Artificial Intelligence-Based Framework for Analyzing Health Care Staff Security Practice: Mapping Review and Simulation Study.
Blocklisting malicious activities in health care is challenging in relation to access control in health care security practices due to the fear of preventing legitimate access for therapeutic reasons. Inadvertent prevention of legitimate access can contravene the availability trait of the confidentiality, integrity, and availability triad, and may result in worsening health conditions, leading to serious consequences, including deaths. Therefore, health care staff are often provided with a wide range of access such as a "breaking-the-glass" or "self-authorization" mechanism for emergency access. However, this broad access can undermine the confidentiality and integrity of sensitive health care data because breaking-the-glass can lead to vast unauthorized access, which could be problematic when determining illegitimate access in security practices. A review was performed to pinpoint appropriate artificial intelligence (AI) methods and data sources that can be used for effective modeling and analysis of health care staff security practices. Based on knowledge obtained from the review, a framework was developed and implemented with simulated data to provide a comprehensive approach toward effective modeling and analyzing security practices of health care staff in real access logs. The flow of our approach was a mapping review to provide AI methods, data sources and their attributes, along with other categories as input for framework development. To assess implementation of the framework, electronic health record (EHR) log data were simulated and analyzed, and the performance of various approaches in the framework was compared. Among the total 130 articles initially identified, 18 met the inclusion and exclusion criteria. A thorough assessment and analysis of the included articles revealed that K-nearest neighbor, Bayesian network, and decision tree (C4.5) algorithms were predominantly applied to EHR and network logs with varying input features of health care staff security practices. Based on the review results, a framework was developed and implemented with simulated logs. The decision tree obtained the best precision of 0.655, whereas the best recall was achieved by the support vector machine (SVM) algorithm at 0.977. However, the best F1-score was obtained by random forest at 0.775. In brief, three classifiers (random forest, decision tree, and SVM) in the two-class approach achieved the best precision of 0.998. The security practices of health care staff can be effectively analyzed using a two-class approach to detect malicious and nonmalicious security practices. Based on our comparative study, the algorithms that can effectively be used in related studies include random forest, decision tree, and SVM. Deviations of security practices from required health care staff's security behavior in the big data context can be analyzed with real access logs to define appropriate incentives for improving conscious care security practice.


Expression profile of oestrogen receptors and oestrogen-related receptors is organ specific and sex dependent: the Japanese medaka Oryzias latipes model.
Gene expression of all known subtypes of oestrogen receptor (ER) and oestrogen-related receptor (ERR) in multiple organs and both sexes of the Japanese medaka Oryzias latipes was profiled and systematically analysed. As revealed by statistical analyses and low-dimensional projections, the expressions of ERRs proved to be organ and sex dependent, which is in contrast with the ubiquitous nature of ERs. Moreover, expressions of specific ERR isoforms (ERRγ1, ERRγ2) were strongly correlated with that of all ERs (ERα, ERβ1 and ERβ2), suggesting the existence of potential interactions. Findings of this study shed light on the co-regulatory role of particular ERRs in oestrogen-ERs signalling and highlight the potential importance of ERRs in determining organ and sex-specific oestrogen responses. Using O. latipes as an alternative vertebrate model, this study provides new directions that call for collective efforts from the scientific community to unravel the mechanistic action of ER-ERR cross-talks, and their intertwining functions, in a cell and sex-specific manner in vivo.


Toward Improving Early Diagnosis of Congenital Chagas Disease in an Endemic Setting.
Congenital Trypanosoma cruzi transmission is now estimated to account for 22% of new infections, representing a significant public health problem across Latin America and internationally. Treatment during infancy is highly efficacious and well tolerated, but current assays for early detection fail to detect >50% of infected neonates, and 9-month follow-up is low. Women who presented for delivery at 2 urban hospitals in Santa Cruz Department, Bolivia, were screened by rapid test. Specimens from infants of infected women were tested by microscopy (micromethod), quantitative PCR (qPCR), and immunoglobulin (Ig)M trypomastigote excreted-secreted antigen (TESA)-blots at birth and 1 month and by IgG serology at 6 and 9 months. Among 487 infants of 476 seropositive women, congenital T. cruzi infection was detected in 38 infants of 35 mothers (7.8%). In cord blood, qPCR, TESA-blot, and micromethod sensitivities/specificities were 68.6%/99.1%, 58.3%/99.1%, and 16.7%/100%, respectively. When birth and 1-month results were combined, cumulative sensitivities reached 84.2%, 73.7%, and 34.2%, respectively. Low birthweight and/or respiratory distress were reported in 11 (29%) infected infants. Infants with clinical signs had higher parasite loads and were significantly more likely to be detected by micromethod. The proportion of T. cruzi-infected infants with clinical signs has fallen since the 1990s, but symptomatic congenital Chagas disease still represents a significant, albeit challenging to detect, public health problem. Molecular methods could facilitate earlier diagnosis and circumvent loss to follow-up but remain logistically and economically prohibitive for routine screening in resource-limited settings.


Effectiveness of India's National Programme to save the girl child: experience of Beti Bachao Beti Padao (B3P) programme from Haryana State.
The Government of India launched a nationwide programme to save and educate the girl child, Beti Bachao Beti Padhao (B3P), by stringent prohibition of sex-selective abortion, enforcement of Preconception and Prenatal Diagnostic Technique (PC-PNDT) and Medical Termination of Pregnancy (MTP) Acts, and social mobilization. We undertook this study to assess the effectiveness of intervention in Haryana state to improve sex ratio at birth (SRB). The monthly data on SRB (represented as girls per 1000 boys) were collected from civil registration system for the entire state of Haryana to evaluate the impact of B3P programme. The segmented time-series regression analysis was used to estimate the change in SRB after B3P programme. In this process, the seasonal auto regressive integrated moving average model was used to control the seasonality, autocorrelation and secular trend imbibed in the data before calculating the estimate of change in slope using regression equation. Overall, the sex ratio at birth in Haryana increased from 827 girls per 1000 boys in January 2005 to 900 girls per 1000 boys in September 2016. The estimates from segmented time-series regression analysis show that there was an insignificant change in SRB of -0.012 units before the intervention. Post slope was estimated to be 1.684, which suggested an increase in SRB of 1.696 [(confidence interval: 0.23, 3.15), P = 0.025] in terms of the difference between pre- and post-slope. This indicates a statistically significant increase of SRB by 1.696 per month attributable to B3P programme. B3P programme has resulted in an improvement of SRB in Haryana.


Interleukin-1 alpha, epidermal growth factor, and transforming growth factor-beta exhibit differential kinetics on endothelin-1 synthesis in amnion cells.
To investigate the effects of three cytokines, interleukin-1 alpha (IL-1 alpha), epidermal growth factor (EGF), and transforming growth factor-beta (TGF-beta), on the regulation of endothelin-1 (ET-1) mRNA and protein production in human amnion cells. Human amnion cells were harvested from uncomplicated pregnancies undergoing elective cesarean delivery at term and grown in primary monolayer culture. Cells were treated with IL-1 alpha, EGF, and TGF-beta for dose-response and time course experiments. Northern analysis was used to determine ET-1 mRNA expression, and enzyme-linked immunosorbent assay was used for ET-1 peptide determination. Interleukin-1 alpha, EGF, and TGF-beta induced the expression of ET-1 mRNA and protein in a dose- and time-dependent fashion. The kinetics of ET-1 mRNA production did not differ markedly with respect to the inducing cytokine, but the kinetics of ET-1 protein production was quite different. Interleukin-1 alpha and EGF stimulated a rapid increase in ET-1 that peaked by 24 hours, and the levels declined to just above the detection limit by 72 hours. In contrast, TGF-beta-stimulated cells showed modest ET-1 production at early times (4-24 hours) and then gradually increased and peaked at 72 hours. Cytokines modulate the expression of ET-1 mRNA and its cognate protein in human amnion cells. The differential kinetics of ET-1 peptide expression in amnion cells suggests that ET metabolism as well as synthesis contribute to the net expression of endothelin in amnion.


Interplay between COVID-19, pollution, and weather features on changes in the incidence of acute coronary syndromes in early 2020.
Coronavirus disease 2019 (COVID-19) has caused an unprecedented change in the apparent epidemiology of acute coronary syndromes (ACS). However, the interplay between this disease, changes in pollution, climate, and aversion to activation of emergency medical services represents a challenging conundrum. We aimed at appraising the impact of COVID-19, weather, and environment features on the occurrence of ST-elevation myocardial infarction (STEMI) and non-ST-elevation myocardial infarction (NSTEMI) in a large Italian region and metropolitan area. Italy was hit early on by COVID-19, such that state of emergency was declared on January 31, 2020, and national lockdown implemented on March 9, 2020, mainly because the accrual of cases in Northern Italy. In order to appraise the independent contribution on changes in STEMI and NSTEMI daily rates of COVID-19, climate and pollution, we collected data on these clinical events from tertiary care cardiovascular centers in the Lazio region and Rome metropolitan area. Multilevel Poisson modeling was used to appraise unadjusted and adjusted effect estimates for the daily incidence of STEMI and NSTEMI cases. The sample included 1448 STEMI and 2040 NSTEMI, with a total of 2882 PCI spanning 6 months. Significant reductions in STEMI and NSTEMI were evident already in early February 2020 (all p<0.05), concomitantly with COVID-19 spread and institution of national countermeasures. Changes in STEMI and NSTEMI were inversely associated with daily COVID-19 tests, cases, and/or death (p<0.05). In addition, STEMI and NSTEMI incidences were associated with daily NO2, PM10, and O3 concentrations, as well as temperature (p<0.05). Multi-stage and multiply adjusted models highlighted that reductions in STEMI were significantly associated with COVID-19 data (p<0.001), whereas changes in NSTEMI were significantly associated with both NO2 and COVID-19 data (both p<0.001). Reductions in STEMI and NSTEMI in the COVID-19 pandemic may depend on different concomitant epidemiologic and pathophysiologic mechanisms. In particular, recent changes in STEMI may depend on COVID-19 scare, leading to excess all-cause mortality, or effective reduced incidence, whereas reductions in NSTEMI may also be due to beneficial reductions in NO2 emissions in the lockdown phase.


