Burnout, job satisfaction, and medical malpractice among physicians.
Our objective was to estimate the incidence of recent burnout in a large sample of Taiwanese physicians and analyze associations with job related satisfaction and medical malpractice experience. We performed a cross-sectional survey. Physicians were asked to fill out a questionnaire that included demographic information, practice characteristics, burnout, medical malpractice experience, job satisfaction, and medical error experience. There are about 2% of total physicians. Physicians who were members of the Taiwan Society of Emergency Medicine, Taiwan Surgical Association, Taiwan Association of Obstetrics and Gynecology, The Taiwan Pediatric Association, and Taiwan Stroke Association, and physicians of two medical centers, three metropolitan hospitals, and two local community hospitals were recruited. There is high incidence of burnout among Taiwan physicians. In our research, Visiting staff (VS) and residents were more likely to have higher level of burnout of the emotional exhaustion (EE) and depersonalization (DP), and personal accomplishment (PA). There was no difference in burnout types in gender. Married had higher-level burnout in EE. Physicians who were 20~30 years old had higher burnout levels in EE, those 31~40 years old had higher burnout levels in DP, and PA. Physicians who worked in medical centers had a higher rate in EE, DP, and who worked in metropolitan had higher burnout in PA. With specialty-in-training, physicians had higher-level burnout in EE and DP, but lower burnout in PA. Physicians who worked 13-17hr continuously had higher-level burnout in EE. Those with ≥41 times/week of being on call had higher-level burnout in EE and DP. Physicians who had medical malpractice experience had higher-level burnout in EE, DP, and PA. Physicians who were not satisfied with physician-patient relationships had higher-level burnout than those who were satisfied. Physicians in Taiwan face both burnout and a high risk in medical malpractice. There is high incidence of burnout among Taiwan physicians. This can cause shortages in medical care human resources and affect patient safety. We believe that high burnout in physicians was due to long working hours and several other factors, like mental depression, the evaluation assessment system, hospital culture, patient-physician relationships, and the environment. This is a very important issue on public health that Taiwanese authorities need to deal with.


Anesthetic considerations on adrenal gland surgery.
Adrenal gland surgery needs a multidisciplinary team including endocrinologist, radiologist, anesthesiologist, and surgeon. The indications for adrenal gland surgery include hormonal secreting and non-hormonal secreting tumors. Adrenal hormonal secreting tumors present to the anesthesiologist unique challenges requiring good preoperative evaluation, perioperative hemodynamic control, corrections of all electrolytes and metabolic abnormalities, a detailed and careful anesthetic strategy, overall knowledge about the specific diseases, control and maintaining of postoperative adrenal function, and finally a good collaboration with other involved colleagues. This review will focus on the endocrine issues, as well as on the above-mentioned aspects of anesthetic management during hormone secreting adrenal gland tumor resection.


Synthesis of sterically hindered 4,5-diarylphenanthrenes via acid-catalyzed bisannulation of benzenediacetaldehydes with alkynes.
The synthesis of sterically hindered phenanthrenes via acid-catalyzed bisannulation reaction is described. Treatment of 1,4-benzenediacetaldehyde with terminal aryl alkynes in the presence of B(C6F5)3 provides 4,5-diarylphenanthrenes in good yields with excellent regioselectivity. The use of internal alkyne substrates enabled the synthesis of sterically hindered 3,4,5,6-tetrasubstituted phenanthrenes displaying augmented backbone helicity. Furthermore, 1,5-disubstituted, 1,8-disubstituted, 1,2,5,6-tetrasubstituted, and 1,2,7,8-tetrasubstituted phenanthrenes can be obtained through the reaction of alkynes with 1,3-benzenediacetaldehyde or 1,2-benzenediacetaldehyde disilyl acetal.


Primary brain tumours and specific serum immunoglobulin E: a case-control study nested in the European Prospective Investigation into Cancer and Nutrition cohort.
Case-control studies suggest that patients with allergic diseases have a lower risk of developing glioma but not meningioma or schwannoma. However, those data can be differentially biased. Prospective studies with objective measurements of immunologic biomarkers, like immunoglobulin E (IgE), in blood obtained before cancer diagnosis could help to clarify whether an aetiological association exists. The present case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) measured specific serum IgE as a biomarker for the most common inhalant allergens in 275 glioma, 175 meningioma and 49 schwannoma cases and 963 matched controls using the ImmunoCAP specific IgE test. Subjects with an IgE level ≥0.35 kUA/l (kilo antibody units per litre) were classified as sensitized by allergens. Odds ratios (OR) and 95% confidence intervals (CI) were estimated by adjusted conditional logistic regression models for each tumour subtype. The effect of dose-response relationship was assessed in five increasing IgE level categories to estimate P-values for trend. The risk of glioma was inversely related to allergic sensitization (OR = 0.73; 95% CI 0.51-1.06), especially pronounced in women (OR = 0.53; 95% CI 0.30-0.95). In dose-response analyses, for high-grade glioma, the lowest OR was observed in sera with the highest IgE levels (P for trend = 0.04). No association was seen for meningioma and schwannoma. The results, based on serum samples prospectively collected in a cohort study, provide some support for the hypothesis that individuals with allergic sensitization are at reduced risk of glioma and confirm results from previous case-control studies.


The sensory origin of the sense of effort is context-dependent.
The origin of the sense of effort has been debated for several decades and there is still no consensus among researchers regarding the underlying neural mechanisms. Some advocate that effort perception mainly arises from an efference copy originating within the brain while others believe that it is predominantly carried by muscle afferent signals. To move the debate forward, we here tested the hypothesis that there is not one but several senses of effort which depend on the way it is evaluated. For this purpose, we used two different psychophysical tests designed to test effort perception in elbow flexors. One was a bilateral isometric force-matching task in which subjects were asked to direct similar amounts of effort toward their two arms, while the other consisted of a unilateral voluntary isometric contraction in which subjects had to rate their perceived effort using a Borg scale. Throughout two distinct experiments, effort perception was evaluated before and following different tendon vibration protocols intended to differentially desensitize muscle spindles and Golgi tendon organs, and to affect the gain between the central effort and muscle contraction intensity. By putting all the results together, we found that spindle afferents played divergent roles across tasks. Namely, while they only acted as modulators of motor pathway excitability during the bilateral task, they clearly intervened as the predominant psychobiological signal of effort perception during the unilateral task. Therefore, the sensory origin of the sense of effort is not central or peripheral. Rather, it is context-dependent.


Update on diagnostic and treatment of uncomplicated and complicated malaria in adults and selected vulnerable populations.
Although malaria remains one of the most important infectious causes of morbidity and mortality world-wide with 40% of the global population at risk, significant progress has been made toward elimination, notably with the development and use of rapid diagnostic tests, insecticide-treated bed nets, indoor residual spraying, and artemisinin-based combination therapies (ACTs). P. falciparum infection remains the most common cause of severe infection and death, but non-P. P. falciparum infections, including the recently emerged 5(th) plasmodium species, P. knowlesi, are increasingly recognized as causes of severe disease, especially in southeast Asia. Chemotherapy for severe infections has been revolutionized following results of the SEQUAMAT and AQUAMAT trials showing that parenteral artesunate (versus quinine) reduced severe malaria mortality by 34.7% and 22.5% in Asian adults and African children, respectively, making it the drug of choice for severe malaria. However, rising rates of artemisinin resistance, currently confined to the Greater Mekong sub-region, are threatening the long-term efficacy of artemisinins. HIV infection remains an important risk factor for death and severe disease due to malaria. The full amplitude of mutual interactions between these conditions is only beginning to be elucidated while the complex, multi-directional and pharmacokinetic interactions between antimalarial agents and HIV drugs continue to emerge.


In vitro characterization of noradrenergic modulation of chemosensitive neurons in the retrotrapezoid nucleus.
Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO2/H(+) changes and serve as an integration center for other autonomic centers, including brain stem noradrenergic neurons. Norepinephrine (NE) contributes to respiratory control and chemoreception, and, since disruption of NE signaling may contribute to several breathing disorders, we sought to characterize effects of NE on RTN chemoreception. All neurons included in this study responded similarly to CO2/H(+) but showed differential sensitivity to NE; we found that NE activated (79%), inhibited (7%), or had no effect on activity (14%) of RTN chemoreceptors. The excitatory effect of NE on RTN chemoreceptors was dose dependent, retained in the presence of neurotransmitter receptor blockers, and could be mimicked and blocked by pharmacological manipulation of α1-adrenergic receptors (ARs). In addition, NE-activation was blunted by XE991 (KCNQ channel blocker), and partially occluded the firing response to serotonin, suggesting involvement of KCNQ channels. However, in whole cell voltage clamp, activation of α1-ARs decreased outward current and conductance by what appears to be a mixed effect on multiple channels. The inhibitory effect of NE on RTN chemoreceptors was blunted by an α2-AR antagonist. A third group of RTN chemoreceptors was insensitive to NE. We also found that chemosensitive RTN astrocytes do not respond to NE with a change in voltage or by releasing ATP to enhance activity of chemosensitive neurons. These results indicate NE modulates subsets of RTN chemoreceptors by mechanisms involving α1- and α2-ARs.


Iron regulation and pathogenicity in Erwinia chrysanthemi 3937: role of the Fur repressor protein.
Low iron availability is a triggering signal for coordinated expression of the genes encoding pectate lyases PelB, PelC, PelD, and PelE, and chrysobactin iron transport functions, which are two main determinants of phytopathogenicity of the Erwinia chrysanthemi strain 3937. The possible implication of the ferric uptake regulation (Fur) protein in this process was investigated. The E. chrysanthemi fur gene was cloned by functional complementation of an Escherichia coli fur mutant and sequenced. The 444-bp open reading frame identified was found to code for a protein highly similar to the E. coli Fur regulator. An E. chrysanthemi fur null mutant was constructed by reverse genetics. This mutant showed altered growth capacity and reduced pathogenicity on African violets. In a fur background, transcriptional lacZ fusions to genes belonging to the E. chrysanthemi high affinity iron transport systems were constitutively expressed. Transcription of the pelA, pelD, and pelE genes was analyzed, using fusions to the uidA reporter gene. Iron availability and a fur mutation did not influence the expression of pelA. In the presence of iron, pelD and pelE transcription levels were higher in the fur mutant than in the parental strain. Furthermore, iron deficiency stimulated the expression of both fusions in the fur mutant. These findings indicate that, in E. chrysanthemi 3937, (i) Fur negatively controls iron transport and genes encoding PelD and PelE, and (ii) additional factor(s) mediate iron regulation of the pel genes.


