Church Attendance; Prayer; Church Membership; Religious Identity
Although research focused on African Americans with mental illness has been increasing, few researchers have addressed gender and age differences in beliefs, attitudes, and coping.
To examine African Americans' beliefs about mental illness, attitudes toward seeking mental health services, preferred coping behaviors, and whether these variables differ by gender and age.
An exploratory, cross-sectional survey design was used. Participants were 272 community-dwelling African Americans aged 25-72 years. Data analysis included descriptive statistics and general linear regression models.
Depression was the most common mental illness and there were no gender differences in prevalence. Both men and women believed they knew some of the symptoms and causal factors of mental illness. Their attitudes suggested they are not very open to acknowledging psychological problems, are very concerned about stigma associated with mental illness, and are somewhat open to seeking mental health services, but they prefer religious coping. Significant gender and age differences were evident in attitudes and preferred coping.
Our findings have implications for gender and age-specific psychoeducation interventions and future research. For instance, psychoeducation or community awareness programs designed to increase openness to psychological problems and reducing stigma are needed. Also, exploration of partnerships between faith-based organizations and mental health services could be helpful to African Americans.
African Americans; mental illness; beliefs; coping behaviors
Phenylacetic acid (PAA) is the active moiety in sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB, HPN-100), both are approved for treatment of urea cycle disorders (UCDs) - rare genetic disorders characterized by hyperammonemia. PAA is conjugated with glutamine in the liver to form phenylacetyleglutamine (PAGN), which is excreted in urine. PAA plasma levels ≥500 μg/dL have been reported to be associated with reversible neurological adverse events (AEs) in cancer patients receiving PAA intravenously. Therefore, we have investigated the relationship between PAA levels and neurological AEs in patients treated with these PAA pro-drugs as well as approaches to identifying patients most likely to experience high PAA levels.
The relationship between nervous system AEs, PAA levels and the ratio of plasma PAA to PAGN were examined in 4683 blood samples taken serially from:  healthy adults , UCD patients ≥2 months of age, and  patients with cirrhosis and hepatic encephalopathy (HE). The plasma ratio of PAA to PAGN was analyzed with respect to its utility in identifying patients at risk of high PAA values.
Only 0.2% (11) of 4683 samples exceeded 500 ug/ml. There was no relationship between neurological AEs and PAA levels in UCD or HE patients, but transient AEs including headache and nausea that correlated with PAA levels were observed in healthy adults. Irrespective of population, a curvilinear relationship was observed between PAA levels and the plasma PAA:PAGN ratio, and a ratio > 2.5 (both in μg/mL) in a random blood draw identified patients at risk for PAA levels > 500 μg/ml.
The presence of a relationship between PAA levels and reversible AEs in healthy adults but not in UCD or HE patients may reflect intrinsic differences among the populations and/or metabolic adaptation with continued dosing. The plasma PAA:PAGN ratio is a functional measure of the rate of PAA metabolism and represents a useful dosing biomarker.
BUPHENYL; glycerol phenylbutyrate; HPN-100; neurological adverse events; pharmacokinetics; RAVICTI; sodium phenylbutyrate
The current study relies upon the 2004 National Politics Study to examine the association between exposure to race-based messages within places of worship and White race-based policy attitudes. The present study challenges the notion that, for White Americans, religiosity inevitably leads to racial prejudice. Rather, we argue, as others have, that religion exists on a continuum that spans from reinforcing to challenging the status quo of social inequality. Our findings suggests that the extent to which Whites discuss race along with the potential need for public policy solutions to address racial inequality within worship spaces, worship attendance contributes to support for public policies aimed at reducing racial inequality. On the other hand, apolitical and non-structural racial discussions within worship settings do seemingly little to move many Whites to challenge dominant idealistic perceptions of race that eschews public policy interventions as solutions to racial inequality.
