Trends and predictors of new HIV diagnosis and time since last test at testing encounters among adults in Kilifi, Kenya, 2006-2017.
Background: Little is known about HIV retesting uptake among key populations (KP) and general populations (GP) in Kenya. We assessed trends and predictors of new HIV diagnosis, first-time testing (FTT), and late retesting (previous test more than one year ago for GP or three months for KP). Methods: Data was collected routinely at three voluntary counselling and testing (VCT) centres in Kilifi County between 2006 and 2017. We analysed test encounters among adults 18-39 years, categorized as GP men, GP women, men who have sex with men (MSM), and female sex workers (FSW). Results: Based on 25,670 test encounters (32% FTT), we observed significant declines in HIV positivity (proportion of encounters with a new HIV diagnosis) among GP men, GP women, and first-time testers, but not among MSM and FSW. FTT and late retesting decreased for both GP and KP, but remained much higher in KP than GP. In 2017, less than 20% of KP were testing quarterly as recommended. HIV positivity was higher at FTT and late retesting encounters (relative to on-time retesting); at FSW and MSM encounters; and at encounters with clients reporting lower educational attainment, sexually transmitted infection (STI) symptoms, or no religious affiliation. HIV positivity was lower in GP men and younger clients. FTT was associated with town, risk group, age 18-24 years, never-married status, low educational attainment, and STI symptoms. Late retesting was less common among encounters with GP individuals who were never married, had Muslim or no religious affiliation, had lower educational attainment, or reported STI symptoms. Conclusions: New HIV diagnoses were most common among first-time testers and late re-testers. While late retesting decreased steadily over the period reviewed, achievement of the county's 90% HIV diagnosis target will require redoubled efforts to increase retesting among the most at risk populations.


Differential control of insulin secretion and somatostatin-receptor recruitment in isolated pancreatic islets.
Somatostatin receptors appear to be localized to secretory granules in pancreatic islet homogenates. Recruitment of these receptors to the islet-cell surfaces may mark the contact event between secretory granules and plasma membranes before release of insulin by fission. Isethionate, an impermeant anionic replacement for chloride, blocks the release step but does not affect receptor recruitment. By contrast, low concentrations of phenothiazine drugs, such as trifluoperazine and promethazine, inhibit both receptor recruitment and secretion. Scatchard analysis of phenothiazine effects on somatostatin receptors reveals that these drugs reduce the number of receptors but do not affect the affinity of the receptor for somatostatin. These data indicate that membrane contact and fission steps during exocytosis can be biochemically separated.


Inverse association between coffee consumption and risk of cholecystectomy in women but not in men.
There is conflicting epidemiologic evidence on whether coffee consumption reduces the risk of gallstone disease. We examined the association between coffee consumption and risk of cholecystectomy (as a proxy for symptomatic gallstone disease) in a prospective cohort study. We collected data from 30,989 women (born 1914-1948) and 40,936 men (born 1918-1952) from the Swedish Mammography Cohort and the Cohort of Swedish Men. Baseline information on coffee consumption was collected by using a food-frequency questionnaire; subjects were followed up for procedures of cholecystectomy from 1998 through 2011 by linkage to the Swedish Patient Register. Hazard ratios (HRs) were estimated by using Cox proportional hazard models. During a total follow-up period of 905,933 person-years, we identified 1057 women and 962 men who had undergone a cholecystectomy. After adjustment for potential confounders, the HR of cholecystectomy was 0.58 (95% confidence interval [CI], 0.44-0.78) for women who drank ≥6 cups of coffee/day compared with women who drank <2 cups/day. In contrast, there was no association in men (HR, 0.96; 95% CI, 0.75-1.24). Because of this sex difference, we examined and found evidence of effect modification by menopausal status and use of hormone replacement therapy (HRT) (Pinteraction = .026). An inverse association was observed only in women who were premenopausal (HR, 0.17; 95% CI, 0.05-0.55) or used HRT (HR, 0.44; 95% CI, 0.28-0.70). We observed an inverse association between coffee consumption and risk of cholecystectomy in women who were premenopausal or used HRT but not in other women or in men.


Immunogold labeling to enhance contrast in optical coherence microscopy of tissue engineered corneal constructs.
Our lab has used an optical coherence microscope (OCM) to assess both the structure of tissue-engineered corneal constructs and their transparency. Currently, we are not able to resolve cells versus collagen matrix material in the images produced. We would like to distinguish cells in order to determine if they are viable while growing in culture and also if they are significantly contributing to the light scattering in the tissue. In order to do this, we are currently investigating the use of immunogold labeling. Gold nanoparticles are high scatterers and can create contrast in images. We have conjugated gold nanoparticles to antibodies specific to the alpha/sub 5/beta/sub 1/ integrins expressed in some corneal cells. This choice of target should allow assessment of the phenotypic behavior of the cells in the tissue, as different integrins are expressed in different phenotypes. This study applies the immunogold technique to study cultured corneal cells using the OCM with the ultimate goal of monitoring cellular behavior in engineered tissue and corroborating results from standard histological methods.


Protocol for a process evaluation of a cluster randomised controlled trial to improve management of multimorbidity in general practice: the 3D study.
As an increasing number of people are living with more than 1 long-term condition, identifying effective interventions for the management of multimorbidity in primary care has become a matter of urgency. Interventions are challenging to evaluate due to intervention complexity and the need for adaptability to different contexts. A process evaluation can provide extra information necessary for interpreting trial results and making decisions about whether the intervention is likely to be successful in a wider context. The 3D (dimensions of health, drugs and depression) study will recruit 32 UK general practices to a cluster randomised controlled trial to evaluate effectiveness of a patient-centred intervention. Practices will be randomised to intervention or usual care. The aim of the process evaluation is to understand how and why the intervention was effective or ineffective and the effect of context. As part of the intervention, quantitative data will be collected to provide implementation feedback to all intervention practices and will contribute to evaluation of implementation fidelity, alongside case study data. Data will be collected at the beginning and end of the trial to characterise each practice and how it provides care to patients with multimorbidity. Mixed methods will be used to collect qualitative data from 4 case study practices, purposively sampled from among intervention practices. Qualitative data will be analysed using techniques of constant comparison to develop codes integrated within a flexible framework of themes. Quantitative and qualitative data will be integrated to describe case study sites and develop possible explanations for implementation variation. Analysis will take place prior to knowing trial outcomes. Study approved by South West (Frenchay) National Health Service (NHS) Research Ethics Committee (14/SW/0011). Findings will be disseminated via a final report, peer-reviewed publications and practical guidance to healthcare professionals, commissioners and policymakers. ISRCTN06180958.


The Prevalence of Comorbid Personality Disorders in Treatment-Seeking Problem Gamblers: A Systematic Review and Meta-Analysis.
The aim of this study was to systematically review and meta-analyze the prevalence of comorbid personality disorders among treatment-seeking problem gamblers. Almost one half (47.9%) of problem gamblers displayed comorbid personality disorders. They were most likely to display Cluster B disorders (17.6%), with smaller proportions reporting Cluster C disorders (12.6%) and Cluster A disorders (6.1%). The most prevalent personality disorders were narcissistic (16.6%), antisocial (14.0%), avoidant (13.4%), obsessive-compulsive (13.4%), and borderline (13.1%) personality disorders. Sensitivity analyses suggested that these prevalence estimates were robust to the inclusion of clinical trials and self-selected samples. Although there was significant variability in reported rates, subgroup analyses revealed no significant differences in estimates of antisocial personality disorder according to problem gambling severity, measure of comorbidity employed, and study jurisdiction. The findings highlight the need for gambling treatment services to conduct routine screening and assessment of co-occurring personality disorders and to provide treatment approaches that adequately address these comorbid conditions.


Acquisition of doxorubicin resistance facilitates migrating and invasive potentials of gastric cancer MKN45 cells through up-regulating aldo-keto reductase 1B10.
Continuous exposure to doxorubicin (DOX) accelerates hyposensitivity to the drug-elicited lethality of gastric cells, with increased risks of the recurrence and serious cardiovascular side effects. However, the detailed mechanisms underlying the reduction of DOX sensitivity remain unclear. In this study, we generated a DOX-resistant variant upon continuously treating human gastric cancer MKN45 cells with incremental concentrations of the drug, and investigated whether the gain of DOX resistance influences gene expression of four aldo-keto reductases (AKRs: 1B10, 1C1, 1C2 and 1C3). RT-PCR analysis revealed that among the enzymes AKR1B10 is most highly up-regulated during the chemoresistance induction. The up-regulation of AKR1B10 was confirmed by analyses of Western blotting and enzyme activity. The DOX sensitivity of MKN45 cells was reduced and elevated by overexpression and inhibition of AKR1B10, respectively. Compared to the parental MKN45 cells, the DOX-resistant cells had higher migrating and invasive abilities, which were significantly suppressed by addition of AKR1B10 inhibitors. Zymographic and real-time PCR analyses also revealed significant increases in secretion and expression of matrix metalloproteinase (MMP) 2 associated with DOX resistance. Moreover, the overexpression of AKR1B10 in the parental cells remarkably facilitated malignant progression (elevation of migrating and invasive potentials) and MMP2 secretion, which were lowered by the AKR1B10 inhibitors. These results suggest that AKR1B10 is a DOX-resistance gene in the gastric cancer cells, and is responsible for elevating the migrating and invasive potentials of the cells through induction of MMP2.


