Characterization of the G-quadruplexes in the duplex nuclease hypersensitive element of the PDGF-A promoter and modulation of PDGF-A promoter activity by TMPyP4.
The proximal 5'-flanking region of the human platelet-derived growth factor A (PDGF-A) promoter contains one nuclease hypersensitive element (NHE) that is critical for PDGF-A gene transcription. On the basis of circular dichroism (CD) and electrophoretic mobility shift assay (EMSA), we have shown that the guanine-rich (G-rich) strand of the DNA in this region can form stable intramolecular parallel G-quadruplexes under physiological conditions. A Taq polymerase stop assay has shown that the G-rich strand of the NHE can form two major G-quadruplex structures, which are in dynamic equilibrium and differentially stabilized by three G-quadruplex-interactive drugs. One major parallel G-quadruplex structure of the G-rich strand DNA of NHE was identified by CD and dimethyl sulfate (DMS) footprinting. Surprisingly, CD spectroscopy shows a stable parallel G-quadruplex structure formed within the duplex DNA of the NHE at temperatures up to 100 degrees C. This structure has been characterized by DMS footprinting in the double-stranded DNA of the NHE. In transfection experiments, 10 microM TMPyP4 reduced the activity of the basal promoter of PDGF-A approximately 40%, relative to the control. On the basis of these results, we have established that ligand-mediated stabilization of G-quadruplex structures within the PDGF-A NHE can silence PDGF-A expression.


Office-based Methadone Prescribing for Opioid Use Disorder: The Canadian Model.
In the context of the US overdose crisis, improving access to medications for opioid use disorder is urgently needed. The Canadian model of methadone treatment, whereby clinicians can prescribe methadone for opioid use disorder in office-based settings and methadone can be dispensed through community pharmacies, offers a compelling model for adoption in the US. Office-based settings in which methadone is prescribed often adopt a rapid-access model, allowing walk-in appointments and same-day initiation of methadone. Prescribing authorization requirements have been relaxed over the past 25 years to improve access to methadone. This paper summarizes the model of office-based methadone prescribing in Canada, highlighting the regulatory structures, prescribing practices, and interprofessional collaborations that enable methadone treatment in office-based settings. Potential implementation strategies for adopting office-based prescribing in the US are discussed.


RBM39: A druggable metabolic sensor linking RNA splicing, transcriptional regulation, and metabolic reprogramming in cancer.
In a recent issue of Cell, Mossmann et al.1 describe a novel role for an emerging cancer target, RNA-binding motif protein 39, as a metabolic sensor of the conditionally essential amino acid arginine.


Conversion therapy with an immune checkpoint inhibitor and an antiangiogenic drug for advanced hepatocellular carcinoma: A review.
Hepatocellular carcinoma (HCC) has been the fifth most common malignancy worldwide and is the second most common cause of tumor-related mortality globally. In China, a high proportion of patients with HCC present with an advanced stage of the disease, so HCC is a major challenge to the healthcare system and a substantial socioeconomic burden. The last decade has witnessed an expansion of the treatment landscape for HCC. Various approaches have been explored as potential conversion therapies for advanced HCC. Despite controversies, mounting data have indicated that successful conversion therapy followed by subsequent surgery is achievable in a population of patients with advanced HCC. This conversion therapy is a safe and promising treatment strategy to prolong long-term outcomes. Based on preliminary research, this review has assembled and summarized current clinical experience with and evidence of the efficacy of conversion therapies followed by subsequent surgery for advanced HCC.


The effects of perioperative goal-directed therapy on acute kidney injury after cardiac surgery in the early period.
Background: This study aims to investigate the effects of goaldirected fluid therapy on the development of acute kidney injury in the perioperative period in patients undergoing cardiopulmonary bypass. Methods: Between November 2019 and May 2021, a total of 60 patients (46 males, 14 females; mean age: 62.5±9.6 years; range, 44 to 76 years) who were scheduled for elective coronary artery bypass grafting or valve surgery under cardiopulmonary bypass were included in the study. The patients were divided into two groups as the study group (Group S, n=30) and control group (Group C, n=30). The patients in Group C were treated with standard therapy, while the patients in Group S were treated with goal-directed fluid therapy. The Kidney Disease: Improving Global Outcomes (KDIGO) classification and renal biomarkers were used for the evaluation of acute kidney injury. Results: Acute kidney injury rates were similar in both groups (30%). Postoperative fluid requirement, intra-, and postoperative erythrocyte suspension requirements were significantly lower in Group S than Group C (p=0.002, p=0.02, and p=0.002, respectively). Cystatin-C was lower in Group S (p<0.002). The kidney injury molecule-1, glomerular filtration rate, and creatinine levels were similar in both groups. The length of hospital stay was longer in Group C than Group S (p<0.001). Conclusion: Although goal-directed fluid therapy does not change the incidence of acute kidney injury in patients undergoing cardiac surgery, it can significantly decrease Cystatin-C levels. Goal-directed fluid therapy can also decrease fluid and erythrocyte requirements with shorter length of hospital stay.


Modeling reverse-phi motion-selective neurons in cortex: double synaptic-veto mechanism.
Reverse-phi motion is the illusory reversal of perceived direction of movement when the stimulus contrast is reversed in successive frames. Livingstone, Tsao, and Conway (2000) showed that direction-selective cells in striate cortex of the alert macaque monkey showed reversed excitatory and inhibitory regions when two different contrast bars were flashed sequentially during a two-bar interaction analysis. While correlation or motion energy models predict the reverse-phi response, it is unclear how neurons can accomplish this. We carried out detailed biophysical simulations of a direction-selective cell model implementing a synaptic shunting scheme. Our results suggest that a simple synaptic-veto mechanism with strong direction selectivity for normal motion cannot account for the observed reverse-phi motion effect. Given the nature of reverse-phi motion, a direct interaction between the ON and OFF pathway, missing in the original shunting-inhibition model, it is essential to account for the reversal of response. We here propose a double synaptic-veto mechanism in which ON excitatory synapses are gated by both delayed ON inhibition at their null side and delayed OFF inhibition at their preferred side. The converse applies to OFF excitatory synapses. Mapping this scheme onto the dendrites of a direction-selective neuron permits the model to respond best to normal motion in its preferred direction and to reverse-phi motion in its null direction. Two-bar interaction maps showed reversed excitation and inhibition regions when two different contrast bars are presented.


Devising new lipid-coated calcium phosphate/carbonate hybrid nanoparticles for controlled release in endosomes for efficient gene delivery.
Lipid-coated calcium phosphate (LCP) nanoparticles (NPs) are proven to be effective vehicles for the delivery of genes and some drugs, while it is not desirable for NPs to release genes/drugs in late endosomes/lysosomes. To achieve the early endosomal release and escape, we have designed and developed new lipid-coated calcium carbonate/phosphate (LCCP) hybrid NPs. These new hybrid LCCP NPs have a spherical structure with an average diameter of 40 nm and high gene loading capacity. We particularly demonstrate that the loaded dsDNA/siRNA is mostly released under mildly acidic conditions (pH 6.0-5.5). LCCP NPs are also effectively internalized by B16F10 cells in a dose and time dependent way. The delivery efficacy has been further demonstrated using two functional siRNAs, i.e. programmed death ligand 1 (PD-L1) siRNA for PD-L1 silencing and polo-like kinase 1 (PLK1) siRNA for growth inhibition of B16F10. Consistently, the LCCP loaded PD-L1 siRNA shows quicker PD-L1-mRNA inhibition than LCP NPs, indicating that LCCP NPs improved the siRNA release in endosomes.


Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.
The regulation of ion channel activity by specific lipid molecules is widely recognized as an integral component of electrical signalling in cells. In particular, phosphatidylinositol 4,5-bisphosphate (PIP(2)), a minor yet dynamic phospholipid component of cell membranes, is known to regulate many different ion channels. PIP(2) is the primary agonist for classical inward rectifier (Kir2) channels, through which this lipid can regulate a cell's resting membrane potential. However, the molecular mechanism by which PIP(2) exerts its action is unknown. Here we present the X-ray crystal structure of a Kir2.2 channel in complex with a short-chain (dioctanoyl) derivative of PIP(2). We found that PIP(2) binds at an interface between the transmembrane domain (TMD) and the cytoplasmic domain (CTD). The PIP(2)-binding site consists of a conserved non-specific phospholipid-binding region in the TMD and a specific phosphatidylinositol-binding region in the CTD. On PIP(2) binding, a flexible expansion linker contracts to a compact helical structure, the CTD translates 6 Å and becomes tethered to the TMD and the inner helix gate begins to open. In contrast, the small anionic lipid dioctanoyl glycerol pyrophosphatidic acid (PPA) also binds to the non-specific TMD region, but not to the specific phosphatidylinositol region, and thus fails to engage the CTD or open the channel. Our results show how PIP(2) can control the resting membrane potential through a specific ion-channel-receptor-ligand interaction that brings about a large conformational change, analogous to neurotransmitter activation of ion channels at synapses.


Neurosurgery residency program in Yogyakarta, Indonesia: improving neurosurgical care distribution to reduce inequality.
Educating future neurosurgeons is of paramount importance, and there are many aspects that must be addressed within the process. One of the essential issues is the disproportion in neurosurgical care, especially in low- and middle-income countries (LMICs). As stated in their report "Global Surgery 2030," The Lancet Commission on Global Surgery has emphasized that the availability of adequate neurosurgical care does not match the burden of neurosurgical disease. A strong partnership with the local and national government is very desirable to improve the way everyone addresses this issue. In addition, international collaborative effort is absolutely essential for the transfer of knowledge and technology from a developed country to an LMIC. This paper shows what the authors have done in Yogyakarta to build an educational model that helps to improve neurosurgical care distribution in Indonesia and reduce the inequity between provinces. The authors gathered data about the number of neurosurgical procedures that were performed in the sister hospital by using data collected by their residents. Information about the distribution of neurosurgeons in Indonesia was adapted from the Indonesian Society of Neurological Surgeons. The data show that there remains a huge disparity in terms of distribution of neurosurgeons in Indonesia. To tackle the issue, the authors have been able to develop a model of collaboration that can be applied not only to the educational purpose but also for establishing neurosurgical services throughout Indonesia. Currently they have signed a memorandum of understanding with four sister hospitals, while an agreement with one sister hospital has come to an end. There were more than 400 neurosurgical procedures, ranging from infection to trauma, treated by the authors' team posted outside of Yogyakarta. Indonesia has a high level of inequality in neurological surgery care. This model of collaboration, which focuses on the development of healthcare providers, universities, and related stakeholders, might be essential in reducing such a disparity. By using this model, the authors hope they can be involved in achieving the vision of The Lancet Commission on Global Surgery, which is "universal access to safe, affordable surgical and anesthesia care when needed."