Have vehicle emissions of primary NO2 peaked?
Reducing ambient concentrations of nitrogen dioxide (NO2) remains a key challenge across many European urban areas, particularly close to roads. This challenge mostly relates to the lack of reduction in emissions of oxides of nitrogen (NOx) from diesel road vehicles relative to the reductions expected through increasingly stringent vehicle emissions legislation. However, a key component of near-road concentrations of NO2 derives from directly emitted (primary) NO2 from diesel vehicles. It is well-established that the proportion of NO2 (i.e. the NO2/NOx ratio) in vehicle exhaust has increased over the past decade as a result of vehicle after-treatment technologies that oxidise carbon monoxide and hydrocarbons and generate NO2 to aid the emissions control of diesel particulate. In this work we bring together an analysis of ambient NOx and NO2 measurements with comprehensive vehicle emission remote sensing data obtained in London to better understand recent trends in the NO2/NOx ratio from road vehicles. We show that there is evidence that NO2 concentrations have decreased since around 2010 despite less evidence of a reduction in total NOx. The decrease is shown to be driven by relatively large reductions in the amount of NO2 directly emitted by vehicles; from around 25 vol% in 2010 to 15 vol% in 2014 in inner London, for example. The analysis of NOx and NO2 vehicle emission remote sensing data shows that these reductions have been mostly driven by reduced NO2/NOx emission ratios from heavy duty vehicles and buses rather than light duty vehicles. However, there is also evidence from the analysis of Euro 4 and 5 diesel passenger cars that as vehicles age the NO2/NOx ratio decreases. For example the NO2/NOx ratio decreased from 29.5 ± 2.0% in Euro 5 diesel cars up to one year old to 22.7 ± 2.5% for four-year old vehicles. At some roadside locations the reductions in primary NO2 have had a large effect on reducing both the annual mean and number of hourly exceedances of the European Limit Values of NO2.


Unreliable evoked responses in autism.
Autism has been described as a disorder of general neural processing, but the particular processing characteristics that might be abnormal in autism have mostly remained obscure. Here, we present evidence of one such characteristic: poor evoked response reliability. We compared cortical response amplitude and reliability (consistency across trials) in visual, auditory, and somatosensory cortices of high-functioning individuals with autism and controls. Mean response amplitudes were statistically indistinguishable across groups, yet trial-by-trial response reliability was significantly weaker in autism, yielding smaller signal-to-noise ratios in all sensory systems. Response reliability differences were evident only in evoked cortical responses and not in ongoing resting-state activity. These findings reveal that abnormally unreliable cortical responses, even to elementary nonsocial sensory stimuli, may represent a fundamental physiological alteration of neural processing in autism. The results motivate a critical expansion of autism research to determine whether (and how) basic neural processing properties such as reliability, plasticity, and adaptation/habituation are altered in autism.


Human pre-valvular endocardial cells derived from pluripotent stem cells recapitulate cardiac pathophysiological valvulogenesis.
Genetically modified mice have advanced our understanding of valve development and disease. Yet, human pathophysiological valvulogenesis remains poorly understood. Here we report that, by combining single cell sequencing and in vivo approaches, a population of human pre-valvular endocardial cells (HPVCs) can be derived from pluripotent stem cells. HPVCs express gene patterns conforming to the E9.0 mouse atrio-ventricular canal (AVC) endocardium signature. HPVCs treated with BMP2, cultured on mouse AVC cushions, or transplanted into the AVC of embryonic mouse hearts, undergo endothelial-to-mesenchymal transition and express markers of valve interstitial cells of different valvular layers, demonstrating cell specificity. Extending this model to patient-specific induced pluripotent stem cells recapitulates features of mitral valve prolapse and identified dysregulation of the SHH pathway. Concurrently increased ECM secretion can be rescued by SHH inhibition, thus providing a putative therapeutic target. In summary, we report a human cell model of valvulogenesis that faithfully recapitulates valve disease in a dish.


Diagnostic criteria for Parkinson disease.
The clinical diagnosis of Parkinson disease (PD) is based on the identification of some combination of the cardinal motor signs of bradykinesia, rigidity, tremor, and postural instability, but few attempts have been made to develop explicit diagnostic criteria. We propose a clinical diagnostic classification based on a comprehensive review of the literature regarding the sensitivity and specificity of the characteristic clinical features of PD. Three levels of diagnostic confidence are differentiated: Definite, Probable, and Possible. The diagnoses of Possible and Probable PD are based on clinical criteria alone. Neuropathologic confirmation is required for the diagnosis of Definite PD in patients with the clinical diagnosis of Possible or Probable PD. Criteria for histopathologic confirmation of PD are also presented.


A guide to utilization of the microbiology laboratory for diagnosis of infectious diseases: 2013 recommendations by the Infectious Diseases Society of America (IDSA) and the American Society for Microbiology (ASM)(a).
The critical role of the microbiology laboratory in infectious disease diagnosis calls for a close, positive working relationship between the physician and the microbiologists who provide enormous value to the health care team. This document, developed by both laboratory and clinical experts, provides information on which tests are valuable and in which contexts, and on tests that add little or no value for diagnostic decisions. Sections are divided into anatomic systems, including Bloodstream Infections and Infections of the Cardiovascular System, Central Nervous System Infections, Ocular Infections, Soft Tissue Infections of the Head and Neck, Upper Respiratory Infections, Lower Respiratory Tract infections, Infections of the Gastrointestinal Tract, Intraabdominal Infections, Bone and Joint Infections, Urinary Tract Infections, Genital Infections, and Skin and Soft Tissue Infections; or into etiologic agent groups, including Tickborne Infections, Viral Syndromes, and Blood and Tissue Parasite Infections. Each section contains introductory concepts, a summary of key points, and detailed tables that list suspected agents; the most reliable tests to order; the samples (and volumes) to collect in order of preference; specimen transport devices, procedures, times, and temperatures; and detailed notes on specific issues regarding the test methods, such as when tests are likely to require a specialized laboratory or have prolonged turnaround times. There is redundancy among the tables and sections, as many agents and assay choices overlap. The document is intended to serve as a reference to guide physicians in choosing tests that will aid them to diagnose infectious diseases in their patients.


A comparative review of the outcomes of using arterial versus venous conduits in coronary artery bypass graft (CABG).
Nowadays one of the most frequent reasons of death in the world is coronary artery disease. CABG is a portion of a common revascularization mediation that is done to supervise CAD by applying vessels that are grafted to revascularize vessels distal from the blockage. Different sources of grafts are included veins (specifically saphenous) and arteries (include mammary and radial arteries). Multiple conduits are used to this end, but the most suitable is left internal mammary artery (LIMA) to the left anterior descending artery (LAD) as a golden standard. Saphenous vein grafts were the guiding approach applied by the vast majority of cardiac surgeons in the 1970s, even though all approaches were supported by doctors. Although the radial artery graft was introduced simultaneously, this approach due to its complications was not as prevalent. This article is aimed to define the pros and cons of applying each kind of grafts according to the results furnished by existent studies. It has also examined the benefits provided by total arterial coronary artery bypass graft against CABG including venous graft for patients with CAD from the perspective of surgeons.


Incremental pacing maneuver for atrial flutter recurrence reduction after ablation: Vallès: yield of incremental pacing after flutter ablation.
A < 20 ms increase in the interval between cavo-tricuspid isthmus (CTI) double potentials during incremental pacing (IP) is a highly specific marker differentiating functional from complete CTI block during typical flutter (AFL) ablation. Long-term effects of IP remain unclear. We aimed to assess the impact of IP in reducing AFL recurrences after CTI ablation. One hundred and thirty-four patients (age 67 ± 13 years, 78% males) undergoing successful CTI ablation were included and divided into 2 groups: Group 1 (n = 68), in which ablation was performed before the IP maneuver was incorporated, with CTI block confirmed by at least 1 non-local and 1 local electrogram-based previously established criteria; and Group 2 (n = 66), in which IP maneuver was used to confirm complete CTI block. No intergroup differences were noted in baseline characteristics, ablation settings and fluoroscopy/radiofrequency times. Long-term AFL recurrences were observed in 14 out of 134 patients (10.4%), and were more common in Group 1 (19%, vs 1.5% among Group 2 patients, p < 0,001). Despite a longer follow-up period among the former group (1603 ± 734 vs. 964 ± 289 days, respectively), the adjusted AFL recurrence rate was still higher among Group 1 patients (4.3%/year vs. 0.6%/year, p < 0,001). Cox-regression analysis confirmed inclusion in Group 1 as the only predictor of AFL recurrences (HR = 8.2, CI 1.04-64.7, p = 0.046). The addition of the IP maneuver for the diagnosis of complete CTI block reduces AFL long-term recurrences after ablation.


Receiver performance evaluation using photocounting cumulants with application to atmospheric turbulence.
A new technique for evaluating optical communication system performance directly from the photocounting cumulants is presented. This technique is most useful in situations where exact, explicit, closed form solutions exist for the photocounting cumulants, but do not exist for the photocounting distribution, such as in the generalized case of communication through lognormal atmospheric turbulence. Using this technique, theoretical probability of error curves are presented for communication through lognormal atmospheric turbulence, for a superposed coherent-in-chaotic signal, embedded in additive independent Poisson noise, with arbitrary ratio of sampling time to source coherence time, arbitrary ratio of coherent to chaotic component, arbitrary mean frequencies of the coherent and chaotic components, and where the chaotic component need not be stationary and may have arbitrary spectral distribution. Since no solution exists for the photocounting distribution itself in this generalized case, the corresponding performance calculation has not previously been possible. The case described applies to the detection of radiation originating from a multimode laser or scattered from a rough target, and passing through atmospheric turbulence. A special case of these results is shown to be in excellent agreement with previous calculations [Rosenberg and Teich, Applied Optics12, 2625 (1973)] for a lognormally modulated coherent signal.


