Tracking development assistance for health from China, 2007-2017.
In recent years, China has increased its international engagement in health. Nonetheless, the lack of data on contributions has limited efforts to examine contributions from China. Existing estimates that track development assistance for health (DAH) from China have relied primarily on one dataset. Furthermore, little is known about the disbursing agencies especially the multilaterals through which contributions are disbursed and how these are changing across time. In this study, we generated estimates of DAH from China from 2007 through 2017 and disaggregated those estimates by disbursing agency and health focus area. We identified the major government agencies providing DAH. To estimate DAH provided by each agency, we leveraged publicly available development assistance data in government agencies' budgets and financial accounts, as well as revenue statements from key international development agencies such as the WHO. We reported trends in DAH from China, disaggregated contributions by disbursing bilateral and multilateral agencies, and compared DAH from China with other traditional donors. We also compared these estimates with existing estimates. DAH provided by China grew dramatically, from US$323.1 million in 2007 to $652.3 million in 2017. During this period, 91.8% of DAH from China was disbursed through its bilateral agencies, including the Ministry of Commerce ($3.7 billion, 64.1%) and the National Health Commission ($917.1 million, 16.1%); the other 8.2% was disbursed through multilateral agencies including the WHO ($236.5 million, 4.1%) and the World Bank ($123.1 million, 2.2%). Relative to its level of economic development, China provided substantially more DAH than would be expected. However, relative to population size and government spending, China's contributions are modest. In the current context of plateauing in the growth rate of DAH contributions, China has the potential to contribute to future global health financing, especially financing for health system strengthening.


Barriers to improving primary care of depression: perspectives of medical group leaders.
Using clinical trials, researchers have demonstrated effective methods for treating depression in primary care, but improvements based on these trials are not being implemented. This might be because these improvements require more systematic organizational changes than can be made by individual physicians. We interviewed 82 physicians and administrative leaders of 41 medical groups to learn what is preventing those organizational changes. The identified barriers to improving care included external contextual problems (reimbursement, scarce resources, and access to/communication with specialty mental health), individual attitudes (physician and patient resistance), and internal care process barriers (organizational and condition complexity, difficulty standardizing and measuring care). Although many of these barriers are challenging, we can overcome them by setting clear priorities for change and allocating adequate resources. We must improve primary care of depression if we are to reduce its enormous adverse social and economic impacts.


Killing of intracellular Leishmania donovani by lymphokine-stimulated human mononuclear phagocytes. Evidence that interferon-gamma is the activating lymphokine.
We have found that the crude lymphokines, which prime the human monocyte-derived macrophage to generate H2O2 and exert microbicidal activity against intracellular Leishmania donovani, are rich in interferon (IFN)-gamma (600-3,000 U/ml). To determine the role of this specific lymphocyte product in macrophage activation, lymphokines were pretreated with a monoclonal antibody that neutralizes human IFN-gamma. Antibody exposure completely abolished the capacity of both mitogen- and antigen-stimulated lymphokines to either enhance macrophage H2O2 release or induce leishmanicidal activity. In addition, partially purified and pure recombinant human IFN-gamma were as effective as crude lymphokines in activating macrophages, and 3 d of treatment with 300 U/ml resulted in a seven- to eightfold increase in H2O2 generation and the intracellular killing of both L. donovani promastigotes and amastigotes. The ability of crude lymphokines to induce monocytes and macrophages from a patient with chronic granulomatous disease to kill L. donovani promastigotes was similarly abrogated by anti-IFN-gamma antibody, and could also be achieved by IFN-gamma alone. These results suggest that IFN-gamma is the key macrophage-activating molecule present within human lymphokines, and indicate that IFN-gamma can enhance both the oxygen-dependent and -independent antiprotozoal mechanisms of human mononuclear phagocytes.