High-resolution crystal structure of the subclass B3 metallo-beta-lactamase BJP-1: rational basis for substrate specificity and interaction with sulfonamides.
Metallo-β-lactamases (MBLs) are important enzymatic factors in resistance to β-lactam antibiotics that show important structural and functional heterogeneity. BJP-1 is a subclass B3 MBL determinant produced by Bradyrhizobium japonicum that exhibits interesting properties. BJP-1, like CAU-1 of Caulobacter vibrioides, overall poorly recognizes β-lactam substrates and shows an unusual substrate profile compared to other MBLs. In order to understand the structural basis of these properties, the crystal structure of BJP-1 was obtained at 1.4-Å resolution. This revealed significant differences in the conformation and locations of the active-site loops, determining a rather narrow active site and the presence of a unique N-terminal helix bearing Phe-31, whose side chain binds in the active site and represents an obstacle for β-lactam substrate binding. In order to probe the potential of sulfonamides (known to inhibit various zinc-dependent enzymes) to bind in the active sites of MBLs, the structure of BJP-1 in complex with 4-nitrobenzenesulfonamide was also obtained (at 1.33-A resolution), thereby revealing the mode of interaction of these molecules in MBLs. Interestingly, sulfonamide binding resulted in the displacement of the side chain of Phe-31 from its hydrophobic binding pocket, where the benzene ring of the molecule is now found. These data further highlight the structural diversity shown by MBLs but also provide interesting insights in the structure-function relationships of these enzymes. More importantly, we provided the first structural observation of MBL interaction with sulfonamides, which might represent an interesting scaffold for the design of MBL inhibitors.


Oxidative stress plays a critical role in inactivating mutant BRAF by geldanamycin derivatives.
The geldanamycin derivatives 17-allylamino-17-demethoxygeldanamycin (17-AAG) and 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) are promising chemotherapeutic drugs that inhibit heat shock protein 90 (HSP90) function. Previous studies have shown that 17-AAG/DMAG treatment induces the degradation of mutant BRAF (V600E) and inhibits the activation of mitogen-activated protein/extracellular signal-regulated kinase 1/2 (MEK1/2). We have found, however, that HSP90 inhibition alone is not sufficient for efficient BRAF(V600E) degradation in some cells. HSP90 inhibitors structurally unrelated to geldanamycin, radicicol and novobiocin, while inducing the degradation of the HSP90 client protein RAF-1 fail to induce BRAF(V600E) degradation or inhibit MEK1/2 activation in HT29 human colon cancer cells. Moreover, after treatment with 17-DMAG, the kinase activity of residual, undegraded BRAF(V600E) was also lost. Incubation of cells with a reactive oxygen species (ROS) scavenger, N-acetyl cysteine, partially restored kinase activity and also partially prevented BRAF(V600E) degradation due to 17-DMAG treatment. Conversely, treatment with the ROS producing drug menadione clearly inhibited MEK1/2 and reduced BRAF(V600E). These results suggest that in addition to direct inhibition of HSP90, the antitumor effect of geldanamycin and its derivatives is also mediated though the production of ROS, which may directly inactivate tumorigenic mutant BRAF(V600E).


Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice.
CELF1 is a multifunctional RNA-binding protein that controls several aspects of RNA fate. The targeted disruption of the Celf1 gene in mice causes male infertility due to impaired spermiogenesis, the postmeiotic differentiation of male gametes. Here, we investigated the molecular reasons that underlie this testicular phenotype. By measuring sex hormone levels, we detected low concentrations of testosterone in Celf1-null mice. We investigated the effect of Celf1 disruption on the expression levels of steroidogenic enzyme genes, and we observed that Cyp19a1 was upregulated. Cyp19a1 encodes aromatase, which transforms testosterone into estradiol. Administration of testosterone or the aromatase inhibitor letrozole partly rescued the spermiogenesis defects, indicating that a lack of testosterone associated with excessive aromatase contributes to the testicular phenotype. In vivo and in vitro interaction assays demonstrated that CELF1 binds to Cyp19a1 mRNA, and reporter assays supported the conclusion that CELF1 directly represses Cyp19a1 translation. We conclude that CELF1 downregulates Cyp19a1 (Aromatase) posttranscriptionally to achieve high concentrations of testosterone compatible with spermiogenesis completion. We discuss the implications of these findings with respect to reproductive defects in men, including patients suffering from isolated hypogonadotropic hypogonadism and myotonic dystrophy type I.


Topical management of anterior epistaxis: a national survey.
The use of nasal creams and ointments in the conservative management of anterior epistaxis is well documented and supported. This study set out to obtain a national opinion, in order to establish current practice. A survey of all Scotland-based otolaryngology clinicians was conducted. Participants were asked which topical treatment they used in their practice, how often and for how long they advocated its use, and how they advised their patients to apply it. The overall response rate was 91 per cent. We discuss and compare the varying responses for the questions posed, and discuss the possible reasons for these in greater detail. This study demonstrates a high degree of variation in this practice, arising from a lack of concrete evidence and influenced by anecdotal experience and personal preferences. Definitive comparative studies are required if a 'gold standard' topical approach for the management of anterior epistaxis is to emerge.


Targeted Busulfan therapy with a steady-state concentration of 600-700 ng/mL in patients with sickle cell disease receiving HLA-identical sibling bone marrow transplant.
Busulfan (BU) has a narrow therapeutic window and the average concentration of BU at steady state (Css) is critical for successful engraftment in children receiving BU as part of the preparative regimen for allogeneic transplants. Sixteen patients with sickle cell disease (SCD) underwent allogeneic bone marrow transplant (BMT) from HLA-identical siblings. The preparative regimen consisted of intravenous BU 0.8-1 mg/kg/dose for 16 doses, cytoxan (CY) of 50 mg/kg daily for four doses and equine anti-thymocyte globulin (ATG) 30 mg/kg daily for three doses. BU levels were adjusted to provide a total exposure Css of 600-700 ng/mL. The median age at the time of transplant was 6.2 years (range 1.2-19.3). Fourteen (87%) patients required adjustment of the BU dose to achieve a median Css of 652 ng/mL (range 607-700). All patients achieved neutrophil and platelet engraftment without significant toxicity. Median donor engraftment at the last follow-up was 100% (range 80-100). None of the patients experienced sickle cell-related complications post transplant. With a median follow-up of 3 years (range 1.3-9), the event-free survival (EFS) and overall survival (OS) are both 100%. We conclude that targeting of BU Css between 600 and 700 ng/mL in this regimen can result in excellent and sustained engraftment in young patients with SCD.


X radiation causes a persistent induction of reactive oxygen species and a delayed reinduction of TP53 in normal human diploid fibroblasts.
Multiple genetic changes are required for the development of a malignant cell. The frequency of such changes in cancer cells is higher than can be explained through random mutation, and it was proposed that a subpopulation of cells develop a persistent mutator phenotype. Evidence for such a phenotype has been observed in mammalian cells after treatment with ionizing radiation. The mechanism that promotes this effect has not been defined, but proposed explanations include increased levels of reactive oxygen species (ROS) in irradiated cells and their progeny. The tumor suppressor TP53 is of prime importance in coordinating the cellular response to damage, and it has been suggested to have a role in regulating the cellular redox state. We investigated the persistence of induced levels of ROS in normal diploid human cells for 1 month after X-ray exposure and the role of TP53 in this oxidant response. X radiation induced an oxidant response that persisted for 2 weeks after exposure in cells with normal TP53 function. ROS levels in cells with abrogated TP53 function were decreased in magnitude and duration. X radiation caused a primary transient induction of TP53 followed by a reinduction of TP53 5 days after irradiation. This reinduction persisted for at least 2 days and coincided with the largest induction of apoptosis. The persistently elevated levels of ROS and delayed reinduction of TP53 reported here are further evidence of the delayed effects of ionizing radiation and add to the growing number of such observations.


Solvent affects the conformation of virginiamycin M1 (pristinamycin IIA, streptogramin A).
The streptogramins are antibiotics which act by binding two different components at separate nearby sites on the bacterial 50S ribosome, inhibiting protein synthesis. The first component, a macrolactone, is common to many of the streptogramin antibiotics and, thus, is referred to by many names including virginiamycin M1(VM1), pristinamycin IIA, ostreogrycin A and streptogramin A. X-Ray crystallographic studies of VM1 bound to ribosomes and to a deactivating enzyme show a different conformation to that of VM1 in chloroform solution. We now report the results of high resolution 2D NMR experiments that show that the conformation of VM1 in dimethyl sulfoxide and methanol differs from both that in chloroform solution and in the bound form. The 3D structure and the 1H NMR and 13C NMR chemical shifts of VM1 in dimethyl sulfoxide and methanol are described.


Budd-Chiari syndrome secondary to inflammatory pseudotumor of the liver: Report of a case with a 10-year follow-up.
Inflammatory pseudotumor (IPT) of the liver is a rare benign tumor of unknown origin, it has the appearance of a malignant tumor but has a benign histology and clinical course. We report a case of a 63-year-old man diagnosed of IPT of the liver and followed for 10 years. During the clinical course, he developed a secondary Budd-Chiari syndrome, with a successful response to a transjugular intrahepatic portosystemic shunt over a 5-year follow-up period.


