Nature of virally mediated changes in membrane permeability to small molecules.
1. The changes in membrane permeability to small molecules caused by Sendai virus [Pasternak & Micklem (1973) J. Membr. Biol. 14, 293-303] have been further characterized. The uptake of substances that are concentrated within cells is inhibited. Choline and 2-deoxyglucose, which become phosphorylated, and aminoisobutyrate and glycine, which are driven by a Na+-linked mechanism, are examples. The uptake of each compound under conditons where its diffusion across the plasma membrane is rate-limiting is stimulated by virus. Choline, 2-deoxyglucose and amino acids at high concentration, amino acids in Na+-free medium, and most substances at low temperature, are examples. It is concluded that virally mediated decrease of uptake is due to one of two causes. Substances that are accumulated by phosphorylation are not retained because of leakage of the phosphorylated metabolites out of cells. Substances that are accumulated by linkage to a Na+ gradient are no longer accumulated because of collapse of the gradient resulting from an increased permeability to Nat 2. Increased permeability to K+ and Na+ results in (a) membrane depolarization and (b) cell swelling. The latter event leads to haemolysis (for erythrocytes) and can lead to giant-cell (polykaryon) formation (for several cell types). 3. Recovery of cells can be temporarily achieved by the addition of Ca2+; permanent recovery requires incubation for some hours at 37 degrees C. 4. The possible significance of virally mediated permeability changes, with regard to clinical situations and to cell biology, is discussed.


Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings.
Probands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort. Every child born in Finland in 1991-2005 and diagnosed with ADHD in 1995-2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981-2007 and diagnosed in 1981-2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations. 44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0-2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1-6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5-4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3-4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4-3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4-2.8), and intellectual disability (RR = 2.4; 95% CI 2.0-2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases. The results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies.


Hepatectomy Followed by mFOLFOX6 Versus Hepatectomy Alone for Liver-Only Metastatic Colorectal Cancer (JCOG0603): A Phase II or III Randomized Controlled Trial.
Adjuvant chemotherapy after hepatectomy is controversial in liver-only metastatic colorectal cancer (CRC). We conducted a randomized controlled trial to examine if adjuvant modified infusional fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) is superior to hepatectomy alone for liver-only metastasis from CRC. In this phase II or III trial (JCOG0603), patients age 20-75 years with confirmed CRC and an unlimited number of liver metastatic lesions were randomly assigned to hepatectomy alone or 12 courses of adjuvant mFOLFOX6 after hepatectomy. The primary end point of phase III was disease-free survival (DFS) in intention-to-treat analysis. Between March 2007 and January 2019, 300 patients were randomly assigned to hepatectomy alone (149 patients) or hepatectomy followed by chemotherapy (151 patients). At the third interim analysis of phase III with median follow-up of 53.6 months, the trial was terminated early according to the protocol because DFS was significantly longer in patients treated with hepatectomy followed by chemotherapy. With median follow-up of 59.2 months, the updated 5-year DFS was 38.7% (95% CI, 30.4 to 46.8) for hepatectomy alone compared with 49.8% (95% CI, 41.0 to 58.0) for chemotherapy (hazard ratio, 0.67; 95% CI, 0.50 to 0.92; one-sided P = .006). However, the updated 5-year overall survival (OS) was 83.1% (95% CI, 74.9 to 88.9) with hepatectomy alone and 71.2% (95% CI, 61.7 to 78.8) with hepatectomy followed by chemotherapy. In the chemotherapy arm, the most common grade 3 or higher severe adverse event was neutropenia (50% of patients), followed by sensory neuropathy (10%) and allergic reaction (4%). One patient died of unknown cause after three courses of mFOLFOX6 administration. DFS did not correlate with OS for liver-only metastatic CRC. Adjuvant chemotherapy with mFOLFOX6 improves DFS among patients treated with hepatectomy for CRC liver metastasis. It remains unclear whether chemotherapy improves OS.


Personal and social factors associated with the remission of psychiatric symptoms.
Most studies of "spontaneous remission" involve samples of untreated psychiatric patients. This selection process limits the generalizability of findings to the population of persons with neurotic disturbances. This report concerns a community sample of people with neurotic disorders. Fifty subjects were followed up for five years, using both clinical and quantitative techniques. Almost half lost their symptoms during this time. Various sociodemographic factors, personality assets, and liabilities contribute to the process through which such remissions occur.


Task-related versus stimulus-specific practice.
When people repeatedly practice the same cognitive task, their response times (RT) invariably decrease. Dutilh, Vandekerckhove, Tuerlinckx, and Wagenmakers (2009) argued that the traditional focus on how mean RT decreases with practice offers limited insight; their diffusion model analysis showed that the effect of practice is multifaceted, involving an increase in rate of information processing, a decrease in response caution, adjusted response bias, and, unexpectedly, a strong decrease in nondecision time. In this study, we aim to further disentangle these effects into stimulus-specific and task-related components. The data of a transfer experiment, in which repeatedly presented sets and new sets of stimuli were alternated, show that the practice effects on both speed of information processing and time needed for peripheral processing are partly task-related and partly stimulus-specific. The effects on response caution and response bias appear to be task-related. This diffusion model decomposition provides a perspective on practice that is more detailed and more informative than the traditional analysis of mean RT.


ES-dRNN: A Hybrid Exponential Smoothing and Dilated Recurrent Neural Network Model for Short-Term Load Forecasting.
Short-term load forecasting (STLF) is challenging due to complex time series (TS) which express three seasonal patterns and a nonlinear trend. This article proposes a novel hybrid hierarchical deep-learning (DL) model that deals with multiple seasonality and produces both point forecasts and predictive intervals (PIs). It combines exponential smoothing (ES) and a recurrent neural network (RNN). ES extracts dynamically the main components of each individual TS and enables on-the-fly deseasonalization, which is particularly useful when operating on a relatively small dataset. A multilayer RNN is equipped with a new type of dilated recurrent cell designed to efficiently model both short and long-term dependencies in TS. To improve the internal TS representation and thus the model's performance, RNN learns simultaneously both the ES parameters and the main mapping function transforming inputs into forecasts. We compare our approach against several baseline methods, including classical statistical methods and machine learning (ML) approaches, on STLF problems for 35 European countries. The empirical study clearly shows that the proposed model has high expressive power to solve nonlinear stochastic forecasting problems with TS including multiple seasonality and significant random fluctuations. In fact, it outperforms both statistical and state-of-the-art ML models in terms of accuracy.


Preclinical toxicology profile of misoprostol.
The toxicity of misoprostol has been extensively examined in a variety of in vitro and in vivo studies. Preclinical studies evaluated acute and chronic toxicity, mutagenicity and carcinogenicity, and reproductive toxicity. Single oral dose studies in rodents and non-rodents indicate a safety margin of at least 500 to 1000 fold between lethal doses in animals and therapeutic doses in humans. Chronic toxicity studies (52 weeks) have been performed at daily oral doses of up to 300 and 9000 micrograms/kg body weight in dogs and rats, respectively. Rectal temperatures were increased at 100 and 300 micrograms/kg in dogs and serum iron was increased at 9000 micrograms/kg in rats. Stomach weights were increased in dogs and rats in a dose-correlated manner related, at least in part, to an increase in the number of normal epithelial cells (gastric hyperplasia). When drug treatment was stopped rectal temperatures, serum iron and stomach weights reverted to normal. Electron microscope studies on hyperplastic tissue showed that the ultrastructure was not affected. Hyperostosis has been observed, mainly in female mice, following prolonged drug treatment at high doses. Histological studies of bone tissues of rats and dogs and radiological studies of long bones of dogs following chronic administration of misoprostol showed that bone development was normal in all respects. Mutagenicity studies were negative and misoprostol was not fetotoxic or teratogenic in rats at oral doses up to 10000 micrograms/kg body weight, or in rabbits at doses up to 1000 micrograms/kg body weight.(ABSTRACT TRUNCATED AT 250 WORDS)


Analysis on the relationship and mechanism of high blood pressure and vascular aging on the condition that the gender and age matches.
The relationship between hypertension and the mechanism of the expression of T-lymphocyte Kv1.3 channels in vascular aging has been analyzed in this study based on the gender and age matches' principle. Thirty patients have been consecutively chosen with vascular aging caused by hypertension (group A), while 30 cases of high blood pressure not merged with vascular aging (group B) were chosen, and 30 cases of healthy volunteers (group C), conforming to gender and age 1:1 and the closest matching principle, were studied. The aim of this study was to separate the peripheral blood mononuclear cells and give intervention of 0.2 nmol/L ANGII to CD4 + T-lymphocytes, and store them in the incubator 48 h. The difference of Kv1.3 channel current of CD4 + T-lymphocyte, mRNA, angiotensin receptor (AT1R) protein mRNA, and IFN-γ density has also been compared. The membrane capacitance, peak current, and current density of group A, are higher than those of the other two groups, and the differences have statistical significance (p<0.05). After adding ANGII intervention to group A, the expression levels of T-lymphocyte Kv1.3 potassium channels mRNA, AT1R mRNA, and IFN-γ are significantly increased, so that the difference has statistical significance p<0.05, while the other two groups have no significant change (p>0.05). The levels of Kv1.3 potassium channels, AT1R mRNA, and IFN-γ of group A before and after the intervention are significantly higher than those of the other two groups, and the differences are statistically significant (p<0.05). Vascular aging caused by hypertension may be linked to the increase of Kv1.3 potassium channel activity of T-lymphocyte, while ANGII can improve the high expression of Kv1.3 potassium channel and AT1R, to stimulate lymph cells to secrete IFN-γ.