Albuminuria and cardiovascular events in patients with acute coronary syndromes: Results from the TRACER trial.
Albuminuria is associated with cardiovascular (CV) outcomes. We evaluated albuminuria, alone and in combination with estimated glomerular filtration rate (eGFR), as a predictor of mortality and CV morbidity in 12,944 patients with non-ST-segment elevation acute coronary syndromes. Baseline serum creatinine and urinary dipsticks were obtained, with albuminuria stratified into no/trace albuminuria, microalbuminuria (≥30 but <300 mg/dL), or macroalbuminuria (≥300 mg/dL). Kaplan-Meier rates and proportional Cox hazards models of CV death, overall mortality, CV death or myocardial infarction (MI), and bleeding were calculated. Incidence of acute kidney injury, identified by adverse event reporting and creatinine increase (absolute ≥0.3 mg/dL or relative ≥50%), was descriptively reported. Both dipstick albuminuria and creatinine values were available in 9473 patients (73.2%). More patients with macroalbuminuria, versus no/trace albuminuria, had diabetes (66% vs 27%) or hypertension (86% vs 68%). Rates for CV death and overall mortality per strata were 3.1% and 4.8% (no/trace albuminuria); 5.8% and 9.0% (microalbuminuria); and 7.7% and 12.6% (macroalbuminuria) at 2 years of follow-up. Corresponding rates for CV death or MI were 12.2%, 16.9%, and 23.5%, respectively. Observed acute kidney injury rates were 0.6%, 1.2%, and 2.9% (n = 79), respectively. Adjusted HRs for macroalbuminuria on CV mortality were 1.65 (95% CI 1.15-2.37), and after adjustment with eGFR, 1.37 (95% CI 0.93-2.01). Corresponding HRs for overall mortality were 1.82 (95% CI 1.37-2.42) and 1.47 (95% CI 1.08-1.98). High-risk patients with non-ST-segment elevation acute coronary syndromes and albuminuria have increased morbidity and increased overall mortality independent of eGFR.


Wronger than wrong: Graded mapping of the errors of an avatar in the performance monitoring system of the onlooker.
EEG studies show that observing errors in one's own or others' actions triggers specific electro-cortical signatures in the onlooker's brain, but whether the brain error-monitoring system operates according to graded or discrete rules is still largely unknown. To explore this issue, we combined immersive virtual reality with EEG recording in participants who observed an avatar reaching-to-grasp a glass from a first-person perspective. The avatar could perform correct or erroneous actions. Erroneous grasps were defined as small or large depending on the magnitude of the trajectory deviation from the to-be-grasped glass. Results show that electro-cortical indices of error detection (indexed by ERN and mid-frontal theta oscillations), but not those of error awareness (indexed by error-Positivity), were gradually modulated by the magnitude of the observed errors. Moreover, the phase connectivity analysis revealed that enhancement of mid-frontal theta phase synchronization paralleled the magnitude of the observed error. Thus, theta oscillations represent an electro-cortical index of the degree of control exerted by mid-frontal regions whose activation depends on how much an observed action outcome results maladaptive for the onlooker. Our study provides novel neurophysiological evidence that the error monitoring system maps observed errors of different magnitude according to fine-grain, graded rather than all-or-none rules.


Comparison of alphabetical versus categorical display format for medication order entry in a simulated touch screen anesthesia information management system: an experiment in clinician-computer interaction in anesthesia.
Anesthesia information management system (AIMS) records should be designed and configured to facilitate the accurate and prompt recording of multiple drugs administered coincidentally or in rapid succession. We proposed two touch-screen display formats for use with our department's new EPIC touch-screen AIMS. In one format, medication "buttons" were arranged in alphabetical order (i.e. A-C, D-H etc.). In the other, buttons were arranged in categories (Common, Fluids, Cardiovascular, Coagulation etc.). Both formats were modeled on an iPad screen to resemble the AIMS interface. Anesthesia residents, anesthesiologists, and Certified Registered Nurse Anesthetists (n = 60) were then asked to find and touch the correct buttons for a series of medications whose names were displayed to the side of the entry screen. The number of entries made within 2 minutes was recorded. This was done 3 times for each format, with the 1st format chosen randomly. Data were analyzed from the third trials with each format to minimize differences in learning. The categorical format had a mean of 5.6 more drugs entered using the categorical method in two minutes than the alphabetical format (95% confidence interval [CI] 4.5 to 6.8, P < 0.0001). The findings were the same regardless of the order of testing (i.e. alphabetical-categorical vs. categorical - alphabetical) and participants' years of clinical experience. Most anesthesia providers made no (0) errors for most trials (N = 96/120 trials, lower 95% limit 73%, P < 0.0001). There was no difference in error rates between the two formats (P = 0.53). The use of touch-screen user interfaces in healthcare is increasingly common. Arrangement of drugs names in a categorical display format in the medication order-entry touch screen of an AIMS can result in faster data entry compared to an alphabetical arrangement of drugs. Results of this quality improvement project were used in our department's design of our final intraoperative electronic anesthesia record. This testing approach using cognitive and usability engineering methods can be used to objectively design and evaluate many aspects of the clinician-computer interaction in electronic health records.