Acute upper respiratory infections (URI) are the second most common diagnosis in primary care offices. As treatments have limited effectiveness, patient counseling regarding expectations for the course of the URI is an important aspect of care. It is unknown how accurate patients, clinicians or questionnaires such as the Wisconsin Upper Respiratory Symptom Survey (WURSS) instrument are at predicting URI severity and duration, and whether these predictions should be used to counsel patients.
Seven hundred and nineteen individuals with recent onset cold in community clinic settings participated. Participants and clinicians predicted the severity and duration of the URI and participants completed the WURSS instrument at initial visit. Subsequent URI global severity was calculated as area under the curve using an average of twice-daily WURSS-21 self-reports as the y-axis and illness duration as the x-axis. URI duration was determined by self-report of beginning and end of illness. Linear regression analysis was used to correlate baseline predictions with subsequent outcomes. Analyses by gender, age and income were also performed.
There was no significant association between participant and clinician predictions of severity or duration. Initial WURSS values explained 0.119 (95% CI: 0.074–0.163) of the variance in subsequent severity outcomes. There were no significant differences in associations by age, gender or income.
Clinicians should not use their predictive assessments or their patients’ predictions when advising patients on the expected course of a URI. This study also suggests that the WURSS instrument could give some predictive information, but whether this is clinically useful is uncertain.
Decision making; evidence-based medicine; family practice; patient-centered care; prognosis; upper respiratory tract infections.
Melanopsin-based phototransduction is involved in non-image forming light responses including circadian entrainment, pupil constriction, suppression of pineal melatonin synthesis, and direct photic regulation of sleep in vertebrates. Given that the functions of melanopsin involve the measurement and summation of total environmental luminance, there would appear to be no need for the rapid deactivation typical of other G-protein coupled receptors. In this study, however, we demonstrate that heterologously expressed mouse melanopsin is phosphorylated in a light-dependent manner, and that this phosphorylation is involved in regulating the rate of G-protein activation and the lifetime of melanopsin's active state. Furthermore, we provide evidence for light-dependent phosphorylation of melanopsin in the mouse retina using an in situ proximity ligation assay (PLA). Finally, we demonstrate that melanopsin preferentially interacts with the GRK2/3 family of G-protein coupled receptor kinases through co-immunoprecipitation assays. Based on the complement of G-protein receptor kinases present in the melanopsin-expressing retinal ganglion cells, GRK2 emerges as the best candidate for melanopsin's cognate GRK.
The purpose was to investigate patient–doctor agreement on clinical trial discussion cross-culturally.
In the International Breast Cancer Study Group Trial 33-03 on shared decision-making for early breast cancer in Australian/New Zealand (ANZ) and Swiss/German/Austrian (SGA) centers, doctor and patient characteristics plus doctor stress and burnout were assessed. Within 2 weeks post-consultation about treatment options, the doctor and patient reported independently, whether a trial was discussed. Odds ratios of agreement for covariables were estimated by generalized estimating equations for each language cohort, with doctor as a random effect.
In ANZ, 21 doctors and 339 patients were eligible; in SGA, 41 doctors and 427 patients. In cases where the doctor indicated ‘no trial discussed’, 82% of both ANZ and SGA patients agreed; if the doctor indicated ‘trial discussed’, 50% of ANZ and 38% of SGA patients agreed, respectively. Factors associated with higher agreement were: low tumor grade and fewer patients recruited into clinical trials in SGA; public institution, patient born in ANZ (versus other), higher doctor depersonalization and personal accomplishment in ANZ.
There is discordance between oncologists and their patients regarding clinical trial discussion, particularly when the doctor indicates that a trial was discussed. Factors contributing to this agreement vary by culture.
breast cancer; communication skills training; cross-cultural differences; patient–doctor agreement; shared decision-making
Neurocognitive impairment occurs in children and adults with sickle cell anemia, but little is known about neurodevelopment in very young children. We examined the neurodevelopmental status of infants participating in the Pediatric Hydroxyurea Phase III Clinical Trial (Baby Hug) to determine relationships with age, cerebral blood flow velocity, and hemoglobin concentration.
