Rare variants in single-minded 1 (SIM1) are associated with severe obesity.
Single-minded 1 (SIM1) is a basic helix-loop-helix transcription factor involved in the development and function of the paraventricular nucleus of the hypothalamus. Obesity has been reported in Sim1 haploinsufficient mice and in a patient with a balanced translocation disrupting SIM1. We sequenced the coding region of SIM1 in 2,100 patients with severe, early onset obesity and in 1,680 controls. Thirteen different heterozygous variants in SIM1 were identified in 28 unrelated severely obese patients. Nine of the 13 variants significantly reduced the ability of SIM1 to activate a SIM1-responsive reporter gene when studied in stably transfected cells coexpressing the heterodimeric partners of SIM1 (ARNT or ARNT2). SIM1 variants with reduced activity cosegregated with obesity in extended family studies with variable penetrance. We studied the phenotype of patients carrying variants that exhibited reduced activity in vitro. Variant carriers exhibited increased ad libitum food intake at a test meal, normal basal metabolic rate, and evidence of autonomic dysfunction. Eleven of the 13 probands had evidence of a neurobehavioral phenotype. The phenotypic similarities between patients with SIM1 deficiency and melanocortin 4 receptor (MC4R) deficiency suggest that some of the effects of SIM1 deficiency on energy homeostasis are mediated by altered melanocortin signaling.


Tuning the nonlinear optical absorption of reduced graphene oxide by chemical reduction.
Reduced graphene oxides with varying degrees of reduction have been produced by hydrazine reduction of graphene oxide. The linear and nonlinear optical properties of both graphene oxide as well as the reduced graphene oxides have been measured by single beam Z-scan measurement in the picosecond region. The results reveal both saturable absorption and two-photon absorption, strongly dependent on the intensity of the pump pulse: saturable absorption occurs at lower pump pulse intensity (~1.5 GW/cm2 saturation intensity) whereas two-photon absorption dominates at higher intensities (≥5.7 GW/cm2). Intriguingly, we find that the two-photon absorption coefficient (from 1.5 cm/GW to 4.5cm/GW) and the saturation intensity (from 1 GW/cm2 to 2 GW/cm2) vary with chemical reduction, which is ascribed to the varying concentrations of sp2 domains and sp2 clusters in the reduced graphene oxides. Our results not only provide an insight into the evolution of the nonlinear optical coefficient in reduced graphene oxide, but also suggest that chemical engineering techniques may usefully be applied to tune the nonlinear optical properties of various nano-materials, including atomically thick graphene sheets.


Replication-restricted vaccinia as a cytokine gene therapy vector in cancer: persistent transgene expression despite antibody generation.
As antitumoral immunity requires the generation of local immunity directed against tissue proteins, we attempted to recreate within tumors the same environment found within tissues affected by autoimmune diseases (i.e., prolonged cytokine expression). Vaccinia virus (VV) has not been widely used as a cytokine gene therapy vector because of presumed high immunogenicity that would likely make repeated injections impossible; therefore, we modified it by inserting the cytokine gene into the thymidine kinase region, rendering it replication-restricted. The cytokine chosen was human interleukin-2 (IL-2); a molecule with powerful antitumoral effects. Six patients with the treatment-resistant tumor malignant mesothelioma received intratumoral (i.t.) VV-IL-2 therapy for 12 weeks by injection of 10(7) plaque-forming units of VV-IL-2 per dose. Serial tumor biopsies, sputum, urine, and blood samples were tested for VV-IL-2 mRNA expression; VV culture and T-cell infiltrates were evaluated by immunohistochemistry. Patients and contacts of patients were monitored for changes in VV immunoglobulin G (IgG) levels and clinical evidence of VV infection. VV-IL-2 was not excreted and was only cultured in one patient from tumor biopsies. A T-cell infiltrate was detected in 50% of tumor biopsies. VV-IL-2 mRNA expression was highest on days 1-3 postinjection and was detected for up to 3 weeks after each injection even though VV IgG levels rose in all patients. No significant toxicities, infection of patient contacts, or tumor regressions were observed. I.t. VV-IL-2 administration is safe, is associated with minimal toxicity, and results in i.t. expression of VV-IL-2 for up to 3 weeks postinjection regardless of the level of anti-VV IgG titers generated. This suggests that VV may be a good vector for repeated cytokine gene therapy of solid human cancer.


Cultural factors weaken but do not reverse left-to-right spatial biases in numerosity processing: Data from Arabic and English monoliterates and Arabic-English biliterates.
Directional response biases due to a conceptual link between space and number, such as a left-to-right hand bias for increasing numerical magnitude, are known as the SNARC (Spatial-Numerical Association of Response Codes) effect. We investigated how the SNARC effect for numerosities would be influenced by reading-writing direction, task instructions, and ambient visual environment in four literate populations exemplifying opposite reading-writing cultures-namely, Arabic (right-to-left script) and English (left-to-right script). Monoliterates and biliterates in Jordan and the U.S. completed a speeded numerosity comparison task to assess the directionality and magnitude of a SNARC effect in their numerosity processing. Monoliterates' results replicated previously documented effects of reading-writing direction and task instructions: the SNARC effect found in left-to-right readers was weakened in right-to-left readers, and the left-to-right group exhibited a task-dependency effect (SNARC effect in the smaller condition, reverse SNARC effect in the larger condition). Biliterates' results did not show a clear effect of environment; instead, both biliterate groups resembled English monoliterates in showing a left-to-right, task-dependent SNARC effect, albeit weaker than English monoliterates'. The absence of significant biases in all Arabic-reading groups (biliterates and Arabic monoliterates) points to a potential conflict between distinct spatial-numerical mapping codes. This view is explained in terms of the proposed Multiple Competing Codes Theory (MCCT), which posits three distinct spatial-numerical mapping codes (innate, cardinal, ordinal) during numerical processing-each involved at varying levels depending on individual and task factors.


Training and certification of the surgical oncologist.
Surgical Oncology has evolved as a distinct subspecialty of General Surgery with a well-defined curriculum focused on surgical care of the cancer patient, specific areas of clinical and basic science research focus and specialty journals dedicated to the discipline. The Society of Surgical Oncology (SSO), originally formed as the James Ewing Society, has provided leadership in developing training programs in Surgical Oncology and for three decades has been involved in the approval and oversight of Surgical Oncology training programs. Over this time, Surgical Oncology Fellowship training has expanded and in 2013 there were 103 applicants for 56 fellowship positions in 21 programs. The basic tenants of Surgical Oncology training has remained devoted to the core principles of multidisciplinary care, surgical management of cancer patients and a focus on education in research, clinical trials, community outreach, patient advocacy and leadership in oncology. With the maturation of Surgical Oncology as a separate specialty, Surgical Oncology training programs are now accredited by the Accreditation Council on Graduate Medical Education (ACGME) and graduates of the programs will soon be offered subspecialty certification in Complex General Surgical Oncology (CGSO) by the American Board of Surgery, which has created a component Surgical Oncology Board (SOB). Similar expansion has occurred in other specialty areas including an expansion of Breast Fellowships, which are still being approved by the SSO. In the 2013 SSO Breast Oncology Match, there were 67 applicants for 54 positions in 39 Breast Fellowship programs. Continued advances in cancer biology and technology will challenge us to evolve training programs in Surgical Oncology to produce surgeons capable of advancing the multidisciplinary care of cancer patients.


Reaction and diffusion on growing domains: scenarios for robust pattern formation.
We investigate the sequence of patterns generated by a reaction-diffusion system on a growing domain. We derive a general evolution equation to incorporate domain growth in reaction-diffusion models and consider the case of slow and isotropic domain growth in one spatial dimension. We use a self-similarity argument to predict a frequency-doubling sequence of patterns for exponential domain growth and we find numerically that frequency-doubling is realized for a finite range of exponential growth rate. We consider pattern formation under different forms for the growth and show that in one dimension domain growth may be a mechanism for increased robustness of pattern formation.


Long-chain omega-3 fatty acids and the brain: a review of the independent and shared effects of EPA, DPA and DHA.
Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega-3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer's disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega-3 PUFA biochemistry and metabolism, with particular focus on the central nervous system (CNS), where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzyme-derived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed. With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined.


Development of left occipitotemporal systems for skilled reading in children after a phonologically- based intervention.
A range of neurobiological investigations shows a failure of left hemisphere posterior brain systems to function properly during reading in children and adults with reading disabilities. Such evidence of a disruption in the normal reading pathways provides a neurobiological target for reading interventions. In this study, we hypothesized that the provision of an evidence-based, phonologically mediated reading intervention would improve reading fluency and the development of the fast-paced occipitotemporal systems serving skilled reading. Functional magnetic resonance imaging was used to study the effects of a phonologically based reading intervention on brain organization and reading fluency in 77 children aged 6.1-9.4 years (49 with reading disability and 28 control subjects). Children comprised three experimental groups: experimental intervention (n = 37), community intervention (n = 12), and community control subjects (n = 28). Immediately after the year-long intervention, children taught with the experimental intervention had made significant gains in reading fluency and demonstrated increased activation in left hemisphere regions, including the inferior frontal gyrus and the middle temporal gyrus; 1 year after the experimental intervention had ended these children were activating bilateral inferior frontal gyri and left superior temporal and occipitotemporal regions. These data indicate that the nature of the remedial educational intervention is critical to successful outcomes in children with reading disabilities and that the use of an evidence-based phonologic reading intervention facilitates the development of those fast-paced neural systems that underlie skilled reading.


