Reconstructing the Neanderthal Eustachian Tube: New Insights on Disease Susceptibility, Fitness Cost, and Extinction.
Neanderthals are among the best studied and yet most enigmatic fossil human groups with aspects of their anatomy and functional morphology remaining poorly understood. We present the first anatomical reconstruction of the Neanderthal cartilaginous Eustachian tube (CET), a vital component of the upper respiratory tract and nexus for the middle ear and postnasal airway. The Eustachian (auditory, pharyngotympanic) tube, comprised of a bony and cartilaginous (CET) portion, is integral to normal physiological functions such as middle ear aeration and pressure equilibration. Findings indicate that Neanderthal tubal morphology may have predisposed them to high rates of middle ear disease (otitis media [OM]). In living humans, mechanical CET dysfunction underlies OM in infants and young children, with sequelae including hearing loss, meningitis, and pneumonia. Despite proven linkage of CET malfunction with OM, the role of CET morphology in Neanderthal health and disease remains unstudied. We reconstructed Neanderthal CET morphology, comparing their crania to a modern human growth series. Methods included geometric morphometrics and univariate measures among Procrustes-fitted coordinates. Results showed Neanderthal adults exhibiting primitively tall and narrow nasopharynges with infant-like horizontal CET and choanal orientation. As horizontal CET orientation is associated with increased OM incidence in infants and children until around age six, its appearance in Neanderthal adults strongly indicates persistence of high OM susceptibility at this time. This could have compromised fitness and disease load relative to sympatric modern humans, affecting Neanderthals' ability to compete within their ecological niche, and potentially contributing to their rapid extinction. Anat Rec, 302:2109-2125, 2019. © 2019 American Association for Anatomy.


Search for new physics with a monojet and missing transverse energy in pp collisions at √s = 7 TeV.
A study of events with missing transverse energy and an energetic jet is performed using pp collision data at a center-of-mass energy of 7 TeV. The data were collected by the CMS detector at the LHC, and correspond to an integrated luminosity of 36 pb(-1). An excess of these events over standard model contributions is a signature of new physics such as large extra dimensions and unparticles. The number of observed events is in good agreement with the prediction of the standard model, and significant extension of the current limits on parameters of new physics benchmark models is achieved.


Specificity and heterogeneity of terahertz radiation effect on gene expression in mouse mesenchymal stem cells.
We report that terahertz (THz) irradiation of mouse mesenchymal stem cells (mMSCs) with a single-frequency (SF) 2.52 THz laser or pulsed broadband (centered at 10 THz) source results in irradiation specific heterogenic changes in gene expression. The THz effect depends on irradiation parameters such as the duration and type of THz source, and on the degree of stem cell differentiation. Our microarray survey and RT-PCR experiments demonstrate that prolonged broadband THz irradiation drives mMSCs toward differentiation, while 2-hour irradiation (regardless of THz sources) affects genes transcriptionally active in pluripotent stem cells. The strictly controlled experimental environment indicates minimal temperature changes and the absence of any discernable response to heat shock and cellular stress genes imply a non-thermal response. Computer simulations of the core promoters of two pluripotency markers reveal association between gene upregulation and propensity for DNA breathing. We propose that THz radiation has potential for non-contact control of cellular gene expression.


National influenza surveillance systems in five European countries: a qualitative comparative framework based on WHO guidance.
Influenza surveillance systems vary widely between countries and there is no framework to evaluate national surveillance systems in terms of data generation and dissemination. This study aimed to develop and test a comparative framework for European influenza surveillance. Surveillance systems were evaluated qualitatively in five European countries (France, Germany, Italy, Spain, and the United Kingdom) by a panel of influenza experts and researchers from each country. Seven surveillance sub-systems were defined: non-medically attended community surveillance, virological surveillance, community surveillance, outbreak surveillance, primary care surveillance, hospital surveillance, mortality surveillance). These covered a total of 19 comparable outcomes of increasing severity, ranging from non-medically attended cases to deaths, which were evaluated using 5 comparison criteria based on WHO guidance (granularity, timing, representativeness, sampling strategy, communication) to produce a framework to compare the five countries. France and the United Kingdom showed the widest range of surveillance sub-systems, particularly for hospital surveillance, followed by Germany, Spain, and Italy. In all countries, virological, primary care and hospital surveillance were well developed, but non-medically attended events, influenza cases in the community, outbreaks in closed settings and mortality estimates were not consistently reported or published. The framework also allowed the comparison of variations in data granularity, timing, representativeness, sampling strategy, and communication between countries. For data granularity, breakdown per risk condition were available in France and Spain, but not in the United Kingdom, Germany and Italy. For data communication, there were disparities in the timeliness and accessibility of surveillance data. This new framework can be used to compare influenza surveillance systems qualitatively between countries to allow the identification of structural differences as well as to evaluate adherence to WHO guidance. The framework may be adapted for other infectious respiratory diseases.


Effect of imatinib on the signal transduction cascade regulating telomerase activity in K562 (BCR-ABL-positive) cells sensitive and resistant to imatinib.
Imatinib mesylate (IM) is a tyrosine kinase inhibitor selective for BCR-ABL and indicated for the treatment of chronic myeloid leukemia. It has recently been demonstrated that IM also targets other cellular components. Considering the significant role of telomerase in malignant transformation, we studied the effect of IM on telomerase activity (TA) and regulation in BCR-ABL-positive and -negative cells, sensitive and resistant to IM. Through combining telomeric repeat amplification protocol for detecting TA, reverse transcription polymerase chain reaction and Western blots for detecting RNA and protein levels of telomerase regulating proteins and fluorescence-activated cell sorting analysis, we showed that IM targets telomerase and the signal transduction cascade upstream of it. IM significantly inhibited TA in BCR-ABL-positive and -negative cells and in chronic myeloid leukemia patients. TA inhibition was also observed in BCR-ABL positive cells resistant to IM at drug concentrations that did not lead to a reduction in BCR-ABL expression. In addition, a reduction in phosphorylated AKT and phosphorylated PDK-1 was also detected following IM incubation. We demonstrate an inhibitory effect of IM on TA and on the AKT/PDK pathway. Because this effect was observed in cell expressing the BCR-ABL protein as well as cells not expressing it, and in cells sensitive as well as resistant to IM, it is reasonable to assume that the inhibitory effect of IM on TA is not mediated through known IM targets. The results of this study show that cells resistant to IM with regard to its effect on BCR-ABL could still be sensitive to IM treatment regarding other cellular components.


Evidence for discrete landmark use by pigeons during homing.
Considerable efforts have been made to investigate how homing pigeons (Columba livia f. domestica) are able to return to their loft from distant, unfamiliar sites while the mechanisms underlying navigation in familiar territory have received less attention. With the recent advent of global positioning system (GPS) data loggers small enough to be carried by pigeons, the role of visual environmental features in guiding navigation over familiar areas is beginning to be understood, yet, surprisingly, we still know very little about whether homing pigeons can rely on discrete, visual landmarks to guide navigation. To assess a possible role of discrete, visual landmarks in navigation, homing pigeons were first trained to home from a site with four wind turbines as salient landmarks as well as from a control site without any distinctive, discrete landmark features. The GPS-recorded flight paths of the pigeons on the last training release were straighter and more similar among birds from the turbine site compared with those from the control site. The pigeons were then released from both sites following a clock-shift manipulation. Vanishing bearings from the turbine site continued to be homeward oriented as 13 of 14 pigeons returned home. By contrast, at the control site the vanishing bearings were deflected in the expected clock-shift direction and only 5 of 13 pigeons returned home. Taken together, our results offer the first strong evidence that discrete, visual landmarks are one source of spatial information homing pigeons can utilize to navigate when flying over a familiar area.


A new species of Pimelodella (Siluriformes: Heptapteridae) from the Guiana Shield, Brazil.
A new species of Pimelodella is described from the Rio Ipitinga, Rio Jari basin, a left bank tributary of the Rio Amazonas in Brazil. The new species is diagnosed from all congeners by having a dark oval mark on the humeral region. It also differs from all congeners by a unique set of characters, including the presence of 47 to 49 total vertebrae, unpigmented areas dorsally and ventrally adjacent to the dark midlateral stripe, and maxillary barbels reaching at least to vertical through caudal fin insertion. Faunal similarities between the southern part of the eastern Guiana Shield and coastal drainages in the Guianas and Suriname are discussed.


Yeast vaginitis during pregnancy: susceptibility testing of 13 antifungal drugs and boric acid and the detection of four virulence factors.
A higher prevalence of vulvovaginal candidiasis (VVC) is seen in pregnant women compared with those who are not pregnant. Recurrence is also more common in pregnant women, and therapeutic responses are reduced. In this investigation, 207 vaginal yeast isolates recovered from pregnant women were tested for susceptibility to 13 antifungal drugs and boric acid and through these studies four virulence factors were also determined. The isolates were recovered from vaginal samples of patients with acute VVC [AVVC, (n = 73)], symptomatic recurrent VVC [RVVC, (n = 89)], asymptomatic RVVC (n = 27), and those without signs and symptoms (n = 18). Candida albicans was the most common species found (59.9%), followed by C. glabrata (19.8%), other Candida spp., (19.8%), and Saccharomyces cerevisiae (0.5%). Antifungal susceptibility testing was performed as described in CLSI document M27-A3. Additionally, we examined phospholipase and proteinase production, adhesion to vaginal epithelial cells and hemolytic activity. Notably, the MIC values of Candida spp. isolates derived from patients with VVC were no different from those of the controls (P > 0.05). In addition, Candida isolates derived from patients with AVVC or RVVC produced significantly higher amounts of phospholipase and proteinase compared with the controls (P < 0.05). Antifungal testing and the determination of virulence factors may lead to the effective and prompt treatment of VVC, particularly in pregnant women.


