Perceived Stress Among Resident Doctors in Jordanian Teaching Hospitals: Cross-Sectional Study.
Medical residents in Jordanian hospitals are involved in many clinical and nonclinical tasks that expose them to various stress factors. High stress and burnout have the potential to negatively impact work performance and patient care, including medication errors, suboptimal care, clinical errors, and patient dissatisfaction. This study aimed to determine the perceived stress among medical residents in Jordanian hospitals and its associated risk factors. A cross-sectional study was conducted among residents in Jordanian hospitals. A cluster sample of 5 hospitals with residency programs was selected from different health sectors. All residents who were working in the selected hospitals were invited to participate in this study, during the period from April to July 2017. A total of 555 residents agreed to participate in this study, giving a response rate of 84%. The perceived stress scale (PSS) was used for assessment. A total of 398 male and 157 female residents were included in this study. The mean PSS score in this study was 21.6; 73% (405/555) of the residents had moderate level of stress, and 18% (100/555) had high level of stress. About 6.7% (37/555) of the residents had hypertension, 2.7% (15/555) had diabetes, 3.2% (18/555) had heart disease, and 8.5% (47/555) were anemic. 233 (42%) respondents complained of back pain, and 161 (29%) of the respondents complained of insomnia. Stress was associated with higher workload, sleep deprivation, and dissatisfaction in the relationship with colleagues, with income, and with the program. In multivariate analysis, the following factors were significantly associated with stress: female gender, dissatisfaction with working environment, and facing work-related, academic, and family stressors. The majority of medical residents in Jordanian hospitals felt nervous and stressed. Conducting stress management programs during residency and improving the work environment are strongly recommended.


Telomerase is required for zebrafish lifespan.
Telomerase activity is restricted in humans. Consequentially, telomeres shorten in most cells throughout our lives. Telomere dysfunction in vertebrates has been primarily studied in inbred mice strains with very long telomeres that fail to deplete telomeric repeats during their lifetime. It is, therefore, unclear how telomere shortening regulates tissue homeostasis in vertebrates with naturally short telomeres. Zebrafish have restricted telomerase expression and human-like telomere length. Here we show that first-generation tert(-/-) zebrafish die prematurely with shorter telomeres. tert(-/-) fish develop degenerative phenotypes, including premature infertility, gastrointestinal atrophy, and sarcopaenia. tert(-/-) mutants have impaired cell proliferation, accumulation of DNA damage markers, and a p53 response leading to early apoptosis, followed by accumulation of senescent cells. Apoptosis is primarily observed in the proliferative niche and germ cells. Cell proliferation, but not apoptosis, is rescued in tp53(-/-)tert(-/-) mutants, underscoring p53 as mediator of telomerase deficiency and consequent telomere instability. Thus, telomerase is limiting for zebrafish lifespan, enabling the study of telomere shortening in naturally ageing individuals.


Room-temperature preparation and characterization of poly (ethylene glycol)-coated silica nanoparticles for biomedical applications.
Monodisperse, spherical, polyethylene glycol (PEG)-coated silica nanoparticles have been prepared at room temperature and characterized for the purpose of biomedical applications. The particles were synthesized by the hydrolysis of tetramethyl orthosilicate (TMOS) in alcohol media under catalysis by ammonia, and their size can range from about 50-350 nm in diameter. We studied the particle size and size distribution using a scanning electron microscope (SEM) and an asymmetric field-flow fractionation (AFFF) multiangle static light-scattering instrument. The chemical and/or physical binding of PEG to the silica nanoparticles was studied by infrared spectroscopy, and the weight percentage of PEG attached to the particles was quantified. The PEG-coated silica nanoparticles showed enhanced colloidal stability when redispersed into aqueous solutions from the dried state as a result of the steric stabilization function of the PEG polymer grafted on the surface of particles. A nonspecific protein-binding test was also carried out to show that the PEG coating can help reduce the protein adsorption onto the surface of the particles, relating to the biocompatibility of these PEG-coated particles. Also, the inclusion of magnetic nanoparticles into the silica particles was shown as an example of the possible applications of PEG-coated silica particles. These silica nanoparticles, as a matrix for encapsulation of certain reagents, have potential for applications to in vivo diagnosis, analysis, and measurements inside intact biologic systems.


Sample features associated with success rates in population-based EGFR mutation testing.
Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of patients with advanced non-small-cell lung cancer. This study involves a large cohort and epidemiologically unselected series of EGFR mutation testing for patients with nonsquamous non-small-cell lung cancer in a North American population to determine sample-related factors that influence success in clinical EGFR testing. Data from consecutive cases of Canadian province-wide testing at a centralized diagnostic laboratory for a 24-month period were reviewed. Samples were tested for exon-19 deletion and exon-21 L858R mutations using a validated polymerase chain reaction method with 1% to 5% detection sensitivity. From 2651 samples submitted, 2404 samples were tested with 2293 samples eligible for analysis (1780 histology and 513 cytology specimens). The overall test-failure rate was 5.4% with overall mutation rate of 20.6%. No significant differences in the failure rate, mutation rate, or mutation type were found between histology and cytology samples. Although tumor cellularity was significantly associated with test-success or mutation rates in histology and cytology specimens, respectively, mutations could be detected in all specimen types. Significant rates of EGFR mutation were detected in cases with thyroid transcription factor (TTF)-1-negative immunohistochemistry (6.7%) and mucinous component (9.0%). EGFR mutation testing should be attempted in any specimen, whether histologic or cytologic. Samples should not be excluded from testing based on TTF-1 status or histologic features. Pathologists should report the amount of available tumor for testing. However, suboptimal samples with a negative EGFR mutation result should be considered for repeat testing with an alternate sample.


A comprehensive review on nanocomposite biomaterials based on gelatin for bone tissue engineering.
The creation of a suitable scaffold is a crucial step in the process of bone tissue engineering (BTE). The scaffold, acting as an artificial extracellular matrix, plays a significant role in determining the fate of cells by affecting their proliferation and differentiation in BTE. Therefore, careful consideration should be given to the fabrication approach and materials used for scaffold preparation. Natural polypeptides such as gelatin and collagen have been widely used for this purpose. The unique properties of nanoparticles, which vary depending on their size, charge, and physicochemical properties, have demonstrated potential in solving various challenges encountered in BTE. Therefore, nanocomposite biomaterials consisting of polymers and nanoparticles have been extensively used for BTE. Gelatin has also been utilized in combination with other nanomaterials to apply for this purpose. Composites of gelatin with various types of nanoparticles are particularly promising for creating scaffolds with superior biological and physicochemical properties. This review explores the use of nanocomposite biomaterials based on gelatin and various types of nanoparticles together for applications in bone tissue engineering.


Hippo Signaling-Mediated Mechanotransduction in Cell Movement and Cancer Metastasis.
The evolutionarily conserved Hippo kinase signaling cascade governs cell proliferation, tissue differentiation and organ size, and can promote tumor growth and cancer metastasis when dysregulated. Unlike conventional signaling pathways driven by ligand-receptor binding to initiate downstream cascades, core Hippo kinases are activated not only by biochemical cues but also by mechanical ones generated from altered cell shape, cell polarity, cell-cell junctions or cell-extracellular matrix adhesion. In this review, we focus on recent advances showing how mechanical force acts through the actin cytoskeleton to regulate the Hippo pathway during cell movement and cancer invasion. We also discuss how this force affects YAP-dependent tissue growth and cell proliferation, and how disruption of that homeostatic relationship contributes to cancer metastasis.


The Geneva brain collection.
The University of Geneva brain collection was founded at the beginning of the 20th century. Today, it consists of 10,154 formaldehyde- or buffered formaldehyde-fixed brains obtained from the autopsies of the Department of Psychiatry and, since 1971, from the Department of Geriatrics. More than 100,000 paraffin-embedded blocks and 200,000 histological slides have also been collected since 1901. From the time of its creation, this collection has served as an important resource for pathological studies and clinicopathological correlations, primarily in the field of dementing illnesses and brain aging research. These materials have permitted a number of original neuropathological observations, such as the classification of Pick's disease by Constantinidis, or the description of dyshoric angiopathy and laminar sclerosis by Morel. The large number of cases, including some very rare conditions, provides a unique resource and an opportunity for worldwide collaborations.


The simultaneous inhibition of the mTOR and MAPK pathways with Gnetin-C induces apoptosis in acute myeloid leukemia.
Acute myelogenous leukemia (AML) is a clinically heterogeneous disease that is frequently associated with relapse and a poor prognosis. Among the various subtypes, AML with the monosomal karyotype (AML-MK) has an extremely unfavorable prognosis. We performed screening to identify antitumor compounds that are capable of inducing apoptosis in primary leukemia cells harboring the AML-MK karyotype and identified a naturally occurring stilbene, Gnetin-C, with potent anti-tumor activities against AML cells from patients with various cytogenetic abnormalities, including patients with the AML-MK karyotype. Gnetin-C simultaneously inhibits the ERK1/2 and the AKT/mTOR pathways, two signals that are essential for the survival of leukemia cells. A combination of Gnetin-C with low doses of chemotherapeutic drugs led to synergistic anti-tumor effects against AML cells. In an immunodeficient mouse model of human leukemia, Gnetin-C attenuated the formation of leukemia, depleted leukemia cells and improved survival. These findings suggest that Gnetin-C has antitumor activities in AML and supports the therapeutic potential of blocking two different pathways in AML.


Use of shared faculty in U.S. and Canadian dental schools.
Dental schools are facing substantial financial challenges and a shortage of faculty members. One solution to address these issues has been to hire "shared" faculty members, i.e., faculty members whose primary appointment is at one institution who are hired by another institution to teach a course or part of a course. This is a controversial concept. A survey of academic deans at U.S. and Canadian dental schools was conducted for this study; thirty-nine (54 percent) of the seventy-two academic deans completed the online survey. This survey found that the use of shared faculty members is not rare amongst U.S. and Canadian dental schools and that the opinions of the academic deans about the use of shared faculty members ranged widely-from strong support to strong disapproval. Using shared faculty members has advantages and disadvantages for students, the shared faculty members, and both institutions. Many of the disadvantages could be potentially minimized by stakeholders' working together to develop collaborative arrangements. Networks could be developed in which institutions coordinate hiring of shared faculty members based on what expertise is needed. Financial challenges and shortages of faculty members are unlikely to be resolved in the near future, but use of shared faculty members is one promising approach to begin to meet these challenges.


