in signaling with overexpression of the spleen tyrosine kinase (SYK) or reduced activation of the inhibitory Src homology 2 (SH2)-containing inositol phosphatases (SHIP)-related pathways. In CSU, two major endotypes exist based on the primary receptor activating mechanism: type I hypersensitivity (IgE-mediated, directed against auto-allergens) and type IIb (autoimmune, via IgG autoantibodies directed against IgE or the IgE-receptor). Their treatment responses vary. We discuss in vitro and in vivo biomarkers. Patients with auto-allergic CSU have clinical characteristics that can distinguish them partly from those with autoimmune CSU. Most importantly, their disease generally presents a less aggressive course, a better response to second generation (up-dosed) antihistamines and a good response to omalizumab, if necessary. Meanwhile, autoimmune CSU/CindU patients fare less well and often need immunosuppressive drugs. Biomarkers that might help endotype CSU/CindU patients and select the most appropriate treatment, dose, and duration, e.g., for autoallergic CSU, high total IgE and IgE against auto-allergens; for autoimmune CSU, low IgE, basopenia, and IgG against autoantigens like thyroid peroxidase and a positive autologous serum skin test (but sometimes also positive in autoallergy). Some biomarkers are easily accessible but of low specificity; others are highly specific but more futuristic.


Vital indication for erythropoietin in a chronic haemodialysis patient. A case report.
A markedly anaemic, haemodialysis patient with a mixed deficiency of erythropoietin (EPO) and iron developed a life-threatening worsening of anaemia during an episode of severe rectal bleeding. Despite frequently recurring episodes of considerable ischaemic cardiac pain, the patient's religious conviction did not permit blood transfusion. Consequently, combination therapy with both recombinant human EPO (rhEPO) and oral iron was instituted. In this haemodialysis patient, the vitally significant replacement therapy of rhEPO and iron was followed by a steady and uncomplicated restoration of subnormal hematocrit and complete disappearance of cardiac ischaemia.


Novel and efficient synthesis of insulating gas- heptafluoroisobutyronitrile from hexafluoropropylene.
A novel and efficient preparation route of insulating gas-heptafluoroisobutyronitrile was developed. The synthetic route involved halogen-exchange fluorination, decomposition of bis-(perfluoroisopropyl) ketone and dehydration reaction. Overall, the desired compound was produced without the use of extremely toxic and expensive substances. Structures of the as-obtained products were determined by 19F NMR, 13C NMR, IR and GC-MS. The effects of several variables on reaction yield including nature of potassium fluoride, the catalyst dosage, temperature, solvent and molar ratio of raw materials were all investigated. The results indicated that the total yield of heptafluoroisobutyronitrile could reach 42% from original materials under optimal conditions and the mechanism of the reaction was proposed.


A sequence-based approach to identify reference genes for gene expression analysis.
An important consideration when analyzing both microarray and quantitative PCR expression data is the selection of appropriate genes as endogenous controls or reference genes. This step is especially critical when identifying genes differentially expressed between datasets. Moreover, reference genes suitable in one context (e.g. lung cancer) may not be suitable in another (e.g. breast cancer). Currently, the main approach to identify reference genes involves the mining of expression microarray data for highly expressed and relatively constant transcripts across a sample set. A caveat here is the requirement for transcript normalization prior to analysis, and measurements obtained are relative, not absolute. Alternatively, as sequencing-based technologies provide digital quantitative output, absolute quantification ensues, and reference gene identification becomes more accurate. Serial analysis of gene expression (SAGE) profiles of non-malignant and malignant lung samples were compared using a permutation test to identify the most stably expressed genes across all samples. Subsequently, the specificity of the reference genes was evaluated across multiple tissue types, their constancy of expression was assessed using quantitative RT-PCR (qPCR), and their impact on differential expression analysis of microarray data was evaluated. We show that (i) conventional references genes such as ACTB and GAPDH are highly variable between cancerous and non-cancerous samples, (ii) reference genes identified for lung cancer do not perform well for other cancer types (breast and brain), (iii) reference genes identified through SAGE show low variability using qPCR in a different cohort of samples, and (iv) normalization of a lung cancer gene expression microarray dataset with or without our reference genes, yields different results for differential gene expression and subsequent analyses. Specifically, key established pathways in lung cancer exhibit higher statistical significance using a dataset normalized with our reference genes relative to normalization without using our reference genes. Our analyses found NDUFA1, RPL19, RAB5C, and RPS18 to occupy the top ranking positions among 15 suitable reference genes optimal for normalization of lung tissue expression data. Significantly, the approach used in this study can be applied to data generated using new generation sequencing platforms for the identification of reference genes optimal within diverse contexts.


