Interventions for chronic palmoplantar pustulosis.
Chronic palmoplantar pustulosis (PPP) is a chronic inflammatory skin condition characterised by crops of sterile pustules (yellow pus spots) on the palms and soles which erupt repeatedly over months or years. The affected areas tend to become red and scaly; cracks may form and these are often painful. Many different treatments have been used for palmoplantar pustulosis but none is generally accepted as being reliably effective. To assess the effects of treatments for palmoplantar pustulosis, both in reducing disease severity and in maintaining remission once achieved. We searched the Cochrane Skin Group Specialised Register (January 2003), the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2003), MEDLINE (1966 to February 2003), EMBASE (1988 to February 2003). We also cross-checked with the Salford Database of Psoriasis Trials and reference lists of articles. We also contacted authors included trials, members of the Cochrane Skin Group and dermatologists interested in psoriasis. Any randomised controlled trial in which patients with chronic palmoplantar pustulosis were randomised to receive one or more interventions. At least two reviewers independently assessed trial eligibility and quality. Study authors were contacted for additional information. Adverse effects information was collected from the trials. Twenty-three trials involving 724 people were included. There is evidence supporting the use of systemic retinoids (improvement rate difference 44%, 95 CI 28 to 59%), oral PUVA (improvement rate difference 44%, 95 CI 26 to 62%). However, a combination of PUVA and retinoids is better than the individual treatments. The use of topical steroid under hydrocolloid occlusion is beneficial. It would also appear that low dose ciclosporin, tetracycline antibiotics and Grenz Ray Therapy may be useful in treating PPP. Colchicine has a lot of side effects and it is unclear if it is effective and neither was topical PUVA (rate difference of 0.00, 95% CI -0.04 to +0.04). There is no evidence to suggest that short-term treatment with hydroxycarbamide (hydroxyurea) is effective. Many different interventions were reported to produce "improvement" in PPP. There is, however, no standardised method for assessing response to treatment, and reductions in pustule counts or other empirical semi-quantitative scoring systems may be of little relevance to the patient. This review has shown that the ideal treatment for PPP remains elusive and that the standards of study design and reporting need to be improved to inform patients and those treating them of the relative merits of the many treatments available to them.


Semantic and perceptual processing of number symbols: evidence from a cross-linguistic fMRI adaptation study.
The ability to process the numerical magnitude of sets of items has been characterized in many animal species. Neuroimaging data have associated this ability to represent nonsymbolic numerical magnitudes (e.g., arrays of dots) with activity in the bilateral parietal lobes. Yet the quantitative abilities of humans are not limited to processing the numerical magnitude of nonsymbolic sets. Humans have used this quantitative sense as the foundation for symbolic systems for the representation of numerical magnitude. Although numerical symbol use is widespread in human cultures, the brain regions involved in processing of numerical symbols are just beginning to be understood. Here, we investigated the brain regions underlying the semantic and perceptual processing of numerical symbols. Specifically, we used an fMRI adaptation paradigm to examine the neural response to Hindu-Arabic numerals and Chinese numerical ideographs in a group of Chinese readers who could read both symbol types and a control group who could read only the numerals. Across groups, the Hindu-Arabic numerals exhibited ratio-dependent modulation in the left IPS. In contrast, numerical ideographs were associated with activation in the right IPS, exclusively in the Chinese readers. Furthermore, processing of the visual similarity of both digits and ideographs was associated with activation of the left fusiform gyrus. Using culture as an independent variable, we provide clear evidence for differences in the brain regions associated with the semantic and perceptual processing of numerical symbols. Additionally, we reveal a striking difference in the laterality of parietal activation between the semantic processing of the two symbols types.


SU-E-J-177: Characterization of the Effect of 'Lung Detail' CT Reconstruction Algorithm on Radiation Therapy Dose Calculation.
Precise tumor delineation is important in thoracic radiation therapy planning, and using a 'lung detail' computed tomography (CT) reconstruction algorithm can assist in visualizing the tumor. We seek to determine the dosimetric impact of utilizing a lung detail algorithm versus a standard algorithm on calculated dose in radiation treatment planning. Ten patients, with 12 tumors, were analyzed in this study. Two CT scans, one reconstructed using a standard algorithm and one using a lung detail algorithm, were generated for each of 12 lung tumors. Treatment plans were calculated for each CT scan, with 7 tumors receiving stereotactic ablative radiotherapy (SABR) and 5 receiving intensity-modulated radiation therapy (IMRT). The Hounsfield unit (HU) and dose values for each voxel of the planning tumor volume (PTV), esophagus, spinal cord, and contralateral lung in both the CT and dose images were exported to MATLAB. For each contour, the voxel-by-voxel differences in the HU and dose distributions between the two scans were analyzed along with dose-volume histogram (DVH) data. Despite changes in HU values, the voxel-by-voxel analysis showed a negligible shift in dose values. The mean differences in dose for PTV, esophagus, spinal cord, and contralateral lung ranged from -12.12 to 22.57, -2.21 to 7.40, -0.50 to 5.93, and -1.12 to 7.41 cGy, respectively. DVH comparisons demonstrated no meaningful difference between plans. The mean PTV, esophagus, spinal cord, and contralateral lung doses measured from the DVH shifted between plans an average of 3.5, 2.93, -0.6 and -0.35 cGy, respectively. These dose differences are all less than 1% of the dose prescribed to the tumor and are not measurable by current technology. The lung detail reconstruction algorithm, when applied to thoracic radiation treatment planning CT scans, can help precisely delineate tumor with negligible dosimetric impact.


A variant upstream of HLA-DRB1 and multiple variants in MICA influence susceptibility to cervical cancer in a Swedish population.
In a genome-wide association study, we have previously identified and performed the initial replication of three novel susceptibility loci for cervical cancer: rs9272143 upstream of HLA-DRB1, rs2516448 adjacent to MHC class I polypeptide-related sequence A gene (MICA), and rs3117027 at HLA-DPB2. The risk allele T of rs2516448 is in perfect linkage disequilibrium with a frameshift mutation (A5.1) in MICA exon 5, which results in a truncated protein. To validate these associations in an independent study and extend our prior work to MICA exon 5, we genotyped the single-nucleotide polymorphisms at rs9272143, rs2516448, rs3117027 and the MICA exon 5 microsatellite in a nested case-control study of 961 cervical cancer patients (827 carcinoma in situ and 134 invasive carcinoma) and 1725 controls from northern Sweden. The C allele of rs9272143 conferred protection against cervical cancer (odds ratio [OR] = 0.73, 95% confidence interval [CI] = 0.65-0.82; P = 1.6 × 10(-7)), which is associated with higher expression level of HLA-DRB1, whereas the T allele of rs2516448 increased the susceptibility to cervical cancer (OR = 1.33, 95% CI = 1.19-1.49; P = 5.8 × 10(-7)), with the same association shown with MICA-A5.1. The direction and the magnitude of these associations were consistent with our previous findings. We also identified protective effects of the MICA-A4 (OR = 0.80, 95% CI = 0.68-0.94; P = 6.7 × 10(-3)) and MICA-A5 (OR = 0.60, 95% CI = 0.50-0.72; P = 3.0 × 10(-8)) alleles. The associations with these variants are unlikely to be driven by the nearby human leukocyte antigen (HLA) alleles. No association was observed between rs3117027 and risk of cervical cancer. Our results support the role of HLA-DRB1 and MICA in the pathogenesis of cervical cancer.


Recent advances on the roles of epidermal growth factor receptor in psoriasis.
Epidermal growth factor receptor (EGFR) is a well-characterized receptor tyrosine kinase that involved in many vital activities in cell development, such as cellular homeostasis, proliferation, division, differentiation and apoptosis. Natural activation of EGFR and the concomitant downstream signaling pathways regulation are substantial to maintain normal cellular functions. In recent studies, EGFR was demonstrated to be a fundamental modulator in the control of skin inflammatory responses. Several dermatologic diseases including psoriasis are related to the anomalous activation of EGFR signaling. It has been proved that the expression and activity of EGFR and its endogenous ligands are overexpressed in the active epidermis lesions of psoriasis. Moreover, the remarkable therapeutic improvement of chronic psoriasis in cancer patients during the treatment of EGFR inhibitors or anti-EGFR monoclonal antibodies are also recorded, suggesting that the EGFR-mediated signaling may conduct a crucial role in the pathophysiology of psoriasis.


Guidelines regarding negative wound therapy (NPWT) in the diabetic foot.
The purpose of these guidelines is to the summarize consensus of a multidisciplinary expert advisory panel convened to determine appropriate use of negative pressure wound therapy (NPWT), also known as Vacuum-Assisted Closure or V.A.C. Therapy, in the treatment of diabetic foot wounds. The Tucson Expert Consensus Conference (TECC) on V.A.C. Therapy was convened in an effort to guide the direction for future research either to confirm or refute current consensus while providing practical guidance to the clinician currently treating diabetic foot wounds. The consensus committee discussed and commented on the following ten key questions regarding NPWT: 1) How long should NPWT be used in the treatment of a diabetic foot wound? 2) Should NPWT be applied to a wound that has not been debrided? 3) How should the patient using NPWT be evaluated on an outpatient basis? 4) When should NPWT be applied following lower-extremity bypass? 5) When should NPWT be applied after incision and drainage of infection? 6) How should NPWT be used in patients with osteomyelitis? 7) How should nonadherence (i.e., noncompliance) be defined in the patient on NPWT? When should NPWT be discontinued in this population? 8) How should NPWT be used in combination with other modalities? 9) Should small, superficial, noninfected wounds be considered for NPWT? 10) How should we define success in future studies of NPWT?


Harmonising conflicts between science, regulation, perception and environmental impact: the case of soil conditioners from bioenergy.
As the global population is expected to reach 9 billion by 2050, humanity needs to balance an ever increasing demand for food, energy and natural resources, with sustainable management of ecosystems and the vital services that they provide. The intensification of agriculture, including the use of fertilisers from finite sources, has resulted in extensive soil degradation, which has increased food production costs and CO2 emissions, threatening food security. The Bioenergy sector has significant potential to contribute to the formation of a circular economy. This paper presents the scientific, regulatory and socioeconomic barriers to the use of the nutrient waste streams from biomass thermal conversion (ash) and anaerobic digestion (digestate) as sustainable soil amendments for use in place of traditional fertilisers. It is argued that whilst the ability of combined ash and digestate to remedy many threats to ecosystems and provide a market to incentivise the renewable bio-energy schemes is promising, a step-change is required to alter perceptions of 'waste', from an expensive problem, to a product with environmental and economic value. This can only be achieved by well-informed interactions between scientists, regulators and end users, to improve the spread and speed of innovation with this sector.