Differential binding of Haemophilus influenzae to human tissues by fimbriae.
The hypothesis was investigated that tissue tropism of Haemophilus influenzae during colonisation and infection is associated with the ability of fimbriate bacteria to bind to the organs and cell types involved. H. influenzae type b with fimbriae (strain 770235f+) bound to several cell types, including ciliated columnar epithelial cells, pneumocytes, ependymal cells, glial cells, connective tissue fibroblasts, synovial cells, antigen-presenting cells, lymphocytes, erythrocytes and endothelial cells. Binding of H. influenzae to kidney, liver and conjunctiva cells was poor. Fimbriae-specific monoclonal antibody (MAb 6HE8) inhibited this binding. Some binding to endothelial cells and macrophages was also observed with non-fimbriate strains. This binding was not inhibited by MAb 6HE8. We conclude that in-vitro binding of fimbriate H. influenzae is mainly to those tissues and cells where H. influenzae is found during colonisation and infection. The data suggest that a shift to the non-fimbriate form is required for bacteria in the bloodstream to escape clearance mechanisms mediated by blood cells.


Three-dimensional structure of A1A0 ATP synthase from the hyperthermophilic archaeon Pyrococcus furiosus by electron microscopy.
The archaeal ATP synthase is a multisubunit complex that consists of a catalytic A(1) part and a transmembrane, ion translocation domain A(0). The A(1)A(0) complex from the hyperthermophile Pyrococcus furiosus was isolated. Mass analysis of the complex by laser-induced liquid bead ion desorption (LILBID) indicated a size of 730 +/- 10 kDa. A three-dimensional map was generated by electron microscopy from negatively stained images. The map at a resolution of 2.3 nm shows the A(1) and A(0) domain, connected by a central stalk and two peripheral stalks, one of which is connected to A(0), and both connected to A(1) via prominent knobs. X-ray structures of subunits from related proteins were fitted to the map. On the basis of the fitting and the LILBID analysis, a structural model is presented with the stoichiometry A(3)B(3)CDE(2)FH(2)ac(10).


"Nutrothorax" complicating a misplaced nasogastric feeding tube in a severely ill patient.
Introduction of nasogastric feeding tubes is usually blindly performed and is generally considered a safe procedure. However, the rate of complications of a blind insertion technique varies from 0.3 to 15%, and is usually related to inadvertent insertion of nasogastric tubes into the trachea and distal airways. The main predisposing factors related to tube malpositioning and complications are altered mental status with decreased cough or gag reflex, a preexisting endotracheal tube and severe illness. Complications include severe aspiration pneumonia, hydrothorax, hemothorax, empyema and pneumothorax. The mortality related to misplacement of a nasogastric tube is around 0.1-0.3% of the procedures. This 61-year old female had a history of poor appetite, weight loss, dyspnea and fever. A chest axial computerized tomography showed enlarged mediastinal lymph nodes. Laboratory showed hypercalcemia with normal PTH and hypokalemia. As the patient remained anorectic, a nasogastric feeding tube was placed, through which the administration of enteral diet, by continuous infusion pump, was started. After 12 -en.jpg-en.jpghours the patient developed dyspnea, hypoxemia and hypotension. During orotracheal intubation, it was disclosed the presence of the nasogastric tube in the trachea as well as the infused diet within the respiratory tract. Autopsy revealed an unusual complication of a nasogastric tube misplacement, which led to a massive collection of enteral nutrition fluid into the pleural space - a "nutrothorax". Additionally, an underlying stage IV anaplastic large cell lymphoma with interstitial lung and bronchial mucosa involvement was diagnosed.


Poorly differentiated adenocarcinoma in the ascending colon with peritoneal dissemination: case report of a patient who survived more than eleven years.
Poorly differentiated adenocarcinoma of the large bowel is a rare condition known as having a poor prognosis. We report herein a case of a patient with a poorly differentiated adenocarcinoma in the ascending colon with peritoneal dissemination who survived more than eleven years thanks to adjuvant chemotherapy. A 53-year-old woman with continuous diarrhea was referred to our hospital. Physical examination revealed a fist-sized mass in the right lower quadrant. Barium enema study and colonoscopy showed an ascending colon tumor. Abdominal computed tomography showed extensive ascites and masses besides the ascending colon and in the upper abdomen. Laparotomy confirmed dissemination to the peritoneum, the pouch of Douglas and the omentum. Right hemicolectomy was performed and two masses of the omentum were removed in a palliative intent. Twenty mg of mitomicin C were given intraperitoneally. The resected specimen revealed an ulcerated hard mass 5 x 5 cm in size with unclear margin. Histology showed a poorly differentiated adenocarcinoma with dissemination to the omentum. A continuous infusion of 3000 mg of 5-fluorouracil per 48 hours was given weekly for four weeks followed by 450 mg of oral UFT-E (Uracil:Tegafur) per day as post-operative chemotherapy. The postoperative course was uneventful. Although she underwent removal of a breast cancer eight years after the operation for colon cancer, no sign of tumor progression has been observed for 132 months since the initial operation, by taking UFT-E without any adverse events.


Disturbing the balance: effect of contact lens use on the ocular proteome and microbiome.
Contact lens wear is a popular, convenient and effective method for vision correction. In recent years, contact lens practice has expanded to include new paradigms, including orthokeratology; however, their use is not entirely without risk, as the incidence of infection has consistently been reported to be higher in contact lens wearers. The explanations for this increased susceptibility have largely focused on physical damage, especially to the cornea, due to a combination of hypoxia, mechanical trauma, deposits and solution cytotoxicity, as well as poor compliance with care routines leading to introduction of pathogens into the ocular environment. However, in recent years, with the increasing availability and reduced cost of molecular techniques, the ocular environment has received greater attention with in-depth studies of proteins and other components. Numerous proteins were found to be present in the tears and their functions and interactions indicate that the tears are far more complex than formerly presumed. In addition, the concept of a sterile or limited microbial population on the ocular surface has been challenged by analysis of the microbiome. Ocular microbiome was not considered as one of the key sites for the Human Microbiome Project, as it was thought to be limited compared to other body sites. This was proven to be fallacious, as a wide variety of micro-organisms were identified in the analyses of human tears. Thus, the ocular environment is now recognised to be more complicated and interference with this ecological balance may lead to adverse effects. The use of contact lenses clearly changes the situation at the ocular surface, which may result in consequences which disturb the balance in the healthy eye.


Anti-Müllerian hormone deficiency in females with Fanconi anemia.
In females with Fanconi anemia (FA), infertility is often accompanied by diminished ovarian reserve and hypergonadotropic amenorrhea before the age of 30 years, suggesting primary ovarian insufficiency (POI). POI is typically diagnosed only after perimenopausal symptoms are observed. The objective of the study was to assess whether serum anti-Müllerian hormone (AMH) levels can serve as a cycle-independent marker for the diagnosis of POI in patients with FA. This observational study used the National Cancer Institute's inherited bone marrow failure syndrome cohort at the National Institutes of Health Clinical Center. The study included 22 females with FA, 20 unaffected female relatives of patients with FA, and 21 unrelated healthy females under 41 years of age. Serum AMH, a marker of ovarian reserve, was measured in all participants. Females with FA had very low AMH levels (median 0.05 ng/mL; range 0-2.32 ng/mL; P < .001) when compared with unaffected relatives (median 2.10 ng/mL; range 0.04-4.73 ng/mL) and unrelated healthy females (median 1.92 ng/mL; range 0.31-6.64 ng/mL). All patients with FA older than 25 years of age were diagnosed with POI and had undetectable AMH levels. AMH deficiency appears to be a shared trait across this heterogeneous FA cohort. Substantially reduced AMH levels in females with FA suggest a primary ovarian defect associated with reduced fertility. Measurement of AMH at the time of FA diagnosis and subsequent monitoring of AMH levels at regular intervals may be useful for the timely management of complications related to POI such as subfertility/infertility, osteoporosis, and menopausal symptoms.


Ectopic Liver Tissue Attached to the Gallbladder Wall: a case report.
Ectopic liver tissue is a rare entity, reported to occur in several intra-, retro- and extra- peritoneal sites, including the gallbladder. It is usually detected incidentally, during laparoscopy, laparotomy, or autopsy. Several possible mechanisms may explain the development of liver ectopia. Although ectopic liver tissue is usually asymptomatic, it behaves like orthotopic liver, developing the same pathologic conditions. We describe the case of a 54-year-old woman who was found to have a nodule attached to the gallbladder wall without any connection with the main liver, during an elective laparoscopic cholecystectomy for gallstone disease. The nodule was removed with the gallbladder and identified histologically as normal ectopic liver tissue. It would seem sensible to resect the ectopic tissue if encountered during cholecystectomy for gallstones. Laparoscopic management of ectopic liver can be feasible.


[Acid-base equilibrium in sportsmen during physical exercise].
Acid-base balance in venous blood of basketball players was studied under specific loadings of various intensity by means of the micro-Astrup device. It is established that under acyclic loadings (throwing the ball into the basket) the state of metabolic acidosis is developed in the sportsmen and the more intensive the work, the higher the degree of the state of metabolic acidosis. The efficiency of actions of the persons examined was in inverse dependence on the degree of metabolic disturbances, i.e. the least efficiency was marked under the most profound acidosis.


Possible Role of Staphylococcal Enterotoxin B in the Pathogenesis of Autoimmune Diseases.
As a member of superantigens (SAgs) produced by Staphylococcus aureus, staphylococcal enterotoxin B (SEB) is a exotoxin superantigen that can regulate the activity of immunomodulatory and pro-inflammatory cell types. In addition, SEB plays a critical role in the pathogenesis of autoimmune disorders either by initiating the autoimmune process or by inducing a relapse in an individual in clinical remission from an autoimmune disorder. SEB can directly activate T lymphocytes, leading to the release of cytokines, superoxides, or other mediators of inflammation either directly or indirectly, because of its unique ability to cross-link human major histocompatibility complex (MHC) class II and T cell receptors (TCR), forming a trimolecular complex. This review discusses the potential effects of SEB in the pathogenesis of autoimmune diseases such as multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis, and explores some updated therapeutic medications to neutralize SEB.


Stability of tin etiopurpurin.
Formulations of the tin etiopurpurin (SnET2) have been observed to undergo a spectral change on storage in dimethylformamide solution. This results in an alteration in the action spectrum, with enhanced photodynamic activity at lower wavelengths and decreased activity at 660 nm. On the basis of structural considerations, a reduced analog of SnET2 was prepared with an absorbance maximum at 640 nm. Formation of this product, termed SnET2H(2) relieves steric strain inherent in the parent molecule. Nuclear magnetic resonance, spectral and photodynamic data are consistent with the formation of SnET2H(2) during SnET2 storage. Slight modifications in the original synthesis are also reported, resulting in improved yields of intermediate products.