Progressive renal papillary calcification and ureteral stone formation in mice deficient for Tamm-Horsfall protein.
Mammalian urine contains a range of macromolecule proteins that play critical roles in renal stone formation, among which Tamm-Horsfall protein (THP) is by far the most abundant. While THP is a potent inhibitor of crystal aggregation in vitro and its ablation in vivo predisposes one of the two existing mouse models to spontaneous intrarenal calcium crystallization, key controversies remain regarding the role of THP in nephrolithiasis. By carrying out a long-range follow-up of more than 250 THP-null mice and their wild-type controls, we demonstrate here that renal calcification is a highly consistent phenotype of the THP-null mice that is age and partially gene dosage dependent, but is gender and genetic background independent. Renal calcification in THP-null mice is progressive, and by 15 mo over 85% of all the THP-null mice develop spontaneous intrarenal crystals. The crystals consist primarily of calcium phosphate in the form of hydroxyapatite, are located more frequently in the interstitial space of the renal papillae than intratubularly, particularly in older animals, and lack accompanying inflammatory cell infiltration. The interstitial deposits of hydroxyapatite observed in THP-null mice bear strong resemblances to the renal crystals found in human kidneys bearing idiopathic calcium oxalate stones. Compared with 24-h urine from the wild-type mice, that of THP-null mice is supersaturated with brushite (calcium phosphate), a stone precursor, and has reduced urinary excretion of citrate, a stone inhibitor. While less frequent than renal calcinosis, renal pelvic and ureteral stones and hydronephrosis occur in the aged THP-null mice. These results provide direct in vivo evidence indicating that normal THP plays an important role in defending the urinary system against calcification and suggest that reduced expression and/or decreased function of THP could contribute to nephrolithiasis.


COVID-19 and Treatment and Immunization of Children-The Time to Redefine Pediatric Age Groups is Here.
Children are infected with coronavirus disease 2019 (COVID-19) as often as adults, but with fewer symptoms. During the first wave of the COVID-19 pandemic, multisystem inflammatory syndrome (MIS) in children (MIS-C), with symptoms similar to Kawasaki syndrome, was described in young minors testing positive for COVID-19. The United States (US) Centers for Disease Control and Prevention (CDC) defined MIS-C as occurring in <21-year-olds, triggering hundreds of PubMed-listed papers. However, postpubertal adolescents are no longer children biologically; the term MIS-C is misleading. Furthermore, MIS also occurs in adults, termed MIS-A by the CDC. Acute and delayed inflammations can be triggered by COVID-19. The 18th birthday is an administrative not a biological age limit, whereas the body matures slowly during puberty. This blur in defining children leads to confusion regarding MIS-C/MIS-A. United States and European Union (EU) drug approval is handled separately for children, defined as <18-year-olds, ascribing non-existent physical characteristics up to the 18th birthday. This blur between the administrative and the physiological meanings for the term child is causing flawed demands for pediatric studies in all drugs and vaccines, including those against COVID-19. Effective treatment of all conditions, including COVID-19, should be based on actual physiological need. Now, the flawed definition for children in the development of drugs and vaccines and their approval is negatively impacting prevention and treatment of COVID-19 in minors. This review reveals the necessity for redefining pediatric age groups to rapidly establish recommendations for optimal prevention and treatment in minors.


An FMRI study of frontostriatal circuits during the inhibition of eye blinking in persons with Tourette syndrome.
The authors sought to study activity in neural circuits that subserve the inhibition of a semi-involuntary motor behavior, eye blinking, in children and adults with Tourette syndrome and in healthy comparison subjects. Functional magnetic resonance imaging was used to scan 120 participants (51 with Tourette syndrome and 69 comparison subjects) as they either blinked normally or successfully inhibited eye blinking. The authors compared the blood-oxygen-level dependent signal during these two conditions across the Tourette and comparison groups. Relative to comparison subjects, patients with Tourette syndrome activated more strongly the frontal cortex and striatum during eye blink inhibition. Activation increased more with age in the dorsolateral and inferolateral prefrontal cortex and caudate nucleus in the Tourette group relative to comparison subjects. In addition, the Tourette group more strongly activated the middle frontal gyrus, dorsal anterior cingulate, and temporal cortices. The severity of tic symptoms in the Tourette group correlated inversely with activation in the putamen and inferolateral prefrontal cortex. Frontostriatal activity is increased in persons with Tourette syndrome during the inhibition of eye blinks. Activation of frontostriatal circuits in this population may help to maintain regulatory control over semi-involuntary behaviors, whether these are tics or eye blinks.


Health-related quality of life and flourishing in current and former recreational and elite cricketers.
Health related quality of life (HRQoL) and flourishing are constructs that encompasses a holistic representation of physical, psychological, and social health. The underlying psychological factors that can affect HRQoL and flourishing in sports participants is poorly understood. The purpose of this study was to i) evaluate HRQoL (physical and mental-components) and flourishing in recreational and elite and current and former cricketers; ii) determine the effect of resilience, playing-standard, and playing status on HRQoL and flourishing in cricketers. The Cricket Health and Wellbeing Study (n = 2598 current and former cricketers, aged ≥18 years) collected cross-sectional questionnaire data including the Flourishing Scale, Short Form-8 (physical (PCS) and mental (MCS) component scores), resilience (European Social Survey), highest standard-of-play, and playing status. Multivariable linear regressions with fractional polynomials were utilised, adjusted for age, gender, total cricket-seasons, comorbidity, ≥ 4-week time-loss injury, and orthopaedic surgery. Two thousand two hundred eighty individuals (aged (mean (SD)) 51.7(14.7) years, 61% played recreationally, 37% former cricketers) were included in analyses. The median (IQR) PCS was 51.4(46.9-55.9), MCS was 54.3(50.0-58.6), and Flourishing Scale score was 48 [ (1-7)] .Greater resilience was associated with better PCS (effect (95% CI) 1.41(0.70-2.11)), MCS (4.78(4.09-5.48)), and flourishing (2.07(2.55-3.59)) compared to less resilience. Playing standard was not associated with HRQoL. Playing at an elite standard was associated with greater flourishing (1.21(0.68, 1.73)), compared with playing recreationally. Current cricket participation was associated with better PCS (3.61(2.92-4.30)) and flourishing scores (0.53(0.02-1.04)), compared to former cricket participation. Cricketers reported high levels of mental-components of HRQoL and flourishing, and this was similar in recreational, elite, current and former cricketers. Current cricket participation and a higher standard-of-play was associated with greater flourishing. Current cricket participation was also associated with better PCS, however playing-status was not related to MCS. Further research is needed to understand if cricket participation may have psychological benefits that persist beyond cricket retirement.


CellMiner: a web-based suite of genomic and pharmacologic tools to explore transcript and drug patterns in the NCI-60 cell line set.
High-throughput and high-content databases are increasingly important resources in molecular medicine, systems biology, and pharmacology. However, the information usually resides in unwieldy databases, limiting ready data analysis and integration. One resource that offers substantial potential for improvement in this regard is the NCI-60 cell line database compiled by the U.S. National Cancer Institute, which has been extensively characterized across numerous genomic and pharmacologic response platforms. In this report, we introduce a CellMiner (http://discover.nci.nih.gov/cellminer/) web application designed to improve the use of this extensive database. CellMiner tools allowed rapid data retrieval of transcripts for 22,379 genes and 360 microRNAs along with activity reports for 20,503 chemical compounds including 102 drugs approved by the U.S. Food and Drug Administration. Converting these differential levels into quantitative patterns across the NCI-60 clarified data organization and cross-comparisons using a novel pattern match tool. Data queries for potential relationships among parameters can be conducted in an iterative manner specific to user interests and expertise. Examples of the in silico discovery process afforded by CellMiner were provided for multidrug resistance analyses and doxorubicin activity; identification of colon-specific genes, microRNAs, and drugs; microRNAs related to the miR-17-92 cluster; and drug identification patterns matched to erlotinib, gefitinib, afatinib, and lapatinib. CellMiner greatly broadens applications of the extensive NCI-60 database for discovery by creating web-based processes that are rapid, flexible, and readily applied by users without bioinformatics expertise.


Trends in traumatic brain injury mortality in China, 2006-2013: A population-based longitudinal study.
Traumatic brain injury (TBI) is a significant global public health problem, but has received minimal attention from researchers and policy-makers in low- and middle-income countries (LMICs). Epidemiological evidence of TBI morbidity and mortality is absent at the national level for most LMICs, including China. Using data from China's Disease Surveillance Points (DSPs) system, we conducted a population-based longitudinal analysis to examine TBI mortality, and mortality differences by sex, age group, location (urban/rural), and external cause of injury, from 1 January 2006 to 31 December 2013 in China. Mortality data came from the national DSPs system of China, which has coded deaths using the International Classification of Diseases-10th Revision (ICD-10) since 2004. Crude and age-standardized mortality with 95% CIs were estimated using the census population in 2010 as a reference population. The Cochran-Armitage trend test was used to examine the significance of trends in mortality from 2006 to 2013. Negative binomial models were used to examine the associations of TBI mortality with location, sex, and age group. Subgroup analysis was performed by external cause of TBI. We found the following: (1) Age-adjusted TBI mortality increased from 13.23 per 100,000 population in 2006 to 17.06 per 100,000 population in 2008 and then began to fall slightly. In 2013, age-adjusted TBI mortality was 12.99 per 100,000 population (SE = 0.13). (2) Compared to females and urban residents, males and rural residents had higher TBI mortality risk, with adjusted mortality rate ratios of 2.57 and 1.71, respectively. TBI mortality increased substantially with older age. (3) Motor vehicle crashes and falls were the 2 leading causes of TBI mortality between 2006 and 2013. TBI deaths from motor vehicle crashes in children aged 0-14 years and adults aged 65 years and older were most often in pedestrians, and motorcyclists were the first or second leading category of road user for the other age groups. (4) TBI mortality attributed to motor vehicle crashes increased for pedestrians and motorcyclists in all 7 age groups from 2006 to 2013. Our analysis was limited by the availability and quality of data in the DSPs dataset, including lack of injury-related socio-economic factors, policy factors, and individual and behavioral factors. The dataset also may be incomplete in TBI death recording or contain misclassification of mortality data. TBI constitutes a serious public health threat in China. Further studies should explore the reasons for the particularly high risk of TBI mortality among particular populations, as well as the reasons for recent increases in certain subgroups, and should develop solutions to address these challenges. Interventions proven to work in other cultures should be introduced and implemented nationwide. Examples of these in the domain of motor vehicle crashes include policy change and enforcement of laws concerning helmet use for motorcyclists and bicyclists, car seat and booster seat use for child motor vehicle passengers, speed limit and drunk driving laws, and alcohol ignition interlock use. Examples to prevent falls, especially among elderly individuals, include exercise programs, home modification to reduce fall risk, and multifaceted interventions to prevent falls in all age groups.


