Where should infants sleep? A comparison of risk for suffocation of infants sleeping in cribs, adult beds, and other sleeping locations.
To ascertain whether the number of sudden infant deaths as a result of suffocation in cribs, in adult beds, on sofas or chairs, and on other sleep surfaces was increasing whether attributable to increased reporting, diagnostic shift, or an actual increase in suffocation deaths and to compare the risk of reported accidental suffocation for infants on sleep surfaces designed for infants with the risk on adult beds. We reviewed all accidental suffocation deaths among infants < or =11 months of age reported to the United States Consumer Product Safety Commission from 1980 through 1983 and 1995 through 1998. We compared infants' ages and other demographic data, the sleep location and surface used, and the reported mechanism or pattern of death. For 1995-1998, we used data on sleep location from an annual survey of randomly selected households of living infants younger than 8 months, collected as part of the National Infant Sleep Position Study at the National Institute of Child Health and Human Development, to calculate risk for death as a result of suffocation in cribs, in adult beds, and on sofas or chairs. The number of reported suffocation deaths by location were compared between the 1980s and 1990s using logistic regression modeling to calculate odds ratios (OR), 95% confidence intervals (CI), and P values. Comparative risks for suffocation deaths on a given sleep surface for infants in the 1990s were examined by calculating rates of death per 100 000 exposed infants and comparing the 95% CI for overlap. From the 1980s, 513 cases of infant suffocation were considered; from the 1990s, 883 cases. The number of reported suffocation deaths in cribs fell from 192 to 107, the number of reported deaths in adult beds increased from 152 to 391, and the number of reported deaths on sofas or chairs increased from 33 to 110. Using cribs as the reference group and adjusting for potential confounders, the multivariate ORs showed that infant deaths in adult beds were 8.1 times more likely to be reported in the 1990s than in the 1980s (95% CI: 3.2-20.3), and infant deaths on sofas and chairs were 17.2 times more likely to be reported in the 1990s than in the 1980s (95% CI: 5.0-59.3). The sleep location of a subset of cases from the 1990s, 348 infants younger than 8 months at death, was compared with the sleep location of 4220 living infants younger than 8 months. The risk of suffocation was approximately 40 times higher for infants in adult beds compared with those in cribs. The increase in risk remained high even when overlying deaths were discounted (32 times higher) or the estimate of rates of bedsharing among living infants doubled (20 times higher). Reported deaths of infants who suffocated on sleep surfaces other than those designed for infants are increasing. The most conservative estimate showed that the risk of suffocation increased by 20-fold when infants were placed to sleep in adult beds rather than in cribs. The public should be clearly informed of the attendant risks.


Empirically derived subtypes of lifetime anxiety disorders: developmental and clinical correlates in U.S. adolescents.
The current study examined the sex- and age-specific structure and comorbidity of lifetime anxiety disorders among U.S. adolescents. The sample consisted of 2,539 adolescents (1,505 females and 1,034 males) from the National Comorbidity Survey-Adolescent Supplement who met criteria for Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev. [DSM-IV-TR]) lifetime anxiety disorders (American Psychiatric Association, 2000). Adolescents ranged in age from 13 to 18 years (M = 15.2 years, SE = 0.08 years) and were 39% non-White. Multiple-group latent class analysis was conducted by adolescent sex and age to identify subgroups of adolescents with similar anxiety disorder profiles. Developmental and clinical correlates of empirically derived classes were also examined to assess the nomological validity of identified subgroups. A 7-class solution provided the best fit to the data, with classes defined primarily by one rather than multiple anxiety disorders. Results also indicated that classes displayed similar diagnostic profiles across age, but varied by sex. Classes characterized by multiple anxiety disorders were consistently associated with a greater degree of persistence, clinical severity, impairment, and comorbidity with other DSM-IV-TR psychiatric disorders. The presentation of lifetime anxiety disorders among adolescents and the observation of unique correlates of specific classes provide initial evidence for the utility of individual DSM-IV-TR anxiety disorder categories. Although findings of the present study should be considered preliminary, results emphasize the potential value of early intervention and gender-specific conceptualization and treatment of anxiety disorders.


A causal relationship between face-patch activity and face-detection behavior.
The primate brain contains distinct areas densely populated by face-selective neurons. One of these, face-patch ML, contains neurons selective for contrast relationships between face parts. Such contrast-relationships can serve as powerful heuristics for face detection. However, it is unknown whether neurons with such selectivity actually support face-detection behavior. Here, we devised a naturalistic face-detection task and combined it with fMRI-guided pharmacological inactivation of ML to test whether ML is of critical importance for real-world face detection. We found that inactivation of ML impairs face detection. The effect was anatomically specific, as inactivation of areas outside ML did not affect face detection, and it was categorically specific, as inactivation of ML impaired face detection while sparing body and object detection. These results establish that ML function is crucial for detection of faces in natural scenes, performing a critical first step on which other face processing operations can build.


Integrating actors into a simulation program: a primer.
We describe our more than 10 years' experience working with actors and provide a "how-to" guide to recruiting, auditioning, hiring, training, and mentoring actors for work as simulated patients in simulation programs. We contend that trained actors add great realism, richness, and depth to simulation-based training programs. The actors experience satisfaction from their contributions, and their skill and improvisational talent allow programs to offer ethical and relational training, customized to a wide range of practitioners and adapted across a variety of health care conversations. Such learning opportunities can directly address Accreditation Council for Graduate Medical Education core competencies in preparing capable, confident, and empathic health care practitioners.


Is the syndrome of pathological laughing and crying a manifestation of pseudobulbar palsy?
A case of angiographically occult brainstem vascular malformation presenting solely with pathological laughing and crying is reported. Although this emotional syndrome has been seen in association with several different pathological entities, review of the literature failed to identify its occurrence as the only clinical expression of angiographically occult brainstem vascular malformation, or as a solitary symptom in any disease. Our data suggest that pathological laughing and crying can occur without any other manifestation of pseudobulbar palsy. An attempt is made to correlate this patient's clinical and radiological findings. This case was treated by stereotactic Bragg-peak proton beam therapy.


Effect of acupuncture on bronchial asthma.
1. Needle acupuncture was performed at three sites in twenty patients in a clinical attack of bronchial asthma. 2. In all patients the symptoms of bronchoconstriction improved during the attacks when the correct site was stimulated, and in five patients wheezing was abolished. 3. Stimulation at the correct site produced a significant increase in the mean FEV1-0 (58%) and FVC (29%) but not in maximal mid-expiratory flow rate (MMFR; 76%), when compared with the findings before acupuncture, along with a significant fall in the Pa,CO2 and an insignificant fall in Pa,O2. A mild tachycardia was also observed. 4. After acupuncture a greater improvement in FEV1-0, FVC and MMFR was produced by inhalation of isoprenaline. 5. No significant changes in FEV1-0, FVC, MMFR, pulse rate or arterial blood gas tensions occurred after acupuncture at control sites. 6. In four of the patients during clinical remission acupuncture was performed before and after histamine aerosol challenge, but there was no effect on either the severity or the duration of the histamine-induced bronchoconstriction. 7. It is concluded that acupunture probably reduced the reflex component of the bronchoconstriction, but failed to influence direct smooth muscle constriction caused by histamine.


Healthcare Resource Use and Cost Implications in the MOMENTUM 3 Long-Term Outcome Study.
The MOMENTUM 3 trial compares the centrifugal HeartMate 3 (HM3) with the axial HeartMate II (HMII) continuous-flow left ventricular assist system in patients with advanced heart failure, irrespective of the intended goal of therapy. The trial's 2-year clinical outcome (n=366) demonstrated superiority of the HM3 for the primary end point (survival free of a disabling stroke or reoperation to replace or remove a malfunctioning pump). This analysis evaluates health resource use and cost implications of the observed differences between the 2 devices while patients were enrolled in the trial. We analyzed all hospitalizations and their associated costs occurring after discharge from the implant hospitalization until censoring (study withdrawal, heart transplantation, and pump exchange with a nonstudy device or death). Each adjudicated episode of hospital-based care was used to calculate costs (device-attributable and non-device-attributable event costs), estimated by using trial data and payer administrative claims databases. Cost savings stratified by subgroups (study outcome [transplant, death, or ongoing on device], intended goal of therapy, type of insurance, or sex) were also assessed. In 366 randomly assigned patients, 361 comprised the as-treated group (189 in the HM3 group and 172 in the HMII group), of whom 337 (177 in the HM3 group and 160 in the HMII group) were successfully discharged following implantation. The HM3 arm experienced fewer total hospitalizations per patient-year (HM3: 2.1±0.2 versus HMII: 2.7±0.2; P=0.015) and 8.3 fewer hospital days per patient-year on average (HM3: 17.1 days versus HMII: 25.5 days; P=0.003). These differences were driven by patients hospitalized for suspected pump thrombosis (HM3: 0.6% versus HMII: 12.5%; P<0.001) and stroke (HM3: 2.8% versus HMII: 11.3%; P=0.002). Controlled for time spent in the study (average cumulative cost per patient-year), postdischarge HM3 arm costs were 51% lower than with the HMII (HM3: $37 685±4251 versus HMII: $76 599±11 889, P<0.001) and similar in either bridge to transplant or destination therapy intent. In this 2-year outcome economic analysis of the MOMENTUM 3 trial, the HM3 demonstrated a reduction in rehospitalizations, hospital days spent during rehospitalizations, and a significant cost savings following discharge in comparison with the HMII left ventricular assist system, irrespective of the intended goal of therapy. URL: https://www.clinicaltrials.gov . Unique identifier: NCT02224755.


Nonsteroidal anti-inflammatory drugs, gastroprotection, and benefit-risk.
Gastroprotective agents (GPA) substantially reduce morbidity and mortality with long-term nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. To evaluate efficacy of NSAIDs, protection against NSAID-induced gastrointestinal harm, and balance of benefit and risk. Free text searches of PubMed (December 2012) supplemented with "related citation" and "cited by" facilities on PubMed and Google Scholar for patient requirements, NSAID effectiveness, pain relief benefits, gastroprotective strategies, adherence to gastroprotection prescribing, and serious harm with NSAIDs and GPA. Patients want 50% reduction in pain intensity and improved fatigue, distress, and quality of life. Meta-analyses of NSAID trials in musculoskeletal conditions had bimodal responses with good pain relief or little. Number needed to treat (NNTs) for good pain relief were 3 to 9. Proton pump inhibitors (PPI) and high-dose histamine-2 receptor antagonists (H2 RA) provided similar gastroprotection, with no conclusive evidence of greater PPI efficacy compared with high-dose H2 RA. Prescriber adherence to guidance on use of GPA with NSAIDS was 49% in studies published since 2005; patient adherence was less than 100%. PPI use at higher doses over longer periods is associated with increased risk of serious adverse events, including fracture; no such evidence was found for H2 RA. Patients with chronic conditions are more willing to accept risk of harm for successful treatment than their physicians. Guidance on NSAIDs use should ensure that patients have a good level of pain relief and that gastroprotection is guaranteed for the NSAID delivering good pain relief. Fixed-dose combinations of NSAID plus GPA offer one solution.