A novel two-component signaling system that activates transcription of an enterohemorrhagic Escherichia coli effector involved in remodeling of host actin.
Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is responsible for worldwide outbreaks of bloody diarrhea, hemorrhagic colitis, and life-threatening hemolytic uremic syndrome. After colonizing the large intestine, EHEC forms attaching and effacing (AE) lesions on intestinal epithelial cells. These lesions cause destruction of the microvilli and elicit actin rearrangement to form pedestals that cup each bacterium individually. EHEC responds to a signal produced by the intestinal microbial flora, autoinducer-3 (AI-3), and the host hormones epinephrine and norepinephrine to activate transcription of the genes involved in AE lesion formation. These three signals, involved in interkingdom communication, are sensed by bacterial sensor kinases. Here we describe a novel two-component system, QseEF (quorum-sensing E. coli regulators E and F), which is part of the AI-3/epinephrine/norepinephrine signaling system. QseE is the sensor kinase and QseF the response regulator. The qseEF genes are cotranscribed, and transcription of qseEF is activated by epinephrine through the QseC sensor. A qseF mutant does not form AE lesions. QseF activates transcription of the gene encoding EspFu, an effector protein translocated to the host cell by the EHEC, which mimics a eukaryotic SH2/SH3 adapter protein to engender actin polymerization during pedestal formation. Expression of the espFu gene from a plasmid restored AE lesion formation to the qseF mutant, suggesting that lack of espFu expression in this mutant was responsible for the loss of pedestal formation. These findings suggest the QseEF is a two-component system involved in the regulation of AE lesion formation by EHEC.


Large Brains, Small Guts: The Expensive Tissue Hypothesis Supported within Anurans.
Brain size differs substantially among species, and several hypotheses have been proposed to explain the evolution of brain size. Because the brain is among the most energetically expensive organs in the vertebrate body, trade-offs have been hypothesized to exert constraints on brain size evolution. Prominently, the expensive tissue hypothesis (ETH) proposes that reducing the size of another expensive organ, such as the gut, should compensate for the cost of a large brain. But energetic constraints may also drive covariation between the brain and other costly traits-such as body maintenance, locomotion, or reproduction-as formulated in the energy trade-off hypothesis. To date, these hypotheses have mainly been tested in homeothermic animals and within the ectothermic animals, primarily in fishes. Here, we undertake a comparative test of the interplay between energetic limitations and brain size evolution within amphibians. After controlling for phylogenetic relationships and body size, we find a negative correlation between brain mass and the length of the digestive tract within 30 species of anurans. We further find that the evolution of large brain size is accompanied by an increase in female reproductive investment into egg size. Our results suggest that the evolution of brain size follows general patterns across vertebrate clades.


A study of in vitro attachment of Streptococcus sanguis and Actinomyces viscosus to saliva-treated titanium.
This study examined the initial attachment of Streptococcus sanguis G9-B and Actinomyces viscosus T14V to saliva-treated powdered enamel and titanium surfaces. Using an in vitro adherence model, significantly lower numbers of Actinomyces viscosus T14V bound to the saliva-treated titanium surface when compared to that of the similarly treated enamel. The binding of Streptococcus sanguis G9-B to titanium or enamel did not vary significantly. A comparison of the percentage of cells bound to the titanium surface revealed that S sanguis cells attached in significantly higher numbers when compared to the A viscosus cells.


Suppression of local haze variations in MERIS images over turbid coastal waters for retrieval of suspended sediment concentration.
Atmospheric correction over turbid waters can be problematic if atmospheric haze is spatially variable. In this case the retrieval of water quality is hampered by the fact that haze variations could be partly mistaken for variations in suspended sediment concentration (SSC). In this study we propose the suppression of local haze variations while leaving sediment variations intact. This is accomplished by a multispectral data projection (MDP) method based on a linear spectral mixing model, and applied prior to the actual standard atmospheric correction. In this linear model, the hazesediment spectral mixing was simulated by a coupled water-atmosphere radiative transfer (RT) model. As a result, local haze variations were largely suppressed and transformed into an approximately homogenous atmosphere over the MERIS top-of-atmosphere (TOA) radiance scene. The suppression of local haze variations increases the number of satellite images that are still suitable for standard atmospheric correction processing and subsequent water quality analysis.


A systematic review and Canadian consensus recommendations on the use of biomarkers in the treatment of non-small cell lung cancer.
Greater understanding of molecular pathways important in cell growth and proliferation of thoracic malignancies, particularly non-small cell lung cancer (NSCLC), has resulted in intense clinical and translational research. There is now considerable interest in personalizing treatment based on an understanding of tumor histology and molecular abnormalities. However, there is a multiplicity of data, often with discordant results resulting in confusion and uncertainty among clinicians. We conducted a systematic review and a consensus meeting of Canadian lung cancer oncologists and pathologists to make recommendations on the use of biomarkers in NSCLC. PubMed covering 2005 to March 2010 was searched using MESH terms for NSCLC and randomized trials, plus text words for the biomarkers of interest. Conference proceedings from 2005 to 2009 ASCO, ESMO, IASLC, and USCAP were also searched. The articles were reviewed by pairs of oncologists and pathologists to determine eligibility for inclusion. Ten oncologists and pathologists reviewed and summarized the literature at a meeting attended by 37 individuals. Draft recommendations were formulated and agreed upon by consensus process. There is some evidence that histology is prognostic for survival. There is evidence from multiple randomized clinical trials to recommend the following: histologic subtype is predictive of treatment efficacy and for some agents toxicity. Immunohistochemistry testing should be performed on NSCLC specimens that cannot be classified accurately with conventional H&E staining. As EGFR mutations are predictive of benefit from tyrosine kinase inhibitors, diagnostic NSCLC samples should be routinely tested for EGFR-activating mutations. Clinical data on K-RAS mutations are inconsistent, therefore testing is not recommended. There is insufficient evidence to recommend other biomarker testing. No biomarkers to date reliably predict improved efficacy for anti-VEGF therapy. Routine assessment for EML4/ALK mutations is not recommended at present, although emerging data suggest that it may become valuable in the near future. Assessment of NSCLC biomarkers is becoming increasingly important. Therefore, adequate diagnostic material must be obtained for accurate histologic subtyping and relevant molecular biology assays.


Down-regulation of c-myc and Cyclin D1 genes by antisense oligodeoxy nucleotides inhibits the expression of E2F1 and in vitro growth of HepG2 and Morris 5123 liver cancer cells.
A number of genetic interactions are involved in the control of cell cycle, but their role and nature have not been completely clarified. The knowledge of the behavior of these interactions in hepatocellular carcinoma, could optimize preventive and therapeutic strategies based on cell cycle restraint. We studied downstream events following c-MYC and CYCLIN D1 gene inhibition, by lipoplex-delivered MYC and CYCLIN D1 antisense oligodeoxy nucleotides (aODNM, aODND1), in in vitro cultured human HepG2 and rat Morris 5123 hepatoma cells. 0.5-20 micro M aODN(M) and aODND1 inhibited in vitro growth of both cell types. Scramble oligomer (SCR) and sense ODNs had no or relatively poor effect. Ten micromolar aODNM and aODND1, but not SCR, also induced a significant increase in the apoptotic index of HepG2 and 5123 cells, and inhibited colony formation in soft agar by HepG2 cells. Treatment of the cells with aODNM plus aODND1 had no additive effect on growth and apoptosis. aODNM and aODND1 induced >50% decrease in c-MYC and CYCLIN D1 gene expression, respectively, at both mRNA and protein level. The inhibition of gene expression by aODNs was highly specific, and SCR was without effect. The reduction in c-MYC and CYCLIN D1 expression by aODNs, was associated with a >50% decrease in E2F1 mRNA and protein production, without changes in CYCLIN A and CYCLIN E expression. These results suggest the involvement of both c-MYC and CYCLIN D1 on E2F1 gene function, and indicate that aODNM and aODND1 may inhibit hepatoma cell growth through down-regulation of the E2F1 gene. The inhibition of E2F1 gene expression by E2F1 aODN, was associated with strong growth restraint of HepG2 cells. Thus, interactions of c-MYC and CYCLIN D1 with E2F1 gene are essential for cell cycle activity in hepatoma cells, and their inhibition may have a therapeutic effect.


Nonnucleoside pyrrolopyrimidines with a unique mechanism of action against human cytomegalovirus.
Based upon a prior study which evaluated a series of nonnucleoside pyrrolo[2,3-d]pyrimidines as inhibitors of human cytomegalovirus (HCMV), we have selected three active analogs for detailed study. In an HCMV plaque-reduction assay, compounds 828, 951, and 1028 had 50% inhibitory concentrations (IC(50)s) of 0.4 to 1.0 microM. Similar results were obtained when 828 and 951 were examined by HCMV enzyme-linked immunosorbent assay (IC(50)s = 1.9 and 0.4 microM, respectively) and when 828 was tested in a viral DNA-DNA hybridization assay (IC(50) = 1.3 microM). In yield-reduction assays with a low multiplicity of infection (MOI), all three compounds caused multiple log(10) reductions in virus titer, and the activities of these compounds were comparable to the activity of ganciclovir (GCV; IC(90) = 0.2 microM). In contrast to the reduction of viral titers by GCV, the reduction of viral titers by 828, 951, and 1028 decreased with increasing MOI. Cytotoxicity in human foreskin fibroblasts and KB cells ranged from 32 to >100 microM. In addition, 828 (the only compound tested) was less toxic against human bone marrow progenitor cells than GCV. Time-of-addition and time-of-removal studies established that the three pyrrolopyrimidines inhibited HCMV replication before GCV had an effect on viral DNA synthesis but after viral adsorption. Compound 828 was equally effective against GCV-sensitive and GCV-resistant HCMV clinical isolates. Combination studies with 828 and GCV showed that the effects of the two compounds on HCMV were additive but not synergistic. Taken together, the data indicate that these pyrrolopyrimidines target a viral protein that is required in an MOI-dependent manner and that is expressed early in the HCMV replication cycle.