Gilsonicaris from the Lower Devonian Hunsrück slate is a eunicidan annelid and not the oldest crown anostracan crustacean.
The Lower Devonian (Lower Emsian, -400 Myr) roof slates of the Hunsrück in southeastern Germany have delivered a highly diverse and exceptionally preserved marine fauna that provides a unique snapshot into the anatomy and ecology of a wide range of Palaeozoic animals. Several of the described taxa, however, remain enigmatic in their affinity, at least until new pyritized features hidden under the surface of the slate are revealed using X-ray radiography or micro-computed tomography (µCT). Here, we redescribe such an enigmatic fossil, the putative anostracan crustacean Gilsonicaris rhenanus Van Straelen, 1943. Using µCT scanning, we unveil unprecedented details of its anatomy, including a ventral oral opening and four pairs of recalcitrant jaw elements. These jaws are morphologically consistent with the scolecodonts of eunicidan polychaetes, which along with the gross anatomy of the body and head unambiguously identifies G. rhenanus as a polychaete rather than an arthropod. While this discovery firmly discards the Early Devonian record of crown anostracans in the fossil record, it adds a new record of eunicidan soft tissues, which are surprisingly rare considering the abundant microfossil record of scolecodonts.


Samonellosis and meat hygiene: red meat.
The association between salmonellosis in man and the infection in food animals has been clearly established. There is, moreover, little doubt that abattoir by-products, effluent and solid waste may allow the recycling of infection in animals. The potential hazard posed by salmonellosis to human and animal health will be reduced only by a greater control over the slaughter of infected farm livestock, improved isolation and casualty slaughter accommodation, a stricter control of slaughterhouse hygiene and the provision and full utilisation of adequate laboratory facilities for the bacteriological examination of meat and the abattoir environment.


Parameter optimization for the visco-hyperelastic constitutive model of tendon using FEM.
Numerous constitutive models describing the mechanical properties of tendons have been proposed during the past few decades. However, few were widely used owing to the lack of implementation in the general finite element (FE) software, and very few systematic studies have been done on selecting the most appropriate parameters for these constitutive laws. In this work, the visco-hyperelastic constitutive model of the tendon implemented through the use of three-parameter Mooney-Rivlin form and sixty-four-parameter Prony series were firstly analyzed using ANSYS FE software. Afterwards, an integrated optimization scheme was developed by coupling two optimization toolboxes (OPTs) of ANSYS and MATLAB for estimating these unknown constitutive parameters of the tendon. Finally, a group of Sprague-Dawley rat tendons was used to execute experimental and numerical simulation investigation. The simulated results showed good agreement with the experimental data. An important finding revealed that too many Maxwell elements was not necessary for assuring accuracy of the model, which is often neglected in most open literatures. Thus, all these proved that the constitutive parameter optimization scheme was reliable and highly efficient. Furthermore, the approach can be extended to study other tendons or ligaments, as well as any visco-hyperelastic solid materials.


Toward high-performance digital logic technology with carbon nanotubes.
The slow-down in traditional silicon complementary metal-oxide-semiconductor (CMOS) scaling (Moore's law) has created an opportunity for a disruptive innovation to bring the semiconductor industry into a postsilicon era. Due to their ultrathin body and ballistic transport, carbon nanotubes (CNTs) have the intrinsic transport and scaling properties to usher in this new era. The remaining challenges are largely materials-related and include obtaining purity levels suitable for logic technology, placement of CNTs at very tight (∼5 nm) pitch to allow for density scaling and source/drain contact scaling. This review examines the potential performance advantages of a CNT-based computing technology, outlines the remaining challenges, and describes the recent progress on these fronts. Although overcoming these issues will be challenging and will require a large, sustained effort from both industry and academia, the recent progress in the field is a cause for optimism that these materials can have an impact on future technologies.


[Sexuality on nursing assistance: reflections on a cultural perspective].
This study aimed to understand sexuality and how the construction of its meanings, symbols, feelings, and values is developed. The data were collected through focal group techniques and individual interviews with nurses. The emerging feelings were: embarrassment; fear; surprise; challenge; sorrow; worry, and personal satisfaction. The experience with the sexuality on nursing assistance revealed: the presence of a pathological and biological perspective in the action of nursing, showing this dimension as something that needs to be medically treated; on the other hand, it showed that this theme can be a way to self-knowledge, rethinking concepts, values and conflicts, as well as producing nursing care in a more ethical, committed and empathetic way, thus valuing the dignity of the ones cared for and the ones who take care.


Somatostatin receptor subtypes in hormone-refractory (castration-resistant) prostatic carcinoma.
The aim of this study was to examine the tissue expression and localisation of the somatostatin receptors (SSTRs) in hormone-refractory (HR) prostate cancer (PCa). Five SSTRs were evaluated immunohistochemically in 20 radical prostatectomies (RPs) with Gleason score (GS) 3+3=6 PCa, in 20 RPs with GS 4+4=8 and 4+5=9 PCa, and 20 transurethral resection of the prostate specimens with HR PCa. The mean values in the cytoplasm (all five SSTRs were expressed), membrane (only SSTR3 and SSTR4 were expressed) and nuclei (only SSTR4 and SSTR5 were expressed) of the glands in HR PCa were 20-70% lower than in the other two groups, the differences being statistically significant. All five SSTRs were expressed in the smooth muscle and endothelial cells of HR PCa, the mean values being lower than in the other two groups. In conclusion, this study expands our knowledge on the expression and localisation of five SSTRs in the various tissue components in the HR PCa compared with hormone-sensitive PCa.


Lemierre's syndrome and genetic polymorphisms: a case report.
Lemierre's syndrome presents a classic clinical picture, the pathophysiology of which remains obscure. Attempts have been made to trace genetic predispositions that modify the host detection of pathogen or the resultant systemic reaction. A 17-year old female, with no previous medical history, was admitted to the intensive care unit for septic shock, acute respiratory distress syndrome and Lemierre's syndrome. Her DNA was assayed for single nucleotide polymorphisms previously incriminated in the detection of the pathogen, the inflammatory response and the coagulation cascade. We observed functional variations in her Toll like 5 receptor (TLR 5) gene and two coagulation variations (Tissue Factor (TF) 603 and Plasminogen-Activator-Inhibitor-1 (PAI-1) 4G-4G homozygosity) associated with thrombotic events. The innate immune response and the prothrombogenic mutations could explain, at least in part, the symptoms of Lemierre's syndrome. Genomic study of several patients with Lemierre's syndrome may reveal its pathophysiology.


Long-term Outcomes After Liver Transplantation Among Human Immunodeficiency Virus-Infected Recipients.
Early outcomes after human immunodeficiency virus (HIV) + liver transplantation (LT) are encouraging, but data are lacking regarding long-term outcomes and comparisons with matched HIV- patients. We examined outcomes among 180 HIV+ LT, and compared outcomes to matched HIV- counterfactuals (Scientific Registry of Transplant Recipients 2002-2011). Iterative expanding radius matching (1:10) on recipient age, race, body mass index, hepatitis C virus (HCV), model for end-stage liver disease score, and acute rejection; and donor age and race, cold ischemia time, and year of transplant. Patient survival and graft survival were estimated using Kaplan-Meier methodology and compared using log-rank and Cox proportional hazards. Subgroup analyses were performed by transplant era (early: 2002-2007 vs. modern: 2008-2011) and HCV infection status. Compared to matched HIV- controls, HIV+ LT recipients had a 1.68-fold increased risk for death (adjusted hazard ratio [aHR], 1.68, 95% confidence interval [95% CI], 1.28-2.20; P < 0.001), and a 1.70-fold increased risk for graft loss (aHR, 1.70; 95% CI, 1.31-2.20; P < 0.001). These differences persisted independent of HCV infection status. However, in the modern transplant era risk for death (aHR, 1.11; 95% CI, 0.52-2.35; P = 0.79) and graft loss (aHR, 0.89; 95% CI, 0.42-1.88; P = 0.77) were similar between monoinfected and uninfected LT recipients. In contrast, independent of transplant era, coinfected LT recipients had increased risk for death (aHR, 2.24; 95% CI, 1.43-3.53; P < 0.001) and graft loss (aHR, 2.07; 95% CI, 1.33-3.22; P = 0.001) compared to HCV+ alone LT recipients. These results suggest that outcomes among monoinfected HIV+ LT recipients have improved over time. However, outcomes among HIV+ LT recipients coinfected with HCV remain concerning and motivate future survival benefit studies.


Activation of mitogen-activated protein kinase pathways by cyclic GMP and cyclic GMP-dependent protein kinase in contractile vascular smooth muscle cells.
Vascular smooth muscle cells (VSMC) exist in either a contractile or a synthetic phenotype in vitro and in vivo. The molecular mechanisms regulating phenotypic modulation are unknown. Previous studies have suggested that the serine/threonine protein kinase mediator of nitric oxide (NO) and cyclic GMP (cGMP) signaling, the cGMP-dependent protein kinase (PKG) promotes modulation to the contractile phenotype in cultured rat aortic smooth muscle cells (RASMC). Because of the potential importance of the mitogen-activated protein kinase (MAP kinase) pathways in VSMC proliferation and phenotypic modulation, the effects of PKG expression in PKG-deficient and PKG-expressing adult RASMC on MAP kinases were examined. In PKG-expressing adult RASMC, 8-para-chlorophenylthio-cGMP activated extracellular signal- regulated kinases (ERK1/2) and c-Jun N-terminal kinase (JNK). The major effect of PKG activation was increased activation by MAP kinase kinase (MEK). The cAMP analog, 8-Br-cAMP inhibited ERK1/2 activation in PKG-deficient and PKG-expressing RASMC but had no effect on JNK activity. The effects of PKG on ERK and JNK activity were additive with those of platelet-derived growth factor (PDGF), suggesting that PKG activates MEK through a pathway not used by PDGF. The stimulatory effects of cGMP on ERK and JNK activation were also observed in low-passaged, contractile RASMC still expressing endogenous PKG, suggesting that the effects of PKG expression were not artifacts of cell transfections. These results suggest that in contractile adult RASMC, NO-cGMP signaling increases MAP kinase activity. Increased activation of these MAP kinase pathways may be one mechanism by which cGMP and PKG activation mediate c-fos induction and increased proliferation of contractile adult RASMC.


