Unmet informational and supportive care needs of patients with muscle invasive bladder cancer: A systematic review of the evidence.

BACKGROUND: Little is known about the unmet supportive care needs of patients affected by muscle invasive bladder cancer (MIBC). We set out to determine the different domains of unmet supportive care needs for patients affected by MIBC. LITERATURE SEARCH: A systematic review was conducted according to the PRISMA Statement Guidelines. A sensitive search was performed in electronic databases (DARE, Cochrane, MEDLINE, BNI, PsychINFO, EMBASE and CIHAHL) from the earliest date available to January 2017. DATA EVALUATION: 1405 references were retrieved, 8 articles met the eligibility criteria and were appraised and ranked by strength using the levels of evidence. SYNTHESIS: Individual unmet needs were classified into the following domains: patient-clinician communication, daily living needs, health system/information needs, practical needs, family-related needs, social needs, psychological needs, physical needs and intimacy needs. Patients reported high unmet needs at diagnosis and into survivorship. CONCLUSIONS: This review contributes to a greater understanding of the unmet supportive care needs of patients affected by MIBC. Findings reflect a paucity of research, but existing studies indicated needs commonly related to intimacy, informational, physical and psychological needs. Despite the emerging evidence-base, the current within study limitations precludes our understanding about how the needs of patients evolve over time.

Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans.

Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive 11 C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates the application of novel imaging techniques to investigate pharmacogenetic properties in humans.

The Convective Transport of Active Species in the Tropics (CONTRAST) Experiment.

The Convective Transport of Active Species in the Tropics (CONTRAST) experiment was conducted from Guam (13.5° N, 144.8° E) during January-February 2014. Using the NSF/NCAR Gulfstream V research aircraft, the experiment investigated the photochemical environment over the tropical western Pacific (TWP) warm pool, a region of massive deep convection and the major pathway for air to enter the stratosphere during Northern Hemisphere (NH) winter. The new observations provide a wealth of information for quantifying the influence of convection on the vertical distributions of active species. The airborne in situ measurements up to 15 km altitude fill a significant gap by characterizing the abundance and altitude variation of a wide suite of trace gases. These measurements, together with observations of dynamical and microphysical parameters, provide significant new data for constraining and evaluating global chemistry climate models. Measurements include precursor and product gas species of reactive halogen compounds that impact ozone in the upper troposphere/lower stratosphere. High accuracy, in-situ measurements of ozone obtained during CONTRAST quantify ozone concentration profiles in the UT, where previous observations from balloon-borne ozonesondes were often near or below the limit of detection. CONTRAST was one of the three coordinated experiments to observe the TWP during January-February 2014. Together, CONTRAST, ATTREX and CAST, using complementary capabilities of the three aircraft platforms as well as ground-based instrumentation, provide a comprehensive quantification of the regional distribution and vertical structure of natural and pollutant trace gases in the TWP during NH winter, from the oceanic boundary to the lower stratosphere.

Fast diffusion kurtosis imaging of fibrotic mouse kidneys.

Diffusion kurtosis imaging (DKI) is sensitive to tissue microstructure and may therefore be useful in the diagnosis and monitoring of disease in brain and body organs. Generally, diffusion magnetic resonance imaging (dMRI) in the body is challenging because of the heterogeneous body composition, which can cause image artefacts as a result of chemical shifts and susceptibility differences. In addition, the abdomen possesses physiological factors (e.g. breathing, heartbeat, blood flow) which may severely reduce image quality, especially when echo planar imaging is employed, as is typical in dMRI. Collectively, these challenging measurement conditions impede the use and exploration of DKI in the body. This impediment is further exacerbated by the traditionally large amount of data required for DKI and the low signal-to-noise ratio at the b-values needed to effectively probe the kurtosis regime. Recently introduced fast DKI techniques reduce the challenge of DKI in the body by decreasing the data requirement substantially, so that, for example, triggering and breath-hold techniques may be applied for the entire DKI acquisition without causing unfeasible scan times. One common pathological condition for which body DKI may be of immediate clinical value is kidney fibrosis, which causes progressive changes in organ microstructure. With its sensitivity to microstructure, DKI is an obvious candidate for a non-invasive evaluation method. We present preclinical evidence indicating that the rapidly obtainable tensor-derived mean kurtosis ( W̅) distinguishes moderately fibrotic kidneys from healthy controls. The presence and degree of fibrosis are confirmed by histology, which also indicates fibrosis as the main driver behind the DKI differences observed between groups. We therefore conclude that fast kurtosis is a likely candidate for an MRI-based method for the detection and monitoring of renal fibrosis. We provide protocol recommendations for fast renal DKI in humans based on a b-value optimisation performed using data acquired at 3 T in normal human kidney.