Standardized measures of infant neurodevelopment were administered to 193 infants with hemoglobin SS or hemoglobin S-β0 thalassemia between 7 and 18 months of age at the time of their baseline evaluation. Associations between neurodevelopmental scores and age, family income, parent education, hemoglobin concentration, and transcranial Doppler velocity were examined.
Mean functioning on the baseline neurodevelopment scales was in the average range. There were no mental development scores <70 (impaired); 22 children had scores in the clinically significant range, 11 with impaired psychomotor scores and 11 with problematic behavior rating scores. Significantly poorer performance was observed with older age at baseline. Behavior rating scores were an average of 2.82 percentile points lower per month of age, with similar patterns observed with parent report using adaptive behavior scales. Parent-reported functional abilities and hemoglobin were negatively associated with higher transcranial Doppler velocities.
Whereas overall functioning was in the normal range, behavioral and adaptive function was poorer with older age, even in this very young group of children. Explanatory mechanisms for this association between poorer developmental function and older age need to be identified.
sickle cell disease; cognitive development; transcranial Doppler; Bayley Scales; toddlers
Hepatocellular carcinoma (HCC) represents an increasing fraction of liver transplant indications; the role of living donor liver transplant (LDLT) remains unclear. Recurrence and post-transplant mortality rates were compared in LDLT and deceased donor liver transplant (DDLT) patients with at least one potential living donor evaluated. HCC recurrence and post-transplant mortality were evaluated among 100 LDLT and 97 DDLT recipients in the Adult-to-Adult Living Donor Liver Transplantation Cohort Study. Mortality from date of evaluation of each recipient’s first potential living donor was analyzed. LDLT recipients had shorter time to transplant, were more likely to have tumors exceeding Milan criteria, higher alpha-fetoprotein levels, and less likely to have received pre-operative loco-regional therapy than DDLT recipients. Unadjusted 5-year HCC recurrence was significantly higher after LDLT (38%) than DDLT (11%), (p=0.0004). After adjustment for tumor characteristics, HCC recurrence remained significantly different between LDLT and DDLT recipients (hazard ratio (HR) = 2.35; p=0.04) for the overall cohort but not for recipients transplanted following the introduction of MELD prioritization. Five-year post-transplant survival was similar in LDLT and DDLT recipients from time of transplant (HR=1.32; p=0.27) and from date of LDLT evaluation (HR=0.73; p=0.36). We conclude that the higher recurrence observed after LDLT is likely due to differences in tumor characteristics, pre-transplant HCC management, and waiting time.
Recurrence; MELD score; Milan criteria; loco-regional therapy; survival
Clinical complications of sickle cell anemia begin in infancy. BABY HUG (ClinicalTrials.gov, NCT00006400) was a NHLBI-NICHD supported randomized phase III placebo-controlled trial of hydroxyurea (HU) in infants (recruited at 9–18 months) unselected for clinical severity with sickle cell anemia. This secondary analysis of data from BABY HUG examines the influence of anemia on the incidence of sickle cell related complications, and the impact of hydroxyurea therapy in altering these events by comparing children with lower (<25th percentile) and higher (>75th percentile) hemoglobin concentrations at study entry.
Infants were categorized by: 1) age-adjusted hemoglobin quartiles as determined by higher (Hi) and lower (Lo) hemoglobin concentrations at study entry (9 to12 months old: <8.0 gm/dL and >10.0gm/dL; 12 to 18 months old: <8.1 gm/dL and >9.9gm/dL) and 2) treatment arm (hydroxyurea or placebo). Four subgroups were created: placebo (PL) LoHb (n=25), PL HiHb (n=27), hydroxyurea (HU) LoHb (n=21), and HU HiHb (n=18). The primary and secondary endpoints of BABY HUG were analyzed by subgroup.
Infants with lower hemoglobin at baseline were more likely to have a higher incidence of clinical events (acute chest syndrome, pain crisis, fever) as well as higher TCD velocities and lower neuropsychological scores at study exit. Hydroxyurea reduced the incidence of these findings.
Infants with more severe anemia are at risk for increased clinical events that may be prevented by early initiation of hydroxyurea.