Whole genome sequence analyses of brain imaging measures in the Framingham Study.
We sought to identify rare variants influencing brain imaging phenotypes in the Framingham Heart Study by performing whole genome sequence association analyses within the Trans-Omics for Precision Medicine Program. We performed association analyses of cerebral and hippocampal volumes and white matter hyperintensity (WMH) in up to 2,180 individuals by testing the association of rank-normalized residuals from mixed-effect linear regression models adjusted for sex, age, and total intracranial volume with individual variants while accounting for familial relatedness. We conducted gene-based tests for rare variants using (1) a sliding-window approach, (2) a selection of functional exonic variants, or (3) all variants. We detected new loci in 1p21 for cerebral volume (minor allele frequency [MAF] 0.005, p = 10-8) and in 16q23 for hippocampal volume (MAF 0.05, p = 2.7 × 10-8). Previously identified associations in 12q24 for hippocampal volume (rs7294919, p = 4.4 × 10-4) and in 17q25 for WMH (rs7214628, p = 2.0 × 10-3) were confirmed. Gene-based tests detected associations (p ≤ 2.3 × 10-6) in new loci for cerebral (5q13, 8p12, 9q31, 13q12-q13, 15q24, 17q12, 19q13) and hippocampal volumes (2p12) and WMH (3q13, 4p15) including Alzheimer disease- (UNC5D) and Parkinson disease-associated genes (GBA). Pathway analyses evidenced enrichment of associated genes in immunity, inflammation, and Alzheimer disease and Parkinson disease pathways. Whole genome sequence-wide search reveals intriguing new loci associated with brain measures. Replication of novel loci is needed to confirm these findings.


Thomas Willis Lecture: Is Translational Stroke Research Broken, and if So, How Can We Fix It?
Based on research, mainly in rodents, tremendous progress has been made in our basic understanding of the pathophysiology of stroke. After many failures, however, few scientists today deny that bench-to-bedside translation in stroke has a disappointing track record. I here summarize many measures to improve the predictiveness of preclinical stroke research, some of which are currently in various stages of implementation: We must reduce preventable (detrimental) attrition. Key measures for this revolve around improving preclinical study design. Internal validity must be improved by reducing bias; external validity will improve by including aged, comorbid rodents of both sexes in our modeling. False-positives and inflated effect sizes can be reduced by increasing statistical power, which necessitates increasing group sizes. Compliance to reporting guidelines and checklists needs to be enforced by journals and funders. Customizing study designs to exploratory and confirmatory studies will leverage the complementary strengths of both modes of investigation. All studies should publish their full data sets. On the other hand, we should embrace inevitable NULL results. This entails planning experiments in such a way that they produce high-quality evidence when NULL results are obtained and making these available to the community. A collaborative effort is needed to implement some of these recommendations. Just as in clinical medicine, multicenter approaches help to obtain sufficient group sizes and robust results. Translational stroke research is not broken, but its engine needs an overhauling to render more predictive results.


Soil type-dependent effects of a potential biocontrol inoculant on indigenous bacterial communities in the rhizosphere of field-grown lettuce.
Bacterial biocontrol strains used as an alternative to chemical fungicides may influence bacterial communities in the rhizosphere and effects might differ depending on the soil type. Here we present baseline data on the effects of Pseudomonas jessenii RU47 on the bacterial community composition in the rhizosphere of lettuce grown in diluvial sand, alluvial loam and loess loam at the same field site. 16S rRNA gene fragments amplified from total community DNA were analyzed by denaturing gradient gel electrophoresis (DGGE) and pyrosequencing. DGGE fingerprints revealed that in three consecutive years (2010-2012) RU47 had a slight but statistically significant effect on the bacterial community composition in one (2010), two (2011) or all the three soils (2012). However, these effects were much less pronounced compared with the influence of soil types. Additional pyrosequence analysis of samples from 2011 showed that significant changes in bacterial community compositions in response to RU47 inoculation occurred only in alluvial loam. Different taxonomic groups responded to the RU47 application depending on the soil type. Most remarkable was the increased relative abundance of OTUs belonging to the genera Bacillus and Paenibacillus in alluvial loam. Pyrosequencing allowed side-effects of the application of bacterial inoculants into the rhizosphere to be identified.


The Highs and Lows of Immune-Checkpoint Blockade in Lymphoma.
Immunologic approaches to treating patients with cancer have shown promise, and immune-checkpoint blockade has been particularly successful. In many solid tumors, the presence of intratumoral immune cells has been predictive of a response to therapy, and blockade of inhibitory signals that dampen an effective antitumor response has resulted in clinical benefit for patients. Lymphoid malignancies, including Hodgkin lymphoma and non-Hodgkin lymphoma, are cancers of the immune system, and in these diseases, the malignant cells interact with the immune system and commonly provide signals that regulate immune function. Therefore, many of the immunologic lessons learned from solid tumors may not directly translate to lymphoid malignancies, and the mechanisms of effective antitumor responses in these diseases may be different. In Hodgkin lymphoma, for example, immune-checkpoint blockade has resulted in response rates of 65% to 75%. In contrast, in non-Hodgkin lymphoma, responses to immune-checkpoint blockade in phase II trials have been seen in fewer than 10% of patients, and the reasons for this substantial difference are largely unknown. Combination approaches are likely needed, particularly in the various subtypes of non-Hodgkin lymphoma, and combinations that include cytotoxic agents seem more effective than combinations of immunologic therapies. Successful therapeutic combinations in lymphomas may require an approach that simultaneously blocks inhibitory immune signals, provides direct activation of the immune response, and directly inhibits the malignant clone.


[Antifungal agents in the treatment of systemic infections: Relevance of mechanism of action, activity profile and resistances].
The availability of different therapeutic alternatives has modified the treatment of systemic fungal infections. There commendations of antifungal therapy vary according to species which causes the mycosis and its susceptibility. Consequently, the knowledge of action mechanism, activity profile and resistances to antifungal agents are essential for the clinical practice. Amphotericin B is the antifungal agent exhibiting the broadest spectrum of activity, it is a fungicidal drug and resistances have been hardly ever described. The triazoles compounds also have a broad spectrum, but their massive use for some therapeutic indications has led to emergence of strains and species of yeasts with resistance to fluconazole and of filamentous fungi itraconazole resistant. The echinocandins exhibit fungicidal effects for yeasts andafungistatic activity against moulds, and secondary resistance to these agents is uncommon.


Predicting Outcome after Pediatric Traumatic Brain Injury by Early Magnetic Resonance Imaging Lesion Location and Volume.
Brain lesions after traumatic brain injury (TBI) are heterogeneous, rendering outcome prognostication difficult. The aim of this study is to investigate whether early magnetic resonance imaging (MRI) of lesion location and lesion volume within discrete brain anatomical zones can accurately predict long-term neurological outcome in children post-TBI. Fluid-attenuated inversion recovery (FLAIR) MRI hyperintense lesions in 63 children obtained 6.2±5.6 days postinjury were correlated with the Glasgow Outcome Scale Extended-Pediatrics (GOS-E Peds) score at 13.5±8.6 months. FLAIR lesion volume was expressed as hyperintensity lesion volume index (HLVI)=(hyperintensity lesion volume / whole brain volume)×100 measured within three brain zones: zone A (cortical structures); zone B (basal ganglia, corpus callosum, internal capsule, and thalamus); and zone C (brainstem). HLVI-total and HLVI-zone C predicted good and poor outcome groups (p<0.05). GOS-E Peds correlated with HLVI-total (r=0.39; p=0.002) and HLVI in all three zones: zone A (r=0.31; p<0.02); zone B (r=0.35; p=0.004); and zone C (r=0.37; p=0.003). In adolescents ages 13-17 years, HLVI-total correlated best with outcome (r=0.5; p=0.007), whereas in younger children under the age of 13, HLVI-zone B correlated best (r=0.52; p=0.001). Compared to patients with lesions in zone A alone or in zones A and B, patients with lesions in all three zones had a significantly higher odds ratio (4.38; 95% confidence interval, 1.19-16.0) for developing an unfavorable outcome.


A follow-up cross-sectional study of environmental lead exposure in early childhood in urban South Africa.
Lead exposure has significant detrimental effects on the health and wellbeing of children. In resource-poor countries, information on the extent of lead exposure is often inadequate owing to the lack of surveillance and screening programmes. To determine the degree of lead exposure in children residing in South African urban areas. A cross-sectional survey was conducted in schools in Johannesburg, Cape Town and Kimberley in 2007 - 2008. Blood lead levels were assessed in a total of 1 349 grade 1 children using the LeadCare Analyser system. Parents completed a structured questionnaire on sociodemographic profiles and risk factors to provide information about socioeconomic status and other risk factors for lead exposure. Blood lead levels ranged from 0.8 - 32.3 μg/dl. The mean blood lead level in the total sample was 7.97 μg/dl; 74% had blood lead levels ≥5 μg/dl. The highest proportion (84%) of children with blood lead levels ≥5 μg/dl was in Johannesburg. In the multivariate analysis, socioeconomic status was significantly associated with blood lead levels ≥5 μg/dl. Lead exposure in South African urban areas remains widespread. The risk of lead poisoning in some areas and certain groups of children may be increasing despite the phasing out of lead-containing petrol. Children living in poverty continue to be the most vulnerable.