Pharmacokinetics-Pharmacodynamics of Enmetazobactam Combined with Cefepime in a Neutropenic Murine Thigh Infection Model.
Third-generation cephalosporin (3GC)-resistant Enterobacteriaceae are classified as critical priority pathogens, with extended-spectrum β-lactamases (ESBLs) as principal resistance determinants. Enmetazobactam (formerly AAI101) is a novel ESBL inhibitor developed in combination with cefepime for empirical treatment of serious Gram-negative infections in settings where ESBLs are prevalent. Cefepime-enmetazobactam has been investigated in a phase 3 trial in patients with complicated urinary tract infections or acute pyelonephritis. This study examined pharmacokinetic-pharmacodynamic (PK-PD) relationships of enmetazobactam, in combination with cefepime, for ESBL-producing isolates of Klebsiella pneumoniae in 26-h murine neutropenic thigh infection models. Enmetazobactam dose fractionation identified the time above a free threshold concentration (fT > CT ) as the PK-PD index predictive of efficacy. Nine ESBL-producing isolates of K. pneumoniae, resistant to cefepime and piperacillin-tazobactam, were included in enmetazobactam dose-ranging studies. The isolates encoded CTX-M-type, SHV-12, DHA-1, and OXA-48 β-lactamases and covered a cefepime-enmetazobactam MIC range from 0.06 to 2 μg/ml. Enmetazobactam restored the efficacy of cefepime against all isolates tested. Sigmoid curve fitting across the combined set of isolates identified enmetazobactam PK-PD targets for stasis and for a 1-log10 bioburden reduction of 8% and 44% fT > 2 μg/ml, respectively, with a concomitant cefepime PK-PD target of 40 to 60% fT > cefepime-enmetazobactam MIC. These findings support clinical dose selection and breakpoint setting for cefepime-enmetazobactam.


The Lyme vaccine: a cautionary tale.
People living in endemic areas acquire Lyme disease from the bite of an infected tick. This infection, when diagnosed and treated early in its course, usually responds well to antibiotic therapy. A minority of patients develops more serious disease, particularly after a delay in diagnosis or therapy, and sometimes chronic neurological, cardiac, or rheumatological manifestations. In 1998, the FDA approved a new recombinant Lyme vaccine, LYMErix, which reduced new infections in vaccinated adults by nearly 80%. Just 3 years later, the manufacturer voluntarily withdrew its product from the market amidst media coverage, fears of vaccine side-effects, and declining sales. This paper reviews these events in detail and focuses on the public communication of risks and benefits of the Lyme vaccine and important lessons learned.


Smell and taste disorders: a primary care approach.
Smell and taste disorders are common in the general population, with loss of smell occurring more frequently. Although these disorders can have a substantial impact on quality of life and may represent significant underlying disease, they are often overlooked by the medical community. Patients may have difficulty recognizing smell versus taste dysfunction and frequently confuse the concepts of "flavor" and "taste." While the most common causes of smell disturbance are nasal and sinus disease, upper respiratory infection and head trauma, frequent causes of taste disturbance include oral infections, oral appliances (e.g., dentures), dental procedures and Bell's palsy. Medications can interfere with smell and taste, and should be reviewed in all patients with reported dysfunction. In addition, advancing age has been associated with a natural impairment of smell and taste ability. A focused history and a physical examination of the nose and mouth are usually sufficient to screen for underlying pathology. Computed tomographic scanning or magnetic resonance imaging of affected areas, as well as commercially available standardized tests, may be useful in selected patients. The causes of olfactory dysfunction that are most amenable to treatment include obstructing polyps or other masses (treated by excision) and inflammation (treated with steroids). Enhancement of food flavor and appearance can improve quality of life in patients with irreversible dysfunction.


Intracerebellar hemispheres schwannoma: a case report.
Brain parenchyma schwannoma is a rare intracranial tumor, and especially rare in cerebellar hemisphere. In this report, a case of cerebellar schwannoma in a 52-year-old woman, was studied by computed tomography (CT), magnetic resonance image (MRI) and PET-CT. This tumor was totally removed by surgery. The histological diagnosis of schwannoma was confirmed by histological, HE and immunohistological staining examination (positivity for the S-100 protein and vimentin, and partly positivity for P53 (70 %+), and negative for GFAP). The patient has been followed-up for more than one year, and she lives in good condition and brain MRI shows no recurrence. Surgery is the most effective treatment for cerebellar schwannoma.


A cross-sectional comparison of three guidelines for intrapartum cardiotocography.
To compare the cardiotocography classification systems outlined by the International Federation of Gynecology and Obstetrics (FIGO) in 2015 and the UK National Institute for Health and Care Excellence (NICE) in 2007 and 2014. A cross-sectional observational study of cardiotocography practices at a UK hospital was conducted among labor ward staff (n=21) from November 1 to November 31, 2015. All observers classified ten cardiotocography traces according to the three guidelines using a bespoke form. Outcome measures included interobserver agreement (κ values), percentage agreement, intervention rate, and perceived ease of use. The κ values were 0.38 (FIGO 2015), 0.37 (NICE 2007), and 0.34 (NICE 2014). The percentage agreement was identical across the three systems for both normal cardiotocography results (100.0%) and for intermediate or suspicious results (80.9%). By contrast, the percentage agreement for abnormal or pathological findings was 47.6% for NICE 2014, 76.2% for FIGO 2015, and 91.0% for NICE 2007 guidelines. Among 210 observations, intervention was deemed necessary for 48 (22.9%) for FIGO 2015, 29 (13.8%) for NICE 2014, and 56 (26.7%) for NICE 2007 guidelines. The FIGO 2015 system was considered the easiest to use by 13 (61.9%) observers. Interobserver agreement of cardiotocography classification is suboptimal. The FIGO 2015 system offered favorable agreement scores, perceived ease of use, and a moderate intervention rate.


Current Activities of the Coalition of Cancer Cooperative Groups.
The Coalition of Cancer Cooperative Groups is an organization representing the interests of patients and researchers who conduct research through the National Cancer Institute-supported National Clinical Trials Network (NCTN). The NCTN provides a crucial mechanism for executing practice-changing cancer clinical research to achieve both cancer control and development of new therapeutic agents or modality approaches. Public funding, largely through the National Cancer Institute, ensures that the work of the NCTN achieves important research that would not otherwise be accomplished in the private sector. In fall 2017, the Coalition of Cancer Cooperative Groups convened a Scientific Leadership Council to review the current state of the network with regard to research capabilities and to develop a list of research questions to be prioritized by the network. This report presents the results of this meeting, detailing a roadmap for future work by the NCTN.


Economic burden of malaria and predictors of cost variability to rural households in south-central Ethiopia.
While recognizing the recent remarkable achievement in the global malaria reduction, the disease remains a challenge to the malaria endemic countries in Africa. Beyond the huge health consequence of malaria, policymakers need to be informed about the economic burden of the disease to the households. However, evidence on the economic burden of malaria in Ethiopia is scanty. The aims of this study were to estimate the economic burden of malaria episode and to identify predictors of cost variability to the rural households. A prospective costing approach from a household perspective was employed. A total of 190 malaria patients were enrolled to the study from three health centers and nine health posts in Adami Tullu district in south-central Ethiopia, in 2015. Primary data were collected on expenditures due to malaria, forgone working days because of illness, socioeconomic and demographic situation, and households' assets. Quantile regression was applied to predict factors associated with the cost variation. Socioeconomic related inequality was measured using concentration index and concentration curve. The median cost of malaria per episode to the household was USD 5.06 (IQR: 2.98-8.10). The direct cost accounted for 39%, while the indirect counterpart accounted for 61%. The history of malaria in the last six months and the level of the facility visited in the health system predominantly influenced the direct cost. The indirect cost was mainly influenced by the availability of antimalarial drugs in the health facility. The concentration curve and the concentration index for direct cost indicate significant pro-rich inequality. Plasmodium falciparum is significantly more costly for households compared to Plasmodium vivax. The economic burden of malaria to the rural households in Ethiopia was substantial-mainly to the poor-indicating that reducing malaria burden could contribute to the poverty reduction as well.


Carotid endarterectomy with regional anesthesia: an audit of 71 cases.
The aim of carotid endarterectomy (CEA) is the successful removal of the atherosclerotic plaque and meticulous anatomical and physiological reconstruction of the carotid artery without any perioperative complications. Endarterectomy can also be carried out with regional anesthesia, which allows monitoring of the neurological status. This study reviews patients who underwent CEA with regional anesthesia. A total of 71 consecutive patients were planned to undergo carotid endarterectomy under regional anesthesia between 2000 and 2006. All of these patients, assessed by our neurovascular team, were recruited prospectively and the data was analyzed retrospectively. The study group consisted of 23 women and 48 men with a mean age of 62 (range 37-79). 67 patients (94,4%) had symptomatic, and 4 (5,6%) had asymptomatic (5.6%) carotid stenosis. Six patients (8.45%) were intolerant to carotid clamping (8,45%). The stroke morbidity rate was 1.4% and the mortality rate was 1.4%. The mean hospitalization time was 2.07 (range 1-10) days. Carotid endarterectomy performed under regional anesthesia can be a safe method which may lead to better neurological outcome. This method offers several advantages including monitorization of the cerebral ischemia during surgery, usage of selective shunting, decreased need for intensive care and shorter hospitalization time.


Demonstrating the potential of a novel spider venom-based biopesticide for target-specific control of the small hive beetle, a serious pest of the European honeybee.
The parasitic small hive beetle (Aethina tumida) feeds on pollen, honey and brood of the European honey bee (Apis mellifera); establishment in North America and Australia has resulted in severe economic damage to the apiculture industry. We report potential for the "in-hive" use of a novel biopesticide that is toxic to this invasive beetle pest but harmless to honeybees. Constructs encoding the spider venom neurotoxin ω-hexatoxin-Hv1a (Hv1a) linked to the N- or C-terminus of snowdrop lectin (GNA) were used to produce recombinant Hv1a/GNA and GNA/Hv1a fusion proteins. Both were similarly toxic to beetles by injection (respective LD50s 1.5 and 0.9 nmoles/g larvae), whereas no effects on adult honeybee survival were observed at injection doses of > 200 nmoles/g insect. When fed to A. tumida larvae, GNA/Hv1a was significantly more effective than Hv1a/GNA (LC50s of 0.52 and 1.14 mg/ml diet, respectively), whereas both proteins were similarly toxic to adults. Results suggested that the reduced efficacy of Hv1a/GNA against larvae was attributable to differences in the susceptibility of the fusion proteins to cleavage by gut serine proteases. In laboratory assays, A. tumida larval survival was significantly reduced when brood, inoculated with eggs, was treated with GNA/Hv1a.