Sickle Cell Anemia; Hydroxyurea; Acute Chest Syndrome; Pain; Transcranial Doppler; Renal; Spleen
Ovarian cancer is the most lethal gynaecological cancer. Progression-free and overall survival is significantly related to surgical success and residual disease volume. It is unclear whether this survival advantage is due to an intrinsic biological element of the tumour cells which enables successful surgery and improved prognosis, or alternatively the number of tumour sustaining cells remaining irrespective of differences in biology.
A systematic review of the literature was performed identifying studies that have investigated the association between biomarkers and surgical outcomes. We attempted validation of these results using The Cancer Genome Atlas ovarian cancer data sets.
Thirty studies were identified of which sixteen determined protein expression, eight gene expression and one DNA methylation in association with surgical debulking. Individualised linear models adjusting for batch, stage and age identified only expression of the genes MTDH and insulin-like growth factor-1 receptor (IGF1R) to be significantly associated with debulking surgery (P<0.05, false discovery rate (FDR)<5%), although in the case of IGF1R this was in the opposite direction to previous findings.
The majority of studies are limited by design, include heterogeneous samples and lack adjustment for major confounding factors. High quality detailed clinical annotations should be routinely collected in future to more accurately evaluate biomarkers of surgical outcome.
ovarian cancer; debulking surgery; molecular biomarkers
The promise of epigenome-wide association studies and cancer-specific somatic DNA methylation changes in improving our understanding of cancer, coupled with the decreasing cost and increasing coverage of DNA methylation microarrays, has brought about a surge in the use of these technologies. Here, we aim to provide both a review of issues encountered in the processing and analysis of array-based DNA methylation data and a summary of the advantages of recent approaches proposed for handling those issues, focusing on approaches publicly available in open-source environments such as R and Bioconductor. We hope that the processing tools and analysis flowchart described herein will facilitate researchers to effectively use these powerful DNA methylation array-based platforms, thereby advancing our understanding of human health and disease.
DNA methylation; microarray; processing; analysis; bioconductor and R packages
Despite improved outcomes in multiple myeloma (MM), a cure remains elusive. However, even before the current therapeutic era, 5% of patients survived >10 years and we propose that immune factors contribute to this longer survival. We identified patients attending our clinic, who had survived >10 years (n=20) and analysed their blood for the presence of T-cell clones, T-regulatory cells (Tregs) and T helper 17 (Th17) cells. These results were compared with MM patients with shorter follow-up and age-matched healthy control donors. The frequency of cytotoxic T-cell clonal expansions in patients with <10 years follow-up (MM patients) was 54% (n=144), whereas it was 100% (n=19/19) in the long-survivors (LTS-MM). T-cell clones from MM patients proliferated poorly in vitro, whereas those from LTS-MM patients proliferated readily (median proliferations 6.1% and 61.5%, respectively (P<0.0001)). In addition, we found significantly higher Th17 cells and lower Tregs in the LTS-MM group when compared with the MM group. These results indicate that long-term survival in MM is associated with a distinct immunological profile, which is consistent with decreased immune suppression.