Skeletal phenotypes in adult patients with osteogenesis imperfecta-correlations with COL1A1/COL1A2 genotype and collagen structure.

Osteogenesis imperfecta (OI) is characterized by a high fracture rate and great heterogeneity. This cross-sectional study presents skeletal investigations and protein analyses in 85 adult OI patients. We find significant differences in bone mass, architecture, and fracture rate that correlate well with the underlying biochemical and molecular abnormalities. INTRODUCTION: OI is a hereditary disease characterized by compromised connective tissue predominantly caused by mutations in collagen type 1 (COL-1) encoding genes. Widespread symptoms reflect the ubiquity of COL-1 throughout the body. The purpose of this study was to improve our understanding of clinical manifestations by investigating anthropometry and skeletal phenotypes (DXA, HRpQCT) in an adult OI population and compare the findings to underlying COL-1 genotype and structure. METHODS: The study comprised 85 OI patients aged 45 (19-78) years, Sillence type I (n = 58), III (n = 12), and IV (n = 15). All patients underwent DXA, HRpQCT, spine X-ray, biochemical testing, and anthropometry. COL1A1 and COL1A2 were sequenced and 68 OI causing mutations identified (46 in COL1A1, 22 in COL1A2). Analysis of COL-1 structure (quantitative/qualitative defect) by SDS-PAGE was performed in a subset (n = 67). RESULTS: A qualitative collagen defect predisposed to a more severe phenotype with reduced aBMD, more fractures, and affected anthropometry compared to patients with a quantitative COL-1 defect (p < 0.05). HRpQCT revealed significant differences between patients with OI type I and IV. Patients with type I had lower vBMD (p < 0.005), thinner cortexes (p < 0.001), and reduced trabecular number (p < 0.005) compared to patients with type IV indicating that HRpQCT may distinguish type I from type IV better than DXA. CONCLUSION: The defective collagen in patients with OI has pronounced effects on the skeleton. The classical OI types based on the clinical classification show profound differences in bone mass and architecture and the differences correlate well with the underlying biochemical and molecular collagen abnormalities.

Epiphytic bacterial communities of the alga Fucus vesiculosus in oil-contaminated water areas of the Barents Sea.

Taxonomic compositions of epiphytic bacterial communities in water areas differing in levels of oil pollution were revealed. In total, 82 bacterial genera belonging to 16 classes and 11 phyla were detected. All detected representatives of epiphytic bacterial communities belonged to the phyla Actinobacteria, Bacteroidetes, Planctomycetes, Proteobacteria, Verrucomicrobia, Acidobacteria, Cyanobacteria, Firmicutes, and Fusobacteria and candidate division TM7. The ratio of the phyla in the communities varied depending on the levels of oil pollution. New data on taxonomic composition of uncultivated epiphytic bacterial communities of Fucus vesiculosus were obtained.

A mathematical model approach quantifying patients' response to changes in mechanical ventilation: Evaluation in pressure support.