Prevalence of Metabolic Syndrome and Associated Factors in a Cohort of Individuals With Treatment-Resistant Depression: Results From the FACE-DR Study.
The aim of this study was to estimate the prevalence of metabolic syndrome (MetS) and its components in a cohort of French patients with treatment-resistant depression (TRD) and to determine correlations with sociodemographic, clinical, and treatment-related factors. From 2012 to 2018, 205 patients who met DSM-IV criteria for major depressive episode with moderate-to-severe symptoms (Montgomery-Asberg Depression Rating Scale score ≥ 20), and at least Stage II resistance according to Thase and Rush criteria were enrolled in the FondaMental Advanced Centers of Expertise in Resistant Depression (FACE-DR) cohort. Data on sociodemographic and clinical characteristics, lifestyle information, and treatment and comorbidities were collected, and a blood sample was drawn. MetS was defined according to the criteria of the International Diabetes Federation. Overall, 38% of individuals with TRD met criteria for MetS. The frequency of MetS was significantly higher in men than in women only for patients aged 40 years or older (46.3% vs 35.2%, P = .0427). Moreover, whereas the management for diabetes was good, less than one-third of the patients with high blood pressure or dyslipidemia were treated for these conditions. Multivariate analysis showed that individuals with abnormal plasma c-reactive protein levels had a 3-fold increased risk (95% CI, 1.5-5.2) of having MetS, independent of other potential confounders. The prevalence of MetS is higher in patients with TRD than in those with other psychiatric disorders and characterized by a considerable undertreatment of some components of MetS in this population. Diagnosis and treatment of the components of MetS should be systematically performed to prevent the occurrence of cardiovascular diseases in patients with TRD. These findings highlight the need for integrated care, with more interaction and coordination between psychiatrists and primary care providers.


Base sequence context effects on nucleotide excision repair.
Nucleotide excision repair (NER) plays a critical role in maintaining the integrity of the genome when damaged by bulky DNA lesions, since inefficient repair can cause mutations and human diseases notably cancer. The structural properties of DNA lesions that determine their relative susceptibilities to NER are therefore of great interest. As a model system, we have investigated the major mutagenic lesion derived from the environmental carcinogen benzo[a]pyrene (B[a]P), 10S (+)-trans-anti-B[a]P-N(2)-dG in six different sequence contexts that differ in how the lesion is positioned in relation to nearby guanine amino groups. We have obtained molecular structural data by NMR and MD simulations, bending properties from gel electrophoresis studies, and NER data obtained from human HeLa cell extracts for our six investigated sequence contexts. This model system suggests that disturbed Watson-Crick base pairing is a better recognition signal than a flexible bend, and that these can act in concert to provide an enhanced signal. Steric hinderance between the minor groove-aligned lesion and nearby guanine amino groups determines the exact nature of the disturbances. Both nearest neighbor and more distant neighbor sequence contexts have an impact. Regardless of the exact distortions, we hypothesize that they provide a local thermodynamic destabilization signal for repair.


Improving postural control by applying mechanical noise to ankle muscle tendons.
The application of subthreshold mechanical vibrations with random frequencies (white mechanical noise) to ankle muscle tendons is known to increase muscle proprioceptive information and to improve the detection of ankle movements. The aim of the present study was to analyze the effect of this mechanical noise on postural control, its possible modulation according to the sensory strategies used for postural control, and the consequences of increasing postural difficulty. The upright stance of 20 healthy young participants tested with their eyes closed was analyzed during the application of four different levels of noise and compared to that in the absence of noise (control) in three conditions: static, static on foam, and dynamic (sinusoidal translation). The quiet standing condition was conducted with the eyes open and closed to determine the subjects' visual dependency to maintain postural stability. Postural performance was assessed using posturographic and motion analysis evaluations. The results in the static condition showed that the spectral power density of body sway significantly decreased with an optimal level of noise and that the higher the spectral power density without noise, the greater the noise effect, irrespective of visual dependency. Finally, noise application was ineffective in the foam and dynamic conditions. We conclude that the application of mechanical noise to ankle muscle tendons is a means to improve quiet standing only. These results suggest that mechanical noise stimulation may be more effective in more impaired populations.


NFkappaB1 (p50)-deficient mice are not susceptible to multiple low-dose streptozotocin-induced diabetes.
Insulin-dependent diabetes mellitus (IDDM) is a disease characterized by the autoimmune destruction of the pancreatic beta-cells, which requires the expression of a number of immune-related genes including major histocompatibility complex proteins, cytokines, chemokines, and cytotoxic enzymes, many of which are regulated by the transcription factor, NFkappaB. Inhibition of the entire NFkappaB family of transcription factors may be harmful, as these factors are involved in many normal physiological processes. However, identifying and targeting specific NFkappaB subunits critical for the pathogenesis of disease may prove to be valuable in designing new therapeutic strategies. To assess the potential role of the NFkappaB subunit, p50, in the development of IDDM, mice with gene disruption for NFkappaB (p50) were investigated for susceptibility to IDDM. We found that p50-deficient mice were fully resistant against multiple low-dose streptozotocin-induced diabetes, a model of diabetes with a strong autoimmune component. The site of involvement of NFkappaB (p50) lies at an early, critical juncture of immune activation and proinflammatory mediator production, because: (1) isolated islets of Langerhans from NFkappaB (p50)-deficient mice were not protected from the islet dysfunction induced by in vitro application of proinflammatory cytokines; (2) p50-deficient mice were not resistant to diabetes induced by a single high dose of streptozotocin, a model with a large oxidant component and no autoimmune involvement; and (3) diabetes induced up-regulation of nitric oxide and interleukin-12 was blocked in the p50-deficient mice. Our data suggest that NFkappaB (p50) has an essential role in the development of autoimmune diabetes. Selective therapeutic blockade of this subunit may be beneficial in preventing IDDM.


The importance of mechanisms for the evolution of cooperation.
Studies aimed at explaining the evolution of phenotypic traits have often solely focused on fitness considerations, ignoring underlying mechanisms. In recent years, there has been an increasing call for integrating mechanistic perspectives in evolutionary considerations, but it is not clear whether and how mechanisms affect the course and outcome of evolution. To study this, we compare four mechanistic implementations of two well-studied models for the evolution of cooperation, the Iterated Prisoner's Dilemma (IPD) game and the Iterated Snowdrift (ISD) game. Behavioural strategies are either implemented by a 1 : 1 genotype-phenotype mapping or by a simple neural network. Moreover, we consider two different scenarios for the effect of mutations. The same set of strategies is feasible in all four implementations, but the probability that a given strategy arises owing to mutation is largely dependent on the behavioural and genetic architecture. Our individual-based simulations show that this has major implications for the evolutionary outcome. In the ISD, different evolutionarily stable strategies are predominant in the four implementations, while in the IPD each implementation creates a characteristic dynamical pattern. As a consequence, the evolved average level of cooperation is also strongly dependent on the underlying mechanism. We argue that our findings are of general relevance for the evolution of social behaviour, pleading for the integration of a mechanistic perspective in models of social evolution.


Light adaptation, rods, and the human cone flicker ERG.
During the course of light adaptation, the amplitude and implicit time of the human cone ERG change systematically. In the present study, the effect of adapting field luminance on these ERG changes was assessed, and the hypothesis that light adaptation of the rod system is the primary determining factor was evaluated. Cone ERG responses, isolated through the use of 31.1-Hz flicker, were obtained from two visually normal subjects, initially under dark-adapted conditions and then repeatedly for 30 min following the onset of each of a series of ganzfeld adapting fields with luminances that ranged from -1.2 to 2.1 log cd/m2. The increase in flicker ERG amplitude and decrease in implicit time during light adaptation were greatest at the highest adapting field luminances. Photopically equivalent achromatic and long-wavelength adapting fields induced comparable increases in flicker ERG amplitude, while scotopically equivalent adapting fields had considerably different effects. This latter finding demonstrates that the rod system is not a major determinant of the adaptation-induced increase in cone ERG amplitude.


Renal gene expression in embryonic and newborn diabetic mice.
Several novel genes that are upregulated in diabetic kidneys have been identified. Recently, transforming growth factor beta driven secreted proteins, i.e., connective tissue growth factor and gremlin (bone morphogenetic protein 2), have been identified, and their expression has been correlated with the tissue changes seen in diabetic nephropathy in the adult population. However, there are very few studies reported in the literature that describe the gene expression in the diabetic state during embryonic and neonatal life. It is well known that exposure to glucose or its epimer, i.e., mannose, induces marked dysmorphogenesis of the embryonic metanephros in an organ culture system. These changes are associated with ATP depletion and marked apoptosis, suggesting an oxidant stress in the induction of dysmorphogenesis of the embryonic metanephros. In view of the glucose-induced changes in the fetal metanephros, a diabetic state was induced by the administration of streptozotocin during pregnancy, and newborn mouse kidneys were processed for suppression subtractive hybridization-PCR. In addition, a diabetic state was induced in newborn diabetic mice, and after 1 week their kidneys were harvested and subjected to representational difference analysis of cDNA. Four novel genes with upregulated mRNA expression were identified. They included: (1) a translocase inner mitochondrial membrane 44 that is involved in the ATP-dependent import of preproteins from the cytosol into the mitochondrial matrix; (2) a kidney-specific aldo-keto reductase that utilizes NADPH and NADH as cofactors in the reduction of aromatic aldehydes and aldohexoses; (3) Rap1b, a Ras-related small GTP-binding protein that behaves as a GTPase and cycles between GTP-bound (active) and GDP-bound (inactive) states associated with conformational change, and (4) a fusion protein of ubiquitin polypeptide and ribosomal protein L40 (UbA(52) or ubiquitin/60) that is intimately involved in the ubiquitin-dependent proteasome pathway related to the accelerated degradation of proteins under various stress conditions, such as those seen in patients with cancer and diabetes mellitus.