HER2 testing in a population-based study of patients with metastatic breast cancer treated with trastuzumab.
The development of trastuzumab has led to new therapeutic strategies for patients with breast cancer. Trastuzumab has been shown to only be effective in those patients whose cancers are HER2 positive by either immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH). To determine the accuracy of HER2 testing in 2 provinces in Canada. Patients with metastatic breast cancer diagnosed between 1999 and 2002 who were HER2 positive in the local laboratories were included in this study. All cases were retested centrally, by IHC (using 4 methods) and FISH. In addition, 205 locally reported HER2-negative metastatic breast cancer cases were retested centrally. Concordance between the 505 local IHC-positive cases with central IHC testing varied between 79.3% and 89.6% depending on the IHC method and scoring method used. HER2 gene amplification by FISH was present in 86.1% of local IHC-positive cases. Concordance between the 205 local IHC-negative tumors with central testing ranged between 94.8% and 100% for IHC and was 98.5% for FISH. This study demonstrated that locally reported HER2-negative results were highly accurate, but less accuracy was demonstrated with local HER2-positive results. These results emphasize the need for participation in a quality assurance program.


Data Based Prediction of Blood Glucose Concentrations Using Evolutionary Methods.
Predicting glucose values on the basis of insulin and food intakes is a difficult task that people with diabetes need to do daily. This is necessary as it is important to maintain glucose levels at appropriate values to avoid not only short-term, but also long-term complications of the illness. Artificial intelligence in general and machine learning techniques in particular have already lead to promising results in modeling and predicting glucose concentrations. In this work, several machine learning techniques are used for the modeling and prediction of glucose concentrations using as inputs the values measured by a continuous monitoring glucose system as well as also previous and estimated future carbohydrate intakes and insulin injections. In particular, we use the following four techniques: genetic programming, random forests, k-nearest neighbors, and grammatical evolution. We propose two new enhanced modeling algorithms for glucose prediction, namely (i) a variant of grammatical evolution which uses an optimized grammar, and (ii) a variant of tree-based genetic programming which uses a three-compartment model for carbohydrate and insulin dynamics. The predictors were trained and tested using data of ten patients from a public hospital in Spain. We analyze our experimental results using the Clarke error grid metric and see that 90% of the forecasts are correct (i.e., Clarke error categories A and B), but still even the best methods produce 5 to 10% of serious errors (category D) and approximately 0.5% of very serious errors (category E). We also propose an enhanced genetic programming algorithm that incorporates a three-compartment model into symbolic regression models to create smoothed time series of the original carbohydrate and insulin time series.


Technological Developments and Strategic Management for Overcoming the COVID-19 Challenge within the Hospital Setting in Israel.
The coronavirus disease 2019 (COVID-19) pandemic has remarkably challenged health care organizations and societies. A key strategy for confronting the disease implications on individuals and communities was based on harnessing multidisciplinary efforts to develop technologies for mitigating the disease spread and its deleterious clinical implications. One of the main challenging characteristics of COVID-19 is the provision of medical care to patients with a highly infective disease mandating the use of isolation measures. Such care is complicated by the need for complex critical care, dynamic treatment guidelines, and a vague knowledge regarding the disease's pathophysiology. A second key component of this challenge was the overwhelming surge in patient burden and the relative lack of trained staff and medical equipment which required rapid re-organization of large systems and augmenting health care efficiencies to unprecedented levels. In contrast to the risk management strategies employed to mitigate other serious threats and the billions of dollars that are invested in reducing these risks annually by governments around the world, no such preparation has been shown to be of effect during the current COVID-19 pandemic. Unmet needs were identified within the newly opened COVID-19 departments together with the urgent need for reliable information for effective decision-making at the state level.This review article describes the early research and development response in Israel under the scope of in-hospital patient care, such as non-contact sensing of patients' vital signs, and how it could potentially be weaved into a practical big picture at the hospital or national level using a strategic management system. At this stage, some of the described technologies are still in developmental or clinical evidence generation phases with respect to COVID-19 settings. While waiting for future publications describing the results of the ongoing evidence generation efforts, one should be aware of this trend as these emerging tools have the potential to further benefit patients as well as caregivers and health care systems beyond the scope of the current pandemic as well as confronting future surges in the number of cases.


Perceived Conflicting Desires to Delay the First Birth: A Household-Level Exploration in Nepal.
It is accepted as the norm that couples in South Asia begin childbearing immediately after marriage and that, even if they would like to delay, they are pressured to have children by household members. Little research, however, has explored the desire to delay childbearing among newly married couples and their household members in Nepal-a setting with changing marriage formation patterns, increasing women's education and falling fertility. To explore the dynamics of current childbearing desires, in-depth interviews of 20 intact triads of newly married women, their husbands and their mothers-in-law were conducted in one district of Nepal in February-March 2017. Using thematic analysis, interviews were read and coded separately by type (wives, husbands, mothers-in-law), and then the triads were read together and coded to determine household-level patterns and themes. Most newly married women and men want to delay their first birth, but have not communicated with each other about this. Even though couples are often in agreement about delaying, they feel pressured by in-laws and society to bear children early. Contrary to expectations, some mothers-in-law support delaying childbearing to allow their daughter-in-law to mature, continue her education or earn wages; however, they too perceive societal pressure. Male migration for work also contributes to early childbearing pressure. Helping couples to sort through conflicting fertility norms and desires may be important to delay childbearing when desired. Programs should engage all household members, and work to increase couples' and household communication to address misperceptions about fertility desires.


Older people and falls: health status, quality of life, lifestyle, care networks, prevention and views on service use following a recent fall.
This study has investigated older people's experiences of a recent fall, its impact on their health, lifestyle, quality of life, care networks, prevention and their views on service use. Falls are common in older people and prevalence increases with age. Falls prevention is a major policy and service initiative. An exploratory, qualitative design involving two time points. A convenience sample of 27 older people from two primary care trusts who had a recent fall. Taped semi structured qualitative interviews were conducted and repeated at follow up to detect change over time and repeat falls. Data were collected on their experience of falls, health, activities of living, lifestyle, quality of life, use of services, prevention of falls, informal care and social networks. Content analysis of transcribed interviews identified key themes. The majority of people fell indoors (n = 23), were repeat fallers (n = 22) with more than half alone when they fell (n = 15). For five people it was their first ever fall. Participants in primary care trust 1 had a higher mean age than those in primary care trust 2 and had more injurious falls (n = 12, mean age 87 years vs. n = 15, mean age 81 years). The majority of non-injurious falls went unreported to formal services. Falls can result in a decline in health status, ability to undertake activities of living, lifestyle and quality of life. Local informal care and support networks are as important as formal care for older people at risk of falls or who have fallen. Access to falls prevention programmes and services is limited for people living in more rural communities. Falls prevention initiatives and services should work with local communities, agencies and informal carers to ensure equitable access and provision of information, resources and care to meet the needs of older people at risk or who have fallen.


Real-time measurement of cytosolic free calcium concentration in Jurkat cells during ELF magnetic field exposure and evaluation of the role of cell cycle.
Extremely low frequency magnetic fields (ELF MF) have been reported to alter a number of cell signaling pathways, including those involved in proliferation, differentiation and apoptosis where cytosolic free calcium ([Ca(2+)](c)) plays an important role. To better understand the biological conditions under which ELF MF exposure might alter [Ca(2+)](c), we measured [Ca(2+)](c) by ratiometric fluorescence spectrophotometry during exposure to ELF MF in Jurkat E6.1 cells synchronized to different phases of the cell cycle. Suspensions of cells were exposed either to a near zero MF (Null) or a 60 Hz, 100 microT sinusoidal MF superimposed upon a collinear 78.1 microT static MF (AC + DC). An initial series of experiments indicated that the maximum increase in [Ca(2+)](c) above baseline after stimulation with anti-CD3 was significantly higher in samples exposed to AC + DC (n = 30) compared to Null (n = 30) with the largest difference in G2-M enriched samples. However, in a second study with G2-M enriched cells, samples treated with AC + DC (n = 17) were not statistically different from Null-treated samples (n = 27). Detailed analysis revealed that the dynamics in [Ca(2+)](c) before and after stimulation with anti-CD3 were dissimilar between Null samples from each study. From the results, we concluded (i) that the ELF MF increased [Ca(2+)](c) during an antibody-induced signaling event, (ii) that the ELF MF effect did not depend to a large degree on cell cycle, and (iii) that a field-related change in [Ca(2+)](c) signaling appeared to correlate with features in the [Ca(2+)](c) dynamics. Future work could evaluate [Ca(2+)](c) dynamics in relation to the phase of the cell cycle and inter-study variation, which may reveal factors important for the observation of real-time effects of ELF MF on [Ca(2+)](c).


Herpes simplex encephalitis is linked with selective mitochondrial damage; a post-mortem and in vitro study.
Herpes simplex virus type-1 (HSV-1) encephalitis (HSE) is the most commonly diagnosed cause of viral encephalitis in western countries. Despite antiviral treatment, HSE remains a devastating disease with high morbidity and mortality. Improved understanding of pathogenesis may lead to more effective therapies. Mitochondrial damage has been reported during HSV infection in vitro. However, whether it occurs in the human brain and whether this contributes to the pathogenesis has not been fully explored. Minocycline, an antibiotic, has been reported to protect mitochondria and limit brain damage. Minocycline has not been studied in HSV infection. In the first genome-wide transcriptomic study of post-mortem human HSE brain tissue, we demonstrated a highly preferential reduction in mitochondrial genome (MtDNA) encoded transcripts in HSE cases (n = 3) compared to controls (n = 5). Brain tissue exhibited a significant inverse correlation for immunostaining between cytochrome c oxidase subunit 1 (CO1), a MtDNA encoded enzyme subunit, and HSV-1; with lower abundance for mitochondrial protein in regions where HSV-1 was abundant. Preferential loss of mitochondrial function, among MtDNA encoded components, was confirmed using an in vitro primary human astrocyte HSV-1 infection model. Dysfunction of cytochrome c oxidase (CO), a mitochondrial enzyme composed predominantly of MtDNA encoded subunits, preceded that of succinate dehydrogenase (composed entirely of nuclear encoded subunits). Minocycline treated astrocytes exhibited higher CO1 transcript abundance, sustained CO activity and cell viability compared to non-treated astrocytes. Based on observations from HSE patient tissue, this study highlights mitochondrial damage as a critical and early event during HSV-1 infection. We demonstrate minocycline preserves mitochondrial function and cell viability during HSV-1 infection. Minocycline, and mitochondrial protection, offers a novel adjunctive therapeutic approach for limiting brain cell damage and potentially improving outcome among HSE patients.