Federated inference and belief sharing.
This paper concerns the distributed intelligence or federated inference that emerges under belief-sharing among agents who share a common world-and world model. Imagine, for example, several animals keeping a lookout for predators. Their collective surveillance rests upon being able to communicate their beliefs-about what they see-among themselves. But, how is this possible? Here, we show how all the necessary components arise from minimising free energy. We use numerical studies to simulate the generation, acquisition and emergence of language in synthetic agents. Specifically, we consider inference, learning and selection as minimising the variational free energy of posterior (i.e., Bayesian) beliefs about the states, parameters and structure of generative models, respectively. The common theme-that attends these optimisation processes-is the selection of actions that minimise expected free energy, leading to active inference, learning and model selection (a.k.a., structure learning). We first illustrate the role of communication in resolving uncertainty about the latent states of a partially observed world, on which agents have complementary perspectives. We then consider the acquisition of the requisite language-entailed by a likelihood mapping from an agent's beliefs to their overt expression (e.g., speech)-showing that language can be transmitted across generations by active learning. Finally, we show that language is an emergent property of free energy minimisation, when agents operate within the same econiche. We conclude with a discussion of various perspectives on these phenomena; ranging from cultural niche construction, through federated learning, to the emergence of complexity in ensembles of self-organising systems.


Wireless Deep Brain Stimulation by Ultrasound-Responsive Molecular Piezoelectric Nanogenerators.
Implantable neural stimulation devices are becoming prevalent in bioelectronic medicine for the precise treatment of various clinical diseases. Nevertheless, the limited lifespan and buckling size of the implanted devices remain significant obstacles for chronic clinical application. In this study, we developed an ultrasound-driven battery-free neurostimulator based on a high-performance mini-sized nanogenerator and demonstrated its successful application for the deep-brain-stimulation (DBS) therapy of Parkinson's disease in a rat model. This soft piezoelectric-triboelectric hybrid nanogenerators (PTNG) are made of porous thin-films of molecular piezoelectric materials, which have great advantages of facile, scalable, low-temperature, and flexible processing. Without any bucky accessory control circuits, the subcutaneously implanted soft PTNG can function as a wirelessly powered neurostimulator, allowing for the adjustment of stimulation parameters through external programmable ultrasound pulses. This DBS electroceutical application of energy-harvesting thin-film devices based on molecular piezoelectric materials provides valuable insight into the development of a soft high-performance bioelectronic device.


Identification of the first mutation in a BRE motif of the β-globin gene and its inheritance with two other α-globin gene mutations in a Lebanese family.
A 7-year old boy presented with a history of recurrent respiratory infections and hypochromic microcytic anemia. Iron profiles were normal thereby prompting genetic analysis of α- and β-globin mutations. The first mutation in a BRE motif of the β-globin gene in the proband, sibling and the mother was identified. The proband and his sibling also inherited common α-globin mutations from the father and mother. In all cases, no serious thalassemia disease was detected.


Elevated galanin receptor type 2 primarily contributes to mechanical hypersensitivity after median nerve injury.
In this study, we investigated temporal changes in galanin receptor type 2 (GalR2) expression in NF200-, galanin-, neuropeptide Y (NPY)-, and neuronal nitric oxide synthase (nNOS)-like immunoreactive (LI) dorsal root ganglion (DRG) neurons after median nerve chronic constriction injury (CCI), and the effects of GalR2 on c-Fos expression in the cuneate nucleus (CN). Double immunofluorescence labeling methods were used to appraise changes in GalR2 expression in NF200-LI, galanin-LI, NPY-LI, and nNOS-LI DRG neurons after CCI. The von Frey assay was used to assess the efficiency of intraplantar administration of saline, M871 (a GalR2 antagonist), or AR-M1896 (a GalR2 agonist) on neuropathic signs of rats with CCI. The effects of alterations in c-Fos expression were assessed in all treatments. The percentage of GalR2-LI neurons in lesioned DRGs increased and peaked at 1 week after CCI. We further detected that percentages of GalR2-LI neurons labeled for NF200, galanin, NPY, and nNOS significantly increased following CCI. Furthermore, M871 remarkably attenuated tactile allodynia, but the sensation was slightly aggravated by AR-M1896 after CCI. Consequentially, after electrical stimulation of the CCI-treated median nerve, the number of c-Fos-LI neurons in the cuneate nucleus (CN) was significantly reduced in the M871 group, whereas it increased in the AR-M1896 group. These results suggest that activation of GalR2, probably through NPY or nitric oxide, induces c-Fos expression in the CN and transmits mechanical allodynia sensations to the thalamus.


Reductive cyclodimerization of chalcones: exploring the "self-adaptability" of galvanostatic electrosynthesis.
The "self-adaptability" of galvanostatic electrolysis was shown to assist a multistage unprecedented chemo- and diastereoselective electrochemically promoted cyclodimerization of chalcones. The process, all involving the reductive events, delivered densely functionalized cyclopentanes featuring five contiguous stereocenters (25 examples, yields of up to 95%, dr values up to >20 : 1). Dedicated and combined experimental as well as electrochemical investigation revealed the key role of a dynamic kinetic resolution of the aldol intermediate for the reaction mechanism.


Kinetics of peripheral blood neutrophils in severe coronavirus disease 2019.
Emerging evidence of dysregulation of the myeloid cell compartment urges investigations on neutrophil characteristics in coronavirus disease 2019 (COVID-19). We isolated neutrophils from the blood of COVID-19 patients receiving general ward care and from patients hospitalised at intensive care units (ICUs) to explore the kinetics of circulating neutrophils and factors important for neutrophil migration and activation. Multicolour flow cytometry was exploited for the analysis of neutrophil differentiation and activation markers. Multiplex and ELISA technologies were used for the quantification of protease, protease inhibitor, chemokine and cytokine concentrations in plasma. Neutrophil polarisation responses were evaluated microscopically. Gelatinolytic and metalloproteinase activity in plasma was determined using a fluorogenic substrate. Co-culturing healthy donor neutrophils with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) allowed us to investigate viral replication in neutrophils. Upon ICU admission, patients displayed high plasma concentrations of granulocyte-colony-stimulating factor (G-CSF) and the chemokine CXCL8, accompanied by emergency myelopoiesis as illustrated by high levels of circulating CD10-, immature neutrophils with reduced CXCR2 and C5aR expression. Neutrophil elastase and non-metalloproteinase-derived gelatinolytic activity were increased in plasma from ICU patients. Significantly higher levels of circulating tissue inhibitor of metalloproteinase 1 (TIMP-1) in patients at ICU admission yielded decreased total MMP proteolytic activity in blood. COVID-19 neutrophils were hyper-responsive to CXCL8 and CXCL12 in shape change assays. Finally, SARS-CoV-2 failed to replicate inside human neutrophils. Our study provides detailed insights into the kinetics of neutrophil phenotype and function in severe COVID-19 patients, and supports the concept of an increased neutrophil activation state in the circulation.


Using Actigraphy to Predict the Ecological Momentary Assessment of Mood, Fatigue, and Cognition in Older Adulthood: Mixed-Methods Study.
Sleep quality has been associated with cognitive and mood outcomes in otherwise healthy older adults. However, most studies have evaluated sleep quality as aggregate and mean measures, rather than addressing the impact of previous night's sleep on next-day functioning. This study aims to evaluate the ability of previous night's sleep parameters on self-reported mood, cognition, and fatigue to understand short-term impacts of sleep quality on next-day functioning. In total, 73 cognitively healthy older adults (19 males, 54 females) completed 7 days of phone-based self-report questions, along with 24-hour actigraph data collection. We evaluated a model of previous night's sleep parameters as predictors of mood, fatigue, and perceived thinking abilities the following day. Previous night's sleep predicted fatigue in the morning and midday, as well as sleepiness or drowsiness in the morning; however, sleep measures did not predict subjective report of mood or perceived thinking abilities the following day. This study suggests that objectively measured sleep quality from the previous night may not have a direct or substantial relationship with subjective reporting of cognition or mood the following day, despite frequent patient reports. Continued efforts to examine the relationship among cognition, sleep, and everyday functioning are encouraged.


[Greenhouses with a curvilinear planting surface].
The laws of light distribution in plants sown on the flat plane, spherical or cylindrical surfaces were investigated. In mhicrogravity where the plants are arranged radially the level of illumination of lower leaf strata is higher on curvilinear than on flat surfaces. This is due to the following: as the plants grow they get separated; also, the concentration of the light flux increases with depth of plants on the curvilinear surfaces. In view of this, a space green-house is suggested, the design of which provides high productivity per unit volume and per unit energy of the incident flux of photosynthetically active radiation.


Ulnar lengthening in the treatment of Kienböck's disease.
Twenty patients with Kienböck's disease were treated with a modification of the Persson ulnar-lengthening procedure to remove compressive stress from the damaged lunate. After an average follow-up of thirty-seven months, relief of pain was satisfactory in eighteen patients who had returned to work (nine of whom had strenuous occupations), and two patients were dissatisfied because they had persistent pain and were not able to return to their previous occupations. Non-union at the site of the ulnar osteotomy occurred in three patients who were treated early in the series and was the result of inadequate internal fixation or insufficient duration of protective splinting. All three of the patients had satisfactory results after replating and bone-grafting. The procedure appears to help to maintain carpal height, prevent further collapse of the lunate, encourage consolidation of the fragmented lunate, and increase grip strength. Except for ulnar deviation, which the procedure may further diminish, the postoperative motions of the wrist were moderately improved.


Degradation of isoproturon and bentazone in peat- and compost-based biomixtures.
The composition and properties of a biomixture used in a biobed are decisive for pesticide sorption and degradation. This study was performed to investigate the capability of compost-based substrates in mixtures with citrus peel and vine branch straw and peat-based substrates in mixtures with soil and vine branch straw at different levels in order to degrade isoproturon and bentazone. Dissipation and mineralisation rates of both pesticides were determined, and metabolic activity was followed as respiration. Compost-based substrates showed faster pesticide dissipation in the presence of lignocellulosic materials, as in garden compost and vine branch straw. The increasing content of vine branch straw in peat-based substrates does not seem to affect dissipation of the parent compounds. Low mineralisation rate was observed in all treatments. Higher pesticide degradation was observed in the lignocellulosic substrates, probably because of the development of lignin-degrading microorganisms which have shown to be robust and are able to degrade recalcitrant pesticides. Copyright © 2010 Society of Chemical Industry.