Blast injuries to the hand: Pathomechanics, patterns and treatment.
To characterize the common patterns of injury in detail in cases of blast injuries to the hand and to outline the possible pathomechanics of these patterns of injury while describing the treatment modalities for the same as practiced in our center. A review of admitted patients in our department from september 2009 through december 2010 of blast injuries to the hand was made. Each patient had a careful characterization of their injuries as mild, moderate or severe with the help of X-rays, clinical photographs and operative notes. The treatment of these patients during hospital stay was also documented. Of the 55 patients studied, 5 patients suffered mild injuries with no bony injuries or dislocations, 26 patients had moderate injuries characterized by fractures and dislocations in addition to soft tissue injuries and 24 patients had severe injuries characterized by variable degrees of amputations. The most common injury type was to the radial aspect of the hand characterized by a first web split and a dislocation of the CMC joint of the thumb associated with fracture of the central metacarpals and amputations of the index and long fingers in some cases. Injury to the ulnar aspect was rare. Injuries were treated by repair as well as replacement done mostly in a serial fashion. Depending on the mode of injury, blast injuries to the hand can have varying patterns of injury, which can have important implications in the treatment and rehabilitation of a patient.


Prospective memory rehabilitation using smartphones in patients with TBI.
The aim of the present study was to investigate the effectiveness of a prospective memory aid that combines smartphones with Internet-based calendars among community-dwelling patients with traumatic brain injury. An uncontrolled pre- and post-assessment design was employed to study the use of unmodified, low-cost, off-the-shelf smartphones combined with Internet-calendars as a compensatory memory strategy in community-dwelling patients with traumatic brain injury. Thirteen participants received a 6-week group-based intervention with pre-, post- and 2-month follow-up-assessments by questionnaires and by daily assessment of target behaviors for 2-week periods. Participants reported significantly fewer retro- and prospective memory problems on questionnaires after the intervention and at follow-up with large effect sizes. The performance of target behaviors, however, improved insignificantly with moderate effect sizes. There were no changes in quality of life or symptoms of emotional distress. This study adds to a growing body of evidence that smartphones are a useful compensatory aid in rehabilitation of prospective memory that should routinely be considered in rehabilitation of traumatic brain injury patients. Implication for rehabilitation Smartphones are easy-to-use and accessible assistive technology for compensatory memory rehabilitation to most traumatic brain injury patients. By using low-cost, off-the-shelf devices, the technology becomes available to a broader range of patients. By combining smartphones with Internet-based and cross-platform services (e.g., calendars, contacts) the participants are less device-dependent and less vulnerable to data loss. Smartphones should routinely be considered as compensatory aid in rehabilitation of prospective memory of traumatic brain injured patients.


The use of calcium sulfate and calcium phosphate composite graft to augment screw purchase in osteoporotic ankles.
Screws placed in the distal fibula may not have satisfactory purchase during internal fixation of an osteoporotic ankle fracture. Tibia-pro-fibula screws that extend from the fibula into the distal tibial metaphysis provide additional purchase. The purpose of this study was to investigate if purchase of these screws can be enhanced further by injecting calcium sulfate and calcium phosphate composite graft into the drill holes prior to insertion of the screws. Bone density was quantified using a DEXA scan in paired cadaver legs. One leg from each pair was randomly selected for injection of composite graft into the screw holes before insertion of the screws. Two screws were inserted through the fibula into the distal tibial metaphysis in each leg, at the level of the syndesmosis under fluoroscopy in a standardized fashion in an MTS machine. After testing 4 pairs of cadaver legs, a statistically significant difference was noted in displacement (p = 0.018 distal, p = 0.0093 proximal), failure load, (p = 0.0185 distal, p = 0.0238 proximal), and failure energy (p = 0.0071 distal, p = 0.0115 proximal) between augmented and non-augmented screws, with the augmented screws being considerably stronger. Screws augmented with composite graft provide significantly greater purchase in an osteoporotic fibular fracture model. Composite graft augmented screws inserted into the distal tibia from the fibula may enhance the stability of internal fixation of an osteoporotic ankle fracture. This may enable earlier weightbearing and return to function which is important in elderly patients.


Undertreatment of Men in Their Seventies with High-risk Nonmetastatic Prostate Cancer.
Many elderly men with high-risk nonmetastatic prostate cancer (HRnMPCa) do not receive radical treatment, despite the high mortality associated with conservative management. To investigate how age and comorbidity affect treatment of men with HRnMPCa. This was an observational nationwide register study during 2001-2012. We identified 19 190 men of <80 yr of age diagnosed with HRnMPCa in the National Prostate Cancer Register of Sweden and 95 948 age-matched men without prostate cancer in the register of the total population. The outcome was the proportion of men with HRnMPCa receiving radical treatment (radical prostatectomy or radiotherapy). Vital status and the Charlson comorbidity index (CCI) were obtained from nationwide registers. The 10-yr survival of men without prostate cancer, stratified by age and CCI, was used as a measure of the life expectancy of the men with prostate cancer. The proportions receiving radical treatment varied with life expectancy among men younger than 70 yr, whereas use of these treatments did not match the long life expectancy of men in their seventies with CCI 0-1. Only 10% of men aged 75-80 yr with CCI 0 received radical treatment despite 52% probability of 10-yr life expectancy, compared with approximately half of the men younger than 70 yr with a similar life expectancy. The use of radical treatment for HRnMPCa increased with time in all Swedish counties, but a threefold difference between counties remained in 2009-2012 for patients aged 70-80 yr with CCI 0-1. Uncertain external validity is a study limitation, and the impact of physician versus patient preferences on treatment selection could not be assessed. Otherwise healthy men in their seventies with HRnMPCa were less likely to receive radical treatment than younger men with a similar life expectancy, although increasing use of radical treatment was observed during the study period. Our findings highlight the need for improved methods for clinical decision-making, including improved assessment of life expectancy. We performed a nationwide register study that showed that many healthy men in their seventies live for at least another 10 yr. Despite this long life expectancy, men in their seventies with high-risk nonmetastatic prostate cancer were often not treated with radical prostatectomy or radiotherapy, possibly because their life expectancy was underestimated. Our study highlights the need for improved clinical decision-making, which should incorporate an assessment of the patient's life expectancy.


The pseudo-mitochondrial genome influences mistakes in heteroplasmy interpretation.
Nuclear mitochondrial pseudogenes (numts) are a potential source of contamination during mitochondrial DNA PCR amplification. This possibility warrants careful experimental design and cautious interpretation of heteroplasmic results. Here we report the cloning and sequencing of numts loci, amplified from human tissue and rho-zero (rho0) cells (control) with primers known to amplify the mitochondrial genome. This paper is the first to fully sequence 46 paralogous nuclear DNA fragments that represent the entire mitochondrial genome. This is a surprisingly small number due primarily to the primer sets used in this study, because prior to this, BLAST searches have suggested that nuclear DNA harbors between 400 to 1,500 paralogous mitochondrial DNA fragments. Our results indicate that multiple numts were amplified simultaneously with the mitochondrial genome and increased the load of pseudogene signal in PCR reactions. Further, the entire mitochondrial genome was represented by multiple copies of paralogous nuclear sequences. These findings suggest that mitochondrial genome disease-associated biomarkers must be rigorously authenticated to preclude any affiliation with paralogous nuclear pseudogenes. Importantly, the common perception that mitochondrial template "swamps" numts loci precluding detectable amplification, depends on the region of the mitochondrial genome targeted by the PCR reaction and the number of pseudogene loci that may co-amplify. Cloning and relevant sequencing data will facilitate the correct interpretation. This is the first complete, wet-lab characterization of numts that represent the entire mitochondrial genome.


Paired-pulse plasticity in the strength and latency of light-evoked lateral inhibition to retinal bipolar cell terminals.
Synapses in the inner plexiform layer of the retina undergo short-term plasticity that may mediate different forms of adaptation to regularities in light stimuli. Using patch-clamp recordings from axotomized goldfish Mb bipolar cell (BC) terminals with paired-pulse light stimulation, we isolated and quantified the short-term plasticity of GABAergic lateral IPSCs (L-IPSCs). Bright light stimulation evoked ON and OFF L-IPSCs in axotomized BCs, which had distinct onset latencies (∼50-80 and ∼70-150 ms, respectively) that depended on background light adaptation. We observed plasticity in both the synaptic strength and latency of the L-IPSCs. With paired light stimulation, latencies of ON L-IPSCs increased at paired-pulse intervals (PPIs) of 50 and 300 ms, whereas OFF L-IPSC latencies decreased at the 300 ms PPI. ON L-IPSCs showed paired-pulse depression at intervals <1 s, whereas OFF L-IPSCs showed depression at intervals ≤1 s and amplitude facilitation at longer intervals (1-2 s). This biphasic form of L-IPSC plasticity may underlie adaptation and sensitization to surround temporal contrast over multiple timescales. Block of retinal signaling at GABA(A)Rs and AMPARs differentially affected ON and OFF L-IPSCs, confirming that these two types of feedback inhibition are mediated by distinct and convergent retinal pathways with different mechanisms of plasticity. We propose that these plastic changes in the strength and timing of L-IPSCs help to dynamically shape the time course of glutamate release from ON-type BC terminals. Short-term plasticity of L-IPSCs may thus influence the strength, timing, and spatial extent of amacrine and ganglion cell inhibitory surrounds.


CD36 may determine our desire for dietary fats.
There is a strong link between high fat intake and obesity. In addition to its high caloric density, dietary fat has a hyperphagic effect, in part as a result of its high palatability. The recent identification by Laugerette et al. of CD36 as a taste receptor for fatty acids provides insight into the molecular basis of our preference for fat (see the related article beginning on page 3177). As we gain more information regarding the function of this receptor, we may be able to devise better strategies to address the addictive potential of dietary fat.