Dietary glutamine supplementation reduces cellular adhesion molecule expression and tissue myeloperoxidase activity in mice with gut-derived sepsis.
This study investigated the effects of glutamine (Gln) on plasma intracellular adhesion molecule-1 levels and leukocyte integrin (CD11a/CD18 and CD11b/CD18) expressions in gut-derived sepsis. Myeloperoxidase (MPO) activities in organs were also analyzed to identify the extent of tissue injury resulting from neutrophil infiltration. Mice were randomly assigned to a normal group (NC), a control group, or a Gln group. The NC group was fed standard chow diet; the control group was fed a common semipurified diet; and the Gln group received a diet in which part of the casein was replaced by Gln, which provided 25% of total amino acid nitrogen. After 3 wk, sepsis was induced by cecal ligation and puncture (CLP) in the control and Gln groups. Mice in the experimental groups were killed at 0, 6, 12, and 24 h after CLP. Mice in the NC group were killed when CLP was performed. Blood and organ samples were collected for further analysis. Plasma intracellular adhesion molecule-1 levels were significantly lower in the Gln group than in the control group at 6, 12, and 24 h after CLP. Expressions of lymphocyte CD11a/CD18 were significantly higher, whereas polymorphonuclear lymphocyte expressions of CD11b/CD18 were lower in the Gln group than in the corresponding control group at 6 and 12 h after CLP. In comparisons of MPO activities in various organs, the Gln group had lower MPO activities at 6 and 12 h in the lung, at 6, 12, and 24 h in the liver, at 12 and 24 h in the kidneys, and at 12 h in the intestine than those in the control group. Results of this study demonstrate that a Gln-supplemented enteral diet increased lymphocyte CD11a/CD18 expressions, whereas neutrophil CD11b/CD18 expressions, circulating intracellular adhesion molecule-1 levels, and MPO activities in various organs decreased with gut-derived sepsis. These findings suggest that, under septic conditions, Gln administration may enhance lymphocyte function, attenuate interactions between polymorphonuclear lymphocytes and endothelium, and thus may decrease neutrophil infiltration into tissues.


Beta blockade, diuretics, and salt restriction for the management of mild hypertension: a randomised double blind trial.
Ninety four patients with mild hypertension (average supine diastolic blood pressure (phase V) 95-110 mm Hg) were allocated at random to receive restriction of dietary sodium (maximum allowed 70 mmol(mEq)/24 h) or a normal diet. In addition, they received in random order 25 mg chlorthalidone, 200 mg metoprolol (slow release), and a fixed combination of these two drugs. Each drug treatment was given for four weeks and alternated with four weeks of placebo. Forty four patients were allocated to sodium restriction (group 1) and 50 to normal diet (group 2). The mean 24 hour urinary sodium excretion in group 1 was 74 (SD 31) mmol(mEq)/24 h, and in group 2 132 (51) mmol/24 h. Compared with the screening blood pressure the average decrement of the supine blood pressure in group 1 was 16.0/8.6 mm Hg with placebo, 21.7/11.5 mm Hg with the diuretic, 28.5/17.8 mm Hg with the beta blocker, and 28.9/18.4 mm Hg with the combined agent; in group 2 these values were 13.3/6.1, 20.3/9.7, 21.3/12.9, and 29.4/16.8 mm Hg, respectively. There was a sharp decrease of the average potassium concentration during chlorthalidone and combination treatment periods (average value 3.3 mmol(mEq)/1). These results suggest that moderate salt restriction used as sole treatment has a limited though demonstrable blood pressure lowering effect but that when it is used as an adjuvant to beta blocker treatment its value is greatly enhanced.


Causality and Anticipation: Analysis of the concept of anticipation can contribute to the philosophy of biology.
I have discussed the problem whether an explanation of the phenomena of life can be deduced from an exclusive reliance on causal relationship as in the currently accepted physical description, or whether attention should be given to something more. For this more the concept of anticipation is taken. Starting from what we observe in our own minds various notions involved in the idea of anticipation have been brought forward. The picture is derived from the philosophy of A. N. Whitehead. It is admissible in this philosophy to postulate an influence of anticipation on the statistical weights which play a part in quantum physics. This influence could change the probability distribution of the results of atomic reactions and thus account for living beings having a way of behavior of their own. I have also tried to show that an inquiry into the possibility that living organisms possess features not covered by present-day physics need not lead to a belief in supernatural phenomena. The idea of purpose should not be condemned. It does not mean being directed toward a definite goal for some billions of years. Although no quantitative relations have come forward the role of anticipation can be discussed on a rational basis and finds support in an important philosophical system. It introduces some attractive features into the definition of life and it can help to probe the depth of problems which the reductionist principle leaves unanswered. It might be considered as a picture complementary to the physical picture.


Treatment Patterns and Early Outcomes of ALK-Positive Non-Small Cell Lung Cancer Patients Receiving Ceritinib: A Chart Review Study.
This study aimed to provide the first real-world description of the characteristics, treatments, dosing patterns, and early outcomes of patients with ALK-positive non-small cell lung cancer (NSCLC) who received ceritinib in US clinical practice. US oncologists provided data from medical charts of adult patients diagnosed with locally advanced or metastatic ALK-positive NSCLC who received ceritinib following crizotinib. Patient characteristics, treatment patterns, ceritinib dosing, early outcomes, and occurrence of gastrointestinal adverse events (AEs) by dose and instructions on food intake were assessed, and Kaplan-Meier analysis was used to describe clinician-defined progression-free survival (PFS) on ceritinib. Medical charts of 58 ALK-positive NSCLC patients treated with ceritinib were reviewed (median age 63 years; 41% male; 21% with prior chemotherapy experience). At ceritinib initiation, 44 patients had multiple distant metastases, most commonly in the liver (60%), bone (53%), and brain (38%). Initial ceritinib dose varied: 71% received 750 mg, 19% 600 mg, and 10% 450 mg. Although median follow-up after ceritinib initiation was short (3.8 months), most patients achieved either a complete or partial response (69%) on ceritinib, regardless of metastatic sites present at initiation or initial dose. Median PFS on ceritinib was 12.9 months. 17% of patients had a gastrointestinal AE reported during follow-up. The majority of events occurred in patients instructed to fast; no patients instructed to take a lower dose of ceritinib with food reported gastrointestinal AEs. These early findings of ceritinib use in clinical practice suggest that ceritinib is effective at treating crizotinib-experienced ALK-positive NSCLC patients, regardless of metastatic sites or initial dose, and dosing ceritinib with food may lead to fewer gastrointestinal AEs. Future studies with larger sample size and longer follow-up are warranted, including an ongoing randomized trial to assess the gastrointestinal tolerability of ceritinib 450 and 600 mg with low-fat meals. Novartis Pharmaceutical Corporation.


Human T-cell leukemia virus type 1 (HTLV-1) tax requires CADM1/TSLC1 for inactivation of the NF-κB inhibitor A20 and constitutive NF-κB signaling.
Persistent activation of NF-κB by the Human T-cell leukemia virus type 1 (HTLV-1) oncoprotein, Tax, is vital for the development and pathogenesis of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). K63-linked polyubiquitinated Tax activates the IKK complex in the plasma membrane-associated lipid raft microdomain. Tax also interacts with TAX1BP1 to inactivate the NF-κB negative regulatory ubiquitin-editing A20 enzyme complex. However, the molecular mechanisms of Tax-mediated IKK activation and A20 protein complex inactivation are poorly understood. Here, we demonstrated that membrane associated CADM1 (Cell adhesion molecule1) recruits Ubc13 to Tax, causing K63-linked polyubiquitination of Tax, and IKK complex activation in the membrane lipid raft. The c-terminal cytoplasmic tail containing PDZ binding motif of CADM1 is critical for Tax to maintain persistent NF-κB activation. Finally, Tax failed to inactivate the NF-κB negative regulator ubiquitin-editing enzyme A20 complex, and activate the IKK complex in the lipid raft in absence of CADM1. Our results thus indicate that CADM1 functions as a critical scaffold molecule for Tax and Ubc13 to form a cellular complex with NEMO, TAX1BP1 and NRP, to activate the IKK complex in the plasma membrane-associated lipid rafts, to inactivate NF-κB negative regulators, and maintain persistent NF-κB activation in HTLV-1 infected cells.


Influence of glucocorticoids on mammary prolactin receptors in pregnant mice after ovariectomy.
Regulation of mammary prolactin receptors by steroid hormones was investigated in ovariectomized mid-pregnant mice. Ovariectomy increased the number of mammary prolactin receptors per cell with no effect or a slight decrease in dissociation constant (Kd). The simultaneous removal of adrenals prevented this increase in numbers. A single injection of glucocorticoid (corticosterone or cortisol) in ovariectomized-adrenalectomized mice restored the number of prolactin receptors in mammary glands to the same level as that in ovariectomized controls without changing the Kd. Aldosterone, deoxycorticosterone and oestradiol did not affect the number of mammary prolactin receptors after ovariectomy-adrenalectomy. Serum concentration of prolactin was not influenced by the hormone manipulation except with injections of oestradiol or cortisol and apparently did not correlate with the number of prolactin receptors. These results indicated that glucocorticoids are required for the increase in the number of mammary prolactin receptors induced by ovariectomy in mid-pregnant mice.


Supporting carers of people diagnosed with schizophrenia: evaluating change in nursing practice following training.
United Kingdom legislation and clinical standards for schizophrenia challenge nurses to re-examine the support that they provide to carers. Nurses are in a key position to provide this support but may lack the necessary skills to do so. The training programme evaluated in the present study aimed to address this problem. To evaluate change in clinical practice brought about by post-registration training for mental health nurses in supporting carers of people diagnosed with schizophrenia. The study was undertaken in collaboration between the Universities of Dundee and Glasgow, and Tayside National Health Service (NHS) Trust (Scotland). Respondents were nine nurses who completed training and then delivered a planned programme of support to carers. Data on nursing practice were gathered through semi-structured interviews with nurses before training and after providing support. Following the support intervention, carers also commented on the nurses' practice. Eight of the nine nurses reported changes in practice in five key areas: They built collaborative relationships with carers, developed a carer focused approach to their practice, acknowledged and supported the carer role, and made progress in identifying carer needs and accessing resources to meet these needs. Nurses experienced difficulties supporting carers who had mental health problems or previous negative experiences of services. Those who lacked community experience also found it difficult to adjust to working in a community setting. Although clinical supervision helped them to work through these difficulties, they remain largely unresolved. Findings from this study indicate that appropriate training may enable nurses to improve the support provided to carers of people diagnosed with schizophrenia. This study represents an important stage in determining the nature of support offered to carers by nurses. While developed to help nurses to meet clinical standards set for schizophrenia in the UK, findings may have clinical significance for nurses in other countries.