Individual-level needle and syringe coverage in Melbourne, Australia: a longitudinal, descriptive analysis.
Coverage is used as one indicator of needle and syringe program (NSP) effectiveness. At the individual level, coverage is typically defined as an estimate of the proportion of a person who injects drugs' (PWID) injecting episodes that utilise a sterile syringe. In this paper, we explore levels of individual syringe coverage and its changes over time. Data were extracted from 1889 interviews involving 502 participants drawn from the Melbourne drug user cohort study (MIX). We asked questions relating to participants syringe acquisition, distribution and injecting frequency within the two weeks before interview. We created a dichotomous coverage variable that classified participants as sufficiently (≥100 %) covered if all their injecting episodes utilised at least one sterile syringe, and insufficiently (<100 %) covered if not. We categorised participants as "consistently covered" if they were sufficiently covered across interviews; as "consistently uncovered" if they were insufficiently covered across interviews; and "inconsistently covered" if they oscillated between coverage states. Chi-square statistics tested proportions of insufficient coverage across sub-groups using broad demographic, drug use and service utilisation domains. Logistic regression tested predictors of insufficient coverage and inconsistently covered categorisation. Across the sample, levels of insufficient coverage were substantial (between 22-36 % at each interview wave). The majority (50 %) were consistently covered across interviews, though many (45 %) were inconsistently covered. We found strong statistical associations between insufficient coverage and current hepatitis C virus (HCV) infection (RNA+). Current prescription of opioid substitution therapy (OST) and using NSPs as the main source of syringe acquisition were protective against insufficient coverage. Insufficient coverage across the sample was substantial and mainly driven by those who oscillated between states of coverage, suggesting the presence of temporal factors. We recommend a general expansion of NSP services and OST prescription to encourage increases in syringe coverage.


Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case-Control Consortium (PanC4).
Heavy alcohol drinking has been related to pancreatic cancer, but the issue is still unsolved. To evaluate the role of alcohol consumption in relation to pancreatic cancer, we conducted a pooled analysis of 10 case-control studies (5585 cases and 11,827 controls) participating in the International Pancreatic Cancer Case-Control Consortium. We computed pooled odds ratios (ORs) by estimating study-specific ORs adjusted for selected covariates and pooling them using random effects models. Compared with abstainers and occasional drinkers (< 1 drink per day), we observed no association for light-to-moderate alcohol consumption (≤ 4 drinks per day) and pancreatic cancer risk; however, associations were above unity for higher consumption levels (OR = 1.6, 95% confidence interval 1.2-2.2 for subjects drinking ≥ 9 drinks per day). Results did not change substantially when we evaluated associations by tobacco smoking status, or when we excluded participants who reported a history of pancreatitis, or participants whose data were based upon proxy responses. Further, no notable differences in pooled risk estimates emerged across strata of sex, age, race, study type, and study area. This collaborative-pooled analysis provides additional evidence for a positive association between heavy alcohol consumption and the risk of pancreatic cancer.


Mixed methods research.
Mixed methods research involves the use of qualitative and quantitative data in a single research project. It represents an alternative methodological approach, combining qualitative and quantitative research approaches, which enables nurse researchers to explore complex phenomena in detail. This article provides a practical overview of mixed methods research and its application in nursing, to guide the novice researcher considering a mixed methods research project.


A fiducial detection algorithm for real-time image guided IMRT based on simultaneous MV and kV imaging.
The advantage of highly conformal dose techniques such as 3DCRT and IMRT is limited by intrafraction organ motion. A new approach to gain near real-time 3D positions of internally implanted fiducial markers is to analyze simultaneous onboard kV beam and treatment MV beam images (from fluoroscopic or electronic portal image devices). Before we can use this real-time image guidance for clinical 3DCRT and IMRT treatments, four outstanding issues need to be addressed. (1) How will fiducial motion blur the image and hinder tracking fiducials? kV and MV images are acquired while the tumor is moving at various speeds. We find that a fiducial can be successfully detected at a maximum linear speed of 1.6 cm/s. (2) How does MV beam scattering affect kV imaging? We investigate this by varying MV field size and kV source to imager distance, and find that common treatment MV beams do not hinder fiducial detection in simultaneous kV images. (3) How can one detect fiducials on images from 3DCRT and IMRT treatment beams when the MV fields are modified by a multileaf collimator (MLC)? The presented analysis is capable of segmenting a MV field from the blocking MLC and detecting visible fiducials. This enables the calculation of nearly real-time 3D positions of markers during a real treatment. (4) Is the analysis fast enough to track fiducials in nearly real time? Multiple methods are adopted to predict marker positions and reduce search regions. The average detection time per frame for three markers in a 1024 x 768 image was reduced to 0.1 s or less. Solving these four issues paves the way to tracking moving fiducial markers throughout a 3DCRT or IMRT treatment. Altogether, these four studies demonstrate that our algorithm can track fiducials in real time, on degraded kV images (MV scatter), in rapidly moving tumors (fiducial blurring), and even provide useful information in the case when some fiducials are blocked from view by the MLC. This technique can provide a gating signal or be used for intra-fractional tumor tracking on a Linac equipped with a kV imaging system. Any motion exceeding a preset threshold can warn the therapist to suspend a treatment session and reposition the patient.


Focus on: biologics that affect therapeutic agents in dermatology.
Tumor necrosis factor (TNF)-alpha is one of the oldest known cytokines in human physiology. It is involved in both normal and pathologic states. Virtually every cell and organ in the body are affected by TNF-alpha. Though TNF-alpha is usually involved in inflammation as a normal host defense response, when overproduced, it can become pathologic and affect almost every organ system. In this article, we address the role of TNF-alpha in diseases such as rheumatoid arthritis, Crohn's disease, psoriasis, and ankylosing spondylitis as well as the drugs used to modulate TNF-alpha. Specifically, we look at the structure, mechanism of action, and clinical use for etanercept, infliximab, and adalimumab. Historically, we also review the drug lenercept, another TNF-alpha modulator. These drugs offer alternative effective treatments to rheumatologic and dermatologic diseases without as many of the toxic side effects of some of the traditional therapies. The traditional agents target TNF-alpha in addition to several other modes of action (disease modifying anti-rheumatic drugs [DMARDS] such as cyclosporine and methotrexate) (Table 1). Though TNF-alpha immunomodulation seems to be a very effective, promising treatment in several TNF-alpha mediated disease processes, long-term studies need to be performed to assess the risk-benefit ratio of using these drugs over an extended period of time.


Toxicity of Thermopsis montana in cattle.
Cattle had severe signs of toxicosis when gavaged dried ground Thermopsis montana (false lupine, poison bean, mountain thermopsis) at doses of 0.6-2.8 g/kg/day in a water suspension. Signs included depression, anorexia, swollen eye lids, arched back, tucked abdomen, rough hair coat, and in extremis a prolonged recumbency lasting up to 9 days. Plant potency varied among collections. Total alkaloid doses in collections eliciting severe signs varied from 1.1-11.3 mg/kg/day. There were 5 major alkaloids in each collection that varied in concentration among the collections perhaps accounting for variation in severity of signs elicited. Four of the alkaloids were identified by GC retention time, MS fragmentation patterns and OR analysis as N-methylcytisine, cytisine, (-)-thermopsine, and (-)-anagyrine. Measurements showed a very marked increase of 10X-20X in levels of certain serum enzymes--SGOT, CPK, and LDH that persisted during the period of maximum clinical signs.


A Neurometabolic Pattern of Elevated Myo-Inositol in Children Who Are HIV-Exposed and Uninfected: A South African Birth Cohort Study.
Exposure to maternal HIV in pregnancy may be a risk factor for impaired child neurodevelopment during the first years of life. Altered neurometabolites have been associated with HIV exposure in older children and may help explain the mechanisms underlying this risk. For the first time, we explored neurometabolic profiles of children who are HIV-exposed and uninfected (CHEU) compared to children who are HIV-unexposed (CHU) at 2-3 years of age. The South African Drakenstein Child Health Study enrolled women during pregnancy and is following mother-child pairs through childhood. MRI scans were acquired on a sub-group of children at 2-3 years. We used single voxel magnetic resonance spectroscopy to measure brain metabolite ratios to total creatine in the parietal grey matter, and left and right parietal white matter of 83 children (36 CHEU; 47 CHU). Using factor analysis, we explored brain metabolite patterns in predefined parietal voxels in these groups using logistic regression models. Differences in relative concentrations of individual metabolites (n-acetyl-aspartate, myo-inositol, total choline, and glutamate) to total creatine between CHEU and CHU groups were also examined. Factor analysis revealed four different metabolite patterns, each one characterized by covarying ratios of a single metabolite in parietal grey and white matter. The cross-regional pattern dominated by myo-inositol, a marker for glial reactivity and inflammation, was associated with HIV exposure status (OR 1.63; 95% CI 1.11-2.50) which held after adjusting for child age, sex, and maternal alcohol use during pregnancy (OR 1.59; 95% CI 1.07 -2.47). Additionally, higher relative concentrations of myo-inositol to total creatine were found in left and right parietal white matter of CHEU compared to CHU (p=0.025 and p=0.001 respectively). Increased ratios of myo-inositol to total creatine in parietal brain regions at age 2-3 years in CHEU are suggestive of early and ongoing neuroinflammatory processes. Altered relative concentrations of neurometabolites were found predominantly in the white matter, which is sensitive to neuroinflammation, and may contribute to developmental risk in this population. Future work on the trajectory of myo-inositol over time in CHEU, alongside markers of neurocognitive development, and the potential for specific neurodevelopmental interventions will be useful.


In vitro evaluation of the effect of a novel immunosuppressive agent, FTY720, on the function of feline neutrophils.
To use in vitro assays to evaluate the effects of a novel immunosuppressive agent, FTY720, on biological functions (migration, phagocytosis, and production of reactive-oxygen species [ROS]) of feline peripheral neutrophils and determine the cytotoxic effects of FTY720 on feline peripheral neutrophils. Peripheral neutrophils obtained from 8 healthy cats. Peripheral neutrophils were isolated from blood samples obtained from the 8 cats and exposed to the phosphorylated form of FTY720 (FTY720-P). A fluorescence-based in vitro evaluation of migration was performed. Phagocytosis of microbes and production of ROS were evaluated by use of a 2-color flow cytometry system. Samples of whole blood obtained from the cats were incubated with various concentrations of FTY720-P, fluorescein-labeled Staphylococcus aureus, and dihydroethidium. Cytotoxic effects were evaluated by use of propidium iodide staining. Addition of FTY720-P caused a slight non-significant decrease in phagocytosis and production of ROS by feline peripheral neutrophils. Migration activity of feline peripheral neutrophils was significantly increased by the addition of FTY720-P. Addition of FTY720-P at concentrations considered for clinical use did not increase the death rate of feline peripheral neutrophils. FTY720 does not inhibit critical functions of feline peripheral neutrophils in vitro.