Starch plays a key role in sporosorus formation by the powdery scab pathogen Spongospora subterranea.
Powdery scab disease, caused by the soilborne protist Spongospora subterranea f. sp. subterranea, poses a major constraint to potato production worldwide. Disease symptoms include damage to the tuber skin and the formation of root galls. This study aimed to investigate the potential mechanism behind the formation of sporosori, which are aggregates of resting spores, within root galls. Scanning electron microscopy analysis revealed that the early stage of gall formation, characterized by a white color, involved the accumulation of starch grains, which later disappeared as the gall matured and turned brown. The mature brown galls were found to contain fully formed sporosori. Light microscopy examination of ultramicrotome sections of the root galls showed that the high-amylopectin starches were surrounded by a plasmodium, a precursor to sporosorus. These findings suggest that starch grains contribute to the formation of a sponge-like structure within the sporosori. A significant reduction in total starch levels in both the root galls and their associated roots was observed compared to healthy roots. These findings indicate starch consumption by sporosori during the maturation of root galls. Interestingly, analysis of the transcript levels of starch-related genes showed downregulation of genes encoding starch degrading enzymes and a amylopectin-debranching enzyme, whereas genes encoding a starch synthase and a protein facilitating starch synthesis were upregulated in the root galls. Overall, our results demonstrate that starch is consumed during sporosorus formation, and the pathogen likely manipulates starch homeostasis to its advantage for sporosorus development within the root galls.


Desirable attributes of theories, models, and frameworks for implementation strategy design in healthcare: a scoping review protocol.
Background: Implementation strategies can facilitate the adoption of evidence-based practices and policies. A wide range of theoretical approaches-theories, models, and frameworks-can be used to inform implementation strategy design in different ways (e.g., guiding barrier and enabler assessment to implementing evidence-based interventions). While selection criteria and attributes of theoretical approaches for use in implementation strategy design have been studied, they have never been synthesized. Furthermore, theoretical approaches have never been classified according to desirable criteria and attributes for use in implementation strategy design. This scoping review aims to a) identify the literature reporting on the selection of theoretical approaches for informing implementation strategy design in healthcare and b) understand the suggested use of these approaches in implementation strategy design. Methods: The Joanna Briggs Institute methodological guidelines will be used to conduct this scoping review. A search of three bibliographical databases (MEDLINE, Embase, CINAHL) will be conducted for peer-reviewed discussion, methods, protocol, or review papers. Data will be managed using the Covidence software. Two review team members will independently perform screening, full text review and data extraction. Results: Results will include a list of selection criteria and attributes of theoretical approaches for use in research on implementation strategy design. Descriptive data regarding selection criteria and attributes will be synthesized graphically and in table format. Data regarding the suggested use of theoretical approaches in implementation strategy design will be presented narratively. Conclusions: Results will be used to classify existing theoretical approaches according to the attributes and selection criteria identified in this scoping review. Envisioned next steps include an online tool that will be created to assist researchers in selecting theories, models, and frameworks for implementation strategy design.


Novel hollow MoS2@C@Cu2S heterostructures for high zinc storage performance.
Heterostructured materials have great potential as cathodes for zinc-ion batteries (ZIBs) because of their fast Zn2+ transport channels. Herein, hollow MoS2@C@Cu2S heterostructures are innovatively constructed using a template-engaged method. The carbon layer improves the electrical conductivity, provides a high in situ growth area, and effectively restricts volume expansion during the recycling process. MoS2 nanosheets are grown on the surfaces of hollow C@Cu2S nanocubes using the in situ template method, further expanding the specific surface area and exposing more active sites to enhance the electrical conductivity. As expected, an admirable reversible capacity of 197.2 mA h g-1 can be maintained after 1000 cycles with a coulombic efficiency of 91.1%. Therefore, we firmly believe that this work points the way forward for high-performance materials design and energy storage systems.