Family carers' perspectives of the Alzheimer Café in Ireland.
Background: The Alzheimer Café is a psychosocial intervention shown to have benefits for family carers of people with dementia. Family carers experience a period of change across all aspects of their lives following the dementia diagnosis, and require new skills and tools to navigate these new landscapes. The objective of this research was to investigate family carers' perspectives of the Alzheimer Café in Ireland, and explore how attendance may translate into broader benefits in their lives. This paper also provides an overview of Alzheimer Café models, which exist internationally. Methods: Semi-structured interviews were conducted with nine family carers of people with dementia who were currently attending or had attended an Alzheimer Café in the preceding six months. The research was conducted in three Alzheimer Cafés in Ireland. Data analysis was conducted using Braun and Clarke's six step thematic analysis framework. Results: Community, atmosphere, activity and information were described as core features of the Alzheimer Café in Ireland. The Alzheimer Café was described as a community with a good atmosphere encompassing emotional support, friendship, equality and inclusion. Family carer also highlighted Alzheimer Cafés could potentially facilitate wider community awareness and engagement. The Alzheimer Café was shown to provide an activity which facilitated relationship building within care dyads as well as with other attendees. Several information streams were identified, including guest speaker input, attendees' shared experiences, and specific advice from healthcare professionals. Conclusion: The Alzheimer Café offers strong personal support to family carers of people with dementia. Our findings suggest that Alzheimer Cafés can build family carers' capacity to manage new social, environmental and cultural challenges associated with dementia. While it is important the Alzheimer Café is enjoyable, has useful information and is supportive, it is equally important that these features generate sustained improvements for family carers external to the Alzheimer Café.


Adaptive evolution in urban ecosystems.
Urban ecologists have demonstrated that cities are functioning ecosystems. It follows then that species living in these contexts should participate in and experience the same suite of biological processes, including evolution, that have occupied scientists for centuries in more "natural" contexts. In fact, urban ecosystems with myriad novel contexts, pressures, and species rosters provide unprecedentedly potent evolutionary stimuli. Here, we present the case for studying adaptive evolution in urban settings. We then review and synthesize techniques into a coherent approach for studying adaptive evolution in urban settings that combines observations of phenotypic divergence, measurements of fitness benefits of novel genetically based phenotypes, and experimental manipulations of potential drivers of adaptation. We believe that studying evolution in urban contexts can provide insights into fundamental evolutionary biology questions on rate, direction, and repeatability of evolution, and may inform species and ecosystem service conservation efforts.


Lyme borreliosis as a cause of myocarditis and heart muscle disease.
Lyme borreliosis (LB) is a multisystem disorder that may cause self-limiting or chronic diseases of the skin, the nervous system, the joints, heart and other organs. The aetiological agent is the recently discovered Borrelia burgdorferi. In 1980, cardiac manifestations of LB were first described, including acute conduction disorders, atrioventricular block, transient left ventricular dysfunction and even cardiomegaly. Pathohistological examination showed spirochaetes in cases of acute perimyocarditis. Recently, we were able to cultivate Borrelia burgdorferi from the myocardium of a patient with long-standing dilated cardiomyopathy. In this study, we have examined 54 consecutive patients suffering from chronic heart failure for antibodies to Borrelia burgdorferi. On ELISA, 32.7% were clearly seropositive. The endomyocardial biopsy of another patient also revealed spirochaetes in the myocardium by a modified Steiner's silver stain technique. These findings give further evidence that LB is associated with chronic heart muscle disease.


Polyanhydrides as localized drug delivery carrier: an update.
There is a continuing thrust to increase the efficacy and reduce the toxicity of existing and new drug molecules for their better usage to treat disease. Localized drug delivery has been explored in the same way, which can provide a platform to target local diseased tissues and can reduce the burden on the body by reducing the dose size and hence the dose-related toxicity of the molecules. Various polymers have evolved for the purpose of localized drug delivery, however, polyanhydrides are considered the best, supported by products in the clinical phases. To demonstrate the advantages of localized delivery using basic concepts and describing polyanhydride carrier with products such as Gliadel and Septacin. The rationale behind localized drug delivery and the carrier for the same are dealt with. Polyanhydrides discussed in detail are those from subclasses that have been given less emphasis previously and have been developed or investigated in the last 5 years. From the recent update on polyanhydrides, it can be concluded that these polymers have great potential as localized drug delivery carriers due to the versatility of their properties. However, the quest to stabilize the system in order to achieve a long shelf life remains ongoing.


[Underreporting of occupational injuries to the Labour Inspection].
The Labour Inspection investigates occupational accidents and publishes injury statistics annually. Information is based upon two main sources: Copies of reports to the National Insurance Service and mandatory reports from employers to the Labour Inspection. Occupational injuries treated by Oslo Emergency Ward and Oslo Ambulance Service during a period of three months were compared with injuries recorded by the Labour Inspection. Four months after the end of the study period, the Labour Inspection had received reports from the National Insurance Service on 150 (13%) of the 1,153 injuries recorded by Oslo Emergency Ward/Oslo Ambulance Service. Among all injuries registered, 208 were serious according to the criteria of the Labour Inspection. Only 19 (9%) of these were reported directly to the Labour Inspection from employers in accordance with the legal requirement. The study recorded 17 serious injuries caused by violence affecting employees; none of these were reported directly to the Labour Inspection. Data on occupational injuries collected by the Labour Inspection are far from complete. In Oslo alone, the Labour Inspection may annually overlook some 900-1,000 serious injuries. Data quality can be improved and delayed reporting avoided by using information from doctors and medical institutions that provide treatment.


Multiple listing in kidney transplantation.
The increasing number of patients with end-stage renal disease and the expanding waiting lists for various solid-organ transplants, particularly kidney transplants, has compelled prospective transplant recipients and their care teams to explore novel ways to accelerate this process, initiating the practice of multiple listing. Multiple listing is defined as being listed for an organ transplant at more than 1 transplant center. Current policy allows patients to be listed at more than 1 transplant center in 1 or more organ procurement organization. Multiple listing can be beneficial for different groups of transplant candidates. Current data support a beneficial effect for the patient on multiple waiting lists, most notably portending a survival advantage for transplant recipients. The kidney transplant list has the most patients who are multiply listed (4.7%), followed by the liver transplant list at 3.8%. The main potential downside of multiple listing is its effect on patients not on multiple lists, as well as the cost accrued to achieve multiple listings. With the newly clarified policy of the United Network for Organ Sharing, a pivotal role for nephrologists in educating patients about the option of multiple listing becomes more apparent. In this article, current practices and policies regarding multiple listing are reviewed and opinions and ethics relating to the practice are discussed.


A critical look at adjusted fetal weights in rats.
A new derived (i.e., calculated) endpoint of developmental toxicology has appeared in a very few studies since 1990. This endpoint is adjusted mean live fetal weight per litter or adjusted fetal weight. Given our lack of familiarity with the endpoint, we evaluated the basis, prevalence, methods, and usefulness in embryo-fetal developmental toxicity (EFDT) studies in rats. Literature searches were performed with key terms using PubMed and Google Scholar. Major textbooks were consulted but lack of any mention of the endpoint. Unpublished EFDT data, which are readily available online, were utilized to test adjustment methods. Pertinent information on factors that influence fetal weight goes back a century. Four papers utilizing rats were found in which fetal weights were adjusted using either statistical or formula-based methods to adjust fetal weights. Only one study showed a clear benefit to the endpoint when there was a marked decrease in live litter size; this pointed to situations in which the new endpoint might be useful. The lone formula-based adjustment method was found to be lacking adequate testing and justifications. A new experimental alternative formula-based adjustment is shown to produce results very similar to statistical methods. From this assessment, we recommend that adjusted fetal weight should not be a routine endpoint at this time. However, there are likely cases where this derived endpoint could aid interpretation. We encourage other investigators to examine previous EFDT study data to establish guidance on the use of adjusted mean live fetal weights.


Barriers associated with the failure to return for intrauterine device insertion following first-trimester abortion.
The aim of the study was to identify barriers associated with the failure to return for delayed intrauterine device (IUD) insertion postabortion. This study had two components: (a) a retrospective cohort study of women who chose an IUD as their postabortion contraceptive method to compare characteristics of those who did and did not receive a device within 6 months of the procedure and (b) a prospective survey of women intending IUD use postabortion to assess actual IUD use at 6 weeks, barriers to access and attitudes on insertion timing. Of the 500 abortion patient charts available for review during the study period, 53 women intended IUD use postabortion. At 6 months, only 32% intending an IUD received one, and there were no significant demographic differences between the groups. For the prospective portion, the response rate at 6 weeks was 54% (27/50), with only 26% (7/27) of responders reporting IUD insertion by this time. The principal reported barrier to IUD insertion was time needed for an additional visit (41%). Most women (67%) desired immediate insertion and believed that they would be more likely to have an IUD inserted if it is performed immediately postabortion (63%). Monthly income was the only statistically significant difference between those who responded to the 6-week follow-up (US$1409.50) and those who did not (US$937.50, p=.05). A significant number of women that express a preference for IUD use after first-trimester abortion do not return to obtain a device. Most would prefer to have the option of immediate insertion.


Efficacy of metabarcoding for identification of fish eggs evaluated with mock communities.
There is urgent need for effective and efficient monitoring of marine fish populations. Monitoring eggs and larval fish may be more informative than that traditional fish surveys since ichthyoplankton surveys reveal the reproductive activities of fish populations, which directly impact their population trajectories. Ichthyoplankton surveys have turned to molecular methods (DNA barcoding & metabarcoding) for identification of eggs and larval fish due to challenges of morphological identification. In this study, we examine the effectiveness of using metabarcoding methods on mock communities of known fish egg DNA. We constructed six mock communities with known ratios of species. In addition, we analyzed two samples from a large field collection of fish eggs and compared metabarcoding results with traditional DNA barcoding results. We examine the ability of our metabarcoding methods to detect species and relative proportion of species identified in each mock community. We found that our metabarcoding methods were able to detect species at very low input proportions; however, levels of successful detection depended on the markers used in amplification, suggesting that the use of multiple markers is desirable. Variability in our quantitative results may result from amplification bias as well as interspecific variation in mitochondrial DNA copy number. Our results demonstrate that there remain significant challenges to using metabarcoding for estimating proportional species composition; however, the results provide important insights into understanding how to interpret metabarcoding data. This study will aid in the continuing development of efficient molecular methods of biological monitoring for fisheries management.