[Objective and subjective working conditions and psychophysical disorders].
The relationship between working conditions, psychophysical disorders, and employees' attitudes towards their jobs were analyzed in a pharmaceutical factory in Mexico. A cross-sectional study was conducted using three instruments: guided observation of job processes, guided evaluation of health and safety conditions, and an epidemiological questionnaire (N = 377). Tasks were found to be automated to a considerable degree, but organization was basically Fordist. Strong associations were found between sets of job requirements and certain groups of health outcomes. In the study population, perception of the job (attitude, satisfaction, control, and social support) showed an association with certain health problems. The study concluded that both subjective and objective occupational conditions play an important role in workers' health.


Nonhealing, progressive stress fractures of the foot in a 13-year-old basketball player: is vitamin K deficiency a risk factor?
[Purpose] To report an adolescent male basketball player with nonhealing stress fractures of the foot and discuss the probable factors. [Subject and Methods] A 13-year-old basketball player presented with right foot pain. He had been playing basketball for three years and practicing 5 days/week. He denied any increase in daily training intensity. Magnetic resonance imaging confirmed stress fractures of the cuboid and cuneiform, with mild edema of the soft tissues between the tarsal bones and tenosynovitis of the flexor hallucis and flexor digitorum longi. The foot was immobilized for 4 weeks, with progressive weight bearing introduced at the fifth week. At the 6th week, while still restricted to partial weight bearing, he reported diffuse severe pain. The entire foot was painful with palpation, and new imaging showed stress fractures of the talus, cuboid, cuneiform, and proximal first metatarsal bones, and tenosynovitis of the flexor hallucis longus and flexor digitorum longus tendons with progression of the soft tissue edema around the tarsal bones. Acute phase reactants were elevated; vitamin K level was low. [Results] He started participating in games again at the 6th month post-injury. [Conclusion] Management of patients with stress fractures includes immobilization, physical therapy, and biomechanical arrangements. If the expected healing does not occur, a deficiency of vitamin K might be considered as a factor. Questioning on dietary habits of the patient and encouraging adequate intake of the deficient nutrient might assist in the healing process.


Prenatal-choline supplementation differentially modulates timing of auditory and visual stimuli in aged rats.
Choline supplementation of the maternal diet has a long-term facilitative effect on the interval-timing ability and temporal memory of the offspring. Here, we examined whether prenatal-choline supplementation has modality-specific effects on duration discrimination in aged (20 mo) male rats. Adult offspring of rats that were given sufficient choline in their chow (CON: 1.1 g/kg) or supplemental choline added to their drinking water (SUP: 3.5 g/kg) during embryonic days (ED) 12-17 were trained and tested on a two-modality (auditory and visual signals) duration bisection procedure (2 s vs. 8 s). Intensity (high vs. low) of the auditory and visual timing signals was systematically manipulated across test sessions such that all combinations of signal intensity by modality were tested. Psychometric response functions indicated that prenatal-choline supplementation systematically increased sensitivity to auditory signals relative to visual signals, thereby magnifying the modality effect that sounds are judged to be longer than lights of equivalent duration. In addition, sensitivity to signal duration was greater in rats given prenatal-choline supplementation, particularly at low intensities of both the auditory and visual signals. Overall, these results suggest that prenatal-choline supplementation impacts interval timing by enhancing the differences in temporal integration between auditory and visual stimuli in aged subjects.


Recognition of an unnatural difluorophenyl nucleotide by uracil DNA glycosylase.
The DNA repair enzyme uracil DNA glycosylase (UDG) utilizes base flipping to recognize and remove unwanted uracil bases from the genome but does not react with its structural congener, thymine, which differs by a single methyl group. Two factors that determine whether an enzyme flips a base from the duplex are its shape and hydrogen bonding properties. To probe the role of these factors in uracil recognition by UDG, we have synthesized a DNA duplex that contains a single difluorophenyl (F) nucleotide analogue that is an excellent isostere of uracil but possesses no hydrogen bond donor or acceptor groups. By using binding affinity measurements, solution (19)F NMR, and solid state (31)P[(19)F] rotational-echo double-resonance (REDOR) NMR measurements, we establish that UDG partially unstacks F from the duplex. However, due to the lack of hydrogen bonding groups that are required to support an open-to-closed conformational transition in UDG, F cannot stably dock in the UDG active site. We propose that F attains a metastable unstacked state that mimics a previously detected intermediate on the uracil-flipping pathway and suggest structural models of the metastable state that are consistent with the REDOR NMR measurements.


DNA protein cross-links produced by NSC 652287, a novel thiophene derivative active against human renal cancer cells.
2, 5-bis(5-Hydroxymethyl-2-thienyl)furan (NSC 652287), is a representative of a series of thiophene derivatives that exhibit potent and selective antitumor activity against several tumor cell lines in the National Cancer Institute Anticancer Drug Screen. NSC 652287 has noticeable activity for the renal cell lines and produces cures in certain corresponding xenografts. The cellular mechanisms of action of NSC 652287 were therefore investigated in this study in greater detail. The most sensitive renal carcinoma cell line, A498, exhibited cell cycle arrest in G(0)-G(1) and G(2)-M at 10 nM NSC 652287, with increased p53 and p21(WAF1) protein. At higher concentrations, NSC 652287 still induced p53 elevation but with p21(WAF1) reduction and massive apoptosis. These results collectively suggested that NSC 652287 induced DNA damage. Using alkaline elution techniques, we found that NSC 652287 induced both DNA-protein and DNA-DNA cross-links with no detectable DNA single-strand breaks. These DNA-protein cross-links (DPC) persisted for at least 12 h after drug removal and their frequency was correlated with cytotoxicity in the renal cell lines studied. The most sensitive cells (A498) produced the highest DPC followed by the cell line with intermediate sensitivity (TK-10). DPC were minimal in the two resistant cell lines, ACHN and UO-31. Nonetheless, a similar degree of DPC occurred at doses imparting equitoxic effects. These results indicate that DNA is a primary target for the novel and potent anticancer thiophene derivative, NSC 652287. NSC 652287 did not cross-link purified DNA or mammalian topoisomerase I suggesting the importance of active metabolite(s) for the cross-linking activity.


AFLP mapping of soybean maturity gene E4.
Days to flowering and maturity are controlled by genes E1-E7 and J in soybean. Previous studies revealed that E1-E5 and E7 influence tolerances to low-temperature-induced seed coat browning in different directions at various intensities. The E4 locus is useful for the development of early maturing cultivars with chilling tolerance because the recessive allele conditions both the early-maturing habit and chilling tolerance. This study was conducted to obtain a fine map of E4 by amplified fragment length polymorphism (AFLP) analysis using a F(8:9) family segregating for E4 that was developed from a cross between photoperiod-insensitive Japanese landraces, Sakamotowase (E4) and Miharudaizu (e4). AFLP analysis using a total of 4096 primer pairs detected 20 polymorphic markers between near-isogenic lines for E4. Linkage mapping incorporated 16 AFLP markers into a previously constructed genetic map around E4 in linkage group I. Eight AFLP markers were localized to unfilled areas between E4 and the closest markers identified previously. Two AFLP markers flanking E4, e48m41-8 and e18m38-8, were mapped at positions 0.6 and 5.4 cM apart from E4, respectively. They were dominant and in cis arrangement with the recessive allele (e4) conditioning the photoperiod insensitivity and chilling tolerance. These markers can be used in developing more precise markers for fine mapping and marker-assisted selection and in isolating the underlying gene via genome walking approaches.


FLT4 as a marker for predicting prognostic risk of refractory acute myeloid leukemia.
Treating patients with refractory acute myeloid leukemia (AML) remains challenging. Currently there is no effective treatment for refractory AML. Increasing evidence has demonstrated that refractory/relapsed AML is associated with leukemic blasts which can confer resistance to anticancer drugs. We have previously reported that high expression of Fms-related tyrosine kinase 4 (FLT4) is associated with increased cancer activity in AML. However, the functional role of FLT4 in leukemic blasts remains unknown. Here, we explored the significance of FLT4 expression in leukemic blasts of refractory patients and mechanisms involved in the survival of AML blasts. Inhibition or absence of FLT4 in AML blasts suppressed homing to bone marrow of immunocompromised mice and blocked engraftment of AML blasts. Moreover, FLT4 inhibition by MAZ51, an antagonist, effectively reduced the number of leukemic cell-derived colony-forming units and increased apoptosis of blasts derived from refractory patients when it was co-treated with cytosine arabinoside under vascular endothelial growth factor C, its ligand. AML patients who expressed high cytosolic FLT4 were linked to an AML-refractory status by internalization mechanism. In conclusion, FLT4 has a biological function in leukemogenesis and refractoriness. This novel insight will be useful for targeted therapy and prognostic stratification of AML.


Zinc-dependent carbapenemases in clinical isolates of family Enterobacteriaceae.
The emergence and spread of zinc-dependent carbapenem resistance has become a diagnostic challenge for clinical microbiologists. The objective of the present study was to screen zinc-dependent carbapenemase activity in clinical isolates of family Enterobacteriaceae. A total of 102 multidrug-resistant organisms (MDROs), non-repeat clinical isolates of family Enterobacteriaceae from two tertiary care centres in Delhi, were screened for carbapenemase production by a modified Hodge test (MHT) and additionally by a re-modified Hodge test, EDTA double disc synergy test, and combined disc test (or disc enhancement test) to determine zinc dependence of carbapenemases harbouring bacteria. Of the total 102 clinical isolates (June through November 2010), 91 were from urine and 11 were from blood specimens. The isolates were obtained from patients visiting the outpatient department (18 isolates), admitted in non-ICU inpatient care units (74 isolates) and patients admitted in ICUs (4 isolates). MHT identified 92 (90.2%) isolates as carbapenemases producers. Among those found negative for MHT (n=10), metallo-beta-lactamases (MBLs) activity was demonstrated through the EDTA disc diffusion synergy test and the combined disc test in 8 and 9 isolates respectively. A total of 63 (61.7%) isolates demonstrated MBL activity despite in vitro sensitivity to Imipenem. The study demonstrated that supplementing the MHT with at least one of the screening methods increases the likelihood of picking up such isolates that may be missed by the MHT. The study also demonstrates the wide-spread presence of MBLs in Enterobacteriaceae members from patients visiting hospitals in east Delhi.