Identifying the components of clinical vignettes describing Alzheimer's disease or other dementias: a scoping review.
Clinical vignettes are often used to elicit information about health conditions in research studies. This review summarizes the components of clinical vignettes describing Alzheimer's disease (AD) or other dementias. The purpose is to provide recommendations for the development of standardized vignettes that may be used in future studies. MEDLINE, EMBASE, PsycINFO, ASSIA, CINAHL were searched from their inception to June 2014. Primary English-language studies employing vignettes to describe AD or similar disorders (including other dementias and Parkinson's disease) were included in the review. Included studies had to describe the content of the vignettes in the published manuscripts. The characteristics of the included studies and the vignettes were extracted in tabular form and summarized qualitatively. Forty-two studies were included in the review. Twenty-four of the studies contained at least one AD vignette, 11 had vignettes focusing on non-AD dementias, and seven contained vignettes describing conditions other than dementia. In total, 58 vignettes were obtained from the 42 included studies. Key aspects to consider when constructing vignettes for AD or other dementias include writing the vignettes from a third-person perspective and presenting hypothetical patients as being at least 65 years of age. Researchers should develop standardized vignettes for use across studies.


Cognitive impairment and sedentary behavior predict health-related attrition in a prospective longitudinal Parkinson's disease study.
In Parkinson's disease (PD), the high burden of motor and non-motor symptoms, such as cognitive impairment or falls, is associated with rapid disease progression and mortality. This is often reflected by an increased drop-out rate of PD patients in longitudinal studies. Active physical behavior can impact the disease course beneficially and has an overall positive effect on health. Contrarily, sedentary behavior is associated with cognitive impairment in PD. The aim of this study was to investigate whether sedentary physical behavior assessed in the home environment and cognitive impairment can predict health-related study attrition due to sickness and death in PD. Data of 45 PD patients, longitudinally assessed, were analyzed. Of those, 20 patients completed six yearly visits, 16 dropped out due to sickness or death, and nine for other reasons. All patients wore a mobile device to assess physical behavior and completed cognitive testing. Logistic regression revealed global cognition was the primary predictor for health-related drop-out in varying models (p ≤ .04). In the survival analysis, cognitive impairment (p = .005) and longer sedentary mean bout length (p = .02) were associated with drop-out due to sickness and death. The occurrence of health-related study drop-out or death was highest in patients with both impaired cognition and longer sedentary bouts. Cognition was the primary predictor for study drop-out due to sickness and death. However, it seems that sedentary behavior might have a potential negative influence on PD patients' health, especially those with cognitive impairment.


Absence of endothelial cells, central necrosis, and fibrosis are associated with aggressive inflammatory breast cancer.
We recently established a new human inflammatory breast cancer (IBC) xenograft (WIBC-9) originating from a patient with IBC. The graft was transplantable in BALB/c nude and severe combined immunodeficient (SCID) mice. WIBC-9 was frequently accompanied by lung metastasis and exhibited erythema of the overlying skin, reflecting its human counterpart. Histological study of the original tumor and WIBC-9 revealed invasive ductal carcinoma with a hypervascular structure of solid nests and marked lymphatic permeation in the overlying dermis. In the central part of the solid nests, absence of endothelial cells, central necrosis, and fibrosis were observed. In vitro, WIBC-9 formed tube-like structures and loops, reflecting its in vivo feature and its human counterpart. WIBC-9 exhibited aneuploidy, ErbB-2 gene amplification, and an absence of estrogen receptor and progesterone receptor, which is consistent with IBC. Comparative studies of WIBC-9, three established non-IBC xenografts, and a human breast cancer cell line (SK-BR3) by reverse transcription-PCR, ELISA, and immunohistochemistry indicated that certain human genes (interleukin 8, vascular epidermal growth factor, basic fibroblast growth factor, angiopoietin 13, Flt-1, Tie-2, and Tie-1) and certain murine genes (integrin alpha(v)beta3, flt-1, tie-2, vascular epidermal growth factor, and CD31) were overexpressed in exposure to tumor cells. The molecular basis and these unique histological features may be associated with aggressive IBC on angiogenic and nonangiogenic pathways.


Real-World Results of Intravitreal Ranibizumab, Bevacizumab, or Triamcinolone for Diabetic Macular Edema.
To compare the visual and anatomical outcomes of intravitreal ranibizumab (group 1), bevacizumab (group 2), and triamcinolone (group 3) for center-involving diabetic macular edema. We retrospectively enrolled 275 eyes of 208 consecutive patients. Visual acuity (VA) in Early Treatment Diabetic Retinopathy Study (ETDRS) letters and central macular thickness (CMT) values on optical coherence tomography were extracted. Reported side effects were noted. At 6 months, the mean changes in VA in group 1, group 2, and group 3 were +4.9, +4.3, and +4.6 letters, respectively (p = 0.911). Improvement of CMT at 6 and 24 months was significantly better in group 3 compared to groups 1 and 2 (p = 0.012 and p = 0.001, respectively). At 24 months, the only independent variable affecting the change in VA was initial VA (p = 0.020). Cataract and glaucoma prevalences were higher in group 3 (p = 0.000 and p = 0.001, respectively). Three treatment methods had similar effects with regard to improvement in VA; however, intravitreal triamcinolone provided additional anatomical improvement.


Evolving and Expanding the Roles of Mitophagy as a Homeostatic and Pathogenic Process.
The central functions fulfilled by mitochondria as both energy generators essential for tissue homeostasis and gateways to programmed apoptotic and necrotic cell death mandate tight control over the quality and quantity of these ubiquitous endosymbiotic organelles. Mitophagy, the targeted engulfment and destruction of mitochondria by the cellular autophagy apparatus, has conventionally been considered as the mechanism primarily responsible for mitochondrial quality control. However, our understanding of how, why, and under what specific conditions mitophagy is activated has grown tremendously over the past decade. Evidence is accumulating that nonmitophagic mitochondrial quality control mechanisms are more important to maintaining normal tissue homeostasis whereas mitophagy is an acute tissue stress response. Moreover, previously unrecognized mitophagic regulation of mitochondrial quantity control, metabolic reprogramming, and cell differentiation suggests that the mechanisms linking genetic or acquired defects in mitophagy to neurodegenerative and cardiovascular diseases or cancer are more complex than simple failure of normal mitochondrial quality control. Here, we provide a comprehensive overview of mitophagy in cellular homeostasis and disease and examine the most revolutionary concepts in these areas. In this context, we discuss evidence that atypical mitophagy and nonmitophagic pathways play central roles in mitochondrial quality control, functioning that was previously considered to be the primary domain of mitophagy.


Adhesion mechanisms of curli subunit CsgA to abiotic surfaces.
Curli fibers are functional amyloids that play a key role in biofilm structure and adhesion to various surfaces. Strong bioinspired adhesives comprising curli fibers have recently been created; however, the mechanisms curli uses to attach onto abiotic surfaces are still uncharacterized. Toward a materials-by-design approach for curli-based adhesives and multifunctional materials, we examine curli subunit adsorption onto graphene and silica surfaces through atomistic simulation. We find that both structural features and sequence influence adhesive strength, enabling the CsgA subunit to adhere strongly to both polar and nonpolar surfaces. Specifically, flexible regions facilitate adhesion to both surfaces, charged and polar residues (Arg, Lys, and Gln) enable strong interactions with silica, and six-carbon aromatic rings (Tyr and Phe) adsorb strongly to graphene. We find that adsorption not only lowers molecular mobility but also leads to loss of secondary structure, factors that must be well balanced for effective surface attachment. Both events appear to propagate through the CsgA structure as correlated motion between clusters of residues, often H-bonded between rows on adjacent β strands. To quantify this, we present a correlation analysis approach to detecting collective motion between residue groups. We find that certain clusters of residues have a higher impact on the stability of the rest of the protein structure, often polar and bulky groups within the helix core. These findings lend insight into bacterial adhesion mechanisms and reveal strategies for theory-driven design of engineered curli fibers that harness point mutations and conjugates for stronger adhesion.


Analysis of hospital facility growth: are we super-sizing healthcare?
A retrospective analysis of space planned for selected clinical areas in acute healthcare facilities between the years 1980-2008 was conducted. Findings revealed that, during the 28-year period, incremental growth occurred in both room size and departmental square feet in adult inpatient units as well as interventional services. This observed growth and-in many instances- super-sized or excessive growth may be attributed to various factors, depending on the year of construction, regional variability, or level of urbanization. However, at a macro level, growth may be attributed to changes in patient care and operational models; consumer-driven healthcare and market competition; demographics and patient acuity; technology; and regulations and building codes. In the future, forces including but not limited to capital availability, an increased desire for efficiency, and continued escalation in the cost of construction are likely to play an increasing role in offsetting the desire for sizing excess.


In vitro assay of Staphylococcus aureus enterotoxin A activity in food.
Staphylococcus aureus enterotoxin A (SEA) is a leading cause of food poisoning. The current test for functional activity of SEA requires monkeys or kittens. The major drawbacks of animal assays are lack of quantitation, poor reproducibility, low sensitivity, and high cost. In this report we describe and evaluate an alternative assay using T-cell proliferation to measure SEA activity in food. Human and rat lymphocytes proliferate in response to concentrations of SEA as low as 1 pg/ml, well below the pathogenic dose of 100 ng. This proliferation assay is highly sensitive, quantitative, and simple. Nonradioactive assays of T-cell proliferation were also suitable for detecting and measuring SEA, although with a 10-fold lower sensitivity. To evaluate the utility of this assay for food testing, four different food samples were mixed with SEA. In each sample, SEA was detected at a concentration of 1 ng/ml. Heat-inactivated SEA produced no detectable proliferation. These results demonstrate that an in vitro cell proliferation assay is an advantageous alternative to existing animal assays for measuring SEA activity in food.