The Effect of Load Uncertainty and Foreperiod Regularity on Anticipatory and Compensatory Neuromotor Control in Catching.
Muscle activation was measured using EMG in 28 males (n = 28) while participants caught visually identical balls of known and unknown weights (50, 1.32, 2.18, and 2.99 kg) under variable (1-10s) and constant (3s) foreperiods. EMG integrals were computed for three time intervals before the catch (anticipatory), and one after (compensatory). Load uncertainty caused the CNS to use an anticipatory strategy characterized by preparation to catch balls of an unknown weight by utilizing about 92% of the muscle activation used to catch the heaviest possible ball under the known weight condition. The CNS appeared to scale anticipatory muscle activation to afford an opportunity to catch a ball of an unknown weight between .50 and 2.99 kg. The constant 3s foreperiod, which permitted temporal anticipation, did not influence the anticipatory neuromotor strategy adopted by the CNS to cope with load uncertainty. Load uncertainty also altered compensatory neuromotor control in catching.


Application of an object-oriented programming paradigm in three-dimensional computer modeling of mechanically active gastrointestinal tissues.
The aim of this study was to develop a novel three-dimensional (3-D) object-oriented modeling approach incorporating knowledge of the anatomy, electrophysiology, and mechanics of externally stimulated excitable gastrointestinal (GI) tissues and emphasizing the "stimulus-response" principle of extracting the modeling parameters. The modeling method used clusters of class hierarchies representing GI tissues from three perspectives: 1) anatomical; 2) electrophysiological; and 3) mechanical. We elaborated on the first four phases of the object-oriented system development life-cycle: 1) analysis; 2) design; 3) implementation; and 4) testing. Generalized cylinders were used for the implementation of 3-D tissue objects modeling the cecum, the descending colon, and the colonic circular smooth muscle tissue. The model was tested using external neural electrical tissue excitation of the descending colon with virtual implanted electrodes and the stimulating current density distributions over the modeled surfaces were calculated. Finally, the tissue deformations invoked by electrical stimulation were estimated and represented by a mesh-surface visualization technique.


Is lipid goal one-size-fits-all: A review of evidence for recommended low-density lipoprotein treatment targets in Asian patients.
The international guideline recommendations for low-density lipoprotein cholesterol (LDL-C) lowering were made based on the results of randomized controlled trials (RCTs), meta-analyses, and observational studies mostly in the White population. It was not clear whether these LDL-C targets could be applicable to other ethnic groups, for example, Asian patients. This review aimed to address major aspects related to the lipid goal and statin therapy in Asia, including the epidemiology of cardiovascular disease, the LDL-C profiles, the lipid goals from localized guidelines, genetics and lifestyles, and the efficacy and safety of statins. Owing to the geographic, ethnic, genetic, and cultural diversity in this region, we observed a geographic pattern of diversity in cardiovascular epidemiology and statin response in Central Asia, East Asia (particularly for Asia-Pacific region), and South Asia. The rapidly growing literature from Asian countries questioning "lower is better" hypothesis was noticed. However, owing to the nature of these dominantly observational data, the conclusion was hardly confirmative. Despite the rapid expansion of the current literature in this region, efforts should be made to ensure an adequate sample size to assess the significance of a given lipid parameter on overall cardiovascular outcomes in this Asian population.


Toxicity and dose-response studies of 1alpha-hydroxyvitamin D2 in a retinoblastoma xenograft model.
Although calcitriol (1,25-dihydroxycholecalciferol) and vitamin D(2) inhibit retinoblastoma growth in the athymic (nude) mouse xenograft (Y-79 cell line) model of retinoblastoma, they can cause severe toxicity. To examine the toxicity of and dose-dependent response for the inhibition of tumor growth for 1alpha-hydroxyvitamin D(2) (1alpha-OH-D(2)), an analogue with reduced systemic toxicity, in the athymic Y-79 mouse model. Mice were randomized into treatment and control groups for 5-week toxicity and dose-response studies. Treatment was via oral gavage 5 times per week. Dose-response studies measured tumor inhibition and drug serum levels. Tumor size and body weight were measured weekly together with various criteria for toxicity. Animals were euthanized at the end of the treatment period. Tumors and kidneys were harvested, and serum was analyzed for calcium and drug levels. Doses of 0.1 to 1.2 microg/d were selected on the basis of toxicity studies for the dose-response trial. Tumor weight and volume in the 0.2-microg and 0.3-microg doses were significantly lower than in controls. Mortality rates and kidney calcification in mice treated with doses of 0.1 to 0.3 microg were lower than those observed in studies of calcitriol and vitamin D(2). A vitamin D analogue, 1alpha-OH-D(2), inhibits tumor growth in this xenograft model of retinoblastoma with less toxicity than calcitriol and vitamin D(2).


Olaparib in combination with irinotecan, cisplatin, and mitomycin C in patients with advanced pancreatic cancer.
Olaparib is an oral inhibitor of polyadenosine 5'-diphosphoribose polymerization (PARP) that has previously shown signs of activity in patients with BRCA mutations and pancreatic ductal adenocarcinoma (PDAC). In this phase 1 dose-escalation trial in patients with unresectable PDAC, we determined the maximum tolerated dose (MTD) of olaparib (tablet formulation) in combination with irinotecan 70 mg/m2 on days 1 and 8 and cisplatin 25 mg/m2 on days 1 and 8 of a 28-day cycle (olaparib plus IC). We then studied the safety and tolerability of adding mitomycin C 5 mg/m2 on day 1 to this regimen (olaparib plus ICM). 18 patients with unresectable PDAC were enrolled. The MTD of olaparib plus IC was olaparib 100 mg twice-daily on days 1 and 8. The addition of mitomycin C to this dose level was not tolerated. Grade ≥3 drug-related adverse events (AEs) were encountered in 16 patients (89%). The most common grade ≥3 drug-related toxicities included neutropenia (89%), lymphopenia (72%), and anemia (22%). Two patients (11%), both of whom had remained on study for more than 12 cycles, developed drug-related myelodysplastic syndrome (MDS). The objective response rate (ORR) for all evaluable patients was 23%. One patient who carried a deleterious germline BRCA2 mutation had a durable clinical response lasting more than four years, but died from complications of treatment-related MDS. Olaparib had substantial toxicity when combined with IC or ICM in patients with PDAC, and this treatment combination did not have an acceptable risk/benefit profile for further study. However, durable clinical responses were observed in a subset of patients and further clinical investigation of PARP inhibitors in PDAC is warranted. This clinical trial was registered on ClinicalTrials.gov as NCT01296763.


Reifications of the intellectual: representations, organization and agency in revolutionary China.
How did 'intellectuals' evolve from a class of subjects in Marxian thoughts to highly visible populations under communism? Such 'reifications of the intellectual' have deeply affected subjectivity, conflict and organization, but received little attention in the political sociology of communism. This essay draws on research on classifications and social boundaries to address the objective and subjective foundations of the reifications and their impact on communist rule. The intellectual is viewed as an identification formed and performed around multiple social axes (most notably family background, educational achievement, occupational history, institutional affiliation and revolutionary rank) that reflected broader patterns of communist political domination. I use the Chinese Communist movement to demonstrate that (1) interaction of political contests, ruling strategies and institutional developments turned a diversity of persons into 'intellectuals' who were allegedly imbued with reprehensible interests and habits linked to privileged economic classes; (2) constant competitions for power and organizational changes led to classificatory ambiguities and, in turn, allowed individuals some control over their identifications; and (3) the developments profoundly influenced identity, state and class formation. Focusing on the dynamics that produced a highly visible but fluid population of 'intellectuals' opens new pathways for comparative research on communism.


Weight-drop model as a valuable tool to study potential neurobiological processes underlying behavioral and cognitive changes secondary to mild traumatic brain injury.
The pathophysiology of post-traumatic brain injury (TBI) behavioral and cognitive changes is not fully understood, especially in its mild presentation. We designed a weight drop TBI model in mice to investigate the role of neuroinflammation in behavioral and cognitive sequelae following mild TBI. C57BL/6 mice displayed depressive-like behavior at 72 h after mild TBI compared with controls, as indicated by a decrease in the latency to first immobility and climbing time in the forced swim test. Additionally, anxiety-like behavior and hippocampal-associated spatial learning and memory impairment were found in the elevated plus maze and in the Barnes maze, respectively. Levels of a set of inflammatory mediators and neurotrophic factors were analyzed at 6 h, 24 h, 72 h, and 30 days after injury in ipsilateral and contralateral hemispheres of the prefrontal cortex and hippocampus. Principal components analysis revealed two principal components (PC), which represented 59.1% of data variability. PC1 (cytokines and chemokines) expression varied between both hemispheres, while PC2 (neurotrophic factors) expression varied only across the investigated brain areas. Our model reproduces mild TBI-associated clinical signs and pathological features and might be a valuable tool to broaden the knowledge regarding mild TBI pathophysiology as well as to test potential therapeutic targets.


Angulated Stents-A Novel Stent Improvisation to Manage Difficult Post-tuberculosis Bronchial Stenosis.
Post-tuberculosis bronchostenosis (PTBS), a complication of endobronchial tuberculosis is currently treated by bronchial stenting. However, in cases of angulated bronchial stenoses, difficulty is often encountered in stent insertion and maintenance, resulting in stent migration, granulation tissue overgrowth, and restenosis. To accommodate the angulated alignment of the stenosis, we devised an "angulated stent"-a novel improvisation of the conventional stent via splicing and suturing to achieve a resultant angulated shape. A retrospective review was undertaken to evaluate the performance of this stent. Among 283 PTBS patients who underwent interventional bronchoscopy at our center from 2004 to 2014, 21 were treated with at least one angulated stent. Clinical outcomes, including the stenting duration were investigated. After a median follow-up of 26 months, stent removal was successful in 7 (33.3%) out of 21 patients. In patients managed with angulated stents, the median duration to stent change or eventual removal was longer than those treated with straight tube stents (392 days vs. 86 days; p < 0.05). Angulated stents are a feasible treatment option in patients with angulated PTBS by reducing complications and prolonging the stent-changing interval.