Primary haemophilus influenzae pyomyositis in an infant: a case report.
Promyositis is a term used to denote primary pyogenic infection of the skeletal muscle. Because striped muscle tissue is normally resistant to bacterial infection, pyomyositis is very rare. In tropical countries, pyomyositis accounts for about 4% of hospital surgical admission, but it is far less common in temperate climates. It is more common in adults and especially in men, but it can occur at any age. We would like to present an 8-month-old infant to make pediatricians aware of the possibility of pyomyositis in cases of a mass over muscle, or of children complaining of joint pain or muscle aches even in the infancy period.


Ultrasonography of the parathyroid glands as an aid in differentiation of acute and chronic renal failure in dogs.
To evaluate whether determination of parathyroid gland size by use of ultrasonography is helpful in differentiating acute renal failure (ARF) from chronic renal failure (CRF) in dogs. Prospective study. 20 dogs with renal failure in which serum creatinine concentration was at least 5 times the upper reference limit. Seven dogs had ARF, and 13 dogs had CRF. Twenty-three healthy dogs were used as controls. Dogs were positioned in dorsal recumbency for ultrasonographic examination of the ventral portion of the neck, A 10-MHz linear-array high-resolution transducer was used. The size of the parathyroid gland was determined by measuring the maximal length of the gland on the screen when it was imaged in longitudinal section. For comparison among groups, the longest linear dimension of any of the parathyroid glands of each dog was used. Size of the parathyroid glands in the control dogs varied from 2.0 to 4.6 mm (median, 3.3 mm). In the dogs with ARF, gland size ranged from 2.4 to 4.0 mm (median, 2.7), which was not significantly different from controls. In dogs with CRF, the glands were more distinctly demarcated from the surrounding thyroid tissue, than those of controls and dogs with ARF. Sizes ranged from 3.9 to 8.1 mm (median, 5.7 mm), which was significantly larger, compared with controls and dogs with ARF. In dogs with severe azotemia, ultrasonographic examination of the parathyroid glands was helpful in differentiating ARF from CRF Size of the parathyroid glands appeared to be related to body weight.


Infections with avian pathogenic and fecal Escherichia coli strains display similar lung histopathology and macrophage apoptosis.
The purpose of this study was to compare histopathological changes in the lungs of chickens infected with avian pathogenic (APEC) and avian fecal (A(fecal)) Escherichia coli strains, and to analyze how the interaction of the bacteria with avian macrophages relates to the outcome of the infection. Chickens were infected intratracheally with three APEC strains, MT78, IMT5155, and UEL17, and one non-pathogenic A(fecal) strain, IMT5104. The pathogenicity of the strains was assessed by isolating bacteria from lungs, kidneys, and spleens at 24 h post-infection (p.i.). Lungs were examined for histopathological changes at 12, 18, and 24 h p.i. Serial lung sections were stained with hematoxylin and eosin (HE), terminal deoxynucleotidyl dUTP nick end labeling (TUNEL) for detection of apoptotic cells, and an anti-O2 antibody for detection of MT78 and IMT5155. UEL17 and IMT5104 did not cause systemic infections and the extents of lung colonization were two orders of magnitude lower than for the septicemic strains MT78 and IMT5155, yet all four strains caused the same extent of inflammation in the lungs. The inflammation was localized; there were some congested areas next to unaffected areas. Only the inflamed regions became labeled with anti-O2 antibody. TUNEL labeling revealed the presence of apoptotic cells at 12 h p.i in the inflamed regions only, and before any necrotic foci could be seen. The TUNEL-positive cells were very likely dying heterophils, as evidenced by the purulent inflammation. Some of the dying cells observed in avian lungs in situ may also be macrophages, since all four avian E. coli induced caspase 3/7 activation in monolayers of HD11 avian macrophages. In summary, both pathogenic and non-pathogenic fecal strains of avian E. coli produce focal infections in the avian lung, and these are accompanied by inflammation and cell death in the infected areas.


Effector protein translocation by the Coxiella burnetii Dot/Icm type IV secretion system requires endocytic maturation of the pathogen-occupied vacuole.
The human pathogen Coxiella burnetii encodes a type IV secretion system called Dot/Icm that is essential for intracellular replication. The Dot/Icm system delivers bacterial effector proteins into the host cytosol during infection. The effector proteins delivered by C. burnetii are predicted to have important functions during infection, but when these proteins are needed during infection has not been clearly defined. Here, we use a reporter system consisting of fusion proteins that have a β-lactamase enzyme (BlaM) fused to C. burnetii effector proteins to study protein translocation by the Dot/Icm system. Translocation of BlaM fused to the effector proteins CBU0077, CBU1823 and CBU1524 was not detected until 8-hours after infection of HeLa cells, which are permissive for C. burnetii replication. Translocation of these effector fusion proteins by the Dot/Icm system required acidification of the Coxiella-containing vacuole. Silencing of the host genes encoding the membrane transport regulators Rab5 or Rab7 interfered with effector translocation, which indicates that effectors are not translocated until bacteria traffic to a late endocytic compartment in the host cell. Similar requirements for effector translocation were discerned in bone marrow macrophages derived from C57BL/6 mice, which are primary cells that restrict the intracellular replication of C. burnetii. In addition to requiring endocytic maturation of the vacuole for Dot/Icm-mediated translocation of effectors, bacterial transcription was required for this process. Thus, translocation of effector proteins by the C. burnetii Dot/Icm system occurs after acidification of the CCV and maturation of this specialized organelle to a late endocytic compartment. This indicates that creation of the specialized vacuole in which C. burnetii replicates represents a two-stage process mediated initially by host factors that regulate endocytic maturation and then by bacterial effectors delivered into host cells after bacteria establish residency in a lysosome-derived organelle.


Eotaxin and FGF enhance signaling through an extracellular signal-related kinase (ERK)-dependent pathway in the pathogenesis of Eosinophilic esophagitis.
Eosinophilic esophagitis (EoE) is characterized by the inflammation of the esophagus and the infiltration of eosinophils into the esophagus, leading to symptoms such as dysphagia and stricture formation. Systemic immune indicators like eotaxin and fibroblast growth factor were evaluated for possible synergistic pathological effects. Moreover, blood cells, local tissue, and plasma from EoE and control subjects were studied to determine if the localized disease was associated with a systemic effect that correlated with presence of EoE disease. Real-time polymerase chain reaction from peripheral blood mononuclear cells (PBMC), immunohistochemistry from local esophageal biopsies, fluid assays on plasma, and fluorescence-activated cell sorting on peripheral blood cells from subjects were used to study the systemic immune indicators in newly diagnosed EoE (n = 35), treated EoE (n = 9), Gastroesophageal reflux disease (GERD) (n = 8), ulcerative colitis (n = 5), Crohn's disease (n = 5), and healthy controls (n = 8). Of the transcripts tested for possible immune indicators, we found extracellular signal-regulated kinase (ERK), Bcl-2, bFGF (basic fibroblast growth factor), and eotaxin levels were highly upregulated in PBMC and associated with disease presence of EoE. Increased FGF detected by immunohistochemistry in esophageal tissues and in PBMC was correlated with low levels of pro-apoptotic factors (Fas, Caspase 8) in PBMC from EoE subjects. Plasma-derived bFGF was shown to be the most elevated and most specific in EoE subjects in comparison to healthy controls and disease control subjects. We describe for the first time a possible mechanism by which increased FGF is associated with inhibiting apoptosis in local esophageal tissues of EoE subjects as compared to controls. Eotaxin and FGF signaling pathways share activation through the ERK pathway; together, they could act to increase eosinophil activation and prolong the half-life of eosinophils in local tissues of the esophagus in EoE subjects.


A method to perform a fast fourier transform with primitive image transformations.
The Fourier transform is one of the most important transformations in image processing. A major component of this influence comes from the ability to implement it efficiently on a digital computer. This paper describes a new methodology to perform a fast Fourier transform (FFT). This methodology emerges from considerations of the natural physical constraints imposed by image capture devices (camera/eye). The novel aspects of the specific FFT method described include: 1) a bit-wise reversal re-grouping operation of the conventional FFT is replaced by the use of lossless image rotation and scaling and 2) the usual arithmetic operations of complex multiplication are replaced with integer addition. The significance of the FFT presented in this paper is introduced by extending a discrete and finite image algebra, named Spiral Honeycomb Image Algebra (SHIA), to a continuous version, named SHIAC.


Potential clinical role of telomere length in human glioblastoma.
Glioblastoma Multiforme (GBM) is the most common and lethal of human primary central nervous system (CNS) tumors. Due to the tumour's intrinsic clinical and molecular heterogeneity, choice of initial treatment, prediction of survival, stratification of patients, prediction and monitoring of response to therapy, represent some of the greatest challenges in the management of GBM patients. Patients, despite optimal surgery, radiation and chemotherapy, still have a median survival of 14-16 months. A reason for this dismal prognosis is because of the relative inaccuracy of current prognostic markers, so far based on clinical or pathological variables. Molecular markers that effectively predict response to therapy and survival outcomes are limited. Consequently, there is a strong need to develop novel and independent markers of prognosis. Ideal biomarkers for solid tumors would serve one or more important functions. Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, regulates important cellular processes, and seem to be implicated in human carcinogenesis. Recently, telomeres have been shown either to be associated with clinical markers of disease progression or to be independent markers of cancer prognosis in solid tumours, including GBM. Nevertheless, a corresponding comprehensive discussion of these promising developments in brain tumours has not yet been available in the literature. Therefore, here we reviewed studies focused on the assessment of telomeric length in brain tumours with the aim to emphasized those findings indicating a potential clinical role of telomeres in GBM. With the aim to enhance the awareness of the potential clinical role of telomeres' length information in GBM, using a southern blot analysis, telomeric length in excised tumour samples was analyzed. Moreover, an attempt to correlated telomere length with patients' overall survival, was also performed. The findings here reviewed shows some contradictory results, due to different tissues used as controls, but mainly to cellular and molecular heterogeneity in GBMs that drive molecular mechanisms controlling telomere length, included telomerase and Alternative Lengthening of Telomeres (ALT), through multiple mechanisms. However, overall these studies, including our own, are consistent with the hypothesis that GBMs' telomeres were always shorter when compared with Normal Brain Tissue (NBT), and together with higher telomerase activity seem to be associated with malignancy and poor outcome; while tumours with ALT phenotype have longer telomeres, "less malignant" behaviour and better prognosis. We conclude that, although not entirely consistent in the type of telomere alteration, i.e., attrition vs. elongation, and unclear on the underlying mechanisms, multiple studies in brain tumours have shown that telomere dysfunctions are associated with parameters of clinical outcome in patients with GBMs and therefore will be part of novel risk assessment and prognostic modalities for patients with these still dismal disease.