Catechol estrogens and the control of gonadotropin and prolactin secretion in man.
The catechol estrogens, the 2- or 4-hydroxylated metabolites of estrone and estradiol, have pharmacologic properties of both estrogens and catecholamines and are formed from estrogens in peripheral tissues and in the brain. This has led to speculation that they may mediate some of the feedback effects of estrogens upon gonadotropins and prolactin (PRL). Studies testing these hypotheses are still few and have not been conclusive. There have been reports that the catechol estrogen 2-hydroxyestrone (2-OHE1) might act as a partial estrogen antagonist, stimulating gonadotropin secretion; and that it might have dopamine-like effects, suppressing the secretion of PRL. In studies testing the chronic and acute effects of catechol estrogens on LH, FSH, and PRL in men and women, we found that they behaved as estrogens, suppressing gonadotropins when given in doses high enough to compensate for their rapid clearance and degradation. We found no evidence that they suppress PRL secretion. The weight of available evidence suggests that these effects are mediated by estrogen receptor interactions; and that the formation of catechol estrogens is not an obligatory step in the feedback effects of estrogens, although it may have a modulatory role. Plasma levels of catechol estrogens are too low for them to exert circulating neuroendocrine effects.


Large-area plasmon enhanced two-dimensional MoS2.
Two-dimensional transition metal chalcogenides (2D TMDCs) show photoluminescence (PL) as a result of direct band-gap transitions at visible wavelengths. Although 2D TMDCs have been considered for use in next-generation optoelectronics, practical applications are restricted by their low absorption and emission efficiency. To overcome these limitations using plasmonic local field enhancement, we propose the integration of gold nanoparticles with 2D TMDCs over a centimeter-scale area. Using self-assembled gold nanoshell monolayers, we produce a 10-fold increase in the PL of 2D TMDCs. We expect our method to provide a means for the large-area, low-cost fabrication of plasmon-enhanced 2D TMDCs for optoelectronic applications.


Recombinant allergen profiles and health-related quality of life in seasonal allergic rhinitis.
We evaluated birch- and timothy-allergic patients for allergen-specific IgE profiles and health-related quality of life (HRQL). We examined 395 patients with seasonal allergic rhinitis against birch or timothy pollen. Sera were analyzed for IgE reactivity to recombinant allergens (Bet v 1, Bet v 2, Bet v 4; Phl p 1/p 5b, Phl p 7, and Phl p 12) and to native pollen extracts (t3 and g6). Subgroup-specific analyses were performed. Patients with cosensitization against structurally unrelated allergens were termed polysensitized. Patients allergic solely to birch or timothy were labeled monosensitized. HRQL was evaluated using an established questionnaire. In patients polysensitized against native birch pollen (n = 233) the prevalence of allergens was 86% for Bet v 1, 15% for Bet v 2, and 5% for Bet v 4. Similar for timothy (n = 256), the prevalence of allergens was 87% rPhl p 1/p 5b, 5% for rPhl p 7, and 14% for rPhl p 12. Values for birch-monosensitized patients (n = 42) were Bet v 1, 100%, and Bet v 2 and Bet v 4, 0%. Values for timothy-monosensitized patients (n = 35) were Phl p 1/p 5b, 100%; rPhl p 7, 0%; and rPhl p 12, 3%. No difference in HRQL existed between patients sensitized solely against major versus minor allergens in birch-allergic patients. Polysensitized cohorts showed sensitization profiles comparable with published data. Monosensitized patients showed IgE against major allergens in 100% of cases. Patients sensitized solely against major or minor allergens showed no differences in HRQL.


Expression of a RhoA-Specific Guanine Nucleotide Exchange Factor, p190RhoGEF, in Mouse Macrophages Negatively Affects M1 Polarization and Inflammatory Responses.
A RhoA-specific guanine nucleotide exchange factor, p190RhoGEF, was first cloned and identified in neuronal cells. In immune cells, we first reported the role of p190RhoGEF in B cells: expression of p190RhoGEF increased after CD40 stimulation and was required for CD40-mediated B cell activation and differentiation. We also showed that over-expression of p190RhoGEF negatively affected dendritic cell function in response to bacterial lipopolysaccharide (LPS). In this study, we examined the role of p190RhoGEF in macrophages using p190RhoGEF over-expressing transgenic (TG) mice. We found macrophages from TG mice to be more round than those from control mice, with enriched polymerized actin at the edge attached to the glass. TG macrophages also responded less to LPS: production of reactive oxygen species, phagocytosis, chemokine-dependent migration, and pro-inflammatory cytokine secretion were all reduced compared with the responses of macrophages from littermate (LTM) control mice. Furthermore, the classical M1 subset population was observed less in the peritoneal macrophages of TG mice than the LTM control mice during LPS-elicited peritoneal inflammation. When the activity of RhoA was inhibited in TG macrophages, their morphology and LPS responses became similar to those of the LTM macrophages. These results suggest that over-expression of p190RhoGEF in macrophages could reduce M1 polarization and inflammatory responses by regulating the actin cytoskeleton.


Limitations of therapy and a guarded prognosis in an American cohort of Takayasu arteritis patients.
To describe the clinical, laboratory, and radiographic manifestations of Takayasu arteritis (TA) in a cohort from the US, evaluate the response to interventions, remission and relapse rates, and disease progression, and compare these observations with those from other cohorts in the US, Japan, India, Italy, and Mexico. Seventy-five patients were retrospectively studied using a uniform database that included clinical, laboratory, and imaging data. Vascular imaging studies were performed at least yearly to monitor disease progression. Common manifestations at disease onset included loss or asymmetry of pulses (57%), limb blood pressure discrepancy (53%), and bruits (53%). Eleven percent of patients were asymptomatic prior to disease diagnosis. Initial angiographic studies showed aortic abnormalities in 79% of patients and frequent involvement of the subclavian (65%) and carotid (43%) arteries.Ninety-three percent of longitudinally followed patients attained disease remission of any duration, but only 28% sustained remission of at least 6 months' duration after prednisone was tapered to <10 mg daily. Both angioplasty and vascular surgery were initially successful, but recurrent stenosis occurred in 78% of angioplasty and 36% of bypass/reconstruction procedures. More than two-thirds of patients had difficulty performing routine daily activities and approximately one-fourth of all patients were unable to work. Our cohort was similar to the National Institutes of Health, Italian, Japanese, and Mexican cohorts in terms of the predominance of female subjects and disease manifestations, but differed from the Indian cohort in that the latter group had a higher frequency of male subjects, abdominal aorta and renal artery involvement, and hypertension. Although improvement of symptoms in TA usually follows glucocorticoid therapy, relapses usually occur with dosage reduction. Attempts to restore vascular patency are often initially successful, but restenosis occurs frequently. Chronic morbidity and disability occur in most patients with TA in the US.


Bioinspired theranostic quantum dots: Paving the road to a new paradigm for cancer diagnosis and therapeutics.
Despite extensive research, a complete cure remains lacking for most types of cancer. Nanotechnology-based carriers, such as liposomes, nanoparticles (NPs), dendrimers, nanoemulsions, and other nanocarriers, can target cancer cells, but their in vivo fate is unpredictable. Bioinspired quantum dots (BQDs) offer enhanced aqueous solubility, exceptionally low toxicity, biocompatibility, easy biofunctionalization, and selective cancer targeting. Due to their photoluminescence, high longitudinal relaxation value, photothermal effect upon laser irradiation, generation of singlet oxygen, and production of H2S for gas therapy, BQDs are excellent cancer theranostic agents. In this review, we highlight the theranostic application of, and existing challenges relating to BQDs.


Negative Mood Induction Increases Choice of Heroin Versus Food Pictures in Opiate-Dependent Individuals: Correlation With Self-Medication Coping Motives and Subjective Reactivity.
Acute growth in negative affect is thought to play a major role in triggering relapse in opiate-dependent individuals. Consistent with this view, three lab studies have demonstrated that negative mood induction increases opiate craving in opiate-dependent individuals. The current study sought to confirm these effects with a behavioral measure of heroin seeking, and test whether the effect is associated with self-reported opiate use to cope with negative affect and subjective reactivity to mood induction. Participants were heroin-dependent individuals engaged with treatment services (n = 47) and control participants (n = 25). Heroin users completed a questionnaire assessing reasons for using heroin: negative affect, social pressure, and cued craving. Baseline heroin choice was measured by preference to enlarge heroin versus food thumbnail pictures in two-alternative forced-choice trials. Negative mood was then induced by depressive statements and music before heroin choice was tested again. Subjective reactivity was indexed by negative and positive mood reported at the pre-induction to post-test timepoints. Heroin users chose heroin images more frequently than controls overall ( p = .001) and showed a negative mood-induced increase in heroin choice compared to control participants (interaction p < .05). Mood-induced heroin choice was associated with self-reported heroin use to cope with negative affect ( p < .05), but not social pressure ( p = .39) or cued craving ( p = .52), and with subjective mood reactivity ( p = .007). These data suggest that acute negative mood is a trigger for heroin seeking in heroin-dependent individuals, and this effect is pronounced in those who report using heroin to cope with negative affect, and those who show greater subjective reactivity to negative triggers. Interventions should seek to target negative coping motives to build resilience to affective triggers for relapse.


Understanding male sexual behaviour in planning HIV prevention programmes: lessons from Laos, a low prevalence country.
Focus group discussions were conducted with a range of young men in Vientiane, Laos; interviews were conducted with male sex workers. A questionnaire survey was conducted with a purposive sample of 800 young men. Most young men initiate sex at an early age and have multiple sex partners. Married men are more likely to pay for sex and most sex for money is negotiated in non-brothel settings. Despite high reported condom use for last intercourse with a casual partner, decisions on condom use are subjective. Many men have extramarital sex when their partner is pregnant and post partum. 18.5% of men report having had sex with another man; most of these men also report having sex with women. Moreover, more men report having had anal sex with a woman than with a man. Although not a probability sample survey, this study of a broad range of young men in Vientiane reveals sexual behaviours that could lead to accelerated HIV transmission. Education should emphasise the need to use condoms in all sexual encounters outside the primary relationship. This needs special emphasis when the partner is pregnant or post partum. Advice on safe sex with other men needs to be integrated into all sexual health education for young men.