Temperature of embryo culture for assisted reproduction.
'Infertility' is defined as the failure to achieve pregnancy after 12 months or more of regular unprotected sexual intercourse. One in six couples experience a delay in becoming pregnant. In vitro fertilisation (IVF) is one of the assisted reproductive techniques used to enable couples to achieve a live birth. One of the processes involved in IVF is embryo culture in an incubator, where a stable environment is created and maintained. The incubators are set at approximately 37°C, which is based on the human core body temperature, although several studies have shown that this temperature may in fact be lower in the female reproductive tract and that this could be beneficial. In this review we have included randomised controlled trials which compared different temperatures of embryo culture. To assess different temperatures of embryo culture for human assisted reproduction, which may lead to higher live birth rates. We searched the following databases and trial registers: the Cochrane Gynaecology and Fertility (CGF) Group Specialised Register of Controlled Trials, the Cochrane Central Register of Studies Online, MEDLINE, Embase, PsycINFO, CINAHL, clinicaltrials.gov, The World Health Organization International Trials Registry Platform search portal, DARE, Web of Knowledge, OpenGrey, LILACS database, PubMed and Google Scholar. Furthermore, we manually searched the references of relevant articles and contacted experts in the field to obtain additional data. We did not restrict the search by language or publication status. We performed the last search on 6 March 2019. Two review authors independently screened the titles and abstracts of articles retrieved by the search. Full texts of potentially eligible randomised controlled trials (RCTs) were obtained and screened. We included all RCTs which compared different temperatures of embryo culture in IVF or intracytoplasmic sperm injection (ICSI), with a minimum difference in temperature between the two incubators of ≥ 0.5°C. The search process is shown in the PRISMA flow chart. Two review authors independently assessed trial eligibility and risk of bias and extracted data from the included studies; the third review author resolved any disagreements. We contacted trial authors to provide additional data. The primary review outcomes were live birth and miscarriage. Clinical pregnancy, ongoing pregnancy, multiple pregnancy and adverse events were secondary outcomes. All extracted data were dichotomous outcomes, and odds ratios (OR) were calculated with 95% confidence intervals (CIs) on an intention-to-treat basis. We assessed the overall quality of the evidence for the main comparisons using GRADE methods. We included three RCTs, with a total of 563 women, that compared incubation of embryos at 37.0°C or 37.1°C with a lower incubator temperature (37.0°C versus 36.6°C, 37.1°C versus 36.0°C, 37.0° versus 36.5°C). Live birth, miscarriage, clinical pregnancy, ongoing pregnancy and multiple pregnancy were reported. After additional information from the authors, we confirmed one study as having no adverse events; the other two studies did not report adverse events. We did not perform a meta-analysis as there were not enough studies included per outcome. Live birth was not graded since there were no data of interest available. The evidence for the primary outcome, miscarriage, was of very low quality. The evidence for the secondary outcomes, clinical pregnancy, ongoing pregnancy and multiple pregnancy was also of very low quality. We downgraded the evidence because of high risk of bias (for performance bias) and imprecision due to limited included studies and wide CIs.Only one study reported the primary outcome, live birth (n = 52). They performed randomisation at the level of oocytes and not per woman, and used a paired design whereby two embryos, one from 36.0°C and one from 37.0°C, were transferred. The data from this study were not interpretable in a meaningful way and therefore not presented. Only one study reported miscarriage. We are uncertain whether incubation at a lower temperature decreases the miscarriage (odds ratio (OR) 0.90, 95% CI 0.52 to 1.55; 1 study, N = 412; very low-quality evidence).Of the two studies that reported clinical pregnancy, only one of them performed randomisation per woman. We are uncertain whether a lower temperature improves clinical pregnancy compared to 37°C for embryo incubation (OR 1.08, 95% CI 0.73 to 1.60; 1 study, N = 412; very low-quality evidence). For the outcome, ongoing pregnancy, we are uncertain if a lower temperature is better than 37°C (OR 1.10, 95% CI 0.75 to 1.62; 1 study, N = 412; very low quality-evidence). Multiple pregnancy was reported by two studies, one of which used a paired design, which made it impossible to report the data per temperature. We are uncertain if a temperature lower than 37°C reduces multiple pregnancy (OR 0.80, 95% CI 0.31 to 2.07; 1 study, N = 412; very low-quality evidence). There was insufficient evidence to make a conclusion regarding adverse events, as no studies reported data suitable for analysis. This review evaluated different temperatures for embryo culture during IVF. There is a lack of evidence for the majority of outcomes in this review. Based on very low-quality evidence, we are uncertain if incubating at a lower temperature than 37°C improves pregnancy outcomes. More RCTs are needed for comparing different temperatures of embryo culture which require reporting of clinical outcomes as live birth, miscarriage, clinical pregnancy and adverse events.


Wolbachia-mediated persistence of mtDNA from a potentially extinct species.
Drosophila quinaria is polymorphic for infection with Wolbachia, a maternally transmitted endosymbiont. Wolbachia-infected individuals carry mtDNA that is only distantly related to the mtDNA of uninfected individuals, and the clade encompassing all mtDNA haplotypes within D. quinaria also includes the mtDNA of several other species of Drosophila. Nuclear gene variation reveals no difference between the Wolbachia-infected and uninfected individuals of D. quinaria, indicating that they all belong to the same interbreeding biological species. We suggest that the Wolbachia and the mtDNA with which it is associated were derived via interspecific hybridization and introgression. The sequences in the Wolbachia and the associated mtDNA are ≥6% divergent from those of any known Drosophila species. Thus, in spite of nearly complete species sampling, the sequences from which these mitochondria were derived remain unknown, raising the possibility that the donor species is extinct. The association between Wolbachia infection and mtDNA type within D. quinaria suggests that Wolbachia may be required for the continued persistence of the mtDNA from an otherwise extinct Drosophila species. We hypothesize that pathogen-protective effects conferred by Wolbachia operate in a negative frequency-dependent manner, thus bringing about a stable polymorphism for Wolbachia infection.


Energy Gap Law for Exciton Dynamics in Gold Cluster Molecules.
The energy gap law relates the nonradiative decay rate to the energy gap separating the ground and excited states. Here we report that the energy gap law can be applied to exciton dynamics in gold cluster molecules. Size-dependent electrochemical and optical properties were investigated for a series of n-hexanethiolate-protected gold clusters ranging from Au25 to Au333. Voltammetric studies reveal that the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) gaps of these clusters decrease with increasing cluster size. Combined femtosecond and nanosecond time-resolved transient absorption measurements show that the exciton lifetimes decrease with increasing cluster size. Comparison of the size-dependent exciton lifetimes with the HOMO-LUMO gaps shows that they are linearly correlated, demonstrating the energy gap law for excitons in these gold cluster molecules.


Tyrosine Coupling Creates a Hyperbranched Multivalent Protein Polymer Using Horseradish Peroxidase via Bipolar Conjugation Points.
Protein polymers of covalently cross-linked protein monomers are highly attractive biomaterials because each monomer unit possesses distinct protein functions. Protein polymers often show enhancement effects on the function by integrating a large number of molecules into one macromolecule. The cross-linking site of component proteins should be precisely controlled to avoid diminishing the protein function. However, preparing protein polymers that are cross-linked site-specifically with a high cross-linking degree is a challenge. Here, we demonstrate the preparation of a site-specifically cross-linked protein polymer that has a hyperbranched polymer-like structure with a high cross-linking degree. A horseradish peroxidase (HRP) reaction was used to achieve the protein polymerization through a peptide tag containing a tyrosine residue (Y-tag). Y-tag sequences were introduced to both N- and C-termini of a model protein, protein G. The dual Y-tagged protein G (Y-pG-Y) was treated with HRP to form a Y-pG-Y polymer possessing average and maximum cross-linking degree of approximately 70-mer and 150-mer, respectively. The Y-pG-Y polymer shows the highest cross-linking degree among the protein polymers reported, which are completely soluble in water and cross-linked via covalent bonding. The Y-pG-Y was cross-linked site-specifically at the Tyr residue in the Y-tag, retaining its function, and the Y-pG-Y polymer showed extremely strong avidity against immunoglobulin G. The reactivities of N- and C-terminal Y-tags were evaluated, and we revealed that the difference in the radical formation rate by HRP was the key for yielding highly cross-linked protein polymers.


Enhancing Force Control of Prosthetic Controller for Hand Prosthesis by Mimicking Biological Properties.
Prosthetic hands are frequently rejected due to frustrations in daily uses. By adopting principles of human neuromuscular control, it could potentially achieve human-like compliance in hand functions, thereby improving functionality in prosthetic hand. Previous studies have confirmed the feasibility of real-time emulation of neuromuscular reflex for prosthetic control. This study further to explore the effect of feedforward electromyograph (EMG) decoding and proprioception on the biomimetic controller. The biomimetic controller included a feedforward Bayesian model for decoding alpha motor commands from stump EMG, a muscle model, and a closed-loop component with a model of muscle spindle modified with spiking afferents. Real-time control was enabled by neuromorphic hardware to accelerate evaluation of biologically inspired models. This allows us to investigate which aspects in the controller could benefit from biological properties for improvements on force control performance. 3 non-disabled and 3 amputee subjects were recruited to conduct a "press-without-break" task, subjects were required to press a transducer till the pressure stabilized in an expected range without breaking the virtual object. We tested whether introducing more complex but biomimetic models could enhance the task performance. Data showed that when replacing proportional feedback with the neuromorphic spindle, success rates of amputees increased by 12.2% and failures due to breakage decreased by 26.3%. More prominently, success rates increased by 55.5% and failures decreased by 79.3% when replacing a linear model of EMG with the Bayesian model in the feedforward EMG processing. Results suggest that mimicking biological properties in feedback and feedforward control may improve the manipulation of objects by amputees using prosthetic hands. Clinical and Translational Impact Statement: This control approach may eventually assist amputees to perform fine force control when using prosthetic hands, thereby improving the motor performance of amputees. It highlights the promising potential of the biomimetic controller integrating biological properties implemented on neuromorphic models as a viable approach for clinical application in prosthetic hands.