Subjective assessment of chewing function of obturator prosthesis wearers.
Assessments of masticatory performance and occlusal force for wearers of obturator prostheses were performed as clinical objective assessments and reported in an earlier study. The purpose of the present study was to evaluate clinically the chewing function of obturator prosthesis wearers by self-evaluations and to examine their relationship to the objective assessments. Twenty patients with maxillofacial obturator prostheses who were having a periodic checkup at the maxillofacial rehabilitation clinic in Kyushu University Hospital were recruited for this study. Chewing function was evaluated by 3 assessment tools: a self-assessment mastication scale, a chewing function score, and a mastication score. In addition, correlations among these assessments and objective tests--ie, masticatory performance and maximum occlusal force--were analyzed by the Spearman rank correlation coefficient. The mean self-assessment mastication scale was 63.2 (SD 31.8), the chewing function score was 54.0 (SD 30.2), and the mastication score was 51.4 (SD 33.3). There was no statistically significant relationship between the self-assessment mastication scale and each objective test. However, there were significant correlations between each semisubjective score--the chewing function score and the mastication score--and masticatory performance. There was no relationship between each semisubjective score and maximum occlusal force. A self-assessment mastication scale was not always in agreement with objective assessments, and assessments made by patients should be taken into consideration when arranging maxillofacial rehabilitation. Conversely, both chewing function and mastication scores corresponded with masticatory performance, and these would be useful as screening tests before performing objective tests.


Gynecomastia following chemotherapy for testicular cancer.
A 22-year-old man received 4 cycles of bleomycin, etoposide and cisplatin combination chemotherapy for clinical stage IIA embryonal cell carcinoma of the right testis. The treatment resulted in complete remission. Five months following cessation of the chemotherapy first on the left and then 2 weeks later on the right side painful gynecomastia developed. His hormonal values are all normal with no evidence of recurrence of the cancer. Gynecomastia on both sides resolved in 8 months spontaneously without any treatment. He is still in clinical remission 14 months after completion of the chemotherapy. We should be aware that gynecomastia following cytotoxic chemotherapy in a young man does not necessarily mean the return of the cancer.


[Amiodarone and thyroid function].
Amiodarone is a drug which is frequently used in cardiology, and which can lead to the appearance of hyper- of hypo-thyroidism in certain cases. A study of the various parameters of thyroid function has shown that these are abnormal in every case treated by this drug, without the biochemical abnormalities necessarily being reflected clinically. The authors outline a method which will allow a distinction to be drawn between patients with a true thyroid malfunction and those whose biochemical results do not appear at first sight to be of any consequence. Regular assays of the T3RIA level are suggested as a means of early detection of thyroid malfunction in patients undergoing treatment with amiodarone.


Progress in systemic therapy for advanced-stage urothelial carcinoma.
Despite recent advances, advanced-stage urothelial carcinoma (aUC) remains incurable, with 5-year survival rates of approximately 10%. Platinum-based chemotherapy has a major role as first-line therapy for most patients with aUC. The approval of the anti-PD-L1 antibody avelumab as maintenance therapy for patients without initial disease progression on platinum-based chemotherapy is an important development that has improved the survival outcomes of patients with this disease. Otherwise, the use of first-line immune-checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 has been restricted to patients who are ineligible for platinum-containing chemotherapy regimens. Other important developments include the FDA-accelerated approval of first-line enfortumab vedotin plus pembrolizumab for patients ineligible to receive cisplatin and the availability of FGFR inhibitors, enfortumab vedotin and sacituzumab govitecan for subsequent lines of therapy. Several research questions remain unaddressed including the lack of adequate biomarkers, how to assign priority to the different treatment options for individual patients and which agents can be effective as monotherapies. The future is promising with the emergence of modalities such as antibody-drug conjugate-like drugs, next-generation ICIs, bispecific antibodies and cellular therapies. In this Review, we summarize the evolution of systemic therapy for patients with aUC and provide insights into the unmet needs.