Factors Affecting the Performance of Champion Silyl-Anchor Carbazole Dye Revealed in the Femtosecond to Second Studies of Complete ADEKA-1 Sensitized Solar Cells.
Record laboratory efficiencies of dye-sensitized solar cells have been recently reported using an alkoxysilyl-anchor dye, ADEKA-1 (over 14 %). In this work we use time-resolved techniques to study the impact of key preparation factors (dye synthesis route, addition of co-adsorbent, use of cobalt-based electrolytes of different redox potential, creation of insulating Al2 O3 layers and molecule capping passivation of the electrode) on the partial charge separation efficiencies in ADEKA-1 solar cells. We have observed that unwanted fast recombination of electrons from titania to the dye, probably associated with the orientation of the dyes on the titania surface, plays a crucial role in the performance of the cells. This recombination, taking place on the sub-ns and ns time scales, is suppressed in the optimized dye synthesis methods and upon addition of the co-adsorbent. Capping treatment significantly reduces the charge recombination between titania and electrolyte, improving the electron lifetime from tens of ms to hundreds of ms, or even to single seconds. Similar increase in electron lifetime is observed for homogenous Al2 O3 over-layers on titania nanoparticles, however, in this case the total solar cells photocurrent is decreased due to smaller electron injection yield from the dye. Our studies should be important for a broader use of very promising silyl-anchor dyes and the further optimization and development of dye-sensitized solar cells.


Exceptional Chromosomal Evolution and Cryptic Speciation of Blind Mole Rats Nannospalax leucodon (Spalacinae, Rodentia) from South-Eastern Europe.
Mole rats are exclusively subterranean and highly specialized rodents. Their long lifespans, remarkable anti-cancer mechanisms, and various distinctive adaptive features make them a useful research model. Moreover, opposing convergence of morphological traits, they have developed extremely high karyotype variability. Thus, 74 chromosomal forms have been described so far and new ones are being revealed continuously. These evolved during the process of rapid radiation and occur in different biogeographical regions. During research into their reproductive biology we have already provided substantial evidence for species-level separation of these taxa. Here, we review diverse chromosomal forms of the lesser blind mole rat, Mediterranean Nannospalax leucodon, distributed in South-eastern Europe, their karyotype records, biogeography, origin, and phylogeny from our extensive research. In the light of new data from molecular genetic studies, we question some former valuations and propose a cryptospecies rank for seven reproductively isolated chromosomal forms with sympatric and parapatric distribution and clear ecogeographical discrepances in their habitats, as well as new experimental and theoretical methods for understanding the courses of speciation of these unique fossorial mammals.


Preferences for active and aggressive intervention among patients with advanced cancer.
Intrinsic to "Patient-Centered Care" is being respectful and responsive to individual patient preferences, expressed needs, and personal values. Establishing a patient's preferences for active and aggressive intervention is imperative and foundational to the development of advance care planning. With the increasing awareness and acceptance of palliative philosophies of care, patients with advanced cancer are increasingly transitioning from active and aggressive medical management (AAMM) to conservative palliative management (CPM). A cross-sectional study based on a prospective and sequential case series of patients referred to a regional palliative medicine consultative program was assembled between May 1, 2005 and June 30, 2006. Patients and/or their substitute decision makers (SDM) completed a questionnaire, at baseline, that assessed their preferences for AAMM en route to their eventual deaths. Seven common interventions constituting AAMM were surveyed: cardiopulmonary resuscitation (CPR) & mechanical ventilation (MV), chemotherapy, antibiotics, anticoagulants, blood transfusions, feeding tubes, and artificial hydration. Multivariable analyses were conducted on the seven interventions individually as well as on the composite score that summed preferences for the seven interventions. 380 patients with advanced cancer agreed to participate in the study. A trend to desire a mostly conservative palliative approach was noted as 42% of patients desired one or fewer interventions. At baseline, most patients and their SDM's were relatively secure about decisions pertaining to the seven interventions as the rates of being "undecided" ranged from a high of 23.4% for chemotherapy to a low of 3.9% for feeding tubes. Multivariable modeling showed that more AAMM was preferred by younger patients (P < 0.0001), non-Caucasians (P = 0.042), patients with higher baseline Palliative Performance Scale scores (P = 0.0002) and where a SDM was involved in the decision process (p = 0.027). Non-statistically significant trends to prefer more AAMM was observed with male gender (p = 0.077) and higher levels of the Charlson Comorbidity index (p = 0.059). There was no association between treatment preferences and cancer class. Although the majority of patients with advanced cancer in this study expressed preferences for CPM, younger age, higher baseline PPSv2, and involvement of SDMs in the decision process were significantly associated with preferences for AAMM.