Walking abnormalities are associated with COPD: An investigation of the NHANES III dataset.
Research on the peripheral effects of COPD has focused on physiological and structural changes. However, different from muscular weakness or decreased physical activity, mechanical abnormalities of the muscular system, e.g. walking, have yet to be investigated. Our purpose was to utilize the National Health and Nutritional Examination Survey (NHANES) dataset to determine whether walking abnormalities are associated with COPD severity. To determine if walking abnormalities were independently associated with COPD severity, our analysis aimed to investigate the association of physical activity levels with COPD severity and with walking abnormalities. The NHANES III dataset that contains data for 31,000 persons that were collected from 1988 to 1994, was used to explore the association of COPD severity on gross walking abnormalities, i.e. limp, shuffle, etc. Logistic regression models were created using FEV(1)/FVC ratio, age, gender, BMI, and smoking status as predictors of walking abnormalities and physical activity in persons aged 40 to 90 years old. Results demonstrated a significant correlation between the presence of walking abnormalities and severe COPD (odds ratio: 1.97; 95% CI: 1.1 to 3.5). This suggests that disease severity can contribute to mechanical outcomes of patients with COPD. In addition, decreased physical activity levels were significantly associated with all COPD severity levels with the exception of mild COPD. The association between altered gait and COPD status may be due to the presence of physical inactivity that is present in patients with COPD. Future research directions should include investigating more closely the mechanical outcomes of persons with COPD.


An Open-Label Evaluator Blinded Study of the Efficacy and Safety of a New Nutritional Supplement in Androgenetic Alopecia: A Pilot Study.
Objective: To evaluate the effectiveness of a novel oral supplement, Forti5®, containing green tea extract, omega 3 and 6 fatty acids, cholecalciferol, melatonin, beta-sitosterol, and soy isoflavones, and in the management of subjects with androgenetic alopecia. Design: A prospective case series of 10 subjects. Setting: Open-label, evaluator-blinded, proof-of-concept study. Participants: Ten adult subjects with androgenetic alopecia completed the study. Subjects were not allowed to use oral or topical hair growth products in the 24 weeks preceding the study or during the study. The nutritional supplement was administered at a dosage of two tablets daily for 24 weeks. Measurements: Clinical evaluations were performed at baseline and at 24 weeks. Efficacy was evaluated using hair mass index measured by cross section trichometer, terminal hair count measured with dermoscopy and Investigator Global Photography Assessment. Results: Overall 80 percent of subjects (8/10) were rated as improved after 24 weeks of supplementation (mean change of +1.4 equivalent to slightly-to-moderately increased). Forty percent of subjects (4/10) were rated as moderately improved (2+), and 10 percent (1/10) were rated as greatly improved (3+). There was a significant improvement in terminal hair count (mean increase of 5.9% or 4.2 more terminal hairs in the area examined, p=0.014) and in Hair Mass Index (mean increase of 9.5% or 4.5 higher Hair Mass Index, p=0.003). Conclusion: These preliminary results indicate that Forti5® a novel nutritional supplement that contains cholecalciferol, omega 3 and 6 fatty acids, melatonin, antioxidants, and botanical 5-alpha reductase inhibitors, may be a useful adjunct in the treatment of androgenetic alopecia.


The modified outer membrane protein Amuc_1100 of Akkermansia muciniphila improves chronic stress-induced anxiety and depression-like behavior in mice.
Akkermansia muciniphila is a next-generation probiotic. The interaction between outer membrane protein Amuc_1100 of A. muciniphila and toll-like receptor 2 (TLR2) in intestinal epithelial cells influences the level of intestinal 5-hydroxytryptamine (5-HT). Amuc_1100Δ80 is a truncated form of Amuc_1100 lacking the first 80 N-terminal amino acids and has a higher affinity for TLR2 than the wild-type protein. Here, we report that Amuc_1100Δ80 could significantly reduce anxiety and depression-like behavior of mice when they were exposed to chronic unpredictable mild stress (CUMS). The experimental results of the rat insulinoma cell line RIN-14B showed that Amuc_1100Δ80 also induced a significantly higher upregulation of tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of intestinal 5-HT synthesis. The imbalance of the gut microflora could be diminished when CUMS mice were fed with Amuc_1100Δ80. These results reveal that Amuc_1100Δ80 could affect the 5-HT level and the downstream 5-HTR1A-CREB-BDNF signal pathway via interacting with TLR2 and by altering the gut microbial composition. In parallel, the downregulation exerted by Amuc_1100Δ80 on the inflammation and hyperactivated HPA axis was closely related to the improvement of depression-like symptoms in CUMS mice. This study not only provides new insights into the antidepressant effect of A. muciniphila and its outer membrane protein Amuc_1100 but also identifies new potential targets and pathways in the gut for future research and the development of antidepressant drugs.


Sp1-dependent regulation of PPARα in bone metabolism.
Successful repair and regeneration in bone tissue engineering vastly depends on proper interaction between the tissue-engineered construct and the recipient's immune system. In clinical application, adverse responses to bioartificial implants may result in chronic inflammation and loss of the implant. It is known that prolonged inflammation linked to NF-κB inflammatory pathways inhibits bone-forming activity of osteoblast cells. Contributing to orchestrate inflammatory processes, the ligand-activated transcription factor peroxisome proliferator-activated receptor alpha (PPARα) holds inhibitory effects on NF-κB and CEBβ activity. Sp1, a widely expressed transcription factor, has been linked to PPAR pathways, cellular homeostasis, and responsiveness to environmental perturbation. Formerly not being characterized, the role of PPARα in inflammatory-mediated bone loss requires further investigation. The aim of the present study was to identify regulatory transcription factor binding sites (TFBS) on the PPAR alpha promoter and to assess the role of Sp1 and associated proteins in its regulation. In a first set of experiments, polymerase chain reaction assessed the presence of PPARα gene expression in isolated murine bone tissue. Deletion mutagenesis was performed on the human PPARα (hPPARα) promoter gene, and the deletion constructs were transiently transfected to murine osteoblasts to identify important TFBS. PPARα promoter-driven reporter gene expression was monitored in response to overexpression and repression of Sp1 to analyze functional transcription factor recruitment to the PPARα promoter. This study could demonstrate that the full-length hPPARα promoter contains inhibiting promoter regions and that hPPARα basal expression can be significantly increased by deletion mutagensis. Sp1 TFBS proved functional in the regulation of PPARα promoter activity, and the first five Sp1 motifs on the PPARα promoter were sufficient to significantly increase PPARα expression. Additional transient co-transfection experiments could not detect any direct effect of NF-κB/IκB downstream pathway on the regulation of PPARα promoter activity. Taken together, we could demonstrate that Sp1 plays a key role in transcriptional regulation of PPARα promoter activity and gene expression. This study provides further insight on Sp1-dependent PPARα regulatory mechanisms and suggests that Sp1-regulated PPARα expression plays a key role in inflammatory mediated bone loss.


Healthy Eating Index-2015 Scores Vary by Types of Food Outlets in the United States.
Diet quality in the United States is improving over time but remains poor. Food outlets influence diet quality and represent the environments in which individuals make choices about food purchases and intake. The objective of this study was to use the Healthy Eating Index-2015 (HEI-2015) to evaluate the quality of foods consumed from the four major outlets where food is obtained-stores, full-service restaurants, quick-services restaurants, and schools-and to assess changes over time. This cross-sectional study used 24 h dietary recall data from eight cycles (2003-2004 to 2017-2018) of the National Health and Nutrition Examination Survey (NHANES). Linear trend estimation was used to test for changes in HEI scores over time, and balanced repeated replicate weighted linear regression was used to test for differences in total and component scores between types of food outlets. Overall, Americans are not consuming a mix of foods from any major category of food outlet that aligns with dietary guidelines. The total score for schools (65/100 points) and stores (62/100 points) was significantly higher than full-service (51/100 points) and quick-service (39/100 points) restaurants (p < 0.0001). HEI scores significantly improved over time for schools (p < 0.001), including an increase in whole grains from less than 1 point in 2003-2004 to 7 out of 10 points in 2017-2018. In 2017-2018, schools received the maximum score for total fruits, whole fruits, and dairy. Continued research on strategies for improving the quality of foods consumed from restaurants and stores is warranted.


Characteristics and composition of watermelon, pumpkin, and paprika seed oils and flours.
The nutritional quality and functional properties of paprika seed flour and seed kernel flours of pumpkin and watermelon were studied, as were the characteristics and structure of their seed oils. Paprika seed and seed kernels of pumpkin and watermelon were rich in oil and protein. All flour samples contained considerable amounts of P, K, Mg, Mn, and Ca. Paprika seed flour was superior to watermelon and pumpkin seed kernel flours in content of lysine and total essential amino acids. Oil samples had high amounts of unsaturated fatty acids with linoleic and oleic acids as the major acids. All oil samples fractionated into seven classes including triglycerides as a major lipid class. Data obtained for the oils' characteristics compare well with those of other edible oils. Antinutritional compounds such as stachyose, raffinose, verbascose, trypsin inhibitor, phytic acid, and tannins were detected in all flours. Pumpkin seed kernel flour had higher values of chemical score, essential amino acid index, and in vitro protein digestibility than the other flours examined. The first limiting amino acid was lysine for both watermelon and pumpkin seed kernel flours, but it was leucine in paprika seed flour. Protein solubility index, water and fat absorption capacities, emulsification properties, and foam stability were excellent in watermelon and pumpkin seed kernel flours and fairly good in paprika seed flour. Flour samples could be potentially added to food systems such as bakery products and ground meat formulations not only as a nutrient supplement but also as a functional agent in these formulations.


Spleen weight distribution in Ibadan and its relationship to disease.
The 5407 autopsies performed during an 8-year period formed the basis of the study; 2444 were infants and children, while 2963 were adults. The histogram of the spleen weight distribution has a fairly smooth contour with a positive skew towards the heavier spleens. The mean adult spleen weight was 271 g, and this was heavier than that of subjects in temperate climates, but comparable to the mean spleen weight of other localities in a holoendemic belt of malaria. The most frequent diagnosis at autopsy were diseases of the respiratory system, infective and parasitic diseases of which malaria is the most common, diseases of the digestive system and neoplasms. In those subjects with spleens weighing more than 500 g, neoplasms, diseases of the haematopoietic system and infectious and parasitic diseases were the most prominent. The role of environmental stimuli in a tropical environment in the hyperplasia of the reticuloendothelial system is discussed. The findings would prove useful in the differential diagnosis of large spleens found in this locality.