Pediatric Thoraco-lumbar Paraspinal Arteriovenous Fistulas along the Segmental Nerve. Diagnosis and Endovascular Treatment.
To characterize the clinical presentation, imaging features and endovascular treatment of paraspinal non-vertebral arteriovenous fistulas along the segmental nerve. Retrospective review was performed on the five patients identified in our database covering 1985 to 2003. All patients presented with an incidentally found continuous murmur over the upper paraspinal or parasternal regions before three years old. In four patients, the AV fistula was in the mid-thoracic level and at L3 in one. All AV fistulas were a high-flow single-hole fistula at the neural foramen with venous drainage into paraspinal and epidural veins without intradural reflux. All fistulas were endovascularly occluded in the same session as the diagnostic angiography. The fistula was occluded with detachable coils in one case and with N-butylcyanoacrylate (NBCA) with flow control in four cases. Complete occlusion of the fistula was obtained in all cases and all patients remained neurologically intact at the last follow up (average six years). Non-vertebral paraspinal arteriovenous fistula along the segmental nerve is a specific disease entity seen in children. Embolization is the first choice of treatment for this disease.


Functional analysis of the superfamily 1 DNA helicases encoded by Mycoplasma pneumoniae and Mycoplasma genitalium.
The DNA recombination and repair machinery of Mycoplasma pneumoniae is composed of a limited set of approximately 11 proteins. Two of these proteins were predicted to be encoded by neighboring open reading frames (ORFs) MPN340 and MPN341. Both ORFs were found to have sequence similarity with genes that encode proteins belonging to the DNA helicase superfamily 1 (SF1). Interestingly, while a homolog of the MPN341 ORF is present in the genome of Mycoplasma genitalium (ORF MG244), MPN340 is an M. pneumoniae-specific ORF that is not found in other mycoplasmas. Moreover, the length of MPN340 (1590 base pairs [bp]) is considerably shorter than that of MPN341 (2148 bp). Examination of the MPN340-encoded amino acid sequence indicated that it may lack a so-called 2B subdomain, which is found in most SF1 DNA helicases. Also, the MPN340-encoded amino acid sequence was found to differ between subtype 1 strain M129 and subtype 2 strain FH at three amino acid positions. Both protein variants, which were termed PcrA(s) M129 and PcrA(s) FH, respectively, as well as the MPN341- and MG244-encoded proteins (PcrA Mpn and PcrA Mge , respectively), were purified, and tested for their ability to interact with DNA. While PcrA Mpn and PcrA Mge were found to bind preferentially to single-stranded DNA, both PcrA(s) M129 and PcrA(s) FH did not demonstrate significant DNA binding. However, all four proteins were found to have divalent cation- and ATP-dependent DNA helicase activity. The proteins displayed highest activity on partially double-stranded DNA substrates carrying 3' single-stranded extensions.


Clinical Practice Guidelines for Cryosurgery of Pancreatic Cancer: A Consensus Statement From the China Cooperative Group of Cryosurgery on Pancreatic Cancer, International Society of Cryosurgery, and Asian Society of Cryosurgery.
Pancreatic cancer (PC), one of the most lethal malignancies, accounts for 8% to 10% of digestive system cancers, and the incidence is increasing. Surgery, chemotherapy, and radiotherapy have been the main treatment methods but are not very effective. Cryosurgery was first used in 1984 for treatment of locally advanced PC and has since become a considerable treatment for most cases of unresectable PC. During the past decade, cryosurgery has been applied in some hospitals in China, and the newly developed technique of computed tomography- and/or ultrasound-guided percutaneous cryosurgery has shown better results than chemotherapy in cases of unresectable locally advanced PC, with the 1-year survival rate reported to be more than 50%. To develop standardized criteria for the application of cryosurgery in PC, the International Society of Cryosurgery and Asian Society of Cryosurgery assembled experts from Austria, Japan, and China to discuss treatment methods and arrive at a consensus on the indications, contraindications, and preferred techniques of PC cryosurgery.


Novel splicing mutation in the ASXL3 gene causing Bainbridge-Ropers syndrome.
Bainbridge-Ropers syndrome (BRPS) is characterized by severe developmental delay, feeding problems, short stature, characteristic facal appearance including arched eyebrows and anteverted nares, and ulnar deviation of the hands. BRPS is caused by a heterozygous mutation in the additional sex combs-like 3 (ASXL3) gene. We describe a patient with severe developmental delay, feeding problems, short stature, autism, and sleep disturbance with a heterozygous de novo splicing mutation in the ASXL3 gene. Reported disease-causing mutations in ASXL3 are located mostly in the first half of exon 11, analogous to ASXL1 mutations of which result in Bohring-Opitz syndrome (BOS). Our findings suggest that the expression of the truncated ASXL3 protein, including ASXN and ASXH domains, give rise to BRPS, which is distinct from but overlaps with BOS. © 2016 Wiley Periodicals, Inc.


Biomedical equipment: maintenance factors, units of measurement, and standards.
The scope of biomedical equipment maintenance in health care institutions is typically determined by the available manpower and time resources. This paper reviews 27 factors that influence this maintenance, discusses the units of measurement that have been used to assess maintenance effectiveness, and outlines the steps needed to develop appropriate standards for determining whether the maintenance is effective.


Inhibition of dUTPase induces synthetic lethality with thymidylate synthase-targeted therapies in non-small cell lung cancer.
Chemotherapies that target thymidylate synthase (TS) continue to see considerable clinical expansion in non-small cell lung cancer (NSCLC). One drawback to TS-targeted therapies is drug resistance and subsequent treatment failure. Novel therapeutic and biomarker-driven strategies are urgently needed. The enzyme deoxyuridine triphosphate nucleotidohydrolase (dUTPase) is reported to protect tumor cells from aberrant misincorporation of uracil during TS inhibition. The goal of this study was to investigate the expression and significance of dUTPase in mediating response to TS-targeted agents in NSCLC. The expression of dUTPase in NSCLC cell lines and clinical specimens was measured by quantitative real-time reverse transcriptase PCR and immunohistochemistry. Using a validated RNA interference approach, dUTPase was effectively silenced in a panel of NSCLC cell lines and response to the fluoropyrimidine fluorodeoxyuridine (FUdR) and the antifolate pemetrexed was analyzed using growth inhibition and clonogenic assays. Apoptosis was analyzed by flow cytometry. Significant variation in the quantity and cellular expression of dUTPase was observed, including clear evidence of overexpression in NSCLC cell line models and tumor specimens at the mRNA and protein level. RNA interference-mediated silencing of dUTPase significantly sensitized NSCLC cells to growth inhibition induced by FUdR and pemetrexed. This sensitization was accompanied by a significant expansion of intracellular dUTP pools and significant decreases in NSCLC cell viability evaluated by clonogenicity and apoptotic analyses. Together, these results strongly suggest that uracil misincorporation is a potent determinant of cytotoxicity to TS inhibition in NSCLC and that inhibition of dUTPase is a mechanism-based therapeutic approach to significantly enhance the efficacy of TS-targeted chemotherapeutic agents.


Plant and soil responses to biosolids application following forest fire.
Soil stability and revegetation is a great concern following forest wildfires. Biosolids application might enhance revegetation efforts and enhance soil stability. In May 1997, we applied Metro Wastewater Reclamation District (Denver, CO, USA) composted biosolids at rates of 0, 5, 10, 20, 40, and 80 Mg ha(-1) to a severely burned, previously forested site near Buffalo Creek, CO to improve soil C and N levels and help establish eight native, seeded grasses. The soils on the site belong to the Sphinx series (sandy-skeletal, mixed, frigid, shallow Typic Ustorthents). Vegetation and soils data were collected for four years following treatment. During the four years following treatment, total plant biomass ranged from approximately 50 to 230 g m(-2) and generally increased with increasing biosolids application. The percentage of bare ground ranged from 4 to 58% and generally decreased with increasing biosolids rate. Higher rates of biosolids application were associated with increased concentrations of N, P, and Zn in tissue of the dominant plant species, streambank wheatgrass [Elymus lanceolatus (Scribn. & J.G. Sm) Gould subsp. lanceolatus], relative to the unamended, unfertilized control. At two months following biosolids application (1997), total soil C and N at soil depths of 0 to 7.5, 7.5 to 15, and 15 to 30 cm showed significant (P < 0.05) linear increases (r2 > 0.88) as biosolids rate increased. The surface soil layer also showed this effect one year after application (1998). For Years 2 through 4 (1999-2001) following treatment, soil C and N levels declined but did not show consistent trends. The increase in productivity and cover resulting from the use of biosolids can aid in the rehabilitation of wildfire sites and reduce soil erosion in ecosystems similar to the Buffalo Creek area.


Identification of a laminin-like substance on the surface of high-malignant murine fibrosarcoma cells.
High- and low-malignant murine fibrosarcoma cells were stained with anti-laminin antibodies using immunoperoxidase techniques and examined by electron microscopy. With the high-malignant cells, specific staining was observed along the cell surface. Use of normal rabbit serum in place of the rabbit anti-laminin or pretreatment of the anti-laminin with soluble laminin completely eliminated this staining. No immunoperoxidase staining was observed with the low-malignant cells. In additional studies, membrane fractions were prepared from the high- and low-malignant cells and used to immunize rabbits. The animals immunized with the membrane fractions from the high-malignant cells produced antibodies that reacted by enzyme-linked immunosorbent assay (ELISA) with murine laminin obtained from the EHS sarcoma. The animals immunized with membrane fractions from the low-malignant cells did not. These studies provide strong evidence that the high-malignant cells (but not the low) express on their cell surface a substance that is immunologically cross-reactive with laminin. In addition, the high-malignant cells (but not the low) secreted a material into the cell culture fluid that could be specifically immunoprecipitated with antilaminin antibodies. The immunoprecipitated material co-migrated with purified laminin when examined by sodium dodecyl sulphate/polyacrylamide gel electrophoresis under reducing conditions. The existence of this substance associated with the surface of the high-malignant cells and its absence from that of the low-malignant cells may explain the previously noted difference between these cells in their ability to attach to type IV collagen. This difference may also contribute to the dissimilarity between these cells in their metastatic potential.