Dynamic regulation of EZH2 from HPSc to hepatocyte-like cell fate.
Currently, drug metabolization and toxicity studies rely on the use of primary human hepatocytes and hepatoma cell lines, which both have conceivable limitations. Human pluripotent stem cell (hPSC)-derived hepatocyte-like cells (HLCs) are an alternative and valuable source of hepatocytes that can overcome these limitations. EZH2 (enhancer of zeste homolog 2), a transcriptional repressor of the polycomb repressive complex 2 (PRC2), may play an important role in hepatocyte development, but its role during in vitro hPSC-HLC differentiation has not yet been assessed. We here demonstrate dynamic regulation of EZH2 during hepatic differentiation of hPSC. To enhance EZH2 expression, we inducibly overexpressed EZH2 between d0 and d8, demonstrating a significant improvement in definitive endoderm formation, and improved generation of HLCs. Despite induction of EZH2 overexpression until d8, EZH2 transcript and protein levels decreased from d4 onwards, which might be caused by expression of microRNAs predicted to inhibit EZH2 expression. In conclusion, our studies demonstrate that EZH2 plays a role in endoderm formation and hepatocyte differentiation, but its expression is tightly post-transcriptionally regulated during this process.


Locally advanced pancreatic head cancer: margin-positive resection or bypass?
Pancreatic cancer is a highly aggressive disease with poor survival. The only effective therapy offering long-term survival is complete surgical resection. In the setting of nonmetastatic disease, locally advanced tumors constitute a technical challenge to the surgeon and may result in margin-positive resection margins. Few studies have evaluated the implications of the latter in depth. The aim of this study was to compare the margin-positive situation to palliative bypass procedures and margin-negative resections in terms of perioperative and long-term outcome. By retrospective analysis of prospectively maintained data from 360 patients operated for pancreatic cancer at our institution, we provide evidence that margin-positive resection still yields a significant survival benefit over palliative bypass procedures. At the same time, perioperative severe morbidity and mortality are not significantly increased. Our observations suggest that pancreatic cancer should be resected whenever technically feasible, including, cases of locally advanced disease.


Cutaneous adrenal cortical carcinoma metastasis in a 6 year-old boy.
We report the case of a six year-old boy with a history of adrenal cortical carcinoma presenting with cutaneous metastasis. Due to the low incidence of cutaneous metastasis arising from adrenal cortical carcinoma, its diagnosis can be challenging based solely on histological analysis. Yet, the clinical history in combination with an immunohistochemical panel consisting of melan-A, alpha inhibin, D11, caretinin, neuron specific enolase, synatophysin, and chromogranin, can be useful in differentiating it from other tumors with similar cytomorphology.


Evaluation of Green Coffee-Roasting Biogas with Modeling Valorization of Possible Solutions.
According to the European Union Directive 2009/28/EC, the goals of obtaining 20% of all energy requirements from renewable sources and a 20% reduction in primary energy use must be fulfilled by 2020. In this work, an evaluation was performed, from the environmental and energy point of view, of anaerobic digestion as a valid solution for the treatment of the byproducts obtained from the coffee-roasting process. In particular, thermophilic anaerobic digestion tests were carried out. Output values from the laboratory were used as input for the MCBioCH4 model to evaluate the produced flow of biogas and biomethane and two different biogas valorization alternatives, namely, the traditional exploitation of biogas for heat/energy production and biomethane conversion. The results of the preliminary simulation showed that a full-scale implementation of the coffee waste biogas production process is technically feasible and environmentally sustainable. Furthermore, the performed analysis validates a general methodology for energy production compatibility planning.


Recent progress in alpha 1-adrenoceptor pharmacology.
The adrenoceptors (ARs) play a key role in the modulation of sympathetic nervous system activity and are a site of action for many clinically important therapeutic agents. The alpha1-adrenoceptor subtypes (alpha1A-, alpha1B-, and alpha1D-AR) play a prominent role in regulating vascular tone and hypertrophic growth of smooth muscle and cardiac cells. Their functional characteristics with respect to ligand binding and second messenger utilization have been well described. Here, we review recent progress on subtype-specific subcellular localization, participation in signaling cascades, and the pivotal function of alpha1-ARs, as delineated through studies on genetically engineered animals. Together, these findings will provide new insights into the physiological and pathophysiological roles of the alpha1-ARs.


Is orthographic information from multiple parafoveal words processed in parallel: An eye-tracking study.
In the current study we investigated whether orthographic information available from 1 upcoming parafoveal word influences the processing of another parafoveal word. Across 2 experiments we used the boundary paradigm (Rayner, 1975) to present participants with an identity preview of the 2 words after the boundary (e.g., hot pan), a preview in which 2 letters were transposed between these words (e.g., hop tan), or a preview in which the same 2 letters were substituted (e.g., hob fan). We hypothesized that if these 2 words were processed in parallel in the parafovea then we may observe significant preview benefits for the condition in which the letters were transposed between words relative to the condition in which the letters were substituted. However, no such effect was observed, with participants fixating the words for the same amount of time in both conditions. This was the case both when the transposition was made between the final and first letter of the 2 words (e.g., hop tan as a preview of hot pan; Experiment 1) and when the transposition maintained within word letter position (e.g., pit hop as a preview of hit pop; Experiment 2). The implications of these findings are considered in relation to serial and parallel lexical processing during reading. (PsycINFO Database Record


Effect of single injection of platelet-rich plasma in comparison with corticosteroid on knee osteoarthritis: a double-blind randomized clinical trial.
Evidence on the effect of platelet-rich plasma (PRP) in treating osteoarthritis (OA) is insufficient. Therefore, the present study compares the effects of a one-time injection of PRP and corticosteroid (CS). In the present randomized double blind clinical trial, the participants who suffered from knee osteoarthritis (Grades II/III), were randomly divided into two groups: intra articular injection of PRP and CS. Knee injury and osteoarthritis outcome score (KOOS), the 20-Meter-Walk Test (20MW), active and passive ranges of motions (ROM), flexion contracture, and pain intensity based on Visual Analog Scale (VAS) were assessed before, 2-months, and 6-months after interventions. Forty-one participants (48 knees) were involved in the research (66.7% women; average age of 61.1±7.0 years old). Compared to the group treated with corticosteroid, pain relief (df: 6, 35; F=11.0; P=0.007), symptom free (df:6, 35; F=23.0; P<0.001), activities of daily living (ADL) (df:6, 35; F=10.7; P=0.005) and quality of life (df:6, 35; F=5.2; P=0.02) in the RPR group were significantly higher, but sporting ability was not different between the two groups (df: 6, 35; F=0.6; P=0.55). PRP was significantly more helpful for relieving patients' pain (VAS) compared to corticosteroids (df: 6, 35; F=32.0; P=0.001). It is also notable that using PRP was more helpful in improving the 20MW test than corticosteroid treatment (df: 6, 35; F=7.4; P=0.04) but none of the treatments had any impact on active flexion ROM، passive flexion ROM and flexion contracture (P>0.05). Our study demonstrated that one shot of PRP injection, decreased joint pain more and longer-term, alleviated the symptoms, and enhanced the activity of daily living and quality of life in short-term duration in comparison with CS.


Memory modulation by post-training intraperitoneal, but not intracerebroventricular, administration of ACTH or epinephrine.
Post-training introparitoneal (ip) administration of ACTH1-24 (25 ng/rat) or epinephrine HCl (625 ng/rat) facilitated retention of a step-down inhibitory avoidance task acquired using a small start platform (5-cm high, 25 X 7 cm) and a low intensity training footshock (0.3 mA, 60 Hz), and caused retrograde amnesia for a similar task acquired using a large platform (5-cm high, 25 X 25 cm) and a high intensity training footshock (0.8 mA, 60 Hz). The post-training intracerebroventricular (icv) administration of 5, 25, or 125 ng/rat of ACTH or of 5, 25, 125, 625, or 1250 ng/rat of epinephrine had no effect on retention of either task. These findings suggest that memory modulation by ACTH and epinephrine is mediated by reflexes initiated at peripheral receptors that affect brain activity during the post-training period.


Impact of Lymphovascular Invasion on Survival Outcome in Patients With Gastric Cancer.
To evaluate the prognostic significance of lymphovascular invasion (LVI) for patients with gastric cancer (GC). A total of 1,720 consecutive patients who underwent curative gastrectomy were retrospectively identified. The association between LVI and clinicopathologic characteristics was determined and its impact on survival outcome was evaluated. LVI was detected in 21.3% of GC patients, 5.9% of patients with early GC, 24.0% of patients with advanced GC, and 6.7% of node-negative patients using H&E staining. Tumor size (odds ratio [OR], 1.509; 95% confidence interval [CI], 1.159-1.965; P < .01), differentiated type (OR, 1.817; 95% CI, 1.377-2.398; P < .001), and the depth of tumor invasion (OR, 3.011; 95% CI, 2.174-4.171; P < .001) were independent predictive factors for LVI. LVI-positive patients have a poorer prognosis than LVI-negative patients, irrespective of tumor stage or lymph node metastasis. LVI was an independent prognostic factor for patients with GC (hazard ratio, 1.299; 95% CI, 1.112-1.518; P < .001). LVI provided additional prognostic information for GC patients, and LVI-positive patients should be considered candidates for adjuvant chemotherapy.


A Case of Reye Syndrome Caused by Influenza A Virus.
Reye syndrome is a rare and potentially life-threatening disease characterized by liver failure and hepatic encephalopathy. Multiple possible etiologies have been suggested, but only aspirin (acetylsalicylic acid) has been statistically proven to be a causative factor. We describe a case of Reye syndrome secondary to influenza A virus. A 2-year-old male with a recent history of influenza-like symptoms presented with neurologic deterioration. He had elevated liver enzymes, hyperammonemia, elevated creatinine, and hypoglycemia. Liver biopsy showed microvesicular steatosis consistent with Reye syndrome. He was given supportive care and recovered after 17 days with normalization of metabolic derangements. At 4-month follow-up, the patient had reached age-specific developmental milestones. The incidence of Reye syndrome has decreased since 1980 when the Centers for Disease Control and Prevention issued a warning against aspirin use in children. Consequently, any new incidence of Reye syndrome warrants investigation of other etiologies. This case adds to the evidence that causes other than aspirin can result in Reye syndrome.


HIV infection in the South African construction industry.
South Africa has one of the highest HIV prevalences in the world, and compared with other sectors of the national economy, the construction industry is disproportionately adversely affected. Using data collected nationally from more than 57,000 construction workers, HIV infection among South African construction workers was estimated, together with an assessment of the association between worker HIV serostatus and worker characteristics of gender, age, nature of employment, occupation, and HIV testing history. The HIV infection of construction workers was estimated to be lower than that found in a smaller 2008 sample. All worker characteristics are significantly associated with HIV serostatus. In terms of most at-risk categories: females are more at risk of HIV infection than males; workers in the 30-49 year old age group are more at risk than other age groups; workers employed on a less permanent basis are more at risk; as are workers not having recently tested for HIV. Among occupations in the construction industry, general workers, artisans, and operator/drivers are those most at risk. Besides yielding more up-to-date estimated infection statistics, this research also identifies vulnerable sub-groups as valuable pointers for more targeted workplace interventions by construction firms.