Biotic interactions shape trait assembly of marine communities across time and latitude.
Assembly processes are highly dynamic with biotic filters operating more intensely at local scales, yet the strength of biotic interactions can vary across time and latitude. Predation, for example, can be stronger at lower latitudes, while competition can intensify at later stages of assembly due to resource limitation. Since biotic filters act upon functional traits of organisms, we explored trait-mediated community assembly in diverse marine assemblages from four regions along the Pacific coast of North and Central America. Using predator exclusion experiments and two assembly stages, we tested the hypotheses that non-random trait patterns would emerge during late assembly at all regions due to competition and at lower latitude regions regardless of assembly stage due to predation. As expected, trait divergence occurred in late assembly but only at higher latitude regions, while in tropical Panama, relaxed predation caused trait divergence during late assembly. Moreover, colonizing trait strategies were common during early assembly while competitive strategies were favoured during late assembly at higher latitude regions. Predation-resistant traits were only favoured in Panama during both assembly stages. Our large-scale manipulative study demonstrates that different biotic interactions across time and latitude can have important consequences for trait assembly.


The SLC2A14 gene, encoding the novel glucose/dehydroascorbate transporter GLUT14, is associated with inflammatory bowel disease.
Background: Variations in intestinal antioxidant membrane transporters are implicated in the initiation and progression of inflammatory bowel disease (IBD). Facilitated glucose transporter member 14 (GLUT14), encoded by the solute carrier family 2 member 14 (SLC2A14) gene, is a putative transporter for dehydroascorbic acid and glucose. Although information on the gene is limited, shorter and longer GLUT14 isoforms have been identified. We hypothesized that GLUT14 mediates glucose and dehydroascorbic acid uptake. If this function could be validated, then genetic variations may associate with IBD.Objective: This study aimed to determine the substrate(s) for the GLUT14 protein and interrogated genetic associations of SLC2A14 with IBD.Design: The uptake of radiolabeled substrates into Xenopus laevis oocytes expressing the 2 GLUT14 isoforms was assessed. Examination of gene-targeted genetic association in the Manitoba Inflammatory Bowel Disease Cohort Study was conducted through the genotyping of single nucleotide polymorphisms (SNPs) representing linkage blocks of the SLC2A14 gene.Results: Both GLUT14 isoforms mediated the uptake of dehydroascorbic acid and glucose into X. laevis oocytes. Three alleles in the SLC2A14 gene associated independently with IBD. The odds of having ulcerative colitis (UC) or Crohn disease (CD) were elevated in carriers of the SLC2A14 SNP rs2889504-T allele (OR: 3.60; 95% CI: 1.95, 6.64 and OR: 4.68; 95% CI: 2.78, 8.50, respectively). Similarly, the SNP rs10846086-G allele was associated with an increased risk of both UC and CD (OR: 2.91; 95% CI: 1.49, 5.68 and OR: 3.00; 95% CI: 1.55, 5.78, respectively). Moreover, the SNP rs12815313-T allele associated with increased susceptibility to CD and UC (OR: 2.12; 95% CI: 1.33, 3.36 and OR: 1.61; 95% CI: 1.01, 2.57, respectively).Conclusion: These findings strengthen the hypothesis that genetically determined local dysregulation of dietary vitamin C or antioxidants transport contributes to IBD development. These transporter proteins are targetable by dietary interventions, opening the avenue to a precision intervention for patients of specific genotypes with IBD. This trial was registered at clinicaltrials.gov as NCT03262649.


The glycosylation of IgA produced by murine B cells is altered by Th2 cytokines.
We sought to determine whether selected cytokines, known to profoundly increase proliferation and/or production of Ig by B cells and their progeny, also have as yet unrecognized effects upon IgA glycosylation. For these studies, we selected CH12LX mouse B lymphoma cells, a widely used model of B cell differentiation. Glycosylation was assessed by detection with enzyme-lectin conjugates in an immunoabsorption assay and verified by profiling and sequencing of the N-linked oligosaccharides. Stimulation of B cells with IL-4 plus IL-5 significantly alters the terminal glycosylation of secreted IgA, whereas LPS has a minor effect, despite the fact that both stimuli are equipotent at inducing Ig class switching and Ig secretion. Moreover, the alteration in terminal glycosylation was more profound on IgA secreted from surface IgM+ than from surface IgA+ CH12LX cells. These results suggest that the increased production of IL-4 and IL-5 by peripheral blood lymphocytes from IgA nephropathy patients might result in the production of abnormally glycosylated IgA. In turn, this abnormally glycosylated IgA may promote deposition of IgA in glomeruli in this disease.


Association of Leptin Gene DNA Methylation With Diagnosis and Treatment Outcome of Anorexia Nervosa.
Epigenetic alterations are increasingly implicated in the pathophysiology of anorexia nervosa (AN) but are as yet poorly understood. We investigated possible associations between the leptin gene (LEP) and the leptin receptor gene (LEPR) DNA promoter methylation and (1) a diagnosis of AN and (2) outcome after a 10 months psychotherapeutic outpatient treatment. 129 (LEPR: n = 135) patients with AN were investigated during the large scale psychotherapeutic Anorexia Nervosa Treatment Outpatient Study (ANTOP) trial, compared to 117 (LEPR: n = 119) age and height matched, normal-weight healthy controls. Blood samples were taken at baseline, the end of therapy (40 weeks) and the 12-months follow-up and compared to controls. Methylation was measured in whole blood via bisulfite sequencing. Within the promoter region 32 (LEP) and 39 CpG sites (LEPR) were analyzed. Two key findings were observed. First, LEP and LEPR methylation at baseline were lower in patients compared to controls (LEP: [%] AN: 30.94 ± 13.2 vs. controls: 34.53 ± 14.6); LEPR ([%] AN: 3.73 ± 5.4 vs. controls: 5.22 ± 8.3, mixed linear models: both P < 0.001). Second, lower DNA methylation of the LEP promoter, with a dynamic upregulation during treatment, was associated with a full recovery in AN patients (% change from baseline to follow-up in full recovery patients: +35.13% (SD: 47.56); mixed linear model: P < 0.0001). To test for potential predictive properties of mean LEP DNA methylation a LEP DNA methylation cut-off (31.25% DNA methylation) was calculated, which significantly discriminated full recovery vs. full syndrome AN patients. This cut-off was then tested in a group of previously unclassified patients (missing follow-up data of the Structured Interview for Anorexic and Bulimic disorders; n = 33). Patients below the cut-off (31.25% LEP DNA methylation) showed an increase in BMI over time, while those above the cut-off had a decrease in BMI (ANOVA at the 12-months follow-up: P = 0.0142). To our knowledge, this is the first study investigating epigenetic alterations in AN over time. Our findings indicate that LEP DNA methylation might be involved in the disease course of AN.


Reduction in Clostridium difficile infection rates after mandatory hospital public reporting: findings from a longitudinal cohort study in Canada.
The role of public reporting in improving hospital quality of care is controversial. Reporting of hospital-acquired infection rates has been introduced in multiple health care systems, but its relationship to infection rates has been understudied. Our objective was to determine whether mandatory public reporting by hospitals is associated with a reduction in hospital rates of Clostridium difficile infection. We conducted a longitudinal, population-based cohort study in Ontario (Canada's largest province) between April 1, 2002, and March 31, 2010. We included all patients (>1 y old) admitted to 180 acute care hospitals. Using Poisson regression, we developed a model to predict hospital- and age-specific monthly rates of C. difficile disease per 10,000 patient-days prior to introduction of public reporting on September 1, 2008. We then compared observed monthly rates of C. difficile infection in the post-intervention period with rates predicted by the pre-intervention predictive model. In the pre-intervention period there were 33,634 cases of C. difficile infection during 39,221,113 hospital days, with rates increasing from 7.01 per 10,000 patient-days in 2002 to 10.79 in 2007. In the first calendar year after the introduction of public reporting, there was a decline in observed rates of C. difficile colitis in Ontario to 8.92 cases per 10,000 patient-days, which was significantly lower than the predicted rate of 12.16 (95% CI 11.35-13.04) cases per 10,000 patient-days (p<0.001). Over this period, public reporting was associated with a 26.7% (95% CI 21.4%-31.6%) reduction in C. difficile cases, or a projected 1,970 cases averted per year (95% CI 1,476-2,500). The effect was specific to C. difficile, with rates of community-acquired gastrointestinal infections and urinary tract infections unchanged. A limitation of our study is that this observational study design cannot rule out the influence of unmeasured temporal confounders. Public reporting of hospital C. difficile rates was associated with a substantial reduction in the population burden of this infection. Future research will be required to discern the direct mechanism by which C. difficile infection rates may have been reduced in response to public reporting. Please see later in the article for the Editors' Summary.


Assessing the effects of quantitative host resistance on the life-history traits of sporulating parasites with growing lesions.
Assessing life-history traits of parasites on resistant hosts is crucial in evolutionary ecology. In the particular case of sporulating pathogens with growing lesions, phenotyping is difficult because one needs to disentangle properly pathogen spread from sporulation. By considering Phytophthora infestans on potato, we use mathematical modelling to tackle this issue and refine the assessment of pathogen response to quantitative host resistance. We elaborate a parsimonious leaf-scale model by convolving a lesion growth model and a sporulation function, after a latency period. This model is fitted to data obtained on two isolates inoculated on three cultivars with contrasted resistance level. Our results confirm a significant host-pathogen interaction on the various estimated traits, and a reduction of both pathogen spread and spore production, induced by host resistance. Most interestingly, we highlight that quantitative resistance also changes the sporulation function, the mode of which is significantly time-lagged. This alteration of the infectious period distribution on resistant hosts may have strong impacts on the dynamics of parasite populations, and should be considered when assessing the durability of disease control tactics based on plant resistance management. This inter-disciplinary work also supports the relevance of mechanistic models for analysing phenotypic data of plant-pathogen interactions.