Lysis of leukemia and lymphoma cells by autologous and allogeneic interferon-activated blood mononuclear cells.
Studies were undertaken to determine whether leukemia and lymphoma cells would be lysed by autologous and allogeneic interferon (IFN) activated peripheral blood mononuclear cells (PBMC). PBMC from healthy donors and from patients were cultured with and without 500 U of highly purified human fibroblast IFN/ml for 24 hr, and then their cytotoxic activity was assayed by a 5-hr 51Cr-release test. Of primary tumor cells isolated from patients, the cells of 5 of 15 patients with acute nonlymphocytic leukemia (ANLL), 5 of 9 patients with acute lymphocytic leukemia (ALL), 2 of 3 patients with chronic phase chronic myelogenous leukemia (CML), 2 of 3 patients with blastic phase CML, 1 patient with hairy cell leukemia, and 6 patients with diffuse non-Hodgkin's lymphoma were sensitive to IFN-activated PBMC of healthy donors, whereas the cells of 3 of the ANLL patients, 2 of the ALL patients, and 3 of the lymphoma patients were sensitive to unstimulated PBMC. Of the ANLL cells tested, myeloblasts, promyelocytes, and monoblasts were sensitive to either unstimulated or IFN-activated PBMC. Compared with the ANLL cells, the lymphoma cells were statistically significantly sensitive to activated effector cells (p less than 0.025). On the basis of the unlabeled target competition test and the recovery of cytotoxic cells within the fractions enriched in natural killer (NK) cells, NK cells appeared to mediate the above unstimulated and IFN-boosted cytotoxicity. In experiments using autologous effector-target cells from 11 patients, the addition of 500 U of IFN/ml enhanced the lytic activity of PBMC against autologous lymphoma cells in 1 patient, and higher concentrations of IFN, i.e., 2500 or 3500 U/ml, enhanced their cytotoxic activity against autologous leukemia or lymphoma cells in 4 of 8 patients. These data indicate that IFN-activated allogeneic PBMC are able to lyse both myeloid and lymphoid tumor cells, whereas higher concentrations of IFN are required to enhance lytic activity against autologous tumor cells.


Efficacy, Safety, and Tolerability of Inclisiran in Patients With Homozygous Familial Hypercholesterolemia: Results From the ORION-5 Randomized Clinical Trial.
Homozygous familial hypercholesterolemia is a genetic disease characterized by extremely high levels of low-density lipoprotein cholesterol (LDL-C) and a high risk of premature cardiovascular events. Phase 2 of ORION (A Study of Inclisiran in Participants With Homozygous Familial Hypercholesterolemia) showed that inclisiran, a small interfering RNA that prevents production of the hepatic PCSK9 protein (proprotein convertase subtilisin/kexin type 9), could lead to durable reductions in LDL-C levels when added to statins and ezetimibe in patients with homozygous familial hypercholesterolemia. ORION-5 was a phase 3, 2-part, multicenter study in 56 patients with homozygous familial hypercholesterolemia and elevated LDL-C levels despite maximum tolerated doses of LDL-C-lowering therapies with or without lipoprotein apheresis. Patients eligible for part 1 (double-blind, 6 months) were randomized 2:1 to receive either 300 mg of inclisiran sodium (equivalent to 284 mg of inclisiran) or placebo. Placebo-treated patients from part 1 were transitioned to inclisiran in part 2 (open-label, 18 months). The primary end point was the percentage change in LDL-C levels from baseline to day 150. The mean age of the patients was 42.7 years, and 60.7% were women. The mean baseline LDL-C levels were 294.0 mg/dL and 356.7 mg/dL in the inclisiran and placebo groups, respectively. The placebo-corrected percentage change in LDL-C level from baseline to day 150 was -1.68% (95% CI, -29.19% to 25.83%; P=0.90), and the difference was not statistically significant between the inclisiran and placebo groups. The placebo-corrected percentage change in PCSK9 levels from baseline to day 150 was -60.6% with inclisiran treatment (P<0.0001); this was sustained throughout the study, confirming the effect of inclisiran on its biological target of PCSK9. No statistically significant differences between the inclisiran and placebo groups were observed in the levels of other lipids and lipoproteins (apolipoprotein B, total cholesterol, and non-high-density lipoprotein cholesterol). Adverse events and serious adverse events did not differ between the inclisiran and placebo groups throughout the study. Inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia despite substantial lowering of PCSK9 levels. Inclisiran was well-tolerated, and the safety findings were consistent with previously reported studies and the overall safety profile. URL: https://www. gov; Unique identifier: NCT03851705.


Identification of regions involved in substrate binding and dimer stabilization within the central domains of yeast Hsp40 Sis1.
Protein folding, refolding and degradation are essential for cellular life and are regulated by protein homeostatic processes such those that involve the molecular chaperone DnaK/Hsp70 and its co-chaperone DnaJ. Hsp70 action is initiated when proteins from the DnaJ family bind an unfolded protein for delivery purposes. In eukaryotes, the DnaJ family can be divided into two main groups, Type I and Type II, represented by yeast cytosolic Ydj1 and Sis1, respectively. Although sharing some unique features both members of the DnaJ family, Ydj1 and Sis1 are structurally and functionally distinct as deemed by previous studies, including the observation that their central domains carry the structural and functional information even in switched chimeras. In this study, we combined several biophysical tools for evaluating the stability of Sis1 and mutants that had the central domains (named Gly/Met rich domain and C-terminal Domain I) deleted or switched to those of Ydj1 to gain insight into the role of these regions in the structure and function of Sis1. The mutants retained some functions similar to full length wild-type Sis1, however they were defective in others. We found that: 1) Sis1 unfolds in at least two steps as follows: folded dimer to partially folded monomer and then to an unfolded monomer. 2) The Gly/Met rich domain had intrinsically disordered characteristics and its deletion had no effect on the conformational stability of the protein. 3) The deletion of the C-terminal Domain I perturbed the stability of the dimer. 4) Exchanging the central domains perturbed the conformational stability of the protein. Altogether, our results suggest the existence of two similar subdomains in the C-terminal domain of DnaJ that could be important for stabilizing each other in order to maintain a folded substrate-binding site as well as the dimeric state of the protein.


Is low level laser therapy or ozone therapy more effective for bone healing? Understanding the mechanisms of HIF-1α, RANKL and OPG.
Periodontitis is a common chronic infection of dental tissues. Ozone therapy (OT) and low level laser therapy (LLLT) are useful treatments for periodontitis. We investigated the effects of OT and LLLT on periodontal disease-induced bone destruction in rats with experimentally induced periodontitis (EP). We used 30 male Wistar rats divided into three groups: control, OT and LLLT. EP was induced by placing a 3.0 silk suture around the cervix of the left mandibular first molar tooth. OT was performed using an ozone generator at 80% concentration. LLLT was applied using a diode laser. Both OT and LLLT were performed for two weeks at two day intervals. Histomorphometric and immunohistochemical analyses also were performed. Alveolar bone loss was significantly less in the LLLT group compared to the control group. The number of HIF-1α positive cells was significantly less in the LLLT group compared to the control group. We found significantly fewer RANKL-positive cells in the OT group compared to the control group. The number of osteoprotegerin (OPG) positive cells was significantly greater for the LLLT group than for the control group. Although both treatments produced positive effects, LLLT appears to be more effective for increasing alveolar bone formation.


Progressive cortical atrophy after forebrain ischemia in diabetic rats.
The morphological changes in the brain of diabetic rats were examined up to 8 weeks after transient forebrain ischemia produced by transient occlusion of both carotid arteries. Using histochemistry, we also examined the extent and rate of development of atrophic changes in the brain, appearance of astrocytes, activated microglia, and glucose transporter 1 (GLUT1) in streptozotocin-treated rat brains after forebrain ischemia. Atrophic changes appeared in the hippocampus in both non-diabetic-- and diabetic--ischemic groups 4 weeks after ischemia. In diabetic--ischemic rats, the atrophic changes were more severe and progressed more rapidly in the hippocampus, and were also observed in the frontal, temporal and parietal cortices, but not in any cortical areas of the non-diabetic--ischemic rats and non-ischemic--diabetic rats. We observed reduced density of GLUT1 in all cortical regions and hippocampus in ischemic-diabetic rats at 4--8 weeks, when the number of activated microglias and astroglias increased in all cortical regions. Although severe atrophic changes were observed in the gray matter, no serious injury was noted in the white matter in the diabetic-ischemic group. Our results indicate that brain ischemia in the presence of diabetes causes more severe late-onset damage culminating in brain atrophy, compared with non-diabetics.


Dual far infrared laser diagnostic of magnetized plasmas.
A dual far infrared laser has been constructed and its properties have been exploited to probe tokamaklike discharges in the CDX toroidal device. Thermal variation of the difference frequency between the two far infrared cavities is slow, although the cavities lack thermal stabilization, simply because their assembly on the same chassis exposes them to virtually identical temperature changes. The optical arrangement beyond the laser permits conversion within minutes between interferometry and density fluctuation observation, and within an hour between different operating wavelengths. Line average densities of 2 x 10(13) cm(-3) and coherent fluctuations in the neighborhood of 20 kHz have been measured with this diagnostic.


Spectral biclustering of microarray data: coclustering genes and conditions.
Global analyses of RNA expression levels are useful for classifying genes and overall phenotypes. Often these classification problems are linked, and one wants to find "marker genes" that are differentially expressed in particular sets of "conditions." We have developed a method that simultaneously clusters genes and conditions, finding distinctive "checkerboard" patterns in matrices of gene expression data, if they exist. In a cancer context, these checkerboards correspond to genes that are markedly up- or downregulated in patients with particular types of tumors. Our method, spectral biclustering, is based on the observation that checkerboard structures in matrices of expression data can be found in eigenvectors corresponding to characteristic expression patterns across genes or conditions. In addition, these eigenvectors can be readily identified by commonly used linear algebra approaches, in particular the singular value decomposition (SVD), coupled with closely integrated normalization steps. We present a number of variants of the approach, depending on whether the normalization over genes and conditions is done independently or in a coupled fashion. We then apply spectral biclustering to a selection of publicly available cancer expression data sets, and examine the degree to which the approach is able to identify checkerboard structures. Furthermore, we compare the performance of our biclustering methods against a number of reasonable benchmarks (e.g., direct application of SVD or normalized cuts to raw data).