Characterizing bread wheat genotypes of Pakistani origin for grain zinc biofortification potential.
Zinc (Zn) is essential for all life forms and its deficiency is a major issue of malnutrition in humans. This study was carried out to characterize 28 wheat genotypes of Pakistani origin for grain zinc biofortification potential, genetic diversity and relatedness. There was low genetic differentiation among the tested genotypes. However, they differed greatly in yield-related traits, grain mineral (Zn, calcium (Ca) and protein) concentrations and Zn bioavailability. Zinc application increased the concentration of Zn in wheat grain (32.1%), embryo (19.8%), aleurone (47%) and endosperm (23.7%), with an increase in bioavailable Zn (22.2%) and a reduction in phytate concentration (6.8%). Application of Zn also enhanced grain protein and Ca concentrations. Among wheat genotypes, Blue Silver had the highest concentration of Zn in grain, embryo, aleurone and endosperm, with high bioavailable Zn, while Kohinoor-83 had low phytate concentration. Wheat genotypes of Pakistan are genetically less diverse owing to continuous focus on the development of high-yielding varieties only. Therefore genetically diverse wheat genotypes with high endospermic Zn concentration and better grain yield should be used in breeding programs approaches, aiming at improving Zn bioavailability. © 2018 Society of Chemical Industry.


Dietary recommendations and identified research needs for The National Children's Study.
Many years of research have resulted in a set of accepted methods for dietary assessment of adult populations in large epidemiologic studies. Yet, relatively little has been done to develop and validate dietary methods for studies of pregnant and lactating women, infants, children, and adolescents. As plans for including dietary assessment in the National Children's Study (NCS) were developed, it became clear that complex methodological issues required further study and clarification. Along with validation of existing and new instruments, research is required to identify key dietary characteristics to be assessed at various stages of childhood and adolescence and how that information can best be collected. The types of instruments used, the mode of data collection (automated vs. nonautomated instruments), the timing of data collection, and differentiation between children and parents as respondents are areas requiring further inquiry. This paper presents the research needs identified through the process followed to provide the NCS with recommendations for the collection of dietary intake data.


Evaluating temperature regulation by field-active ectotherms: the fallacy of the inappropriate question.
We describe a research protocol for evaluating temperature regulation from data on small field-active ectothermic animals, especially lizards. The protocol requires data on body temperatures (Tb) of field-active ectotherms, on available operative temperatures (Te, "null temperatures" for nonregulating animals), and on the thermoregulatory set-point range (preferred body temperatures, Tset). These data are used to estimate several quantitative indexes that collectively summarize temperature regulation: the "precision" of body temperature (variance in Tb, or an equivalent metric), the "accuracy" of body temperature relative to the set-point range (the average difference between Tb and Tset), and the "effectiveness" of thermoregulation (the extent to which body temperatures are closer on the average to the set-point range than are operative temperatures). If additional data on the thermal dependence of performance are available, the impact of thermoregulation on performance (the extent to which performance is enhanced relative to that of nonregulating animals) can also be estimated. A sample analysis of the thermal biology of three Anolis lizards in Puerto Rico demonstrates the utility of the new protocol and its superiority to previous methods of evaluating temperature regulation. We also discuss several ways in which the research protocol can be extended and applied to other organisms.


Dopamine D2-like receptor activation wipes out preferential consolidation of high over low reward memories during human sleep.
Memory formation is a selective process in which reward contingencies determine which memory is maintained and which is forgotten. Sleep plays a pivotal role in maintaining information for the long term and has been shown to specifically benefit memories that are associated with reward. Key to memory consolidation during sleep is a neuronal reactivation of newly encoded representations. However, it is unclear whether preferential consolidation of memories associated with reward requires the reactivation of dopaminergic circuitry known to mediate reward effects at encoding. In a placebo-controlled, double-blind, balanced crossover experiment, we show that the dopamine D2-like receptor agonist pramipexole given during sleep wipes out reward contingencies. Before sleep, 16 men learned 160 pictures of landscapes and interiors that were associated with high or low rewards, if they were identified between new stimuli at retrieval 24 hr later. In the placebo condition, the participants retained significantly more pictures that promised a high reward. In the pramipexole condition, this difference was wiped out, and performance for the low reward pictures was as high as that for high reward pictures. Pramipexole did not generally enhance memory consolidation probably because of the fact that the dopaminergic agonist concurrently suppressed both SWS and REM sleep. These results are consistent with the concept that preferential consolidation of reward-associated memories relies on hippocampus-driven reactivation within the dopaminergic reward system during sleep, whereby during sleep reward contingencies are fed back to the hippocampus to strengthen specific memories, possibly, through dopaminergic facilitation of long-term potentiation.


Some considerations in the design of a high power, pulsed n(2) laser.
Pulsed, megawatt laser power levels at 3371 A from nitrogen gas require the formation of a high density plasma of high electron temperature in the first few nanoseconds of gaseous breakdown. This has been obtained from a laser tube powered by a pulse forming network in the form of a low impedance, parallel plate transmission line. Another low impedance, parallel plate transmission line, charged to 30 kV is used to pulse charge the pulse forming line by means of a synchronized, multiple spark gap switch. The pulse forming transmission line terminates in a continuous high voltage electrode which runs parallel to the axis of the tube, i.e., in the direction of the light beam. The finite, nonzero time required for the gas in the laser tube to break down, permits (a) pulse charging this line to voltages many times larger than the dc breakdown voltage of the nitrogen in the laser tube, and (b) the placement of the switch in the circuit where its impedance does not limit the rate of rise of current during the laser excitation process. Furthermore, it is shown that decreasing the impedance of the pulse forming line increases the laser output power, when the current in the laser circuit is not limited by circuit inductance.


Don't be fooled: false flowers in Asteraceae.
The sunflower or daisy family, Asteraceae, comprises of approximately 10% of all angiosperm species. Their inflorescences form dense flower-like structures, pseudanthia or false flowers that may combine hundreds of individual flowers into a single structure. Recent data suggest that pseudanthia are analogs of single flowers not only morphologically but also at developmental and genetic level, and cannot merely be considered as condensed inflorescences. The large meristem size provides an advantage to study basic principles of patterning as well as inflorescence diversity in this evolutionary successful family. This knowledge has also practical importance in the commercially important crops of the family.


Operative complications and economic outcomes of cholecystectomy for acute cholecystitis.
Recent management of acute cholecystitis favors same admission (SA) or emergent cholecystectomy based on overall shorter hospital stay and therefore cost savings. We adopted the practice of SA cholecystectomy for the treatment of acute cholecystitis at our tertiary care center and wanted to evaluate the economic benefit of this practice. We hypothesized that the existence of complications, particularly among patients with a higher degree of disease severity, during SA cholecystectomy could negate the cost savings. To compare complication rates and hospital costs between SA vs delayed cholecystectomy among patients admitted emergently for acute cholecystitis. Under an IRB-approved protocol, complications and charges for were obtained for SA, later after conservative management (Delayed), or elective cholecystectomies over an 8.5-year period. Patients were identified using the acute care surgery registry and billing database. Data was retrieved via EMR, operative logs, and Revenue Cycle Operations. The severity of acute cholecystitis was graded according to the Tokyo Guidelines. TG18 categorizes acute cholecystitis by Grades 1, 2, and 3 representing mild, moderate, and severe, respectively. Comparisons were analyzed with χ 2, Fisher's exact test, ANOVA, t-tests, and logistic regression; significance was set at P < 0.05. Four hundred eighty-six (87.7%) underwent a SA while 68 patients (12.3%) received Delayed cholecystectomy. Complication rates were increased after SA compared to Delayed cholecystectomy (18.5% vs 4.4%, P = 0.004). The complication rates of patients undergoing delayed cholecystectomy was similar to the rate for elective cholecystectomy (7.4%, P = 0.35). Mortality rates were 0.6% vs 0% for SA vs Delayed. Patients with moderate disease (Tokyo 2) suffered more complications among SA while none who were delayed experienced a complication (16.1% vs 0.0%, P < 0.001). Total hospital charges for SA cholecystectomy were increased compared to a Delayed approach ($44500 ± $59000 vs $35300 ± $16700, P = 0.019). The relative risk of developing a complication was 4.2x [95% confidence interval (CI): 1.4-12.9] in the SA vs Delayed groups. Among eight patients (95%CI: 5.0-12.3) with acute cholecystitis undergoing SA cholecystectomy, one patient will suffer a complication. Patients with Tokyo Grade 2 acute cholecystitis had more complications and increased hospital charges when undergoing SA cholecystectomy. This data supports a selective approach to SA cholecystectomy for acute cholecystitis.


Cobalt chloride, a hypoxia-mimicking agent, modulates redox status and functional parameters of cultured swine granulosa cells.
Hypoxia occurs physiologically during ovarian follicle growth; this deprivation represents a triggering stimulus for the production of vascular endothelial growth factor (VEGF) by proliferating granulosa cells, which are mostly responsible for the growth of the follicle. Moreover, the steroidogenic activity of these cells ensures a receptive environment for the implantation and development of the early embryo. The present paper reports the adaptive response of swine granulosa cells to cobalt chloride (CoCl(2), a chemical hypoxia-mimicking agent. The effects of the treatment were evaluated on cell proliferation, steroidogenesis and VEGF production. In addition, because mithocondrial reactive oxygen species (ROS) are possibly involved in O(2) sensing, ROS levels and scavenging enzyme activity were investigated. In the present study, CoCl 2 had no effect on progesterone production, although it significantly reduced oestradiol synthesis. The addition of CoCl(2) to granulosa cell culture stimulated VEGF production and the generation of hydrogen peroxide. Chemical hypoxia had different effects on scavenger enzyme activities: the activity of superoxide dismutase was enhanced, that of peroxidase reduced and catalase activity was unaffected. The net result is a 'pro-oxidant' state, which appears to be possibly involved in the stimulation of VEGF production, thus inducing follicular angiogenesis.


Water excretion by hydra.
Hydra were cut so that regenerates consisting only of the central gastric region were formed. This region, which has no natural opening to the environment, is capable of osmoregulation and of removing excess fluid from the gut. The fluid is excreted through a break in the body wall created as a result of a strong contraction when the gut is distended with fluid. A normal hydra, therefore, must remove excess fluid by contracting and expelling it through its mouth.