Disposition of tacrolimus (FK 506) in rabbits. Role of red blood cell binding in hepatic clearance.
Tacrolimus is a macrolide immunosuppressive drug undergoing clinical trials for organ transplantation. Whole animal studies were undertaken to assess the rabbit as an animal model for tacrolimus pharmacokinetics. The disposition of tacrolimus in rabbits following 0.5 mg/kg iv and 2.0 mg/kg po doses is similar to man. The apparent plasma clearance 1.67 liters/hr/kg is more than 5-fold higher than blood clearance 0.31 liters/hr/kg. The steady-state volume of distribution is 30.7 liters/kg for plasma and 6.3 liters/kg for whole blood. The bioavailability after oral administration calculated from plasma and whole blood is low with a mean value of 9.7%. The in vitro studies and fitting using a nonlinear red blood cell (RBC)-plasma binding/diffusion model showed slow diffusion of drug from RBC to plasma (t1/2 = 7 min, CLD = 0.085 ml/min). In perfused liver studies, the extraction ratio of tacrolimus from blood with hematocrit of 0.1 is low (0.20). However, extraction of drug from plasma is moderate (0.42), and plasma concentrations are elevated by an average of 28% because of redistribution of tacrolimus from RBC. This creates a lower apparent plasma clearance (DO/AUC) for equilibrated (30 min at 37 degrees C) samples (15.4 ml/min) compared with samples centrifuged within 5 min (22.1 ml/min). RBC efflux was accounted for using a comprehensive perfusion/diffusion model. The intrinsic metabolic clearance averaged 29.2 ml/min. Simulations showed that the apparent plasma clearance of tacrolimus is closely correlated with RBC binding capacity (whole blood:plasma ratio). Higher ratios caused greater apparent plasma clearance (lower concentration of tacrolimus in reservoir plasma) because strong binding of drug by erythrocytes prevents tacrolimus from diffusion into plasma.(ABSTRACT TRUNCATED AT 250 WORDS)


Sudden cardiac death among the young in Sweden from 2000 to 2010: an autopsy-based study.
To study the incidence and aetiology of sudden cardiac death (SCD) in 1- to 35-year-olds in Sweden from 2000 to 2010. We used the database of the Swedish National Board of Forensic Medicine and the Swedish Cause of Death Registry and identified SCD cases by review of forensic files and death certificates. We identified 552 individuals with SCD in 1- to 35-year-olds; 156 (28%) were women. In 393 (71%), a forensic autopsy had been performed; in 131 (24%), a clinical autopsy had been performed; in 28 (5%) with no autopsy, a cardiac disease was diagnosed before death. The incidence of SCD per 100 000 person-years was 1.3 in 1- to 35-year-olds and 1.8 in 15- to 35-year-olds. In women, the incidence rates yearly decreased during the study period by 11% (95% confidence interval 6.6-14.2). The most common aetiology in 1- to 35-year-olds was sudden arrhythmic death syndrome (31%) and coronary artery disease (15%). In cases with forensic autopsy, death occurred during daily activity (48%), sleep (38%), and physical activity (14%); death was unwitnessed in 60%. Co-morbidity in 15- to 35-year-olds, e.g. psychiatric disorder, obesity, or diabetes, was present in 93/340 (27%) (73 men). The incidence of SCD among 1- to 35-year-olds in Sweden during 2000-10 was 1.3 per 100 000 person-years (28% women); incidence was decreasing in women. Sudden arrhythmic death syndrome was the most common diagnosis. Co-morbidity such as psychiatric disorders and obesity was common among men.


Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression.
Transforming growth factor beta1 (TGFB1) acts as a growth inhibitor of normal colonic epithelial cells, however, as a tumor promoter of colorectal cancer (CRC) cells. To explore the association between genetic polymorphisms in the TGFB1 pathway and CRC susceptibility and clinical outcome, we carried out a case-control study on a Swedish population of 308 CRC cases and 585 age- and gender-matched controls. The cases were sampled prospectively and had up to 16 years follow-up, making the study material particularly suitable for survival analysis. On the basis of their reported or predicted functional effect, nine single-nucleotide polymorphisms (TGFB1: Leu10Pro; TGFBR1: 9A/6A and IVS7G+24A; FURIN: C-229T; THBS1: T+42C; LTBP1L: C-256G; LTBP4: T-893G and Thr750Ala; BAMBI: T-779A) were selected for genotyping. We evaluated the associations between genotypes and CRC and Dukes' stage. Survival probabilities were compared between different subgroups. The observed statistically significant associations included a decreased CRC risk for TGFBR1 IVS7G+24A minor allele carriers (odds ratio (OR): 0.72, 95% confidence interval (CI): 0.53-0.97), less aggressive tumors with Dukes' stage A+B for carriers of LTBP4 Thr750Ala and BAMBI T-779A minor alleles (OR: 0.58, 95%CI: 0.36-0.93 and OR: 0.51, 95%CI: 0.29-0.89, respectively) and worse survival for FURIN C-229T heterozygotes (hazard ratio: 1.63, 95%CI: 1.08-2.46). As this is the first study about the influence of the polymorphisms in the TGFB1 pathway on CRC progression, further studies in large independent cohorts are warranted.


The rational choice model in family decision making at the end of life.
Most end-of-life decisions are made by family members. Current ethical guidelines for family decision making are based on a hierarchical model that emphasizes the patient's wishes over his or her best interests. Evidence suggests that the model poorly reflects the strategies and priorities of many families. Researchers observed and recorded 26 decision-making meetings between hospital staff and family members. Semi-structured follow-up interviews were conducted. Transcriptions were analyzed using qualitative techniques. For both staff and families, consideration of a patient's best interests generally took priority over the patient's wishes. Staff generally introduced discussion of the patient's wishes for rhetorical purposes, such as persuasion. Competing moral frameworks, which de-emphasized the salience of patients' autonomy and "right to choose," played a role in family decision making. The priority given to the patients' wishes in the hierarchical model does not reflect the priorities of staff and families in making decisions about end-of-life care.


Reproductive experience of HIV-infected women living in Europe.
The aim of this study was to describe the experience of pregnant and non-pregnant HIV-infected women regarding fertility and childbearing, with a view to inform policies and practices to improve reproductive outcome. A cross-sectional survey collected information on socio-demographic and basic reproductive characteristics of HIV-infected women in Europe. A total of 403 women participated; 121 were pregnant. The median age was 29 years and 84% (228) of women were born in Europe. Overall 68% (275 of 403) had been pregnant at some time. At the time of the survey, 59% (n = 160) of women had no HIV symptoms; severe symptoms were more frequent among non-pregnant than pregnant respondents (36% (65 of 181) versus 5% (4 of 88)). Of the women, 80% reported being in a long-standing relationship; 39% (74 of 190) reported that they became infected by their current partner and, overall, heterosexual infection was reported as the mode of acquisition in 55% (190 of 344). Maternal well-being, no previous live birth and having an uninfected partner were strongly associated with the likelihood of being pregnant. To assess the problems relating to fertility, pregnant and non-pregnant women were considered separately. Overall, 46% of pregnant women reported not using condoms to protect against infection during pregnancy. Of the 60 pregnant women who planned their pregnancies, 10 reported the need for assistance in conceiving: five monitored their ovulation period and five became pregnant through in vitro fertilization. Of 34 non-pregnant women currently trying for a baby, 15 (44%) had done so for more than 18 months. Overall 25 (27%) of 94 women who planned to become pregnant needed reproductive care. Our results suggest that these days knowledge of HIV infection neither influences the desire for children nor the decisions regarding pregnancy in HIV-infected women living in Europe.


Introduction of the 5-HT3B subunit alters the functional properties of 5-HT3 receptors native to neuroblastoma cells.
The identification of a second 5-HT(3) (5-HT(3B)) subunit provides an explanation for 5-HT(3) receptor heterogeneity. We investigated whether introduction of recombinant 5-HT(3B) subunits would alter the functional properties of mouse neuroblastoma 5-HT(3) receptors. RT-PCR analysis revealed that NB41A3 cells contain mRNAs encoding 5-HT(3A) and 5-HT(3B) subunits. 5-HT increased intracellular Ca(2+) concentration ([Ca(2+)](i)) and caused the concentration-dependent activation of inward currents recorded at -60 mV. Both actions of 5-HT were antagonized by ondansetron. The 5-HT concentration-response relationship of NB41A3 cells was indistinguishable from that of the related NG108-15 cell line. The selective 5-HT(3)-receptor agonist mCPBG also elevated [Ca(2+)](i) and activated inward currents. 2-M-5HT was less efficacious than 5-HT as an activator of 5-HT(3) receptors in NB41A3 cells and did not significantly increase [Ca(2+)](i). The 5-HT induced increase in [Ca(2+)](i) did not involve caffeine- or thapsigargin-sensitive intracellular Ca(2+) stores. The introduction of the 5-HT(3B) subunit by transient transfection of NB41A3 cells caused 5-HT to become less potent as an activator of 5-HT(3) receptors and altered the kinetics of 5-HT activated currents so that they resembled currents mediated by 5-HT(3AB) receptors. The 5-HT(3B) subunit also abolished the 5-HT induced [Ca(2+)](i) increase seen in untransfected NB41A3 cells. These data are consistent with the hypothesis that NB41A3 cells predominantly express homomeric 5-HT(3A) receptors that become heteromeric 5-HT(3AB) receptors upon introduction of the recombinant 5-HT(3B) subunit.