PURPOSE: This article evaluates how mathematical models of gas exchange, blood acid-base status, chemical respiratory drive, and muscle function can describe the respiratory response of spontaneously breathing patients to different levels of pressure support. METHODS: The models were evaluated with data from 12 patients ventilated in pressure support ventilation. Models were tuned with clinical data (arterial blood gas measurement, ventilation, and respiratory gas fractions of O2 and CO2) to describe each patient at the clinical level of pressure support. Patients were ventilated up to 5 different pressure support levels, for 15 minutes at each level to achieve steady-state conditions. Model-simulated values of respiratory frequency (fR), arterial pH (pHa), and end-tidal CO2 (FeCO2) were compared to measured values at each pressure support level. RESULTS: Model simulations compared well to measured data with Bland-Altman bias and limits of agreement of fR of 0.7 ± 2.2 per minute, pHa of -0.0007 ± 0.019, and FeCO2 of -0.001 ± 0.003. CONCLUSION: The models describe patients' fR, pHa, and FeCO2 response to changes in pressure support with low bias and narrow limits of agreement.

Evaluating sexual function in women after radical cystectomy as treatment for bladder cancer.

OBJECTIVE: Sexual function remains a relatively unexplored field within urology, especially for female patients who have undergone radical cystectomy (RC). The aim of this study was to shed light on this area. MATERIALS AND METHODS: The Female Sexual Function Index (FSFI) questionnaire and other selective questions regarding sexual function were sent to 71 women who had undergone RC and were alive 1 year postsurgery. Forty-one completed questionnaires were returned and analysed using simple descriptive statistical analysis, owing to the small sample size. RESULTS: The median age of the patients was 67 years (range 39-91 years). Seventy-eight per cent reported being sexually active before surgery and 37% post-surgery. The median FSFI score postsurgery was 4.8 (range 1.2-32). The highest FSFI score was seen in the category of satisfaction, which consists of questions regarding closeness with partner, sexual relationship and overall sex life. Lowest FSFI scores were seen for lubrication, orgasm and pain. Twenty-seven per cent of patients wanted more information on the impact RC would have on their sex lives and many asked for information for their partners. CONCLUSION: Despite being based on a limited number of patients, this study indicates a need for improvement within this field. Most patients scored below 26 on the FSFI questionnaire, the cut-off for sexual dysfunction. However, many reported being satisfied overall. Thus, the physician's main goal is to identify patients in need of more information and guidance before and after surgery.

A mathematical model approach quantifying patients' response to changes in mechanical ventilation: evaluation in volume support.

This paper presents a mathematical model-approach to describe and quantify patient-response to changes in ventilator support. The approach accounts for changes in metabolism (V̇O2, V̇CO2) and serial dead space (VD), and integrates six physiological models of: pulmonary gas-exchange; acid-base chemistry of blood, and cerebrospinal fluid; chemoreflex respiratory-drive; ventilation; and degree of patients' respiratory muscle-response. The approach was evaluated with data from 12 patients on volume support ventilation mode. The models were tuned to baseline measurements of respiratory gases, ventilation, arterial acid-base status, and metabolism. Clinical measurements and model simulated values were compared at five ventilator support levels. The models were shown to adequately describe data in all patients (χ(2), p > 0.2) accounting for changes in V̇CO2, VD and inadequate respiratory muscle-response. F-ratio tests showed that this approach provides a significantly better (p < 0.001) description of measured data than: (a) a similar model omitting the degree of respiratory muscle-response; and (b) a model of constant alveolar ventilation. The approach may help predict patients' response to changes in ventilator support at the bedside.

Next-generation sequencing identifies germline MRE11A variants as markers of radiotherapy outcomes in muscle-invasive bladder cancer.