myeloma; T-cell clones; Tregs; Th17 cells
Peroxisome proliferator-activated receptor (PPAR)-γ modulates substrate metabolism and inflammatory responses. In experimental rats subjected to myocardial ischemia-reperfusion (I/R), thiazolidinedione PPAR-γ activators reduce infarct size and preserve left ventricular function. Troglitazone is the only PPAR-γ activator that has been shown to be protective in I/R in large animals. However, because troglitazone contains both α-tocopherol and thiazolidinedione moieties, whether PPAR-γ activation per se is protective in myocardial I/R in large animals remains uncertain. To address this question, 56 pigs were treated orally for 8 wk with troglitazone (75 mg·kg−1 ·day−1), rosiglitazone (3 mg·kg−1 ·day−1), or α-tocopherol (73 mg·kg−1 ·day−1, equimolar to troglitazone dose) or received no treatment. Pigs were then anesthetized and subjected to 90 min of low-flow regional myocardial ischemia and 90 min of reperfusion. Myocardial expression of PPAR-γ, determined by ribonuclease protection assay, increased with troglitazone and rosiglitazone compared with no treatment. Rosiglitazone had no significant effect on myocardial contractile function (Frank-Starling relations), substrate uptake, or expression of proinflammatory cytokines during I/R compared with untreated pigs. In contrast, preservation of myocardial contractile function and lactate uptake were greater and cytokine expression was attenuated in pigs treated with troglitazone or α-tocopherol compared with untreated pigs. Multivariate analysis indicated that presence of an α-tocopherol, but not a thiazolidinedione, moiety in the test compound was significantly related to greater contractile function and lactate uptake and lower cytokine expression during I/R. We conclude that PPAR-γ activation is not protective in a porcine model of myocardial I/R. Protective effects of troglitazone are attributable to its α-tocopherol moiety. These findings, in conjunction with prior rat studies, suggest interspecies differences in the response to PPAR-γ activation in the heart.
nuclear receptor; thiazolidinedione; energy metabolism; cytokine; ventricular function
Women with polycystic ovary syndrome (PCOS) have increased prevalence of cardiovascular (CV) risk factors. However, data on the incidence of CV events are lacking in this population.
Using Rochester Epidemiology Project resources, we conducted a retrospective cohort study comparing CV events in women with PCOS with those of women without PCOS in Olmsted County, Minnesota.
Between 1966 and 1988, 309 women with PCOS and 343 without PCOS were identified. Mean (SD) age at PCOS diagnosis was 25.0 (5.3) years; mean age at last follow-up was 46.7 years. Mean (SD) follow-up was 23.7 (13.7) years. Women with PCOS had a higher body mass index (29.4 kg/m2 vs 28.3 kg/m2; p=.01). Prevalence of type 2 diabetes mellitus and hypertension and levels of total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol and triglycerides were similar in the two groups. We observed no increase in CV events, including myocardial infarction (adjusted hazard ratio [HR] 0.74; 95% confidence interval [CI] 0.32 to 1.72; p=.48); coronary artery bypass graft surgery (adjusted HR 1.52; 95% CI 0.42 to 5.48; p=.52); death (adjusted HR 1.03; 95% CI, 0.29 to 3.71; p=.96); death due to CV disease (adjusted HR 5.67; 95% CI 0.51 to 63.7; p=.16); or stroke (adjusted HR 1.05; 95% CI 0.28 to 3.92; p=.94).
Although women with PCOS weighed more than controls, there was no increased prevalence of other CV risk factors. Furthermore, we found no increase in CV events. While prospective studies are needed to confirm these findings, women with PCOS do not appear to have adverse CV outcomes in midlife.
Cardiovascular disease; polycystic ovary syndrome; Rochester Epidemiology Project
Mutations that perturb the function of photoreceptor cyclic nucleotide-gated (CNG) channels are associated with several human retinal disorders, but the molecular and cellular mechanisms leading to photoreceptor dysfunction and degeneration remain unclear. Many loss-of-function mutations result in intracellular accumulation of CNG channel subunits. Accumulation of proteins in the endoplasmic reticulum (ER) is known to cause ER stress and trigger the unfolded protein response (UPR), an evolutionarily conserved cellular program that results in either adaptation via increased protein processing capacity or apoptotic cell death. We hypothesize that defective trafficking of cone photoreceptor CNG channels can induce UPR-mediated cell death. To test this idea, CNGA3 subunits bearing the R563H and Q655X mutations were expressed in photoreceptor-derived 661W cells with CNGB3 subunits. Compared to wild type, R563H and Q655X subunits displayed altered degradation rates and/or were retained in the ER. ER retention was associated with increased expression of UPR-related markers of ER stress and with decreased cell viability. Chemical and pharmacological chaperones (TUDCA, 4PBA, and the cGMP analog CPT-cGMP) differentially reduced degradation and/or promoted plasma-membrane localization of defective subunits. Improved subunit maturation was concordant with reduced expression of ER stress markers and improved viability of cells expressing localization-defective channels. These results indicate that ER stress can arise from expression of localization defective CNG channels, and may represent a contributing factor for photoreceptor degeneration.