Single-Study Approvals: Quantum of Evidence Required.
When does a single positive adequate and well-controlled study of a new drug meet the statutory requirement to demonstrate substantial evidence of effectiveness? The answer to this question, particularly with respect to new molecular entities, has been of considerable debate since 1962 when the requirement that new drugs prove their benefit to patients became law. A 1997 revision to the statute provided one pathway to a single-study approval (a single adequate and well-controlled study plus confirmatory evidence), while a 1998 guidance issued by FDA provided additional pathways, one of which is the one that is most frequently cited by FDA (a single statistically very persuasive study). This paper explains these 2 distinct pathways and provides illustrative examples of how FDA uses each of these 2 pathways. Regulators, industry, patients, and investors should each find this exegesis of these 2 independent, yet equally viable and valuable, pathways to an FDA approval both illuminating and invaluable.


The impact of multiple anthropogenic contaminants on the terrestrial environment of the Plitvice Lakes National Park, Croatia.
The anthropogenic impact on the terrestrial environment of the Plitvice Lakes National Park (PLNP) was investigated through the analysis of three groups of major contaminants (persistent organochlorine pollutants including 15 organochlorine pesticides (OCPs) and 17 polychlorinated biphenyls (PCBs), trace elements/heavy metals (6 major and 23 trace constituents), and anthropogenic radionuclides ((90)Sr, (134)Cs, and (137)Cs)) in three terrestrial compartments (soil, air, and bioindicators of air contamination) during 2011-2013. The correlation coefficients of element mass fractions with soil properties indicated that total Fe and Al minerals, soil organic matter (OM), and organic carbon (OC) content affected the mass fractions of most trace elements in the topsoils. The annual and spatial distributions of heavy metals in total deposited matter (TDM) indicated that the metals came from natural sources and long-range transfer of particulate matter. The PCB and OCP levels found in soil and conifer needles corresponded to global environmental pollution levels by persistent organic pollutants and represented the lower end of the mass fraction ranges reported in the relevant literature. Analyses of anthropogenic radionuclides in bioindicators (conifer needles, lichens, and mosses) showed low but measurable activity concentrations of (134)Cs (for the first time after the Chernobyl accident), which indicated origin from the March 2011 Fukushima Nuclear Power Plant accident. Our overall results indicated that human activity inside or near the PLNP had no significant impact either on contaminant spread by air or on their content in topsoils.


The effect of chronic co-administration of fluvoxamine and haloperidol compared to clozapine on the GABA system in the rat frontal cortex.
Clinical studies in schizophrenia patients have shown that adding a selective serotonin reuptake inhibitor (SSRI) to antipsychotics can ameliorate negative symptoms that frequently resist standard treatments. It has been proposed that this combined treatment produces a 'net effect', different from that of the individual drugs and possibly common to that of the atypical antipsychotic, clozapine, which also ameliorates negative symptoms. The present study was initiated to determine the molecular events in the rat frontal cortex resulting from combined treatment of fluvoxamine and haloperidol compared to clozapine. Rats were allocated to five groups and received a daily intraperitoneal injection with one of the following: haloperidol (1 mg/kg), fluvoxamine (11 mg/kg), clozapine (11 mg/kg), haloperidol (1 mg/kg) plus fluvoxamine (11 mg/kg), or vehicle for 30 d. cDNA arrays were used to screen a broad range of genes in the frontal cortex. Several of the most prominent alterations were taken for analysis in real-time RT-PCR and their related proteins were examined by the Western-blotting technique. The gene expression profile of the combined fluvoxamine plus haloperidol treatment was different from that of the individual drugs. Moreover, clozapine showed some degree of homology with the dual treatment. The protein expression changes, specific to the combined treatment, included glutamic acid decarboxylase (GAD67) and protein kinase Cbeta (PKCbeta). The latter showed a similar trend following clozapine treatment. The present findings support the existence of a unique mechanism for SSRI-antipsychotic combination, different from that of the individual drugs and suggest that it may involve modification of the gamma aminobutyric acid (GABA) system.


Expression of the insulin receptor-related receptor is induced by the preovulatory surge of luteinizing hormone in thecal-interstitial cells of the rat ovary.
The insulin receptor-related receptor (IRR) is a member of the insulin receptor family that, on its own, recognizes neither insulin nor any of the identified insulin-related peptides. In both the nervous system and peripheral tissues, IRR mRNA is detected in cells that also express trkA, the nerve growth factor tyrosine kinase receptor. In the ovary, the trkA gene is transiently activated in thecal-interstitial cells of large antral follicles at the time of the preovulatory surge of gonadotropins. The present study shows that the IRR gene is expressed in the same ovarian compartment, that IRR mRNA content increases strikingly in these cells in the afternoon of the first proestrus, and that--as in the case of trkA mRNA--the increase is caused by gonadotropins. The IRR mRNA species primarily affected is that encoding the full-length receptor; its increased abundance was accompanied by a corresponding change in IRR protein content. An extensive molecular search using several approaches, including the screening of cDNA libraries and PCR amplification with degenerate primers, did not yield an IRR ligand. Phylogenetic analysis of 20 insulin-related sequences and 15 relaxin family peptides from selected vertebrates indicated that the mammalian genome is unlikely to contain an additional ligand expressed from a distinct gene that is closely related to the insulin family. Although the functional nature of the relationship between IRR and trkA receptors is unknown, the remarkable temporal and spatial specificities of their coordinated expression in the ovary before ovulation suggests that they target a functionally related set of downstream events associated with the ovulatory process.


Systemic therapies for metastatic renal cell carcinoma in older adults.
The introduction of targeted therapies has radically changed the treatment paradigm for metastatic renal cell carcinoma (mRCC). However, multiple clinical dilemmas have emerged. For instance, limited data are available to juxtapose the safety and efficacy profile of targeted therapies between older and younger adults. Herein, pivotal trials of vascular endothelial growth factor (VEGF)- and mammalian target of rapamycin (mTOR)-directed therapies are assessed in the context of their implications in treating older adults with mRCC. In general, subset analyses from these pivotal studies suggest similar efficacy of targeted therapies amongst older adults. Aging is accompanied by a multitude of physiological changes, as well as an increased prevalence of co-morbidities. The age-related toxicity profiles of targeted agents for mRCC are detailed to provide a framework for the risks and benefits of these therapies in older adults. Ultimately, tools such as the Comprehensive Geriatric Assessment (CGA) that account for physiological (as opposed to chronological) age may prove useful in the evaluation and treatment of older adults with mRCC.


Secondary amine salt catalyzed controlled activation of 2-deoxy sugar lactols towards alpha-selective dehydrative glycosylation.
A new organocatalytic glycosylation method exploiting the lactol functionality has been disclosed. The catalytic generation of glycosyl oxacarbenium ions from lactols under forcible conditions via weakly Brønsted-acidic, readily available secondary amine salts affects the diastereoselective glycosylation of 2-deoxypyranoses and furanoses. This operationally simple iminium catalyzed activation of 2-deoxy hemi-acetals is a potential alternative to the existing cumbersome methods that need specialized handling. The mechanisms for this unique transformation and kinetic/thermodynamic effects have been discussed based on both experimental evidence and theoretical studies.


Prospective study of religious coping among patients undergoing autologous stem cell transplantation.
Considerable attention has focused on relationships between religious or spiritual coping and health outcomes among cancer patients. However, few studies have differentiated among discrete dimensions of religious coping, and there have been surprisingly few prospective investigations. Negative or conflicted aspects of religious coping, in particular, represent a compelling area for investigation. This prospective study examined negative religious coping, positive religious coping, and general religious orientation among 94 myeloma patients undergoing autologous stem cell transplantation. Participants were assessed during stem cell collection, and again in the immediate aftermath of transplantation, when risks for morbidity are most elevated. Outcomes included Brief Symptom Inventory anxiety and depression and Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMI) scales. Negative religious coping at baseline predicted worse post-transplant anxiety, depression, emotional well-being, and transplant-related concerns, after controlling for outcome scores at baseline and other significant covariates. Post-transplant physical well-being was predicted by an interaction between baseline positive and negative religious coping. Results suggest that religious struggle may contribute to adverse changes in health outcomes for transplant patients, and highlight the importance of negative or strained religious responses to illness.


Graphene unit cell imaging by holographic coherent diffraction.
We have imaged a freestanding graphene sheet of 210 nm in diameter with 2 Å resolution by combining coherent diffraction and holography with low-energy electrons. The entire sheet is reconstructed from a single diffraction pattern displaying the arrangement of 660.000 individual graphene unit cells at once. Given the fact that electrons with kinetic energies of the order of 100 eV do not damage biological molecules, it will now be a matter of developing methods for depositing individual proteins onto such graphene sheets.


Follicular B-Cell Lymphoma and Particulate Matter Associated with Environmental Exposure to Wood Dust.
BACKGROUND In humans, wood dust is a carcinogen. Indeed, a strong association between wood dust and lung cancer risk has been reported in woodworkers, as well as in the general population. CASE REPORT The patient was a 58-year-old man with follicular B-cell lymphoma. In the 10 years preceding the cancer diagnosis, he lived within 1/4 mile of a paper mill, where wood was processed. Computed tomography of the chest, abdomen, and pelvis revealed right hilar, mediastinal, abdominal, and retroperitoneal lymphadenopathy, bilateral pleural effusions, and a large soft-tissue mass infiltrating the small bowel mesentery. Analysis of the pleural fluid revealed the presence of a web of thin filopodia-like filaments, which trapped clusters of mesothelial cells and atypical lymphocytes. Single tubular filaments, morphologically similar to tunneling nanotubes, were seen originating from atypical lymphocytes and reaching neighboring cells. Furthermore, long, thick, cylindrical fibers of unknown nature, probably from the external environment, were also observed. CONCLUSIONS Because the patient lived in an unhealthy environment for many years, the possibility that his clinical condition was related to exposure to toxic emissions should be entertained. Considered in this context, the foreign fibers in his pleural fluid could be a direct consequence of inhalation of contaminants in the polluted air.