An Adult Health Care-Based Pediatric to Adult Transition Program for Emerging Adults With Type 1 Diabetes.
Purpose The purpose of the study was to evaluate an adult health care program model for emerging adults with type 1 diabetes transitioning from pediatric to adult care. Methods Evaluation of the Pediatric to Adult Diabetes Transition Clinic at the University of Pennsylvania included a cohort of 72 emerging adults with type 1 diabetes, ages 18 to 25 years. Data were extracted from transfer summaries and the electronic medical record, including sociodemographic, clinical, and follow-up characteristics. Pre- and postprogram assessment at 6 months included mean daily blood glucose monitoring frequency (BGMF) and glycemic control (A1C). Paired t tests were used to examine change in outcomes from baseline to 6 months, and multiple linear regression was utilized to adjust outcomes for baseline A1C or BGMF, sex, diabetes duration, race, and insulin regimen. Open-ended survey responses were used to assess acceptability amongst participants. Results From baseline to 6 months, mean A1C decreased by 0.7% (8 mmol/mol), and BGMF increased by 1 check per day. Eighty-eight percent of participants attended ≥2 visits in 6 months, and the program was rated highly by participants and providers (pediatric and adult). Conclusions This study highlights the promise of an adult health care program model for pediatric to adult diabetes transition.


Physicians' Experiences as Patients with Statin Side Effects: A Case Series.
Physicians are among those prescribed statins and therefore, subject to potential statin adverse effects (AEs). There is little information on the impact of statin AEs on physicians affected by them. We sought to assess the character and impact of statin AEs occurring in physicians and retired physicians, and to ascertain whether/how personal experience of AEs moderated physicians' attitude toward statin use. Seven active or retired physicians from the United States communicated with the Statin Effects Study group regarding their personal experience of statin AEs. AE characteristics, experience with (their own) physicians, and impact of AE was ascertained. We inquired whether or how their experience altered their own attitude toward statins or statin AEs. Patient A: Atorvastatin 40 then 80 mg was followed by cognitive problems, neuropathy, and glucose intolerance in a Radiologist in his 50s (Naranjo criteria: probable causality). Patient B: Atorvastatin 10 mg was followed in 2 months by muscle weakness and myalgia in an Internist in his 40s (probable causality). Patient C: Atorvastatin, ezetimibe/simvastatin, rosuvastatin at varying doses was followed shortly after by irritability, myalgia, and fatigue in a Cardiac Surgeon in his 40s (probable causality). Patient D: Simvastatin 20 then 40 mg was followed in 4 years by mitochondriopathy, myopathy, neuropathy, and exercise intolerance in an Emergency Medicine physician in his 50s (definite causality). Patient E: Simvastatin 20 mg and niacin 1000 mg was followed in one month by muscle weakness and myalgia in a Physical Medicine and Rehabilitation physician in his 50s (probable causality). Patient F: Lovastatin 20 mg then simvastatin 20 mg, atorvastatin 20 mg, rosuvastatin 5 mg, niacin 20 mg and ezetimbe 10 mg was followed by muscle weakness and myalgia in an Obstetrician/Gynecologist in his 70s (definite causality). Patient G: Ezetimibe/simvastatin and atorvastatin (dose unavailable) was followed shortly after by cognitive problems in a Radiologist in her 80s (probable causality). Thus AEs affected multiple quality-of-life relevant domains, often in combination, encompassing muscle (N = 5), fatigue (N = 2), peripheral neuropathy (N = 2), cognitive (N = 2), dysglycemia (N = 1) and behavioral manifestations (N = 1). In five, the AEs affected the physician professionally. Five physicians experienced dismissive attitudes in some of their own healthcare encounters. One noted that his experience helped not only his own attention to statin AEs, but that of other physicians in his community. Several stated that their experience altered their understanding of and/or attitude toward statin AEs, and/or their view of settings in which statin use is warranted. Statin AEs can have profound impact in high functioning professionals with implications to the individual, their professional life, and those whom they serve professionally.


Maternally transmitted target antigen for unrestricted killing by NZB T lymphocytes.
A new target antigen for unrestricted killing was defined by NZB T lymphocytes which were immunized and restimulated with H-2-identical BALB/c spleen cells. These effector cells killed nearly all target cells tested, irrespective of their H-2 type, but did not kill NZB target cells. The response was shown to have three major components: unrestricted killing specific for Qed-1b, H-2d-restricted killing specific for minor histocompatibility antigens, and unrestricted killing specific for a new antigen, Mta. Mta is present on normal and mitogen-stimulated T and B lymphocytes and on several tumor lines. It was found on cells from 26 mouse strains tested, including two substrains of NZB, representing 9 different H-2 types and 14 different non-H-2 backgrounds. Analysis of the NX8 recombinant inbred lines (derived from Mta-NZB/Icr and Mta+C58/J parents) suggested that Mta is maternally transmitted. This was confirmed by typing of reciprocal F1 hybrids and backcrosses between positive and negative strains: Mta+ females bear Mta+ offspring and Mta- females Mta- offspring, irrespective of the phenotype of the males.


A bean cDNA expressed during a hypersensitive reaction encodes a putative calcium-binding protein.
The hypersensitive reaction (HR) is an inducible plant response that is associated with disease resistance. It is characterized by rapid, localized cell death at the site of infection and is believed to inhibit the spread of invading pathogens. We have isolated a cDNA clone, designated Hra32 (for hypersensitive reaction associated), corresponding to an RNA transcript that accumulates in bean during an HR. The predicted protein product of the Hra32 cDNA is an approximately 17 kDa protein of 161 amino acids, with four putative EF-hand calcium-binding domains. The temporal pattern of Hra32 transcript accumulation correlated closely with the onset of the HR in bean after inoculation with incompatible Pseudomonas syringae pv. tabaci and pv. tomato and with tobacco necrosis virus. Hra32 transcript also accumulated in bean in response to compatible P. syringae pv. phaseolicola and was correlated with necrotic cell death associated with disease lesion formation. A more transient pattern of Hra32 transcript accumulation occurred in bean in response to general stimuli that did not result in the HR or host cell death. These treatments included infiltration with a P. syringae pv. tabaci Hrp- mutant, P. syringae pv. tabaci cells treated with kanamycin, Escherichia coli, P. fluorescens, or glutathione, and in response to wounding. Thus, there was differential accumulation of the Hra32 transcript in response to specific stimuli resulting in the HR, compared with general stimuli that did not result in cell death. We hypothesize that the Hra32 product may be a component of the pathway that leads to hypersensitive cell death.


Survival of Entomopathogenic Nematodes in Oil Emulsions and Control Effectiveness on Adult Engorged Ticks (Acari: Ixodida).
Although their control is based on chemical products, the infestations by ticks (Ixodes scapularis Say) are causing great losses and damages in the livestock production worldwide. In this study, the survival of the entomopathogenic nematodes Heterorhabditis bacteriophora, Steinernema carpocapsae and Steinernema websteri in vegetal oil suspension at concentrations of 13% and 33% and their effectiveness to control ticks at concentrations of 50 ± 5 and 100 ± 10 nematodes in oil suspensions of Cymbopogon citratus, Pelargonium sp, Juniperus virginiana, Rosa sp, and Mentha piperita were evaluated in lab conditions. In field conditions, the Lethal Concentration (LC90) of S. websteri in oil suspensions of J. virginiana and C. citratus in dogs infested with ticks was evaluated. In the laboratory, it was found that an oil emulsion of C. citratus and J. virginiana at 13% maintained the survival of S. carpocapsae, H. bacteriophora and S. websteri from 55% to 60% for a period of 96 hr. The combination of the S. websteri nematode with 50 or 100 nematodes in oil emulsions of J. virginiana at 33% presented a control effectiveness of 80-100% in adult ticks 24 hr post-application. In field, the LC90 of 119 juveniles of S. websteri in oil emulsions of J. virginiana at 33% on domestic dogs presented an accumulated a control effectiveness of 89% after 96 hr post-application. The combined application of J. virginiana and S. websteri could be a good alternative for the control of ticks. It was observed that the time of contact and the type of vegetable oil were crucial factors to increase the effectiveness of control. Although their control is based on chemical products, the infestations by ticks (Ixodes scapularis Say) are causing great losses and damages in the livestock production worldwide. In this study, the survival of the entomopathogenic nematodes Heterorhabditis bacteriophora, Steinernema carpocapsae and Steinernema websteri in vegetal oil suspension at concentrations of 13% and 33% and their effectiveness to control ticks at concentrations of 50 ± 5 and 100 ± 10 nematodes in oil suspensions of Cymbopogon citratus, Pelargonium sp, Juniperus virginiana, Rosa sp, and Mentha piperita were evaluated in lab conditions. In field conditions, the Lethal Concentration (LC90) of S. websteri in oil suspensions of J. virginiana and C. citratus in dogs infested with ticks was evaluated. In the laboratory, it was found that an oil emulsion of C. citratus and J. virginiana at 13% maintained the survival of S. carpocapsae, H. bacteriophora and S. websteri from 55% to 60% for a period of 96 hr. The combination of the S. websteri nematode with 50 or 100 nematodes in oil emulsions of J. virginiana at 33% presented a control effectiveness of 80–100% in adult ticks 24 hr post-application. In field, the LC90 of 119 juveniles of S. websteri in oil emulsions of J. virginiana at 33% on domestic dogs presented an accumulated a control effectiveness of 89% after 96 hr post-application. The combined application of J. virginiana and S. websteri could be a good alternative for the control of ticks. It was observed that the time of contact and the type of vegetable oil were crucial factors to increase the effectiveness of control.


The challenge of micropollutants in aquatic systems.
The increasing worldwide contamination of freshwater systems with thousands of industrial and natural chemical compounds is one of the key environmental problems facing humanity. Although most of these compounds are present at low concentrations, many of them raise considerable toxicological concerns, particularly when present as components of complex mixtures. Here we review three scientific challenges in addressing water-quality problems caused by such micropollutants. First, tools to assess the impact of these pollutants on aquatic life and human health must be further developed and refined. Second, cost-effective and appropriate remediation and water-treatment technologies must be explored and implemented. Third, usage and disposal strategies, coupled with the search for environmentally more benign products and processes, should aim to minimize introduction of critical pollutants into the aquatic environment.