Smoking, alcohol and cancer mortality in Eastern European men: Findings from the PrivMort retrospective cohort study.
Eastern European men have among the highest cancer mortality rates globally. Prevalence of smoking and alcohol intake in this region is also high. The aim of our study was to calculate population attributable risk fraction (PARF) of cancer deaths from smoking and alcohol in Russia, Belarus and Hungary, and to examine the contribution of these lifestyle factors to differences in male cancer mortality in the three countries. Data were collected as part of the PrivMort retrospective cohort study. Randomly selected participants living in mid-size towns in Russia, Belarus and Hungary provided information on smoking habits, alcohol consumption, vital status and cause of death (if applicable) of male relatives (fathers, siblings and partners). PARF of cancer deaths (age 35-79) due to smoking, alcohol consumption and both combined was estimated between 2001 and 2013. Among 72,190 men, 4,702 died of cancer. Age standardized cancer mortality rates were similar to official data in all three countries. The estimated PARF (95% CI) associated with measures of smoking, alcohol consumption, both combined, and overall smoking or drinking were 25% (19-30), 2% (0-4), 29% (19-39), 43% (32-53) in Russia, 18% (8-28), 2% (-1 to 6), 28% (20-35), 38% (25-50) in Belarus and 17% (13-20), 1% (0-3), 25% (20-30), 35% (28-42) in Hungary, respectively. These results suggest that in Eastern Europe, at least one third of cancer deaths in males may have been attributable to smoking and/or alcohol consumption in recent years. Health policies targeting these lifestyle factors can have a major impact on population health.


A method for the automated classification of benign and malignant masses on digital breast tomosynthesis images using machine learning and radiomic features.
In digital mammography, which is used for the early detection of breast tumors, oversight may occur due to overlap between normal tissues and lesions. However, since digital breast tomosynthesis can acquire three-dimensional images, tissue overlapping is reduced, and, therefore, the shape and distribution of the lesions can be easily identified. However, it is often difficult to distinguish between benign and malignant breast lesions on images, and the diagnostic accuracy can be reduced due to complications from radiological interpretations, owing to acquisition of a higher number of images. In this study, we developed an automated classification method for diagnosing breast lesions on digital breast tomosynthesis images using radiomics to comprehensively analyze the radiological images. We extracted an analysis area centered on the lesion and calculated 70 radiomic features, including the shape of the lesion, existence of spicula, and texture information. The accuracy was compared by inputting the obtained radiomic features to four classifiers (support vector machine, random forest, naïve Bayes, and multi-layer perceptron), and the final classification result was obtained as an output using a classifier with high accuracy. To confirm the effectiveness of the proposed method, we used 24 cases with confirmed pathological diagnosis on biopsy. We also compared the classification results based on the presence or absence of dimension reduction using least absolute shrinkage and a selection operator (LASSO). As a result, when the support vector machine was used as a classifier, the correct identification rate of the benign tumors was 55% and that of malignant tumors was 84%, with best results. These results indicate that the proposed method may help in more accurately diagnosing cases that are difficult to classify on images.


Computational design of substrate selective inhibition.
Most enzymes act on more than a single substrate. There is frequently a need to block the production of a single pathogenic outcome of enzymatic activity on a substrate but to avoid blocking others of its catalytic actions. Full blocking might cause severe side effects because some products of that catalysis may be vital. Substrate selectivity is required but not possible to achieve by blocking the catalytic residues of an enzyme. That is the basis of the need for "Substrate Selective Inhibitors" (SSI), and there are several molecules characterized as SSI. However, none have yet been designed or discovered by computational methods. We demonstrate a computational approach to the discovery of Substrate Selective Inhibitors for one enzyme, Prolyl Oligopeptidase (POP) (E.C 188.8.131.52), a serine protease which cleaves small peptides between Pro and other amino acids. Among those are Thyrotropin Releasing Hormone (TRH) and Angiotensin-III (Ang-III), differing in both their binding (Km) and in turnover (kcat). We used our in-house "Iterative Stochastic Elimination" (ISE) algorithm and the structure-based "Pharmacophore" approach to construct two models for identifying SSI of POP. A dataset of ~1.8 million commercially available molecules was initially reduced to less than 12,000 which were screened by these models to a final set of 20 molecules which were sent for experimental validation (five random molecules were tested for comparison). Two molecules out of these 20, one with a high score in the ISE model, the other successful in the pharmacophore model, were confirmed by in vitro measurements. One is a competitive inhibitor of Ang-III (increases its Km), but non-competitive towards TRH (decreases its Vmax).


Emergence of pulled fronts in fermionic microscopic particle models.
We study the emergence and dynamics of pulled fronts described by the Fisher-Kolmogorov-Petrovsky-Piscounov (FKPP) equation in the microscopic reaction-diffusion process A+A<-->A on the lattice when only a particle is allowed per site. To this end we identify the parameter that controls the strength of internal fluctuations in this model, namely, the number of particles per correlated volume. When internal fluctuations are suppressed, we explictly see the matching between the deterministic FKPP description and the microscopic particle model.


A Matched Comparison of the Long-Term Outcomes of Cemented and Cementless Total Knee Replacements: An Analysis from the National Joint Registry of England, Wales, Northern Ireland and the Isle of Man.
Total knee replacements (TKRs) can be implanted with or without the use of cement. It is currently uncertain how cemented and cementless TKRs compare overall and in different age groups of the population in the long term. The National Joint Registry collects information on knee replacements inserted in England, Wales, Northern Ireland, and the Isle of Man and was linked for multiple confounders to the National Health Service Hospital Episode Statistics database. With use of propensity score matching techniques, 44,954 cemented and cementless TKRs were compared. Regression models were used to compare the outcomes of revision, reoperation, and mortality both overall and in different age strata. The 10-year implant survival rate with revision as the end point for cemented and cementless TKRs was 96.0% and 95.5%, respectively (hazard ratio [HR] = 1.14; p = 0.01). The 10-year survival rate with reoperation as the end point was 82.7% and 81.4%, respectively (HR = 1.08; p = 0.001). The rate of revision for pain was higher for cementless TKRs (0.5% [cemented] compared with 0.7% [cementless]; p = 0.002), but the rate of revision for infection was lower (0.7% [cemented] compared with 0.5% [cementless]; p = 0.003). No significant interactions with age existed for the outcomes of revision (p = 0.24), reoperation (p = 0.30), or mortality (p = 0.58). We found that matched cemented and cementless TKRs both have 10-year implant survival rates of >95%. Cementless TKRs had a higher revision rate (absolute difference, 0.5%) and reoperation rate (absolute difference, 1.3%). The rate of revision for infection was lower in the cementless group, although the rate of revision for pain was higher. Age did not significantly affect the relative performances. Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.


National ethical guidelines for biomedical & health research involving human participants, 2017: A commentary.
The Indian Council of Medical Research (ICMR) has been at the forefront in setting up the ethical guidance for the conduct of biomedical and health research in India. The latest version of National Guidelines for Biomedical and Health Research Involving Human Participants, 2017 was planned in order to provide a more detailed guidance to the existing topics in view of emerging ethical concerns and to add a number of newer areas in which guidance was lacking. The scope of the guidelines has been expanded to include socio-behavioural research related to health and research involving biological material and datasets. The guidelines have 12 sections which cover a wide range of topics and areas of research. The first six sections are more generic, applying to all types of biomedical and health research, while the next six sections are more subject specific. The guidelines have been revised in consultation with a large number of experts and stakeholders and went through an exhaustive process stretching over a period of two years in its drafting, review, consultation and finalisation. This commentary seeks to explain the process and key components of the Guidelines.


Nutritional Approach for Relief of Joint Discomfort: A 12-week, Open-case Series and Illustrative Case Report.
Tetrahydro iso-α acids (THIAAs), derived from Humulus lupulus (hops), have demonstrated anti-inflammatory effects in vitro and in an animal model of rheumatoid arthritis (RA). Undenatured type 2 collagen has been found to be effective in clinical studies in RA and osteoarthritis (OA). The study intended to evaluate the efficacy and safety of a proprietary tablet containing 150 mg of n-enriched THIAA (nTHIAA) and 10 mg of undenatured type 2 collagen (UC-II) (containing 25% UC-II) in patients with arthritis. The study was an open-label case series. This article also includes a case history for 1 participant. The study was conducted at the Functional Medicine Research Center (FMRC) in Gig Harbor, WA, USA, from February 2013-June 2013. Participants were 17 adults, 12 women, and 5 men aged 39-69 y, who had chronic joint pain involving various joints, 13 with probable OA and 4 with possible RA. Participants took 2 tablets of nTHIAA + UC-II 2 ×/d with meals for 12 wk. Participants completed arthritis-related and quality-of-life questionnaires, at weeks 2, 4, 8, and 12: (1) the visual analog scale for pain (VAS-P); (2) the medical symptoms questionnaire (MSQ), with the analysis particularly focusing on the joint/muscle subscale and total scores; (3) the health and wellness outcome questionnaire (MOS-SF36), with the analysis particularly focusing on the physical and mental subscales; (4) the arthritis impact questionnaire (AIQ), with the analysis particularly focusing on the arthritis symptoms and daily living subscales; (5) the health assessment questionnaire (HAQ-DI) with the analysis particularly focusing on question 26 (Q26), which indicates overall pain during the week prior to the survey; and (6) the arthritis impact measurement scales 2 (AIMS2). At 12 wk, participants also completed the visual analog scale for efficacy (VAS-E). All participants completed the 12-wk evaluation, and all reported improvements in pain. Significant improvements in scores on the questionnaires were observed as early as 2 wk. For example, the total score on the MSQ was significantly decreased from a mean of 20.76 ± 2.90 (SE) at baseline to 12.24 ± 2.81 after 2 wk (P < .001). At 12 wk, the participants rated the supplement's efficacy at 7.6 ± 0.6 of 10. At baseline, 13 of the 17 participants were using analgesics for joint pain, compared with only 4 participants at 12 wk. Two of those 4 had reduced their analgesic dosages. The studied supplement was well tolerated, and no serious side effects occurred. The supplement containing nTHIAA and UC-II is safe and efficacious in participants with chronic joint pain.