Green tea consumption and mortality in Japanese men and women: a pooled analysis of eight population-based cohort studies in Japan.
The aim of our study was to assess the association between green tea consumption and all-cause and cause-specific mortality in a pooled analysis of eight Japanese population-based cohort studies. Pooled hazard ratios (HR) and 95% confidence intervals (CI), derived from random effects models, were used to evaluate the associations between green tea consumption, based on self-report at baseline, and risk of all-cause and cause-specific mortality. During a mean follow-up of 17.3 years, among 313,381 persons, 52,943 deaths occurred. Compared with individuals who consumed < 1 cup/day, those in the highest consumption category (≥ 5 cups/day) had a decreased risk of all-cause mortality [the multivariate-adjusted HR was 0.90 (95% CI 0.87-0.94) for men and 0.82 (0.74-0.90) for women]. A similar inverse association was observed for heart disease mortality [HR 0.82 (0.75-0.90) for men, and 0.75 (0.68-0.84) for women], and cerebrovascular disease mortality [HR 0.76 (0.68-0.85) for men, and 0.78 (0.68-0.89) for women]. Among women, green tea consumption was associated with decreased risk of total cancer mortality: 0.89 (0.83-0.96) for the 1-2 cups/day category and 0.91 (0.85-0.98) for the 3-4 cups/day category. Results for respiratory disease mortality were [HR 0.75 (0.61-0.94)] among 3-4 cup daily consumers and [HR 0.66 (0.55-0.79)] for ≥ 5 cups/day. Higher consumption of green tea is associated with lower risk for all-cause mortality in Japanese, especially for heart and cerebrovascular disease. Moderate consumption decreased the risk of total cancer and respiratory disease mortality in women.


Emerging therapeutic options for celiac disease: potential alternatives to a gluten-free diet.
Celiac disease is an autoimmune disorder of the small intestine that is more common than was previously thought. This disease is caused by an inappropriate immune response to wheat gluten, barley, and rye. Three main pathways cause celiac disease: the environmental trigger (gluten), genetic susceptibility, and unusual gut permeability. The only treatment currently available is a strict gluten-free diet. Unfortunately, a majority of patients have difficulty complying with this diet, and the response to therapy is poor. Therefore, alternative treatments are being developed, and new insights into the pathophysiology of celiac disease have led to research into novel therapies. New treatments include engineering gluten-free grains, decreasing intestinal permeability by blockage of the epithelial zonulin receptor, inducing oral tolerance to gluten with a therapeutic vaccine, and degrading immunodominant gliadin peptides using probiotics with endopeptidases or transglutaminase inhibitors. These nondiet-based therapies provide hope for enhanced, lifelong celiac disease management with improved patient compliance and better quality of life.


2 GHz passively harmonic mode-locked fiber laser by a microfiber-based topological insulator saturable absorber.
We report on the generation of passive harmonic mode locking of a fiber laser using a microfiber-based topological insulator (TI) Bi(2)Te(3) saturable absorber (SA). The optical deposition method was employed to fabricate the microfiber-based TISA. By virtue of the excellent nonlinear optical property of the proposed TISA, the fiber laser could operate at the pulse repetition rate of 2.04 GHz under a pump power of 126 mW, corresponding to the 418th harmonic of fundamental repetition frequency. The results demonstrate that the microfiber-based TI photonic device can operate as both the high nonlinear optical component and the SA in fiber lasers, and could also find other applications in the related fields of photonics.


Rhabdoid glioblastoma is distinguishable from classical glioblastoma by cytogenetics and molecular genetics.
The clinicopathologic and molecular genetic features of 5 cases of rhabdoid glioblastoma, an extremely rare variant of glioblastoma that tends to affect patients at a young age, were investigated by immunohistochemical analysis and focused molecular genetic studies including array-based comparative genomic hybridization. All 5 cases had supratentorial tumors that immunohistochemical analysis revealed to be robustly positive for epithelial membrane antigen, vimentin, p53, and PDGFRα (platelet-derived growth factor receptor, alpha polypeptide) but only focally positive for glial fibrillary acidic protein. Although complete retention of SMARCB1 (INI1) was observed in all 5 cases, epidermal growth factor receptor (EGFR) amplification, PTEN (phosphatase and tensin homolog) loss, homozygous deletion of cyclin-dependent kinase inhibitor 2A, 1p/19q codeletion, and isocitrate dehydrogenase 1 R132/IDH2 R172 mutation were not observed in any case, although a high level of EGFR polysomy was detected in 1 recurrent tumor. Although c-MET (MET protein) expression was focal but robustly positive in 3 cases, met proto-oncogene (MET) fluorescence in situ hybridization revealed low polysomy but not MET amplification. MGMT (O-6-methylguanine-DNA methyl-40 transferase) methylation-specific polymerase chain reaction revealed MGMT methylation in only 1 case. Furthermore, array-based comparative genomic hybridization revealed gain of chromosome 7 and loss of 1p, 6, 8p, 11, 13q, and 18q but no deletion of chromosome 22. In contrast to the classical subtype of primary glioblastoma, the cases studied here were characterized by the absence of EGFR amplification, PTEN loss, and 9p homozygous deletion and overexpression of p53, PDGFRα, and c-MET, suggesting that they can be classified as the proneural or mesenchymal subtype of glioblastoma and benefit from intensive therapy that includes temozolomide.


Selective Sweep at a QTL in a Randomly Fluctuating Environment.
Adaptation is mediated by phenotypic traits that are often near continuous, and undergo selective pressures that may change with the environment. The dynamics of allelic frequencies at underlying quantitative trait loci (QTL) depend on their own phenotypic effects, but also possibly on other polymorphic loci affecting the same trait, and on environmental change driving phenotypic selection. Most environments include a substantial component of random noise, characterized both by its magnitude and its temporal autocorrelation, which sets the timescale of environmental predictability. I investigate the dynamics of a mutation affecting a quantitative trait in an autocorrelated stochastic environment that causes random fluctuations of an optimum phenotype. The trait under selection may also exhibit background polygenic variance caused by many polymorphic loci of small effects elsewhere in the genome. In addition, the mutation at the QTL may affect phenotypic plasticity, the phenotypic response of given genotype to its environment of development or expression. Stochastic environmental fluctuations increase the variance of the evolutionary process, with consequences for the probability of a complete sweep at the QTL. Background polygenic variation critically alters this process, by setting an upper limit to stochastic variance of population genetics at the QTL. For a plasticity QTL, stochastic fluctuations also influences the expected selection coefficient, and alleles with the same expected trajectory can have very different stochastic variances. Finally, a mutation may be favored through its effect on plasticity despite causing a systematic mismatch with optimum, which is compensated by evolution of the mean background phenotype.


Identification of Claudin-6 as a Molecular Biomarker in Pan-Cancer Through Multiple Omics Integrative Analysis.
Claudin-6 (CLDN6) is one of the 27 family members of claudins and majorly involved in the tight junction and cell-to-cell adhesion of epithelial cell sheets, playing a significant role in cancer initiation and progression. To provide a more systematic and comprehensive dimension of identifying the diverse significance of CLDN6 in a variety of malignant tumors, we explored CLDN6 through multiple omics data integrative analysis, including gene expression level in pan-cancer and comparison of CLDN6 expression in different molecular subtypes and immune subtypes of pan-cancer, targeted protein, biological functions, molecular signatures, diagnostic value, and prognostic value in pan-cancer. Furthermore, we focused on uterine corpus endometrial carcinoma (UCEC) and further investigated CLDN6 from the perspective of the correlations with clinical characteristics, prognosis in different clinical subgroups, co-expression genes, and differentially expressed genes (DEGs), basing on discussing the validation of its established monoclonal antibody by immunohistochemical staining and semi-quantification reported in the previous study. As a result, CLDN6 expression differs significantly not only in most cancers but also in different molecular and immune subtypes of cancers. Besides, high accuracy in predicting cancers and notable correlations with prognosis of certain cancers suggest that CLDN6 might be a potential diagnostic and prognostic biomarker of cancers. Additionally, CLDN6 is identified to be significantly correlated with age, stage, weight, histological type, histologic grade, and menopause status in UCEC. Moreover, CLDN6 high expression can lead to a worse overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) in UCEC, especially in different clinical subgroups of UCEC. Taken together, CLDN6 may be a remarkable molecular biomarker for diagnosis and prognosis in pan-cancer and an independent prognostic risk factor of UCEC, presenting to be a promising molecular target for cancer therapy.


Resource allocation and rationing in nursing care: A discussion paper.
Driven by interests in workforce planning and patient safety, a growing body of literature has begun to identify the reality and the prevalence of missed nursing care, also specified as care left undone, rationed care or unfinished care. Empirical studies and conceptual considerations have focused on structural issues such as staffing, as well as on outcome issues - missed care/unfinished care. Philosophical and ethical aspects of unfinished care are largely unexplored. Thus, while internationally studies highlight instances of covert rationing/missed care/care left undone - suggesting that nurses, in certain contexts, are actively engaged in rationing care - in terms of the nursing and nursing ethics literature, there appears to be a dearth of explicit decision-making frameworks within which to consider rationing of nursing care. In reality, the assumption of policy makers and health service managers is that nurses will continue to provide full care - despite reducing staffing levels and increased patient turnover, dependency and complexity of care. Often, it would appear that rationing/missed care/nursing care left undone is a direct response to overwhelming demands on the nursing resource in specific contexts. A discussion of resource allocation and rationing in nursing therefore seems timely. The aim of this discussion paper is to consider the ethical dimension of issues of resource allocation and rationing as they relate to nursing care and the distribution of the nursing resource.


DNA vaccination with glutamic acid decarboxylase (GAD) generates a strong humoral immune response in BALB/c, C57BL/6, and in diabetes-prone NOD mice.
The technique of DNA-based vaccination was used to generate a T-cell-dependent antibody response to glutamic acid decarboxylase (GAD) in BALB/c, C57BL/6, and non-obese diabetic (NOD) mice. Plasmids were constructed in which the expression of the rat GAD65 (rGAD65) or the rat GAD67 (rGAD67) gene was driven by the immediate early region promoter of the human cytomegalovirus (pCMV). This "naked" plasmid DNA was then injected into the regenerating muscles of the studied mice. In the vaccinated animals, antibody responses to GAD65 or to GAD67 were induced. Epitope recognition of GAD was studied by protein footprinting, a technique which makes use of a limited proteolysis of antibody-bound antigen. Different epitope recognition patterns were found, corresponding to strain-specific patterns. Mild trypsin treatment generated 50 kD, 46 kD, 40 kD, 30 kD, and 21 kD proteolytic fragments. In NOD mice, 50, 46 and 40 kD bands were the most prominent signals. In non-diabetes prone BALB/c mice, a faint 40 kD band appeared suggesting a rather weak protection of GAD from tryptic lysis. The pattern observed in C57BL/6 mice was more comparable to the NOD mice pattern with prominent 40 kD and 30 kD signals and a faint 21 kD fragment. Diabetes incidence was unchanged in NOD mice, and no diabetes was observed in C57BL/6 and BALB/c mice, respectively. The data demonstrate that genetic immunization is a suitable novel tool to stimulate and to manipulate an immune response against the diabetes-associated protein glutamic acid decarboxylase. Interestingly, our results indicate that, by genetic vaccination, distinct B-cell epitopes were generated in the various studied mouse strains.