Molecular basis for DNA double-strand break annealing and primer extension by an NHEJ DNA polymerase.
Nonhomologous end-joining (NHEJ) is one of the major DNA double-strand break (DSB) repair pathways. The mechanisms by which breaks are competently brought together and extended during NHEJ is poorly understood. As polymerases extend DNA in a 5'-3' direction by nucleotide addition to a primer, it is unclear how NHEJ polymerases fill in break termini containing 3' overhangs that lack a primer strand. Here, we describe, at the molecular level, how prokaryotic NHEJ polymerases configure a primer-template substrate by annealing the 3' overhanging strands from opposing breaks, forming a gapped intermediate that can be extended in trans. We identify structural elements that facilitate docking of the 3' ends in the active sites of adjacent polymerases and reveal how the termini act as primers for extension of the annealed break, thus explaining how such DSBs are extended in trans. This study clarifies how polymerases couple break-synapsis to catalysis, providing a molecular mechanism to explain how primer extension is achieved on DNA breaks.


Incidence and implications of postoperative supraventricular tachycardia after pulmonary lobectomy.
We sought to determine the rate of postoperative supraventricular tachycardia (POSVT) in patients undergoing pulmonary lobectomy, and its association with adverse outcomes. Using the State Inpatient Database, from the Healthcare Cost and Utilization Project, we reviewed lobectomies performed (2009-2011) in California, Florida, and New York, to determine POSVT incidence. Patients were grouped by presence or absence of POSVT, with or without other complications. Stroke rates were analyzed independently from other complications. Multivariable regression analysis was used to determine factors associated with POSVT. Among 20,695 lobectomies performed, 2449 (11.8%) patients had POSVT, including 1116 (5.4%) with isolated POSVT and 1333 (6.4%) with POSVT with other complications. Clinical predictors of POSVT included age ≥75 years, male gender, white race, chronic obstructive pulmonary disease, congestive heart failure, thoracotomy surgical approach, and pulmonary complications. POSVT was associated with an increase of: stroke (odds ratio [OR] 1.74; 95% confidence interval [CI] 1.03-2.94); in-hospital death (OR 1.85; 95% CI 1.45-2.35); LOS (OR 1.33; 95% CI 1.29-1.37); and readmission (OR 1.29; 95% CI 1.04-1.60). The stroke rate was <1% in patients who had isolated POSVT, and 1.5% in patients with POSVT with other complications. Patients with isolated POSVT had increased readmission and LOS, and a marginal increase in stroke rate, compared with patients with an uncomplicated course. POSVT is common in patients undergoing pulmonary lobectomy and is associated with adverse outcomes. Comparative studies are needed to determine whether strict adherence to recently published guidelines will decrease the rate of stroke, readmission, and death after POSVT in thoracic surgical patients.


Nucleocytoplasmic distribution of budding yeast protein kinase A regulatory subunit Bcy1 requires Zds1 and is regulated by Yak1-dependent phosphorylation of its targeting domain.
In Saccharomyces cerevisiae the subcellular distribution of Bcy1 is carbon source dependent. In glucose-grown cells, Bcy1 is almost exclusively nuclear, while it appears more evenly distributed between nucleus and cytoplasm in carbon source-derepressed cells. Here we show that phosphorylation of its N-terminal domain directs Bcy1 to the cytoplasm. Biochemical fractionation revealed that the cytoplasmic fraction contains mostly phosphorylated Bcy1, whereas unmodified Bcy1 is predominantly present in the nuclear fraction. Site-directed mutagenesis of two clusters (I and II) of serines near the N terminus to alanine resulted in an enhanced nuclear accumulation of Bcy1 in ethanol-grown cells. In contrast, substitutions to Asp led to a dramatic increase of cytoplasmic localization in glucose-grown cells. Bcy1 modification was found to be dependent on Yak1 kinase and, consequently, in ethanol-grown yak1 cells the Bcy1 remained nuclear. A two-hybrid screen aimed to isolate genes encoding proteins that interact with the Bcy1 N-terminal domain identified Zds1. In ethanol-grown zds1 cells, cytoplasmic localization of Bcy1 was largely absent, while overexpression of ZDS1 led to increased cytoplasmic Bcy1 localization. Zds1 does not regulate Bcy1 modification since this was found to be unaffected in zds1 cells. However, in zds1 cells cluster II-mediated, but not cluster I-mediated, cytoplasmic localization of Bcy1 was found to be absent. Altogether, these results suggest that Zds1-mediated cytoplasmic localization of Bcy1 is regulated by carbon source-dependent phosphorylation of cluster II serines, while cluster I acts in a Zds1-independent manner.


Gastroprotection in trauma patients receiving non-steroidal anti-inflammatory drugs.
NSAIDs are commonly used analgesic agents in the orthopaedic trauma setting. Evidence-based guidelines recommend that patients with one or more risk factors for NSAID-associated gastrointestinal (GI) ulcer complications should be prescribed gastroprotective agents to minimise the risk of serious ulcer complications, including gastrointestinal haemorrhage. The purpose of the present audit was to evaluate and improve the adherence to these guidelines in new-NSAID users in a trauma unit at a district general hospital. A retrospective observational cohort study was conducted over an 18-week period to assess pre-intervention practice. Subsequently, an awareness programme, including prescriber and pharmacist education and the use of reminder posters, was implemented. Following this, data were collected prospectively over 9 weeks to assess any change in performance. Assessment involved review of case-notes and prescription charts of all adults (aged ≥ 18 years) who were commenced on regular NSAIDs on or during admission to the Trauma Unit. Patients were risk-stratified according to the number of risk factors, which were defined as age ≥ 65 years, major comorbidity, oral steroids, anticoagulation, history of upper gastrointestinal ulceration or bleeding and prescription above the normal recommended dose of NSAIDs. The American College of Rheumatology guidelines recommend the use of gastroprotective agents when one or more risk factors was present. Prescription of gastroprotective drugs was recorded to measure adherence to evidence-based guidelines. A total of 644 patients were reviewed over the study period, 451 pre-intervention and 193 post-intervention. 100 patients fulfilled the inclusion criteria pre-intervention and 49 post-intervention. Before intervention, the proportion of high-risk NSAID-receivers co-prescribed gastroprotection was low at 25.3%, although the likelihood of adherence improved with the number of risk factors; overall adherence rate improved significantly following intervention at 73.1% (chi² = 18.8, p < 0.001). Furthermore, a smaller proportion of NSAID-receivers fell into the high-risk category from 75% to 56.5% (chi² = 7.25, p < 0.05). (1) The majority of trauma admissions are at high risk for developing gastrointestinal haemorrhage. (2) Initial adherence to national guidelines for safe prescription of NSAIDs in our trauma unit was poor (25.3%) but improved significantly (73.1%) following an awareness programme which included education of prescribers and pharmacists. (3) A lower proportion of NSAID-receivers had multiple risk factors following our awareness programme. (4) Awareness of gastroprotection guidelines must be raised in trauma units to prevent undertreatment and hence minimise the risk of GI haemorrhage.


A systematic review and meta-analysis of tobacco use and prostate cancer mortality and incidence in prospective cohort studies.
An association between tobacco smoking and prostate cancer (PCa) incidence and mortality was suggested in an earlier meta-analysis of 24 prospective studies in which dose-response associations and risks per unit of tobacco use were not examined. We investigated the association between several measures of tobacco use and PCa mortality (primary outcome) and incidence (secondary outcome) including dose-response association. Relevant articles from prospective studies were identified by searching the PubMed and Web of Science databases (through January 21, 2014) and reference lists of relevant articles. Combined relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random effects methods. We also calculated population attributable risk (PAR) for smoking and PCa mortality. We included 51 articles in this meta-analysis (11823 PCa deaths, 50349 incident cases, and 4,082,606 cohort participants). Current cigarette smoking was associated with an increased risk of PCa death (RR: 1.24; 95% CI, 1.18-1.31), with little evidence for heterogeneity and publication bias. The number of cigarettes smoked per day had a dose-response association with PCa mortality (p=0.02; RR for 20 cigarettes per day: 1.20). The PAR for cigarette smoking and PCa deaths in the United States and Europe were 6.7% and 9.5%, respectively, corresponding to >10000 deaths/year in these two regions. Current cigarette smoking was inversely associated with incident PCa (RR: 0.90; 95% CI, 0.85-0.96), with high heterogeneity in the results. However, in studies completed in 1995 or earlier (considered as completed before the prostate-specific antigen screening era), ever smoking showed a positive association with incident PCa (RR: 1.06; 95% CI, 1.00-1.12) with little heterogeneity. Combined evidence from observational studies shows a modest but statistically significant association between cigarette smoking and fatal PCa. Smoking appears to be a modifiable risk factor for PCa death. Smoking increases the chance of prostate cancer death. Not smoking prevents this harm and many other tobacco-related diseases.


Measurement of dijet angular distributions at square root(s) = 1.96 TeV and searches for quark compositeness and extra spatial dimensions.
We present the first measurement of dijet angular distributions in pp collisions at square root(s) = 1.96 TeV at the Fermilab Tevatron Collider. The measurement is based on a dataset corresponding to an integrated luminosity of 0.7 fb(-1) collected with the D0 detector. Dijet angular distributions have been measured over a range of dijet masses, from 0.25 TeV to above 1.1 TeV. The data are in good agreement with the predictions of perturbative QCD and are used to constrain new physics models including quark compositeness, large extra dimensions, and TeV(-1) scale extra dimensions. For all models considered, we set the most stringent direct limits to date.