Evaluating quality of care for patients with type 2 diabetes using electronic health record information in Mexico.
Several low and middle-income countries are implementing electronic health records (EHR). In the near future, EHRs could become an efficient tool to evaluate healthcare performance if appropriate indicators are developed. The aims of this study are: a) to develop quality of care indicators (QCIs) for type 2 diabetes (T2DM) in the Mexican Institute of Social Security (IMSS) health system; b) to determine the feasibility of constructing QCIs using the IMSS EHR data; and c) to evaluate the quality of care (QC) provided to IMSS patients with T2DM. We used a three-stage mixed methods approach: a) development of QCIs following the RAND-UCLA method; b) EHR data extraction and construction of indicators; c) QC evaluation using EHR data from 25,130 T2DM patients who received care in 2009. We developed 18 QCIs, of which 14 were possible to construct using available EHR data. QCIs comprised both process of care and health outcomes. Several flaws in the EHR design and quality of data were identified. The indicators of process and outcomes of care suggested areas for improvement. For example, only 13.0% of patients were referred to an ophthalmologist; 3.9% received nutritional counseling; 63.2% of overweight/obese patients were prescribed metformin, and only 23% had HbA1c <7% (or plasma glucose≤130 mg/dl). EHR data can be used to evaluate QC. The results identified both strengths and weaknesses in the electronic information system as well as in the process and outcomes of T2DM care at IMSS. This information can be used to guide targeted interventions to improve QC.


Grin and bear it: the influence of manipulated facial expression on the stress response.
In the study reported here, we investigated whether covertly manipulating positive facial expressions would influence cardiovascular and affective responses to stress. Participants (N = 170) naive to the purpose of the study completed two different stressful tasks while holding chopsticks in their mouths in a manner that produced a Duchenne smile, a standard smile, or a neutral expression. Awareness was manipulated by explicitly asking half of all participants in the smiling groups to smile (and giving the other half no instructions related to smiling). Findings revealed that all smiling participants, regardless of whether they were aware of smiling, had lower heart rates during stress recovery than the neutral group did, with a slight advantage for those with Duchenne smiles. Participants in the smiling groups who were not explicitly asked to smile reported less of a decrease in positive affect during a stressful task than did the neutral group. These findings show that there are both physiological and psychological benefits from maintaining positive facial expressions during stress.


Ovonic threshold switching in polycrystalline zinc telluride thin films deposited by RF sputtering.
Chalcogenide materials of the amorphous phase with low band gaps were reported to show Ovonic threshold switching (OTS), making them suitable for selection devices in cross-point memory arrays. Herein, we report that ZnTe films with polycrystalline structures show OTS behavior. Nearly stoichiometric ZnTe thin films were deposited by an RF sputtering method. X-ray diffraction analysis indicated that the films were polycrystalline. The optical band gaps of the ZnTe films were estimated as 2.2 eV from UV-visible spectroscopy transmittance measurements. Photoluminescence measurements indicated the existence of deep-level defects in the ZnTe thin films. Although these ZnTe films have a polycrystalline structure with a relatively high band gap, I-V profiles show OTS characteristics, with a selectivity of over 104, fast threshold switching time in the sub-10 ns scale, and thermal stability up to 400 °C. ZnTe also shows switching endurance for more than 109 cycles without Vth drift, maintaining its selectivity of 104. Thus, we improved the threshold switching characteristics by using a wide band-gap and polycrystalline-structured ZnTe-based chalcogenide material. Post-annealing experiments indicated that the thermal budget of the ZnTe thin film was sufficient for stacked cross-point array structures, thereby overcoming a previous limitation of chalcogenide switching materials. This material is promising for application in high-density cross-point memory arrays as the selection device.


Lung Cancer Symptom Scale outcomes in relation to standard efficacy measures: an analysis of the phase III study of pemetrexed versus docetaxel in advanced non-small cell lung cancer.
Patients with advanced non-small cell lung cancer (NSCLC) require care that emphasizes symptom palliation in addition to extending survival. The low response rates and minimal survival gains observed in second-line studies underscore the need to assess treatment efficacy with symptomatic end points. To characterize the relationship between patient-reported health-related quality of life outcomes and efficacy end points (tumor response, overall survival [OS], progression-free survival [PFS]), retrospective analyses were performed on Lung Cancer Symptom Scale (LCSS) data (n = 488) from the phase III study of pemetrexed (500 mg/m2 once every 3 weeks) versus docetaxel (75 mg/m2 once every 3 weeks) in advanced NSCLC. The LCSS data consisted of patient ratings of six symptoms and three summary items using 100-mm visual analogue scales. The mean maximum improvement for each item was categorized according to best tumor response, with statistical analyses based on a two-factor interaction model (with treatment arm and response group as fixed factors). Additional analyses pooled data between treatment arms and examined correlation (nonparametric and Pearson's) of time to first worsening of symptoms (TWS) with PFS and OS. All LCSS items, except hemoptysis, showed mean maximum improvement over baseline for responders and patients with stable disease (p < 0.01), with greater improvement associated with response. Median TWS for each LCSS item ranged between 2.3 months (fatigue) and 7.0 months (cough), with correlation between TWS and PFS and OS (all p values </=0.017). For most NSCLC patients, second-line chemotherapy provides symptomatic improvement that is linked to standard efficacy outcomes. Health-related quality of life data provides complementary efficacy information that can guide routine clinical practice.


Input resistance, electrical excitability, and size of ventral horn cells in cat spinal cord.
Experiments on cat lumbosacral alpha motoneurones showed that, in comparison with cells possessing rapidly conducting axons, the cells with slowly conducting axons have the higher input resistance, that they need weaker stimulating currents to reach the threshold for repetitive firing, and that they need a relatively larger increment in current strength for a given increase in firing rate. Measurements of the number and diameters of dendritic trunks gave larger values for the larger cell bodies. The discussion deals with the interrelation between cell geometry, electrical properties, and the reflex action of alpha motoneurones.


Uncoupling of upper airway motor activity from phrenic bursting by positive end-expired pressure in the rat.
Phasic bursting in the hypoglossal nerve can be uncoupled from phrenic bursting by application of positive end-expired pressure (PEEP). We wished to determine whether similar uncoupling can also be induced in other respiratory-modulated upper airway (UAW) motor outputs. Discharge of the facial, hypoglossal, superior laryngeal, recurrent laryngeal, and phrenic nerves was recorded in anesthetized, ventilated rats during stepwise changes in PEEP with a normocapnic, hyperoxic background. Application of 3- to 6-cmH(2)O PEEP caused the onset inspiratory (I) UAW nerve bursting to precede the phrenic burst but did not uncouple bursting. In contrast, application of 9- to 12-cmH(2)O PEEP uncoupled UAW neurograms such that rhythmic bursting occurred during periods of phrenic quiescence. Single-fiber recording experiments were conducted to determine whether a specific population of UAW motoneurons is recruited during uncoupled bursting. The data indicate that expiratory-inspiratory (EI) motoneurons remained active, while I motoneurons did not fire during uncoupled UAW bursting. Finally, we examined the relationship between motoneuron discharge rate and PEEP during coupled UAW and phrenic bursting. EI discharge rate was linearly related to PEEP during preinspiration, but showed no relationship to PEEP during inspiration. Our results demonstrate that multiple UAW motor outputs can be uncoupled from phrenic bursting, and this response is associated with bursting of EI nerve fibers. The relationship between PEEP and EI motoneuron discharge rate differs during preinspiratory and I periods; this may indicate that bursting during these phases of the respiratory cycle is controlled by distinct neuronal outputs.


Simultaneous material flow analysis of nickel, chromium, and molybdenum used in alloy steel by means of input-output analysis.
Steel is not elemental iron but rather a group of iron-based alloys containing many elements, especially chromium, nickel, and molybdenum. Steel recycling is expected to promote efficient resource use. However, open-loop recycling of steel could result in quality loss of nickel and molybdenum and/or material loss of chromium. Knowledge about alloying element substance flow is needed to avoid such losses. Material flow analyses (MFAs) indicate the importance of steel recycling to recovery of alloying elements. Flows of nickel, chromium, and molybdenum are interconnected, but MFAs have paid little attention to the interconnected flow of materials/substances in supply chains. This study combined a waste input-output material flow model and physical unit input-output analysis to perform a simultaneous MFA for nickel, chromium, and molybdenum in the Japanese economy in 2000. Results indicated the importance of recovery of these elements in recycling policies for end-of-life (EoL) vehicles and constructions. Improvement in EoL sorting technologies and implementation of designs for recycling/disassembly at the manufacturing phase are needed. Possible solutions include development of sorting processes for steel scrap and introduction of easier methods for identifying the composition of secondary resources. Recovery of steel scrap with a high alloy content will reduce primary inputs of alloying elements and contribute to more efficient resource use.