The beta subunit of human chorionic gonadotropin is encoded by multiple genes.
Two recombinant phage clones bearing sequences corresponding to the beta subunit of human chorionic gonadotropin (hCG beta) were isolated from a human genomic library. The beta sequences were mapped by blot hybridization of restriction digests of these phage DNAs and the nonoverlapping inserts were subcloned in pBR322 and sequenced. The nucleotide-sequencing data show that the hCG beta subunit is encoded by at least three nonallelic genes. Moreover, based on restriction analyses of human placental DNA, these genes may be linked in a single cluster with four other hCG beta-like genes. The sequenced genes all differ in their 5' flanking regions, and none of them is completely homologous in sequence to either of two hCG beta cDNA clones used here. In the translated region of one of these genes, three base substitutions result in two changes from the reported amino acid sequence. In the family of beta-containing glycoprotein hormones, the hCG beta subunit is unique in that it contains an extension of 29 amino acids at its COOH end. The DNA sequence corresponding to this region in the sequenced genes is part of a larger exon. These data show that the COOH-terminal extension does not result from splicing of the primary RNA transcript.


Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases.
Abnormalities of chromosome 2p23 with expression of ALK1 and p80 occur in both inflammatory myofibroblastic tumor (IMT) and anaplastic large cell lymphoma. This immunohistochemical study investigates whether the ALK family of neoplasms includes fibroblastic-myofibroblastic, myogenic, and spindle cell tumors. Formalin-fixed paraffin-embedded archival tissues from 10 IMTs and 125 other soft tissue tumors were stained for ALK1 and p80 with standard immunohistochemistry. ALK1 and/or p80 reactivity was observed in a cytoplasmic pattern in IMT (4/10; 40%), malignant peripheral nerve sheath tumor (4/10; 40%), rhabdomyosarcoma (6/31; 19%), leiomyosarcoma (1/10; 10%), and malignant fibrous histiocytoma (1/11; 9%). No staining was observed in nodular fasciitis, desmoid, infantile myofibromatosis, infantile fibrosarcoma, synovial sarcoma, leiomyoma, or myofibrosarcoma. Alveolar rhabdomyosarcomas (4/16; 25%) displayed a distinctive dot-like cytoplasmic positivity. No cases displayed nuclear reactivity. Fluorescent in situ hybridization on 12 of the positive cases revealed a combination of abnormalities including ALK break-apart signals, nucleophosmin (NPM)/ALK fusions, or extra copies of 2p23. This study demonstrates that in addition to IMT, abnormalities of ALK1 and p80 expression with a variety of structural chromosomal changes are found in several sarcomas, especially rhabdomyosarcoma and malignant peripheral nerve sheath tumor. Although immunoreactivity in non-IMTs cannot distinguish between structural abnormalities involving 2p23 or additional copies of 2p23, it supports the concept of ALK involvement in a larger group of neoplasms, some of which have other documented clonal abnormalities. In IMT, immunohistochemistry for ALK1 and p80 is useful as an indicator of a 2p23 abnormality, but it must be interpreted in the context of histologic and other clinicopathologic data if used as an adjunct to differential diagnosis.


Gestational age and chronic 'body-mind' health problems in childhood: dose-response association and risk factors.
Understanding the developmental course of all health issues associated with preterm birth is important from an individual, clinical and public health point-of-view. Both the number of preterm births and proportion of survivors have increased steadily in recent years. The UK Millennium Cohort Study (n = 18,818) was used to examine the association of gestational age with maternal ratings of general health and behavior problems at ages 5 and 11 years using binary and multinomial logistic regression analyses. The association between mothers' ratings of general health and behavior problems was relatively weak at each time point. Children rated as being in poor general health remained constant over time (4.0 % at age 5, 3.8 % at age 11), but children rated as having behavioral problems increased by almost 100 % (5.6 % at 5; 10.5 % at 11). A gradient of increasing risk with decreasing gestational age was observed for a composite health measure (general health problems and/or behavior problems) at age 5, amplified at age 11 and was strongest for those with chronic problems (poor health at both age 5 and age 11). This association was found to be compounded by child sex, maternal characteristics at birth (education, employment, marital status) and duration of breast feeding. Integrated support to at-risk families initiated during, or soon after pregnancy, may prevent chronic problems and might potentially reduce long term health costs for both the individual and health services.