The use of thiafentanil oxalate and azaperone for reversible immobilisation of African buffalo (Syncerus caffer) within a nature reserve - Short communication.
Although thiafentanil oxalate has been widely used for wildlife immobilisation on different species, no report has been published about its usefulness on African buffalo (Syncerus caffer). Thirty-four African buffaloes were successfully immobilised at Loskop Dam Nature Reserve, South Africa in July 2013. The animals were kept in bomas of the nature reserve. The purpose of the immobilisation was to provide opportunity for microchip implantation, ear tag placement, intradermal tuberculin test and blood sampling. All animals were immobilised with thiafentanil oxalate 6 mg/animal (0.007-0.01 mg/kg) and azaperone 40 mg/animal (0.07-0.04 mg/kg) using Dan-inject darts and gun. The opioid reversal agent naltrexone hydrochloride 60 mg/animal (0.07-0.1 mg/kg) was given intravenously to the ear vein. The mean induction time was 3.9 ± 0.2 min, the recovery time was 1.65 ± 0.87 min. The results of the present study indicate that thiafentanil oxalate, this low-volume, high-potency, reversible drug combined with azaperone provides fast induction and smooth recovery. The authors recommend this drug combination as a reliable immobilising regimen for African buffalo.


Investigation of the use of aerobic granules for the treatment of sugar beet processing wastewater.
The treatment of sugar beet processing wastewater in aerobic granular sequencing batch reactor (SBR) was examined in terms of chemical oxygen demand (COD) and nitrogen removal efficiency. The effect of sugar beet processing wastewater of high solid content, namely 2255 ± 250 mg/L total suspended solids (TSS), on granular sludge was also investigated. Aerobic granular SBR initially operated with the effluent of anaerobic digester treating sugar beet processing wastewater (Part I) achieved average removal efficiencies of 71 ± 30% total COD (tCOD), 90 ± 3% total ammonifiable nitrogen (TAN), 76 ± 24% soluble COD (sCOD) and 29 ± 4% of TSS. SBR was further operated with sugar beet processing wastewater (Part II), where the tCOD, TAN, sCOD and TSS removal efficiencies were 65 ± 5%, 61 ± 4%, 87 ± 1% and 58 ± 10%, respectively. This study indicated the applicability of aerobic granular SBRs for the treatment of both sugar beet processing wastewater and anaerobically digested processing wastewater. For higher solids removal, further treatment such as a sedimentation tank is required following the aerobic granular systems treating solid-rich wastewaters such as sugar beet processing wastewater. It was also revealed that the application of raw sugar beet processing wastewater slightly changed the aerobic granular sludge properties such as size, structure, colour, settleability and extracellular polymeric substance content, without any drastic and negative effect on treatment performance.


[Transoral treatment of severe laryngomalacia. Review and presentation of a modified surgical technique].
Laryngomalacia is the most common cause of stridor in children. So far various authors have described surgical techniques in a sense of a supraglottoplasty or an epiglottoplasty to handle the severe form of this disease. We present a modified technique of the so called epiglottopexy. Under the different types of laryngomalacia this study focuses on the treatment of three patients (5 to 10 months) with a posterior displacement of the epiglottis during inspiration. The first step of our technique was to denude a small portion of the base of the tongue from mucosa. A corresponding lesion was created on the lingual surface of the epiglottis. The vaporisation of the mucosa was performed with the CO2 laser at a power setting of 1 Watt and a 0.25 mm spot size. The epiglottis was then fixed transorally to the base of the tongue with 2 single stitch sutures and 1 inverse mattress suture, using a resorbable material. No intra- or postoperative complications were observed. All three patients demonstrated a significant airway improvement without stridor. The presented technique of transoral laser surgical epiglottopexy seems to be a method suitable for the treatment of laryngomalacia caused by posterior displacement of the epiglottis.


Partial nucleotide sequence analysis of a French hepatitis C virus: implications for HCV genetic variability in the E2/NS1 protein.
To contribute to the study of the genetic variability of hepatitis C virus (HCV) we have determined the nucleotide sequence of the E2/NS1 and NS3/NS4 regions of a French isolate using the polymerase chain reaction. Comparison of these nucleotide sequences with those available for American and Japanese isolates showed a significant genetic variability: 5 to 33% and 2 to 30% at the nucleic acid and amino acid levels, respectively. The genetic variability is higher in the E2/NS1 (13 to 33% and 12 to 30% at the nucleic acid and amino acid levels, respectively) than in the NS3/NS4 (5 to 21% and 2 to 7%) regions. The sequence of the French isolate is more closely related to that of the American HCV prototype than to the Japanese HCV isolates. This study confirms the extent of HCV genetic variability.


Changes in bone mineral density and body composition during pregnancy and postpartum. A controlled cohort study.
In a controlled cohort study, bone mineral density (BMD) was measured in 153 women pre-pregnancy; during pregnancy; and 0.5, 4, 9, and 19 months postpartum. Seventy-five age-matched controls, without pregnancy plans, were followed in parallel. Pregnancy and breastfeeding cause a reversible bone loss, which, initially, is most pronounced at trabecular sites but also involves cortical sites during prolonged breastfeeding. Conflicting results have been reported on effects of pregnancy and breastfeeding on BMD and body composition (BC). In a controlled cohort study, we elucidate changes in BMD and BC during and following a pregnancy. We measured BMD and BC in 153 women planning pregnancy (n = 92 conceived), once in each trimester during pregnancy and 15, 129, and 280 days postpartum. Moreover, BMD was measured 19 months postpartum (n = 31). Seventy-five age-matched controls, without pregnancy plans, were followed in parallel. Compared with controls, BMD decreased significantly during pregnancy by 1.8 ± 0.5% at the lumbar spine, 3.2 ± 0.5% at the total hip, 2.4 ± 0.3% at the whole body, and 4.2 ± 0.7% at the ultra distal forearm. Postpartum, BMD decreased further with an effect of breastfeeding. At 9 months postpartum, women who had breastfed for <9 months had a BMD similar to that of the controls, whereas BMD at the lumbar spine and hip was decreased in women who were still breastfeeding. During prolonged breastfeeding, BMD at sites which consist of mostly trabecular bone started to be regained, whereas BMD at sites rich in cortical bone decreased further. At 19 months postpartum, BMD did not differ from baseline at any site. During pregnancy, fat- and lean-tissue mass increased by 19 ± 22% and 5 ± 6% (p < 0.001), respectively. Postpartum, changes in fat mass differed according to breastfeeding status with a slower decline in women who continued breastfeeding. Calcium and vitamin D intake was not associated with BMD changes. Pregnancy and breastfeeding cause a reversible bone loss. At 19 months postpartum, BMD has returned to pre-pregnancy level independently of breastfeeding length. Reversal of changes in fat mass depends on breastfeeding status.


Combined analysis of efficacy: the addition of bevacizumab to fluorouracil/leucovorin improves survival for patients with metastatic colorectal cancer.
Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), a recombinant, humanized anti-vascular endothelial growth factor monoclonal antibody that inhibits tumor angiogenesis, has demonstrated survival benefit in patients with previously untreated metastatic colorectal cancer when combined with irinotecan/fluorouracil (FU)/leucovorin (LV; IFL). Three randomized clinical studies have evaluated bevacizumab in combination with FU/LV alone. A combined analysis of raw data from these studies was performed to better assess the efficacy of bevacizumab with FU/LV. The analysis used primary efficacy data from three independent studies, including 241 patients in a combined control group receiving either FU/LV or IFL and 249 patients receiving FU/LV/bevacizumab (5 mg/kg once every 2 weeks). The efficacy data included response rate, progression-free survival, and overall survival. The median duration of survival was 17.9 months in the FU/LV/bevacizumab group, compared with 14.6 months in the combined control group, corresponding to a hazard ratio for death of 0.74 (P = .008). The median duration of progression-free survival was 8.8 months in the FU/LV/bevacizumab group, compared with 5.6 months in the combined control group, corresponding to a hazard ratio for disease progression of 0.63 (P < or = .0001). The addition of bevacizumab also improved the response rate (34.1% v 24.5%; P = .019). The addition of bevacizumab to FU/LV provides a statistically significant and clinically relevant benefit to patients with previously untreated metastatic colorectal cancer.


Structural heterogeneity and protein composition of exosome-like vesicles (prostasomes) in human semen.
Human seminal fluid contains small exosome-like vesicles called prostasomes. Prostasomes have been reported previously to play an important role in the process of fertilization by boosting survivability and motility of spermatozoa, in addition to modulating acrosomal reactivity. Prostasomes have also been reported to present with sizes varying from 50 to 500 nm and to have multilayered lipid membranes; however, the fine morphology of prostasomes has never been studied in detail. Sucrose gradient-purified prostasomes were visualized by cryo-electron microscopy (EM). Protein composition was studied by trypsin in-gel digestion and liquid chromatography/mass spectrometry. Here we report for the first time the detailed structure of seminal prostasomes by cryo-EM. There are at least three distinct dominant structural types of vesicles present. In parallel with the structural analysis, we have carried out a detailed proteomic analysis of prostasomes, which led to the identification of 440 proteins. This is nearly triple the number of proteins identified to date for these unique particles and a number of the proteins identified previously were cross-validated in our study. From the data reported herein, we hypothesize that the structural heterogeneity of the exosome-like particles in human semen reflects their functional diversity. Our detailed proteomic analysis provided a list of candidate proteins for future structural and functional studies.