BACKGROUND: Muscle-invasive bladder cancer (MIBC) can be cured by radical radiotherapy (RT). We previously found tumour MRE11 expression to be predictive of survival following RT in MIBC, and this was independently validated in a separate institute. Here, we investigated germline MRE11A variants as possible predictors of RT outcomes in MIBC, using next-generation sequencing (NGS). PATIENTS AND METHODS: The MRE11A gene was amplified in germline DNA from 186 prospectively recruited MIBC patients treated with RT and sequenced using bar-coded multiplexed NGS. Germline variants were analysed for associations with cancer-specific survival (CSS). For validation as a prognostic or predictive marker, rs1805363 was then genotyped in a cystectomy-treated MIBC cohort of 256 individuals. MRE11A mRNA isoform expression was measured in bladder cancer cell lines and primary tumour samples. RESULTS: Carriage of at least one of six (five novel) rare variants was associated with the worse RT outcome (hazard ratio [HR] 4.04, 95% confidence interval [95% CI] 1.42-11.51, P = 0.009). The single-nucleotide polymorphism (SNP), rs1805363 (minor allele frequency 11%), was also associated with worse CSS (per-allele HR 2.10, 95% CI 1.34-3.28, Ptrend = 0.001) following RT in MIBC, with a gene-dosage effect observed, but no effect seen on CSS in the cystectomy cohort (Ptrend = 0.89). Furthermore, rs1805363 influenced relative MRE11A isoform expression, with increased isoform 2 expression with carriage of the rs1805363 minor A allele. CONCLUSIONS: Germline MRE11A SNP rs1805363 was predictive of RT, but not of cystectomy outcome in MIBC. If successfully validated in an independent RT-treated cohort, this SNP could be a useful clinical tool for selecting patients for bladder-conserving treatment.

A functional amino acid substitution in the glucose-dependent insulinotropic polypeptide receptor (GIPR) gene is associated with lower bone mineral density and increased fracture risk.

CONTEXT: Food ingestion decreases bone resorption, and glucose-dependent insulinotropic polypeptide (GIP) may mediate this effect. Mice overexpressing GIP have increased osteoblast activity and are rescued from age-related bone loss, whereas GIPR knockout mice have decreased cortical bone mass and compromised bone quality. Carriers of the functional variant GIPR Glu354Gln (rs1800437) have higher plasma glucose 2 hours after glucose ingestion, suggesting that the variant encoding GIPR 354Gln decreases the effect of GIP. OBJECTIVE: The objective of the study was to investigate the effect of GIPR Glu354Gln on bone mineral density (BMD) and fracture risk. DESIGN: This was a prospective, comprehensive, cohort study (number NCT00252408). PARTICIPANTS: A total of 1686 perimenopausal women were included. MAIN OUTCOME MEASURES: Dual-energy X-ray absorptiometry was performed at baseline and after 10 years. Incident fractures were recorded during the follow-up and were obtained from the Danish National Patient Registry, giving a total follow-up time of a minimum 16 years. RESULTS: After 10 years, women with the minor frequency C allele of rs1800437 (354Gln) had significantly lower BMD at the femoral neck compared with carriers of the major G-allele (CC: 0.755 ± 0.015 g/cm(2) vs CG: 747 ± 0.005 g/cm(2); GG: 0.766 ± 0.004 g/cm(2), P < .001). Correspondingly, total hip BMD was significantly lower among C allele carriers (CC: 0.881 ± 0.016 g/cm(2); CG: 0.884 ± 0.005 g/cm(2); and GG: 0.906 ± 0.004 g/cm(2), P < .001). Finally, women homozygous for the variant C allele had an increased risk (hazard ratio 1.6, confidence interval 1.0-2.6, P < .05) of nonvertebral fractures. CONCLUSION: This study demonstrates an association between a functional GIPR polymorphism Glu354Gln (rs1800437) and BMD and fracture risk. These findings further establish GIP to be involved in the regulation of bone density.

Making the most of Papua New Guinea's biodiversity: Establishment of an integrated set of programs that link botanical survey with pharmacological assessment in "The Land of the Unexpected"

An integrated and coordinated set of programs has been established to meet ICBG goals in Papua New Guinea (PNG). Here we give an overview of the PNG ICBG and focus on the key elements and major steps taken to establish a program necessary for the pharmacological assessment of botanicals and traditional medicines in PNG and, by extrapolation, in other developing countries.

Probabilistic modelling of combined sewer overflow using the First Order Reliability Method.