A study of HLA class I and class II 4-digit allele level in Stevens-Johnson syndrome and toxic epidermal necrolysis.
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are represented by rare but life-threatening cutaneous adverse reactions to different drugs. Previous studies have found that in a Han Chinese population from Taiwan and other Asian Countries, a strong genetic association between HLA-class I alleles (B*15:02, B*58:01) and SJS and TEN was induced by carbamazepine and allopurinol, respectively. To identify genetic markers that covered the MHC region, we carried out a case-control association enrolling 20 Caucasian patients with SJS/TEN. Our patient series included 10 cases related to paracetamol, 7 to allopurinol and 3 to different drugs (plaquenil, itraconazol, nabumetone). Healthy controls were represented by 115 Caucasian bone marrow or stem cell donors. The HLA-A*, B*, C*, DRB1*, DQB1*, DQA1* and DPB1* genotyping were determined. The frequencies of HLA-A*33:03 as well as C*03:02 and C*08:01 were significantly higher in SJS/TEN patient subgroup showing allopurinol drug-induced severe cutaneous adverse reactions (SCAR) as compared to controls (28.6% vs 0%, P=0.00002, Pc=0.0011; 28.6% vs 0%, P=0.00002, Pc=0.001; 28.6% vs 0%, P=0.00002, Pc=0.001, respectively). In the same subgroup the frequencies of B*58:01, DRB1*15:02 and DRB1*13:02 alleles, although considerably higher than in control group (42.8% vs 5.2%, P=0.003; 28.6% vs 1.7%, P=0.005; 28.6% vs 3.5%, P=0.037, respectively), appeared no more statistically different after P correction (Pc=0.248; Pc=0.29; Pc=1.00, respectively). In addition, in 10 of the 20 SJS/TEN patient subgroup with paracetamol-induced SCAR no statistically significant association with HLA alleles could be found. However, in the same SJS/TEN patient subgroup showing allopurinol drug-induced SCAR, haplotype analysis indicated that B*58:01, DRB1*13:02 and DRB1*15:02 alleles, that in a single allele analysis lost statistical significance after P correction, may still confer susceptibility, because the B*58:01-DRB1*13:02 and DRB1*15:02-DQB1*05:02 are positively associated with the disease (14.2% vs 0.43%, P= 0.00001, Pc=0.00028; 14.2% vs 0.43%, P=0.00001, Pc=0.00028, respectively). Our results show that in contrast to SCAR-related to paracetamol, where HLA alleles do not appear to be involved, HLA molecules behave as a strong risk factor for SCAR-related to allopurinol even when a limited number of patients are considered.


NDP52, a novel autophagy receptor for ubiquitin-decorated cytosolic bacteria.
Autophagy functions as a cell-autonomous effector mechanism of innate immunity by separating bacteria from cytosolic resources and delivering them for lysosomal destruction. How cytosolic bacteria are targeted for autophagy is incompletely understood. We recently discovered that Salmonella enterica serotype Typhimurium and Streptococcus pyogenes are detected by NDP52 (nuclear dot protein 52 kDa), after these bacteria enter the cytosol of human cells and become decorated with polyubiquitinated proteins. NDP52 binds the bacterial ubiquitin coat as well as ATG8/LC3 and delivers cytosolic bacteria into autophagosomes. In the absence of NDP52 ubiquitin-coated bacteria accumulate outside ATG8/LC3(+) autophagosomes. Cells lacking NDP52 fail to restrict bacterial proliferation, as do cells depleted of TBK1, an IKK family kinase colocalizing with NDP52 at the bacterial surface. Our findings demonstrate the existence of a receptor for the selective autophagy of cytosolic bacteria, suggesting that cells are able to differentiate between antibacterial and other forms of autophagy.