Pooled analysis of stereotactic ablative radiotherapy for primary renal cell carcinoma: A report from the International Radiosurgery Oncology Consortium for Kidney (IROCK).
Stereotactic ablative radiotherapy (SABR) is an emerging therapy for primary renal cell carcinoma. The authors assessed safety, efficacy, and survival in a multi-institutional setting. Outcomes between single-fraction and multifraction SABR were compared. Individual patient data sets from 9 International Radiosurgery Oncology Consortium for Kidney institutions across Germany, Australia, the United States, Canada, and Japan were pooled. Toxicities were recorded using Common Terminology Criteria for Adverse Events, version 4.0. Patient, tumor, and treatment characteristics were stratified according to the number of radiotherapy fractions (single vs multiple). Survival outcomes were examined using Kaplan-Meier estimates and Cox proportional-hazards regression. Of 223 patients, 118 received single-fraction SABR, and 105 received multifraction SABR. The mean patient age was 72 years, and 69.5% of patients were men. There were 83 patients with grade 1 and 2 toxicity (35.6%) and 3 with grade 3 and 4 toxicities (1.3%). The rates of local control, cancer-specific survival, and progression-free survival were 97.8%, 95.7%, and 77.4%, respectively, at 2 years; and they were 97.8%, 91.9%, and 65.4%, respectively, at 4 years. On multivariable analysis, tumors with a larger maximum dimension and the receipt of multifraction SABR were associated with poorer progression-free survival (hazard ratio, 1.16 [P < .01] and 1.13 [P = .02], respectively) and poorer cancer-specific survival (hazard ratio, 1.28 [P < .01] and 1.33 [P = .01], respectively). There were no differences in local failure between the single-fraction cohort (n = 1) and the multifraction cohort (n = 2; P = .60). The mean ( ± standard deviation) estimated glomerular filtration rate at baseline was 59.9 ± 21.9 mL per minute, and it decreased by 5.5 ± 13.3 mL per minute (P < .01). SABR is well tolerated and locally effective for treating patients who have primary renal cell carcinoma and has an acceptable impact on renal function. An interesting observation is that patients who receive single-fraction SABR appear to be less likely to progress distantly or to die of cancer. Cancer 2018;124:934-42. © 2017 American Cancer Society.


The effect of paternal age on semen quality and fertilization outcome in men with normal sperm DNA compaction, reactive oxygen species, and total antioxidant capacity levels.
Studies showed a decrease of the semen analysis parameters and an increase in the average age of first-time fathers over the past several decades. The aim of the present study was to assess the influence of paternal age on semen quality and fertilization outcomes in men with normal sperm DNA fragmentation and chromatin maturation index (DFI and CMI), reactive oxygen species (ROS), and total antioxidant capacity (TAC) levels. The study was performed on 70 men with their wife's age ≤38 years and normal sperm DFI, CMI, ROS, and TAC levels. None of the couples had a history of genital inflammation, chronic diseases, endocrine abnormality, chromosomal aberrations, Y chromosome microdeletion, azoospermia, and leukocytospermia. These men were separated into 2 groups according to their age (group A: age <45 years and group B: age ≥45 years). Semen analysis and fertilization outcome after using the intracytoplasmic sperm injection were assessed in both groups. Sperm concentration showed a significant reduction in group B (p=0.04). Although semen volume, sperm normal morphology, and progressive motility were decreased in group B, the reduction was not significant when compared with group A (p=0.09, p=0.47, and p=0.77, respectively). In addition, the differences of embryo quality with grades A, B, and C and 8-cell embryo formation were not statistically significant between the 2 groups. These results demonstrated that in men with normal sperm DFI, CMI, ROS, and TAC levels, there were no significant changes in semen parameters and fertilization outcomes with an increasing age.


Hydrodynamic stability without eigenvalues.
Fluid flows that are smooth at low speeds become unstable and then turbulent at higher speeds. This phenomenon has traditionally been investigated by linearizing the equations of flow and testing for unstable eigenvalues of the linearized problem, but the results of such investigations agree poorly in many cases with experiments. Nevertheless, linear effects play a central role in hydrodynamic instability. A reconciliation of these findings with the traditional analysis is presented based on the "pseudospectra" of the linearized problem, which imply that small perturbations to the smooth flow may be amplified by factors on the order of 10(5) by a linear mechanism even though all the eigenmodes decay monotonically. The methods suggested here apply also to other problems in the mathematical sciences that involve nonorthogonal eigenfunctions.


Bovine Serum Albumin Adsorption at a Silica Surface Explored by Simulation and Experiment.
Molecular details of BSA adsorption on a silica surface are revealed by fully atomistic molecular dynamics (MD) simulations (with a 0.5 μs trajectory), supported by dynamic light scattering (DLS), zeta potential, multiparametric surface plasmon resonance (MP-SPR), and contact angle experiments. The experimental and theoretical methods complement one another and lead to a wider understanding of the mechanism of BSA adsorption across a range of pH 3-9. The MD results show how the negatively charged BSA at pH7 adsorbs to the negatively charged silica surface, and reveal a unique orientation with preserved secondary and tertiary structure. The experiments then show that the protein forms complete monolayers at ∼ pH6, just above the protein's isoelectric point (pH5.1). The surface contact angle is maximum when it is completely coated with protein, and the hydrophobicity of the surface is understood in terms of the simulated protein conformation. The adsorption behavior at higher pH > 6 is also consistently interpreted using the MD picture; both the contact angle and the adsorbed protein mass density decrease with increasing pH, in line with the increasing magnitude of negative charge on both the protein and the surface. At lower pH < 5 the protein starts to unfold, and the adsorbed mass dramatically decreases. The comprehensive picture that emerges for the formation of oriented protein films with preserved native conformation will help guide efforts to create functional films for new technologies.


An approach to determining anthocyanin synthesis enzyme gene expression in an evolutionary context: an example from Erica plukenetii.
Floral colour in angiosperms can be controlled by variations in the expression of the genes of the anthocyanin pathway. Floral colour shifts influence pollinator specificity. Multiple shifts in floral colour occurred in the diversification of the genus Erica (Ericaceae), from plesiomorphic pink to, for example, red or white flowers. Variation in anthocyanin gene expression and its effects on floral colour in the red-, pink- and white-flowered Erica plukenetii species complex was investigated. Next generation sequencing, reverse transcriptase PCR and real-time reverse transcriptase quantitative PCR were used to quantify anthocyanin gene expression. Non-homologous mutations causing loss of expression of single genes were found, indicating that the cause was likely to be mutations in transcription factor binding sites upstream of the 5'-untranslated region of the genes, and this was confirmed by sequencing. Independent evolution and subsequent loss of expression of anthocyanin genes may have influenced diversification in the E. plukenetii species complex. The approach developed here should find more general application in studies on the role of floral colour shifts in diversification.


Performing a cost analysis in spine outcomes research: comparing ventral and dorsal approaches for cervical spondylotic myelopathy.
Medical cost analysis is increasingly important, but the methodology is complex and varied. To illustrate how different cost analysis methodologies influence conclusions generated from data from a prospective nonrandomized trial for treatment of cervical spondylotic myelopathy. Patients 40 to 85 years of age with degenerative cervical spondylotic myelopathy were enrolled from 7 sites over 2 years (2007-2009). Patients were treated with ventral or dorsal fusion surgery, and outcomes were measured to 1 year postoperatively. A hospital-based cost analysis was performed using Medicare cost-to-charge ratios (CCRs) multiplied by hospital charges from the index hospitalization (CCR method). A society-based cost analysis was performed by estimating costs from the index hospitalization using Medicare coding reimbursement (the Medicare reimbursement method). A separate outpatient cost analysis was performed on a subset of 20 patients. Of the 85 patients analyzed, 72 had 1-year follow-up. The CCR method showed a difference in upfront direct costs between the dorsal and ventral approaches ($27,942 ± 14,220 vs $21,563 ± 8721; P = .02). Overall upfront direct costs with the Medicare reimbursement method were not different. With the CCR method, the ventral approach dominates an incremental cost-effectiveness ratio analysis. With the Medicare reimbursement method, the incremental cost-effectiveness ratio for ventral surgery is $34,533, the cost of 1 additional quality-adjusted life-year gained by using ventral instead of dorsal surgery. In the subanalysis, outpatient costs were less after ventral surgery than dorsal surgery ($1997 ± 1211 vs $4734 ± $2874; P = .006). The choice of cost methodology may substantially influence the final results of an economic study.


Self-Similarity of Plasmon Edge Modes on Koch Fractal Antennas.
We investigate the plasmonic behavior of Koch snowflake fractal geometries and their possible application as broadband optical antennas. Lithographically defined planar silver Koch fractal antennas were fabricated and characterized with high spatial and spectral resolution using electron energy loss spectroscopy. The experimental data are supported by numerical calculations carried out with a surface integral equation method. Multiple surface plasmon edge modes supported by the fractal structures have been imaged and analyzed. Furthermore, by isolating and reproducing self-similar features in long silver strip antennas, the edge modes present in the Koch snowflake fractals are identified. We demonstrate that the fractal response can be obtained by the sum of basic self-similar segments called characteristic edge units. Interestingly, the plasmon edge modes follow a fractal-scaling rule that depends on these self-similar segments formed in the structure after a fractal iteration. As the size of a fractal structure is reduced, coupling of the modes in the characteristic edge units becomes relevant, and the symmetry of the fractal affects the formation of hybrid modes. This analysis can be utilized not only to understand the edge modes in other planar structures but also in the design and fabrication of fractal structures for nanophotonic applications.


Variable antibody-dependent activation of complement by functionalized phospholipid nanoparticle surfaces.
A wide variety of nanomaterials are currently being developed for use in the detection and treatment of human diseases. However, there is no systematic way to measure and predict the action of such materials in biological contexts. Lipid-encapsulated nanoparticles (NPs) are a class of nanomaterials that includes the liposomes, the most widely used and clinically proven type of NPs. Liposomes can, however, activate the complement system, an important branch of innate immunity, resulting in undesirable consequences. Here, we describe the complement response to lipid-encapsulated NPs that are functionalized on the surface with various lipid-anchored gadolinium chelates. We developed a quantitative approach to examine the interaction of NPs with the complement system using in vitro assays and correlating these results with those obtained in an in vivo mouse model. Our results indicate that surface functionalization of NPs with certain chemical structures elicits swift complement activation that is initiated by a natural IgM antibody and propagated via the classical pathway. The intensity of the response is dependent on the chemical structures of the lipid-anchored chelates and not zeta potential effects alone. Moreover, the extent of complement activation may be tempered by complement inhibiting regulatory proteins that bind to the surface of NPs. These findings represent a step forward in the understanding of the interactions between nanomaterials and the host innate immune response and provide the basis for a systematic structure-activity relationship study to establish guidelines that are critical to the future development of biocompatible nanotherapeutics.