Bone-marrow-derived side population cells for myocardial regeneration.
Bone-marrow-derived stem cells have displayed the potential for myocardial regeneration in animal models as well as in clinical trials. Unfractionated bone marrow mononuclear cell (MNC) population is a heterogeneous group of cells known to include a number of stem cell populations. Cells in the side population (SP) fraction have a high capacity for differentiation into multiple lineages. In the current study, we investigated the role of murine and human bone-marrow-derived side population cells in myocardial regeneration. In these studies, we show that mouse bone-marrow-derived SP cells expressed the contractile protein, alpha-actinin, following culture with neonatal cardiomyocytes and after delivery into the myocardium following injury. Moreover, the number of green-fluorescent-protein-positive cells, of bone marrow side population origin, increased progressively within the injured myocardium over 90 days. Transcriptome analysis of these bone marrow cells reveals a pattern of expression consistent with immature cardiomyocytes. Additionally, the differentiation capacity of human granulocyte colony-stimulating factor stimulated peripheral blood stem cells were assessed following injection into injured rat myocardium. Bone marrow mononuclear cell and side population cells were both readily identified within the rat myocardium 1 month following injection. These human cells expressed human-specific cardiac troponin I as determined by immunohistochemistry as well as numerous cardiac transcripts as determined by polymerase chain reaction. Both human bone marrow mononuclear cells and human side population cells augmented cardiac systolic function following a modest drop in function as a result of cryoinjury. The augmentation of cardiac function following injection of side population cells occurred earlier than with bone marrow mononuclear cells despite the fact that the number of side population cells used was one tenth that of bone marrow mononuclear cells (9 x 10(5) cells per heart in the MNC group compared to 9 x 10(4) per heart in the SP group). These results support the hypotheses that rodent and human-bone-marrow derived side population cells are capable of acquiring a cardiac fate and that human bone-marrow-derived side population cells are superior to unfractionated bone marrow mononuclear cells in augmenting left ventricular systolic function following cryoinjury.


Why do mitochondria synthesize fatty acids? Evidence for involvement in lipoic acid production.
The function of acyl carrier protein (ACP) in mitochondria isolated from pea leaves has been investigated. When pea leaf mitochondria were labeled with [2-14C] malonic acid in vitro, radioactivity was incorporated into fatty acids, and, simultaneously, ACP was acylated. [1-14C]Acetate was much less effective as a precursor for fatty acid synthesis, suggesting that mitochondria do not possess acetyl-CoA carboxylase. The incorporation of radioactivity from [2-14C]malonate into fatty acids and the labeling of ACP were inhibited by cerulenin and required ATP and Mg2+. These findings indicate that plant mitochondria contain not only ACP, but all enzymes required for de novo fatty acid synthesis. Over 30% of the radioactive products from pea mitochondria labeled with [2-14C]malonate were recovered in H protein, which is a subunit of glycine decarboxylase and contains lipoic acid as an essential constituent. In similar experiments, the H protein of Neurospora mitochondria was also labeled by [2-14C]malonate. The labeling of pea H protein was inhibited by addition of cerulenin into the assay medium. Together, these findings indicate that ACP is involved in the de novo synthesis of fatty acids in plant mitochondria and that a major function of this pathway is production of lipoic acid precursors.


Chylothorax.
Chylothorax or chylous pleural effusion occurs when chyle accumulates in the pleural space usually secondary to disruption of thoracic lymphatics. Chyle is a milky, white, opalescent fluid that is formed when long-chain triglycerides in the diet are transformed into chylomicrons and very-low-density lipoproteins, which are then secreted into intestinal lacteals. These lymphatic channels coalesce to form the thoracic duct, which transports chyle and ultimately drains it into the left subclavian vein. Any injury to the duct (or its major tributaries) as it courses through the thoracic cavity can lead to a chylous effusion. Diagnosis depends on direct analysis of the fluid by assaying the triglyceride content and, at times, lipid electrophoretic pattern (chylomicrons). Management depends on the underlying cause and the individual clinical circumstances. Nonoperative options include observation, treatment of the underlying disease, dietary modification employing strict medium-chain triglyceride diet or total parenteral nutrition, therapeutic thoracentesis, tube thoracostomy with chemical pleurodesis, and embolization of the thoracic duct. Surgical management may include pleurectomy, talc poudrage, pleuroperitoneal shunting, and repair or ligation of the thoracic duct via thoracoscopy or thoracotomy.


The RNFT2/IL-3Rα axis regulates IL-3 signaling and innate immunity.
Interleukin-3 (IL-3) receptor α (IL-3Rα) is the α subunit of the ligand-specific IL-3R and initiates intracellular signaling in response to IL-3. IL-3 amplifies proinflammatory signaling and cytokine storm in murine sepsis models. Here we found that RNFT2 (RING finger transmembrane-domain containing protein 2, also TMEM118), a previously uncharacterized RING finger ubiquitin E3 ligase, negatively regulated IL-3-dependent cellular responses through IL-3Rα ubiquitination and degradation in the proteasome. In vitro, IL-3 stimulation promoted IL-3Rα proteasomal degradation dependent on RNFT2, and we identified IL-3Rα lysine 357 as a ubiquitin acceptor site. We determined that LPS priming reduces RNFT2 abundance, extends IL-3Rα half-life, and sensitizes cells to the effects of IL-3, acting synergistically to increase proinflammatory signaling. In vivo, IL-3 synergized with LPS to exacerbate lung inflammation in LPS and Pseudomonas aeruginosa-challenged mice; conversely, IL-3 neutralization reduced LPS-induced lung injury. Further, RNFT2 overexpression reduced lung inflammation and injury, whereas Rnft2 knockdown exacerbated inflammatory responses in LPS-induced murine lung injury. Last, we examined RNFT2 and IL-3Rα in human lung explants from patients with cystic fibrosis and also showed that IL-3 is elevated in mechanically ventilated critically ill humans at risk for acute respiratory distress syndrome. These results identify RNFT2 as a negative regulator of IL-3Rα and show a potential role for the RNFT2/IL-3Rα/IL-3 axis in regulating innate immune responses in the lung.


SUMOylation attenuates the aggregation propensity and cellular toxicity of the polyglutamine expanded ataxin-7.
Post-translational modification by SUMO (small ubiquitin-like modifier) was proposed to modulate the pathogenesis of several neurodegenerative diseases. Spinocerebellar ataxia type 7 (SCA7) is a neurodegenerative disorder, whose pathology is caused by an expansion of a polyglutamine stretch in the protein ataxin-7 (ATXN7). Here, we identified ATXN7 as new target for SUMOylation in vitro and in vivo. The major SUMO acceptor site was mapped to lysine 257, which is part of an evolutionarily conserved consensus SUMOylation motif. SUMOylation did not influence the subcellular localization of ATXN7 nor its interaction with components of the TFTC/STAGA complex. Expansion of the polyglutamine stretch did not impair the SUMOylation of ATXN7. Furthermore, SUMO1 and SUMO2 colocalized with ATXN7 in a subset of neuronal intranuclear inclusions in the brain of SCA7 patients and SCA7 knock-in mice. In a COS-7 cellular model of SCA7, in addition to diffuse nucleoplasmic staining we identified two populations of nuclear inclusions: homogenous or non-homogenous. Non-homogenous inclusions showed significantly reduced colocalization with SUMO1 and SUMO2, but were highly enriched in Hsp70, 19S proteasome and ubiquitin. Interestingly, they were characterized by increased staining with the apoptotic marker caspase-3 and by disruption of PML nuclear bodies. Importantly, preventing the SUMOylation of expanded ATXN7 by mutating the SUMO site increased both the amount of SDS-insoluble aggregates and of caspase-3 positive non-homogenous inclusions, which act toxic to the cells. Our results demonstrate an influence of SUMOylation on the multistep aggregation process of ATXN7 and implicate a role for ATXN7 SUMOylation in SCA7 pathogenesis.


The iab-7 polycomb response element maps to a nucleosome-free region of chromatin and requires both GAGA and pleiohomeotic for silencing activity.
In the work reported here we have undertaken a functional dissection of a Polycomb response element (PRE) from the iab-7 cis-regulatory domain of the Drosophila melanogaster bithorax complex (BX-C). Previous studies mapped the iab-7 PRE to an 860-bp fragment located just distal to the Fab-7 boundary. Located within this fragment is an approximately 230-bp chromatin-specific nuclease-hypersensitive region called HS3. We have shown that HS3 is capable of functioning as a Polycomb-dependent silencer in vivo, inducing pairing-dependent silencing of a mini-white reporter. The HS3 sequence contains consensus binding sites for the GAGA factor, a protein implicated in the formation of nucleosome-free regions of chromatin, and Pleiohomeotic (Pho), a Polycomb group protein that is related to the mammalian transcription factor YY1. We show that GAGA and Pho interact with these sequences in vitro and that the consensus binding sites for the two proteins are critical for the silencing activity of the iab-7 PRE in vivo.


Structural and functional characterization of a DARPin which inhibits Ras nucleotide exchange.
Ras mutations are the oncogenic drivers of many human cancers and yet there are still no approved Ras-targeted cancer therapies. Inhibition of Ras nucleotide exchange is a promising new approach but better understanding of this mechanism of action is needed. Here we describe an antibody mimetic, DARPin K27, which inhibits nucleotide exchange of Ras. K27 binds preferentially to the inactive Ras GDP form with a Kd of 4 nM and structural studies support its selectivity for inactive Ras. Intracellular expression of K27 significantly reduces the amount of active Ras, inhibits downstream signalling, in particular the levels of phosphorylated ERK, and slows the growth in soft agar of HCT116 cells. K27 is a potent, non-covalent inhibitor of nucleotide exchange, showing consistent effects across different isoforms of Ras, including wild-type and oncogenic mutant forms.


Evaluation of emergency air evacuation of critically ill patients from cruise ships.
The study objectives were to assess the ship physician's diagnostic accuracy in making the decision to air evacuate critically ill patients from cruise ships, to determine the outcome of these patients, and the overall benefit of air evacuation. From October 1999 to May 2000, we performed a prospective study of critically ill patients coming from cruise ships in the Caribbean and transported to our institution by air ambulance. Demographics, initial diagnosis, and treatment on board were collected by the triage officer at the time of the cruise physician's first call. In route complications and flight team composition were obtained from the air ambulance monitoring log. Patients were followed-up in the hospital for complications, outcome, and final diagnosis. A consecutive series of 104 patients were considered for analysis. There were 65 men and 39 women (mean age: 68.7 years). Cruise physician's diagnosis was correct in more than 90% of the cases. Internal medicine and surgical conditions represented 80.8% and 19.2% of the cases respectively, falling mainly into three categories: cardiac (34.6%), neurological (20.2%), and digestive (14%). Two cardiac arrests and 1 ventricular fibrillation were successfully resuscitated and 5 of 15 myocardial infarctions received thrombolytic therapy on board. Air transfers were warranted in 96.1% of the cases and physician presence in the flight was considered appropriate in 97.6%. In route complications and mortality rate were 5.8% and 2.9% respectively, related to serious cardiac events. Among the 98 hospitalized patients, 10 patients developed new complications and 5 died. The overall mortality rate was 7.7%. The cruise industry appears off to a good start in the medical treatment of passengers needing air evacuation to a land based medical facility. There is room for improvement and adoption of American College of Emergency Physicians (ACEP) and International Council of Cruise Lines (ICCL) Health Care Guidelines are meaningful first steps. Analysis of Caribbean medical facilities and implementation of active telemedicine conferencing represent alternatives to air evacuation that need to be studied.