Using stochastic language models (SLM) to map lexical, syntactic, and phonological information processing in the brain.
Language comprehension involves the simultaneous processing of information at the phonological, syntactic, and lexical level. We track these three distinct streams of information in the brain by using stochastic measures derived from computational language models to detect neural correlates of phoneme, part-of-speech, and word processing in an fMRI experiment. Probabilistic language models have proven to be useful tools for studying how language is processed as a sequence of symbols unfolding in time. Conditional probabilities between sequences of words are at the basis of probabilistic measures such as surprisal and perplexity which have been successfully used as predictors of several behavioural and neural correlates of sentence processing. Here we computed perplexity from sequences of words and their parts of speech, and their phonemic transcriptions. Brain activity time-locked to each word is regressed on the three model-derived measures. We observe that the brain keeps track of the statistical structure of lexical, syntactic and phonological information in distinct areas.


Early phenotypic choices by neuronal precursors, revealed by clonal analysis of the chick embryo hindbrain.
The mechanisms that generate diverse neuronal phenotypes within the central nervous system are thought to involve local cues or cell-cell interactions acting late in neurogenesis, perhaps as late as the last precursor cell division. We describe here a clonal analysis of neuronal development in the chick hindbrain, using an intracellular tracer to mark single precursor cells, that suggests the operation of an alternative strategy. The majority of clones, ranging from 1 to 46 cells, contained neurons of only one of several possible phenotypes. These single-phenotype clones were not positionally restricted within a rhombomere but were interspersed with other clones containing distinct phenotypes. The assignment of neuronal phenotype in this brain region may, therefore, be made in early precursors and remembered through several rounds of mitotic expansion and dispersal.


Fermentation tube test statistics for direct water sampling and comments on the Thomas formula.
This article describes a new interpretation of the Fermentation Tube Test (FTT) performed on water samples drawn from natural waters polluted by faecal bacteria. A novel general procedure to calculate the Most Probable Number of bacteria (MPN) in natural waters has been derived for the FTT for both direct and independent repetitive multiple water sampling. The generalization based on solving the newly proposed equation allows consideration of any a priori frequency distribution g(n) of bacterial concentration in analysed water as opposed to the unbounded uniform a priori distribution g(n) assumed in the standard procedures of the Standard Methods of Examining Water and Wastewater and ISO 8199:1988. Also a statistical analysis of the Thomas formula is presented. It is demonstrated that the Thomas formula is highly inaccurate. The authors propose, therefore, to remove the Thomas formula from the Standard Methods of Examining Water and Wastewater and ISO 8199:1988 altogether and replace it with a solution of the proposed generalized equation.


Soil structure is an important omission in Earth System Models.
Most soil hydraulic information used in Earth System Models (ESMs) is derived from pedo-transfer functions that use easy-to-measure soil attributes to estimate hydraulic parameters. This parameterization relies heavily on soil texture, but overlooks the critical role of soil structure originated by soil biophysical activity. Soil structure omission is pervasive also in sampling and measurement methods used to train pedotransfer functions. Here we show how systematic inclusion of salient soil structural features of biophysical origin affect local and global hydrologic and climatic responses. Locally, including soil structure in models significantly alters infiltration-runoff partitioning and recharge in wet and vegetated regions. Globally, the coarse spatial resolution of ESMs and their inability to simulate intense and short rainfall events mask effects of soil structure on surface fluxes and climate. Results suggest that although soil structure affects local hydrologic response, its implications on global-scale climate remains elusive in current ESMs.


The boron conundrum: which principles underlie the formation of large hollow boron cages?
Extensive optimisation calculations are performed for the B(80) isomers in order to find out which principles underlie the formation of large hollow boron cages. Our analysis shows that the most stable isomers contain triangular B(10) or rhombohedral B(16) building blocks. The lowest-energy isomer has C(3v) symmetry and is characterised by a belt of three interconnected B(16) units and two separate B(10) units. At the B3LYP/6-31G(d) level of theory, this newly discovered isomer is 2.29, 1.48, and 0.54 eV below the leapfrog B(80) of Szwacki et al., the T(h) -B(80) of Wang, and the D(3d) -B(80) of Pochet et al., respectively. Our C(3v) isomer is therefore identified as the most stable hollow cage isomer of B(80) presently known. Its HOMO-LUMO gap of 1.6 eV approaches that of the leapfrog B(80). The leapfrog principle still remains a reliable scheme for producing boron cages with larger HOMO-LUMO gaps, whereas the thermodynamically most stable B(80) cages are formed when all pentagonal faces are capped. We show that large hollow cages of boron retain a preference for fullerene frames. The additional capping is in accordance with the following rules: preference for capping of pentagonal faces, formation of B(10) and/or B(16) units, homogeneous distribution of the hexagonal caps, and hole density approaching 1/9. Although our most stable B(80) isomer still remains higher in energy than the B(80) core-shell structure, we show that by applying the bonding principles to larger structures it is possible to construct boron cages with higher stabilisation energy per boron atom than the core-shell structure; a prototypical example is B(160). This clearly shows the continuous competition between the two suggested construction schemes, namely, the formation of multiple-shell structures and hollow cages.


Applications and societal benefits of plastics.
This article explains the history, from 1600 BC to 2008, of materials that are today termed 'plastics'. It includes production volumes and current consumption patterns of five main commodity plastics: polypropylene, polyethylene, polyvinyl chloride, polystyrene and polyethylene terephthalate. The use of additives to modify the properties of these plastics and any associated safety, in use, issues for the resulting polymeric materials are described. A comparison is made with the thermal and barrier properties of other materials to demonstrate the versatility of plastics. Societal benefits for health, safety, energy saving and material conservation are described, and the particular advantages of plastics in society are outlined. Concerns relating to littering and trends in recycling of plastics are also described. Finally, we give predictions for some of the potential applications of plastic over the next 20 years.


Analysing Normative Influences on the Prevalence of Female Genital Mutilation/Cutting among 0-14 Years Old Girls in Senegal: A Spatial Bayesian Hierarchical Regression Approach.
Female genital mutilation/cutting (FGM/C) is a harmful traditional practice affecting the health and rights of women and girls. This has raised global attention on the implementation of strategies to eliminate the practice in conformity with the Sustainable Development Goals (SDGs). A recent study on the trends of FGM/C among Senegalese women (aged 15-49) which examined how individual- and community-level factors affected the practice, found significant regional variations in the practice. However, the dynamics of the practice among girls (0-14 years old) is not fully understood. This paper attempts to fill this knowledge gap by investigating normative influences in the persistence of the practice among Senegalese girls, identify and map 'hotspots'. We do so by using a class of Bayesian hierarchical geospatial modelling approach implemented in R statistical software (R Foundation for Statistical Computing, Vienna, Austria) using R2BayesX package. We employed Markov Chain Monte Carlo (MCMC) techniques for full Bayesian inference, while model fit and complexity assessment utilised deviance information criterion (DIC). We found that a girl's probability of cutting was higher if her mother was cut, supported FGM/C continuation or believed that the practice was a religious obligation. In addition, living in rural areas and being born to a mother from Diola, Mandingue, Soninke or Poular ethnic group increased a girl's likelihood of being cut. The hotspots identified included Matam, Tambacounda and Kolda regions. Our findings offer a clearer picture of the dynamics of FGM/C practice among Senegalese girls and prove useful in informing evidence-based intervention policies designed to achieve the abandonment of the practice in Senegal.


Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease.
One of the most overlooked of all serious complications of diabetes is cardiovascular autonomic neuropathy. There is now clear evidence that suggests activation of inflammatory cytokines in diabetic patients and that these correlate with abnormalities in sympathovagal balance. Dysfunction of the autonomic system predicts cardiovascular risk and sudden death in patients with type 2 diabetes. It also occurs in prediabetes, providing opportunities for early intervention. Simple tests that can be carried out at the bedside with real-time output of information - within the scope of the practicing physician - facilitate diagnosis and allow the application of sound strategies for management. The window of opportunity for aggressive control of all the traditional risk factors for cardiovascular events or sudden death with intensification of therapy is with short duration diabetes, the absence of cardiovascular disease and a history of severe hypoglycemic events. To this list we can now add autonomic dysfunction and neuropathy, which have become the most powerful predictors of risk for mortality. It seems prudent that practitioners should be encouraged to become familiar with this information and apply risk stratification in clinical practice. Several agents have become available for the correction of functional defects in the autonomic nervous system, and restoration of autonomic balance is now possible.


Angiosarcomas of the breast: a review of 70 cases.
Angiosarcoma arising in the irradiated breast after breast-conserving therapy is being reported with increasing frequency. As more women undergo breast-conserving therapy, the incidence can be expected to increase. The objective of this study was to review breast angiosarcomas diagnosed from 1981 to 2000 from our state cancer registry. A comprehensive review of a population-based registry, Florida Cancer Data System, identified 70 cases of breast angiosarcomas from 1981 to 2000. Descriptive statistical and chi analyses were performed. Of the 70 cases at presentation, 39 were primary breast angiosarcomas (PBAs) and 31 were secondary breast angiosarcomas (SBAs). The mean ages were 59 and 72.9 for the PBA and SBA groups, respectively. In the SBA group the mean age of breast cancer diagnosis was 67.6. The mean time to diagnosis of the angiosarcoma was 5.2 years after breast cancer irradiation. At presentation 82% (n = 32) and 48% (n = 15), in the PBA and SBA groups, respectively had local disease (P = 0.003). The primary treatment was mastectomy in each group. There was no difference in mortality between the 2 groups (PSA; n = 18, SBA; n = 17). Angiosarcoma of the breast is rare and this study reports a review of 70 cases from 1980 to 2000. Angiosarcoma after breast-conserving therapy is increasingly diagnosed in a small but significant portion of breast carcinoma survivors. SBA patients present with more advance disease. Surgical resection is the primary therapy. The aggressive nature of this disease demands further investigation of adjuvant therapy to prevent recurrence of disease after surgery.