Analysis of Epstein-Barr virus reservoirs in paired blood and breast cancer primary biopsy specimens by real time PCR.
Epstein-Barr virus (EBV) is present in over 90% of the world's population. This infection is considered benign, even though in limited cases EBV is associated with infectious and neoplastic conditions. Over the past decade, the EBV association with breast cancer has been constantly debated. Adding to this clinical and biological uncertainty, different techniques gave contradictory results for the presence of EBV in breast carcinoma specimens. In this study, minor groove binding (MGB)-TaqMan real time PCR was used to detect the presence of EBV DNA in both peripheral blood and tumor samples of selected patients. Peripheral blood and breast carcinoma specimens from 24 patients were collected. DNA was extracted and then amplified by MGB-TaqMan real time PCR. Of 24 breast tumor specimens, 11 (46%) were positive for EBV DNA. Of these 11 breast tumor specimens, 7 (64%) were also positive for EBV DNA in the peripheral blood, while 4 (36%) were positive for EBV DNA in the tumor, but negative in the blood. EBV was found at extremely low levels, with a mean of 0.00004 EBV genomes per cell (range 0.00014 to 0.00001 EBV genomes per cell). Furthermore, our finding of the presence of EBV in the tumor specimens coupled to the absence of detection of EBV genomic DNA in the peripheral blood is consistent with the epithelial nature of the virus. Because of the low levels of viral DNA in tumor tissue, further studies are needed to assess the biological input of EBV in breast cancer.


Screening Strategies for the Discovery of Ion Channel Monoclonal Antibodies.
Ion channels play crucial roles in physiology by modulation of cellular functions that include electrical excitability, secretion, cell migration, and gene transcription. They are an important target class for drug discovery and have historically been targeted using small molecule approaches. A significant opportunity exists to target these channels with antibodies and alternative forms of biologics. Antibodies display high specificity, selectivity, and affinity for their target antigen, thus having the potential to target ion channels very precisely. Nonetheless, isolating antibodies to ion channels is challenging due to the difficulties in expression and purification of ion channels in a format suitable for antibody drug discovery and due to the complexities of screening for function. In this overview, we focus on an array of screening methods, ranging from direct antibody binding screens to complex electrophysiological assays, and describe how these assays can be used to identify functional monoclonal antibodies. We also provide some insights into specific considerations which are required to enable these screens to be used for antibody drug discovery. © 2018 by John Wiley & Sons, Inc.


Fine root endophytes under scrutiny: a review of the literature on arbuscule-producing fungi recently suggested to belong to the Mucoromycotina.
Fine root endophytes (FRE) are arbuscule-forming fungi presently considered as a single species-Glomus tenue in the Glomeromycota (Glomeromycotina)-but probably belong within the Mucoromycotina. Thus, FRE are the only known arbuscule-forming fungi not within the arbuscular mycorrhizal fungi (AMF; Glomeromycotina) as currently understood. Phylogenetic differences between FRE and AMF could reflect ecological differences. To synthesize current ecological knowledge, we reviewed the literature on FRE and identified 108 papers that noted the presence of FRE and, in some, the colonization levels for FRE or AMF (or both). We categorized these records by geographic region, host-plant family and environment (agriculture, moderate-natural, low-temperature, high-altitude and other) and determined their influence on the percentage of root length colonized by FRE in a meta-analysis. We found that FRE are globally distributed, with many observations from Poaceae, perhaps due to grasses being widely distributed. In agricultural environments, colonization by FRE often equalled or exceeded that of AMF, particularly in Australasia. In moderate-natural and high-altitude environments, average colonization by FRE (~10%) was lower than that of AMF (~35%), whereas in low-temperature environments, colonization was similar (~20%). Several studies suggested that FRE can enhance host-plant phosphorus uptake and growth, and may be more resilient than AMF to environmental stress in some host plants. Further research is required on the functioning of FRE in relation to the environment, host plant and co-occurring AMF and, in particular, to examine whether FRE are important for plant growth in stressful environments. Targeted molecular primers are urgently needed for further research on FRE.


Medroxyprogesterone acetate alters Mycobacterium bovis BCG-induced cytokine production in peripheral blood mononuclear cells of contraceptive users.
Most individuals latently infected with Mycobacterium tuberculosis (M.tb) contain the infection by a balance of effector and regulatory immune responses. This balance can be influenced by steroid hormones such as glucocorticoids. The widely used contraceptive medroxyprogesterone acetate (MPA) possesses glucocorticoid activity. We investigated the effect of this hormone on immune responses to BCG in household contacts of active TB patients. Multiplex bead array analysis revealed that MPA demonstrated both glucocorticoid and progestogenic properties at saturating and pharmacological concentrations in peripheral blood mononuclear cells (PBMCs) and suppressed antigen specific cytokine production. Furthermore we showed that PBMCs from women using MPA produced significantly lower levels of IL-1α, IL-12p40, IL-10, IL-13 and G-CSF in response to BCG which corresponded with lower numbers of circulating monocytes observed in these women. Our research study is the first to show that MPA impacts on infections outside the genital tract due to a systemic effect on immune function. Therefore MPA use could alter susceptibility to TB, TB disease severity as well as change the efficacy of new BCG-based vaccines, especially prime-boost vaccine strategies which may be administered to adult or adolescent women in the future.


Amygdala regulation of nucleus accumbens dopamine output is governed by the prefrontal cortex.
A dynamic interaction between the prefrontal cortex (PFC), amygdala, and nucleus accumbens (NAc) may be fundamental to regulation of goal-directed behavior by affective and cognitive processes. This study demonstrates that a mechanism for this triadic relationship is an inhibitory control by prefrontal cortex on accumbal dopamine release during amygdala activation. In freely moving rats, microstimulation of basolateral amygdala at intensities that produced mild behavioral activation produced an expected rapid increase in glutamate efflux in the prefrontal cortex and the nucleus accumbens shell region of the ventral striatum. However, during the stimulation, dopamine release increased only in the prefrontal cortex, not in the nucleus accumbens. An increase in accumbal dopamine release was observed during the stimulation if glutamate activation in the prefrontal cortex was inhibited at either presynaptic or postsynaptic levels. Some behaviors expressed during the stimulation were intensified in animals in which prefrontal cortex glutamate activation was blocked. In addition, these animals continued to express stimulus-induced behaviors after the termination of stimulation, whereas normal poststimulus behaviors such as ambulation and grooming were not displayed as frequently. Considering that dopamine neurotransmission in the nucleus accumbens is thought to play an integral role in goal-directed motor behavior, these findings suggest that the prefrontal cortex influences the behavioral impact of amygdala activation via a concomitant active suppression of accumbal dopamine release. Absence of this cortical influence appears to result in an aberrant pattern of behavioral expression in response to amygdala activation, including behavioral perseveration after stimulus termination.


Reduction in energy expenditure during weight loss is higher than predicted based on fat free mass and fat mass in older adults.
The aim of this study was to describe a decrease in resting energy expenditure during weight loss that is larger than expected based on changes in body composition, called adaptive thermogenesis (AT), in overweight and obese older adults. Multiple studies were combined to assess AT in younger and older subjects. Body composition and resting energy expenditure (REE) were measured before and after weight loss. Baseline values were used to predict fat free mass and fat mass adjusted REE after weight loss. AT was defined as the difference between predicted and measured REE after weight loss. The median age of 55 y was used as a cutoff to compare older with younger subjects. The relation between AT and age was investigated using linear regression analysis. In this study 254 (M = 88, F = 166) overweight and obese subjects were included (BMI: 31.7 ± 4.4 kg/m2, age: 51 ± 14 y). The AT was only significant for older subjects (64 ± 185 kcal/d, 95% CI [32, 96]), but not for younger subjects (19 ± 152 kcal/d, 95% CI [-9, 46]). The size of the AT was significantly higher for older compared to younger adults (β = 47, p = 0.048), independent of gender and type and duration of the weight loss program. We conclude that adaptive thermogenesis is present only in older subjects, which might have implications for weight management in older adults. A reduced energy intake is advised to counteract the adaptive thermogenesis.


Birth outcomes following antiretroviral exposure during pregnancy: Initial results from a pregnancy exposure registry in South Africa.
In 2013, a pregnancy exposure registry and birth defects surveillance (PER/BDS) system was initiated in eThekwini District, KwaZulu-Natal (KZN), to assess the impact of antiretroviral treatment (ART) on birth outcomes. At the end of the first year, we assessed the risk of major congenital malformations (CM) and other adverse birth outcomes (ABOs) detected at birth, in children born to women exposed to ART during pregnancy. Data were collected from women who delivered at Prince Mshiyeni Memorial Hospital, Durban, from 07 October 2013 to 06 October 2014, using medicine exposure histories and birth outcomes from maternal interviews, clinical records and neonatal surface examination. Singleton births exposed to only one ART regimen were included in bivariable analysis for CM risk and multivariate risk analysis for ABO risk. Data were collected from 10 417 women with 10 517 birth outcomes (4013 [38.5%] HIV-infected). Congenital malformations rates in births exposed to Efavirenz during the first trimester (T1) (RR 0.87 [95% CI 0.12-6.4; p = 0.895]) were similar to births not exposed to ART during T1. However, T1 exposure to Nevirapine was associated with the increased risk of CM (RR 9.28 [95% CI 2.3-37.9; p = 0.002]) when compared to the same group. Other ABOs were more frequent in the combination of HIV/ART-exposed births compared to HIV-unexposed births (29.9% vs. 26.0%, adjusted RR 1.23 [1.14-1.31; p < 0.001]). No association between T1 use of EFV-based ART regimens and CM was observed. Associations between T1 NVP-based ART regimen and CM need further investigation. HIV- and ART-exposed infants had more ABOs compared to HIV-unexposed infants.