Inhibition of potentially pathogenic yeastlike fungi by clotrimazole in combination with 5-fluorocytosine or amphotericin B.
Clotrimazole (CTM) has a doubtful future with respect to use in treatment of the systemic mycoses. To assess the potential of CTM in combined drug regimens, antifungal effects of CTM together with 5-fluorocytosine (5-FC) or amphotericin B (AMB) were tested in a synthetic liquid medium against Candida albicans, Candida tropicalis, and Torulopsis glabrata. Viable counts were monitored over a 48-h incubation period. Weak inhibitory concentrations of CTM were tested in combination with levels of 5-FC or AMB that alone produced transient antifungal effects followed by rapid recovery of proliferative capacity. Results were similar for each of the organisms studied. Between 24 and 48 h, when cultures containing 5-FC or AMB alone were in the recovery phase, CTM plus 5-FC and CTM plus AMB continued to markedly suppress cell multiplication. It would appear that weak inhibitory concentrations of CTM can act together with 5-FC or AMB to produce antifungal effects greater than that obtained with either of the latter two drugs alone.


Sinapic acid ester metabolism in wild type and a sinapoylglucose-accumulating mutant of arabidopsis.
Sinapoylmalate is one of the major phenylpropanoid metabolites that is accumulated in the vegetative tissue of Arabidopsis thaliana. A thin-layer chromatography-based mutant screen identified two allelic mutant lines that accumulated sinapoylglucose in their leaves in place of sinapoylmalate. Both mutations were found to be recessive and segregated as single Mendelian genes. These mutants define a new locus called SNG1 for sinapoylglucose accumulator. Plants that are homozygous for the sng1 mutation accumulate normal levels of malate in their leaves but lack detectable levels of the final enzyme in sinapate ester biosynthesis, sinapoylglucose:malate sinapoyltransferase. A study of wild-type and sng1 seedlings found that sinapic acid ester biosynthesis in Arabidopsis is developmentally regulated and that the accumulation of sinapate esters is delayed in sng1 mutant seedlings.


Inhibition of invasion and metastasis by DMBT, a novel trehalose derivative, through Akt/GSK-3β/β-catenin pathway in B16BL6 cells.
Invasion, either directly or via metastasis formation, is the main cause of death in cancer patients. Development of efficient anti-invasive agents is an important research challenge. 6,6'-bis (2,3-dimethoxybenzoyl)-a, a-d-trehalose (DMBT), one of brartemicin analogs, was found to be the most potent anti-invasive agent, but the underlying mechanisms are poorly understood. Our current study was to explore the effects of DMBT on invasion and metastasis in B16BL6 cells. Antiproliferation assay and trypan blue exclusion assay showed that no obvious inhibitory or cytotoxic effect of DMBT was found in B16BL6 cells. Wound healing demonstrated that DMBT could inhibit cell migration compared with the normal group. Transwell experiments showed that DMBT could significantly inhibit invasion to the reconstituted basement membrane (P<0.01). We examined the effects of lung metastasis produced by highly metastatic B16BL6 melanoma cells by using experimental metastasis models and BLI analysis. DMBT could significantly suppress lung metastasis in mice. Results from immunohistochemical staining, Western blotting and real-time PCR indicated that the chemopreventive effect of DMBT was attributed to the inhibition of the VEGF and MMP-9 through Akt/GSK-3β/β-catenin and Akt/mTOR signaling pathways. These results suggested that DMBT could be a promising lead molecule for the anti-metastasis and serve as a therapeutic agent to inhibit cancer cell invasion and metastasis.


Managing Clopidogrel Hypersensitivity without Interrupting Therapy: The Toronto Approach.
Clopidogrel remains a widely used antiplatelet agent for patients with established or high risk of atherothrombotic disease, particularly those treated with coronary, carotid or peripheral endovascular stenting. Clopidogrel hypersensitivity is an uncommon but well established adverse drug reaction presenting a challenge for patient management. The clinical presentation ranges from focal or diffuse cutaneous manifestations in most patients to angioedema in some and a systemic immune response in rare cases. The treatment options include drug discontinuation with or without desensitization therapy, switching to alternate ADP receptor antagonists or administration of oral steroids while continuing clopidogrel in patients at high risk of adverse events with clopidogrel discontinuation. In this review the author describes the phenomenon of clopidogrel hypersensitivity, various treatment strategies.


[Comprehensive study of the iris in transformed light in simple glaucoma].
Complex examination of the iris under light transformed by various methods - iridochromoscopy with iridochromophotography, transillumination in red light, and fluorescein angiography - was performed on 26 eyes of patients with simple glaucoma and 24 normal eyes of subjects aged between 42 and 76 years. All the methods employed revealed iris changes in 100% of the simple glaucoma cases. The differences found between the study group and the controls were significant (P = 0.01). A highly positive correlation was found between the results of iris fluorescein angiography and iridochromoscopy with iridochromophotography (r = 0.932; P = 0.0005), as well as between the results of iris fluorescein angiography and transillumination in red light (r = 0.921; P = 0.0005). Complex examination of the iris under transformed light showed the most typical changes in simple glaucoma to be exogenous pigmentation of the pupillary and ciliary regions, partial or complete destruction of the pupillary margin, and stromal atrophy affecting the pupil or the entire iris. Defects and thinning of the posterior iris pigment layer, iris vessel permeability disorders associated with hypoperfusion and microneovascularization in the lesser circle and the ciliary region were also found.


Epidemiology of Femur Fractures in Children: A Descriptive Cross Sectional Study Based on a Rural Population of Nepal.
Femur fracture in children is one of the most common lower limb fractures which require inpatient care. The aim of this study is to determine the epidemiology of femoral shaft fractures in children from a rural population of Karnali Nepal. Hospital records were retrospectively reviewed from May 2017 to April 2020 to identify all the children with femur fracture. Sociodemographic profile, mode of injury, fracture pattern and location, time of presentation, initial treatment by traditional bone setters, treatment method and duration of hospital stay were noted. Data analysis was done using Statistical Package for Social Sciences version 20. Altogether 104 children were identified. The mean age was 5.55 years and boys predominated 65 (62.5%). Falls were the major mode of injury in 65 (62.4%) patients. Fractures were frequently noted between April 15 to August 15. There were four (3.8%) open fractures and concurrent fracture observed in eight (7.6%) patients. Ten (9.6%) children received prior treatment from traditional bonesetters. Treatment methods included hip spica 62 (59.6%), elastic intramedullary nailing 30 (28.8%) and plate fixation 12 (11.5%). The duration of hospital stay in the nailing and plate fixation group was 11.43 days and 18 days respectively. Fracture was common in 2-6 years of age group in boys during summer. Fall from cliff, rooftop and ladder were the major preventable cause of fracture. Delayed presentation and prior treatment with traditional bone setters add special challenges to orthopedic surgeons working in rural teaching hospital.


Are the antioxidant properties of carvedilol important for the protection of cardiac mitochondria?
The cellular role of mitochondria includes ATP generation and the modulation of cytosolic calcium signals, besides being the "crossroads" for several cell death pathways. The maintenance of optimal mitochondrial functioning during the disease process increases the chances for survival. For example, ischaemia followed by reperfusion is known to negatively affect mitochondrial function, namely by inducing a deleterious condition called mitochondrial permeability transition (MPT). The MPT is responsible for mitochondrial dysfunction and can ultimately lead to cell death. Therefore, it seems important to protect mitochondrial function in cardiac disease. Carvedilol, a beta-adrenergic receptor antagonist with antioxidant properties, has a positive impact on cardiac mitochondria during in vitro, ex-vivo and in vivo models of cardiac dysfunction. Particularly, carvedilol was shown to inhibit MPT in isolated heart mitochondria and protect mitochondria against the oxidative damage induced by the xanthine oxidase/hypoxanthine pro-oxidant system. The observation that carvedilol acts as an inhibitor of mitochondrial complex-I is also of importance, since this mitochondrial system was proposed as cause of the cardiotoxicity associated with the anti-neoplasic drug doxorubicin. This review points out the major findings concerning the positive impact of carvedilol on mitochondrial function and its use in the treatment of myocardial diseases where oxidative stress is known to be involved.


Hypnosis in Treatment of Stomatodynia: Preliminary Retrospective Study of 12 Cases.
Stomatodynia is an oral dysesthesia with a psychosomatic component. Twelve consecutive patients with stomatodynia were offered hypnosis sessions. Measures of anxiety, depression, and pain were administered before the first and after the last hypnosis session. Pain severity was assessed with a Numeric Rating Scale (NRS). Anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS). The data were collected retrospectively from medical records on the 12 patients. The difference between NRS pain ratings and HADS scores before and after hypnosis was significant (p < .05). Six patients reported receiving treatment for stomatodynia before hypnotherapy; 3 of them stopped treatment for stomatodynia before completion of the hypnosis intervention. Results provide support for potential positive effects of hypnosis intervention for stomatodynia and point to the need for additional research on this issue.


Glucagon-like peptide-1 regulates brown adipose tissue thermogenesis via the gut-brain axis in rats.
Endogenous intestinal glucagon-like peptide-1 (GLP-1) controls satiation and glucose metabolism via vagal afferent neurons (VANs). Recently, VANs have received increasing attention for their role in brown adipose tissue (BAT) thermogenesis. It is, however, unclear whether VAN GLP-1 receptor (GLP-1R) signaling affects BAT thermogenesis and energy expenditure (EE) and whether this VAN mechanism contributes to energy balance. First, we tested the effect of the GLP-1R agonist exendin-4 (Ex4, 0.3 μg/kg ip) on EE and BAT thermogenesis and whether these effects require VAN GLP-1R signaling using a rat model with a selective Glp1r knockdown (kd) in VANs. Second, we examined the role of VAN GLP-1R in energy balance during chronic high-fat diet (HFD) feeding in VAN Glp1r kd rats. Finally, we used viral transsynaptic tracers to identify the possible neuronal substrates of such a gut-BAT interaction. VAN Glp1r kd attenuated the acute suppressive effects of Ex4 on EE and BAT thermogenesis. Consistent with this finding, the VAN Glp1r kd increased EE and BAT activity, diminished body weight gain, and improved insulin sensitivity compared with HFD-fed controls. Anterograde transsynaptic viral tracing of VANs infected major hypothalamic and hindbrain areas involved in BAT sympathetic regulation. Moreover, retrograde tracing from BAT combined with laser capture microdissection revealed that a population of VANs expressing Glp1r is synaptically connected to the BAT. Our findings reveal a novel role of VAN GLP-1R signaling in the regulation of EE and BAT thermogenesis and imply that through this gut-brain-BAT connection, intestinal GLP-1 plays a role in HFD-induced metabolic syndrome.