Levels of heavy metals and metalloids in critically endangered Iberian lynx and other wild carnivores from Southern Spain.
The Iberian lynx (Lynx pardinus) is the most endangered felid in the world with a wild population which probably stands at less than 200 individuals inhabiting two areas in Southern Spain (Doñana and Sierra Morena) that are known to have been contaminated by heavy metals and metalloids due to a long history of mining activities. This contamination may pose a threat to long term conservation efforts and hence, the concentrations of seven elements (As, Se, Cd, Zn, Cu, Pb, Hg) were determined in the liver, muscle and bone of 9 lynx, as well as 17 red foxes (Vulpes vulpes), 11 Egyptian mongooses (Herpestes ichneumon), 4 common genets (Genetta genetta) and 1 Eurasian badger (Meles meles). The mean concentrations found were below the threshold levels indicative of chronic intoxication in all the species studied. In general, genet and red fox were species with the highest concentrations of several elements in Doñana, whilst Iberian lynx had the lowest levels of most of them. Lynx from Sierra Morena had significantly higher concentrations of bone Pb (2.05 microg/g d.w.) than those from Doñana (0.13 microg/g d.w.), probably due to the mineralised underlying geology and/or the abandoned mine workings in Sierra Morena. Egyptian mongoose presented liver concentrations of Hg up to 9.7 microg/g d.w. A strong relationship between Hg and Se levels was found in liver and muscle samples of all the studied species, especially in mongoose. In conclusion, levels of the studied elements do not appear to represent a significant threat for the lynx or for the other carnivores studied. However, given the critical status of the Iberian lynx, a continuous monitoring scheme remains necessary.


Erratum for the article by Taverno Ross et al in PES 25(2).
In the article by Taverno Ross S, Dowda M, Saunders R, Pate R, "Double dose: The cumulative effect of TV viewing at home and in preschool on children's activity patterns and weight status," in Pediatr Exerc Sci. 25(2), p. 262-272, the authors incorrectly stated that children in the High TV-Combined group had significantly lower levels of MVPA compared with children in the Low TV-Combined group. However, as shown in Table 3, children in the High TV-Combined group had higher MVPA than the Low TV-Combined group. Given that all other differences between High TV and Low TV groups were not significantly different and the erroneously interpreted difference was marginally significant (p =.047), the authors believe that the proper interpretation of the findings is that TV exposure was not associated with children's physical activity.


Arrayed primer extension: solid-phase four-color DNA resequencing and mutation detection technology.
The technology and application of arrayed primer extension (APEX) is presented. We describe an integrated system with DNA chip and template preparation, multiplex primer extension on the array, fluorescence imaging, and data analysis. The method is based upon an array of oligonucleotides, immobilized via the 5' end on a glass surface. A patient DNA is amplified by PCR, digested enzymatically, and annealed to the immobilized primers, which promote sites for template-dependent DNA polymerase extension reactions using four unique fluorescently labeled dideoxy nucleotides. A mutation is detected by a change in the color code of the primer sites. The technology was applied to the analysis of 10 common beta-thalassemia mutations. Nine patient DNA samples, each of which carries a different mutation, and four wild-type DNA samples were correctly identified. The signal-to-noise ratio of this technology is, on the average, 40:1, which enables the identification of heterozygous mutations with a high confidence level. The APEX method can be applied to any DNA target for efficient analysis of mutations and polymorphisms.


Free amino acids in stimulated and unstimulated whole saliva: advantages or disadvantages.
This study determines the mean concentrations of free amino acids in stimulated and unstimulated whole saliva in healthy young adults. Standardised salivary amino acids as a substitute for their counterpart in blood, searched for the source of free amino acids in saliva, the probable correlation between particular amino acids with caries experience. Stimulated and unstimulated whole saliva were collected by the draining method in 31 dental students. Saliva was purified, and amino acids were separated by high-performance liquid chromatography. DMFT scores were recorded, and the relation of amino acids to caries experience was explored by generalised linear model. Almost all amino acids had higher concentration in unstimulated whole saliva than in stimulated saliva. The normal range of amino acids (95% CI) and their natural logarithm were defined. There was a significant relationship between caries experience and threonine (P < 0·008), citrulline (P < 0·023) and ornithine (P < 0·001) as a detrimental factor, whereas serin (P < 0·026), glutamine (P < 0·015) and phenylalanine (P < 0·014) had an inhibiting effect on caries. However, in comparison, salivary flow rate (P < 0·013) was a more preventive factor than amino acids. Amino acids in saliva contribute as a marker, instead of their counterpart in blood. Unstimulated saliva had higher concentration of amino acids. Amino acids have different impact on caries and may be one of underlying risk factors for caries experience.


Pill burden does not influence compliance with oral medication in recipients of renal transplant.
Insights about the predictors of noncompliance are key to develop compliance enhancing strategy in a given therapeutic situation. Renal transplantation is a critical surgical procedure that imposes a large medication burden on patients. There is a suspicion that the large pill burden may lead to noncompliance. Our objective was to ascertain the influence of pill burden on medication compliance in renal transplant patients in the Indian sociocultural context. A longitudinal observational study was conducted in two Tertiary Care Hospitals in Kolkata running renal transplant program - one each from the government and private sectors. Totally 120 literate adult transplant recipients were recruited through purposive sampling and followed up at 3 months intervals for 1 year. Data were collected through interview and review of prescriptions and medical records. Data of 110 subjects were analyzed. The pill burden was high - ranging from 10-21 (median 14) at first visit shortly after discharge to 7-22 (median 11) at last visit at 12 months in the government sector; corresponding figures in the private sector were 14-32 (median 21) and 10-28 (median 17). Pill burden increased with age. Only 60.91% of the patients were fully compliant until 1 year after transplantation. The rate of immunosuppressant noncompliance was 27.78% in government sector and 25.00% in private sector. There was no significant association between median pill burden and medication compliance. Satisfaction with caregiver support was associated with better immunosuppressant compliance. Noncompliance in renal transplant recipients is likely to be multifactorial. Contrary to popular belief, pill burden was not a major determinant of noncompliant behavior.


The effect of H. pylori eradication on meal-associated changes in plasma ghrelin and leptin.
Appetite and energy expenditure are regulated in part by ghrelin and leptin produced in the gastric mucosa, which may be modified by H. pylori colonization. We prospectively evaluated the effect of H. pylori eradication on meal-associated changes in serum ghrelin and leptin levels, and body weight. Veterans referred for upper GI endoscopy were evaluated at baseline and ≥8 weeks after endoscopy, and H. pylori status and body weight were ascertained. During the first visit in all subjects, and during subsequent visits in the initially H. pylori-positive subjects and controls, blood was collected after an overnight fast and 1 h after a standard high protein meal, and levels of eight hormones determined. Of 92 enrolled subjects, 38 were H. pylori-negative, 44 H. pylori-positive, and 10 were indeterminate. Among 23 H. pylori-positive subjects who completed evaluation after treatment, 21 were eradicated, and 2 failed eradication. After a median of seven months following eradication, six hormones related to energy homeostasis showed no significant differences, but post-prandial acylated ghrelin levels were nearly six-fold higher than pre-eradication (p=0.005), and median integrated leptin levels also increased (20%) significantly (p<0.001). BMI significantly increased (5 ± 2%; p=0.008) over 18 months in the initially H. pylori-positive individuals, but was not significantly changed in those who were H. pylori-negative or indeterminant at baseline. Circulating meal-associated leptin and ghrelin levels and BMI changed significantly after H. pylori eradication, providing direct evidence that H. pylori colonization is involved in ghrelin and leptin regulation, with consequent effects on body morphometry.


Comparison of Births by Provider, Place, and Payer in New Hampshire.
This study examines maternity care in a rural state by birth attendant, place of birth, and payer of birth. It is a secondary analysis of birth certificate data in New Hampshire between the years 2005 and 2012. Results revealed that in New Hampshire, the majority of births occurred in the hospital setting (98.6%). Physicians attended 75.8% of births, certified nurse midwives attended 17%, and certified professional midwives attended 1%. Medicaid coverage was the payer source for 28% of all births, compared with 44.9% nationally. Women with a private payer source were more likely than women with Medicaid or other payer sources to have a cesarean section. The findings demonstrate quality of care outcomes among a range of clinicians and settings, providing a policy argument for expanding maternity care options.


ROS-independent JNK activation and multisite phosphorylation of Bcl-2 link diallyl tetrasulfide-induced mitotic arrest to apoptosis.
Garlic-derived organosulfur compounds including diallyl polysulfides are well known for various health-beneficial properties and recent reports even point to a potential role of diallyl polysulfides as chemopreventive and therapeutic agents in cancer treatment due to their selective antiproliferative effects. In this respect, diallyl tri- and tetrasulfide are reported as strong inducers of an early mitotic arrest and subsequent apoptosis, but the underlying molecular mechanisms and the link between these two events are not yet fully elucidated. Our data revealed that diallyl tetrasulfide acts independently of reactive oxygen species and tubulin represents one of its major cellular targets. Tubulin depolymerization prevents the formation of normal spindle microtubules, thereby leading to G2/M arrest. Here, we provide evidence that c-jun N-terminal kinase, which is activated early in response to diallyl tetrasulfide treatment, mediates multisite phosphorylation and subsequent proteolysis of the anti-apoptotic protein B-cell lymphoma 2. As the latter event occurs concomitantly with the onset of apoptosis and the chemical c-jun N-terminal kinase inhibitor SP600125 not only prevented B-cell lymphoma 2 phosphorylation and proteolysis but also apoptosis following diallyl tetrasulfide treatment, we suggest that these c-jun N-terminal kinase-mediated modulations of B-cell lymphoma 2 represent the missing link connecting early microtubule inactivation to the induction of apoptosis.


Apoptotic effect of Gyejibokryunghwan on uterine sarcoma cells (SK-UT-1B).
Diagnosis of uterine sarcomais is a challenging task for clinicians because its position is not easily accessible by current conventional techniques. In addition, standardized treatment for uterine sarcoma has not yet been established due to its rarity and heterogeneity. We investigated the apoptotic cell death of uterine sarcoma cells (SK-UT-1B) induced by Gyejibokryunghwan (GBH). GBH, an herbal medicine, has been widely used for gynecological diseases in Koean medicine. SK-UT-1B cells were treated with GBH of varying concentrations from 0 to 500 µg/ml. The mechanism of cell death was investigated through multiple analysis methods, including flow cytometry, cell cycle, and western blotting. Flow cytometric analysis revealed that the number of apoptotic cells increased in a GBH dose-dependent manner. The cell populations of sub-G1 and G0/G1 phases were increased by GBH treatment, indicating apoptosisand cell arrest, while the population of S and G2/M phases decreased. With GBH, the expression levels of cleaved caspase-3, -6, and -9 were upregulated, while the expression levels of pro-caspase-3, -6, and -9 were down-regulated in SK-UT-1B cells. These results are the first observation of uterine sarcoma cell death induced by GBH and confirmation of the mechanism of cell death, which occurred through the intrinsic apoptotic pathway. Clinically, uterine sarcoma has a poor prognosis with no appropriate treatment. GBH may become a new treatment modality for uterine sarcoma.