Musculoskeletal pain and menopause.
Musculoskeletal pain, arthralgia and arthritis are all more common in women, and their frequency increases with age and in some appears to be associated with the onset of menopause. The clinical assessment, investigation and management of women presenting with musculoskeletal pain, arthralgia or arthritis at the time of menopause are reviewed. Common causes of arthralgia and arthritis in this population are discussed. The epidemiological and trials evidence for the effects of hormone replacement therapy on musculoskeletal pain and arthritis (primarily from RCTs of HRT for other menopausal symptoms) are discussed. Lastly, the possible underlying aetiological roles of sex hormones including estrogen, and their deficiency, in predisposing to musculoskeletal pain and arthritis are overviewed. Although the association appears strong, a causal link between estrogen deficiency and musculoskeletal pain or different types of arthritis is lacking; there have been few studies specifically within this group of symptomatic patients, and there is much still to understand about musculoskeletal pain and arthritis at the time of the menopause, and about how we might prevent or treat this.


Site-directed and global incorporation of orthogonal and isostructural noncanonical amino acids into the ribosomal lasso peptide capistruin.
Expansion of the structural diversity of peptide antibiotics was performed through two different methods. Supplementation-based incorporation (SPI) and stop-codon suppression (SCS) approaches were used for co-translational incorporation of isostructural and orthogonal noncanonical amino acids (ncAAs) into the lasso peptide capistruin. Two ncAAs were employed for the SPI method and five for the SCS method; each of them probing the incorporation of ncAAs in strategic positions of the molecule. Evaluation of the assembly by HR-ESI-MS proved more successful for the SCS method. Bio-orthogonal chemistry was used for post-biosynthetic modification of capistruin congener Cap_Alk10 containing the ncAA Alk (Nε-Alloc-L-lysine) instead of Ala. A second-generation Hoveyda-Grubbs catalyst was used for an in vitro metathesis reaction with Cap_Alk10 and an allyl alcohol, which offers options for post-biosynthetic modifications. The use of synthetic biology allows for the in vivo production of new peptide-based antibiotics from an expanded amino acid repertoire.


The effect of surface charge on oral absorption of polymeric nanoparticles.
Surface charge plays an important role in determining the interactions of nanoparticles with biological components. Substantial studies have demonstrated that surface charge affects the fate of nanoparticles after intravenous administration; however, few studies have investigated the effect of surface charge on the bioavailability and absorption of nanoparticles after oral administration. In this study, polymeric nanoparticles with a similar particle size and surface polyethylene glycol (PEG) density, but with varying surface charges (positive, negative and neutral), were developed to study the effect of surface charge on the oral absorption of polymeric nanoparticles. The nanoparticles were constructed from polyethylene glycol-block-polylactic acid (PEG-PLA) with the incorporation of lipid components with different charges. Our results suggested that the positive surface charge facilitated the cellular uptake and transport of nanoparticles through both Caco-2 cells in vitro and small intestinal epithelial cells in vivo. The positively charged nanoparticles showed a favorable distribution in the small intestine, and significantly improved the oral bioavailability. This study presents valuable information towards the design of nanoparticles for improved oral drug delivery.


Targeted deep sequencing of mucinous ovarian tumors reveals multiple overlapping RAS-pathway activating mutations in borderline and cancerous neoplasms.
Mucinous ovarian tumors represent a distinct histotype of epithelial ovarian cancer. The rarest (2-4 % of ovarian carcinomas) of the five major histotypes, their genomic landscape remains poorly described. We undertook hotspot sequencing of 50 genes commonly mutated in human cancer across 69 mucinous ovarian tumors. Our goals were to establish the overall frequency of cancer-hotspot mutations across a large cohort, especially those tumors previously thought to be "RAS-pathway alteration negative", using highly-sensitive next-generation sequencing as well as further explore a small number of cases with apparent heterogeneity in RAS-pathway activating alterations. Using the Ion Torrent PGM platform, we performed next generation sequencing analysis using the v2 Cancer Hotspot Panel. Regions of disparate ERBB2-amplification status were sequenced independently for two mucinous carcinoma (MC) cases, previously established as showing ERBB2 amplification/overexpression heterogeneity, to assess the hypothesis of subclonal populations containing either KRAS mutation or ERBB2 amplification independently or simultaneously. We detected mutations in KRAS, TP53, CDKN2A, PIK3CA, PTEN, BRAF, FGFR2, STK11, CTNNB1, SRC, SMAD4, GNA11 and ERBB2. KRAS mutations remain the most frequently observed alteration among MC (64.9 %) and mucinous borderline tumors (MBOT) (92.3 %). TP53 mutation occurred more frequently in carcinomas than borderline tumors (56.8 % and 11.5 %, respectively), and combined IHC and mutation data suggest alterations occur in approximately 68 % of MC and as many as 20 % of MBOT. Proven and potential RAS-pathway activating changes were observed in all but one MC. Concurrent ERBB2 amplification and KRAS mutation were observed in a substantial number of cases (7/63 total), as was co-occurrence of KRAS and BRAF mutations (one case). Microdissection of ERBB2-amplified regions of tumors harboring KRAS mutation suggests these alterations are occurring in the same cell populations, while consistency of KRAS allelic frequency in both ERBB2 amplified and non-amplified regions suggests this mutation occurred in advance of the amplification event. Overall, the prevalence of RAS-alteration and striking co-occurrence of pathway "double-hits" supports a critical role for tumor progression in this ovarian malignancy. Given the spectrum of RAS-activating mutations, it is clear that targeting this pathway may be a viable therapeutic option for patients with recurrent or advanced stage mucinous ovarian carcinoma, however caution should be exercised in selecting one or more personalized therapeutics given the frequency of non-redundant RAS-activating alterations.


Regenerative medicine: advances in new methods and technologies.
The articles published in the journal Cell Transplantation - The Regenerative Medicine Journal over the last two years reveal the recent and future cutting-edge research in the fields of regenerative and transplantation medicine. 437 articles were published from 2007 to 2008, a 17% increase compared to the 373 articles in 2006-2007. Neuroscience was still the most common section in both the number of articles and the percentage of all manuscripts published. The increasing interest and rapid advance in bioengineering technology is highlighted by tissue engineering and bioartificial organs being ranked second again. For a similar reason, the methods and new technologies section increased significantly compared to the last period. Articles focusing on the transplantation of stem cell lineages encompassed almost 20% of all articles published. By contrast, the non-stem cell transplantation group which is made up primarily of islet cells, followed by biomaterials and fetal neural tissue, etc. comprised less than 15%. Transplantation of cells pre-treated with medicine or gene transfection to prolong graft survival or promote differentiation into the needed phenotype, was prevalent in the transplantation articles regardless of the kind of cells used. Meanwhile, the majority of non-transplantation-based articles were related to new devices for various purposes, characterization of unknown cells, medicines, cell preparation and/or optimization for transplantation (e.g. isolation and culture), and disease pathology.<br />


Post and core restoration of endodontically treated teeth.
This review discusses the multifactorial nature of tooth strength and concludes that endodontic treatment alone does not weaken intact anterior teeth. Therefore, restoration of such teeth does require post placement or full-coverage restorations. Posterior teeth, however, require full-coverage protection. It appears that the full-crown restoration "covers up" some of the disadvantages or deficiencies of some post and core restorations. The literature supports the use of the amalgam coronal-radicular core or the post-retained amalgam core, as well as the composite post and core. The literature does not support use of the glass ionomer post and cores. As to which post system to select, the literature indicates that the parallel-sided, serrated Para-Post or Para-Post plus is a safe post when seated passively in the canal and cemented with zinc phosphate cements or composite resin cement, or when retained with amalgam. Dentin-retained, stress-producing posts such as the threaded posts should be avoided.


Factors influencing spatial variability in nitrogen processing in nitrogen-saturated soils.
Nitrogen (N) saturation is an environmental concern for forests in the eastern U.S. Although several watersheds of the Fernow Experimental Forest (FEF), West Virginia exhibit symptoms of N saturation, many watersheds display a high degree of spatial variability in soil N processing. This study examined the effects of temperature on net N mineralization and nitrification in N-saturated soils from FEF, and how these effects varied between high N-processing vs. low N-processing soils collected from two watersheds, WS3 (fertilized with [NH4]2SO4) and WS4 (untreated control). Samples of forest floor material (O1 horizon) and mineral soil (to a 5-cm depth) were taken from three subplots within each of four plots that represented the extremes of highest and lowest rates of net N mineralization and nitrification (hereafter, high N and low N, respectively) of untreated WS4 and N-treated WS3: control/low N, control/high N, N-treated/low N, N-treated/high N. Forest floor material was analyzed for carbon (C), lignin, and N. Subsamples of mineral soil were extracted immediately with 1 N KCl and analyzed for NH4+ and NO3- to determine preincubation levels. Extracts were also analyzed for Mg, Ca, Al, and pH. To test the hypothesis that the lack of net nitrification observed in field incubations on the untreated/low N plot was the result of absence of nitrifier populations, we characterized the bacterial community involved in N cycling by amplification of amoA genes. Remaining soil was incubated for 28 d at three temperatures (10, 20, and 30 degrees C), followed by 1 N KCl extraction and analysis for NH4+ and NO3-. Net nitrification was essentially 100% of net N mineralization for all samples combined. Nitrification rates from lab incubations at all temperatures supported earlier observations based on field incubations. At 30 degrees C, rates from N-treated/high N were three times those of N-treated/low N. Highest rates were found for untreated/high N (two times greater than those of N-treated/high N), whereas untreated/low N exhibited no net nitrification. However, soils exhibiting no net nitrification tested positive for presence of nitrifying bacteria, causing us to reject our initial hypothesis. We hypothesize that nitrifier populations in such soil are being inhibited by a combination of low Ca to Al ratios in mineral soil and allelopathic interactions with mycorrhizae of ericaceous species in the herbaceous layer.