Causal Mediation Analysis With Observational Data: Considerations and Illustration Examining Mechanisms Linking Neighborhood Poverty to Adolescent Substance Use.
Understanding the mediation mechanisms by which an exposure or intervention affects an outcome can provide a look into what has been called a "black box" of many epidemiologic associations, thereby providing further evidence of a relationship and possible points of intervention. Rapid methodologic developments in mediation analyses mean that there are a growing number of approaches for researchers to consider, each with its own set of assumptions, advantages, and disadvantages. This has understandably resulted in some confusion among applied researchers. Here, we provide a brief overview of the mediation methods available and discuss points for consideration when choosing a method. We provide an in-depth explication of 2 of the many potential estimators for illustrative purposes: the Baron and Kenny mediation approach, because it is the most commonly used, and a recently developed approach for estimating stochastic direct and indirect effects, because it relies on far fewer assumptions. We illustrate the decision process and analytical procedure by estimating potential school- and peer-based mechanisms linking neighborhood poverty to adolescent substance use in the National Comorbidity Survey Adolescent Supplement.


SorCS2 is required for BDNF-dependent plasticity in the hippocampus.
SorCS2 is a member of the Vps10p-domain receptor gene family receptors with critical roles in the control of neuronal viability and function. Several genetic studies have suggested SORCS2 to confer risk of bipolar disorder, schizophrenia and attention deficit-hyperactivity disorder. Here we report that hippocampal N-methyl-d-aspartate receptor-dependent synaptic plasticity is eliminated in SorCS2-deficient mice. This defect was traced to the ability of SorCS2 to form complexes with the neurotrophin receptor p75NTR, required for pro-brain-derived neurotrophic factor (BDNF) to induce long-term depression, and with the BDNF receptor tyrosine kinase TrkB to elicit long-term potentiation. Although the interaction with p75NTR was static, SorCS2 bound to TrkB in an activity-dependent manner to facilitate its translocation to postsynaptic densities for synaptic tagging and maintenance of synaptic potentiation. Neurons lacking SorCS2 failed to respond to BDNF by TrkB autophosphorylation, and activation of downstream signaling cascades, impacting neurite outgrowth and spine formation. Accordingly, Sorcs2-/- mice displayed impaired formation of long-term memory, increased risk taking and stimulus seeking behavior, enhanced susceptibility to stress and impaired prepulse inhibition. Our results identify SorCS2 as an indispensable coreceptor for p75NTR and TrkB in hippocampal neurons and suggest SORCS2 as the link between proBDNF/BDNF signaling and mental disorders.


Molecular tolerance of voltage-gated calcium channels is evident after short exposures to alcohol in vasopressin-releasing nerve terminals.
Voltage-gated calcium channels (VGCCs) in rat neurohypophysial terminals exhibit molecular tolerance to alcohol, including desensitization to the drug and increased current density, after 3 weeks of alcohol drinking. Moreover, after this time, terminals from drinking rats exhibit diminished alcohol inhibition of vasopressin (AVP) release. We took advantage of organotypic cultures (explants) of the hypothalamo-neurohypophysial system (HNS) to extend our analysis of molecular tolerance to 2 classes of the VGCC. The isolated HNS explant allows much finer temporal resolution of molecular tolerance than do voluntary drinking paradigms. After exposure of the HNS explant to alcohol, terminals are isolated by mechanical treatment and plated in a dish. Patch clamp recording techniques are used to obtain VGCC currents, and immunohistochemistry is used to determine VGCC distribution. A release assay is used to provide functional readout of AVP release. We show that even a brief, 1-hour exposure to a clinically relevant concentration of alcohol is sufficient to evoke similar changes to those observed after several weeks of exposure. Acute ethanol (EtOH) exposure inhibits high K(+) -induced AVP release from naïve terminals. However, terminals pre-exposed to 20 mM EtOH for 1 hour become tolerant to EtOH, and subsequent exposure has significantly less effect on high K(+) -induced AVP release. Electrophysiological recordings indicate that among different types of VGCCs present in the neuronal terminal, the L-type is the most affected by alcohol. The current density of L-type current is significantly increased (approximately 50%), while its responsiveness to alcohol is significantly diminished (approximately 50%), after brief alcohol exposure. Fluorescent imaging results were consistent with the electrophysiology and suggest that the increased current density of VGCCs after brief exposure is attributable to combined synthesis of 1.2 and 1.3 subtypes of the L-type VGCC and redistribution of channel protein into terminal plasma membrane. These data indicate that a brief alcohol exposure affects subsequent alcohol sensitivity of VGCCs and neuropeptide release from presynaptic terminals.