Oxidative stress, aging, and diseases.
Reactive oxygen and nitrogen species (RONS) are produced by several endogenous and exogenous processes, and their negative effects are neutralized by antioxidant defenses. Oxidative stress occurs from the imbalance between RONS production and these antioxidant defenses. Aging is a process characterized by the progressive loss of tissue and organ function. The oxidative stress theory of aging is based on the hypothesis that age-associated functional losses are due to the accumulation of RONS-induced damages. At the same time, oxidative stress is involved in several age-related conditions (ie, cardiovascular diseases [CVDs], chronic obstructive pulmonary disease, chronic kidney disease, neurodegenerative diseases, and cancer), including sarcopenia and frailty. Different types of oxidative stress biomarkers have been identified and may provide important information about the efficacy of the treatment, guiding the selection of the most effective drugs/dose regimens for patients and, if particularly relevant from a pathophysiological point of view, acting on a specific therapeutic target. Given the important role of oxidative stress in the pathogenesis of many clinical conditions and aging, antioxidant therapy could positively affect the natural history of several diseases, but further investigation is needed to evaluate the real efficacy of these therapeutic interventions. The purpose of this paper is to provide a review of literature on this complex topic of ever increasing interest.


Problem-Solving Benefits of Down-Sampled Lexicase Selection.
In genetic programming, an evolutionary method for producing computer programs that solve specified computational problems, parent selection is ordinarily based on aggregate measures of performance across an entire training set. Lexicase selection, by contrast, selects on the basis of performance on random sequences of training cases; this has been shown to enhance problem-solving power in many circumstances. Lexicase selection can also be seen as better reflecting biological evolution, by modeling sequences of challenges that organisms face over their lifetimes. Recent work has demonstrated that the advantages of lexicase selection can be amplified by down-sampling, meaning that only a random subsample of the training cases is used each generation. This can be seen as modeling the fact that individual organisms encounter only subsets of the possible environments and that environments change over time. Here we provide the most extensive benchmarking of down-sampled lexicase selection to date, showing that its benefits hold up to increased scrutiny. The reasons that down-sampling helps, however, are not yet fully understood. Hypotheses include that down-sampling allows for more generations to be processed with the same budget of program evaluations; that the variation of training data across generations acts as a changing environment, encouraging adaptation; or that it reduces overfitting, leading to more general solutions. We systematically evaluate these hypotheses, finding evidence against all three, and instead draw the conclusion that down-sampled lexicase selection's main benefit stems from the fact that it allows the evolutionary process to examine more individuals within the same computational budget, even though each individual is examined less completely.


DNA barcoding of Northern Nearctic Muscidae (Diptera) reveals high correspondence between morphological and molecular species limits.
Various methods have been proposed to assign unknown specimens to known species using their DNA barcodes, while others have focused on using genetic divergence thresholds to estimate "species" diversity for a taxon, without a well-developed taxonomy and/or an extensive reference library of DNA barcodes. The major goals of the present work were to: a) conduct the largest species-level barcoding study of the Muscidae to date and characterize the range of genetic divergence values in the northern Nearctic fauna; b) evaluate the correspondence between morphospecies and barcode groupings defined using both clustering-based and threshold-based approaches; and c) use the reference library produced to address taxonomic issues. Our data set included 1114 individuals and their COI sequences (951 from Churchill, Manitoba), representing 160 morphologically-determined species from 25 genera, covering 89% of the known fauna of Churchill and 23% of the Nearctic fauna. Following an iterative process through which all specimens belonging to taxa with anomalous divergence values and/or monophyly issues were re-examined, identity was modified for 9 taxa, including the reinstatement of Phaonia luteva (Walker) stat. nov. as a species distinct from Phaonia errans (Meigen). In the post-reassessment data set, no distinct gap was found between maximum pairwise intraspecific distances (range 0.00-3.01%) and minimum interspecific distances (range: 0.77-11.33%). Nevertheless, using a clustering-based approach, all individuals within 98% of species grouped with their conspecifics with high (>95%) bootstrap support; in contrast, a maximum species discrimination rate of 90% was obtained at the optimal threshold of 1.2%. DNA barcoding enabled the determination of females from 5 ambiguous species pairs and confirmed that 16 morphospecies were genetically distinct from named taxa. There were morphological differences among all distinct genetic clusters; thus, no cases of cryptic species were detected. Our findings reveal the great utility of building a well-populated, species-level reference barcode database against which to compare unknowns. When such a library is unavailable, it is still possible to obtain a fairly accurate (within ~10%) rapid assessment of species richness based upon a barcode divergence threshold alone, but this approach is most accurate when the threshold is tuned to a particular taxon.


The impact of psoriasis guidelines on appropriateness of referral from primary to secondary care: a randomized controlled trial.
Most patients with psoriasis have limited disease which can be managed effectively in primary care. There is a marked variation in the frequency of referrals between practices reflecting, in part, inadequate training of general practitioners (GPs) in the management of psoriasis. To assess the effectiveness of guidelines and training sessions on the management of psoriasis in reducing inappropriate referrals from primary care. Patients aged 18 years or over with psoriasis were eligible for the cluster-randomized, randomized controlled trial if they were referred by their GP between 9 September 2002 and 31 December 2003 to one of four hospital dermatology departments in Greater Manchester, North-West England. All GPs from 165 health centres were invited to a lecture by a local dermatologist on the diagnosis and management of psoriasis. Health centres in the intervention arm received guidelines on the management of psoriasis in primary care, developed by local dermatologists, supplemented by the offer of a practice-based nurse-led training session; those in the control arm received neither guidelines nor training sessions. Eighty-two health centres were randomized to the intervention arm and 83 to the control arm. Outcome data were available for 188 of the 196 eligible patients referred during the study period. Patients in the intervention arm were significantly more likely to be appropriately referred in comparison with patients in the control arm [difference = 19.1%; odds ratio (OR) 2.47; 95% confidence interval (CI) 1.31-4.68; intracluster correlation coefficient (ICC) = 0]. Only 25 (30%) health centres in the intervention arm took up the offer of training sessions. There was no significant difference in outcome between health centres in the intervention arm that received a training session and those that did not (OR 1.28, 95% CI 0.50-3.29, ICC = 0). Dissemination of guidelines on the management of psoriasis in primary care can significantly enhance the appropriateness of referral of patients to secondary care.


Relation of sensory peripheral neuropathy in Sjögren syndrome to anti-Ro/SSA.
Sjögren syndrome is a common, chronic autoimmune disease that typically produces inflammation and poor function of the salivary and lacrimal glands. Other organs can be affected, including the nervous system. Sensory peripheral neuropathy is a common manifestation of the disease. Eight-eight patients attending a dry eyes-dry mouth clinic were diagnosed to have primary Sjögren syndrome and underwent a neurological examination. Anti-Ro (or SSA) and anti-La (or SSB) were determined using immunodiffusion as well as Inno-Lia and BioPlex ANA screen. Serum vitamin B(12) levels were determined using an enzyme-linked microtiter plate assay. Twenty-seven (31%) of the 88 patients had peripheral neuropathy as defined by loss of light touch, proprioception, or vibratory sensation. Anti-Ro and anti-La were found by immunodiffusion in 12 patients, and 8 of these 12 had neuropathy (χ(2) = 8.46, P = 0.0036, odds ratio = 6.0 compared to those without precipitating anti-Ro and anti-La). Of the 27 patients with only anti-Ro by immunodiffusion, 13 (48.1%) had neuropathy (χ(2) = 5.587, P = 0.018, compared to those without anti-Ro). There was no relationship of the other, more sensitive measures of anti-Ro and anti-La to neuropathy. In addition, we found no association of serum vitamin B(12) levels to neuropathy among these patients with Sjögren syndrome. Sensory peripheral neuropathy is common among patients with Sjögren syndrome and is associated with the presence of anti-Ro and anti-La when determined by immunodiffusion.


Kinetic analysis of inhibition of human immunodeficiency virus type-1 reverse transcriptase by calanolide A.
Calanolide A, first isolated from the tropical rain forest tree Calophyllum lanigerum, is a potent human immunodeficiency virus type-1 (HIV-1) specific reverse transcriptase (RT) inhibitor, broadly active against diverse HIV-1 strains, including nucleoside and nonnucleoside-resistant variants. We examined the biochemical mechanism of inhibition of HIV-1 RT by calanolide A. Two template/primer systems were examined: ribosomal RNA and homopolymeric rA-dT 12-18. Calanolide A inhibited HIV-1 RT by a complex mechanism involving two calanolide A binding sites. With respect to either deoxynucleotide triphosphate (dNTP) or template/primer binding, one site was competitive and the other was uncompetitive. The data indicated that calanolide A bound near the active site of the enzyme and interfered with dNTP binding. Calanolide A inhibited HIV-1 RT in a synergistic fashion with nevirapine, further distinguishing it from the general class of nonnucleoside RT inhibitors. At certain concentrations, calanolide A bound HIV-1 RT in a mutually exclusive fashion with respect to both the pyrophosphate analog, phosphonoformic acid and the acyclic nucleoside analog 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil. This indicates that calanolide A shares some binding domains with both phosphonoformic acid and 1-ethoxymethyl-5-ethyl-6-phenylthio-2-thiouracil, presumably reflecting that it interacts with RT near both the pyrophosphate binding site and the active site of the enzyme.