Stereotactic Radiosurgery vs Conventional Radiotherapy for Localized Vertebral Metastases of the Spine: Phase 3 Results of NRG Oncology/RTOG 0631 Randomized Clinical Trial.
Spine metastasis can be treated with high-dose radiation therapy with advanced delivery technology for long-term tumor and pain control. To assess whether patient-reported pain relief was improved with stereotactic radiosurgery (SRS) as compared with conventional external beam radiotherapy (cEBRT) for patients with 1 to 3 sites of vertebral metastases. In this randomized clinical trial, patients with 1 to 3 vertebral metastases were randomized 2:1 to the SRS or cEBRT groups. This NRG 0631 phase 3 study was performed as multi-institutional enrollment within NRG Oncology. Eligibility criteria included the following: (1) solitary vertebral metastasis, (2) 2 contiguous vertebral levels involved, or (3) maximum of 3 separate sites. Each site may involve up to 2 contiguous vertebral bodies. A total of 353 patients enrolled in the trial, and 339 patients were analyzed. This analysis includes data extracted on March 9, 2020. Patients randomized to the SRS group were treated with a single dose of 16 or 18 Gy (to convert to rad, multiply by 100) given to the involved vertebral level(s) only, not including any additional spine levels. Patients assigned to cEBRT were treated with 8 Gy given to the involved vertebra plus 1 additional vertebra above and below. The primary end point was patient-reported pain response defined as at least a 3-point improvement on the Numerical Rating Pain Scale (NRPS) without worsening in pain at the secondary site(s) or the use of pain medication. Secondary end points included treatment-related toxic effects, quality of life, and long-term effects on vertebral bone and spinal cord. A total of 339 patients (mean [SD] age of SRS group vs cEBRT group, respectively, 61.9 [13.1] years vs 63.7 [11.9] years; 114 [54.5%] male in SRS group vs 70 [53.8%] male in cEBRT group) were analyzed. The baseline mean (SD) pain score at the index vertebra was 6.06 (2.61) in the SRS group and 5.88 (2.41) in the cEBRT group. The primary end point of pain response at 3 months favored cEBRT (41.3% for SRS vs 60.5% for cEBRT; difference, -19 percentage points; 95% CI, -32.9 to -5.5; 1-sided P = .99; 2-sided P = .01). Zubrod score (a measure of performance status ranging from 0 to 4, with 0 being fully functional and asymptomatic, and 4 being bedridden) was the significant factor influencing pain response. There were no differences in the proportion of acute or late adverse effects. Vertebral compression fracture at 24 months was 19.5% with SRS and 21.6% with cEBRT (P = .59). There were no spinal cord complications reported at 24 months. In this randomized clinical trial, superiority of SRS for the primary end point of patient-reported pain response at 3 months was not found, and there were no spinal cord complications at 2 years after SRS. This finding may inform further investigation of using spine radiosurgery in the setting of oligometastases, where durability of cancer control is essential. ClinicalTrials.gov Identifier: NCT00922974.


[Immunoinflammatory changes (myocarditis?) in chronic heart failure in alcoholic patients].
To estimate the contribution of immuno-inflammatory changes to the formation of clinical and hemodynamic features in alcoholic patients with chronic heart failure (CHF). Forty-five males with CHF in the presence of alcohol-induced heart damage (AIHD) who had been admitted to therapeutic units for decompensated heart failure were examined. A control group consisted of 20 men with the CHF severity comparable with the NYHA classification in the presence of prior myocardial infarction. All the patients underwent examination of the immune-inflammatory status--the cytokines: interleukin (IL) 6, IL-8, IL-12, tumor necrosis factor-alpha (TNF-alpha), transforming growth factor-beta1, endotoxin, cellular immune parameters, and cardiac structure and function by echocardiography. The patients with CHF in the presence of AIHD, as compared to those with ischemic cardiomyopathy, showed the higher levels of inflammatory cytokines (IL-6, TNF-alpha, IL-12, and endotoxin) and cell-mediated immunity changes (the smaller count of suppressor T cells, natural killer cells, and a shift of the T-helper/T-suppressor ratio towards the T-helper population). The magnitude of these changes correlated with the severity of CHF and cardiac morphofunctional changes. The relationship of immuno-inflammatory changes to the severity of CHF and the morphofunctional state of the heart irrespective of the etiology of heart failure demonstrated the role of immune inflammation in its pathogenesis particularly in alcoholic patients who were found to have more marked immuno-inflammatory changes than in those with ischemic cardiomyopathy.


Reduced frequency selectivity and the preservation of spectral contrast in noise.
Reduced frequency selectivity associated with sensorineural hearing loss may pose particular problems for hearing-impaired listeners in noisy environments. In these situations, broader-than-normal auditory filters may affect the perception of speech by reducing the contrast between spectral peaks and valleys in at least two ways. First, the peaks and valleys in the internal representation of the speech spectrum become smeared, resulting in less precise frequency analysis. Second, there may be a reduction in the signal-to-noise ratio (S/N) at the output of each auditory filter. In order to examine the relationship between frequency selectivity and identification of speechlike stimuli in noise, hearing-impaired and normal-hearing listeners were trained to assign vowel labels to four harmonic complexes which differed in the frequency locations of four elevated ("peak") harmonics. Peak harmonics were chosen to approximate first- and second-formant frequencies in four English vowels. Listeners were then tested to determine the spectral contrast necessary between peak and background components in order to maintain identification accuracy in the presence of various levels of broadband noise. Results indicated that for these stimuli, normal-hearing listeners required about 1 dB of additional spectral contrast for every doubling of the intensity of noise. The required increase in spectral contrast was generally greater for listeners with broader-than-normal auditory filters at 2000 Hz. This finding suggests indirectly that in the internal representations of speech sounds embedded in noise, the signal-to-noise ratio for listeners with abnormal frequency selectivity is poorer than for listeners with normal frequency selectivity. A poorer-than-normal internal S/N may be one factor underlying the common observation that noise often is more degrading to speech understanding by hearing-impaired listeners than by normal-hearing listeners.


Emerging applications of nanotechnology for the diagnosis and management of vulnerable atherosclerotic plaques.
An estimated 16 million people in the United States have coronary artery disease (CAD), and approximately 325,000 people die annually from cardiac arrest. About two-thirds of unexpected cardiac deaths occur without prior recognition of cardiac disease. A vast majority of these deaths are attributable to the rupture of 'vulnerable atherosclerotic plaques'. Clinically, plaque vulnerability is typically assessed through imaging techniques, and ruptured plaques leading to acute myocardial infarction are treated through angioplasty or stenting. Despite significant advances, it is clear that current imaging methods are insufficiently capable for elucidating plaque composition--which is a key determinant of vulnerability. Further, the exciting improvement in the treatment of CAD afforded by stenting procedures has been buffered by significant undesirable host-implant effects, including restenosis and late thrombosis. Nanotechnology has led to some potential solutions to these problems by yielding constructs that interface with plaque cellular components at an unprecedented size scale. By leveraging the innate ability of macrophages to phagocytose nanoparticles, contrast agents can now be targeted to plaque inflammatory activity. Improvements in nano-patterning procedures have now led to increased ability to regenerate tissue isotropy directly on stents, enabling gradual regeneration of normal, physiologic vascular structures. Advancements in immunoassay technologies promise lower costs for biomarker measurements, and in the near future, may enable the addition of routine blood testing to the clinician's toolbox--decreasing the costs of atherosclerosis-related medical care. These are merely three examples among many stories of how nanotechnology continues to promise advances in the diagnosis and treatment of vulnerable atherosclerotic plaques.


Cationic PAMAM dendrimers disrupt key platelet functions.
Poly(amidoamine) (PAMAM) dendrimers have been proposed for a variety of biomedical applications and are increasingly studied as model nanomaterials for such use. The dendritic structure features both modular synthetic control of molecular size and shape and presentation of multiple equivalent terminal groups. These properties make PAMAM dendrimers highly functionalizable, versatile single-molecule nanoparticles with a high degree of consistency and low polydispersity. Recent nanotoxicological studies showed that intravenous administration of amine-terminated PAMAM dendrimers to mice was lethal, causing a disseminated intravascular coagulation-like condition. To elucidate the mechanisms underlying this coagulopathy, in vitro assessments of platelet functions in contact with PAMAM dendrimers were undertaken. This study demonstrates that cationic G7 PAMAM dendrimers activate platelets and dramatically alter their morphology. These changes to platelet morphology and activation state substantially altered platelet function, including increased aggregation and adherence to surfaces. Surprisingly, dendrimer exposure also attenuated platelet-dependent thrombin generation, indicating that not all platelet functions remained intact. These findings provide additional insight into PAMAM dendrimer effects on blood components and underscore the necessity for further research on the effects and mechanisms of PAMAM-specific and general nanoparticle toxicity in blood.


Ethmoidal dural arteriovenous fistula with unusual drainage route treated by transarterial embolization.
Ethmoidal dural arteriovenous fistulas (AVFs) are rare intracranial lesions associated with a high risk of intracranial hemorrhage. In particular, this entity with reflux drainage directly into the ophthalmic vein is extremely rare. We report a case of ethmoidal dural AVF with direct drainage of the superior ophthalmic vein (SOV) and inferior ophthalmic vein (IOV), successfully treated by endovascular surgery. A 58-year-old man presented with progressive diplopia. Angiography and contrast-enhanced CT showed an ethmoidal dural AVF supplied via the bilateral anterior ethmoidal arteries and venous drainage through the left SOV and IOV. A transarterial approach through the bilateral anterior ethmoidal arteries was used to place the microcatheter close to the fistula site. After intra-arterial embolization with 20% N-butyl cyanoacrylate, the dural AVF was completely occluded. In patients with good vascular access, endovascular transarterial embolization may be an effective and less invasive treatment strategy for ethmoidal dural AVF.


Efficient Learning of Continuous-Time Hidden Markov Models for Disease Progression.
The Continuous-Time Hidden Markov Model (CT-HMM) is an attractive approach to modeling disease progression due to its ability to describe noisy observations arriving irregularly in time. However, the lack of an efficient parameter learning algorithm for CT-HMM restricts its use to very small models or requires unrealistic constraints on the state transitions. In this paper, we present the first complete characterization of efficient EM-based learning methods for CT-HMM models. We demonstrate that the learning problem consists of two challenges: the estimation of posterior state probabilities and the computation of end-state conditioned statistics. We solve the first challenge by reformulating the estimation problem in terms of an equivalent discrete time-inhomogeneous hidden Markov model. The second challenge is addressed by adapting three approaches from the continuous time Markov chain literature to the CT-HMM domain. We demonstrate the use of CT-HMMs with more than 100 states to visualize and predict disease progression using a glaucoma dataset and an Alzheimer's disease dataset.