Cardiovascular Disease Among Transgender Adults Receiving Hormone Therapy: A Narrative Review.
Recent reports estimate that 0.6% of adults in the United States, or approximately 1.4 million persons, identify as transgender. Despite gains in rights and media attention, the reality is that transgender persons experience health disparities, and a dearth of research and evidence-based guidelines remains regarding their specific health needs. The lack of research to characterize cardiovascular disease (CVD) and CVD risk factors in transgender populations receiving cross-sex hormone therapy (CSHT) limits appropriate primary and specialty care. As with hormone therapy in cisgender persons (that is, those whose sex assigned at birth aligns with their gender identity), existing research in transgender populations suggests that CVD risk factors are altered by CSHT. Currently, systemic hormone replacement for cisgender adults requires a nuanced discussion based on baseline risk factors and age of administration of exogenous hormones because of concern regarding an increased risk for myocardial infarction and stroke. For transgender adults, CSHT has been associated with the potential for worsening CVD risk factors (such as blood pressure elevation, insulin resistance, and lipid derangements), although these changes have not been associated with increases in morbidity or mortality in transgender men receiving CSHT. For transgender women, CSHT has known thromboembolic risk, and lower-dose transdermal estrogen formulations are preferred over high-dose oral formulations. In addition, many studies of transgender adults focus predominantly on younger persons, limiting the generalizability of CSHT in older transgender adults. The lack of randomized controlled trials comparing various routes and formulations of CSHT, as well as the paucity of prospective cohort studies, limits knowledge of any associations between CSHT and CVD.


Recent developments in understanding the role of the gut microbiota in brain health and disease.
There is a growing appreciation of the role of the gut microbiota in all aspects of health and disease, including brain health. Indeed, roles for the bacterial commensals in various psychiatric and neurological conditions, such as depression, autism, stroke, Parkinson's disease, and Alzheimer's disease, are emerging. Microbiota dysregulation has been documented in all of these conditions or in animal models thereof. Moreover, depletion or modulation of the gut microbiota can affect the severity of the central pathology or behavioral deficits observed in a variety of brain disorders. However, the mechanisms underlying such effects are only slowly being unraveled. Additionally, recent preclinical and clinical evidence suggest that targeting the microbiota through prebiotic, probiotic, or dietary interventions may be an effective "psychobiotic" strategy for treating symptoms in mood, neurodevelopmental disorders, and neurodegenerative diseases.


Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity.
Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes. Despite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aβ immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aβ immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aβ immunotherapy are significantly exacerbated by the VCID comorbidity. These data suggest that VCID comorbidity with Alzheimer's disease may mute the response to anti-Aβ immunotherapy.


Heart and skeletal muscle inflammation of farmed salmon is associated with infection with a novel reovirus.
Atlantic salmon (Salmo salar L.) mariculture has been associated with epidemics of infectious diseases that threaten not only local production, but also wild fish coming into close proximity to marine pens and fish escaping from them. Heart and skeletal muscle inflammation (HSMI) is a frequently fatal disease of farmed Atlantic salmon. First recognized in one farm in Norway in 1999, HSMI was subsequently implicated in outbreaks in other farms in Norway and the United Kingdom. Although pathology and disease transmission studies indicated an infectious basis, efforts to identify an agent were unsuccessful. Here we provide evidence that HSMI is associated with infection with piscine reovirus (PRV). PRV is a novel reovirus identified by unbiased high throughput DNA sequencing and a bioinformatics program focused on nucleotide frequency as well as sequence alignment and motif analyses. Formal implication of PRV in HSMI will require isolation in cell culture and fulfillment of Koch's postulates, or prevention or modification of disease through use of specific drugs or vaccines. Nonetheless, as our data indicate that a causal relationship is plausible, measures must be taken to control PRV not only because it threatens domestic salmon production but also due to the potential for transmission to wild salmon populations.


Environmental vulnerability of the global ocean epipelagic plankton community interactome.
Marine plankton form complex communities of interacting organisms at the base of the food web, which sustain oceanic biogeochemical cycles and help regulate climate. Although global surveys are starting to reveal ecological drivers underlying planktonic community structure and predicted climate change responses, it is unclear how community-scale species interactions will be affected by climate change. Here, we leveraged Tara Oceans sampling to infer a global ocean cross-domain plankton co-occurrence network-the community interactome-and used niche modeling to assess its vulnerabilities to environmental change. Globally, this revealed a plankton interactome self-organized latitudinally into marine biomes (Trades, Westerlies, Polar) and more connected poleward. Integrated niche modeling revealed biome-specific community interactome responses to environmental change and forecasted the most affected lineages for each community. These results provide baseline approaches to assess community structure and organismal interactions under climate scenarios while identifying plausible plankton bioindicators for ocean monitoring of climate change.


Oscillating dispersed-phase co-flow microfluidic droplet generation: jet length reduction effect.
Microdroplet generation methods are assessed by two important criteria of droplet throughput and size dispersity. The widely-used co-flow droplet generation technique is bottlenecked with droplet polydispersity at high throughputs due to transition to an unstable jetting regime at high dispersed-phase (d-phase) flow rates. In this paper, we introduce a novel technique to oscillate the d-phase nozzle inside the continuous phase (c-phase) channel to suppress the jetting effect. The effect of the nozzle oscillation frequency (0-15 Hz) on the jet length was studied at different d-phase (Qd = 1.8, 2.4 and 3.0 ml min-1) and c-phase (Qc = 6, 12 and 18 ml min-1) flow rates and d-phase viscosities (1, 2.5, and 6 mPa s). The jet length was directly proportional to the d-phase flow rate and inversely proportional to the oscillation frequency. Oscillation-induced jet length reduction was more significant at high jet velocities, but a less steep jet length reduction was always observed at oscillation frequencies higher than 10 Hz. A maximum jet length reduction of 70.8% was obtained at the highest d-phase and lowest c-phase flow rates. Increasing the viscosity of the d-phase resulted in diminishing the effect of oscillation on jet length reduction. Moreover, we observed that nozzle oscillation could disintegrate the long jet into droplets of various sizes that were mostly smaller than the stationary-mode droplets. We hypothesize that oscillating the dispersion nozzle at lower flow rates, without the jetting effect, can simultaneously generate multi-size monodisperse droplets. This active technique can also be implemented into aqueous two-phase systems (ATPSs) in which droplet generation is a difficult task.


Postoperative Sagittal Spinal Alignment Changes Following Corrective Surgery in Adult Spinal Deformity.
There is a paucity of literature covering the spinal alignment changes following adult spinal deformities (ASD) corrective surgeries. In theory, patients' posture and overall alignment may vary with postoperative pain, bracing, and other external variables requiring further radiographic follow-up. The purpose of the study is to investigate changes in sagittal alignment in the first 3 months postoperatively. This is a retrospective case series of ASD patients who underwent deformity surgeries from October 2015 to June 2018. Patients < 40 years old, had < 6 levels fused, had acute proximal junctional kyphosis (PJK) or failure, or lacked imaging were excluded. Physiologic measures, spine alignment changes measured in whole-spine radiographs. Lumbar lordosis (LL), thoracic kyphosis (TK), and sagittal vertical axis (SVA) at immediate and 3-month postoperative time points were measured, then compared via 2-sample Student t tests. Furthermore, TK after upper thoracic to pelvis (UT-P) fusions was compared with lower thoracic to pelvis (LT-P) fusions via paired t test. Thirty-six patients (24 females, 67%) with a mean age of 61.5 years (range, 40-75 years) were included. Spinal alignment comparisons showed a significant increase in TK at the 3-month time point (P = 0.006). Additionally, wide variations in SVA (range, 47-144 mm) were noted, yet not statistically significant, likely due to the changes being in both positive and negative directions (P = 0.18). No significant difference was found when TK was compared in the UT-P vs LT-P groups. Our results suggest that as postoperative pain subsides and the body settles into its new alignment, significant changes occur in spine sagittal parameters in the subacute period following surgery. 4.


[Risk Factors for Predicting the Need for Additional Surgery for Symptomatic Adjacent Segment Disease after Minimally Invasive Surgery-Transforaminal Lumbar Interbody Fusion].
To determine the incidence of and risk factors for symptomatic adjacent segment disease(SASD)requiring additional surgery in patients previously treated with minimally invasive surgery-transforaminal lumbar interbody fusion(MIS-TLIF)for degenerative lumbar disease. A series of 467 consecutive patients who had undergone MIS-TLIF of one or two segments to treat degenerative lumbar disease was identified. The mean age of the patients at the time of the index operation was 67.7 years and the mean follow-up period was 33.2 months(range, 6.0-110.1 months). The incidence rate of SASD surgeries was calculated using the Kaplan-Meier method. The log-rank test and Cox regression analysis were used for risk factor analysis based on age, sex, number of fused segments, presence of laminectomy adjacent to index fusion, and L1 plumb line. The overall incidence rate of SASD requiring additional surgery was 2.8%. Kaplan-Meier analysis predicted a disease-free rate of adjacent segments in 94.3% of the patients at 4 years and in 90.8% of the patients at 8 years after the index operation. In the analysis of risk factors, a negative L1 plumb line was associated with a 5.6 times higher incidence of SASD requiring additional surgery than that associated with a positive L1 plumb line(p=0.0096). There was no significant difference in the survival rates based on age, sex, number of fused segments, and concomitant laminectomy to adjacent segment. Approximately 9.2% of the patients were predicted to undergo additional surgery for treating SASD within 8 years of MIS-TLIF. In this study, presence of a negative L1 plumb line indicated higher incidence of additional SASD associated surgeries than that shown by a positive L1 plumb line. Therefore, surgeons should carefully consider this factor while performing MIS-TLIF.