Beryllium detection in human lung tissue using electron probe X-ray microanalysis.
Chronic berylliosis is an uncommon disease that is caused by the inhalation of beryllium particles, dust, or fumes. The distinction between chronic berylliosis and sarcoidosis can be difficult both clinically and histologically, as both entities can have similar presentations and exhibit nonnecrotizing granulomatous inflammation of the lungs. The diagnosis of chronic berylliosis relies on a history of exposure to beryllium, roentgenographic evidence of diffuse nodular disease, and demonstration of beryllium hypersensitivity by ancillary studies, such as lymphocyte proliferation testing. Additional support may be gained by the demonstration of beryllium in lung tissue. Unlike other exogenous particulates, such as asbestos, detection of beryllium in human lung tissue is problematic. The low atomic number of beryllium usually makes it unsuitable for conventional microprobe analysis. We describe a case of chronic berylliosis in which beryllium was detected in lung tissue using atmospheric thin-window energy-dispersive X-ray analysis (ATW EDXA). A woman with a history of occupational exposure to beryllium at a nuclear weapons testing facility presented with progressive cough and dyspnea and a nodular pattern on chest roentgenograph. Open lung biopsy showed nonnecrotizing granulomatous inflammation that was histologically indistinguishable from sarcoidosis. Scanning electron microscopy and ATW EDXA demonstrated particulates containing beryllium within the granulomas. This application of EDXA offers significant advantages over existing methods of beryllium detection in that it is nondestructive, more widely available, and can be performed using routine paraffin sections.


Dopaminergic meso-cortical projections to m1: role in motor learning and motor cortex plasticity.
Although the architecture of a dopaminergic (DA) system within the primary motor cortex (M1) was well characterized anatomically, its functional significance remained obscure for a long time. Recent studies in rats revealed that the integrity of DA fibers in M1 is a prerequisite for successful acquisition of motor skills. This essential contribution of DA for motor learning is plausible as it modulates M1 circuitry at multiple levels thereby promoting plastic changes that are required for information storage: at the network level, DA increases cortical excitability and enhances the stability of motor maps. At the cellular level, DA induces the expression of learning-related genes via the transcription factor c-Fos. At the level of synapses, DA is required for the formation of long-term potentiation, a mechanism that likely is a fingerprint of a motor memory trace within M1. DA fibers innervating M1 originate within the midbrain, precisely the ventral tegmental area (VTA) and the medial portion of substantia nigra (SN). Thus, they could be part of the meso-cortico-limbic pathway - a network that provides information about saliency and motivational value of an external stimulus and is commonly referred as "reward system." However, the behavioral triggers of the release of dopamine in M1 are not yet identified. As alterations in DA transmission within M1 occur under various pathological conditions such as Parkinson disease or ischemic and traumatic brain injury, a deeper understanding of the interaction of VTA/SN and M1 may reveal a deeper insight into a large spectrum of neurological disorders.


Characterization of cholecystokinin binding sites in goldfish brain and pituitary.
The characterization and distribution of cholecystokinin (CCK)/gastrin binding sites were determined in the goldfish central nervous system (CNS). Binding of 125I-sulfated CCK octapeptide (125I-CCK-8s) in tissue sections was found to be saturable, reversible, time dependent, and displaceable by CCK/gastrin-like peptides. Analysis of saturable equilibrium binding revealed a high-affinity binding site (dissociation constant of 0.706 +/- 0.188 nM), which also displayed high affinity for gastrin-17s and caerulein. Lower affinities were observed for the nonsulfated forms of CCK-8 and gastrin-17. These findings suggest that a single primitive CCK/gastrin receptor exists in the goldfish CNS. The distribution of CCK/gastrin binding sites in the goldfish brain and pituitary revealed high densities within the telencephalon and preoptic hypothalamus, as well as within hypothalamic nuclei associated with the brain feeding center. High densities of binding sites were also localized within the midbrain tegmentum and optic tectum of the midbrain, the facial lobe and vagal lobe of the hindbrain, and within the pituitary pars distalis. Overall, these findings support previous studies that indicate that CCK/gastrin-like peptides play a role in the central regulation of feeding behavior and pituitary hormone secretion in fish.


Criterion-Based Assessment in a Norm-Based World: How Can We Move Past Grades?
In the United States, the medical education community has begun a shift from the Flexnerian time-based model to a competency-based medical education model. The graduate medical education (GME) community is substantially farther along in this transition than is the undergraduate medical education (UME) community.GME has largely adopted the use of competencies and their attendant milestones and increasingly is employing the framework of entrustable professional activities (EPAs) to assess trainee competence. The UME community faces several challenges to successfully navigating a similar transition. First is the reliance on norm-based reference standards in the UME-GME transition, comparing students' performance versus their peers' with grades, United States Medical Licensing Examination Step 1 and Step 2 score interpretation, and the structured Medical School Performance Evaluation, or dean's letter. Second is the reliance on proxy assessments rather than direct observation of learners. Third is the emphasis on summative rather than formative assessments.Educators have overcome a major barrier to change by establishing UME outcomes assessment criteria with the advent and general acceptance of the physician competency reference set and the Core EPAs for Entering Residency in UME. Now is the time for the hard work of developing assessments steeped in direct observation that can be accepted by learners and faculty across the educational continuum and can be shown to predict clinical performance in a much more meaningful way than the current measures of grades and examinations. The acceptance of such assessments will facilitate the UME transition toward competency-based medical education.


Alexa fluor-labeled fluorescent cellulose nanocrystals for bioimaging solid cellulose in spatially structured microenvironments.
Methods to covalently conjugate Alexa Fluor dyes to cellulose nanocrystals, at limiting amounts that retain the overall structure of the nanocrystals as model cellulose materials, were developed using two approaches. In the first, aldehyde groups are created on the cellulose surfaces by reaction with limiting amounts of sodium periodate, a reaction well-known for oxidizing vicinal diols to create dialdehyde structures. Reductive amination reactions were then applied to bind Alexa Fluor dyes with terminal amino-groups on the linker section. In the absence of the reductive step, dye washes out of the nanocrystal suspension, whereas with the reductive step, a colored product is obtained with the characteristic spectral bands of the conjugated dye. In the second approach, Alexa Fluor dyes were modified to contain chloro-substituted triazine ring at the end of the linker section. These modified dyes then were reacted with cellulose nanocrystals in acetonitrile at elevated temperature, again isolating material with the characteristic spectral bands of the Alexa Fluor dye. Reactions with Alexa Fluor 546 are given as detailed examples, labeling on the order of 1% of the total glucopyranose rings of the cellulose nanocrystals at dye loadings of ca. 5 μg/mg cellulose. Fluorescent cellulose nanocrystals were deposited in pore network microfluidic structures (PDMS) and proof-of-principle bioimaging experiments showed that the spatial localization of the solid cellulose deposits could be determined, and their disappearance under the action of Celluclast enzymes or microbes could be observed over time. In addition, single molecule fluorescence microscopy was demonstrated as a method to follow the disappearance of solid cellulose deposits over time, following the decrease in the number of single blinking dye molecules with time instead of fluorescent intensity.


Polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and non-ortho-PCBs in eggs of white-tailed sea eagles collected along the Swedish coast in the Baltic Sea.
Concentrations of polychlorinated dibenzo-p-dioxins (PCDD), polychlorinated dibenzofurans (PCDF), and dioxin-like non-ortho-PCBs were measured in white-tailed sea eagle (WTSE) eagle eggs collected along the Swedish coast of the Baltic Sea during the period 1992-2004. The eggs represent two different subpopulations with significantly different nestling brood sizes; the Baltic Proper (BP) with an approximately normal nestling brood size (1.62), and the south Bothnian Sea (sBS) with reduced nestling brood size (1.22) combined with a significantly higher rate of dead eggs. The aim was to investigate if this difference in reproductive outcome was linked to differences in exposure to dioxin-like compounds. Three eggs collected in Greenland in 2000 were included in the study to provide a reference sea eagle population outside of the Baltic Sea region. The concentrations of ∑PCDD, ∑PCDF and ∑non-ortho-PCB in the two subpopulations from the Baltic Sea (BS) region ranged from 0.41-4.1, 1.2-5.3 and 180-970 ng/g lipids, respectively, while in the Greenland population the ranges were 0.11-0.16, 0.22-0.33 and 57-83 ng/g lipid, respectively. 2,3,4,7,8-PCDF was the predominant congener in all areas and accounted for on average 31-49% of the total ∑PCDD/F concentrations. The total toxic equivalents (TEQ) in sBS WTSEs were higher (approximately 39 ng TEQ/g lipid) than reported in eggs for many other birds, and the major contributors to the TEQ in the Baltic Sea were the non-ortho-PCBs. A principal component analysis (PCA) showed a difference in congener pattern between the two Baltic regions that was statistically significant (Hotelling's T(2) test). We found no significant differences in the total TEQ between the two populations (sBS-BP) and thus no evidence was found linking the reproductive impairment in WTSE in sBS to the concentrations of PCDD/Fs or non-ortho-PCBs in the eggs.


Characterization of naturally acquired antibodies to the non-repetitive flanking regions of the circumsporozoite protein of Plasmodium falciparum.
Antibody responses to the circumsporozoite (CS) protein of Plasmodium falciparum have previously been reported against the central repeating tetrapeptides of this protein. Segments of the protein flanking the repeat region also contain B-cell epitopes, but specific antibody responses have not been previously characterized. Longitudinal serum sets from 16 Thai adults who developed acute falciparum malaria were selected to represent a spectrum of antibody response to the repeat region (R32). These sera were assayed by enzyme-linked immunosorbent assay using as capture antigen a recombinant fusion protein, NS1(81)RLF, which contains both flanking regions, but lacks the NANP and NVDP repeats of the P. falciparum CS protein. Antibody responses to the repeatless flanking (RLF) regions were observed in all subjects, including five individuals who lacked detectable anti-R32 antibody responses. Anti-RLF antibody responses induced by natural infection appear to be short-lived and of low-to-moderate magnitude. Thus, if anti-RLF antibodies prove to be protective, derived vaccine candidates may require presentation of these epitopes with adjuvants or delivery systems that enhance immunogenicity.


Experimental investigation of square dissipative soliton generation and propagation.
We have experimentally investigated the generation and propagation of square dissipative solitons emitted from an erbium-doped fiber laser with large normal cavity dispersion. The square pulse exhibits an approximately Gaussian spectral profile and large frequency chirp on its edges. When the square pulse propagates through a segment of single-mode fiber (SMF), it can be shaped to a Gaussian pulse and the corresponding spectrum will have a redshift with a prolonged wing on the longer wavelength. Our experiments show that the pulse evolution in the SMF is determined by the combined effects of the fiber dispersion, intrapulse Raman scattering, and the pulse initial chirps.