Individual Differences in Moral Development: Does Intelligence Really Affect Children's Moral Reasoning and Moral Emotions?
This study investigates the relationship between intelligence and individual differences in children's moral development across a range of different moral transgressions. Taking up prior research that showed morality and intelligence to be related in adolescents and adults, the current study wants to test if these findings can be extended to younger children. The study was designed to address some of the shortcomings in prior research by examining young children aged between 6 years; 4 months and 8 years; 10 months, using a broad concept of moral development including emotional aspects and applying an approach that is closely connected to children's daily lives. Participants (N = 129) completed a standardized intelligence test and were presented four moral transgression stories to assess moral development. Results demonstrated that findings from prior research with adolescents or adults cannot simply be extended to younger participants. No significant correlations of moral development and intelligence were found for any of the presented stories. This provides first evidence that - at least in middle childhood - moral developmental status seems to be independent from children's general intelligence assessed by figural inductive reasoning tests.


Testing projected wild bee distributions in agricultural habitats: predictive power depends on species traits and habitat type.
Species distribution models (SDM) are increasingly used to understand the factors that regulate variation in biodiversity patterns and to help plan conservation strategies. However, these models are rarely validated with independently collected data and it is unclear whether SDM performance is maintained across distinct habitats and for species with different functional traits. Highly mobile species, such as bees, can be particularly challenging to model. Here, we use independent sets of occurrence data collected systematically in several agricultural habitats to test how the predictive performance of SDMs for wild bee species depends on species traits, habitat type, and sampling technique. We used a species distribution modeling approach parametrized for the Netherlands, with presence records from 1990 to 2010 for 193 Dutch wild bees. For each species, we built a Maxent model based on 13 climate and landscape variables. We tested the predictive performance of the SDMs with independent datasets collected from orchards and arable fields across the Netherlands from 2010 to 2013, using transect surveys or pan traps. Model predictive performance depended on species traits and habitat type. Occurrence of bee species specialized in habitat and diet was better predicted than generalist bees. Predictions of habitat suitability were also more precise for habitats that are temporally more stable (orchards) than for habitats that suffer regular alterations (arable), particularly for small, solitary bees. As a conservation tool, SDMs are best suited to modeling rarer, specialist species than more generalist and will work best in long-term stable habitats. The variability of complex, short-term habitats is difficult to capture in such models and historical land use generally has low thematic resolution. To improve SDMs' usefulness, models require explanatory variables and collection data that include detailed landscape characteristics, for example, variability of crops and flower availability. Additionally, testing SDMs with field surveys should involve multiple collection techniques.


Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood.
Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.


Proton transfer in acetaldehyde-water clusters mediated by a single water molecule.
Proton transfer in aqueous media is a ubiquitous process, occurring in acid-base chemistry, biology, and in atmospheric photochemistry. Photoionization mass spectrometry coupled with theoretical calculations demonstrate that a relay-type proton transfer mechanism is operational for single-water-molecule-assisted proton transfer between two acetaldehyde molecules in the gas phase. Threshold photoionization of acetaldehyde-water clusters leads to proton transfer between the formyl groups (-CH[double bond, length as m-dash]O) of one acetaldehyde molecule to another, and the subsequent formation of cationic moieties. Density functional theory computations reveal several plausible pathways of proton transfer in mixed cluster cations. Among these pathways, water-mediated proton transfer is energetically favored. Mass spectra and photoionization efficiency curves confirm these theoretical findings and also demonstrate the increased stability of cluster cations where acetaldehyde molecules are symmetrically bonded to the hydronium ion.


The paradoxical decline and growth of trust as a function of borderline personality disorder trait count: Using discontinuous growth modelling to examine trust dynamics in response to violation and repair.
Borderline personality disorder (BPD) is associated with paradoxical trust cognitions and behaviours. While BPD is associated with difficulty forming trust and maintaining cooperation in trust-based exchanges, design and analytical methodology best suited to reveal the temporal ebb and flow of trust have been underutilized. We used an economic game to examine the trajectories of trust as it forms, dissolves, and restores in response to trust violation and repair, and to explain how these vary as a function of borderline pathology. Young adults (N = 234) played a 15-round trust game in which partner trustworthiness was varied to create three phases: trust formation, trust violation, and trust restoration. Discontinuous growth modelling was employed to capture the trends in trust over time and their relationship with BPD trait count. BPD trait count was associated with an incongruous pattern of trust behaviour in the form of declining trust when interacting with a new and cooperative partner, and paradoxically, increasing trust following multiple instances of trust violation by that partner. BPD trait count was also associated with trust restoring at a faster rate than it was originally formed. By adopting a methodology that recognizes the dynamic nature of trust, this study illustrated at a micro level how relational disturbances may be produced and maintained in those with a moderate to high BPD trait count. Further investigation of the factors and processes that underlie these incongruous trust dynamics is recommended.


Quantifying nitrogen leaching response to fertilizer additions in China's cropland.
Agricultural soils account for more than 50% of nitrogen leaching (LN) to groundwater in China. When excess levels of nitrogen accumulate in groundwater, it poses a risk of adverse health effects. Despite this recognition, estimation of LN from cropland soils in a broad spatial scale is still quite uncertain in China. The uncertainty of LN primarily stems from the shape of nitrogen leaching response to fertilizer additions (N rate) and the role of environmental conditions. On the basis of 453 site-years at 51 sites across China, we explored the nonlinearity and variability of the response of LN to N rate and developed an empirical statistical model to determine how environmental factors regulate the rate of N leaching (LR). The result shows that LN-N rate relationship is convex for most crop types, and varies by local hydro-climates and soil organic carbon. Variability of air temperature explains a half (∼ 52%) of the spatial variation of LR. The results of model calibration and validation indicate that incorporating this empirical knowledge into a predictive model could accurately capture the variation in leaching and produce a reasonable upscaling from site to country. The fertilizer-induced LN in 2008 for China's cropland were 0.88 ± 0.23 TgN (1σ), significantly lower than the linear or uniform model, as assumed by Food and Agriculture Organization and MITERRA-EUROPE models. These results also imply that future policy to reduce N leaching from cropland needs to consider environmental variability rather than solely attempt to reduce N rate.


Satisfaction with and perceived cultural competency of healthcare providers: the minority experience.
It is well known that nonwhite minority participation in clinical research is lower than their representation in the community. The goal of this study was to assess satisfaction of minority community members in Omaha with the care received and cultural competency of healthcare providers. We sought input from Omaha minority communities on how to improve the care they received and asked why they did not participate in healthcare research. Seventy-two minority members representing African Americans, Hispanic Americans, Native Americans, Sudanese, and Vietnamese; and eight whites were surveyed. The results of this study indicated that the majority of our respondents were satisfied with the care they received, but for a small percentage, language, communication and/or culture contributed to dissatisfaction. In addition, some respondents did not think the provider was culturally competent, i.e., not sufficiently knowledgeable about their racial, ethnic and/or cultural background. Some participants indicated that they preferred a provider of similar racial, ethnic and/or cultural background, and/or thought some diseases were better treated by a provider of the same racial, ethnic and/or cultural background. Regardless of the cultural competency of the provider, the overwhelming majority of our respondents (with the exception of African Americans) indicated a willingness to participate in healthcare research. In conclusion, this study found that satisfaction with healthcare providers was not associated with perceived cultural competency and that the cultural competency of the provider did not affect patient willingness to participate in healthcare research; however, we acknowledge that the Hawthorne effect may be in operation.


Factors associated with adherence to COVID-19 prevention measures in the Democratic Republic of the Congo (DRC): results of an online survey.
We aimed to assess the level of adherence to COVID-19 preventive measures in the Democratic Republic of the Congo (DRC) and to identify factors associated with non-adherence. A cross-sectional population-based online survey. The study was conducted in 22 provinces of the DRC. Five provinces with a satisfactory number of respondents were included in the analysis: Haut Katanga, Kasaï-Central, Kasaï-Oriental, Kinshasa and North Kivu. The participants were people aged ≥18 years, living in the DRC. A total of 3268 participants were included in the study analysis. Both convenience sampling (surveyors themselves contacted potential participants in different districts) and snowball sampling (the participants were requested to share the link of the questionnaire with their contacts) methods were used. We computed adherence scores using responses to 10 questions concerning COVID-19 preventive measures recommended by the WHO and the DRC Ministry of Health. We used logistic regression analysis with generalised estimating equations to identify factors of poor adherence. We also asked about the presence or absence of flu-like symptoms during the preceding 14 days, whether a COVID-19 test was done and the test result. Data from 3268 participants were analysed. Face masks were not used by 1789 (54.7%) participants. Non-adherence to physical distancing was reported by 1364 (41.7%) participants. 501 (15.3%) participants did not observe regular handwashing. Five variables were associated with poor adherence: lower education level, living with other people at home, being jobless/students, living with a partner and not being a healthcare worker. Despite compulsory restrictions imposed by the government, only about half of the respondents adhered to COVID-19 preventive measures in the DRC. Disparities across the provinces are remarkable. There is an urgent need to further explore the reasons for these disparities and factors associated with non-adherence.


Common genetic variation associated with increased susceptibility to prostate cancer does not increase risk of radiotherapy toxicity.
Numerous germline single-nucleotide polymorphisms increase susceptibility to prostate cancer, some lying near genes involved in cellular radiation response. This study investigated whether prostate cancer patients with a high genetic risk have increased toxicity following radiotherapy. The study included 1560 prostate cancer patients from four radiotherapy cohorts: RAPPER (n=533), RADIOGEN (n=597), GenePARE (n=290) and CCI (n=150). Data from genome-wide association studies were imputed with the 1000 Genomes reference panel. Individuals were genetically similar with a European ancestry based on principal component analysis. Genetic risks were quantified using polygenic risk scores. Regression models tested associations between risk scores and 2-year toxicity (overall, urinary frequency, decreased stream, rectal bleeding). Results were combined across studies using standard inverse-variance fixed effects meta-analysis methods. A total of 75 variants were genotyped/imputed successfully. Neither non-weighted nor weighted polygenic risk scores were associated with late radiation toxicity in individual studies (P>0.11) or after meta-analysis (P>0.24). No individual variant was associated with 2-year toxicity. Patients with a high polygenic susceptibility for prostate cancer have no increased risk for developing late radiotherapy toxicity. These findings suggest that patients with a genetic predisposition for prostate cancer, inferred by common variants, can be safely treated using current standard radiotherapy regimens.