Source specificity of early calcium neurotoxicity in cultured embryonic spinal neurons.
To examine the role of Ca2+ in early neuronal death, we studied the impact of free intracellular calcium concentration ([Ca2+]i) on survivability in populations of cultured mouse spinal neurons. We asked whether early neurotoxicity was triggered by Ca2+ influx, whether elevated [Ca2+]i was a predictive indicator of impending neuronal death, and whether factors other than [Ca2+]i increases influenced Ca2+ neurotoxicity. We found that when neurons were lethally challenged with excitatory amino acids or high K+, they experienced a biphasic [Ca2+]i increase characterized by a primary [Ca2+]i transient that decayed within minutes, followed by a secondary, sustained, and irreversible [Ca2+]i rise that indicated imminent cell death. We showed that in the case of glutamate-triggered neurotoxicity, processes triggering eventual cell death required Ca2+ influx, and that neurotoxicity was a function of the transmembrane Ca2+ gradient. Fura-2 Ca2+ imaging revealed a "ceiling" on measurable changes in [Ca2+]i that contributed to the difficulty in relating [Ca2+]i to neurotoxicity. We found, by evoking Ca2+ influx into neurons through different pathways, that the chief determinants of Ca2+ neurotoxicity were the Ca2+ source and the duration of the Ca2+ challenge. When Ca2+ source and challenge duration were taken into account, a statistically significant relationship between measured [Ca2+]i and cell death was uncovered, although the likelihood of neuronal death depended much more on Ca2+ source than on the magnitude of the measured [Ca2+]i increase. Thus, neurotoxicity evoked by glutamate far exceeded that evoked by membrane depolarization with high K+ when [Ca2+]i was made to increase equally in both groups. The neurotoxicity of glutamate was triggered primarily by Ca2+ influx through NMDA receptor channels, and exceeded that triggered by non-NMDA receptors and Ca2+ channels when [Ca2+]i was made to rise equally through these separate pathways. The greater neurotoxicity triggered by NMDA receptors was related to some attribute other than an ability to trigger greater [Ca2+]i increases as compared with other Ca2+ sources. We hypothesize that this represents a physical colocalization of NMDA receptors with Ca(2+)-dependent rate-limiting processes that trigger early neuronal degeneration.


Mechanism of spontaneous polarization transfer in high-field SABRE experiments.
We propose an explanation of the previously reported SABRE (Signal Amplification By Reversible Exchange) effect at high magnetic fields, observed in the absence of RF-excitation and relying only on "spontaneous" polarization transfer from parahydrogen (pH2, the H2 molecule in its nuclear singlet spin state) to a SABRE substrate. We propose a detailed mechanism for spontaneous polarization transfer and show that it is comprised of three steps: (i) Generation of the anti-phase Î1zÎ2z spin order of catalyst-bound H2; (ii) spin order conversion Î1zÎ2z→(Î1z+Î2z) due to cross-correlated relaxation, leading to net polarization of H2; (iii) polarization transfer to the SABRE substrate, occurring due to NOE. Formation of anti-phase polarization is due to singlet-to-T0 mixing in the catalyst-bound form of H2, while cross-correlated relaxation originates from fluctuations of dipole-dipole interactions and chemical shift anisotropy. The proposed mechanism is supported by a theoretical treatment, magnetic field-dependent studies and high-field NMR measurements with both pH2 and thermally polarized H2.


Conscientious Objection to Harmful Animal Use within Veterinary and Other Biomedical Education.
Laboratory classes in which animals are seriously harmed or killed, or which use cadavers or body parts from ethically debatable sources, are controversial within veterinary and other biomedical curricula. Along with the development of more humane teaching methods, this has increasingly led to objections to participation in harmful animal use. Such cases raise a host of issues of importance to universities, including those pertaining to curricular design and course accreditation, and compliance with applicable animal welfare and antidiscrimination legislation. Accordingly, after detailed investigation, some universities have implemented formal policies to guide faculty responses to such cases, and to ensure that decisions are consistent and defensible from legal and other policy perspectives. However, many other institutions have not yet done so, instead dealing with such cases on an ad hoc basis as they arise. Among other undesirable outcomes this can lead to insufficient student and faculty preparation, suboptimal and inconsistent responses, and greater likelihood of legal challenge. Accordingly, this paper provides pertinent information about the evolution of conscientious objection policies within Australian veterinary schools, and about the jurisprudential bases for conscientious objection within Australia and the USA. It concludes with recommendations for the development and implementation of policy within this arena.


Micro-optics for microfluidic analytical applications.
This critical review summarizes the developments in the integration of micro-optical elements with microfluidic platforms for facilitating detection and automation of bio-analytical applications. Micro-optical elements, made by a variety of microfabrication techniques, advantageously contribute to the performance of an analytical system, especially when the latter has microfluidic features. Indeed the easy integration of optical control and detection modules with microfluidic technology helps to bridge the gap between the macroscopic world and chip-based analysis, paving the way for automated and high-throughput applications. In our review, we start the discussion with an introduction of microfluidic systems and micro-optical components, as well as aspects of their integration. We continue with a detailed description of different microfluidic and micro-optics technologies and their applications, with an emphasis on the realization of optical waveguides and microlenses. The review continues with specific sections highlighting the advantages of integrated micro-optical components in microfluidic systems for tackling a variety of analytical problems, like cytometry, nucleic acid and protein detection, cell biology, and chemical analysis applications.


The Influence of Hepatitis C Viral Loads on Natural Killer Cell Function.
Hepatitis C virus (HCV) infection has a high rate of chronicity, attributable to its capacity to alter host immunity, including natural killer (NK) cell function. In this study, the interaction between NK cell activity and HCV viral load was investigated. Peripheral blood NK cells were examined for cytotoxicity and interferon (IFN)-γ expression in HCV infected low (LVL, < 800,000 IU/mL, n = 10) and high (HVL, > 800,000 IU/mL, n = 13) viral load patient cohorts. Spontaneous NK cell cytotoxicity was more robust in the LVL cohort resulting in a negative correlation with viral loads (spontaneous, r = -0.437, P = 0.037; IFN-α activated, r = -0.372, P = 0.081). Although the percent of IFN-γ+ NK cells did not associate with viral load, within the LVL cohort there was a marked increase in IFN-γ+ NK cells upon IFN-α activation relative to medium alone (P < 0.01). To examine the inability of NK cells derived from HVL patients to be further activated, the expression of the exhaustion marker programmed cell death protein (PD)-1 was evaluated. PD-1 expression upon NK cell activation correlated with viral load (r = 0.649, P = 0.009). In addition, HCV proteins upregulated PD-1 expression in vitro (P < 0.05), suggesting that HCV can directly promote NK cell exhaustion. Cells from HVL patients were also more likely to produce IFN-γ in response to HCV core protein. The finding that NK cell PD-1 and IFN-γ expression are linked (r = 0.542, P < 0.05) suggests that increased IFN-γ levels may induce PD-1 as a negative feedback mechanism. High HCV loads appear to promote NK exhaustion in chronic HCV infection.


Determination of type I receptor specificity by the type II receptors for TGF-beta or activin.
Transforming growth factor-beta (TGF-beta) and activin signal primarily through interaction with type I and type II receptors, which are transmembrane serine-threonine kinases. Tsk 7L is a type I receptor for TGF-beta and requires coexpression of the type II TGF-beta receptor for ligand binding. Tsk 7L also specifically bound activin, when coexpressed with the type IIA activin receptor. Tsk 7L could associate with either type II receptor and the ligand binding specificity of Tsk 7L was conferred by the type II receptor. Tsk 7L can therefore act as type I receptor for both activin and TGF-beta, and possibly other ligands.


A mixture framework for inferring ancestral gene orders.
Inferring gene orders of ancestral genomes has the potential to provide detailed information about the recent evolution of species descended from them. Current popular tools to infer ancestral genome data (such as GRAPPA and MGR) are all parsimony-based direct optimization methods with the aim to minimize the number of evolutionary events. Recently a new method based on the approach of maximum likelihood is proposed. The current implementation of these direct optimization methods are all based on solving the median problems and achieve more accurate results than the maximum likelihood method. However, both GRAPPA and MGR are extremely time consuming under high rearrangement rates. The maximum likelihood method, on the contrary, runs much faster with less accurate results. We propose a mixture method to optimize the inference of ancestral gene orders. This method first uses the maximum likelihood approach to identify gene adjacencies that are likely to be present in the ancestral genomes, which are then fixed in the branch-and-bound search of median calculations. This hybrid approach not only greatly speeds up the direct optimization methods, but also retains high accuracy even when the genomes are evolutionary very distant. Our mixture method produces more accurate ancestral genomes compared with the maximum likelihood method while the computation time is far less than that of the parsimony-based direct optimization methods. It can effectively deal with genome data of relatively high rearrangement rates which is hard for the direct optimization methods to solve in a reasonable amount of time, thus extends the range of data that can be analyzed by the existing methods.


Low-temperature nanospectroscopy of the structural ferroelectric phases in single-crystalline barium titanate.
We optically investigate the local-scale ferroelectric domain structure of tetragonal, orthorhombic, and rhombohedral barium titanate (BTO) single crystals using scattering-type scanning near-field infrared (IR) optical microscopy (s-SNIM) at temperatures down to 150 K. Thanks to the precisely tunable narrow-band free-electron laser FELBE, we are able to explore the spectral fingerprints and IR resonances of these three phases and their domain orientations in the optical IR near-field. More clearly, every structural phase is analyzed with respect to its near-field resonances close to a wavelength of 17 μm when exploring the (111)-oriented BTO sample surface. Furthermore, near-field imaging at these resonances is performed, that clearly allows for the unambiguous optical identification of different domain orientations. Since our s-SNIM is based on a non-contact scanning force microscope, our s-SNIM findings are backed up by sample-topography and piezoresponse force microscopy (PFM) imaging, providing complementary information in an excellent match to the s-SNIM results.


A comparison of massively parallel nucleotide sequencing with oligonucleotide microarrays for global transcription profiling.
RNA-Seq exploits the rapid generation of gigabases of sequence data by Massively Parallel Nucleotide Sequencing, allowing for the mapping and digital quantification of whole transcriptomes. Whilst previous comparisons between RNA-Seq and microarrays have been performed at the level of gene expression, in this study we adopt a more fine-grained approach. Using RNA samples from a normal human breast epithelial cell line (MCF-10a) and a breast cancer cell line (MCF-7), we present a comprehensive comparison between RNA-Seq data generated on the Applied Biosystems SOLiD platform and data from Affymetrix Exon 1.0ST arrays. The use of Exon arrays makes it possible to assess the performance of RNA-Seq in two key areas: detection of expression at the granularity of individual exons, and discovery of transcription outside annotated loci. We found a high degree of correspondence between the two platforms in terms of exon-level fold changes and detection. For example, over 80% of exons detected as expressed in RNA-Seq were also detected on the Exon array, and 91% of exons flagged as changing from Absent to Present on at least one platform had fold-changes in the same direction. The greatest detection correspondence was seen when the read count threshold at which to flag exons Absent in the SOLiD data was set to t<1 suggesting that the background error rate is extremely low in RNA-Seq. We also found RNA-Seq more sensitive to detecting differentially expressed exons than the Exon array, reflecting the wider dynamic range achievable on the SOLiD platform. In addition, we find significant evidence of novel protein coding regions outside known exons, 93% of which map to Exon array probesets, and are able to infer the presence of thousands of novel transcripts through the detection of previously unreported exon-exon junctions. By focusing on exon-level expression, we present the most fine-grained comparison between RNA-Seq and microarrays to date. Overall, our study demonstrates that data from a SOLiD RNA-Seq experiment are sufficient to generate results comparable to those produced from Affymetrix Exon arrays, even using only a single replicate from each platform, and when presented with a large genome.