This paper presents a new and alternative method (in the context of urban drainage) for probabilistic hydrodynamical analysis of drainage systems in general and especially prediction of combined sewer overflow. Using a probabilistic shell it is possible to implement both input and parameter uncertainties on an application of the commercial urban drainage model MOUSE combined with the probabilistic First Order Reliability Method (FORM). Applying statistical characteristics on several years of rainfall, it is possible to derive a parameterization of the rainfall input and the failure probability and return period of combined sewer overflow to receiving waters can be found.

Relationship between bone strength and dual-energy X-ray absorptiometry measurements in pigs.

Computed tomography and a 3-point bending test were performed on the metacarpal bones of adult production pigs to test the hypothesis that bone strength is strongly correlated with areal bone mineral density (BMD) in this population. The aim of the study was to subject material from adult production pigs grouped by BMD to 3-point bending, to test this hypothesis and determine any correlations. In all, 168 individual computed tomography scans and mechanical tests were performed on the collected material. For evaluation purposes, the material was divided into the categories low, medium, and high BMD (<1, 1 to 1.4, and >1.4 g/cm(2), respectively). The results showed a difference in the maximum load, in the stress at maximum load, and stiffness among each BMD group (P < 0.001) and in elastic modulus between the low BMD group and the 2 other groups (P < 0.001). A correlation between both intrinsic and extrinsic measures of bone strength and BMD was thus demonstrated. The projected change in each of the variables reported, for a 0.1 g/cm(2) alteration in BMD (within the BMD range evaluated in this study), is as follows: maximum load, 708 N; stress at maximum load, 50 N/mm(2); stiffness, 391.6 N/mm; and elastic modulus, 108 N/mm(2) (P < 0.001). The results confirm the relationship between BMD and bone strength and indicate that BMD screening can be used in fracture risk assessments in production pigs.

Development of the mesencephalic dopaminergic neuron system is compromised in the absence of neurogenin 2.

Neurogenin 2 (Ngn2) is a proneural gene involved in neuronal differentiation and subtype specification in various regions of the nervous system. In the ventral midbrain, Ngn2 is expressed in a spatiotemporal pattern that correlates with the generation of mesencephalic dopaminergic (mesDA) neurons. We show here that lack of Ngn2 impairs the development of mesDA neurons, such that less than half of the normal mesDA neuron number remain in Ngn2 mutant mice at postnatal stages. Analysis of Ngn2 mutant mice during mesDA neurogenesis show that medially located precursors are formed but are arrested in their differentiation at a stage when they have not yet acquired the characteristics of mesDA neuron precursors. Loss of Ngn2 function appears to specifically affect the generation of DA neurons, as the development of other types of neurons within the ventral midbrain is unaltered. Ngn2 is the first example of a gene expressed in progenitors in the ventricular zone of the mesDA neuron domain that is essential for proper mesDA neuron differentiation, and whose loss of function causes impaired mesDA neurogenesis without other major abnormalities in the ventral midbrain.

Bioavailability of calcium: comparison of calcium carbonate and milk and the effect of vitamin D, age, and sex using 24-hour urine calcium as a method.

The aim of the present study was to compare the bioavailability of calcium from calcium carbonate and milk and to investigate if 1,200 IU of cholecalciferol a day increased intestinal absorption of calcium. Both young women and a group of older persons of both sexes were included to study the influence of age and sex. In total, 53 healthy women and men were included: a group of 23 younger women (median age 30) and an older group of 15 women and 15 men (median age 66). The study period was 4 weeks; each participant completed four treatment regimens randomly: CaCO(3), CaCO(3 )+ 1,200 IU of cholecalciferol, milk, and placebo. All regimens were distributed three times a day and consisted of 1,200 mg of elementary calcium. The 24-hour urine calcium excretion was used as a method. Total urinary calcium excretion rates (mmol/day) were as follows (mean +/- SD): placebo 4.41 +/- 2.17, milk 5.17 +/- 2.33, CaCO(3) 5.83 +/- 2.03, and CaCO(3 )+ D 6.06 +/- 2.46. All regimens compared to placebo were significant. Addition of cholecalciferol to the CaCO(3) regimen increased calcium excretion but insignificantly: 0.27 +/- 2.84 mmol/day. The increase in calcium excretion during the milk regimen was significant only for the old group: 0.96 vs. 0.28 mmol/day. No other difference was found according to age and sex. The bioavailability of calcium carbonate and milk was demonstrated. Additional cholecalciferol (1,200 IU) to individuals in positive calcium balance with serum 25(OH)D levels >50 nmol/L only marginally increased calcium absorption in a short-term intervention.