Retinal disease; misfolding; chaperone; UPR; membrane localization; ion channel subunit
Memory decline commonly occurs among elderly individuals. This observation is often attributed to early neurodegenerative changes in the hippocampus and related brain regions. However, the contribution of vascular lesions, such as brain infarcts, to hippocampal integrity and age-associated memory decline remains unclear.
We studied 658 elderly participants without dementia from a prospective, community-based study on aging and dementia who received high-resolution structural MRI. Cortical and subcortical infarcts were identified, and hippocampal and relative brain volumes were calculated following standard protocols. Summary scores reflecting performance on tasks of memory, language, processing speed, and visuospatial function were derived from a comprehensive neuropsychological battery. We used multiple regression analyses to relate cortical and subcortical infarcts, hippocampal and relative brain volume, to measures of cognitive performance in domains of memory, language, processing speed, and visuospatial ability.
Presence of brain infarcts was associated with a smaller hippocampus. Smaller hippocampus volume was associated with poorer memory specifically. Brain infarcts were associated with poorer memory and cognitive performance in all other domains, which was independent of hippocampus volume.
Both hippocampal volume and brain infarcts independently contribute to memory performance in elderly individuals without dementia. Given that age-associated neurodegenerative conditions, such as Alzheimer disease, are defined primarily by impairment in memory, these findings have clinical implications for prevention and for identification of pathogenic factors associated with disease symptomatology.
Delimitation of species is an important and controversial area within evolutionary biology. Many species boundaries have been defined using morphological data. New genetic approaches now offer more objective evaluation and assessment of the reliability of morphological variation as an indicator that speciation has occurred. We examined geographic variation in morphology of the continuously distributed skink Chalcides mionecton from Morocco and used Bayesian analyses of nuclear and mitochondrial DNA (mtDNA) loci to examine: (i) their concordance with morphological patterns, (ii) support for species delimitation, (iii) timing of speciation, and (iv) levels of gene flow between species. Four digit individuals were found at sites between Cap Rhir (in the south) and the northern extreme of the range, whereas five-digit individuals were found in two disjunct areas: (i) south of Cap Rhir and (ii) the north of the range where they were often syntopic with four-digit individuals. The pattern of variation in generalized body dimensions was largely concordant with that in digit number, suggesting two general morphotypes. Bayesian analyses of population structure showed that individuals from sites south of Cap Rhir formed one genetic cluster, but that northern four- and five-digit individuals clustered together. Statistical support for delimitation of these genetic clusters into two species was provided by a recent Bayesian method. Phylogenetic–coalescent dating with external time calibrations indicates that speciation was relatively recent, with a 95% posterior interval of 0.46–2.66 mya. This postdates equivalent phylogenetic dating estimates of sequence divergence by approximately 1 Ma. Statistical analyses of a small number of independent loci provide important insights into the history of the speciation process in C. mionecton and support delimitation of populations into two species with distributions that are spatially discordant with patterns of morphological variation.
Methods; molecular ecology; population genetics
Approximately 215,000 people younger than 20 yr of age, or 1 in 500 children and adolescents, had diabetes in the United States in 2010 – and the incidence is rising. We still have insufficient knowledge about the precise mechanisms leading to the autoimmune mediated β-cell destruction in Type 1 diabetes, and the β-cell failure associated with insulin resistance in Type 2 diabetes. Long-term complications are similar: micro-and macrovascular disease occurs prematurely and presents an enormous burden on affected individuals, often as early as in middle age. In Type 1 diabetes, technological advances have clearly improved blood glucose management, but chronic peripheral over-insulinization remains a problem even with the most advanced systems. Thus, in Type 1 diabetes our research must focus on 1) finding the stimulus that ignites the immune response and 2) developing treatments that avoid hyperinsulinemia. In Type 2 diabetes in youth, the challenges start much earlier: most young patients do not even benefit from existing therapies due to non-compliance. Therefore, prevention of Type 2 diabetes and improvement of compliance, especially with non-pharmacological interventions, are the greatest challenges.