Distal tibial vein grafts for limb salvage.
Bypasses below the tibial peroneal trunk, which are not commonly performed, are an effective method of limb salvage. We have done long-term follow-up of all 148 consecutive grafts done during the past 19 years. By careful patient selection, detailed arteriograms, utilization of veins from all extremities, meticulous operating technique, and noninvasive follow-up, we have achieved a limb salvage rate of 75% and a cumulative five-year patency rate of 62%. Diabetics made up 53% of the series and did not affect the results. Seventy-one percent of all failures occurred in the first six months. Considering the charges for hospitalization, amputation, prostheses, and rehabilitation, distal tibial bypass procedures are cost-effective.


Biochemical and functional characterization of the rat liver glucose-transport system. Comparisons with the adipocyte glucose-transport system.
The properties of the glucose-transport systems in rat adipocytes and hepatocytes were compared in cells prepared from the same animals. Hormones and other agents which cause a large stimulation of 3-O-methylglucose transport in adipocytes were without acute effect in hepatocytes. Hepatocytes displayed a lower affinity for 3-O-methylglucose (20 mM) and alternative substrates than adipocytes (6 mM), whereas inhibitor affinities were similar in both cell types. The concentration and distribution of glucose transporters were determined by Scatchard analysis of D-glucose-inhibitable [3H]cytochalasin B binding to subcellular fractions. In liver, most of the transporters were located in the plasma membrane (42 +/- 5 pmol/mg of protein) with a small amount (4 +/- 3 pmol/mg) in the low-density microsomal fraction ('microsomes'), the reverse of the situation in adipocytes. Glucose transporters were covalently labelled with [3H]cytochalasin B by using the photochemical cross-linking agent hydroxysuccinimidyl-4-azidobenzoate and analysed by SDS/polyacrylamide-gel electrophoresis. A single D-glucose-inhibitable peak with a molecular mass of 40-50 kDa was seen in both plasma membrane and low-density microsomes. This peak was further characterized by isoelectric focusing and revealed a single peak of specific [3H]cytochalasin B binding at pI 6.05 in both low-density microsomes and plasma membrane, compared with peaks at pI 6.4 and 5.6 in adipocyte membranes. In summary: the glucose-transport system in hepatocytes has a lower affinity and higher capacity than that in adipocytes, and is also not accurately modulated by insulin; the subcellular distribution of glucose transporters in the liver suggests that few intracellular transporters would be available for translocation; the liver transporter has a molecular mass similar to that of the adipocyte transporter; the liver glucose transporter exists as a single charged form (pI 6.05), compared with the multiple forms in adipocytes. This difference in charge could reflect a functionally important difference in molecular structure between the two cell types.


A pragmatic randomised controlled trial of the Welsh National Exercise Referral Scheme: protocol for trial and integrated economic and process evaluation.
The benefits to health of a physically active lifestyle are well established and there is evidence that a sedentary lifestyle plays a significant role in the onset and progression of chronic disease. Despite a recognised need for effective public health interventions encouraging sedentary people with a medical condition to become more active, there are few rigorous evaluations of their effectiveness. Following NICE guidance, the Welsh national exercise referral scheme was implemented within the context of a pragmatic randomised controlled trial. The randomised controlled trial, with nested economic and process evaluations, recruited 2,104 inactive men and women aged 16+ with coronary heart disease (CHD) risk factors and/or mild to moderate depression, anxiety or stress. Participants were recruited from 12 local health boards in Wales and referred directly by health professionals working in a range of health care settings. Consenting participants were randomised to either a 16 week tailored exercise programme run by qualified exercise professionals at community sports centres (intervention), or received an information booklet on physical activity (control). A range of validated measures assessing physical activity, mental health, psycho-social processes and health economics were administered at 6 and 12 months, with the primary 12 month outcome measure being 7 day Physical Activity Recall. The process evaluation explored factors determining the effectiveness or otherwise of the scheme, whilst the economic evaluation determined the relative cost-effectiveness of the scheme in terms of public spending. Evaluation of such a large scale national public health intervention presents methodological challenges in terms of trial design and implementation. This study was facilitated by early collaboration with social research and policy colleagues to develop a rigorous design which included an innovative approach to patient referral and trial recruitment, a comprehensive process evaluation examining intervention delivery and an integrated economic evaluation. This will allow a unique insight into the feasibility, effectiveness and cost effectiveness of a national exercise referral scheme for participants with CHD risk factors or mild to moderate anxiety, depression, or stress and provides a potential model for future policy evaluations. Current Controlled Trials ISRCTN47680448.


Aging and DNA polymerase alpha: modulation by dietary restriction.
Aging is an inevitable characteristic of biological processes in living organisms. For the last several years, investigators have proposed numerous mechanisms to explain the basic understanding of aging and its intervention and have provided many insights into the molecular bases and the biological events that contribute to the progressive decline in function observed during cellular aging. It is probable that a number of interacting factors, such as increased somatic mutations, changes in genetic expression, and decreased efficiency of protein synthesis, may contribute to the age-dependent deterioration of physiological processes. One cellular function involved in all of the above factors is that of normal DNA synthesis required for maintaining genomic integrity. This suggests that changes in function of DNA replicative enzymes are almost certain to be a factor in one or more of the negative cellular phenomena associated with aging. This is a particularly attractive hypothesis, since the accumulation of inactive or error-prone DNA polymerases during aging would be expected to initiate a sequence of events leading to synthesis of altered proteins and the general dysfunction of a wide range of cellular processes. Dietary restriction is the only anti-aging regimen uniquely suited to identifying these cellular processes and could play a significant role in maintaining cellular mechanisms necessary to reduce the rate at which mutations accumulate during aging. The observation that dietary restriction may impede the age-related decline in the activity and fidelity of DNA polymerases and in the decline of repair DNA synthesis, suggests potential mechanisms by which dietary restriction could extend the lifespan of animals, including humans.


Molecular Docking and In-Silico Analysis of Natural Biomolecules against Dengue, Ebola, Zika, SARS-CoV-2 Variants of Concern and Monkeypox Virus.
The emergence and rapid evolution of human pathogenic viruses, combined with the difficulties in developing effective vaccines, underline the need to develop innovative broad-spectrum antiviral therapeutic agents. The present study aims to determine the in silico antiviral potential of six bacterial antimicrobial peptides (AMPs), two phytochemicals (silvestrol, andrographolide), and two bacterial secondary metabolites (lyngbyabellin A, hapalindole H) against dengue virus, Zika virus, Ebola virus, the major variants of SARS-CoV-2 and monkeypox virus. The comparison of docking scores obtained with natural biomolecules was performed with specific neutralizing antibodies (positive controls for ClusPro) and antiviral drugs (negative controls for Autodock Vina). Glycocin F was the only natural biomolecule tested to show high binding energies to all viral surface proteins and the corresponding viral cell receptors. Lactococcin G and plantaricin ASM1 also achieved high docking scores with all viral surface proteins and most corresponding cell surface receptors. Silvestrol, andrographolide, hapalindole H, and lyngbyabellin A showed variable docking scores depending on the viral surface proteins and cell receptors tested. Three glycocin F mutants with amino acid modifications showed an increase in their docking energy to the spike proteins of SARS-CoV-2 B.1.617.2 Indian variant, and of the SARS-CoV-2 P.1 Japan/Brazil variant, and the dengue DENV envelope protein. All mutant AMPs indicated a frequent occurrence of valine and proline amino acid rotamers. AMPs and glycocin F in particular are the most promising biomolecules for the development of broad-spectrum antiviral treatments targeting the attachment and entry of viruses into their target cell.


Updated guidance for palivizumab prophylaxis among infants and young children at increased risk of hospitalization for respiratory syncytial virus infection.
Guidance from the American Academy of Pediatrics (AAP) for the use of palivizumab prophylaxis against respiratory syncytial virus (RSV) was first published in a policy statement in 1998. Guidance initially was based on the result from a single randomized, placebo-controlled clinical trial conducted in 1996-1997 describing an overall reduction in RSV hospitalization rate from 10.6% among placebo recipients to 4.8% among children who received prophylaxis. The results of a second randomized, placebo-controlled trial of children with hemodynamically significant heart disease were published in 2003 and revealed a reduction in RSV hospitalization rate from 9.7% in control subjects to 5.3% among prophylaxis recipients. Because no additional controlled trials regarding efficacy were published, AAP guidance has been updated periodically to reflect the most recent literature regarding children at greatest risk of severe disease. Since the last update in 2012, new data have become available regarding the seasonality of RSV circulation, palivizumab pharmacokinetics, the changing incidence of bronchiolitis hospitalizations, the effects of gestational age and other risk factors on RSV hospitalization rates, the mortality of children hospitalized with RSV infection, and the effect of prophylaxis on wheezing and palivizumab-resistant RSV isolates. These data enable further refinement of AAP guidance to most clearly focus on those children at greatest risk.


Trace elements bioaccumulation in Porcellionides pruinosus (Brandt, 1833) and related biomarkers of exposure.
In the last years, the increase of anthropogenic activities has led to a progressive pollution of ecosystems. Oniscidean isopods are a group of terrestrial animals known as excellent bio-indicators and bio-accumulators, because of their capacity to accumulate contaminants and to implement appropriate strategies of detoxification. For this study, we collected Porcellionides pruinosus from two different sites in the Corinth region (Greece), a polluted site and a control site, to assess the heavy metal pollution status. We conducted an inductively coupled plasma mass spectrometry (ICP-MS) analysis for the detection of trace elements in animals' hepatopancreas and soil; we performed also immunohistochemistry for detection of metallothioneins 1 (MT1) and heat shock protein 70 (HSP70s). The results suggest a great capacity of the species in trace elements bioaccumulation and the high degree of pollution of the area near Agioi Theodoroi where the metal pollution index (MPI) is threefolds higher than the control site, due to the presence of significantly higher concentration of arsenic, cadmium, cobalt, chromium, manganese, molybdenum, and lead found in hepatopancreas and soil. The environmental stress is confirmed by the expression of the relative biomarkers of exposure MT1 and HSP70. Our study, with a multimarker approach, consents getting a complete analysis of environmental quality and the effect of pollution on organisms and shows for the first time the heavy metals contamination status in certain Greece area. Furthermore, P. pruinosus proved to be an appropriate indicator of pollution in terrestrial ecosystems.