The dynamic interactome and genomic targets of Polycomb complexes during stem-cell differentiation.
Although the core subunits of Polycomb group (PcG) complexes are well characterized, little is known about the dynamics of these protein complexes during cellular differentiation. We used quantitative interaction proteomics and genome-wide profiling to study PcG proteins in mouse embryonic stem cells (ESCs) and neural progenitor cells (NPCs). We found that the stoichiometry and genome-wide binding of PRC1 and PRC2 were highly dynamic during neural differentiation. Intriguingly, we observed a downregulation and loss of PRC2 from chromatin marked with trimethylated histone H3 K27 (H3K27me3) during differentiation, whereas PRC1 was retained at these sites. Additionally, we found PRC1 at enhancer and promoter regions independently of PRC2 binding and H3K27me3. Finally, overexpression of NPC-specific PRC1 interactors in ESCs led to increased Ring1b binding to, and decreased expression of, NPC-enriched Ring1b-target genes. In summary, our integrative analyses uncovered dynamic PcG subcomplexes and their widespread colocalization with active chromatin marks during differentiation.


Spiking neural P systems with weights.
A variant of spiking neural P systems with positive or negative weights on synapses is introduced, where the rules of a neuron fire when the potential of that neuron equals a given value. The involved values-weights, firing thresholds, potential consumed by each rule-can be real (computable) numbers, rational numbers, integers, and natural numbers. The power of the obtained systems is investigated. For instance, it is proved that integers (very restricted: 1, -1 for weights, 1 and 2 for firing thresholds, and as parameters in the rules) suffice for computing all Turing computable sets of numbers in both the generative and the accepting modes. When only natural numbers are used, a characterization of the family of semilinear sets of numbers is obtained. It is shown that spiking neural P systems with weights can efficiently solve computationally hard problems in a nondeterministic way. Some open problems and suggestions for further research are formulated.


Anatomy and histology as socially networked learning environments: some preliminary findings.
An exploratory study to better understand the "networked" life of the medical school as a learning environment. In a recent academic year, the authors gathered data during two six-week blocks of a sequential histology and anatomy course at a U.S. medical college. An eight-item questionnaire captured different dimensions of student interactions. The student cohort/network was 48 first-year medical students. Using social network analysis (SNA), the authors focused on (1) the initial structure and the evolution of informal class networks over time, (2) how informal class networks compare to formal in-class small-group assignments in influencing student information gathering, and (3) how peer assignment of professionalism role model status is shaped more by informal than formal ties. In examining these latter two issues, the authors explored not only how formal group assignment persisted over time but also how it functioned to prevent the tendency for groupings based on gender or ethnicity. The study revealed an evolving dynamic between the formal small-group learning structure of the course blocks and the emergence of informal student networks. For example, whereas formal group membership did influence in-class questions and did prevent formation of groups of like gender and ethnicity, outside-class questions and professionalism were influenced more by informal group ties where gender and, to a much lesser extent, ethnicity influence student information gathering. The richness of these preliminary findings suggests that SNA may be a useful tool in examining an array of medical student learning encounters.


The hippocampus and executive functions in depression.
The relationship between depression, hippocampus (HC), and executive dysfunctions seems complex and has been the focus of research. Recent evidence indicates a possible role of HC in executive dysfunction seen in depression. No such studies on Indian population have been done. To look for changes in HC and executive functions in depression. A cross-sectional analytical controlled study. Sample size 50 (controls 50). Hippocampal volume and executive dysfunction was measured using structural magnetic resonance imaging (MRI) and Wisconsin Card Sorting Test (WCST), respectively. Findings on these two parameters were compared between depressives and healthy matched controls as well as between first episode (FE) and recurrent depressives and across the severity of depression (mild, moderate, and severe). Statistical Package for Social Sciences (SPSS) version 17 was used for analysis. Normally distributed continuous variables were analyzed with independent t-tests. Analysis of variance (ANOVA) was used for multiple comparisons. Categorical data were compared with χ(2) or Fisher's exact test. Clinical correlations were conducted using Pearson correlations. Depressed patients had a smaller left (Lt) hippocampal volume as well as poor performance on several measures of executive functions. Smaller hippocampal volume was found even in FE. Those who had a past burden of depressive illness had an even smaller hippocampal volume. No direct correlation was found between the HC volume and cognitive dysfunction. Depressive illness appears to be toxic to the HC. The relationship between HC and executive dysfunction in depression may be indirect through its functional connections.


Small intestinal absorption in patients with chronic obstructive pulmonary disease complicated by cor pulmonale - A pilot study.
Cor pulmonale is a common complication to Chronic Obstructive Pulmonary Disease (COPD), and may result in increased pressure in the inferior caval vein and stasis of the liver. The chronic pulmonary hypertension may lead to stasis in the veins from the small intestine and thereby compromise absorption of nutrients. To investigate whether patients with pulmonary hypertension have reduced absorption capacity compared to COPD patients without cor pulmonale. Absorption of d-xylose (25 g) and zinc (132 mg), administered as a single dose, was tested in 14 COPD patients, seven with and seven without cor pulmonale. The presence of cor pulmonale was determined by echocardiography. The concentration of d-xylose and zinc were measured in peripheral blood one, two and three hours after ingestion and used as markers of absorption. Furthermore, urine was collected for five hours to determine the amount of excreted d-xylose. No significant difference in absorption of d-xylose (p = 0.28) or zinc (p = 0.51) was found between the two groups. However, a trend towards a delay in d-xylose absorption, as assessed by time-to-peak concentration, was observed in patients with cor pulmonale (p = 0.08). There was no significant difference in the amount of excreted d-xylose in the urine between the groups (p = 0.52). No correlation was found between the tricuspid regurgitation gradient and the absorption of both test-markers (rs = 0.34 and rs = -0.25). Likewise, no correlations were found between the inferior caval pressure during the in- and expiration phases and the absorption of d-xylose (rs = -0.09 rs = 0.23) or zinc (rs = -0.39, rs = -0.39). We found no indications that small intestinal absorption is affected in a clinically relevant degree in patients with cor pulmonale.


A human T lymphoid cell variant resistant to the acyclic nucleoside phosphonate 9-(2-phosphonylmethoxyethyl)adenine shows a unique combination of a phosphorylation defect and increased efflux of the agent.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is a new antiviral agent with activity against herpes viruses and retroviruses, including human immunodeficiency virus, but its metabolism and mechanism of action remain unclear. We have isolated a human T lymphoid cell line (CEMr-1) that is resistant to the antiproliferative effects of PMEA. The antiviral effects of PMEA against human immunodeficiency virus-1 infection were also greatly reduced in CEMr-1 cells, compared with the parental cells. This mutant showed cross-resistance to the related acyclic nucleoside phosphonates 9-(2-phosphonylmethoxyethyl)diaminopurine and 9-(2-phosphonylmethoxyethyl)guanine and the lipophilic prodrug bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine-( bispome-PMEA), as well as partial resistance to the purine nucleosides 2-chlorodeoxyadenosine, 2-fluro-9-beta-D-arabinosylfuranosyladenine, and adenosine, but did not show resistance to 2'-deoxyadenosine or 9-beta-D-arabinosylfuranosyladenine. We compared the uptake and metabolism of [3H]PMEA and [3H]-bispom-PMEA in the mutant and parental cells. The analysis of radioactive products by high pressure liquid chromatography revealed marked alterations in the ability of the mutant cell line to accumulate PMEA and its anabolites, compared with the parental cells. Accumulation of PMEA, PMEA monophosphate, and PMEA bisphosphate (major metabolites formed with either PMEA or bispom-PMEA) decreased by 50, 95, and 97%, respectively. Compared with the parental cells, the variant cells showed a approximately 7-fold increase in the rate of efflux of PMEA and a 2-fold decrease in the activity of adenylate kinase. In contrast, other enzymes of nucleotide metabolism, such as adenosine kinase, deoxycytidine kinase, and 5-phosphoribosyl-1-pyrophosphate synthetase, showed no significant change in the two cell lines. Overall, these results suggest that the mutation in this resistant cell line is of a novel type, involving an alteration in the cellular efflux of PMEA as the major basis for the resistant phenotype.


SBIRT Implementation for Adolescents in Urban Federally Qualified Health Centers.
Alcohol, tobacco, and other drug use remains highly prevalent among US adolescents and is a threat to their well-being and to the public health. Evidence from clinical trials and meta-analyses supports the effectiveness of Screening, Brief Intervention and Referral to Treatment (SBIRT) for adolescents with substance misuse but primary care providers have been slow to adopt this evidence-based approach. The purpose of this paper is to describe the theoretically informed methodology of an on-going implementation study. This study protocol is a multi-site, cluster randomized trial (N=7) guided by Proctor's conceptual model of implementation research and comparing two principal approaches to SBIRT delivery within adolescent medicine: Generalist vs. Specialist. In the Generalist Approach, the primary care provider delivers brief intervention (BI) for substance misuse. In the Specialist Approach, BIs are delivered by behavioral health counselors. The study will also examine the effectiveness of integrating HIV risk screening within an SBIRT model. Implementation Strategies employed include: integrated team development of the service delivery model, modifications to the electronic medical record, regular performance feedback and supervision. Implementation outcomes, include: Acceptability, Appropriateness, Adoption, Feasibility, Fidelity, Costs/Cost-Effectiveness, Penetration, and Sustainability. The study will fill a major gap in scientific knowledge regarding the best SBIRT implementation strategy at a time when SBIRT is poised to be brought to scale under health care reform. It will also provide novel data to inform the expansion of the SBIRT model to address HIV risk behaviors among adolescents. Finally, the study will generate important cost data that offer guidance to policymakers and clinic directors about the adoption of SBIRT in adolescent health care.