Autoimmunity; chronic stress; genetic; leptin; obesity; prevention; sleep deprivation; socioeconomic status; Vitamin D
Treatment of abdominal lymphoma can be associated with bowel stricture or perforation. Rarely, the common bile duct or portal vein can be involved. This is the first case of stricture formation of both the portal vein and common bile duct in a patient following successful treatment of lymphoma. The development of extensive hilar varices rendered surgical management high risk. A staged approach to treatment was used. First, a percutaneous portal vein stent was placed, resulting in resolution of the hilar varices. This was followed by a surgical hepaticojejunostomy, performed without complication. Gastrointestinal complications are rare following treatment of lymphoma but may affect a variety of sites. The safe and effective treatment of this case highlights the benefit of a multidisciplinary approach to complex medical and surgical problems.
Jaundice; Portal vein; Lymphoma; Interventional radiology
The visual pigment melanopsin is expressed in intrinsically photosensitive retinal ganglion cells (ipRGCs) in the mammalian retina, where it is involved in non-image forming light responses including circadian photoentrainment, pupil constriction, suppression of pineal melatonin synthesis, and direct photic regulation of sleep. It has recently been shown that the melanopsin-based light response in ipRGCs is attenuated by the neurotransmitter dopamine. Here, we use a heterologous expression system to demonstrate that mouse melanopsin can be phosphorylated by protein kinase A, and that phosphorylation can inhibit melanopsin signaling in HEK cells. Site-directed mutagenesis experiments revealed that this inhibitory effect is primarily mediated by phosphorylation of sites T186 and S287 located in the second and third intracellular loops of melanopsin, respectively. Furthermore, we show that this phosphorylation can occur in vivo using an in situ proximity-dependent ligation assay (PLA). Based on these data, we suggest that the attenuation of the melanopsin-based light response by dopamine is mediated by direct PKA phosphorylation of melanopsin, rather than phosphorylation of a downstream component of the signaling cascade.
Literature reviews of cancer trials have highlighted the need for better understanding of phase II statistical designs. Understanding the key elements associated with phase II design and knowledge of available statistical designs is necessary to enable appropriate phase II trial design.
A systematic literature review was performed to identify phase II trial designs applicable to oncology trials. The results of the review were used to create a library of currently available designs, and to develop a structured approach to phase II trial design outlining key points for consideration.
A total of 122 papers describing new or adapted phase II trial designs were obtained. These were categorised into nine levels, reflecting the practicalities of implementation, and form a library of phase II designs. Key design elements were identified by data extraction. Along with detailed description of the key elements and the library of designs, a structured thought process was developed to form a guidance document for choice of phase II oncology trial design.
The guidance offers researchers a structured and systematic approach to identifying phase II trial designs, highlighting key issues to be considered by both clinicians and statisticians and encouraging an interactive approach to more informed trial design.
phase II; methodology; systematic review; trial design; guidance manual
Laser scanning technology is one of the most integral parts of today's scientific research, manufacturing, defense, and biomedicine. In many applications, high-speed scanning capability is essential for scanning a large area in a short time and multi-dimensional sensing of moving objects and dynamical processes with fine temporal resolution. Unfortunately, conventional laser scanners are often too slow, resulting in limited precision and utility. Here we present a new type of laser scanner that offers ∼1,000 times higher scan rates than conventional state-of-the-art scanners. This method employs spatial dispersion of temporally stretched broadband optical pulses onto the target, enabling inertia-free laser scans at unprecedented scan rates of nearly 100 MHz at 800 nm. To show our scanner's broad utility, we use it to demonstrate unique and previously difficult-to-achieve capabilities in imaging, surface vibrometry, and flow cytometry at a record 2D raster scan rate of more than 100 kHz with 27,000 resolvable points.