Late Quaternary records of Najas spp. (Najadaceae) from the southwestern Baltic region.

Seeds of the submerged vascular plants Najas marina, Najas minor and Najas flexilis are reported from submarine Holocene deposits from the southwestern part of the Baltic Sea, and we also report on a find of Najas minor from an Eemian deposit in Jutland, which is the first record of this species from the Eemian of Denmark. The common and widespread occurrence of especially the southern extralimital N. minor is indicative of higher than present summer temperatures during the period from 10300 to 8000cal.yearsBP.

Chronic antidepressant treatments decrease pro-opiomelanocortin mRNA expression in the pituitary gland: effects of acute stress and 5-HT(1A) receptor activation.

Consistent findings in depressed patients are hyperactivity in the hypothalamic-pituitary-adrenal (HPA) axis with high plasma concentrations of adrenocorticotropic hormone and cortisol. Long-term antidepressant treatments seem to normalize this hyperactivity, suggesting a link between the HPA axis and the action of antidepressant treatments. The present study was carried out to study the effects of antidepressant treatments on pro-opiomelanocortin (POMC) mRNA expression, with a focus on interaction with acute stress and 5-HT(1A) receptor activation. Male rats were treated for 21 days with saline, citalopram, fluoxetine, moclobemide or desipramine, and the expression of POMC mRNA in the anterior pituitary was analysed by semi-quantitative in situ hybridization. All antidepressants, but not saline, cocaine and haloperidol, reduced POMC mRNA expression. The decrease in POMC mRNA was not observed until 9 days of citalopram treatment. Decreased POMC mRNA levels were also observed after 14 days of repeated electroconvulsive stimulation. The decreased POMC mRNA levels did not affect the stress-induced POMC mRNA increase, measured following swim stress and restraint stress. Finally, using Fos as a marker for neural activity, we showed attenuation of 8-OH-DPAT-stimulated activity in the paraventricular nucleus following 21 days of citalopram treatment. In conclusion, antidepressant treatments decrease basal POMC mRNA expression without affecting the acute stress response, and the reduced POMC mRNA may be related to reduced 5-HT(1A)-stimulated hypothalamic output.

Role of GluR2 expression in AMPA-induced toxicity in cultured murine cerebral cortical neurons.

alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R)-mediated neurotoxicity was studied in relation to subunit expression and the presence of Ca(2+)-permeable receptor channels. AMPA-mediated toxicity had two components: 1) a direct AMPA-R-mediated component, which was not due to Ca(2+) influx through voltage-gated Ca(2+) channels, reversal of the Na(+)/Ca(2+) exchanger or release of calcium from dantrolene-sensitive intracellular Ca(2+) stores, and 2) a minor, indirect component involving activation of NMDA receptor channels, because of glutamate release and removal of the Mg(2+) block of the NMDA receptor on AMPA-R stimulation. The involvement of Ca(2+) influx through AMPA-R was also examined. The number of neurons possessing Ca(2+)-permeable AMPA-R increased during culture development, concurrently with an increasing susceptibility for AMPA-induced toxicity during development. GluR2(R) levels also increased during development, and channel blockers of Ca(2+)-permeable AMPA-R lacking the GluR2(R) subunit (spermine and philanthotoxin) failed to prevent neurotoxicity or increases in [Ca(2+)](i). Thus, the direct AMPA-R-mediated toxicity may be explained by initiation of cell death by Ca(2+) fluxing through AMPA-R containing GluR2(R). The components of direct AMPA-R-mediated toxicity are proposed to be 1) toxicity mediated by GluR2(R)-lacking AMPA-R and 2) toxicity mediated by low-Ca(2+)-permeability AMPA-R containing GluR2(R).