Activin plays a key role in the maintenance of long-term memory and late-LTP.
A recent study has revealed that fear memory may be vulnerable following retrieval, and is then reconsolidated in a protein synthesis-dependent manner. However, little is known about the molecular mechanisms of these processes. Activin betaA, a member of the TGF-beta superfamily, is increased in activated neuronal circuits and regulates dendritic spine morphology. To clarify the role of activin in the synaptic plasticity of the adult brain, we examined the effect of inhibiting or enhancing activin function on hippocampal long-term potentiation (LTP). We found that follistatin, a specific inhibitor of activin, blocked the maintenance of late LTP (L-LTP) in the hippocampus. In contrast, administration of activin facilitated the maintenance of early LTP (E-LTP). We generated forebrain-specific activin- or follistatin-transgenic mice in which transgene expression is under the control of the Tet-OFF system. Maintenance of hippocampal L-LTP was blocked in the follistatin-transgenic mice. In the contextual fear-conditioning test, we found that follistatin blocked the formation of long-term memory (LTM) without affecting short-term memory (STM). Furthermore, consolidated memory was selectively weakened by the expression of follistatin during retrieval, but not during the maintenance phase. On the other hand, the maintenance of memory was also influenced by activin overexpression during the retrieval phase. Thus, the level of activin in the brain during the retrieval phase plays a key role in the maintenance of long-term memory.


Merging with for-profits: flawed strategy. Such affiliations benefit neither the Catholic hospital nor society.
Some Catholic healthcare organizations, seeking new sources of capital, are eyeing mergers with for-profit systems. However, such mergers raise questions about their effects on both the mission of particular Catholic institutions and the well-being of society at large. For-profit organizations are driven by the pursuit of profit. They market ¿products.¿ This pursuit naturally shapes their decision-making rationales, employee relations, and business priorities. Not for-profits, on the other hand, provide ¿public goods¿--goods that for-profits either will not provide or will not provide adequately--and this mission shapes their priorities, decision making, and employee relations differently. What is more, economic power is unequal between the two kinds of organization. Since not-for profits are seeking capital when they merge with for profits, they usually do so from a position of relative disadvantage. When conflicts arise, the for-profit partner generally prevails. The not-for-profit partner then finds itself, not merged with, but acquired by the for-profit. Throughout U.S. history, not-for-profits have performed a function neglected by both government and private companies. Now, in the 1990s, the whole social welfare framework of our society is under attack. A moral-political crisis questions the very concept of the voluntary sector. If Catholic healthcare organizations allow themselves to be swallowed by for-profits, who will care for the voiceless and the vulnerable?


Antidepressant effects of curcumin in the forced swim test and olfactory bulbectomy models of depression in rats.
Curcuma longa is a major constituent of Xiaoyao-san, the traditional Chinese medicinal formula, which has been used to effectively manage stress and depression-related disorders in China. Curcumin is the active component of curcuma longa, and we hypothesized that curcumin would have an influence on depressive-like behaviors. The purpose of the present study was to confirm the putative antidepressant effect of chronic administrations of curcumin (1.25, 2.5, 5 and 10 mg/kg, p.o.) in the forced swimming test and bilateral olfactory bulbectomy (OB) models of depression in rats. In the first study, chronic treatment with curcumin (14 days) reduced the immobility time in the forced swimming test. In the second experiment, curcumin reversed the OB-induced behavioral abnormalities such as hyperactivity in the open field, as well as deficits in step-down passive avoidance. In addition, OB-induced low levels of serotonin (5-HT), noradrenaline (NA), high 5-hydroxyindoleacetic acid (5-HIAA) and 4-dihydroxyphenylacetic acid (DOPAC) in the hippocampus were observed, and were completely reversed by curcumin administration. A slight decrease in 5-HT, NA and dopamine (DA) levels was found in the frontal cortex of OB rats which was also reversed by curcumin treatment. These results confirm the antidepressant effects of curcumin in the forced swim and the OB models of depression in rats, and suggest that these antidepressant effects may be mediated by actions in the central monoaminergic neurotransmitter systems.


Learning features in computer simulation skills training.
New simulation tools imply new opportunities to teach skills and train health care professionals. The aim of this study was to investigate the learning gained from computer simulation skills training. The study was designed for optimal educational settings, which benefit student-centred learning. Twenty-four second year undergraduate nursing students practised intravenous catheterization with the computer simulation program CathSim. Questionnaires were answered before and after the skills training, and after the skills examination. When using CathSim, the students appreciated the variation in patient cases, the immediate feedback, and a better understanding of anatomy, but they missed having an arm model to hold. We concluded that CathSim was useful in the students' learning process and skills training when appropriately integrated into the curriculum. Learning features to be aware of when organizing curricula with simulators are motivation, realism, variation, meaningfulness and feedback.


Efficient synthesis of α-fluoromethylhistidine di-hydrochloride and demonstration of its efficacy as a glutathione S-transferase inhibitor.
Histidine decarboxylase (HDC) is an enzyme that converts histidine to histamine. Inhibition of HDC has several medical applications, and HDC inhibitors are of considerable interest for the study of histidine metabolism. (S)-α-Fluoromethylhistidine di-hydrochloride (α-FMH) is a potent HDC inhibitor that is commercially available at high cost in small amounts only. Here we report a novel, inexpensive, and efficient method for synthesis of α-FMH using methyl 2-aziridinyl-3-(N-triphenylmethyl-4-imidazolyl) propionate and HF/pyridine, with experimental yield of 57%. To identify novel targets for α-FMH, we developed a three step in silico work-flow for identifying physically plausible protein targets. The work-flow resulted in 21 protein target hits, including several enzymes involved in glutathione metabolism, and notably, two isozymes of the glutathione S-transferase (GST) superfamily, which plays a central role in drug metabolism. In view of this predictive data, the efficacy of α-FMH as a GST inhibitor was investigated in vitro. α-FMH was demonstrated to be an effective inhibitor of GST at micromolar concentration, suggesting that off-target effects of α-FMH may limit physiological drug metabolism and elimination by GST-dependent mechanisms. The present study therefore provides new avenues for obtaining α-FMH and for studying its biochemical effects, with potential implications for drug development.


Survival analysis using primary care electronic health record data: A systematic review of the literature.
An emerging body of research involves observational studies in which survival analysis is applied to data obtained from primary care electronic health records (EHRs). This systematic review of these studies examined the utility of using this approach. An electronic literature search of the Scopus, PubMed, Web of Science, CINAHL, and Cochrane databases was conducted. Search terms and exclusion criteria were chosen to select studies where survival analysis was applied to the data extracted wholly from EHRs used in primary care medical practice. A total of 46 studies that met the inclusion criteria for the systematic review were examined. All were published within the past decade (2005-2014) with a majority ( n = 26, 57%) being published between 2012 and 2014. Even though citation rates varied from nil to 628, over half ( n = 27, 59%) of the studies were cited 10 times or more. The median number of subjects was 18,042 with five studies including over 1,000,000 patients. Of the included studies, 35 (76%) were published in specialty journals and 11 (24%) in general medical journals. The many conditions studied largely corresponded well with conditions important to general practice. Survival analysis applied to primary care electronic medical data is a research approach that has been frequently used in recent times. The utility of this approach was demonstrated by the ability to produce research with large numbers of subjects, across a wide range of conditions and with the potential of a high impact. Importantly, primary care data were thus available to inform primary care practice.


Resting state connectivity between default mode network and insula encodes acute migraine headache.
Background Previous functional MRI studies have revealed that ongoing clinical pain in different chronic pain syndromes is directly correlated to the connectivity strength of the resting default mode network (DMN) with the insula. Here, we investigated seed-based resting state DMN-insula connectivity during acute migraine headaches. Methods Thirteen migraine without aura patients (MI) underwent 3 T MRI scans during the initial six hours of a spontaneous migraine attack, and were compared to a group of 19 healthy volunteers (HV). We evaluated headache intensity with a visual analogue scale and collected seed-based MRI resting state data in the four core regions of the DMN: Medial prefrontal cortex (MPFC), posterior cingulate cortex (PCC), and left and right inferior parietal lobules (IPLs), as well as in bilateral insula. Results Compared to HV, MI patients showed stronger functional connectivity between MPFC and PCC, and between MPFC and bilateral insula. During migraine attacks, the strength of MPFC-to-insula connectivity was negatively correlated with pain intensity. Conclusion We show that greater subjective intensity of pain during a migraine attack is associated with proportionally weaker DMN-insula connectivity. This is at variance with other chronic extra-cephalic pain disorders where the opposite was found, and may thus be a hallmark of acute migraine head pain.


Oligomerization of RANTES is required for CCR1-mediated arrest but not CCR5-mediated transmigration of leukocytes on inflamed endothelium.
Chemokines control inflammatory leukocyte recruitment. The propensity of chemokines such as CC chemokine ligand 5 (CCL5)/RANTES (regulated on activation, normal T cell expressed and secreted) to bind to glycosaminoglycans and to form higher order oligomers has been shown to be essential for its in vivo activity. However, the specific functional relevance of RANTES oligomerization for distinct steps of leukocyte recruitment on inflamed endothelium mediated by the RANTES receptors CC chemokine receptor 1 (CCR1) and CCR5 remains undefined. We studied RANTES mutants with deficient oligomerization in an assay in which recruitment of monocytes and CD45RO+ CD4+ T cells is triggered by RANTES immobilized on activated endothelium under flow conditions. Notably, the formation of higher order RANTES oligomers was crucial for CCR1-mediated arrest but not for CCR5-mediated spreading/transmigration in flow or transendothelial chemotaxis of leukocytes. Efficient leukocyte arrest in flow but not transmigration may thus require the presentation of RANTES oligomers to bridge surface-bound RANTES and CCR1.


miR-199a-5p silencing regulates the unfolded protein response in chronic obstructive pulmonary disease and α1-antitrypsin deficiency.
Retention of abnormal α1-antitrypsin (AAT) activates the unfolded protein response in AAT-deficient monocytes. The regulatory role of microRNAs (miRNAs) in unfolded protein responses and chronic obstructive pulmonary disease pathogenesis has not been investigated. To investigate miRNA expression and function in MM and ZZ monocytes and identify miRNA(s) regulating the unfolded protein response. Peripheral blood monocytes were isolated from asymptomatic and symptomatic MM and ZZ individuals for miRNA expression profiling and pyrosequencing analysis. miRNA/gene and protein expression was measured with quantitative polymerase chain reaction and Western blotting. Overexpression and inhibition studies were performed with pre-miR or anti-miR, respectively. Luciferase reporter genes were used to elucidate direct miRNA-target interactions. Inflammatory cytokines were detected using the Meso Scale Discovery Plex assays. Forty-three miRNAs were differentially expressed, with miR-199a-5p most highly up-regulated in asymptomatic ZZ versus MM monocytes. miR-199a-2 promoter hypermethylation inhibits miR-199a-5p expression and was increased in symptomatic MM and ZZ monocytes compared with asymptomatic counterparts. GRP78, activating transcription factor 6, p50, and p65 were increased in symptomatic versus asymptomatic ZZ monocytes. Reciprocal down- or up-regulation of these markers was observed after miRNA modulation. Direct miR-199a-5p targeting of activating transcription factor 6, p50, and p65 by miR-199a-5p was demonstrated using luciferase reporter systems. Overexpression of miR-199a-5p also decreased other arms of the UPR and expression of cytokines that are not putative targets. miR-199a-5p is a key regulator of the unfolded protein response in AAT-deficient monocytes, and epigenetic silencing of its expression regulates this process in chronic obstructive pulmonary disease.