Observing the observer (I): meta-bayesian models of learning and decision-making.
In this paper, we present a generic approach that can be used to infer how subjects make optimal decisions under uncertainty. This approach induces a distinction between a subject's perceptual model, which underlies the representation of a hidden "state of affairs" and a response model, which predicts the ensuing behavioural (or neurophysiological) responses to those inputs. We start with the premise that subjects continuously update a probabilistic representation of the causes of their sensory inputs to optimise their behaviour. In addition, subjects have preferences or goals that guide decisions about actions given the above uncertain representation of these hidden causes or state of affairs. From a Bayesian decision theoretic perspective, uncertain representations are so-called "posterior" beliefs, which are influenced by subjective "prior" beliefs. Preferences and goals are encoded through a "loss" (or "utility") function, which measures the cost incurred by making any admissible decision for any given (hidden) state of affair. By assuming that subjects make optimal decisions on the basis of updated (posterior) beliefs and utility (loss) functions, one can evaluate the likelihood of observed behaviour. Critically, this enables one to "observe the observer", i.e. identify (context- or subject-dependent) prior beliefs and utility-functions using psychophysical or neurophysiological measures. In this paper, we describe the main theoretical components of this meta-Bayesian approach (i.e. a Bayesian treatment of Bayesian decision theoretic predictions). In a companion paper ('Observing the observer (II): deciding when to decide'), we describe a concrete implementation of it and demonstrate its utility by applying it to simulated and real reaction time data from an associative learning task.


Acute non-Q wave cocaine-related myocardial infarction.
Since our initial report in 1984 of six patients with AMI temporally related to cocaine use, we have observed 19 additional patients in whom ischemic chest pain syndromes occurred shortly after intranasal or IV use of cocaine or after smoking the drug. Seventeen patients (89 percent) developed non-Q wave infarction and two had Q-wave infarction. One patient manifested angina with striking ST-segment elevation. None of the patients had diabetes or hypertension, and all but one were cigarette smokers. The serum cholesterol level was 162 +/- 7 mg/dl. Four of the five patients who consented to coronary angiographic studies displayed normal coronary arteries, and one showed proximal stenosis of the right coronary artery. The cold pressor test was performed in seven patients; none had angina or ECG changes induced by cold stimulation. We conclude that T-wave infarction is a common form of an acute cardiac event related to cocaine abuse, and its pathogenesis may involve that of the cocaine-induced coronary vasospasm.


Amino-terminal deletion mutants of the Rous sarcoma virus glycoprotein do not block signal peptide cleavage but can block intracellular transport.
Protein sequence requirements for cleavage of the signal peptide from the Rous sarcoma virus glycoprotein have been investigated through the use of deletion mutagenesis. The phenotypes of these mutants have been characterized by expression of the cloned, mutated env genes in CV-1 cells using a late replacement SV40 vector. The deletion mutations were generated by Ba131 digestion at the XhoI site located near the 5' end of the coding sequence for the structural protein gp85, which is found at the amino terminus of the precursor glycoprotein, Pr95. The results of experiments with three mutants (X1, X2, and X3) are presented. Mutant X1 has a 14 amino acid deletion encompassing amino acids 4-17 of gp85, which results in the loss of one potential glycosylation site. In mutants X2 and X3 the amino terminal nine and six amino acids, respectively, of gp85 are deleted. During the biosynthesis of all three mutant polypeptides, the signal peptide is efficiently and accurately cleaved from the nascent protein, even though in mutants X2 and X3 the cleavage site itself has been altered. In these mutants the alanine/aspartic acid cleavage site has been mutated to alanine/asparagine and alanine/glutamine, respectively. These results are consistent with the concept that sequences C-terminal to the signal peptidase site are unimportant in defining the site of cleavage in eucaryotes. Mutants X2 and X3 behave like wild-type with respect to protein glycosylation, palmitic acid addition, cleavage to gp85 and gp37, and expression on the cell surface. Mutant X1, on the other hand, is defective in intracellular transport. Although it is translocated across the rough endoplasmic reticulum and core-glycosylated, its transport appears to be blocked at an early Golgi compartment. No terminal glycosylation of the protein, cleavage of the precursor protein to the mature products, or expression on the cell surface is observed. The deletion in X1 thus appears to destroy signals required for export to the cell surface.


Interstitial Lung Disease in Children Made Easier…Well, Almost.
Interstitial lung disease (ILD) in pediatric patients is different from that in adults, with a vast array of pathologic conditions unique to childhood, varied modes of presentation, and a different range of radiologic appearances. Although rare, childhood ILD (chILD) is associated with significant morbidity and mortality, most notably in conditions of disordered surfactant function, with respiratory failure in 100% of neonates with surfactant protein B dysfunction and 100% mortality without lung transplantation. The authors present a summary of lung development and anatomy, followed by an organized approach, using the structure and nomenclature of the 2013 update to the chILD Research Network classification system, to aid radiologic diagnosis of chILD. Index radiologic cases with contemporaneous histopathologic findings illustrate a summary of recent imaging studies covering the full spectrum of chILD. chILD is best grouped by age at presentation from infancy (diffuse developmental disorders, lung growth abnormalities, specific conditions of unknown origin, surfactant dysfunction mutations) to later childhood (disorders of the normal host, disorders related to systemic disease processes, disorders related to immunocompromise). Appreciation of the temporal division of chILD into infant and later childhood onset, along with a sound understanding of pulmonary organogenesis and surfactant homeostasis, will aid in providing useful insight into this important group of pediatric conditions. Application of secondary lobular anatomy to interpretation of thin-section computed tomographic images is pivotal to understanding patterns of ILD and will aid in selecting and narrowing a differential diagnosis. ©RSNA, 2017.


On the challenge of classifying 52 hand movements from surface electromyography.
The level of dexterity of myoelectric hand prostheses depends to large extent on the feature representation and subsequent classification of surface electromyography signals. This work presents a comparison of various feature extraction and classification methods on a large-scale surface electromyography database containing 52 different hand movements obtained from 27 subjects. Results indicate that simple feature representations as Mean Absolute Value and Waveform Length can achieve similar performance to the computationally more demanding marginal Discrete Wavelet Transform. With respect to classifiers, the Support Vector Machine was found to be the only method that consistently achieved top performance in combination with each feature extraction method.


Feedback and clinical practice improvement: A tool to assist workplace supervisors and students.
In work integrated learning, students may report difficulties applying theory learned at university to clinical practice. One contributing factor may be students' inability to engage in meaningful reflection and self-correcting behaviours. This paper reports the evaluation of a tool, process and resources developed to assist students to reflect on feedback and engage in self-assessment. Students were assisted to develop self-assessment skills by reflecting on, and engaging with feedback from previous workplace experiences to develop goals, learning outcomes and strategies to improve performance with mostly positive results. A secondary aim was to identify common learning strategies or barriers that impacted on student outcomes. Four themes emerged from the qualitative data: 1) preparing for clinical learning, 2) relationships and engagement levels, 3) shared awareness and, 4) developing clinical practice. Overall students felt the tool assisted them to narrow their attention on what needed to be improved. While supervisors believed the tool helped them to focus on specific needs of each student. Common barriers to clinical practice improvement related to a lack of opportunity in some settings, and lack of staff willingness to support students to achieve identified goals. Students and supervisors found the use of the tools beneficial and assisted students to demonstrate a greater understanding of how to apply feedback received to support their learning in the clinical environment.


The Process of Reporting and Receiving Support Following Exposure to Intimate Partner Violence During Childhood.
While a significant body of research suggests that exposure to intimate partner violence (IPV) during childhood has severe and long-lasting consequences, little is known about how children cope with witnessing IPV, including who they tell about the violence, whether they receive support after disclosing, and the association between childhood disclosure and adulthood mental health. The current study examines these issues in 703 Swedish young adults who endorsed witnessing IPV during childhood. In this sample, 57% reported that they had ever confided in someone about the witnessed violence. The primary reason given for not disclosing was the belief that no one could do anything about it, which was endorsed by 41% of the young adults who kept the violence concealed. Individuals who disclosed the violence were most likely to tell a friend and least likely to use an anonymous hotline. Young adults with higher levels of depression were less likely to have disclosed IPV during their childhood. Individuals' use of formal reporting outlets was endorsed infrequently, with only 5.2% recalling that they had personally reported the violence or someone else had reported it on their behalf. If such reports were filed, it was most likely to the police. These formal reports typically resulted in participants feeling that the problem continued anyway or that they were believed, but no changes were made. Given the infrequent use of formal reporting services, results suggest that for this sample, reporting outlets for IPV exposure may be underutilized and may not be perceived as beneficial.


Utilizing Eisenia andrei to assess the ecotoxicity of platinum mine tailings disposal facilities.
South Africa is an important platinum mining country which results in environmental impacts due to the construction of tailing disposal facilities (TDFs). It is unclear what the effects of ageing are on the ecotoxicity of TDFs and whether it increases or decreases over time. The aim of this study was to determine the ecotoxicity of differently aged TDFs by investigating earthworm (Eisenia andrei) responses viz. growth, reproduction, neutral red retention times (NRRT) and tissue metal concentrations. Further, to evaluate the status of these in terms of a geoaccumulation index (I(geo)), pollution index and integrated pollution index. Results indicated that earthworms showed reduced reproductive success (hatchlings per cocoon) and decreased NRRT in all the sites. Juveniles per cocoon between all of the different treatment groups were; control (2.83 ± 0.54) > site 2 (20 years old; 1.83 ± 0.27) > sites 1 and 3 (40 years old; 1.06 ± 0.15 and 6 years old; 0.88 ± 0.39). This might be ascribed to the elevated levels of Cr (±200 to 1,166 μg g(-1)) and Ni (±100 to 316 μg g(-1)) in all of the sites. Earthworms did not bioaccumulate metals with bioconcentration factors for all the different treatments <0.01. Studies like these could be useful when establishing a ranking of TDFs in the future to provide legislative institutions with an indication of the environmental liabilities of platinum mines.