Towards a quantitative framework for the prediction of DDIs arising from cytochrome P450 induction.
Although CYP induction is not generally considered to be as clinically relevant as CYP inhibition, there are important examples where induction has caused both therapeutic failure, due to insufficient exposure to parent drug, and toxicity, mediated by increased formation of reactive metabolites. Furthermore, while there has been considerable progress in the extrapolation of in vitro data to predict the in vivo consequences of enzyme inhibition, less attention has been given to the quantitative impact of enzyme induction as a mechanism of drug-drug interaction (DDI) and as a component of compound selection and early drug development. We discuss current approaches in the context of a mechanistic framework for the prediction of the extent and time-course of enzyme induction in vivo based on in vitro experimentation. Factors influencing the extent of DDI due to CYP induction are summarised, and areas deficient in information that would allow more accurate prediction within target populations are highlighted.


Clinical performance of the Osia™ system, a new active osseointegrated implant system. Results from a prospective clinical investigation.
Background: Bone-conduction hearing implants are standard of care devices.Aims/Objectives: Evaluation of a new active magnetic bone-conduction hearing implant: Cochlear Osia™ system.Material and methods: This device uses a transcutaneous connection between an external sound-processor and an osseointegrated implant that generates vibrations using a piezoelectricity-based internal bone-conduction system. Nine patients with conductive-hearing loss were implanted. Surgical efficacy, hearing performance and quality-of-life were evaluated. Hearing performance in quiet and in noise was compared with unaided hearing and hearing with the Baha 5 Power® Sound Processor on a softband.Results: Surgery and healing were uneventful. Statistically significant improvements in audibility, speech-understanding, speech-recognition and quality-of-sound in noise and quiet were found for the Osia™ compared to preoperative unaided hearing and aided hearing with the Baha 5 Power® Sound Processor on a softband. The active vibration system provided improvement at low and high frequencies. At 6 months postoperatively, all patients continue to use the device.Conclusions and significance: The Osia™ is safe and effective, improving speech-recognition in quiet and in noise, at low and high frequencies, thus delivering better quality-of-hearing than passive devices.


Structure and location of gene product 8 in the bacteriophage T4 baseplate.
Many bacteriophages, such as T4, T7, RB49, and phi29, have complex, sometimes multilayered, tails that facilitate an almost 100% success rate for the viral particles to infect host cells. In bacteriophage T4, there is a baseplate, which is a multiprotein assembly, at the distal end of the contractile tail. The baseplate communicates to the tail that the phage fibers have attached to the host cell, thereby initiating the infection process. Gene product 8 (gp8), whose amino acid sequence consists of 334 residues, is one of at least 16 different structural proteins that constitute the T4 baseplate and is the sixth baseplate protein whose structure has been determined. A 2.0A resolution X-ray structure of gp8 shows that the two-domain protein forms a dimer, in which each monomer consists of a three-layered beta-sandwich with two loops, each containing an alpha-helix at the opposite sides of the sandwich. The crystals of gp8 were produced in the presence of concentrated chloride and bromide ions, resulting in at least 11 halide-binding sites per monomer. Five halide sites, situated at the N termini of alpha-helices, have a protein environment observed in other halide-containing protein crystal structures. The computer programs EMfit and SITUS were used to determine the positions of six gp8 dimers within the 12A resolution cryo-electron microscopy image reconstruction of the baseplate-tail tube complex. The gp8 dimers were found to be located in the upper part of the baseplate outer rim. About 20% of the gp8 surface is involved in contacts with other baseplate proteins, presumed to be gp6, gp7, and gp10. With the structure determination of gp8, a total of 53% of the volume of the baseplate has now been interpreted in terms of its atomic structure.


A good death from the perspective of palliative cancer patients.
Although previous research has indicated some recurrent themes and similarities between what patients from different cultures regard as a good death, the concept is complex and there is lack of studies from the Nordic countries. The aim of this study was to explore the perception of a good death in dying cancer patients in Sweden. Interviews were conducted with 66 adult patients with cancer in the palliative phase who were recruited from home care and hospital care. Interviews were analysed using qualitative content analysis. Participants viewed death as a process. A good death was associated with living with the prospect of imminent death, preparing for death and dying comfortably, e.g., dying quickly, with independence, with minimised suffering and with social relations intact. Some were comforted by their belief that death is predetermined. Others felt uneasy as they considered death an end to existence. Past experiences of the death of others influenced participants' views of a good death. Healthcare staff caring for palliative patients should consider asking them to describe what they consider a good death in order to identify goals for care. Exploring patients' personal experience of death and dying can help address their fears as death approaches.


Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines.
Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling.


Probing the neurocognitive trajectories of children's reading skills.
Emerging evidence of the high variability in the cognitive skills and deficits associated with reading achievement and dysfunction promotes both a more dimensional view of the risk factors involved, and the importance of discriminating between trajectories of impairment. Here we examined reading and component orthographic and phonological skills alongside measures of cognitive ability and auditory and visual sensory processing in a large group of primary school children between the ages of 7 and 12 years. We identified clusters of children with pseudoword or exception word reading scores at the 10th percentile or below relative to their age group, and a group with poor skills on both tasks. Compared to age-matched and reading-level controls, groups of children with more impaired exception word reading were best described by a trajectory of developmental delay, whereas readers with more impaired pseudoword reading or combined deficits corresponded more with a pattern of atypical development. Sensory processing deficits clustered within both of the groups with putative atypical development: auditory discrimination deficits with poor phonological awareness skills; impairments of visual motion processing in readers with broader and more severe patterns of reading and cognitive impairments. Sensory deficits have been variably associated with developmental impairments of literacy and language; these results suggest that such deficits are also likely to cluster in children with particular patterns of reading difficulty.


Reproduction, food dynamics and exploitation level of Oreochromis niloticus (Perciformes: Cichlidae) from artisanal fisheries in Barra Bonita Reservoir, Brazil.
Nile tilapia (Oreochromis niloticus), which is exotic to South America, is the most common species caught in artisanal fisheries at the Barra Bonita Reservoir, Southeastern Brazil. This species is of great socioeconomic importance for the region and keeps active a population of about 500 fishers. In the present study we assess reproduction, food dynamics and level of exploitation of O. niloticus, caught by artisanal fisheries in the Barra Bonita Reservoir. Specimens were collected monthly, from July 2004-June 2005, and a total of 1 715 specimens were analyzed. Each specimen was examined to obtain biological and biometric data: standard length (cm), total weight (g), reproductive data (sex and stage of maturation), and stomach contents (empty, partly full, and full). We also estimated the sex ratio (by macroscopic observation of gonads), reproductive period (by ovarian development and seasonal average of gonadosomatic index in females), and feeding habits (by stomach contents). The possible relationship between abiotic factors and the reproductive period was statistically verified using Spearman's Rank Correlation. The FiSAT (ELEFAN I) package was used to assess growth parameters, mortality rates and to infer exploitation rate from standard length frequencies. The O. niloticus population had a sex ratio of 1.3:1 (M:F). Results indicated that ripe females were captured throughout the year, with a higher frequency during the winter-2004 (with a frequency of 59%, at a mean temperature of 20.5 degreeC), and in spring-2004 (with a frequency of 60.5% at a mean temperature of 21.18 degreeC). The GSI mean values obtained by season were: winter-2004: 1.71; spring-2004: 1.72; summer-2005: 0.80, and autumn-2005: 1.19. The Spearman correlation indicated positive values with respect to pH, dissolved oxygen, electric conductivity, transparency and chlorophyll a, and negative values with respect to temperature, accumulated rainfall and altimetric benchmark. The main food items were phytoplankton and periphytic algae, observed in 99.6% of the analyzed stomachs. The estimated growth and mortality parameters were: Linfinity=33.60cm, k=0.63/year, longevity= 4.76years, Z=2.81/ year, M=1.20/year and F=1.61/year. The weight-length relationship was Ln Wt=-2.8532+2.8835 Ln Lp. The estimated yield per recruit values were as follows: E=0.570, Emax=0.776, E0.1=0.604 and E0.5=0.349. These results indicate that a well established population of O. niloticus is present at Barra Bonita Reservoir; with an active reproduction throughout the year, more intense during winter and spring, and that O. niloticus is a phyto-planktophagus species. There were no indications that this species is being overfished, we therefore recommend that, due to its exotic condition, no restrictions need to be taken on its fishing activities.


Modified tumour antigen-encoding mRNA facilitates the analysis of naturally occurring and vaccine-induced CD4 and CD8 T cells in cancer patients.
The development of effective anti-cancer vaccines requires precise assessment of vaccine-induced immunity. This is often hampered by low ex vivo frequencies of antigen-specific T cells and limited defined epitopes. This study investigates the applicability of modified, in vitro-transcribed mRNA encoding a therapeutically relevant tumour antigen to analyse T cell responses in cancer patients. In this study transfection of antigen presenting cells, by mRNA encoding the tumour antigen NY-ESO-1, was optimised and applied to address spontaneous and vaccine-induced T cell responses in cancer patients. Memory CD8+ T cells from lung cancer patients having detectable humoral immune responses directed towards NY-ESO-1 could be efficiently detected in peripheral blood. Specific T cells utilised a range of different T cell receptors, indicating a polyclonal response. Specific killing of a panel of NY-ESO-1 expressing tumour cell lines indicates recognition restricted to several HLA allelic variants, including a novel HLA-B49 epitope. Using a modified mRNA construct targeting the translated antigen to the secretory pathway, detection of NY-ESO-1-specific CD4+ T cells in patients could be enhanced, which allowed the in-depth characterisation of established T cell clones. Moreover, broad CD8+ and CD4+ T cell responses covering multiple epitopes were detected following mRNA stimulation of patients treated with a recombinant vaccinia/fowlpox NY-ESO-1 vaccine. This approach allows for a precise monitoring of responses to tumour antigens in a setting that addresses the breadth and magnitude of antigen-specific T cell responses, and that is not limited to a particular combination of known epitopes and HLA-restrictions.