Removal of the natural hormone estrone from aqueous solutions using nanofiltration and reverse osmosis.
The ability of a variety of nanofiltration and reverse osmosis membranes to retain the natural hormone estrone are examined here as a function of solution conditions. While size exclusion dominates retention with the tighter membranes, both size exclusion and adsorptive effects appear to be instrumental in maintaining high retention on nanofiltration membranes that otherwise exhibit relatively low ion retentions. These adsorptive effects may be driven by hydrogen bonding between estrone and the membrane. Electrostatic attraction appears to aid retention with an apparent slight decrease in retention at high NaCl concentrations. Deprotonation of estrone leads to a significant decrease in retention, most likely as a result of the effect of strong electrostatic repulsive forces decreasing the proximity of the negatively charged estrone to the negatively charged membrane surface and thus lowering the potential for adsorptive retention. This deprotonation effect is absent for tight RO membranes. The results reported here indicate that while open nanofiltration membranes may be effective in retaining estrone under some conditions, the extent of retention may be very susceptible to maintenance of adsorptive capacity at the membrane surface and depend on solution chemistry.


Transitive inference reasoning is impaired by focal lesions in parietal cortex rather than rostrolateral prefrontal cortex.
Transitive inference reasoning involves the examination and comparison of a given number of relational pairs in order to understand overall group hierarchy (e.g., A>B, B>C, C>D; therefore is A>D?). A number of imaging studies have demonstrated the role of the parietal cortex for resolving transitive inferences. Some studies also identify the rostrolateral prefrontal cortex as being critical for "relational integration" processes supporting transitive reasoning. To clarify this issue, we carried out a transitive inference study involving neurological patients with focal lesions to the rostrolateral prefrontal (n=5) or parietal cortices (n=7), as well as normal controls (n=6). The patients and controls were statistically matched on age, education, pre-injury IQ, general memory, working memory, and performance/full IQ, though the rostrolateral patients did score significantly higher than the normal controls on verbal IQ. Results indicate that patients with focal lesions to the parietal cortex were impaired in the task relative to both the patients with focal lesions to rostrolateral prefrontal cortex and the control group, and there was no difference in task performance between the rostrolateral prefrontal and the control groups. This result continued to hold after controlling for verbal IQ as a covariate. These findings point to a critical role for the parietal cortex, rather than the rostrolateral prefrontal, in transitive inference. Since the groups performed similarly on a working memory task, working memory cannot fully account for the result, suggesting a specific role of parietal cortex in transitive inference.


Working conditions in hospitals revisited: A moderated-mediated model of job context and presenteeism.
This study examines whether the relationship between the employees' perceived job autonomy may be prone to the contextual influence of supervisor support and presenteeism climate in explaining the attendance behaviors of presenteeism-the employees' decision to attend work despite being ill or not feeling well. Does work context play a role on presenteeism climate and the specific act of presenteeism? This study includes 213 health care employees (e.g., nurses, doctors) working in one private hospital in Lebanon. We used the ordinary least squared (OLS) regressions path analytical framework and bootstrapping methods to estimate the hypothesized moderated-mediation models. Our findings indicate that healthcare job resources (job autonomy) is correlated with the presenteeism climate and the occurrence of presenteeism attendance behaviors. We also found that this relationship is mediated by presenteeism climate and that supervisor support moderates the observed indirect relationship. This study extends the organizational attendance research domain to presenteeism climate by explaining for both doctors and nurses how contextual variables explains the relationship between jobs resources and presenteeism attendance behaviors. Supervisor support plays an important role in encouraging task autonomy and thus allowing employees increase their perception of empowerment to manage their actions at work. Overall, healthcare managers should ensure that employees understand their roles and duties and have an up-to-date, clearly defined role (e.g., job description) so that they can meet their organizations' goals.


Short- and long-term operation of the lutein-epoxide cycle in light-harvesting antenna complexes.
The lutein-5,6-epoxide (Lx) cycle operates in some plants between lutein (L) and its monoepoxide, Lx. Whereas recent studies have established the photoprotective roles of the analogous violaxanthin cycle, physiological functions of the Lx cycle are still unknown. In this article, we investigated the operation of the Lx cycle in light-harvesting antenna complexes (Lhcs) of Inga sapindoides Willd, a tropical tree legume accumulating substantial Lx in shade leaves, to identify the xanthophyll-binding sites involved in short- and long-term responses of the Lx cycle and to analyze the effects on light-harvesting efficiency. In shade leaves, Lx was converted into L upon light exposure, which then replaced Lx in the peripheral V1 site in trimeric Lhcs and the internal L2 site in both monomeric and trimeric Lhcs, leading to xanthophyll composition resembling sun-type Lhcs. Similar to the violaxanthin cycle, the Lx cycle was operating in both photosystems, yet the light-induced Lx --> L conversion was not reversible overnight. Interestingly, the experiments using recombinant Lhcb5 reconstituted with different Lx and/or L levels showed that reconstitution with Lx results in a significantly higher fluorescence yield due to higher energy transfer efficiencies among chlorophyll (Chl) a molecules, as well as from xanthophylls to Chl a. Furthermore, the spectroscopic analyses of photosystem I-LHCI from I. sapindoides revealed prominent red-most Chl forms, having the lowest energy level thus far reported for higher plants, along with reduced energy transfer efficiency from antenna pigments to Chl a. These results are discussed in the context of photoacclimation and shade adaptation.


Aspect ratio of elongated polychromatic far-field speckles of continuous and discrete spectral distribution with respect to surface roughness characterization.
Here polychromatic speckle patterns generated either by a polychromatic light source that emits at discrete frequencies or by a light source showing a continuous narrow-band spectral distribution are studied. The purpose here is the application of polychromatic speckle-pattern analysis to an in-process surface roughness characterization. To compare the coherence properties of the different polychromatic light sources, first a modified definition of the coherence length is introduced. Furthermore, the relevant optical phenomena, namely, the speckle elongation caused by the angular dispersion and the roughness-dependent speckle decorrelation, are summarized. It is shown that light sources with a continuous spectral distribution have essential advantages in comparison with discrete wavelength sources. The theoretical results are confirmed by experimental investigations based on a digital algorithm for the evaluation of CCD images of polychromatic speckle patterns, which are recorded in the Fourier plane of a Fourier-transforming lens.


Introducing case management for people with dementia in primary care: a mixed-methods study.
Case management may be a feasible solution to the problem of service fragmentation for people with dementia. To adapt a US model of primary care-based case management for people with dementia and test it in general practice. Mixed-methodology case studies of case management implementation in four general practices: one rural, one inner-city, and two urban practices. Practice nurses undertook the case manager role in the rural and inner-city practices, and were allocated one session per week for case management by their practices. A seconded social worker worked full time for the two urban practices. Participants were community-dwelling patients with dementia who were living at home with a family carer, and who were not receiving specialist care coordination. Case study methods included analysis of case loads and interviews with patients, carers, local NHS and other stakeholders, and case managers. Measures included numbers of patients with dementia and their carers, number of unmet needs identified, and actions taken to meet needs. Case manager records were compared with findings from interviews with patients and carers, and with other stakeholders. The number of eligible patients was smaller than expected. No practice achieved its recruitment target. Researchers identified more unmet needs than case managers. The practice nurse case managers reported lack of time and found research documentation burdensome. Patients and carers were positive about case management as a first point of contact with the practice, as a 'safety net', and for creating a one-to-one therapeutic relationship. Further investigation is required before case management for people with dementia and their carers can be implemented in primary care.


HERPESVIRUSES INCLUDING NOVEL GAMMAHERPESVIRUSES ARE WIDESPREAD AMONG PHOCID SEAL SPECIES IN CANADA.
Little is known about herpesviruses in Canadian pinnipeds. We measured prevalence of antibodies to herpesviruses in the sera from Canadian phocid seals by an indirect enzyme-linked immunosorbent assay. Wild harbor seals (Phoca vitulina) and captive harbor seals were positive for antibodies to Phocid herpesvirus 1 (PhoHV-1) at prevalences of 91% and 100%, respectively. Sera from wild hooded seals (Cystophora cristata), harp seals (Pagophilus groenlandica), and grey seals (Halichoerus grypus) were positive for antibodies to PhoHV-1 antigenically related herpesvirus antigens at 73%, 79%, and 96%, respectively. We isolated new herpesviruses in cell culture from two hunter-harvested ringed seals (Pusa hispida) in poor body condition from Ulukhaktok, Northwest Territories, Canada; one lethargic hooded seal from the St. Lawrence Estuary, Québec, Canada; and one captive, asymptomatic harp seal from the Magdalen Islands, Québec. Partial sequencing of the herpesvirus DNA polymerase gene revealed that all four virus isolates were closely related to PhoHV-2, a member of the Gammaherpesvirinae subfamily, with nucleotide similarity ranging between 92.8% and 95.3%. The new seal herpesviruses were genetically related to other known pinniped herpesviruses, such as PhoHV-1, Otariid herpesvirus 3, Hawaiian monk (Monachus schauinslandi) seal herpesvirus, and Phocid herpesvirus 5 with 47-48%, 55%, 77%, and 70-77% nucleotide similarities, respectively. The harp seal herpesvirus and both ringed seal herpesviruses were almost identical to each other, whereas the hooded seal herpesvirus was genetically different from the three others (92.8% nucleotide similarity), indicating detection of at least two novel seal herpesviruses. These findings are the first isolation, partial genome sequencing, and identification of seal gammaherpesviruses in three species of Canadian phocid seals; two species of which were suspected of exposure to one or more antigenically related herpesviruses based on serologic analyses.


Cell death following BNCT: a theoretical approach based on Monte Carlo simulations.
In parallel to boron measurements and animal studies, investigations on radiation-induced cell death are also in progress in Pavia, with the aim of better characterisation of the effects of a BNCT treatment down to the cellular level. Such studies are being carried out not only experimentally but also theoretically, based on a mechanistic model and a Monte Carlo code. Such model assumes that: (1) only clustered DNA strand breaks can lead to chromosome aberrations; (2) only chromosome fragments within a certain threshold distance can undergo misrejoining; (3) the so-called "lethal aberrations" (dicentrics, rings and large deletions) lead to cell death. After applying the model to normal cells exposed to monochromatic fields of different radiation types, the irradiation section of the code was purposely extended to mimic the cell exposure to a mixed radiation field produced by the (10)B(n,α) (7)Li reaction, which gives rise to alpha particles and Li ions of short range and high biological effectiveness, and by the (14)N(n,p)(14)C reaction, which produces 0.58 MeV protons. Very good agreement between model predictions and literature data was found for human and animal cells exposed to X- or gamma-rays, protons and alpha particles, thus allowing to validate the model for cell death induced by monochromatic radiation fields. The model predictions showed good agreement also with experimental data obtained by our group exposing DHD cells to thermal neutrons in the TRIGA Mark II reactor of the University of Pavia; this allowed to validate the model also for a BNCT exposure scenario, providing a useful predictive tool to bridge the gap between irradiation and cell death.