Emergency care research ethics in low-income and middle-income countries.
A large proportion of the total global burden of disease is caused by emergency medical conditions. Emergency care research is essential to improving emergency medicine but this research can raise some distinctive ethical challenges, especially with regard to (1) standard of care and risk-benefit assessment; (2) blurring of the roles of clinician and researcher; (3) enrolment of populations with intersecting vulnerabilities; (4) fair participant selection; (5) quality of consent; and (6) community engagement. Despite the importance of research to improve emergency care in low-income and middle-income countries (LMICs) and the widely acknowledged ethical challenges, very little has been written on the ethics of emergency care research in LMICs. This paper examines the ethical and regulatory challenges to conducting emergency care research with human participants in LMICs. We outline key challenges, present potential solutions or frameworks for addressing these challenges, and identify gaps. Despite the ethical and regulatory challenges, conducting high-quality, ethical emergency care research in LMICs is possible and it is essential for global health.


Simulation training in an obstetric clerkship: a randomized controlled trial.
To estimate the effect of simulation training on the confidence of medical students to perform a vaginal delivery. Medical students on 12 consecutive rotations were recruited and randomly assigned to a traditional lecture on performing a vaginal delivery or a lecture plus hands-on vaginal delivery simulation. Participants completed confidence assessment questionnaires at baseline and 4 weeks after training. End-of-rotation examination scores were also compared. One-hundred thirteen students participated (94.9% of those eligible). Students receiving simulation training were significantly more confident in their ability to perform a vaginal delivery immediately after assessment than students who did not receive the simulation training (P<.01); however, these differences narrowed over time. Compared with lecture-only students, simulation students scored significantly higher on their oral (P=.004) and written examinations (P=.009) 4 weeks after the intervention. A single obstetric simulation is more effective than lecture only for increasing students' end-of-rotation oral and written examination scores. I.


Construction of confidence regions in the ROC space after the estimation of the optimal Youden index-based cut-off point.
After establishing the utility of a continuous diagnostic marker investigators will typically address the question of determining a cut-off point which will be used for diagnostic purposes in clinical decision making. The most commonly used optimality criterion for cut-off point selection in the context of ROC curve analysis is the maximum of the Youden index. The pair of sensitivity and specificity proportions that correspond to the Youden index-based cut-off point characterize the performance of the diagnostic marker. Confidence intervals for sensitivity and specificity are routinely estimated based on the assumption that sensitivity and specificity are independent binomial proportions as they arise from the independent populations of diseased and healthy subjects, respectively. The Youden index-based cut-off point is estimated from the data and as such the resulting sensitivity and specificity proportions are in fact correlated. This correlation needs to be taken into account in order to calculate confidence intervals that result in the anticipated coverage. In this article we study parametric and non-parametric approaches for the construction of confidence intervals for the pair of sensitivity and specificity proportions that correspond to the Youden index-based optimal cut-off point. These approaches result in the anticipated coverage under different scenarios for the distributions of the healthy and diseased subjects. We find that a parametric approach based on a Box-Cox transformation to normality often works well. For biomarkers following more complex distributions a non-parametric procedure using logspline density estimation can be used.


Association of metabolic syndrome traits with urinary biomarkers in Japanese adults.
Although metabolic syndrome traits are risk factors for chronic kidney disease, few studies have examined their association with urinary biomarkers. Urinary biomarkers, including A-megalin, C-megalin, podocalyxin, albumin, α1-microglobulin, β2-microglobulin, and N-acetyl-β-D-glucosaminidase, were cross-sectionally assessed in 347 individuals (52.7% men) with a urine albumin-to-creatinine ratio (ACR) < 300 mg/g in a health checkup. Metabolic syndrome traits were adopted from the National Cholesterol Education Program (third revision) of the Adult Treatment Panel criteria modified for Asians. Participants had a mean body mass index, estimated glomerular filtration rate (eGFR), and median ACR of 23.0 kg/m2, 74.8 mL/min/1.73 m2, and 7.5 mg/g, respectively. In age- and sex-adjusted logistic regression analysis, A-megalin and albumin were significantly associated with the clustering number of metabolic syndrome traits (3 or more). After further adjustment with eGFR, higher quartiles of A-megalin and albumin were each independently associated with the clustering number of metabolic syndrome traits (adjusted odds ratio for A-megalin: 1.30 per quartile, 95% CI 1.03-1.64; albumin: 1.42 per quartile, 95% CI 1.12-1.79). Both urinary A-megalin and albumin are associated with the clustering number of metabolic syndrome traits. Further research on urinary A-megalin is warranted to examine its role as a potential marker of kidney damage from metabolic risk factors.


Clinical implications of discordance between low-density lipoprotein cholesterol and particle number.
The amount of cholesterol per low-density lipoprotein (LDL) particle is variable and related in part to particle size, with smaller particles carrying less cholesterol. This variability causes concentrations of LDL cholesterol (LDL-C) and LDL particles (LDL-P) to be discordant in many individuals. LDL-P measured by nuclear magnetic resonance spectroscopy, calculated LDL-C, and carotid intima-media thickness (IMT) were assessed at baseline in the Multi-Ethnic Study of Atherosclerosis, a community-based cohort of 6814 persons free of clinical cardiovascular disease (CVD) at entry and followed for CVD events (n = 319 during 5.5-year follow-up). Discordance, defined as values of LDL-P and LDL-C differing by ≥ 12 percentile units to give equal-sized concordant and discordant subgroups, was related to CVD events and to carotid IMT in models predicting outcomes for a 1 SD difference in LDL-C or LDL-P, adjusted for age, gender, and race. LDL-C and LDL-P were associated with incident CVD overall: hazard ratios (HR 1.20, 95% CI [CI] 1.08-1.34; and 1.32, 95% CI 1.19-1.47, respectively, but for those with discordant levels, only LDL-P was associated with incident CVD (HR 1.45, 95% CI 1.19-1.78; LDL-C HR 1.07, 95% CI 0.88-1.30). IMT also tracked with LDL-P rather than LDL-C, ie, adjusted mean IMT of 958, 932, and 917 microm in the LDL-P > LDL-C discordant, concordant, and LDL-P < LDL-C discordant subgroups, respectively, with the difference persisting after adjustment for LDL-C (P = .002) but not LDL-P (P = .60). For individuals with discordant LDL-C and LDL-P levels, the LDL-attributable atherosclerotic risk is better indicated by LDL-P.


Host specific sensing of coronaviruses and picornaviruses by the CARD8 inflammasome.
Hosts have evolved diverse strategies to respond to microbial infections, including the detection of pathogen-encoded proteases by inflammasome-forming sensors such as NLRP1 and CARD8. Here, we find that the 3CL protease (3CL pro ) encoded by diverse coronaviruses, including SARS-CoV-2, cleaves a rapidly evolving region of human CARD8 and activates a robust inflammasome response. CARD8 is required for cell death and the release of pro-inflammatory cytokines during SARS-CoV-2 infection. We further find that natural variation alters CARD8 sensing of 3CL pro , including 3CL pro -mediated antagonism rather than activation of megabat CARD8. Likewise, we find that a single nucleotide polymorphism (SNP) in humans reduces CARD8's ability to sense coronavirus 3CL pros , and instead enables sensing of 3C proteases (3C pro ) from select picornaviruses. Our findings demonstrate that CARD8 is a broad sensor of viral protease activities and suggests that CARD8 diversity contributes to inter- and intra-species variation in inflammasome-mediated viral sensing and immunopathology.


Distress tolerance, coping motives, and alcohol craving and consumption: Two experiments testing momentary responses to a mood induction.
The current studies examined the relationship between state and trait distress tolerance (DT), drinking-related variables (alcohol craving and consumption), and the moderating role of drinking to cope with negative affect (i.e., coping motives). Study 1 was a laboratory-based experiment. Participants (n=71) completed measures of trait DT, craving, coping motives, and affect valence prior to a negative mood induction task. Post-mood induction, participants completed measures of affect valence, alcohol craving, and state DT. Next, participants completed an alcohol taste task, measuring alcohol consumption. Study 2 was completed online. Participants (n=592) completed the same pre- and post-mood induction measures as study 1, but were randomized to a mood condition (neutral, negative, or positive). Study 2 did not include alcohol consumption. Negative mood induction lowered reported affect in both studies. In study 1, higher coping motives predicted increased craving in response to negative mood induction but state and trait DT did not predict craving change alone. Contrary to our hypothesis, individuals with higher coping motives showed a positive relationship between trait DT and craving. Analyses predicting alcohol consumption were not significant. In study 2, lower trait DT predicted post-mood induction craving prior to inclusion of interactions in the model. Higher coping motives were the strongest and most consistent predictor of craving. Other predictors (state DT, mood condition) and interaction terms were not significant. Findings broadly align with previous research suggesting that coping motives are predictive of craving and indicate that trait DT may also impact craving.


Population differentiation of 2 forms of Bryde's whales in the Indian and Pacific Oceans.
Accurate identification of units for conservation is particularly challenging for marine species as obvious barriers to gene flow are generally lacking. Bryde's whales (Balaenoptera spp.) are subject to multiple human-mediated stressors, including fisheries bycatch, ship strikes, and scientific whaling by Japan. For effective management, a clear understanding of how populations of each Bryde's whale species/subspecies are genetically structured across their range is required. We conducted a population-level analysis of mtDNA control region sequences with 56 new samples from Oman, Maldives, and Bangladesh, plus published sequences from off Java and the Northwest Pacific. Nine diagnostic characters in the mitochondrial control region and a maximum parsimony phylogenetic analysis identified 2 genetically recognized subspecies of Bryde's whale: the larger, offshore form, Balaenoptera edeni brydei, and the smaller, coastal form, Balaenoptera edeni edeni. Genetic diversity and differentiation indices, combined with a reconstructed maximum parsimony haplotype network, indicate strong differences in the genetic diversity and population structure within each subspecies. Discrete population units are identified for B. e. brydei in the Maldives, Java, and the Northwest Pacific and for B. e. edeni between the Northern Indian Ocean (Oman and Bangladesh) and the coastal waters of Japan.