Clonidine for pain-related distress in Aboriginal children on a penicillin regimen to prevent recurrence of rheumatic fever.
Indigenous children and adolescents in Australia and globally bear the burden of acute rheumatic fever (ARF). It has been virtually eliminated in well-resourced, developed settings. ARF is an autoimmune response to infection with group A Streptococcus. The mainstay of management is long-acting intramuscular penicillin injections to prevent recurrence of ARF and development of rheumatic heart disease (RHD), comprising valvular pathology and attendant complications. In Australia, penicillin injections are currently prescribed every 28 days for 5-10 years after diagnosis of ARF, depending on cardiac involvement. Adherence to this regimen reduces ARF recurrences and RHD progression. 'Days at risk' of ARF recurrence are calculated as the number of days after day 28 that an injection is not received. Adherence to the injection schedule has been reported as difficult in most global locations due to the painful nature of the injections, the long timeframes of the prescription, young age of patients, access problems and costs in some locations. The newly updated Australian guideline on the prevention, diagnosis and management of ARF and RHD has a chapter dedicated to secondary prophylaxis. This chapter takes into account cultural considerations and advises on ways to minimise pain and distress of injections in children such as pain gate strategies, distraction techniques and concurrent injection of local anaesthetic. Some children continue to find the injection regimen traumatising despite strategies to reduce pain and fear. Clinicians providing the injections to children also find the injecting episodes distressing if pain is not effectively minimised. An Aboriginal Community Controlled Health Service in a remote setting in northern Australia addressed the issue of severe trauma of injection episodes experienced by an Aboriginal boy aged 7 years. Usual strategies were not effective, so advice was sought from an expert anaesthetist at a tertiary hospital. As a result, oral clonidine 3 µg/kg was trialled 45 minutes prior to the penicillin injection. Procedural coaching and monitoring protocols specific to administration of clonidine in children under their care were created by the health service. The initial dose of clonidine was delivered with the child as an inpatient. Clonidine was successful in reducing pain related distress and facilitating adherence to the penicillin regimen. Subsequent doses were delivered and monitored in a remote setting by nurses. After 18 months, the boy no longer required clonidine due to his increased coping capacity. A second child was recognised with similar trauma and has been taking clonidine for pre-procedural sedation for 6 months with good effect and no adverse effects. An additional child was similarly prescribed clonidine without success. Failure in that instance was attributed to lack of procedural coaching and receiving the initial dose of clonidine in an emergency department in hurried circumstances. Individualised child-focused and culturally appropriate care in remote settings is feasible: in this instance team planning for use of clonidine and procedural coaching when other measures have failed. However, for children with RHD, or other comorbidities, advice from the child's treating cardiologist is required prior to prescribing clonidine due to possible adverse consequences. These include hypotension and atrioventricular block, which could lead to haemodynamic compromise in the setting of moderate to severe RHD.


Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study.
Since December, 2019, Wuhan, China, has experienced an outbreak of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Epidemiological and clinical characteristics of patients with COVID-19 have been reported but risk factors for mortality and a detailed clinical course of illness, including viral shedding, have not been well described. In this retrospective, multicentre cohort study, we included all adult inpatients (≥18 years old) with laboratory-confirmed COVID-19 from Jinyintan Hospital and Wuhan Pulmonary Hospital (Wuhan, China) who had been discharged or had died by Jan 31, 2020. Demographic, clinical, treatment, and laboratory data, including serial samples for viral RNA detection, were extracted from electronic medical records and compared between survivors and non-survivors. We used univariable and multivariable logistic regression methods to explore the risk factors associated with in-hospital death. 191 patients (135 from Jinyintan Hospital and 56 from Wuhan Pulmonary Hospital) were included in this study, of whom 137 were discharged and 54 died in hospital. 91 (48%) patients had a comorbidity, with hypertension being the most common (58 [30%] patients), followed by diabetes (36 [19%] patients) and coronary heart disease (15 [8%] patients). Multivariable regression showed increasing odds of in-hospital death associated with older age (odds ratio 1·10, 95% CI 1·03-1·17, per year increase; p=0·0043), higher Sequential Organ Failure Assessment (SOFA) score (5·65, 2·61-12·23; p<0·0001), and d-dimer greater than 1 μg/mL (18·42, 2·64-128·55; p=0·0033) on admission. Median duration of viral shedding was 20·0 days (IQR 17·0-24·0) in survivors, but SARS-CoV-2 was detectable until death in non-survivors. The longest observed duration of viral shedding in survivors was 37 days. The potential risk factors of older age, high SOFA score, and d-dimer greater than 1 μg/mL could help clinicians to identify patients with poor prognosis at an early stage. Prolonged viral shedding provides the rationale for a strategy of isolation of infected patients and optimal antiviral interventions in the future. Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences; National Science Grant for Distinguished Young Scholars; National Key Research and Development Program of China; The Beijing Science and Technology Project; and Major Projects of National Science and Technology on New Drug Creation and Development.


Lethals, steriles and deficiencies in a region of the X chromosome of Caenorhabditis elegans.
Twenty-one X-linked recessive lethal and sterile mutations balanced by an unlinked X-chromosome duplication have been identified following EMS treatment of the small nematode, Caenorhabditis elegans. The mutations have been assigned by complementation analysis to 14 genes, four of which have more than one mutant allele. Four mutants, all alleles, are temperature-sensitive embryonic lethals. Twelve mutants, in ten genes, are early larval lethals. Two mutants are late larval lethals, and the expression of one of these is influenced by the number of X chromosomes in the genotype. Two mutants are maternal-effect lethals; for both, oocytes made by mutant hermaphrodites are rescuable by wild-type sperm. One of the maternal-effect lethals and two larval lethals are allelic. One mutant makes defective sperm. The lethals and steriles have been mapped by recombination and by complementation testing against 19 deficiencies identified after X-ray treatment. The deficiencies divide the region, about 15% of the X-chromosome linkage map, into at least nine segments. The deficiencies have also been used to check the phenotypes of hemizygous lethal and sterile hermaphrodites.


What You See Is What You Remember: Visual Chunking by Temporal Integration Enhances Working Memory.
Human memory benefits from information clustering, which can be accomplished by chunking. Chunking typically relies on expertise and strategy, and it is unknown whether perceptual clustering over time, through temporal integration, can also enhance working memory. The current study examined the attentional and working memory costs of temporal integration of successive target stimulus pairs embedded in rapid serial visual presentation. ERPs were measured as a function of behavioral reports: One target, two separate targets, or two targets reported as a single integrated target. N2pc amplitude, reflecting attentional processing, depended on the actual number of successive targets. The memory-related CDA and P3 components instead depended on the perceived number of targets irrespective of their actual succession. The report of two separate targets was associated with elevated amplitude, whereas integrated as well as actual single targets exhibited lower amplitude. Temporal integration thus provided an efficient means of processing sensory input, offloading working memory so that the features of two targets were consolidated and maintained at a cost similar to that of a single target.


Adaptation of Oxford Nanopore technology for hepatitis C whole genome sequencing and identification of within-host viral variants.
Hepatitis C (HCV) and many other RNA viruses exist as rapidly mutating quasi-species populations in a single infected host. High throughput characterization of full genome, within-host variants is still not possible despite advances in next generation sequencing. This limitation constrains viral genomic studies that depend on accurate identification of hemi-genome or whole genome, within-host variants, especially those occurring at low frequencies. With the advent of third generation long read sequencing technologies, including Oxford Nanopore Technology (ONT) and PacBio platforms, this problem is potentially surmountable. ONT is particularly attractive in this regard due to the portable nature of the MinION sequencer, which makes real-time sequencing in remote and resource-limited locations possible. However, this technology (termed here 'nanopore sequencing') has a comparatively high technical error rate. The present study aimed to assess the utility, accuracy and cost-effectiveness of nanopore sequencing for HCV genomes. We also introduce a new bioinformatics tool (Nano-Q) to differentiate within-host variants from nanopore sequencing. The Nanopore platform, when the coverage exceeded 300 reads, generated comparable consensus sequences to Illumina sequencing. Using HCV Envelope plasmids (~ 1800 nt) mixed in known proportions, the capacity of nanopore sequencing to reliably identify variants with an abundance as low as 0.1% was demonstrated, provided the autologous reference sequence was available to identify the matching reads. Successful pooling and nanopore sequencing of 52 samples from patients with HCV infection demonstrated its cost effectiveness (AUD$ 43 per sample with nanopore sequencing versus $100 with paired-end short read technology). The Nano-Q tool successfully separated between-host sequences, including those from the same subtype, by bulk sorting and phylogenetic clustering without an autologous reference sequence (using only a subtype-specific generic reference). The pipeline also identified within-host viral variants and their abundance when the parameters were appropriately adjusted. Cost effective HCV whole genome sequencing and within-host variant identification without haplotype reconstruction are potential advantages of nanopore sequencing.


Neuroendocrine Regulation of Growth Hormone Secretion.
This article reviews the main findings that emerged in the intervening years since the previous volume on hormonal control of growth in the section on the endocrine system of the Handbook of Physiology concerning the intra- and extrahypothalamic neuronal networks connecting growth hormone releasing hormone (GHRH) and somatostatin hypophysiotropic neurons and the integration between regulators of food intake/metabolism and GH release. Among these findings, the discovery of ghrelin still raises many unanswered questions. One important event was the application of deconvolution analysis to the pulsatile patterns of GH secretion in different mammalian species, including Man, according to gender, hormonal environment and ageing. Concerning this last phenomenon, a great body of evidence now supports the role of an attenuation of the GHRH/GH/Insulin-like growth factor-1 (IGF-1) axis in the control of mammalian aging.