Novel identification of arsenolipids using chemical derivatizations in conjunction with RP-HPLC-ICPMS/ESMS.
The identification of molecular structures of an arsenolipid is pivotal for its toxicological assessment and in understanding the arsenic cycling in the environment. However, the analysis of these compounds in a lipid matrix is an ongoing challenge. So far, only a few arsenolipids have been reported, including arsenic fatty acids (AsFAs) and arsenic hydrocarbons (AsHCs). By means of RP-HPLC-ICPMS/ESMS, we investigated Capelin oil ( Mallotus villosus ) for possible new species of arsenolipids. Twelve arsenolipids were identified in the fish oil including three AsFAs and seven AsHCs. Among the AsHCs, four that were identified had protonotated molecular masses of 305, 331, 347, and 359 and have not been reported before. In addition, the compounds with molecular formulas C20H44AsO(+) and C24H44AsO(+) were found in low concentrations and showed chromatographic properties and MS data consistent with cationic trimethylarsenio fatty alcohols. Derivatization by acetylation and thiolation coupled with accurate mass spectrometry was successfully used to establish the occurrence of this new class of arsenolipids as cationic trimethylarsenio fatty alcohols (TMAsFOH).


Identifying patient-reported outcomes in rheumatoid arthritis: the impact of foot symptoms on self-perceived quality of life.
The importance of patient-reported outcome measures in healthcare is increasingly recognized but these need to be patient generated. Given that foot symptoms are very common in rheumatoid arthritis (RA), we chose a patient-centred model with which to investigate the patients' perspective on how their foot symptoms affected them as individuals and impacted on their self-perceived quality of life, rather than using the traditional approaches of clinical examination (e.g. prevalence of deformities) or radiological assessments. A 33-item self-administered postal questionnaire was sent to all people with RA attending outpatient clinics in three hospitals over the course of one month (n=390). The questionnaire used both quantitative and qualitative approaches to enquire about the nature and extent of foot complaints and how respondents believed this affected their quality of life. In total, 190 usable replies were received (49%). Nearly all respondents (n=177; 93.2%) reported that their quality of life was adversely affected by their foot complaint(s), with over half describing their quality of life as being badly or very badly affected. When asked to rate how severely foot complaints affected their quality of life using a 10 cm visual analogue scale, the mean score was 5.36 (range 0-10 ± SD 3), indicating that foot complaints have a moderate-to-severe effect on quality of life. Those aspects of daily living most significantly affected were: the ability to walk and the ability to wear a variety of shoes. This study demonstrated that people with RA focus on different aspects of the impact of their disease to doctors. Rather than foot deformity or ulceration, disease activity score or health assessment questionnaire score, patients were easily able to pinpoint the key negativities of living with RA in their feet and indicated choice of footwear and ability to walk as crucial. This study and similar ones are key to identifying appropriate patient-reported outcome measures.


Downregulation of genes involved in metabolism and oxidative stress in the peripheral leukocytes of Huntington's disease patients.
Huntington's disease (HD) is caused by expanded CAG repeats encoding a polyglutamine tract in the huntingtin (HTT) protein. A number of differentially-expressed protein molecules have been identified in striatum of HD animal models. Here we examined if the expression changes could be visualized in the peripheral leukocytes of HD patients and pre-symptomatic HD (PreHD) carriers. The expression levels of 17 candidate genes that differentially expressed in striatum between transgenic HD and wild-type mice in literature were measured in the peripheral leukocytes of 4 PreHD carriers, 16 HD patients and 20 healthy controls. Four genes majorly involved in metabolism and oxidative stress response, including AHCY1, ACO2, OXCT1 and CAP1, demonstrated consistent downregulation in peripheral leukocytes of both PreHD carriers and HD patients, while UCP2 was only down-regulated in HD patients. These results provide potential peripheral biomarkers to indicate disease onset in preclinical stage, and to monitor the efficacy of early treatment. Further studies of a large series of preHD carriers and symptomatic HD patients will be warranted to verify the findings and examine if these markers correlate with clinical features.


Kinetics of the radical-radical reaction, O(3P(J)) + OH(X2Pi omega) --> O2 + H, at temperatures down to 39 K.
The kinetics of the reaction between O atoms and OH radicals, both in their electronic ground state, have been investigated at temperatures down to ca. 39 K. The experiments employed a CRESU (Cinétique deRéaction en Ecoulement Supersonique Uniforme) apparatus to attain low temperatures. Both reagents were created using pulsed laser photolysis at 157.6 nm of mixtures containing H2O and O2 diluted in N2 carrier gas. OH radicals were formed by both direct photolysis of H2O and the reaction between O(1D) atoms and H2O. O(3P) atoms were formed both as a direct product of O2 photolysis and by the rapid quenching of O(1D) atoms formed in that photolysis by N2 and O2. The rates of removal of OH radicals were observed by laser-induced fluorescence, and concentrations of O atoms were estimated from a knowledge of the absorption cross-section for O2 at 157.6 nm and of the measured fluence from the F2 laser at this wavelength. To obtain a best estimate of the rate constants for the O + OH reaction, we had to correct the raw experimental data for the following: (a) the decrease in the laser fluence along the jet due to the absorption by O2 in the gas mixture, (b) the increase in temperature, and consequent decrease in gas density, as a result of energy released in the photochemical and chemical processes that occurred, and (c) the formation of OH(v = 0) as a result of relaxation, particularly by O2, of OH radicals formed in levels v > 0. Once these corrections were made, the rate constant for reaction between OH and O(3P) atoms showed little variation in the temperature range of 142 to 39 K and had a value of (3.5 +/- 1.0) x 10(-11) cm3 molecule(-1) s(-1). It is recommended that this value is used in future chemical models of dense interstellar clouds.