Assessing drug sensitivity of Plasmodium vivax to halofantrine or choroquine in southern, central Vietnam using an extended 28-day in vivo test and polymerase chain reaction genotyping.
Chloroquine-resistant Plasmodium vivax malaria is emerging in Oceania, Asia, and Latin America. We assessed the drug sensitivity of P. vivax to chloroquine or halofantrine in two villages in southern, central Vietnam. This area has chloroquine-resistant Plasmodium falciparum but no documented chloroquine-resistant P. vivax. Standard dose chloroquine (25 mg/kg, over 48 hours) or halofantrine (8 mg/kg, 3 doses) was administered to 29 and 25 patients, respectively. End points were parasite sensitivity or resistance determined at 28 days. Of the evaluable patients, 23/23 100% (95% confidence interval [CI] 85.1-100) chloroquine and 21/24 (87.5%) (95% CI 67.6-97.3) halofantrine-treated patients were sensitive. Three halofantrine recipients had initial clearance but subsequent recurrence of their parasitemias. Genotyping of the recurrent and Day 0 parasitemias differed, suggesting either new infections or relapses of liver hypnozoites from antecedent infections. Among these Vietnamese patients, P. vivax was sensitive to chloroquine and halofantrine. Genotyping was useful for differentiating the recurrent vivax parasitemias.


Analysis of the recent cluster of invasive fungal sinusitis at the Toronto Hospital for Sick Children.
The aim of this study was to review the eight histopathologically proven cases of invasive fungal sinusitis that occurred at the Toronto Hospital for Sick Children between 1985 and 1995, seven of which that clustered between March 1990 and February 1992. A retrospective review of the relevant cases and a review of the literature are presented. A clinical review of this rare, life-threatening entity, occurring almost exclusively in severely neutropenic patients is presented and compared to the relevant clinical findings from an analysis of this series, the largest reported to date and first to document a significant clustering (p < .01). We conclude, based on epidemiologic evidence, that this clustering was directly related to the release of airborne fungal spores from dormant soil reservoirs disturbed during hospital construction. Therefore, we strongly advocate increased vigilance with respect to precautions against airborne pathogens wherever severely neutropenic hosts are treated.


Prenatal diagnosis of Sex determining region Y -box transcription factor 2 anophthalmia syndrome caused by germline mosaicism using next-generation sequencing: A case report.
Sex determining region Y box transcription factor 2 (SOX2) mutations lead to bilateral anophthalmia with autosomal dominant human inheritance. SOX2 mutations could result in severe ocular phenotypes usually associated with variable systemic defects. Most patients described with SOX2 anophthalmia syndrome possessed de novo mutations in this gene. In this case report, we describe 2 brothers with mental retardation and bilateral anophthalmia caused due to SOX2 germline mosaicism in unaffected parents. Next-generation DNA sequencing was carried out to determine the family's possible cause of genetic mutation. Sanger sequencing was performed on the patients and their parents. Prenatal diagnosis was done in both pregnancies of the older brother's wife via chorionic villus sampling. A novel heterozygous pathogenic frameshift deletion variant (exon1:c.58_80del:p.G20fs) was identified in the SOX2 gene, which was confirmed by Sanger sequencing in both affected brothers and did not exist in healthy parents, indicating germline mosaicism. Most SOX2 mutations known look to arise de novo in probands and are diagnosed through anophthalmia or microphthalmia. Prenatal diagnosis should be offered to healthy parents with a child with SOX2 mutation every pregnancy.


Nuclear factor 45 (NF45) is a regulatory subunit of complexes with NF90/110 involved in mitotic control.
Nuclear factor 90 (NF90) and its C-terminally extended isoform, NF110, have been isolated as DNA- and RNA-binding proteins together with the less-studied protein NF45. These complexes have been implicated in gene regulation, but little is known about their cellular roles and whether they are redundant or functionally distinct. We show that heterodimeric core complexes, NF90-NF45 and NF110-NF45, exist within larger complexes that are more labile and contain multiple NF90/110 isoforms and additional proteins. Depletion of the NF45 subunit by RNA interference is accompanied by a dramatic decrease in the levels of NF90 and NF110. Reciprocally, depletion of NF90 but not of NF110 greatly reduces the level of NF45. Coregulation of NF90 and NF45 is a posttranscriptional phenomenon, resulting from protein destabilization in the absence of partners. Depletion of NF90-NF45 complexes retards cell growth by inhibition of DNA synthesis. Giant multinucleated cells containing nuclei attached by constrictions accumulate when either NF45 or NF90, but not NF110, is depleted. This study identified NF45 as an unstable regulatory subunit of NF90-NF45 complexes and uncovered their critical role in normal cell division. Furthermore, the study revealed that NF90 is functionally distinct from NF110 and is more important for cell growth.


Older Adult Spouses with Multiple Chronic Conditions: Challenges, Rewards, and Coping Strategies.
There is a paucity of research exploring how spouses to older adults with multiple chronic conditions make meaning of their caregiving experience. For this study, we asked: What is the experience of spousal caregivers to persons with multiple chronic conditions? We applied Thorne's interpretive description approach, interviewing 18 spouses who provided a rich description of their caregiving experience; interviews were transcribed verbatim and thematically analysed. Themes were categorized according to challenges encountered, rewards gleaned, and sustaining strategies employed by participants in caregiving to their spouse with multiple chronic conditions. Unique findings relate to the challenges inherent in decision-making within the context of multiple chronic conditions. This article begins to address the gap in the literature regarding the caregiving experience within the context of multiple chronic conditions.


Evidence that two latency-associated transcripts of herpes simplex virus type 1 are nonlinear.
The latency-associated transcripts (LATs) of herpes simplex virus type 1 (HSV-1) are the only viral gene products that accumulate to abundant levels in latently infected cells. Others have reported species of 2.0, 1.50, and 1.45 kb; only the 2.0-kb species is seen in productively infected cells, and there is evidence that it behaves as an intron. We examined the LATs both in trigeminal ganglia of latently infected mice and in productively infected cultures of monkey CV-1 cells. After glyoxalation, RNA was subjected to high-resolution agarose gel electrophoresis and Northern (RNA) analysis, a procedure capable of resolving linear and nonlinear RNA species. Under these conditions, we resolved the 2.0-kb LAT into two species; the slower species was much more abundant and had a mobility significantly slower than expected for a linear RNA. To test the hypothesis that this RNA was in fact nonlinear, we used partial hydrolysis by sodium carbonate and oligonucleotide-directed RNase H digestion. These procedures changed the mobility of the slower species into that of the faster species. Similarly, the mobility of the 1.50-kb LAT, which was much more abundant than the 1.45-kb LAT, was changed by these procedures to that of the 1.45-kb LAT. Our data show that the two major LAT species are nonlinear, and they support an interpretation of stable lariat structures.


Vision Loss Secondary to Facial and Periorbital Steroid Injection: A Systematic Review.
The risk of ophthalmic and retinal artery occlusions following facial and periorbital steroid injection has not been explored. This systematic review examines the prevalence, risk factors, and treatment outcomes of steroid-induced vision losses. A literature search in Evidence Based Medicine Reviews, MEDLINE, Embase, Pubmed, ClinicalTrials, and WHO ICTRP was performed for vision loss following facial and periorbital corticosteroid injections through July 2020. Of 35 case reports, series, and reviews, 49 patients (56 eyes) with steroid-induced vision loss were analyzed. Injection sites predominantly involved the nose (45%) and periocular regions (10%). The most common type of steroid is triamcinolone (54%). Most cases were unilateral, except 7 cases of bilateral vision losses, 4 of which resulted from unilateral steroid injection. Symptoms were reported during or immediately after injections in 49% of cases. Most occlusions occurred in the ophthalmic (53%) or central retinal artery (33%). Vision most commonly presented as no light perception (37%), and 90% were 20/200 or worse. Final visual outcomes varied from 20/200 or worse (56%), 20/40 or better (30%), to in between (13%). Most vision losses resulted from steroid injections in the nasal and periorbital area. Triamcinolone was the most common offending agent, likely due to large particle size, low solubility, and extensive particle aggregation. Dexamethasone has the opposite pharmacologic properties and has never been reported in association with vascular occlusion related vision loss. Careful steroid selection, injection techniques, and treatment strategies should be considered to prevent and treat artery occlusion.


A History and Overview of Telecommunicator Cardiopulmonary Resuscitation (T-CPR).
Few events in pre-hospital medicine inspire as much attention and resources as out-of-hospital cardiac arrest (OHCA), yet the survival rate for such events has remained stagnant and unacceptably low. The first links in the chain of survival are early recognition and early CPR; yet EMS services do not arrive to the scene of a medical call for on average 7 minutes. Emergency dispatchers are generally the first trained individuals involved in medical emergencies; they can provide pre-arrival instructions, specifically telecommunicator CPR (T-CPR), and represent the potential to double the bystander CPR rate and increase return of spontaneous circulation. Yet, according to survey data, fewer than half of all public safety answering points (PSAPs) provide any T-CPR and even fewer provide hands-only CPR instruction.1 This article will provide a brief overview, history and introduction to the evidence supporting the use of T-CPR to improve outcomes in OHCA.


Possible interaction of genotypes at cystathionine beta-synthase and methylenetetrahydrofolate reductase (MTHFR) in neural tube defects. NTD Collaborative Group.
Neural tube defects are a common, complex disorder with genetic and environmental components to risk. We investigated the previously reported interaction between homozygosity for the thermolabile variant at the methylenetetrahydrofolate reductase and heterozygosity for the 844ins68 allele at the cystathionine beta-synthase loci in cases with lumbosacral myelomeningocele and their parents. Using control allele frequencies from our sample pooled with those published in the literature, we confirm a marginally significant interaction at these two loci. This finding suggests that additional, larger studies are warranted to investigate this possible interaction in more detail.