The cholinergic basal forebrain in the ferret and its inputs to the auditory cortex.
Cholinergic inputs to the auditory cortex can modulate sensory processing and regulate stimulus-specific plasticity according to the behavioural state of the subject. In order to understand how acetylcholine achieves this, it is essential to elucidate the circuitry by which cholinergic inputs influence the cortex. In this study, we described the distribution of cholinergic neurons in the basal forebrain and their inputs to the auditory cortex of the ferret, a species used increasingly in studies of auditory learning and plasticity. Cholinergic neurons in the basal forebrain, visualized by choline acetyltransferase and p75 neurotrophin receptor immunocytochemistry, were distributed through the medial septum, diagonal band of Broca, and nucleus basalis magnocellularis. Epipial tracer deposits and injections of the immunotoxin ME20.4-SAP (monoclonal antibody specific for the p75 neurotrophin receptor conjugated to saporin) in the auditory cortex showed that cholinergic inputs originate almost exclusively in the ipsilateral nucleus basalis. Moreover, tracer injections in the nucleus basalis revealed a pattern of labelled fibres and terminal fields that resembled acetylcholinesterase fibre staining in the auditory cortex, with the heaviest labelling in layers II/III and in the infragranular layers. Labelled fibres with small en-passant varicosities and simple terminal swellings were observed throughout all auditory cortical regions. The widespread distribution of cholinergic inputs from the nucleus basalis to both primary and higher level areas of the auditory cortex suggests that acetylcholine is likely to be involved in modulating many aspects of auditory processing.


Modulation of the proteoglycan receptor PTPσ promotes recovery after spinal cord injury.
Contusive spinal cord injury leads to a variety of disabilities owing to limited neuronal regeneration and functional plasticity. It is well established that an upregulation of glial-derived chondroitin sulphate proteoglycans (CSPGs) within the glial scar and perineuronal net creates a barrier to axonal regrowth and sprouting. Protein tyrosine phosphatase σ (PTPσ), along with its sister phosphatase leukocyte common antigen-related (LAR) and the nogo receptors 1 and 3 (NgR), have recently been identified as receptors for the inhibitory glycosylated side chains of CSPGs. Here we find in rats that PTPσ has a critical role in converting growth cones into a dystrophic state by tightly stabilizing them within CSPG-rich substrates. We generated a membrane-permeable peptide mimetic of the PTPσ wedge domain that binds to PTPσ and relieves CSPG-mediated inhibition. Systemic delivery of this peptide over weeks restored substantial serotonergic innervation to the spinal cord below the level of injury and facilitated functional recovery of both locomotor and urinary systems. Our results add a new layer of understanding to the critical role of PTPσ in mediating the growth-inhibited state of neurons due to CSPGs within the injured adult spinal cord.


Establishment of a camptothecin analogue (CPT-11)-resistant cell line of human non-small cell lung cancer: characterization and mechanism of resistance.
Camptothecin-11 (CPT-11) is a new derivative of camptothecin, a plant alkaloid antitumor agent, and a good candidate for clinical trials because of higher antitumor activity, less toxicity, and high aqueous solubility. CPT-11 is known to be altered into an active form, SN-38, by esterase in in vivo. CPT-11-resistant cells (PC-7/CPT) established from a human non-small cell lung cancer cell (PC-7) by stepwise, continuous treatment with CPT-11 exhibit about a 10-fold increase in resistance to the drug. CPT-11-resistant cells show a moderate cross-resistance to camptothecin (x8.6) and SN-38 (x8.6), and weak cross-resistance to Adriamycin (x2.2) and 5-fluorouracil (x2.4). The comparative studies between the parent (PC-7) and resistant (PC-7/CPT) cell lines with respect to their growth characterization shows a longer cell doubling time (45.8 versus 35.5 h), a lower cloning efficiency (3.2 versus 7.1%), and a lower population of S-phase cells (26.4 versus 36.0%) in the CPT-11-resistant cells. This observation may partly explain the resistance to CPT-11, a drug whose activity is cell cycle specific. Accumulation of CPT-11 is nearly the same in both cell lines. However, the intracellular concentration of SN-38 formed in the parent cells was 2-fold greater than in the CPT-11-resistant cells. This alteration may affect to some extent to the resistance. As assayed by relaxation of supercoiled plasmid DNA, the total activity of DNA topoisomerase I from the CPT-11-resistant cells was shown to be reduced to one-fourth its level in sensitive cells. The reduced activity was caused by a reduction of amount of DNA topoisomerase I. Furthermore, the enzyme from the resistant cells was shown to be 5-fold more resistant to CPT-11 than the enzyme from the parent cells. Thus, decreased total activity of topoisomerase I may play an important role in cellular resistance to CPT-11, and it appears that this decreased activity is due to a resistant form of topoisomerase I in CPT-11 resistant cells.


Sharing real-world experiences to optimize the management of olaparib toxicities: a practical guidance from an Italian expert panel.
Olaparib is the first poly(ADP-ribose) polymerase inhibitor approved as maintenance therapy of recurrent ovarian cancer (OC) patients with a BRCA mutation. To achieve the maximum clinical benefit, adherence to olaparib must be persistent. However, in clinical practice, this is challenged by the frequent suboptimal management of toxicities. In view of the expanding use of olaparib also in Italy, physicians must learn how to adequately and promptly manage drug toxicities not to unnecessarily interrupt or reduce the dose. The experts agreed that nausea,vomiting, anemia, and fatigue are the most frequent events experienced by OC patients on olaparib, and that these toxicities usually develop early during treatment, are mainly of grade 1-2 and transient and can be managed with simple non-pharmacological interventions. By sharing their real-world experiences, the panel prepared, for each toxicity, an algorithm organized by grade and besides the procedures indicated in the local label, included supportive care interventions based also on nutritional and lifestyle modifications and psycho-oncology consultation. Moreover, in view of the tablet entry into the Italian market, the full and reduced dosages of capsules and tablets were compared. This practical guidance is intended to be a tool to support especially less-experienced physicians in the management of these complex patients, with the aim to help preventing the worsening of patients' conditions and the unnecessary interruption/reduction of olaparib dosage, which may jeopardize treatment efficacy.


Stochastic Thermodynamics of Oscillators' Networks.
We apply the stochastic thermodynamics formalism to describe the dynamics of systems of complex Langevin and Fokker-Planck equations. We provide in particular a simple and general recipe to calculate thermodynamical currents, dissipated and propagating heat for networks of nonlinear oscillators. By using the Hodge decomposition of thermodynamical forces and fluxes, we derive a formula for entropy production that generalises the notion of non-potential forces and makes transparent the breaking of detailed balance and of time reversal symmetry for states arbitrarily far from equilibrium. Our formalism is then applied to describe the off-equilibrium thermodynamics of a few examples, notably a continuum ferromagnet, a network of classical spin-oscillators and the Frenkel-Kontorova model of nano friction.


Health promotion in the digital era: a critical commentary.
A range of digitized health promotion practices have emerged in the digital era. Some of these practices are voluntarily undertaken by people who are interested in improving their health and fitness, but many others are employed in the interests of organizations and agencies. This article provides a critical commentary on digitized health promotion. I begin with an overview of the types of digital technologies that are used for health promotion, and follow this with a discussion of the socio-political implications of such use. It is contended that many digitized health promotion strategies focus on individual responsibility for health and fail to recognize the social, cultural and political dimensions of digital technology use. The increasing blurring between voluntary health promotion practices, professional health promotion, government and corporate strategies requires acknowledgement, as does the increasing power wielded by digital media corporations over digital technologies and the data they generate. These issues provoke questions for health promotion as a practice and field of research that hitherto have been little addressed.


Castor oil for induction of labour: not harmful, not helpful.
Castor oil is one of the most popular drugs for induction of labour in a non-medical setting; however, published data on safety and effectiveness of this compound to induce labour remain sparse. To assess the safety and effectiveness of castor oil for induction of labour in pregnancies with an ultrasound estimated gestational at birth of more than 40 weeks. Data were extracted from hospital-based records of all pregnant women who attended antenatal clinics on the Thai-Burmese border and who were more than 40 weeks pregnant. The effectiveness of castor oil to induce labour was expressed as time to birth and analysed with a Cox proportional hazards regression model. Measures associated with safety were fetal distress, meconium-stained amniotic fluid, tachysystole of the uterus, uterine rupture, abnormal maternal blood pressure during labour, Apgar scores, neonatal resuscitation, stillbirth, post-partum haemorrhage, severe diarrhoea and maternal death. Proportions were compared using Fisher's exact test. Of 612 women with a gestation of more than 40 weeks, 205 received castor oil for induction and 407 did not. The time to birth was not significantly different between the two groups (hazard ratio 0.99 (95% confidence interval: 0.81 to 1.20; n = 509)). Castor oil use was not associated with any harmful effects on the mother or fetus. Castor oil for induction of labour had no effect on time to birth nor were there any harmful effects observed in this large series. Our findings leave no justification for recommending castor oil for this purpose.


Neural encoding of sensory and behavioral complexity in the auditory cortex.
Converging evidence now supports the idea that auditory cortex is an important step for the emergence of auditory percepts. Recent studies have extended the list of complex, nonlinear sound features coded by cortical neurons. Moreover, we are beginning to uncover general properties of cortical representations, such as invariance and discreteness, which reflect the structure of auditory perception. Complexity, however, emerges not only through nonlinear shaping of auditory information into perceptual bricks. Behavioral context and task-related information strongly influence cortical encoding of sounds via ascending neuromodulation and descending top-down frontal control. These effects appear to be mediated through local inhibitory networks. Thus, auditory cortex can be seen as a hub linking structured sensory representations with behavioral variables.