[Prevalence of Gilbert syndrome and its genetic determinants in Chile].
In Europeans the TATA box TA7 repeat promoter variant in the UGT1A1 gene (UGT1A1*28) is the major determinant of bilirubin levels. To study the prevalence of Gilbert Syndrome (GS) and its genetic determinants in Chile. Three different studies were conducted. The prevalence of GS in Chile was assessed in 991 subjects with normal liver tests (ALT and GGT) from the 2nd National Health Survey. We defined GS as a total bilirubin (TB) between 1.4-5mg/dL. The second study assessed the genotype prevalence of SNP rs6742078 (in LD with UGT1A1*28) and rs4149056 in 500 DNA samples of non-related Hispanics. Finally, a case-control study was designed to assess the phenotype-genotype correlation. UGT1A1*28 and rs4149056 variants were determined by direct sequencing and allelic discrimination assays (TaqMan), respectively. Prevalence of GS in the general Chilean population was 2.6% (4.5% in males and 0.5% in female). No correlation with age, educational level or home location was found. Genotypes for UGT1A1*28 (TA6/6 50.5%, TA6/7 37.8%, TA7/7 11.7%) and rs4149056 (TT 74.1%, CT 22.8%, and CC 3.1%) variants were similar to Europeans. In the case-control study, most patients with GS were homozygotes for UGT1A1*28 (TA7/7, 74%). Of note, 44% of patients with intermediate TB levels were also TA7/7, compared to 7% in normal subjects. SLCO1B1 genotype was not correlated with TB levels. While the prevalence of GS was lower in Chile compared to Europeans (~5%), the prevalence of UGT1A1*28 homozygotes was similar (~12%). In Chilean Hispanics, the UGT1A1*28 variant explain 75% of GS phenotype.


The Combination of Vitamin K3 and Vitamin C Has Synergic Activity against Forms of Trypanosoma cruzi through a Redox Imbalance Process.
Chagas' disease is an infection that is caused by the protozoan Trypanosoma cruzi, affecting millions of people worldwide. Because of severe side effects and variable efficacy, the current treatments for Chagas' disease are unsatisfactory, making the search for new chemotherapeutic agents essential. Previous studies have reported various biological activities of naphthoquinones, such as the trypanocidal and antitumor activity of vitamin K3. The combination of this vitamin with vitamin C exerted better effects against various cancer cells than when used alone. These effects have been attributed to an increase in reactive oxygen species generation. In the present study, we evaluated the activity of vitamin K3 and vitamin C, alone and in combination, against T. cruzi. The vitamin K3 + vitamin C combination exerted synergistic effects against three forms of T. cruzi, leading to morphological, ultrastructural, and functional changes by producing reactive species, decreasing reduced thiol groups, altering the cell cycle, causing lipid peroxidation, and forming autophagic vacuoles. Our hypothesis is that the vitamin K3 + vitamin C combination induces oxidative imbalance in T. cruzi, probably started by a redox cycling process that leads to parasite cell death.


An evidence synthesis of strategies, enablers and barriers for keeping secrets online regarding the procurement and supply of illicit drugs.
This systematic review attempts to understand how people keep secrets online, and in particular how people use the internet when engaging in covert behaviours and activities regarding the procurement and supply of illicit drugs. With the Internet and social media being part of everyday life for most people in western and non-western countries, there are ever-growing opportunities for individuals to engage in covert behaviours and activities online that may be considered illegal or unethical. A search strategy using Medical Subject Headings terms and relevant key words was developed. A comprehensive literature search of published and unpublished studies in electronic databases was conducted. Additional studies were identified from reference lists of previous studies and (systematic) reviews that had similar objectives as this search, and were included if they fulfilled our inclusion criteria. Two researchers independently screened abstracts and full-texts for study eligibility and evaluated the quality of included studies. Disagreements were resolved by a consensus procedure. The systematic review includes 33 qualitative studies and one cross-sectional study, published between 2006 and 2018. Five covert behaviours were identified: the use of communication channels; anonymity; visibility reduction; limited posts in public; following forum rules and recommendations. The same technologies that provide individuals with easy access to information, such as social networking sites and forums, digital devices, digital tools and services, also increase the prevalence of inaccurate information, loss of privacy, identity theft and disinhibited communication. This review takes a rigorous interdisciplinary approach to synthesising knowledge on the strategies adopted by people in keeping secrets online. Whilst the focus is on the procurement and supply of illicit drugs, this knowledge is transferrable to a range of contexts where people keep secrets online. It has particular significance for those who design online/social media applications, and for law enforcement and security agencies.


XANAP: A real-world, prospective, observational study of patients treated with rivaroxaban for stroke prevention in atrial fibrillation in Asia.
ROCKET AF and its East Asian subanalysis demonstrated that rivaroxaban was non-inferior to warfarin for stroke/systemic embolism (SE) prevention in patients with non-valvular atrial fibrillation (NVAF), with a favorable benefit-risk profile. XANAP investigated the safety and effectiveness of rivaroxaban in routine care in Asia-Pacific. XANAP was a prospective, real-world, observational study in patients with NVAF newly starting rivaroxaban. Patients were followed at ~3-month intervals for 1 year, or for ≥30 days after permanent discontinuation. Primary outcomes were major bleeding events, adverse events (AEs), serious AEs and all-cause mortality; secondary outcomes included stroke/SE. Major outcomes were adjudicated centrally. XANAP enrolled 2273 patients from 10 countries: mean age was 70.5 years and 58.1% were male. 49.8% of patients received rivaroxaban 20 mg once daily (od), 43.8% 15 mg od and 5.9% 10 mg od. Mean treatment duration was 296 days, and 72.8% of patients had received prior anticoagulation therapy. Co-morbidities included heart failure (20.1%), hypertension (73.6%), diabetes mellitus (26.6%), prior stroke/non-central nervous system SE/transient ischemic attack (32.8%) and myocardial infarction (3.8%). Mean CHADS2, CHA2DS2-VASc and HAS-BLED scores were 2.3, 3.7 and 2.1, respectively. The rates (events/100 patient-years [95% confidence interval]) of treatment-emergent major bleeding, stroke and all-cause mortality were 1.5 (1.0-2.1), 1.7 (1.2-2.5) and 2.0 (1.4-2.7), respectively. Persistence was 66.2% at the study end. The real-world XANAP study demonstrated low rates of stroke and bleeding in rivaroxaban-treated patients with NVAF from Asia-Pacific. The results were consistent with the real-world XANTUS study and ROCKET AF.


CRAGE enables rapid activation of biosynthetic gene clusters in undomesticated bacteria.
It is generally believed that exchange of secondary metabolite biosynthetic gene clusters (BGCs) among closely related bacteria is an important driver of BGC evolution and diversification. Applying this idea may help researchers efficiently connect many BGCs to their products and characterize the products' roles in various environments. However, existing genetic tools support only a small fraction of these efforts. Here, we present the development of chassis-independent recombinase-assisted genome engineering (CRAGE), which enables single-step integration of large, complex BGC constructs directly into the chromosomes of diverse bacteria with high accuracy and efficiency. To demonstrate the efficacy of CRAGE, we expressed three known and six previously identified but experimentally elusive non-ribosomal peptide synthetase (NRPS) and NRPS-polyketide synthase (PKS) hybrid BGCs from Photorhabdus luminescens in 25 diverse γ-Proteobacteria species. Successful activation of six BGCs identified 22 products for which diversity and yield were greater when the BGCs were expressed in strains closely related to the native strain than when they were expressed in either native or more distantly related strains. Activation of these BGCs demonstrates the feasibility of exploiting their underlying catalytic activity and plasticity, and provides evidence that systematic approaches based on CRAGE will be useful for discovering and identifying previously uncharacterized metabolites.


Clinical Utility of the Inventory of Depression and Anxiety Symptoms (IDAS).
Depressive and anxiety disorders are severe and disabling conditions that result in substantial cost and global societal burden. Accurate and efficient identification is thus vital to proper diagnosis and treatment of these disorders. The Inventory of Depression and Anxiety Symptoms (IDAS) is a reliable and well-validated measure that provides dimensional assessment of both mood and anxiety disorder symptoms. The current study examined the clinical utility of the IDAS by establishing diagnostic cutoff scores and severity ranges using a large mixed sample (N = 5,750). Results indicated that the IDAS scales are good to excellent predictors of their associated Structured Clinical Interview for DSM-IV diagnoses. These findings were replicated using Diagnostic and Statistical Manual of Mental Disorders-Fifth edition(DSM-5) criteria assessed via the Mini-International Neuropsychiatric Interview. We provide three cutoff scores for each scale that can be used differentially depending on the goal of their use: screening, efficiency, or diagnosis confirmation. The identified severity ranges allow users to characterize individuals as mild, moderate, or severe, providing clinical information beyond diagnostic status. Finally, the 10-item IDAS Dysphoria scale and 20-item General Depression scale demonstrate strong ability to predict internalizing diagnoses and may represent an efficient way to screen for the presence of internalizing psychopathology.


Spatially resolved small-angle X-ray scattering for characterizing mechanoresponsive liposomes using microfluidics.
Atherosclerosis gives rise to blood vessel occlusion associated with blood flow alteration and substantial increase of average wall shear stress. This modification was proved acting as a purely physical trigger for targeted vasodilator release from a particular type of liposomes composed of 1,3-diaminophospholipids (Pad-PC-Pad). The flow-induced structural changes of these faceted liposomes, however, are completely unknown. Therefore, spatially resolved small-angle X-ray scattering was combined with microfluidics to uniquely study the purely physical mechanisms, which give rise to the highly efficient drug release from mechanoresponsive liposomes of nanometer size. The microfluidic device, designed to mimic a stenotic blood vessel, consisted of a 1-mm-wide channel with a constriction, 125 μm in diameter. Here, the changes of the average bilayer thickness and the mean size of the mechanoresponsive liposomes have been locally detected under flow conditions. Overall shape and bilayer thickness do change already near the constriction inlet, but the alteration is dominant near the outlet. At a flow rate of 0.2 μL/s, the liposome's bilayer thickness increased by 30 % compared to the situation well before the constriction and under static condition. The detected bilayer thickness increase of the faceted liposomes is in line with the mechanically induced loss of interdigitation between the phospholipid amide chains. These results imply that rather the gradient force than the wall shear stress provokes structural changes of Pad-PC-Pad liposomes and the related drug release at stenoses. The approach, i.e. the combination of microfluidics and spatially resolved small-angle X-ray scattering, paves the way to design highly efficient and specific systems for the targeted drug delivery at constrictions with predefined morphology.