Travel-related control measures to contain the COVID-19 pandemic: a rapid review.
In late 2019, first cases of coronavirus disease 2019, or COVID-19, caused by the novel coronavirus SARS-CoV-2, were reported in Wuhan, China. Subsequently COVID-19 spread rapidly around the world. To contain the ensuing pandemic, numerous countries have implemented control measures related to international travel, including border closures, partial travel restrictions, entry or exit screening, and quarantine of travellers. To assess the effectiveness of travel-related control measures during the COVID-19 pandemic on infectious disease and screening-related outcomes. We searched MEDLINE, Embase and COVID-19-specific databases, including the WHO Global Database on COVID-19 Research, the Cochrane COVID-19 Study Register, and the CDC COVID-19 Research Database on 26 June 2020. We also conducted backward-citation searches with existing reviews. We considered experimental, quasi-experimental, observational and modelling studies assessing the effects of travel-related control measures affecting human travel across national borders during the COVID-19 pandemic. We also included studies concerned with severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) as indirect evidence. Primary outcomes were cases avoided, cases detected and a shift in epidemic development due to the measures. Secondary outcomes were other infectious disease transmission outcomes, healthcare utilisation, resource requirements and adverse effects if identified in studies assessing at least one primary outcome. One review author screened titles and abstracts; all excluded abstracts were screened in duplicate. Two review authors independently screened full texts. One review author extracted data, assessed risk of bias and appraised study quality. At least one additional review author checked for correctness of all data reported in the 'Risk of bias' assessment, quality appraisal and data synthesis. For assessing the risk of bias and quality of included studies, we used the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool for observational studies concerned with screening, ROBINS-I for observational ecological studies and a bespoke tool for modelling studies. We synthesised findings narratively. One review author assessed certainty of evidence with GRADE, and the review author team discussed ratings. We included 40 records reporting on 36 unique studies. We found 17 modelling studies, 7 observational screening studies and one observational ecological study on COVID-19, four modelling and six observational studies on SARS, and one modelling study on SARS and MERS, covering a variety of settings and epidemic stages. Most studies compared travel-related control measures against a counterfactual scenario in which the intervention measure was not implemented. However, some modelling studies described additional comparator scenarios, such as different levels of travel restrictions, or a combination of measures. There were concerns with the quality of many modelling studies and the risk of bias of observational studies. Many modelling studies used potentially inappropriate assumptions about the structure and input parameters of models, and failed to adequately assess uncertainty. Concerns with observational screening studies commonly related to the reference test and the flow of the screening process. Studies on COVID-19 Travel restrictions reducing cross-border travel Eleven studies employed models to simulate a reduction in travel volume; one observational ecological study assessed travel restrictions in response to the COVID-19 pandemic. Very low-certainty evidence from modelling studies suggests that when implemented at the beginning of the outbreak, cross-border travel restrictions may lead to a reduction in the number of new cases of between 26% to 90% (4 studies), the number of deaths (1 study), the time to outbreak of between 2 and 26 days (2 studies), the risk of outbreak of between 1% to 37% (2 studies), and the effective reproduction number (1 modelling and 1 observational ecological study). Low-certainty evidence from modelling studies suggests a reduction in the number of imported or exported cases of between 70% to 81% (5 studies), and in the growth acceleration of epidemic progression (1 study). Screening at borders with or without quarantine Evidence from three modelling studies of entry and exit symptom screening without quarantine suggests delays in the time to outbreak of between 1 to 183 days (very low-certainty evidence) and a detection rate of infected travellers of between 10% to 53% (low-certainty evidence). Six observational studies of entry and exit screening were conducted in specific settings such as evacuation flights and cruise ship outbreaks. Screening approaches varied but followed a similar structure, involving symptom screening of all individuals at departure or upon arrival, followed by quarantine, and different procedures for observation and PCR testing over a period of at least 14 days. The proportion of cases detected ranged from 0% to 91% (depending on the screening approach), and the positive predictive value ranged from 0% to 100% (very low-certainty evidence). The outcomes, however, should be interpreted in relation to both the screening approach used and the prevalence of infection among the travellers screened; for example, symptom-based screening alone generally performed worse than a combination of symptom-based and PCR screening with subsequent observation during quarantine. Quarantine of travellers Evidence from one modelling study simulating a 14-day quarantine suggests a reduction in the number of cases seeded by imported cases; larger reductions were seen with increasing levels of quarantine compliance ranging from 277 to 19 cases with rates of compliance modelled between 70% to 100% (very low-certainty evidence). With much of the evidence deriving from modelling studies, notably for travel restrictions reducing cross-border travel and quarantine of travellers, there is a lack of 'real-life' evidence for many of these measures. The certainty of the evidence for most travel-related control measures is very low and the true effects may be substantially different from those reported here. Nevertheless, some travel-related control measures during the COVID-19 pandemic may have a positive impact on infectious disease outcomes. Broadly, travel restrictions may limit the spread of disease across national borders. Entry and exit symptom screening measures on their own are not likely to be effective in detecting a meaningful proportion of cases to prevent seeding new cases within the protected region; combined with subsequent quarantine, observation and PCR testing, the effectiveness is likely to improve. There was insufficient evidence to draw firm conclusions about the effectiveness of travel-related quarantine on its own. Some of the included studies suggest that effects are likely to depend on factors such as the stage of the epidemic, the interconnectedness of countries, local measures undertaken to contain community transmission, and the extent of implementation and adherence.


Analysis on novel coronavirus (COVID-19) using machine learning methods.
In this paper, we are working on a pandemic of novel coronavirus (COVID-19). COVID-19 is an infectious disease, it creates severe damage in the lungs. COVID-19 causes illness in humans and has killed many people in the entire world. However, this virus is reported as a pandemic by the World Health Organization (WHO) and all countries are trying to control and lockdown all places. The main objective of this work is to solve the five different tasks such as I) Predicting the spread of coronavirus across regions. II) Analyzing the growth rates and the types of mitigation across countries. III) Predicting how the epidemic will end. IV) Analyzing the transmission rate of the virus. V) Correlating the coronavirus and weather conditions. The advantage of doing these tasks to minimize the virus spread by various mitigation, how well the mitigations are working, how many cases have been prevented by this mitigations, an idea about the number of patients that will recover from the infection with old medication, understand how much time will it take to for this pandemic to end, we will be able to understand and analyze how fast or slow the virus is spreading among regions and the infected patient to reduce the spread based clear understanding of the correlation between the spread and weather conditions. In this paper, we propose a novel Support Vector Regression method to analysis five different tasks related to novel coronavirus. In this work, instead of simple regression line we use the supported vectors also to get better classification accuracy. Our approach is evaluated and compared with other well-known regression models on standard available datasets. The promising results demonstrate its superiority in both efficiency and accuracy.


[Therapeutic drug monitoring of tyrosine-kinase inhibitors in the treatment of chronic myelogenous leukaemia: interests and limits].
During the last decade, imatinib was current gold standard treatment of chronic myelogenous leukemia (CML), showing a great effectiveness. Thus, the Therapeutic Drug Monitoring (TDM), rarely applied in clinical oncology practice, did not appear necessary at the moment. However, the absence of response among patients and the metabolic profile of imatinib (involving the CYP3A4) suggested the existence of a great interindividual variability. During the last 4 years, studies about the pharmacokinetic/pharmacodynamic relationship have confirmed this variability and highlighted a relation between the trough concentrations of imatinib and the clinical response. An effectiveness threshold, close to 1000 ng/mL, seems to be correlated with better cytogenetic and molecular responses. Consequently, TDM could assist in investigation of the observance, the absence of response, the drug-drug interactions, but the proof of its utility requires complementary studies. In conclusion, the level of proof of imatinib TDM in LMC varies between levels "recommended" and "potentially useful".


Trade-offs Influencing the Physiological Ecology of Hibernation in Temperate-Zone Bats.
Seasonality of temperature and food availability can lead to trade-offs between the benefits of immediate reproduction and costs associated with mortality risk from starvation, inclement weather, or predation. Hibernating mammals exhibit an enormous seasonal shift in physiology and behavior and provide a useful system to examine the effect of this trade-off on key events in the annual cycle. Most of what we understand about the ecological energetics and phenology of hibernation comes from studies of rodent hibernators such as ground squirrels, chipmunks, and dormice. Temperate-zone, insectivorous bats, however, provide another useful model system to examine trade-offs influencing seasonal change within individuals. Here, I review recent studies from my laboratory on little brown bats (Myotis lucifugus) from central Canada to understand the interplay between capacity for energy storage, energy expenditure during hibernation, and the timing of key events in the annual cycle of hibernating mammals. These studies have relied on measurements of body condition to assess energetic status, biologging of skin temperature using temperature telemetry, and use of passive transponders (i.e., PIT tags) to quantify emergence timing. In general, these studies suggest that, in part due to constraints associated with flight, bats exhibit unique, or at least unusual, adaptations for extreme energy savings during winter. The results also support the optimization hypothesis that current energetic status and future energy requirements influence energy expenditure during hibernation and the timing of emergence from hibernation in spring. Taken together, this work provides insight into the influence of reproductive timing and energy availability on hibernation behavior and physiology. It also has implications for understanding responses of bat populations to anthropogenic impacts like climate change and white-nose syndrome.


Physical activity, sedentary behaviors and dietary habits among Saudi adolescents relative to age, gender and region.
Few lifestyle factors have been simultaneously studied and reported for Saudi adolescents. Therefore, the purpose of the present study was to report on the prevalence of physical activity, sedentary behaviors and dietary habits among Saudi adolescents and to examine the interrelationships among these factors using representative samples drawn from three major cities in Saudi Arabia. This school-based cross-sectional study was conducted during the years 2009-2010 in three cities: Al-Khobar, Jeddah and Riyadh. The participants were 2908 secondary-school males (1401) and females (1507) aged 14-19 years, randomly selected using a multistage stratified sampling technique. Measurements included weight, height, sedentary behaviors (TV viewing, playing video games and computer use), physical activity using a validated questionnaire and dietary habits. A very high proportion (84% for males and 91.2% for females) of Saudi adolescents spent more than 2 hours on screen time daily and almost half of the males and three-quarters of the females did not meet daily physical activity guidelines. The majority of adolescents did not have a daily intake of breakfast, fruit, vegetables and milk. Females were significantly (p < 0.05) more sedentary, much less physically active, especially with vigorous physical activity, and there were fewer days per week when they consumed breakfast, fruit, milk and diary products, sugar-sweetened drinks, fast foods and energy drinks than did males. However, the females' intake of French fries and potato chips, cakes and donuts, and candy and chocolate was significantly (p < 0.05) higher than the males'. Screen time was significantly (p < 0.05) correlated inversely with the intake of breakfast, vegetables and fruit. Physical activity had a significant (p < 0.05) positive relationship with fruit and vegetable intake but not with sedentary behaviors. The high prevalence of sedentary behaviors, physical inactivity and unhealthy dietary habits among Saudi adolescents is a major public health concern. There is an urgent need for national policy promoting active living and healthy eating and reducing sedentary behaviors among children and adolescents in Saudi Arabia.