High repeatability of circadian prolactin rhythm assessment results in children.
In normal conditions, prolactin (Prl) secretion manifests a circadian pattern. So far, there have only been but few studies, concerning intrasubject variability and repeatability of the circadian Prl secretion pattern, based on pulse analysis. It seems, that macroscopic analysis based on measurement of Prl concentration at nine time points every 3 hours during 24 hours is an appropriate method to assess Prl profile for clinical purposes. The aim of the study was to assess the repeatability of that circadian Prl secretion pattern in a group of short children without hormonal disorders. The analysis comprised the results of two circadian Prl profiles, performed from 2 to 14 months in 23 prepubertal children (16 boys) with idiopathic short stature, aged: 10.3+/-2.4 yrs. There were no statistical differences between Prl concentrations at the same time points in the two consecutive profiles, but the comparison of Prl concentrations at 8:00 gave results which were close to the border of statistical significance (p=0.055), what indicated low repeatability of measurement results at that particular time point. There were no statistical differences between the values of particular parameters in macroscopic profile analysis in the first and in the second test. Circadian Prl profile, based on nine Prl concentration measurements, taken every 3 hours during one day, is characterized by high repeatability of the results and low intrasubject variability in children, despite the results of Prl concentration at 08:00 o'clock.


Renal expression of intercellular adhesion molecule-1 in different forms of glomerulonephritis.
1. Expression of intercellular adhesion molecule-1 was investigated in five normal kidneys and 47 renal biopsies with the use of monoclonal antibody 7F7 and immunoperoxidase staining. 2. In the normal kidney, intercellular adhesion molecule-1 was expressed on endothelial cells of glomerular and peritubular capillaries, on Bowman's capsule, on some interstitial cells and weakly in the mesangium. 3. Increased glomerular staining was detected in early cases of rapidly progressing glomerulonephritis (5/8) and in some cases of non-IgA mesangioproliferative glomerulonephritis (5/9), IgA nephropathy (3/5), Henoch-Schoenlein purpura (2/2), lupus nephritis (5/6) and focal segmental glomerulosclerosis (1/3). A decrease in intercellular adhesion molecule-1 expression was noted in advanced rapidly progressive glomerulonephritis (3/8), two cases of membraneous nephropathy, one severe mesangioproliferative glomerulonephritis biopsy, the two membranoproliferative glomerulonephritis biopsies and in sclerotic loops in focal segmental glomerulosclerosis. 4. Expression de novo on tubular epithelial cells occurred in rapidly progressive glomerulonephritis, in membranoproliferative glomerulonephritis, and to a lesser extent in some cases of membraneous nephropathy, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, a severe case of mesangioproliferative glomerulonephritis and in the mixed essential cryoglobulinaemia case. In 63% of positive tubuli, intraluminal cells which expressed CD18, the common beta-chain of leucocyte-function-associated antigen-1, Mac-1 and p150,95, were present. 5. Intercellular adhesion molecule-1 was also found on the majority (59%) of infiltrating mononuclear cells in all forms of glomerulonephritis.


Management of Immunotherapy-Related Toxicities, Version 1.2022, NCCN Clinical Practice Guidelines in Oncology.
The aim of the NCCN Guidelines for Management of Immunotherapy-Related Toxicities is to provide guidance on the management of immune-related adverse events resulting from cancer immunotherapy. The NCCN Management of Immunotherapy-Related Toxicities Panel is an interdisciplinary group of representatives from NCCN Member Institutions, consisting of medical and hematologic oncologists with expertise across a wide range of disease sites, and experts from the areas of dermatology, gastroenterology, endocrinology, neurooncology, nephrology, cardio-oncology, ophthalmology, pulmonary medicine, and oncology nursing. The content featured in this issue is an excerpt of the recommendations for managing toxicities related to CAR T-cell therapies and a review of existing evidence. For the full version of the NCCN Guidelines, including recommendations for managing toxicities related to immune checkpoint inhibitors, visit NCCN.org.


Neuroprotective impact of a vitamin trace element composition - a randomized, double blind, placebo controlled clinical trial with healthy volunteers.
Neurotoxic metabolites and oxidative and nitrosative stress reactions play a crucial role in the pathways leading to neuronal cell death and neurodegeneration. The bioavailability of the many antioxidant ingredients a vitamin and trace element composition was investigated, to reveal the neuroprotective (preventive) potential of the composition. We recruited 159 healthy volunteers, assigned them randomly and double blind to a placebo and verum group. Physicians excluded volunteers with severe chronic diseases or interfeering medications. 142 participants finished the six month trial. Laboratory parameters were determined 1) before participation, and 2) after three and 3) six months. We confirmed the bioavailability of ingredients, and determined metabolic parameters associated with the integrity of the blood brain barrier, mitochondrial deficiency (Q 10), neurodegeneration (homocystein), and antioxidative capacity (e.g. lipidperoxidation), and superoxiddismutase activity. Starting from baseleine, after three months neuroprotective ingredients increased within their physiological borders, folic acid (p<0.003), pyridoxin (p<0.001), cobalamin (p=0.001), and the fat soluble vitamin tocopherol (p<0.001). In parallel, homocytein decreased after 3 and 6 months (p<0.001, and p<0.025, respectively). Other paramters like zinc reacted slower, significant changes were observed only after 6 months. The observed metabolic changes and alteration of the oxidative status after 3 and six month of regular intake underlines the compositions' potential to ameliorate neurodegenerative processes. We conclude that the subsitution of vitamins and trace-elements with natural source in a proper manner may be effective for neuroprotection in healthy population.


Mode of action and mechanisms of resistance for antimalarial drugs.
Understanding the mode of action of and mechanism of resistance to drugs is central to optimising their use, and discovering new therapeutics with novel targets. We have limited understanding of how antimalarial drugs work and how resistance emerges. With few exceptions, antimalarial drugs in current use belong to a limited collection of chemical structures that act on a small number of partially characterised biochemical targets. Resistance has emerged to many of these compounds. The use of closely related compounds has promoted the spread of multidrug resistant parasites. This review intends to collate contemporary knowledge, and also to highlight conflicting views on unresolved issues.


Enhanced resistance to Cucumber mosaic virus in the Arabidopsis thaliana ssi2 mutant is mediated via an SA-independent mechanism.
The Arabidopsis thaliana SSI2 gene encodes a plastid-localized stearoyl-ACP desaturase. The recessive ssi2 mutant allele confers constitutive accumulation of the pathogenesis-related-1 (PR-1) gene transcript and salicylic acid (SA), and enhanced resistance to bacterial and oomycete pathogens. In addition, the ssi2 mutant is a dwarf and spontaneously develops lesions containing dead cells. Here, we show that the ssi2 mutant also confers enhanced resistance to Cucumber mosaic virus (CMV). Compared with the wild-type plant, viral multiplication and systemic spread were diminished in the ssi2 mutant plant. However, unlike the ssi2-conferred resistance to bacterial and oomycete pathogens, the ssi2-conferred enhanced resistance to CMV was retained in the SA-deficient ssi2 nahG plant. In addition, SA application was not effective in limiting CMV multiplication and systemic spread in the CMV-susceptible wild-type plant. The acd1, acd2, and cpr5 mutants which, like the ssi2 mutant, accumulate elevated SA levels, constitutively express the PR-1 gene, spontaneously develop lesions containing dead cells, and are dwarfs, are, however, fully susceptible to CMV. Our results suggest that dwarfing, cell death, and constitutive activation of SA signaling are not important for the ssi2-conferred enhanced resistance to CMV. However, the sfd1 and sfd4 mutations, which affect lipid metabolism, suppress the ssi2-conferred enhanced resistance to CMV, thus implicating a lipid or lipids in the ssi2-conferred resistance to CMV. Interestingly, the ssi2-conferred resistance to CMV was compromised in the ssi2 eds5 plant, suggesting the involvement of an SA-independent, EDS5-dependent mechanism in the ssi2-conferred resistance to CMV.


Preferences for aspects of a dermatology consultation.
General practitioners with special interests (GPSIs) are increasingly being used to provide dermatology services in the U.K. Little is known about U.K. dermatology patient attitudes to proposed variations in secondary care service delivery or the values they attach to aspects of the care they receive. To quantify preferences for different attributes of care within dermatology secondary care services. Attributes of care that are important to dermatology patients were derived using in-depth qualitative interviews with 19 patients at different points in the care pathway. A discrete choice experiment using 'best-worst scaling' was sent by post to 119 patients referred to secondary care dermatology services and suitable for GPSI care who had agreed to participate in research. Four attributes were derived from the qualitative work: waiting, expertise, thorough care and convenience. For the discrete choice experiment, 99 patients returned questionnaires, 93 of which contained sufficient data for analysis. All attributes were found to be quantitatively important. The attribute of greatest importance was expertise of the doctor, while waiting time was of least importance. Respondents were willing to wait longer than the current 3 months maximum to receive care that was thorough, 2.1 months to see a team led by an expert and 1.3 months to attend a consultation that is easy to get to. Although the need to reduce outpatient waiting times is a key policy driver behind the expansion of GPSI services, this does not appear to be the most important issue for patients. The thoroughness with which the consultation is provided and the expertise of the clinician seen are higher priorities.


Hemin-catalyzed sulfonium ylide formation and subsequently reactant-controlled chemoselective rearrangements.
Hemin-catalyzed competing routes of [1,2]-Stevens and Sommelet-Hauser rearrangements of benzyl sulfonium ylides through an iron porphyrin carbenoid were established. These rearrangements can be controlled by the electronic property of the substituents on the benzyl group together with solvent effects. Electron-donating or weak electron-withdrawing groups lead to the [1,2]-Stevens rearrangement, whereas strong electron-withdrawing groups at the para-position favor the latter pathway under aqueous conditions.