Unfolding and partial refolding of a cellulase from the SDS-denatured state: From β-sheet to α-helix and back.
Globular proteins are typically unfolded by SDS to form protein-decorated micelle-like structures. Several proteins have been shown subsequently to refold by addition of the nonionic surfactant octaethylene glycol monododecyl ether (C12E8). Thus SDS converts β-lactoglobulin, which has mainly β-sheet secondary structure, into a state rich in α-helicality, while addition of C12E8 leads to refolding and recovery of the original β-sheet structure. Here we extend these studies to the large β-sheet-rich cellulase Cel7b from Humicola insolens whose enzymatic activity provides a very sensitive refolding parameter. The enzymes widespread usage in the detergent industry makes it an obvious model system for protein-surfactant interactions. SDS-unfolding and subsequent refolding using C12E8 were investigated at pH 4.2 using near- and far-UV circular dichroism (CD), small-angle X-ray scattering (SAXS), isothermal titration calorimetry (ITC), size-exclusion chromatography (SEC) and activity measurements. The Cel7b:SDS complex can be described as a random configuration of 3-4 connected core-shell structures in which the protein is converted to a mainly α-helical secondary structure. Addition of C12E8 recovers almost all the secondary structure, part of the tertiary structure, about 50% of the activity and dissociates part of the protein population completely from detergent micelles. The lack of complete refolding may be due to charge neutralisation of Cel7b by SDS, kinetically trapping the enzyme into aggregated structures. In support of this, aggregates did not form when C12E8 was first mixed with Cel7b followed by addition of SDS. Formation of such aggregates may be a general phenomenon hampering quantitative refolding from the SDS-denatured state.


Diabetes and carotid artery disease: a narrative review.
Diabetes mellitus (DM) has been linked to an increased prevalence and severity of carotid artery disease, as well as polyvascular disease. Carotid disease is also associated with obesity and abnormal peri-organ and intra-organ fat (APIFat) deposition (i.e., excess fat accumulation in several organs such as the liver, heart and vessels). In turn, DM is associated with APIFat. The coexistence of these comorbidities confers a greater risk of vascular events. Clinicians should also consider that carotid bruits may predict cardiovascular risk. DM has been related to a greater risk of adverse outcomes after carotid endarterectomy or stenting. Whether modifying risk factors (e.g., glycaemia and dyslipidaemia) in DM patients can improve the outcomes of these procedures needs to be established. Furthermore, DM is a risk factor for contrast-induced acute kidney injury (CI-AKI). The latter should be recorded in DM patients undergoing carotid stenting since it can influence both short- and long-term outcomes. From a pathophysiological perspective, functional changes in the carotid artery may precede morphological ones. Furthermore, carotid plaque characteristics are increasingly being studied in terms of vascular risk stratification and monitoring short-term changes attributed to treatment. The present narrative review discusses the recent (2019) literature on the associations between DM and carotid artery disease. Physicians and vascular surgeons looking after patients with carotid disease and DM should consider these links that may influence outcomes. Further research in this field is also needed to optimise the treatment of such patients.


Clinical Utility of Combinatorial Pharmacogenomics-Guided Antidepressant Therapy: Evidence from Three Clinical Studies.
DNA of 258 patients with treatment-resistant depression was collected in three 8-10 week, two-arm, prospective clinical trials. Forty-four allelic variations were measured in genes for the cytochrome P450 (CYP) enzymes CYP2D6, CYPC19, and CYP1A2, the serotonin transporter (SLC6A4), and the 5-HT2A receptor (HTR2A). The combinatorial pharmacogenomic (CPGx™) GeneSight test results were provided to clinicians to support medication changes from baseline (guided arm), or they were provided at the end of each study to clinicians of unguided patients who were treated as usual (TAU). TAU subjects who at baseline were prescribed medications genetically discordant for them showed only a 12% symptom improvement, far less than the 32.5% or 28.5% improvements of the TAU subjects on yellow-category ('use with caution'; p = 0.002) or green-category medications ('use as recommended'; p = 0.02), respectively. The odds of a clinical response were increased 2.3-fold among all GeneSight-guided compared to all TAU subjects (p = 0.004), and overall, the guided group had a 53% greater improvement in depressive symptoms (p = 0.0002), a 1.7-fold relative improvement in response (p = 0.01), and a number needed to treat for one clinical response above that seen in the TAU group of 6.07.


Emotional, cognitive and behavioral reactions to paranoid symptoms in clinical and nonclinical populations.
Background: Paranoia is a disruptive belief that can vary across a continuum, ranging from persecutory delusions presented in clinical settings to paranoid cognitions that are highly prevalent in the general population. The literature suggests that paranoid thoughts derive from the activation of a paranoid schema or information processing biases that can be sensitive to socially ambiguous stimuli and influence the processing of threatening situations. Method: Four groups (Schizophrenic participants in active psychotic phases, n=6; stable participants in remission, n=30; participants' relatives, n=32; and healthy controls, n=64) were assessed with self-report questionnaires to determine how the reactions to paranoia of clinical patients differ from healthy individuals. Cognitive, emotional and behavioral dimensions of their reactions to these paranoid thoughts were examined. Results: Paranoid individuals were present in all groups. Most participants referred the rejection by others as an important trigger of paranoid ideations, while active psychotic were unable to identify triggering situations to their thoughts and reactions. This may be determinant to the different reactions and the different degree of invalidation caused by paranoid thoughts observed across groups. Conclusion: Clinical and non-clinical expressions of paranoid ideations differ in terms of their cognitive, emotional and behavioral components. It is suggested that, in socially ambiguous situations, paranoid participants (presenting lower thresholds of paranoid schema activation) lose the opportunity to disconfirm their paranoid beliefs by resourcing to more maladaptive coping strategies. Consequently, by dwelling on these thoughts, the amount of time spent thinking about their condition and the disability related to the disease increases.


31 years of lung cancer in the canton of Zurich, Switzerland: incidence trends by sex, histology and laterality.
Lung cancer belongs to the most common cancers in Switzerland. We examined trends in lung cancer incidence, with focus on sex, histology and laterality, in the Canton of Zurich since 1980. Registry data consisting of 16 798 lung cancer cases from 1980 to 2010 were analysed. Cases were classified into adenocarcinoma (ADC), squamous cell carcinoma (SCC), small-cell carcinoma (SCLC), large cell tumour and carcinoid tumour. Age-standardised (European standard) incidence rates (IR) per 100 000 person-years, male-to-female incidence-rate ratio (M/F-IRR), and left-to-right lung incidence-rate ratio (L/R-IRR) were calculated. Over the study period, ADC occurred most frequently (31.9%), followed by SCC (29.1%), SCLC (15.4%), large cell carcinoma (6.3%), and carcinoid tumour (1.5%). Other/unspecified subtypes accounted for 15.7%. In men, the IR of SCC decreased from 34.2/100 000 (95% confidence interval [CI] 32.5-35.9) in 1980 to 12.8/100 000 (12.0-13.6) in 2010, but increased in women from 3.4/100 000 (2.7-4.0) to 4.0/100 000 (3.4-4.5). The IR of ADC increased in women from 5.1/100 000 (4.1-5.8) to 12.6/100 000 (11.8-13.4) and in men from 15.1/100 000 (14.0-16.3) to 19.4/100 000 (18.4-20.4). Overall M/F-IRR was 2.61; the highest ratio (5.8) was seen for SCC and the lowest (0.77) for carcinoid tumour. All histological subtypes showed a higher susceptibility of the right lung. Our data reflect the global increase of lung cancer in women. ADC increased over time in women and men, whereas SCC decreased markedly among men. These trends may have occurred owing to changes in smoking behaviour and cigarette composition.


Hyperostosing sphenoid wing meningiomas: surgical outcomes and strategy for bone resection and multidisciplinary orbital reconstruction.
Hyperostosing sphenoid wing meningiomas cause bony hyperostosis that may extend into the orbit, resulting in proptosis, restriction of extraocular movements, and/or compressive optic neuropathy. The extent of bony removal necessary and the optimal reconstruction strategy to prevent enophthalmos is debated. Herein, the authors present their surgical outcomes and reconstruction results. This is a retrospective review of 54 consecutive patients undergoing resection of sphenoid wing meningiomas associated with bony hyperostosis. The majority of cases were operated on by the senior author. Extent of tumor resection, volumetric bone resection, radiographic exophthalmos index, complications, and recurrence were analyzed. The median age of the cohort was 52.1 years, with women comprising 83% of patients. Proptosis was a presenting symptom in 74%, and 52% had decreased visual acuity. The WHO grade was I (85%) or II (15%). The median follow-up was 2.6 years. On volumetric analysis, a median 86% of hyperostotic bone was resected. Gross-total resection of the intracranial tumor was achieved in 43% and the orbital tumor in 27%, and of all intracranial and orbital components in 20%. Orbital reconstruction was performed in 96% of patients. Postoperative vision was stable or improved in 98% of patients and diplopia improved in 89%. Postoperative complications occurred in 44% of patients, and 26% of patients underwent additional surgery for complication management. The most frequent complications were medical complications and extraocular movement deficits. The median preoperative exophthalmos index was 1.26, which improved to 1.12 immediately postoperatively and to 1.09 at the 6-month follow-up (p < 0.001). Postoperatively, 18 patients (33%) underwent adjuvant radiotherapy after subtotal resection. Tumors recurred/progressed in 12 patients (22%). Resection of hyperostosing sphenoid wing meningiomas, particularly achieving gross-total resection of hyperostotic bone with a good aesthetic result, is challenging and associated with notable medical and ocular morbidity. Recurrence rates in this series are higher than previously reported. Nevertheless, the authors were able to attain improvement in proptosis and visual symptoms in the majority of patients by using a multidisciplinary approach.