Helicobacter pylori genotypes are associated with clinical outcome in Portuguese patients and show a high prevalence of infections with multiple strains.
Clinical outcome of Helicobacter pylori infection is associated with virulence-associated bacterial genotypes. This study assessed the relationships between vacA, cagA and iceA genotypes and gastric diseases in Portuguese patients. A total of 319 patients were endoscoped and gastric biopsy specimens were studied by PCR and reverse hybridization (LiPA). vacA genotypes s1/m1, s1/m2 and s2/m2 were observed in 53%, 14.5% and 32.5% of the cases, respectively. The majority (93.4%) of the s1 cases were s1b and 6.6% were s1a. Multiple vacA genotypes were found in 37.3% of the cases. Gastric ulcer and gastric carcinoma were associated with the presence of vacA s1 (P = 0.008 and P < 0.001, respectively) and vacA m1 genotypes (P = 0.007 and P < 0.001, respectively). Duodenal ulcers were associated with vacA s1 (P < 0.001) but not with the vacA m genotype (P = 0.221). cagA was present in 71.2% of the cases and was associated with duodenal ulcer (P < 0.001), gastric ulcer (P = 0.009) and gastric carcinoma (P < 0.001). iceA1 was found in 27.3% and iceA2 in 32.3% of the cases. In 36.7% of the isolates both iceA alleles were found, and 3.8% were negative for iceA. The iceA genotype was not associated with clinical outcome. vacA s1 and cagA+ H. pylori strains are associated with duodenal ulcer, gastric ulcer or gastric carcinoma. vacA m1 is associated with gastric ulcer or carcinoma but not with duodenal ulcer. Infection with multiple H. pylori strains is remarkably high in Portugal and is more frequent in duodenal ulcer patients.


Expression patterns of neurturin and its receptor components in developing and degenerative mouse retina.
Neurturin (NTN) and its receptor components (GFRalpha2 and Ret) play an important role in the survival of different populations of neurons in the central and peripheral nervous systems. To gain insight into their possible functions throughout normal retinal development and during retinal neuronal apoptosis, the retinal distribution of expression of NTN and GFRalpha2 mRNAs and Ret protein were compared in control and retinal degeneration (rd) mice. Eyes from control and rd animals were fixed in paraformaldehyde before sectioning. For in situ hybridization, retinal sections were hybridized with 35S-radiolabeled sense and antisense riboprobes for murine NTN and GFRalpha2 and were autoradiographed. Ret localization was detected by immunofluorescence. Neurturin mRNA expression was modulated through normal postnatal retinal development and was localized primarily to the inner retina and photoreceptor outer segments. GFRalpha2 mRNA displayed a diffuse developmental pattern of expression, but in the mature normal retina, NTN and GFRalpha2 mRNAs were more closely colocalized. Ret protein was localized particularly at the outer segments of photoreceptors, inner retina, and ganglion cell layers, but there were no prominent differences among genotypes. Increased NTN mRNA expression was detected in the retinal pigment epithelium and neural retina in concert with photoreceptor degeneration in rd mouse. In contrast, the level of GFRalpha2 mRNA was lower in rd compared with that in normal retina. These results suggest that NTN and its receptor are involved in retinal postnatal development and maintenance and that alterations in their transcription patterns are associated with inherited retinal degeneration.


Effects of a central cholinesterase inhibitor on reducing falls in Parkinson disease.
To investigate if a central cholinesterase inhibitor will reduce falling frequency in subjects with Parkinson disease (PD) with advanced postural instability. Falling due to postural instability is a significant problem in advancing PD, and is minimally impacted by dopaminergic therapy. Anticholinergic medications increase falling in the elderly. Further, CNS cholinergic neuron loss occurs in PD. We hypothesized that acetylcholine augmentation may reduce frequent falling in subjects with PD. We enrolled 23 subjects with PD who reported falling or nearly falling more than 2 times per week. In a randomized, placebo-controlled, crossover design, subjects were given 6 weeks of donepezil or placebo with a 3-week washout between phases. The primary outcomes were daily falls and near falls reported on postcards. Secondary outcomes included scores on the Activities of Balance Confidence Scale, Berg Balance Scale, Clinical Global Impression of Change, Folstein Mini-Mental State Examination, and the motor section of the Unified Parkinson's Disease Rating Scale. Fall frequency per day on placebo was 0.25 ± 0.08 (SEM) compared with 0.13 ± 0.03 on donepezil (p < 0.05). The frequency of near falls was not significantly different between phases. The secondary outcomes did not differ; however, there was a trend to improvement on the subject-completed Global Impression of Change scale. Subjects with PD fell approximately half as often during the 6 weeks on donepezil than on placebo. Larger trials of cholinergic augmentation are warranted in subjects with PD with frequent falls. This study provides Class II evidence that donepezil (maximum 10 mg per day) significantly reduced the number of falls in patients with PD (0.13 falls/day, SEM = 0.03) than when taking placebo (0.25 falls/day, SEM = 0.08, p = 0.049).


Therapeutic targeting of HMGB1 during experimental sepsis modulates the inflammatory cytokine profile to one associated with improved clinical outcomes.
Sepsis remains a significant health burden and a major clinical need exists for therapeutics to dampen the excessive and uncontrolled immune activation. Nuclear protein high mobility group box protein 1 (HMGB1) is released following cell death and is a late mediator in sepsis pathogenesis. While approaches targeting HMGB1 have demonstrated reduced mortality in pre-clinical models of sepsis, the impact of HMGB1 blockade on the complex septic inflammatory milieu and the development of subsequent immunosuppression remain enigmatic. Analysis of plasma samples obtained from septic shock patients established an association between increased HMGB1 and non-survival, higher APACHE II scores, and increased pro-inflammatory cytokine responses. Pre-clinically, administration of neutralising ovine anti-HMGB1 polyclonal antibodies improved survival in murine endotoxaemia and caecal ligation and puncture-induced sepsis models, and altered early cytokine profiles to one which corresponded to patterns observed in the surviving patient cohort. Additionally, anti-HMGB1 treated murine sepsis survivors were significantly more resistant to secondary bacterial infection and exhibited altered innate immune cell phenotypes and cytokine responses. These findings demonstrate that anti-HMGB1 antibodies alter inflammation in murine sepsis models and reduce sepsis mortality without potentiating immunosuppression.


Effects of training attendance on muscle strength of young men after 11 weeks of resistance training.
Training attendance is an important variable for attaining optimal results after a resistance training (RT) program, however, the association of attendance with the gains of muscle strength is not well defined. Therefore, the purpose of the present study is to verify if attendance would affect muscle strength gains in healthy young males. Ninety two young males with no previous RT experience volunteered to participate in the study. RT was performed 2 days a week for 11 weeks. One repetition maximum (1RM) in the bench press and knee extensors peak torque (PT) were measured before and after the training period. After the training period, a two step cluster analysis was used to classify the participants in accordance to training attendance, resulting in three groups, defined as high (92 to 100%), intermediate (80 to 91%) and low (60 to 79%) training attendance. According to the results, there were no significant correlations between strength gains and training attendance, however, when attendance groups were compared, the low training attendance group showed lower increases in 1RM bench press (8.8%) than the other two groups (17.6% and 18.0% for high and intermediate attendance, respectively). Although there is not a direct correlation between training attendance and muscle strength gains, it is suggested that a minimum attendance of 80% is necessary to ensure optimal gains in upper body strength.


Association between spirituality and attitudes toward older adults in nursing students: a cross-sectional study.
This study aimed to determine the correlation between spirituality and attitudes toward older adults among nursing students. The study was designed as a cross-sectional study. This study was conducted with nursing students in the nursing department of a university in Eastern Turkey. The study was completed with 366 nursing students. An information form, the Spirituality Scale, and Kogan's Attitudes toward Old People Scale were used. The mean score of the Spirituality Scale was 104.18 ± 18.79, and the mean score of the Kogan's Attitudes toward Old People Scale was 99.11 ± 13.57. There was a small but significant correlation between spirituality and attitudes toward older adults (r = 0.342, p < 0.01). Moreover, the results indicated that spirituality is positive and significantly predicted attitudes toward older adults (β = 0.342, t = 19.495, p < 0.01) and explained 11.7% of the variance in attitudes toward older adults. A small but significant correlation was found between spirituality and attitudes toward older adults. Further study on the causal relationship between spirituality and attitudes toward older adults among nursing students is necessary.


The Christmas season as a risk factor for chronic obstructive pulmonary disease exacerbations.
Epidemics of hospitalization for chronic obstructive pulmonary disease (COPD) occur annually during the Christmas holidays, and COPD exacerbations commonly coincide with respiratory viral infections. To compare the incidence and determinants of COPD exacerbations occurring between the Christmas holiday period and the remainder of the winter season. Seventy-one subjects with COPD of mixed severity faxed daily symptom diaries to a computer monitoring system from December 1, 2006, to April 30, 2007. Possible exacerbations prompted a home visit for assessment, spirometry and specimen collection for virological testing. Study subjects submitted a total of 95.4% of possible daily symptom diary sheets by fax. Of 114 possible COPD exacerbations detected using the faxed diaries, 110 met the Anthonisen criteria for true exacerbations. A total of 47 exacerbations (mean 6.7/week) occurred during the Christmas holiday period, while 63 exacerbations (mean 4.3/week) occurred during the remainder of winter. Of the Christmas period exacerbations and of those in the balance of winter, 21 (44%) and 20 (32%), respectively, coincided with respiratory viral infections. The incidence of COPD exacerbations during the Christmas period was greater than during the rest of winter in 2006/2007 and peaked immediately before Christmas - in contrast to hospital presentation for COPD, which peaked during the Christmas week. No clear role of respiratory viral infections in the increased rate of exacerbations during the Christmas period was established in the present study. COPD patients were highly compliant with daily symptom reporting using faxed daily diaries, which permitted nearly complete detection of all exacerbations that occurred at incidence.