SIAM (Suicide intervention assisted by messages): the development of a post-acute crisis text messaging outreach for suicide prevention.
Suicidal behaviour and deliberate self-harm are common among adults. Research indicates that maintaining contact either via letter or postcard with at-risk adults following discharge from care services can reduce reattempt risk. Feasibility trials demonstrated that intervention through text message was also effective in preventing suicide repetition amongst suicide attempters. The aim of the current study is to investigate the effect of text message intervention versus traditional treatment on reducing the risk of suicide attempt repetition among adults after self-harm. The study will be a 2-year multicentric randomized controlled trial conducted by the Brest University Hospital, France. Participants will be adults discharged after self-harm, from emergency services or after a short hospitalization. Participants will be recruited over a 12-month period. The intervention is comprised of an SMS that will be sent at h48, D7, D15 and monthly. The text message enquires about the patients' well-being and includes information regarding individual sources of help and evidence-based self help strategies. Participants will be assessed at the baseline, month 6 and 13. As primary endpoint, we will assess the number of patients who reattempt suicide in each group at 6 months. As secondary endpoints, we will assess the number of patients who reattempt suicide at 13 month, the number of suicide attempts in the intervention and control groups at 6 and 13 month, the number of death by suicide in the intervention and control groups at month 6 and 13. In both groups, suicidal ideations, will be assessed at the baseline, month 6 and 13. Medical costs and satisfaction will be assessed at month 13. This paper describes the design and deployment of a trial SIAM; an easily reproducible intervention that aims to reduce suicide risk in adults after self-harm. It utilizes several characteristics of interventions that have shown a significant reduction in the number of suicide reattempts. We propose to assess its efficacy in reducing suicide reattempt in the suicide attempter (SA) population. The study was registered on Clinical Trials Registry (clinicaltrials.gov): NCT02106949, registered on 06 June 2014.


MTO1 mutations are associated with hypertrophic cardiomyopathy and lactic acidosis and cause respiratory chain deficiency in humans and yeast.
We report three families presenting with hypertrophic cardiomyopathy, lactic acidosis, and multiple defects of mitochondrial respiratory chain (MRC) activities. By direct sequencing of the candidate gene MTO1, encoding the mitochondrial-tRNA modifier 1, or whole exome sequencing analysis, we identified novel missense mutations. All MTO1 mutations were predicted to be deleterious on MTO1 function. Their pathogenic role was experimentally validated in a recombinant yeast model, by assessing oxidative growth, respiratory activity, mitochondrial protein synthesis, and complex IV activity. In one case, we also demonstrated that expression of wt MTO1 could rescue the respiratory defect in mutant fibroblasts. The severity of the yeast respiratory phenotypes partly correlated with the different clinical presentations observed in MTO1 mutant patients, although the clinical outcome was highly variable in patients with the same mutation and seemed also to depend on timely start of pharmacological treatment, centered on the control of lactic acidosis by dichloroacetate. Our results indicate that MTO1 mutations are commonly associated with a presentation of hypertrophic cardiomyopathy, lactic acidosis, and MRC deficiency, and that ad hoc recombinant yeast models represent a useful system to test the pathogenic potential of uncommon variants, and provide insight into their effects on the expression of a biochemical phenotype.


Study protocol: a randomized controlled trial of a computer-based depression and substance abuse intervention for people attending residential substance abuse treatment.
A large proportion of people attending residential alcohol and other substance abuse treatment have a co-occurring mental illness. Empirical evidence suggests that it is important to treat both the substance abuse problem and co-occurring mental illness concurrently and in an integrated fashion. However, the majority of residential alcohol and other substance abuse services do not address mental illness in a systematic way. It is likely that computer delivered interventions could improve the ability of substance abuse services to address co-occurring mental illness. This protocol describes a study in which we will assess the effectiveness of adding a computer delivered depression and substance abuse intervention for people who are attending residential alcohol and other substance abuse treatment. Participants will be recruited from residential rehabilitation programs operated by the Australian Salvation Army. All participants who satisfy the diagnostic criteria for an alcohol or other substance dependence disorder will be asked to participate in the study. After completion of a baseline assessment, participants will be randomly assigned to either a computer delivered substance abuse and depression intervention (treatment condition) or to a computer-delivered typing tutorial (active control condition). All participants will continue to complete The Salvation Army residential program, a predominantly 12-step based treatment facility. Randomisation will be stratified by gender (Male, Female), length of time the participant has been in the program at the commencement of the study (4 weeks or less, 4 weeks or more), and use of anti-depressant medication (currently prescribed medication, not prescribed medication). Participants in both conditions will complete computer sessions twice per week, over a five-week period. Research staff blind to treatment allocation will complete the assessments at baseline, and then 3, 6, 9, and 12 months post intervention. Participants will also complete weekly self-report measures during the treatment period. This study will provide comprehensive data on the effect of introducing a computer delivered, cognitive behavioral therapy based co-morbidity treatment program within a residential substance abuse setting. If shown to be effective, this intervention can be disseminated within other residential substance abuse programs. Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12611000618954.


Hemodynamic characterization of geometric cerebral aneurysm templates.
Hemodynamics are currently considered to a lesser degree than geometry in clinical practices for evaluating cerebral aneurysm (CA) risk and planning CA treatment. This study establishes fundamental relationships between three clinically recognized CA geometric factors and four clinically relevant hemodynamic responses. The goal of the study is to develop a more combined geometric/hemodynamic basis for informing clinical decisions. Flows within eight idealized template geometries were simulated using computational fluid dynamics and measured using particle image velocimetry under both steady and pulsatile flow conditions. The geometric factor main effects were then analyzed to quantify contributions made by the geometric factors (aneurysmal dome size (DS), dome-to-neck ratio (DNR), and parent-vessel contact angle (PV-CA)) to effects on the hemodynamic responses (aneurysmal and neck-plane root-mean-square velocity magnitude (Vrms), aneurysmal wall shear stress (WSS), and cross-neck flow (CNF)). Two anatomical aneurysm models were also examined to investigate how well the idealized findings would translate to more realistic CA geometries. DNR made the greatest contributions to effects on hemodynamics including a 75.05% contribution to aneurysmal Vrms and greater than 35% contributions to all responses. DS made the next greatest contributions, including a 43.94% contribution to CNF and greater than 20% contributions to all responses. PV-CA and several factor interactions also made contributions of greater than 10%. The anatomical aneurysm models and the most similar idealized templates demonstrated consistent hemodynamic response patterns. This study demonstrates how individual geometric factors, and combinations thereof, influence CA hemodynamics. Bridging the gap between geometry and flow in this quantitative yet practical way may have potential to improve CA evaluation and treatment criteria. Agreement among results from idealized and anatomical models further supports the potential for a template-based approach to play a useful role in clinical practice.


Population pharmacokinetics of dolutegravir: influence of drug-drug interactions in a real-life setting.
Dolutegravir is widely prescribed owing to its potent antiviral activity, high genetic barrier and good tolerability. The aim of this study was to characterize dolutegravir's pharmacokinetic profile and variability in a real-life setting and to identify individual factors and co-medications affecting dolutegravir disposition. A population pharmacokinetic model was developed using NONMEM®. Relevant demographic factors, clinical factors and co-medications were tested as potential covariates. Simulations based on the final model served to compare expected dolutegravir concentrations under standard and alternative dosage regimens in the case of drug-drug interactions. A total of 620 dolutegravir plasma concentrations were collected from 521 HIV-infected individuals under steady-state conditions. A one-compartment model with first-order absorption and elimination best characterized dolutegravir pharmacokinetics. Typical dolutegravir apparent clearance (CL/F) was 0.93 L/h with 32% between-subject variability, the apparent volume of distribution was 20.2 L and the absorption rate constant was fixed to 2.24 h-1. Older age, higher body weight and current smoking were associated with higher CL/F. Atazanavir co-administration decreased dolutegravir CL/F by 38%, while darunavir modestly increased CL/F by 14%. Rifampicin co-administration showed the largest impact on CL/F. Simulations suggest that average dolutegravir trough concentrations are 63% lower after 50 mg/12h with rifampicin compared with a standard dosage of 50 mg/24h without rifampicin. Average trough concentrations after 100 mg/24h and 100 mg/12h with rifampicin are 92% and 25% lower than the standard dosage without rifampicin, respectively. Patients co-treated with dolutegravir and rifampicin might benefit from therapeutic drug monitoring and individualized dosage increase, up to 100 mg/12 h in some cases.


Antidiabetic, antihyperlipidemic and antioxidant activities of a novel proteoglycan from ganoderma lucidum fruiting bodies on db/db mice and the possible mechanism.
Previously, we screened a proteoglycan for anti-hyperglycemic, named FYGL, from Ganoderma Lucidum. For further research of the antidiabetic mechanisms of FYGL in vivo, the glucose homeostasis, activities of insulin-sensitive enzymes, glucose transporter expression and pancreatic function were analyzed using db/db mice as diabetic models in the present work. FYGL not only lead to a reduction in glycated hemoglobin level, but also an increase in insulin and C-peptide level, whereas a decrease in glucagons level and showed a potential for the remediation of pancreatic islets. FYGL also increased the glucokinase activities, and simultaneously lowered the phosphoenol pyruvate carboxykinase activities, accompanied by a reduction in the expression of hepatic glucose transporter protein 2, while the expression of adipose and skeletal glucose transporter protein 4 was increased. Moreover, the antioxidant enzyme activities were also increased by FYGL treatment. Thus, FYGL was an effective antidiabetic agent by enhancing insulin secretion and decreasing hepatic glucose output along with increase of adipose and skeletal muscle glucose disposal in the late stage of diabetes. Furthermore, FYGL is beneficial against oxidative stress, thereby being helpful in preventing the diabetic complications.


From Entry to Practice to Advanced Nurse Practitioner - The Progression of Competencies and How They Assist in Delivery of eHealth Programs for Healthy Ageing.
Most of the health issues encountered in persons of older age are the result of one or more chronic diseases. The evidence base reports that chronic diseases can be prevented or delayed by engaging in healthy behaviors. Education provides a cost effective intervention on both economic grounds in addition to delivery of optimal patient outcomes. Information and Communication Technology (ICT) increasingly is viewed as a critical utility in eHealth delivery, providing scope for expanding online education facilities for older persons. Developing nursing competencies in the delivery of eHealth solutions to deliver user education programs therefore makes sense. This chapter discusses nursing competencies on the development of targeted eHealth programs for healthy ageing. The role of Advanced Nurse Practitioner in Ireland and its associated competency set identifies how a strong action learning model can be designed to deliver eHealth educational programs for effective delivery of healthy ageing in place.