In vitro characterization of rat bone marrow-derived dendritic cells and their precursors.
Although the rat is commonly used for basic immunology and transplantation research, phenotypic and functional characterization of rat dendritic cells (DCs) lags behind similar studies in the human and mouse. Therefore, these features were examined using DCs propagated from cultures of rat bone marrow maintained in a medium supplemented with granulocyte-monocyte colony-stimulating factor. Analysis of cytospin preparations of cultured cells showd that DCs arise from OX7+ myelomonocytic precursors. Typical mature rat DCs were morphologically similar to their mouse and human counterparts and expressed major histocompatibility complex (MHC) class II (common part determinant of Ia), OX62 (integrin molecule), OX7 (CD90), ICAM-1 (CD54), and CTLA4 counterreceptor, but were negative for OX8 (CD8), OX19 (CD5), W3/25 (CD4), and ED2, a rat macrophage marker. Functional analysis of OX62+ sorted DCs showed that they could effectively present the soluble antigen ovalbumin to naive T cells in vitro. A combination of anti-MHC class II monoclonal antibody and CTLA4-immunoglobulin inhibited allostimulatory ability more effectively than either reagent alone. Implications for studying the role of DCs in immune responses in the rat are discussed.


Atherogenic index as a predictor of atherosclerosis in subjects with familial Mediterranean fever.
Numerous inflammatory and innate immune pathways are involved in atherogenesis. We aimed to investigate the atherogenic index and other lipid parameters in individuals with familial Mediterranean fever (FMF), as a predictor of atherosclerosis. A total of 60 patients with FMF and 60 healthy age- and sex-matched controls were included in this study. The patients with acute infection, chronic metabolic and rheumatic diseases, use of drugs other than colchicine and smoking history were excluded. CRP, ESR, total cholesterol, triglycerides, LDL-C, and HDL-C levels of patients and the control group were measured. Atherogenic index (TG/HDL-C) was calculated. We found that the atherogenic index values of the patients were significantly higher than those of the control group. HDL-C levels were lower and ESR and TG levels were higher in patients. Total cholesterol, LDL-C and CRP levels did not differ significantly between the two groups. There was no significant difference in the values of total cholesterol, LDL-C, triglycerides (TG), HDL-C, and atherogenic indexes between the groups of patients with and without M694V mutation. Elaboration of clinical models of inflammation-induced atherogenesis may further advance our knowledge of multiple inflammatory pathways implicated in atherogenesis and provide a useful tool for cardiovascular prevention. We believe that the atherogenic index also be used as a preliminary indication of accelerated atherosclerosis in FMF. However, large-scale prospective studies on this issue are needed.


Automated spectral smoothing with spatially adaptive penalized least squares.
A variety of data smoothing techniques exist to address the issue of noise in spectroscopic data. The vast majority, however, require parameter specification by a knowledgeable user, which is typically accomplished by trial and error. In most situations, optimized parameters represent a compromise between noise reduction and signal preservation. In this work, we demonstrate a nonparametric regression approach to spectral smoothing using a spatially adaptive penalized least squares (SAPLS) approach. An iterative optimization procedure is employed that permits gradual flexibility in the smooth fit when statistically significant trends based on multiscale statistics assuming white Gaussian noise are detected. With an estimate of the noise level in the spectrum the procedure is fully automatic with a specified confidence level for the statistics. Potential application to the heteroscedastic noise case is also demonstrated. Performance was assessed in simulations conducted on several synthetic spectra using traditional error measures as well as comparisons of local extrema in the resulting smoothed signals to those in the true spectra. For the simulated spectra, a best case comparison with the Savitzky-Golay smoothing via an exhaustive parameter search was performed while the SAPLS method was assessed for automated application. The application to several dissimilar experimentally obtained Raman spectra is also presented.