Prenatal life and post-natal psychopathology: evidence for negative gene-birth weight interaction.
Many studies suggest that pregnancy and birth complications (PBCs) are environmental risk factors for child psychopathology. However, it is not known whether the effects of PBCs occur independently of genetic predisposition. The current study examined the possibility of gene-environment interaction in a twin design. The East Flanders Prospective Twin Survey prospectively records the births of all twin pairs born in East Flanders, Belgium. The current study included 760 twin pairs aged 6-17 years. Multilevel regression analysis was used to assess the effects of several PBCs collected around the time of birth. Using structural equation modelling, ACE models assuming additive genetic (A), shared environmental (C) and unique environmental (E) influences, were compared in order to examine whether the contribution of genetic factors to parent-rated child problem behaviour varied as a function of exposure to dichotomously and continuously defined PBCs. A main independent effect of lower birth weight, corrected for gestational age (small for gestational age--SGA), on child problem behaviour was found. In addition, there was an interaction between genetic influence and SGA, in that being smaller for gestational age resulted in less influence of additive genetic factors on individual differences in problem behaviour. Results are suggestive of negative gene-birth weight interaction. Children who are SGA are less sensitive to the genetic effects, and those with high genetic vulnerability are less sensitive to the effects of being SGA in bringing about post-natal mental health effects.


Critical evaluation of the role of the Toll-like receptor 18-Wheeler in the host defense of Drosophila.
Essential aspects of innate immune responses to microbial infections appear to be conserved between insects and mammals. In particular, in both groups, transmembrane receptors of the Toll superfamily play a crucial role in activating immune defenses. The Drosophila Toll family member 18-Wheeler had been proposed to sense Gram-negative infection and direct selective expression of peptides active against Gram-negative bacteria. Here we re-examine the role of 18-Wheeler and show that in adults it is dispensable for immune responses. In larvae, 18wheeler is required for normal fat body development, and in mutant larvae induction of all antimicrobial peptide genes, and not only of those directed against Gram-negative bacteria, is compromised. 18-Wheeler does not qualify as a pattern recognition receptor of Gram-negative bacteria.


Reduced Physical Activity in People Following Ankle Fractures: A Longitudinal Study.
Longitudinal observational cohort. The impact of ankle fracture on physical activity and sitting time and the course of recovery of physical activity are unclear. To assess the course of recovery of physical activity after ankle fracture and the extent to which this population may be less physically active and more sedentary than the general population. A cohort of individuals with ankle fracture was derived from a randomized trial and assessed with the International Physical Activity Questionnaire-Short Form (IPAQ-SF) at immobilization removal and 1, 3, and 6 months later. Total metabolic equivalent (MET) minutes per week were calculated to evaluate the course of recovery of physical activity. Sitting time (minutes per day) and the percentage of those who met the World Health Organization physical activity guidelines were calculated. Normative data were derived from a population-based cohort study that assessed physical activity using the IPAQ-SF. In people with ankle fracture (n = 214), physical activity increased in the first month (from a median of 99 at immobilization removal to 979 MET min/wk) and leveled off by 6 months (1386 MET min/wk). Only 22% of the ankle fracture cohort met World Health Organization guidelines at immobilization removal, compared to 80% of the cohort from the general population (P<.001). This difference diminished over time. Sitting time in the ankle fracture cohort was higher than population norms at all time points (P<.001). People with ankle fracture are less physically active and more sedentary than the general population. Strategies to increase physical activity must be considered. LEVEL OF EVIDENCE Prognosis, level 4.


Complete Revascularization of Simultaneous Multiple Culprit Lesions in a Septuagenarian with ST-Elevation Myocardial Infarction.
BACKGROUND ST-elevation myocardial infarction (STEMI) is usually caused by rupture of unstable plaque with thrombus formation and abrupt cessation of blood flow through a single coronary artery that is deemed the culprit. The simultaneous thrombotic occlusions of multiple coronary arteries in the setting of STEMI is a rare occurrence with implications for patient management and outcome not fully addressed in the current STEMI guidelines, although more recent studies suggest a benefit of complete revascularization compared to culprit vessel-only treatment in the setting of STEMI. CASE REPORT A 74-year-old female presented with STEMI. Coronary angiography revealed simultaneous multiple coronary thrombotic occlusions involving the right coronary, left circumflex, and ramus intermedius arteries successfully treated with primary percutaneous revascularization at the same setting with good outcome and short hospital length of stay. CONCLUSIONS Although the most appropriate timing to treat simultaneous multiple culprit lesions has yet to be definitively defined, multi-vessel percutaneous coronary intervention in the setting of a STEMI with multiple culprit lesions is feasible with good outcome as shown by our index case.


Ganglioglioma arising in a Peutz-Jeghers patient: a case report with molecular implications.
The Peutz-Jeghers syndrome (PJS), an autosomal dominant disorder caused by inactivating germline mutations in the serine-threonine kinase gene LKB1, is characterized by mucocutaneous pigmentation, multiple gastrointestinal hamartomatous polyps, and by an increased risk for developing tumors involving several different organs. To date, no brain tumors have been described in PJS patients. In this report, we describe a case of ganglioglioma in a 22-year-old PJS patient. Single-strand conformation polymorphism-Heteroduplex analysis evidenced an abnormal pattern in exon 6 of the LKB1 gene. Sequencing revealed a 821delTinsAC mutation creating a termination codon 29 nucleotides downstream (p.Asn274fsX11). RNA studies showed an out-of-frame LKB1 isoform derived from the wild type allele and generated by exon 4 skipping. Since the LKB1 gene is expressed in the fetal and adult brain, our data would suggest its likely involvement in the pathogenesis of a subset of gangliogliomas.


Immunomodulatory effect of protease hydrolysates from ovotransferrin.
Proteins and bioactive peptides in avian egg white exert diverse biological activities. This study is designed to investigate the effect of protease hydrolysates from ovotransferrin (OVT) on bone marrow-derived dendritic cells (BMDCs) maturation. The results show that OVT-derived pepsin hydrolysate effectively inhibits lipopolysaccharide (LPS)-induced BMDCs maturation by reducing the expression levels of MHC-II, CD83, CD86 and the production of TNF-α, IL-12p70, and RANTES, but increases the production of IL-10. In addition, OVT-derived pepsin hydrolysate impairs the ability of LPS-stimulated BMDCs to induce allogeneic T lymphocyte proliferation and decreases the production of IFN-γ by activated T cells. In contrast, OVT-derived trypsin hydrolysate induces DCs maturation in terms of increasing the expression levels of MHC-II and the costimulatory molecules CD83 and CD86 and the production of TNF-α, IL-12p70 and RANTES. Furthermore, OVT-derived trypsin hydrolysate improves the ability of LPS-stimulated DCs to induce allogeneic T lymphocyte activation. Blockage of LPS-induced p38 MAPK and JNK activation and inducing ERK activation contribute to the inhibitory effect of OVT-derived pepsin hydrolysate on DCs, whereas OVT-derived trypsin hydrolysate induces DCs maturation through JNK and ERK activation. These results indicate that OVT-derived protease hydrolysate have an immunomodulatory function and could be applied as a potential functional food ingredient to regulate body immunity by modulating DC maturation.


Four-Week Ankle-Rehabilitation Programs in Adolescent Athletes With Chronic Ankle Instability.
Researchers have shown that rehabilitation programs incorporating resistance-band and balance-board exercises are effective for improving clinical measures of function and patient-reported outcomes in individuals with chronic ankle instability (CAI). However, whether combining the 2 exercises increases improvement is unknown. To determine the effectiveness of 3 rehabilitation programs on clinical measures of balance and self-reported function in adolescent patients with CAI. Randomized controlled clinical trial (Trail Registration Number: ClinicalTrails.gov: NCT03447652). High school athletic training facilities. Forty-three patients with CAI (age = 16.37 ± 1.00 years, height = 171.75 ± 12.05 cm, mass = 69.38 ± 18.36 kg) were block randomized into 4 rehabilitation groups. Protocols were completed 3 times per week for 4 weeks. The resistance-band group performed 3 sets of 10 repetitions of ankle plantar flexion, dorsiflexion, inversion, and eversion with a resistance band. The Biomechanical Ankle Platform System group performed 5 trials of clockwise and counterclockwise rotations, changing direction every 10 seconds during each 40-second trial. The combination group completed resistance-band and Biomechanical Ankle Platform System programs during each session. The control group did not perform any exercises. Variables were assessed before and after the intervention: time-in-balance test, foot-lift test, Star Excursion Balance Test, side-hop test, figure-8 hop test, Foot and Ankle Ability Measure, and Cumberland Ankle Instability Tool. We conducted 4 separate multivariate repeated-measures analyses of variance, followed by univariate analyses for any findings that were different. Using the time-in-balance test, foot-lift test, Star Excursion Balance Test (medial, posteromedial, and posterolateral directions), and figure-8 hop test, we detected improvement for each rehabilitation group compared with the control group (P < .05). However, no intervention group was superior. All 3 rehabilitation groups demonstrated improvement compared with the control group, yet the evidence was too limited to support a superior intervention. Over a 4-week period, either of the single-task interventions or the combination intervention can be used to combat the residual deficits associated with CAI in an adolescent patient population.


Knowledge gaps for functional outcomes after multilobar resective and disconnective pediatric epilepsy surgery: Conference Proceedings of the Patient-Centered Stakeholder Meeting 2019.
For children with medication-resistant epilepsy who undergo multilobar or hemispheric surgery, the goal of achieving seizure freedom is met with a variety of potential functional consequences, both favorable and unfavorable. However, there is a paucity of literature that comprehensively addresses the cognitive, medical, behavioral, orthopedic, and sensory outcomes across the lifespan following large epilepsy surgeries in childhood, leaving all stakeholders underinformed with regard to counseling and expectations. Through collaboration between clinicians, researchers, and patient/caregiver stakeholders, the "Functional Impacts of Large Resective or Disconnective Pediatric Epilepsy Surgery: Identifying Gaps and Setting PCOR Priorities" meeting was convened on July 18, 2019, to identify gaps in knowledge and inform various patient-centered research initiatives. Clinicians and researchers with content expertise presented the best available data in each functional domain which is summarized here. As a result of the meeting, the top three consensus priorities included research focused on postoperative: (1) hydrocephalus; (2) mental health issues; and (3) literacy and other educational outcomes. The proceedings of this meeting mark the first time research on functional outcomes after resective and disconnective pediatric epilepsy surgery has been codified and shared among multidisciplinary stakeholders. This joint initiative promotes continued collaboration in the field and ensures that advancements align with actual patient and family needs and experiences. Collaboration around common objectives will lead to better informed counseling around postoperative expectations and management for children undergoing epilepsy surgery.