Incidence of misdiagnosed and unsuspected choroidal melanomas. A 50-year experience.
The eye pathology files at Ohio State University, Columbus, were examined for a 50-year period to determine the percentage of misdiagnosis of uveal melanomas in three separate time periods (1931 through 1959, 1960 through 1969, and 1970 through 1981) and the percentage of unsuspected melanomas during these same periods. Of 395 eyes enucleated for choroidal melanoma, 369 had clear media. Histologic examination of these eyes showed that 13 (3.5%) did not contain a melanoma. The incidence of misdiagnosis decreased from 10.9% in 1931 through 1959 to 1.7% in 1960 through 1981. Of 411 choroidal melanomas present on histologic examination, 37 (9%) were unsuspected. All had opaque media. This percentage, when categorized by the aforementioned periods, decreased from 19.6% to 13.3% to 2.4%, respectively. These results confirm the reliability of indirect ophthalmoscopy, widely used since the 1960s, in the diagnosis of melanoma in the presence of clear media and the reliability of ultrasonography, used since 1970, in the diagnosis of melanoma in eyes with opaque media.


Clumsiness and disturbed cerebellar development: insights from animal experiments.
Cerebellar functioning has been implied in the fine adjustments of muscle tone, in the coordination and the feed-forward control of movements and posture, as well as in the establishment and performance of motor skills. The cerebellar cortex in mammals develops late in neuro-ontogeny and an extrapolation from experimental results indicates that in the human the proliferation of the granule cells and the development of circuitry in the cerebellar cortex starts only in the last trimester of pregnancy and lasts until beyond the first birthday. This late development makes the cerebellar development particularly vulnerable to situations like an insufficient supply of nutrients, which may follow placental dysfunction, or to side effects of pharmacological treatments like the administration of corticosteroids in the postnatal period. We studied whether such situations might also lead to motor impairments. In rats, the effects of undernutrition during the brain growth spurt were investigated as well as those of corticosteroids administered in a period that is analogous to the 7th to 8th month of pregnancy in the human. Both these interferences affect cerebellar development and our results in rats indicate that they also lead to retardations in the emergence of certain reflexes, as well as to longer lasting motor impairments during locomotion. Extrapolation of these results strongly suggests that a disturbed cerebellar development should be considered as an important etiological factor in clumsiness in human children.


Ethics in Health Informatics.
Contemporary bioethics was fledged and is sustained by challenges posed by new technologies. These technologies have affected many lives. Yet health informatics affects more lives than any of them. The challenges include the development and the appropriate uses and users of machine learning software, the balancing of privacy rights against the needs of public health and clinical practice in a time of Big Data analytics, whether and how to use this technology, and the role of ethics and standards in health policy. Historical antecedents in statistics and evidence-based practice foreshadow some of the difficulties now faced, but the scope and scale of these challenges requires that ethics, too, be brought to scale in parallel, especially given the size of contemporary data sets and the processing power of new computers. Fortunately, applied ethics affords a variety of tools to help identify and rank applicable values, support best practices, and contribute to standards. The bioethics community can in partnership with the informatics community arrive at policies that promote the health sciences while reaffirming the many and varied rights that patients expect will be honored.


Finite-difference time-domain simulation of spacetime cloak.
In this work, we present a numerical method that remedies the instabilities of the conventional FDTD approach for solving Maxwell's equations in a space-time dependent magneto-electric medium with direct application to the simulation of the recently proposed spacetime cloak. We utilize a dual grid FDTD method overlapped in the time domain to provide a stable approach for the simulation of a magneto-electric medium with time and space varying permittivity, permeability and coupling coefficient. The developed method can be applied to explore other new physical possibilities offered by spacetime cloaking, metamaterials, and transformation optics.


Current challenges for clinical trials of cardiovascular medical devices.
Several features of cardiovascular devices raise considerations for clinical trial conduct. Prospective, randomized, controlled trials remain the highest quality evidence for safety and effectiveness assessments, but, for instance, blinding may be challenging. In order to avoid bias and not confound data interpretation, the use of objective endpoints and blinding patients, study staff, core labs, and clinical endpoint committees to treatment assignment are helpful approaches. Anticipation of potential bias should be considered and planned for prospectively in a cardiovascular device trial. Prospective, single-arm studies (often referred to as registry studies) can provide additional data in some cases. They are subject to selection bias even when carefully designed; thus, they are generally not acceptable as the sole basis for pre-market approval of high risk cardiovascular devices. However, they complement the evidence base and fill the gaps unanswered by randomized trials. Registry studies present device safety and effectiveness in day-to-day clinical practice settings and detect rare adverse events in the post-market period. No single research design will be appropriate for every cardiovascular device or target patient population. The type of trial, appropriate control group, and optimal length of follow-up will depend on the specific device, its potential clinical benefits, the target patient population and the existence (or lack) of effective therapies, and its anticipated risks. Continued efforts on the part of investigators, the device industry, and government regulators are needed to reach the optimal approach for evaluating the safety and performance of innovative devices for the treatment of cardiovascular disease.


Removal of petroleum hydrocarbons from contaminated groundwater by the combined technique of adsorption onto perlite followed by the O3/H2O2 process.
Groundwater contaminated with petroleum hydrocarbons was treated using a combined system of adsorption onto powdered expanded perlite (PEP) followed by the O3/H2O2 process. The pretreatment investigations indicated a high capacity for PEP to remove petroleum hydrocarbons from the contaminated water. An experimental total petroleum hydrocarbon (TPH) adsorption capacity of 275 mg/g PEP was obtained at the natural pH of water. The experimental data fit best with the Freundlich isotherm model and pseudo-second-order adsorption model. The second phase of the experiment evaluated the performance of the O3/H2O2 process in the removal of residual TPH from pretreated water and compared the results with that of raw water. The O3/H202 process attained a maximum TPH removal rate for the pretreated water after 70 min, when 93% of the residual TPH in the effluent of the adsorption system was removed. Overall, the combination of adsorption onto PEP for 100 min and the subsequent treatment with the O3/H2O2 process for 70min eliminated over 99% of the TPH of highly petroleum-contaminated groundwater, with initial values of 162 mg/L. Therefore, we can conclude that the developed treatment system is an appropriate method of remediation for petroleum-contaminated waters.


Molecular beam scattering from liquid surfaces.
By means of controlled collisions of atoms and molecules with liquid surfaces, molecular beam experiments can be used to probe how gases stick to, rebound from, and exchange energy with molecules in the liquid phase. This report describes measurements of energy exchange in collisions between gases (neon, xenon, and sulfur hexafluoride) and polyatomic liquids (squalane and perfluoropolyether). Energy transfer depends critically on liquid composition and is more efficient for the hydrocarbon than for the perfluorinated ether.


Prevalence of iron deficiency in patients aged 75 years or older with heart failure.
The latest studies presented at the American Heart Association (AHA) meeting on heart failure and the update of the European Cardiology Society's (ECS) recommendations on heart failure in 2016 recommend intravenous iron supplementation in patients with heart failure, reduced ejection fraction and iron deficiency for improves walking performance and quality of life, and reduces morbidity. In the present study, we investigated the prevalence of iron deficiency in heart failure patients aged 75 years or older, as there is currently no data on these patients. We performed an observational study on hospitalized patients in Geriatric Cardiology Department. Among the 462 patients hospitalized during eight months, 176 were eligible for inclusion; 22 patients was significant interference with an inflammatory syndrome (high ferritin with high C-reactive protein), and for 13 patients iron-related data were not available. For each patient included, a complete iron assessment and type of heart failure was available. A total of 141 patients were included, the mean age was 88 years (range: 75-101), and there were 52 (36.9%) of patients with reduced ejection fraction (EF), 37 (26.2%) with mid-range EF, and 52 (36.9%) with preserved EF. Irrespective of heart failure type, 73.8% had iron deficiency (95% CI: 65.7%-80.8%); this was found in 57.7% (95% CI: 43.2%-71.3%) of those with reduced EF, 78.4% (95% CI: 61.8%-90.2%) of those with mid-range EF, and 86.5% (95% CI: 74.2%-94.4%) of those with preserved EF (P = 0.003). The prevalence of iron deficiency was very high in very elderly patients with heart failure, especially those with HF with mid-range EF or HF with preserved EF.


Profile: a native son comes home to help.
In December 1996, Omu Anzala returned to Kenya after completing his Ph.D. work in Canada on HIV's interactions with the immune system to work with a collaborative AIDS research project started by researchers from his university and the University of Manitoba. Now the International AIDS Vaccine Initiative has funded Anzala and his collaborators to fashion an AIDS vaccine based on a strain of HIV circulating in Kenya.


Congenital H-type tracheoesophageal fistula: A multicenter review of outcomes in a rare disease.
To perform a multicenter review of outcomes in patients with H-type tracheoesophageal fistula (TEF) in order to better understand the incidence and causes of post-operative complications. H-type TEF without esophageal atresia (EA) is a rare anomaly with a fundamentally different management algorithm than the more common types of EA/TEF. Outcomes after surgical treatment of H-type TEF are largely unknown, but many authoritative textbooks describe a high incidence of respiratory complications. A multicenter retrospective review of all H-type TEF patients treated at 14 tertiary children's hospital from 2002-2012 was performed. Data were systematically collected concerning associated anomalies, operative techniques, hospital course, and short and long-term outcomes. Descriptive analyses were performed. We identified 102 patients (median 9.5 per center, range 1-16) with H-type TEF. The overall survival was 97%. Most patients were repaired via the cervical approach (96%). The in-hospital complication rate, excluding vocal cord issues, was 16%; this included an 8% post-operative leak rate. Twenty-two percent failed initial extubation after repair. A total of 22% of the entire group had vocal cord abnormalities (paralysis or paresis) on laryngoscopy that were likely because of recurrent laryngeal nerve injury. Nine percent required a tracheostomy. Only 3% had a recurrent fistula, all of which were treated with reoperation. There is a high rate of recurrent laryngeal nerve injury after H-type TEF repair. This underscores the need for meticulous surgical technique at the initial repair and suggests that early vocal cord evaluation should be performed for any post-operative respiratory difficulty. Routine evaluation of vocal cord function after H-type TEF repair should be considered. Level IV.