Peripheral T cell lymphopenia in COVID-19: potential mechanisms and impact.
Immunopathogenesis involving T lymphocytes, which play a key role in defence against viral infection, could contribute to the spectrum of COVID-19 disease and provide an avenue for treatment. To address this question, a review of clinical observational studies and autopsy data in English and Chinese languages was conducted with a search of registered clinical trials. Peripheral lymphopenia affecting CD4 and CD8 T cells was a striking feature of severe COVID-19 compared with non-severe disease. Autopsy data demonstrated infiltration of T cells into organs, particularly the lung. Seventy-four clinical trials are on-going that could target T cell-related pathogenesis, particularly IL-6 pathways. SARS-CoV-2 infection interrupts T cell circulation in patients with severe COVID-19. This could be due to redistribution of T cells into infected organs, activation induced exhaustion, apoptosis, or pyroptosis. Measuring T cell dynamics during COVID-19 will inform clinical risk-stratification of hospitalised patients and could identify those who would benefit most from treatments that target T cells.


The role of magnetic nanoparticles in the localization and treatment of breast cancer.
The role of magnetic nanoparticles (MNPs) in medical applications is rapidly developing. Advances in nanotechnology are bringing us closer to the development of dual and multifunctional nanoparticles that are challenging the traditional distinction between diagnostic and treatment agents. The current use of MNPs in breast cancer falls into four main groups: (1) imaging of primary and metastatic disease, (2) sentinel lymph node biopsy (SLNB), (3) drug delivery systems, and (4) magnetic hyperthermia. The current evidence for the use of MNPs in these fields is mounting, and potential cutting-edge clinical applications, particularly with relevance to the fields of breast oncological surgery, are emerging.


Phase II double-blind placebo-controlled randomized study of armodafinil for brain radiation-induced fatigue.
Common acute-term side effects of brain radiotherapy (RT) include fatigue, drowsiness, decreased physical functioning, and decreased quality of life (QOL). We hypothesized that armodafinil (a wakefulness-promoting drug known to reduce fatigue and increase cognitive function in breast cancer patients receiving chemotherapy) would result in reduced fatigue and sleepiness for patients receiving brain RT. A phase II, multi-institutional, placebo-controlled randomized trial assessed feasibility of armodafinil 150 mg/day in participants receiving brain RT, from whom we obtained estimates of variability for fatigue, sleepiness, QOL, cognitive function, and treatment effect. From September 20, 2010, to October 20, 2012, 54 participants enrolled with 80% retention and 94% self-reported compliance. There were no grade 4-5 toxicities, and the incidence of grade 2-3 toxicities was similar between treatment arms, the most common of which were anxiety and nausea (15%), headaches (19%), and insomnia (20%). There were no statistically significant differences in end-RT or 4 week post-RT outcomes between armodafinil and placebo in any outcomes (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue, Brief Fatigue Inventory, Epworth Sleepiness Scale, FACT-Brain, and FACIT-cognitive function). However, in participants with more baseline fatigue, those treated with armodafinil did better than those who received the placebo on the end-RT assessments for several outcomes. Armodafinil 150 mg/day was well tolerated in primary brain tumor patients undergoing RT with good compliance. While there was no overall significant effect on fatigue, those with greater baseline fatigue experienced improved QOL and reduced fatigue when using armodafinil. These data suggest that a prospective, phase III randomized trial is warranted for patients with greater baseline fatigue.


Geometric calibration of head-mounted displays and its effects on distance estimation.
Head-mounted displays (HMDs) allow users to observe virtual environments (VEs) from an egocentric perspective. However, several experiments have provided evidence that egocentric distances are perceived as compressed in VEs relative to the real world. Recent experiments suggest that the virtual view frustum set for rendering the VE has an essential impact on the user's estimation of distances. In this article we analyze if distance estimation can be improved by calibrating the view frustum for a given HMD and user. Unfortunately, in an immersive virtual reality (VR) environment, a full per user calibration is not trivial and manual per user adjustment often leads to mini- or magnification of the scene. Therefore, we propose a novel per user calibration approach with optical see-through displays commonly used in augmented reality (AR). This calibration takes advantage of a geometric scheme based on 2D point - 3D line correspondences, which can be used intuitively by inexperienced users and requires less than a minute to complete. The required user interaction is based on taking aim at a distant target marker with a close marker, which ensures non-planar measurements covering a large area of the interaction space while also reducing the number of required measurements to five. We found the tendency that a calibrated view frustum reduced the average distance underestimation of users in an immersive VR environment, but even the correctly calibrated view frustum could not entirely compensate for the distance underestimation effects.


The combined effect of determinants on coverage of intermittent preventive treatment of malaria during pregnancy in the Kilombero Valley, Tanzania.
Intermittent preventive treatment during pregnancy (IPTp) at routine antenatal care (ANC) clinics is an important and efficacious intervention to reduce adverse health outcomes of malaria infections during pregnancy. However, coverage for the recommended two IPTp doses is still far below the 80% target in Tanzania. This paper investigates the combined impact of pregnant women's timing of ANC attendance, health workers' IPTp delivery and different delivery schedules of national IPTp guidelines on IPTp coverage. Data on pregnant women's ANC attendance and health workers' IPTp delivery were collected from ANC card records during structured exit interviews with ANC attendees and through semi-structured interviews with health workers in south-eastern Tanzania. Women's timing of ANC visits and health worker's timing of IPTp delivery were analyzed in relation to the different national IPTp schedules and the outcome on IPTp coverage was modelled. Among all women eligible for IPTp, 79% received a first dose of IPTp and 27% were given a second dose. Although pregnant women initiated ANC attendance late, their timing was in line with the national guidelines recommending IPTp delivery between 20-24 weeks and 28-32 weeks of gestation. Only 15% of the women delayed to the extent of being too late to be eligible for a first dose of IPTp. Less than 1% of women started ANC attendance after 32 weeks of gestation. During the second IPTp delivery period health workers delivered IPTp to significantly less women than during the first one (55% vs. 73%) contributing to low second dose coverage. Simplified IPTp guidelines for front-line health workers as recommended by WHO could lead to a 20 percentage point increase in IPTp coverage. This study suggests that facility and policy factors are greater barriers to IPTp coverage than women's timing of ANC attendance. To maximize the benefit of the IPTp intervention, revision of existing guidelines is needed. Training on simplified IPTp messages should be consolidated as part of the extended antenatal care training to change health workers' delivery practices and increase IPTp coverage. Pregnant women's knowledge about IPTp and the risks of malaria during pregnancy should be enhanced as well as their ability and power to demand IPTp and other ANC services.


Impact of the National Emergency Access Target policy on emergency departments' performance: A time-trend analysis for New South Wales, Australian Capital Territory and Queensland.
To evaluate the impact of the Australian National Emergency Access Target (NEAT) policy introduced in 2012 on ED performance. A longitudinal cohort study of NEAT implementation using linked data, for 12 EDs across New South Wales (NSW), Australian Capital Territory (ACT) and Queensland (QLD) between 2008 and 2013. Segmented regression in a multi-level model was used to analyse ED performance over time before and after NEAT introduction. The main outcomes measures were ED length of stay ≤4 h, access block, number of ED presentations, short-stay admission (≤24 h), >24 h admissions, unplanned ED re-attendances within 7 days and 'left at own risk' (including 'did not wait for assessment'). Two years after NEAT introduction, ED length of stay ≤4 h increased in NSW and QLD (odds ratio [OR] = 2.48 and 3.24; P < 0.001) and access block decreased (OR = 0.41 and 0.22; P < 0.001), but not in ACT (OR = 1.28; P > 0.05). ED presentations increased over time before and after NEAT introduction with a significant increase above the projected trend in NSW after NEAT (mean ratio = 1.07). Short-stay admissions increased in QLD (OR = 2.60), ACT (OR = 1.68) and NSW (OR = 1.35). Unplanned ED re-attendances did not change significantly. Those who left at their own risk decreased significantly in NSW and QLD (OR = 0.38 and 0.67). ED presentations continued to increase over time in all jurisdictions. NSW and QLD, but not ACT, showed significant improvements in time-based measures. Significant increases in short-stay admissions suggest a strategic change in ED process associated with NEAT implementation. Rates of unplanned ED re-attendances and those leaving at their own risk showed no evidence for adverse effects from NEAT.


Acute, subchronic and genotoxicity studies conducted with Oligonol, an oligomerized polyphenol formulated from lychee and green tea extracts.
Oligonol is a phenolic product derived from lychee fruit extract and green tea extract, containing catechin-type monomers and oligomers of proanthocyanidins, produced by a manufacturing process which converts polyphenol polymers into oligomers. The safety of Oligonol was assessed in acute and subchronic studies and genotoxicity assays. In a single dose acute study of Oligonol, male and female rats were administered 2000mg/kg body weight (bw) Oligonol in water by gavage. Oligonol caused no adverse effects and body weight gain and food consumption were within normal range, thus the LD(50) of Oligonol was determined to be greater than 2000mg/kg. A 90 day subchronic study (100, 300 and 1000mg/kgbw/day, oral gavage) in male and female rats reported no significant adverse effects in food consumption, body weight, mortality, clinical chemistry, haematology, gross pathology and histopathology. Similarly, no adverse effects were observed in mice fed diets providing 2, 20 or 200mg/kgbw Oligonol or 200mg/kgbw lychee polyphenol for 90 days. Oligonol did not show any potential to induce gene mutations in reverse mutation tests using Salmonella typhimurium TA98, TA100, TA1535, TA1537 and Escherichia coli WP2uvrA strains. Oligonol did not induce chromosomal aberrations in cultured Chinese hamster lung cells, but it showed increased polyploidy. In a micronucleus assay in mice, Oligonol did not induce any micronuclei or suppress bone marrow, indicating it does not cause chromosome aberrations. The results from these safety studies and previous reports support the safety of Oligonol for human consumption.