Modifications of Sarcoplasmic Reticulum Function Prevent Progression of Sarcomere-Linked Hypertrophic Cardiomyopathy Despite a Persistent Increase in Myofilament Calcium Response.
Hypertrophic cardiomyopathy (HCM) is a genetic disorder caused by mutations in different genes mainly encoding myofilament proteins and therefore called a "disease of the sarcomere." Despite the discovery of sarcomere protein mutations linked to HCM almost 30 years ago, the cellular mechanisms responsible for the development of this disease are not completely understood and likely vary among different mutations. Moreover, despite many efforts to develop effective treatments for HCM, these have largely been unsuccessful, and more studies are needed to better understand the cellular mechanisms of the disease. In experiments reported here, we investigated a mouse model expressing the mutant cTnT-R92Q, which is linked to HCM and induces an increase in myofilament Ca2+ sensitivity and diastolic dysfunction. We found that early correction of the diastolic dysfunction by phospholamban knockout (PLNKO) was able to prevent the development of the HCM phenotype in troponin T (TnT)-R92Q transgenic (TG) mice. Four groups of mice in FVB/N background were generated and used for the experiments: (1) non-transgenic (NTG)/PLN mice, which express wild-type TnT and normal level of PLN; (2) NTG/PLNKO mice, which express wild-type TnT and no PLN; (3) TG/PLN mice, which express TnT-R92Q and normal level of PLN; (4) TG/PLNKO mice, which express TnT-R92Q and no PLN. Cardiac function was determined using both standard echocardiographic parameters and speckle tracking strain measurements. We found that both atrial morphology and diastolic function were altered in TG/PLN mice but normal in TG/PLNKO mice. Histological analysis showed a disarray of myocytes and increased collagen deposition only in TG/PLN hearts. We also observed increased Ca2+/calmodulin-dependent protein kinase II (CaMKII) phosphorylation only in TG/PLN hearts but not in TG/PLNKO hearts. The rescue of the HCM phenotype was not associated with differences in myofilament Ca2+ sensitivity between TG/PLN and TG/PLNKO mice. Moreover, compared to standard systolic echo parameters, such as ejection fraction (EF), speckle strain measurements provided a more sensitive approach to detect early systolic dysfunction in TG/PLN mice. In summary, our results indicate that targeting diastolic dysfunction through altering Ca2+ fluxes with no change in myofilament response to Ca2+ was able to prevent the development of the HCM phenotype and should be considered as a potential additional treatment for HCM patients.


Soliton trapping of dispersive waves in tapered optical fibers.
We show that trapping of dispersive waves by solitons is significantly enhanced in tapered optical fibers as compared with nontapered fibers. For the trapping process to occur, the soliton must be decelerating; in nontapered fiber, the cause of soliton deceleration is Raman self-scattering to spectral regions of lower group velocity. It is shown here that deceleration of the soliton due to the changing group velocities in a tapered optical fiber also enables and enhances the trapping process, independently of Raman gain. This explains the enhanced blue spectral extension observed for supercontinuum generation in tapered optical fibers. This result also indicates that trapping of dispersive waves by solitons will also be possible in fibers or waveguides made from materials with negligible Raman self-scattering.


Laser Doppler flowmetry in manual medicine research.
Laser Doppler flowmetry (LDF) is commonly used in combination with reactivity tests to noninvasively evaluate skin sympathetic nerve activity and skin microvascular function. In manual medicine research, LDF has been used as a marker for global peripheral sympathetic nervous system function, but these results should be considered with caution because skin sympathetic nerve activity physiology is often overlooked. Another limitation of LDF in manual medicine research is the processing of LDF recordings. Two methods have been suggested: the time-domain analysis and the frequency-domain analysis. Standardization is required for data collection and processing in either domain to accurately interpret these changes in skin blood flow that occur after manual procedures. For physiologic studies using LDF, the authors recommend the use of noninvasive reactivity tests (positive controls) to evaluate the different mechanisms involved in overall skin blood flow changes and to compare the magnitude of these changes with those specifically elicited by manual procedures.


Factors Affecting Uptake of NaF-18 by the Normal Skeleton.
The primary aim of this study was to examine if factors such as renal function, height, weight and age could affect the uptake of sodium fluoride-18 (NaF-18) by the normal bone. This is the first study to examine the possible factors that can influence NaF-18 uptake in the normal bone. A retrospective study was done on NaF-18 PET/CT bone scans from January 2010 to May 2012 at our institution. All NaF-18 PET/CT studies used the same clinical protocol. Our excluding criteria were patients with abnormal renal function and patients with past history of cancer and metabolic bone diseases. Spearman's correlation was used to analyze the data. From our study (n = 11 patients), no correlation was found between SUVmax and serum creatinine and between SUVmax and age. However, significant correlations were found between SUVmax and height (cm) and between SUVmax and weight (kg) for thoracic 5, 7, 12 and lumbar 2 vertebral levels. Based on our findings, SUVmax values in NaF-18 PET/CT bone scans can vary depending on the patient's height, weight and bone region. This information can be helpful in diagnosing and monitoring bone pathologies and can help explain the clinical findings.


Discovering Genetic Interactions in Large-Scale Association Studies by Stage-wise Likelihood Ratio Tests.
Despite the success of genome-wide association studies in medical genetics, the underlying genetics of many complex diseases remains enigmatic. One plausible reason for this could be the failure to account for the presence of genetic interactions in current analyses. Exhaustive investigations of interactions are typically infeasible because the vast number of possible interactions impose hard statistical and computational challenges. There is, therefore, a need for computationally efficient methods that build on models appropriately capturing interaction. We introduce a new methodology where we augment the interaction hypothesis with a set of simpler hypotheses that are tested, in order of their complexity, against a saturated alternative hypothesis representing interaction. This sequential testing provides an efficient way to reduce the number of non-interacting variant pairs before the final interaction test. We devise two different methods, one that relies on a priori estimated numbers of marginally associated variants to correct for multiple tests, and a second that does this adaptively. We show that our methodology in general has an improved statistical power in comparison to seven other methods, and, using the idea of closed testing, that it controls the family-wise error rate. We apply our methodology to genetic data from the PROCARDIS coronary artery disease case/control cohort and discover three distinct interactions. While analyses on simulated data suggest that the statistical power may suffice for an exhaustive search of all variant pairs in ideal cases, we explore strategies for a priori selecting subsets of variant pairs to test. Our new methodology facilitates identification of new disease-relevant interactions from existing and future genome-wide association data, which may involve genes with previously unknown association to the disease. Moreover, it enables construction of interaction networks that provide a systems biology view of complex diseases, serving as a basis for more comprehensive understanding of disease pathophysiology and its clinical consequences.


Expression and nuclear localization of BLM, a chromosome stability protein mutated in Bloom's syndrome, suggest a role in recombination during meiotic prophase.
Bloom's syndrome (BS) is a recessive human genetic disorder characterized by short stature, immunodeficiency and elevated risk of malignancy. BS cells have genomic instability and an increased frequency of sister chromatid exchange. The gene mutated in BS, BLM, encodes a 3'-5' helicase (BLM) with homology to bacterial recombination factor, RecQ. Human males homozygous for BLM mutations are infertile and heterozygous individuals display increased frequencies of structural chromosome abnormalities in their spermatozoa. Also, mutations in the Saccharomyces cerevisiae homolog of BLM, Sgs1, cause a delay in meiotic nuclear division and a reduction in spore viability. These observations suggest that BLM may play a role during meiosis. Our antibodies raised against the C terminus of the human protein specifically recognize both mouse and human BLM in western blots of cell lines and in successive developmental stages of spermatocytes, but fail to detect BLM protein in a cell line with a C-terminally truncated protein. BLM protein expression and location are detected by immunofluorescence and immunoelectron microscopy as discrete foci that are sparsely present on early meiotic prophase chromosome cores, later found abundantly on synapsed cores, frequently in combination with the recombinases RAD51 and DMC1, and eventually as pure BLM foci. The colocalization of RAD51/DMC1 with BLM and the statistically significant excess of BLM signals in the synapsed pseudoautosomal region of the X-Y chromosomes, which is a recombinational hot spot, provide indications that BLM protein may function in the meiotic recombination process.


Four-year impact of an alert notification system on closed-loop communication of critical test results.
One of the patient safety goals proposed by the Joint Commission urges hospitals to develop a policy for communicating critical test results and to measure adherence to that policy. We evaluated the impact of an alert notification system on policy adherence for communicating critical imaging test results to referring providers and assessed system adoption over the first 4 years after implementation. This study was performed in a 753-bed academic medical center. The intervention, an automated alert notification system for critical results, was implemented in January 2010. The primary outcome was adherence to institutional policy for timely closed-loop communication of critical imaging results, and the secondary outcome was system adoption. Policy adherence was determined through manual review of a random sample of radiology reports from the first 4 years after the intervention (n = 37,604) compared with baseline outcomes 1 year before the intervention (n = 9430). Adoption was evaluated by quantifying the use of the system overall and the proportion of alerts that used noninterruptive communication as a percentage of all reports generated by 320 radiologists (n = 1,538,059). A statistical analysis of the trend at 6-month intervals over 4 years was performed using a chi-square trend test. Adherence to the policy increased from 91.3% before the intervention to 95.0% after the intervention (p < 0.0001). There was a ninefold increase in the critical results communicated via the system (chi-square trend test, p < 0.0001). During the first 4 years after the intervention, 41,445 alerts (41% of the total number of alerts) used the system's noninterruptive process for communicating less urgent critical results, which was substantially unchanged over the 4 years postintervention, thus reducing unnecessary paging interruptions. An automated alert notification system for communicating critical imaging results was successfully adopted and was associated with increased adherence to institutional policy for communicating critical test results and with reduced workflow interruptions.