A systematic review of lifestyle interventions for chronic diseases in rural communities.
Rural Americans suffer disproportionately from lifestyle-related chronic diseases (e.g., obesity, diabetes, hypertension, cardiovascular disease, and breast cancer). Interventions that consider the distinctive characteristics of rural communities (e.g., access to healthcare, income, and education) are needed. As an initial step in planning future research, we completed a systematic review of dietary intake and physical activity interventions targeting rural populations. Manuscripts focused on dietary intake and physical activity and published through March 15, 2016, were identified by use of PubMed and CINAHL databases and MeSH terms and keyword searches. A total of 18 studies met the inclusion criteria. Six involved randomized controlled trials; 7 used quasi-experimental designs; 4 had a pre-/post-design; and 1 was an observational study. Eight studies were multi-site (or multi-county), and 3 focused on churches. Primary emphasis by racial/ethnic group included: African Americans (6); Whites (2); Hispanics (3); and two or more groups (7). Most studies (17) sampled adults; one included children. Two studies targeted families. Additional lifestyle intervention research is needed to identify effective approaches promoting healthy diet and exercise and chronic disease prevention in rural communities. Studies that include rigorous designs, adequate sample sizes, and generalizable results are needed to overcome the limitations of published studies.


Oral care measures for preventing nursing home-acquired pneumonia.
Pneumonia occurring in residents of long-term care facilities and nursing homes can be termed 'nursing home-acquired pneumonia' (NHAP). NHAP is the leading cause of mortality among residents. NHAP may be caused by aspiration of oropharyngeal flora into the lung, and by failure of the individual's defence mechanisms to eliminate the aspirated bacteria. Oral care measures to remove or disrupt oral plaque might be effective in reducing the risk of NHAP. To assess effects of oral care measures for preventing nursing home-acquired pneumonia in residents of nursing homes and other long-term care facilities. Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 15 November 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2017, Issue 10), MEDLINE Ovid (1946 to 15 November 2017), and Embase Ovid (1980 to 15 November 2017) and Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1937 to 15 November 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. We also searched the Chinese Biomedical Literature Database, the China National Knowledge Infrastructure, and the Sciencepaper Online to 20 November 2017. We included randomised controlled trials (RCTs) that evaluated the effects of oral care measures (brushing, swabbing, denture cleaning mouthrinse, or combination) in residents of any age in nursing homes and other long-term care facilities. At least two review authors independently assessed search results, extracted data, and assessed risk of bias in the included studies. We contacted study authors for additional information. We pooled data from studies with similar interventions and outcomes. We reported risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, and hazard ratio (HR) for time-to-event outcomes, using random-effects models. We included four RCTs (3905 participants), all of which were at high risk of bias. The studies all evaluated one comparison: professional oral care versus usual oral care. We did not pool the results from one study (N = 834 participants), which was stopped at interim analysis due to lack of a clear difference between groups.We were unable to determine whether professional oral care resulted in a lower incidence rate of NHAP compared with usual oral care over an 18-month period (hazard ratio 0.65, 95% CI 0.29 to 1.46; one study, 2513 participants analysed; low-quality evidence).We were also unable to determine whether professional oral care resulted in a lower number of first episodes of pneumonia compared with usual care over a 24-month period (RR 0.61, 95% CI 0.37 to 1.01; one study, 366 participants analysed; low-quality evidence).There was low-quality evidence from two studies that professional oral care may reduce the risk of pneumonia-associated mortality compared with usual oral care at 24-month follow-up (RR 0.41, 95% CI 0.24 to 0.72, 507 participants analysed).We were uncertain whether or not professional oral care may reduce all-cause mortality compared to usual care, when measured at 24-month follow-up (RR 0.55, 95% CI 0.27 to 1.15; one study, 141 participants analysed; very low-quality evidence).Only one study (834 participants randomised) measured adverse effects of the interventions. The study identified no serious events and 64 non-serious events, the most common of which were oral cavity disturbances (not defined) and dental staining.No studies evaluated oral care versus no oral care. Although low-quality evidence suggests that professional oral care could reduce mortality due to pneumonia in nursing home residents when compared to usual care, this finding must be considered with caution. Evidence for other outcomes is inconclusive. We found no high-quality evidence to determine which oral care measures are most effective for reducing nursing home-acquired pneumonia. Further trials are needed to draw reliable conclusions.


Inferior Meatal Antrostomy as a Prophylactic Maneuver to Prevent Sinusitis After Zygomatic Implant Placement Using the Intrasinusal Technique.
To determine whether performing an inferior meatal antrostomy as a prophylactic intraoperative maneuver in patients who underwent zygomatic implant surgery significantly reduces the incidence of postoperative sinusitis. A double-blind randomized controlled trial was implemented. The study included 44 patients seen at the Oral and Maxillofacial Surgery Department at Universidad El Bosque in Bogota, Colombia, who required zygomatic implant surgery. Patients were randomly allocated to either group 1 (without inferior meatal antrostomy) or group 2 (with inferior meatal antrostomy). Patients were evaluated clinically and radiographically 15 days and 3 months after surgery, and classified depending on whether they did or did not develop sinusitis. Results were analyzed using descriptive and bivariate statistics. The control group event rate, experimental group event rate, relative risk, relative risk reduction, absolute risk reduction, and number needed to treat values were calculated for further analysis. Three patients allocated to group 1 showed clinical and radiographic signs of sinusitis after zygomatic implant surgery, for an overall rate of sinusitis of 13.6%. No patient in group 2 developed clinical or radiographic signs of sinusitis. The results of this study suggest that performing an inferior meatal antrostomy as a prophylactic intraoperative maneuver in patients who require zygomatic implant surgery is an effective method to prevent postoperative sinusitis.


Primary care physicians shortage: a Korean example.
A mismatch in the demand and supply of primary care physicians could give rise to a disorganization of the health care system and public confusion about health care access. There is much evidence in Korea of the existence of a primary care physician shortage. The appropriate required ratio of primary care physicians to the total number of physicians is estimated by analyzing data for primary care insurance consumption in Korea. Sums of primary care expenditure and claims were calculated to estimate the need for primary care physicians by analyzing the nationwide health insurance claims data of the Korean National Medical Insurance Management Corporation (KNMIMC) between the years 1989-1998. The total number of physicians increased 183% from 1989 to 1998. However, the number of primary care physicians including general physicians, family physicians, general internists, and general pediatricians showed an increase of only 169% in those 10 years. The demand for primary care physicians reaches at least 58.6%, and up to 83.7%, of the total number of physicians in Korea. However, the number of primary care physicians comprises up to 22.0% of the total number of active physicians during the same research period, which showed a large gap between demand and supply of primary care physicians in Korea. To provide high quality care overall, a balanced supply of primary care physicians and specialists is required, based on the nation's demand for health services.


Individual Differences in Numeracy and Cognitive Reflection, with Implications for Biases and Fallacies in Probability Judgment.
Despite evidence that individual differences in numeracy affect judgment and decision making, the precise mechanisms underlying how such differences produce biases and fallacies remain unclear. Numeracy scales have been developed without sufficient theoretical grounding, and their relation to other cognitive tasks that assess numerical reasoning, such as the Cognitive Reflection Test (CRT), has been debated. In studies conducted in Brazil and in the USA, we administered an objective Numeracy Scale (NS), Subjective Numeracy Scale (SNS), and the CRT to assess whether they measured similar constructs. The Rational-Experiential Inventory, inhibition (go/no-go task), and intelligence were also investigated. By examining factor solutions along with frequent errors for questions that loaded on each factor, we characterized different types of processing captured by different items on these scales. We also tested the predictive power of these factors to account for biases and fallacies in probability judgments. In the first study, 259 Brazilian undergraduates were tested on the conjunction and disjunction fallacies. In the second study, 190 American undergraduates responded to a ratio-bias task. Across the different samples, the results were remarkably similar. The results indicated that the CRT is not just another numeracy scale, that objective and subjective numeracy scales do not measure an identical construct, and that different aspects of numeracy predict different biases and fallacies. Dimensions of numeracy included computational skills such as multiplying, proportional reasoning, mindless or verbatim matching, metacognitive monitoring, and understanding the gist of relative magnitude, consistent with dual-process theories such as fuzzy-trace theory.


Originality of divergent thinking is associated with working memory-related brain activity: Evidence from a large sample study.
The originality of creativity measured by divergent thinking (CMDT) is a unique variable that is positively correlated with psychometric intelligence and other psychological measures. Here, we aimed to determine the associations of CMDT originality/fluency scores and brain activity associated with working memory (WM) and simple cognitive processes during the N-back paradigm in a cohort of 1221 young adults. We observed that originality/fluency scores were associated with greater brain activity during the 0-back simple cognitive task and 2-back WM task in key nodes of the ventral attention system in the right hemisphere. Further, subjects with higher originality/fluency scores showed lower task-induced deactivations in areas of the default mode network, especially during the 2-back task. Psychological analyses revealed the associations of originality/fluency scores with both psychometric intelligence and systemizing. We also observed the effects of interaction between sex and originality/fluency scores on functional activity during the 0-back task in posterior parts of the default mode network together with other areas as well as simple processing speed. These results indicate that the originality of CMDT is associated with (a) greater activation of the ventral attention system, which is involved in reorienting attention and (b) reduced task-induced deactivation of the default mode network, which is indicative of alterations in attentional reallocation, and (c) cognitive correlates of originality of CMDT and revealed sex differences in these associations.