Social Disparities in Obesogenic Behaviors in Adolescents.
Demographic and social characteristics, such as sex, race/ethnicity, and income, have been implicated as risk and protective factors for behavior change regarding obesogenic behaviors in adolescents. The purpose of this study was to determine the social disparities in obesogenic behaviors and compare social disparities in obesogenic behaviors between adolescents who are overweight/obese and non-overweight adolescents using an alternative methodology for calculating disparities. Data were obtained from the 2013 Massachusetts Youth Risk Behavior Surveillance Systems. Social disparities ratios for meeting fruit and vegetable recommendation, daily breakfast consumption, physical activity, and non-sedentary activity were calculated using the Extended Gastwirth Index Method. Independent sample t tests were used to compare social disparities between non-overweight and overweight/obese participants. Racial disparities were the largest contributor to overall disparities for meeting fruit and vegetables recommendations, daily breakfast, and non-sedentary activity, while sex disparities were the largest contributor to overall disparities for meeting physical activity recommendations. The non-overweight group had lower free/reduced lunch disparities for all behaviors when compared to the overweight/obese group. The results of this study confirmed that social disparities exist for obesogenic behaviors. The methodology allowed for the determination of the percentage change needed in behavior to eliminate disparities between groups. These calculations are a useful tool for identifying groups that should be targeted for intervention if disparities are to be reduced.


Synthesis of 6,8-diazabicyclo
[formula: see text] Starting with the proteinogenic amino acid (S)-glutamate, a general method for the synthesis of 3-(piperazin-2-yl)propionic acid esters 7 with various substituents at N-4 of the piperazine ring system is presented. An intramolecular ester condensation of 7 is the key step in the formation of the 6,8-diazabicyclo[3.2.2]nonane derivatives 8-10, which are of interest as conformationally restricted piperazines.


Prolonged production of TNF-alpha exacerbates illness during respiratory syncytial virus infection.
CD8(+) CTL are the main effector cells responsible for resolving viral infections. However, the CTL response to respiratory syncytial virus (RSV) infection in mice facilitates viral clearance at the expense of significant immunopathology. Previous reports have shown a strong correlation between the mechanism of CTL activity and the severity of RSV-induced illness. Furthermore, experiments in perforin knockout mice revealed that antiviral cytokine production temporally correlated with RSV-induced illness. In the current study, we show that TNF-alpha is the dominant mediator of RSV-associated illness, and it is also important for clearance of virus-infected cells during the early stages of infection. We also demonstrate that IFN-gamma plays a protective role in conjunction with perforin/granzyme-mediated killing. Preliminary experiments in gld mice that express nonfunctional Fas ligand (FasL) revealed that RSV-induced illness is significantly reduced in the absence of FasL-mediated killing. Antiviral cytokine production was not elevated in the absence of FasL, suggesting a possible link between FasL and antiviral cytokine activity. This work shows that multiple phenotypic subsets of CD8(+) CTLs respond to RSV infection, each with varying capacities for clearance of virus-infected cells and the induction of illness. In addition, the revelation that TNF-alpha is the principal mediator of RSV-induced illness means that administration of TNF receptor antagonists, in combination with antiviral therapy, may be an effective method to treat RSV infections.


Cerebral (cortical) biostimulation.
Presently, stimulation of the surface of the brain in order to provide artificial vision or hearing for the blind and deaf is in its infant stages. Those observations which are accumulating now have as their aim the investigation of the feasibility of such prosthetic devices. Whether such devices will ever be of real therapeutic benefit remains uncertain and can only be determined by this type of very labor-intensive, expensive and interdisciplinary investigation. When one considers, on the other hand, that there are between one-quarter and one-half million individuals in the United States and Canada who are profoundly deaf and a similar number who are legally blind, the value of the pursuit of such investigation requires little defense.


Global Survey of Perceptions of the Surgical Safety Checklist Among Medical Students, Trainees, and Early Career Providers.
The Surgical Safety Checklist (SSC) has been shown to reduce perioperative complications across global health systems. We sought to assess perceptions of the SSC and suggestions for its improvement among medical students, trainees, and early career providers. From July to September 2019, a survey assessing perceptions of the SSC was disseminated through InciSioN, the International Student Surgical Network comprising medical students, trainees, and early career providers pursuing surgery. Individuals with ≥2 years of independent practice after training were excluded. Respondents were categorized according to any clinical versus solely non-clinical SSC exposure. Logistic regression was used to evaluate associations between clinical/non-clinical exposure and promoting future use of the SSC, adjusting for potential confounders/mediators: training level, human development index, and first perceptions of the SSC. Thematic analysis was conducted on suggestions for SSC improvement. Respondent participation rate was 24%. Three hundred and eighteen respondents were included in final analyses; 215 (67%) reported clinical exposure and 190 (60%) were promoters of future SSC use. Clinical exposure was associated with greater odds of promoting future SSC use (aOR 1.81 95% CI [1.03-3.19], p = 0.039). A greater proportion of promoters reported "Improved Operating Room Communication" as a goal of the SSC (0.21 95% CI [0.15-0.27]-vs.-0.12 [0.06-0.17], p = 0.031), while non-promoters reported the SSC goals were "Not Well Understood" (0.08 95% CI [0.03-0.12]-vs.-0.03 [0.01-0.05], p = 0.032). Suggestions for SSC improvement emphasized context-specific adaptability and earlier formal training. Clinical exposure to the SSC was associated with promoting its future use. Earlier formal clinical training may improve perceptions and future use among medical students, trainees, and early career providers.


Consensus document of the Spanish Society of Paediatric Infectious Diseases and the Advisory Committee on Vaccines of the Spanish Association of Pediatrics for vaccination of immunosuppressed individuals.
The number of people with immunosuppression is increasing considerably due to their greater survival and the use of new immunosuppressive treatments for various chronic diseases. This is a heterogeneous group of patients in whom vaccination as a preventive measure is one of the basic pillars of their wellbeing, given their increased risk of contracting infections. This consensus, developed jointly by the Sociedad Española de Infectología Pediátrica (Spanish Society of Pediatric Infectious Diseases) and the Advisory Committee on Vaccines of the Asociación Española de Pediatría (Spanish Association of Paediatrics), provides guidelines for the development of a personalised vaccination schedule for patients in special situations, including general recommendations and specific recommendations for vaccination of bone marrow and solid organ transplant recipients, children with inborn errors of immunity, oncologic patients, patients with chronic or systemic diseases and immunosuppressed travellers.


Electronic medical summaries in general practice--considering the patient's contribution.
Data entry into electronic records is intrinsically complex. Errors may occur in the primary (paper) record and further errors when data is transferred to the electronic record. To elicit patients' ideas about their personal medical summaries, specifically considering accuracy, level of agreement between doctors and patients, and patients' concerns about computerisation and access to their records. Qualitative study using semi-structured interviews. Nineteen patients aged 20 to 65 years from a large training general practice (eight partners) in a deprived area in the West Midlands. Patients agreeing to be interviewed were mailed a copy of their electronic summary, which contained 'active problems', 'significant (not active) problems', 'allergies', and 'present medication'. Semi-structured interviews were conducted, which were tape recorded and transcribed. The constant comparative method of grounded theory was used to analyse the data. Patients saw the summaries as a tool for the doctor's own use. They expected their general practitioners (GPs) to select the information relevant for their medical care, keep it updated, make it quickly available across the health service where needed, and limit access appropriately. The saw potential benefits of computerisation in supporting continuity of care. No patients had previously asked to see their notes, but most welcomed the opportunity to discuss the content of the summaries, correct any errors, and negotiate a description of problems that more closely reflected their perspective. Over half of the summaries were altered by the GP after discussion. Patients trust their personal doctors, both as caretakers of their notes and as gatekeepers for access. Electronic medical summaries in general practice are inaccurate to a worrying extent. Negotiation with patients can result in a more accurate summary that includes the patient's perspective. Further studies are needed to look at the feasibility of patient participation in such a process and to see what benefits, in terms of improved continuity of care and improved doctor-patient relationship, may result.


[Berlin dye laser].
The conditions for an optimal ophthalmic coagulating system are derived from the absorption spectra of xanthophyll, melanin and hemoglobin. Coagulation is effected by a dye laser with two dyes. The continuously tunable range of 570 nm to 680 nm opens up new horizons in photocoagulation of the retina.


Aesthetic Crown Lengthening Using Chu Aesthetic Gauges And Evaluation of Biologic Width Healing.
The principles of biologic width have governed the literature and served as a clinical guideline during the evaluation of perio- restorative interrelationships. An adequate understanding of this concept is paramount to ensure adequate form, function, aesthetics and comfort of the dentition. Biologic width violation has become a common problem as most of the practitioners tend to underestimate the amount of tooth structure that must be exposed during a crown lengthening procedure. Also, adding to the confusion, there is a lack of general agreement regarding the amount of tooth structure that must be exposed above the crest of bone for restorative purposes. The aim of this study was to perform aesthetic crown lengthening using Chu aesthetic gauges and evaluate the healing of biologic width. A total of 90 teeth in 15 patients were included into the study of which 30 teeth required crown lengthening and 60 teeth shared a proximal surface with the experimental teeth. Aesthetic crown lengthening was performed using the Chu aesthetic gauges. Presurgical and intraoperative data were recorded at baseline, three and six months at six sites per tooth. The computed data suggest that although the positional changes of the periodontal tissues stabilize by three months, the biologic width if adequate crown lengthening is carried out re-establishes itself by three months to the original vertical levels and further gets stabilized by six months. A step by step approach to periodontal aesthetic crown lengthening using Chu aesthetic gauge can serve to be vital for successful, predictable, and aesthetic restorative outcome.


[Recommendations on the pathological report of pituitary tumors. A consensus of experts of the Spanish Society of Endocrinology and Nutrition and the Spanish Society of Pathology].
Pituitary neuroendocrine tumors (PitNETs) constitute, together with other tumors of the sellar region, 15-25% of intracranial neoplasms. In 2017, the World Health Organization proposed a new classification of PitNETs. The main innovation with respect to the 2004 classification was the recommendation to include in the immunohistochemical evaluation of PitNETs the determination of the transcription factors of the 3 pituitary cell lineages: Pit-1, Tpit and SF-1. Additionally, other clinicopathological classifications with a predictive capacity of tumor behavior during follow-up were proposed. Given these changes, it is appropriate to adapt the knowledge generated during the last 15 years to the daily practice of the treatment and monitoring of PitNETs at the Centers of Excellence in Pituitary Pathology. This document includes the positioning of the Spanish Society of Endocrinology and Nutrition (SEEN) and the Spanish Society of Pathology (SEAP) on the classification and denomination of the PitNETs and the information that the pathologist should provide to the clinician to facilitate the treatment and monitoring of these tumors.