Reduced training frequencies and maintenance of increased aerobic power.
The purpose of this study was to obtain information regarding the minimum training frequency necessary to maintain the exercise-induced increase in maximum oxygen uptake (VO2max). Twelve subjects (average age = 23 yr) participated in an endurance exercise program of bicycling and running 40 min/d, 6 d/wk. After 10 wk, they continued to train either 4 d/wk or 2 d/wk for an additional 15 wk. Intensity and duration for the additional 15 wk remained the same as on the tenth week of training. The average increase of VO2max in response to 10 wk of training was 25% when measured during bicycle testing and 20% when measured during treadmill testing. VO2max in the 4 d/wk and 2 d/wk groups remained essentially the same as the trained levels when determined at 5-wk intervals of reduced training. These results provide evidence that more exercise is required to increase VO2max, than that required to maintain it at the trained level in young adults performing high-intensity exercise. Furthermore, it is possible to maintain the increased VO2max for at least 15 wk by training at high intensity for 2 d/wk or 4 d/wk.


Progesterone receptor status modifies the association between body mass index and prognosis in women diagnosed with estrogen receptor positive breast cancer.
The role of progesterone receptor (PR) status on the association between obesity and prognosis of estrogen receptor positive (ER+) breast cancer (BC) remains poorly understood. We aim to examine whether this association varies according to the tumor PR status. Data for 3,747 women diagnosed with nonmetastatic ER+ invasive BC between 1995 and 2010 were analyzed. Women were classified according to their body mass index (BMI) (<18.5, 18.5-24.9, 25.0-29.9 or ≥30.0 kg/m2 ). Tumor PR status (PR-, PR+) was evaluated by immunohistochemistry. Hazard ratios (HR) for survival outcomes were estimated using multivariable Cox regression models. Effect modification was assessed on both additive and multiplicative scales using relative excess risk due to interaction and ratio of HRs, respectively. After a median follow-up of 5.9 years (range: 3.4-9.2), women with PR- tumors and underweight (HR = 2.76, 95% CI: 1.40-4.91), overweight (HR = 2.02, 95% CI: 1.43-2.81) or obese (HR = 2.51, 95% CI: 1.67-3.65) had increased risk of all-cause mortality, when compared to normal weight women with PR+ tumors. A similar pattern of associations was observed for BC-specific mortality. In contrast, women with PR+ tumors had similar risks for both mortality outcomes, regardless of BMI. On the additive scale, all-cause mortality was modified by PR status for overweight and obese women, whereas for BC-specific mortality, it was only modified for underweight women. The same observations were found on the multiplicative scale. These results suggest that poorer survival associated with low and high BMI among women diagnosed with ER+ BC may depend on the tumor PR status.


Beyond denitrification: The role of microbial diversity in controlling nitrous oxide reduction and soil nitrous oxide emissions.
Many biotic and abiotic processes contribute to nitrous oxide (N2 O) production in the biosphere, but N2 O consumption in the environment has heretofore been attributed primarily to canonical denitrifying microorganisms. The nosZ genes encoding the N2 O reductase enzyme, NosZ, responsible for N2 O reduction to dinitrogen are now known to include two distinct groups: the well-studied Clade I which denitrifiers typically possess, and the novel Clade II possessed by diverse groups of microorganisms, most of which are non-denitrifiers. Clade II N2 O reducers could play an important, previously unrecognized role in controlling N2 O emissions for several reasons, including: (1) the consumption of N2 O produced by processes other than denitrification, (2) hypothesized non-respiratory functions of NosZ as an electron sink or for N2 O detoxification, (3) possible differing enzyme kinetics of Clade II NosZ compared to Clade I NosZ, and (4) greater nosZ gene abundance for Clade II compared to Clade I in soils of many ecosystems. Despite the potential ecological significance of Clade II NosZ, a census of 800 peer-reviewed original research articles discussing nosZ and published from 2013 to 2019 showed that the percentage of articles evaluating or mentioning Clade II nosZ increased from 5% in 2013 to only 22% in 2019. The census revealed that the slowly spreading awareness of Clade II nosZ may result in part from disciplinary silos, with the percentage of nosZ articles mentioning Clade II nosZ ranging from 0% in Agriculture and Agronomy journals to 32% in Multidisciplinary Sciences journals. In addition, inconsistent nomenclature for Clade I nosZ and Clade II nosZ, with 17 different terminologies used in the literature, may have created confusion about the two distinct groups of N2 O reducers. We provide recommendations to accelerate advances in understanding the role of the diversity of N2 O reducers in regulating soil N2 O emissions.