Digital biosensors with built-in logic for biomedical applications--biosensors based on a biocomputing concept.
This article reviews biomolecular logic systems for bioanalytical applications, specifically concentrating on the prospects and fundamental and practical challenges of designing digitally operating biosensors logically processing multiple biochemical signals. Such digitally processed information produces a final output in the form of a yes/no response through Boolean logic networks composed of biomolecular systems, and hence leads to a high-fidelity biosensing compared with traditional single (or parallel) sensing devices. It also allows direct coupling of the signal processing with chemical actuators to produce integrated "smart" "sense/act" (biosensor-bioactuator) systems. Unlike common biosensing devices based on a single input (analyte), devices based on biochemical logic systems require a fundamentally new approach for the sensor design and operation and careful attention to the interface of biocomputing systems and electronic transducers. As common in conventional biosensors, the success of the enzyme logic biosensor would depend, in part, on the immobilization of the biocomputing reagent layer. Such surface confinement provides a contact between the biocomputing layer and the transducing surface and combines efficiently the individual logic-gate elements. Particular attention should thus be given to the composition, preparation, and immobilization of the biocomputing surface layer, to the role of the system scalability, and to the efficient transduction of the output signals. By processing complex patterns of multiple physiological markers, such multisignal digital biosensors should have a profound impact upon the rapid diagnosis and treatment of diseases, and particularly upon the timely detection and alert of medical emergencies (along with immediate therapeutic intervention). Other fields ranging from biotechnology to homeland security would benefit from these advances in new biocomputing biosensors and the corresponding closed-loop "add/act" operation.


Correlation of pretransplant and early post-transplant response assessment with outcomes after reduced-intensity allogeneic hematopoietic stem cell transplantation for non-Hodgkin's lymphoma.
Chemotherapy sensitivity, defined simply as at least a partial response to chemotherapy, is an important outcome predictor for non-Hodgkin lymphoma (NHL) patients undergoing reduced-intensity allogeneic hematopoietic stem cell transplantation (allo-HCT). The authors hypothesized that further differentiation of chemotherapy sensitivity by specific response, complete remission (CR) versus partial remission (PR) versus stable disease (SD) versus progression of disease (PD), correlates with post-transplant outcomes. The impact of pretransplant and early (28 days) post-transplant disease response on transplant outcomes was analyzed in 63 NHL patients treated with reduced-intensity allo-HCT. The 3-year event-free survival (EFS) and overall survival (OS) (median potential follow-up after reduced-intensity allo-HCT = 58 months) for all patients was 37% and 47%, respectively. The 3-year EFS based on pretransplant response was: CR = 50%; PR = 66%; SD = 18%; no patient with PD pretransplant reached 3-year follow-up. The 3-year OS based on pretransplant response was: CR = 63%; PR = 69%; SD = 45%. The 3-year EFS based on post-transplant response was: CR = 57%; PR = 32%; SD = 33%; no patient with PD post-transplant reached 3-year follow-up. The 3-year OS based on post-transplant response was: CR = 65%; PR = 43%; SD = 50%. In multivariate analyses, pretransplant response was the best predictor of EFS (P < .0001). Pretransplant response (P < .0001) and age (P = .0035) were jointly associated with OS. These data suggest that NHL patients with pretransplant SD, generally considered inappropriate candidates, may benefit from reduced-intensity allo-HCT, and patients with pretransplant PD should only receive this therapy in clinical trials.


The yeast RSC chromatin-remodeling complex is required for kinetochore function in chromosome segregation.
The accurate segregation of chromosomes requires the kinetochore, a complex protein machine that assembles onto centromeric DNA to mediate attachment of replicated sister chromatids to the mitotic spindle apparatus. This study reveals an important role for the yeast RSC ATP-dependent chromatin-remodeling complex at the kinetochore in chromosome transmission. Mutations in genes encoding two core subunits of RSC, the ATPase Sth1p and the Snf5p homolog Sfh1p, interact genetically with mutations in genes encoding kinetochore proteins and with a mutation in centromeric DNA. RSC also interacts genetically and physically with the histone and histone variant components of centromeric chromatin. Importantly, RSC is localized to centromeric and centromere-proximal chromosomal regions, and its association with these loci is dependent on Sth1p. Both sth1 and sfh1 mutants exhibit altered centromeric and centromere-proximal chromatin structure and increased missegregation of authentic chromosomes. Finally, RSC is not required for centromeric deposition of the histone H3 variant Cse4p, suggesting that RSC plays a role in reconfiguring centromeric and flanking nucleosomes following Cse4p recruitment for proper chromosome transmission.


The F-box protein ACRE189/ACIF1 regulates cell death and defense responses activated during pathogen recognition in tobacco and tomato.
Virus-induced gene silencing identified the Avr9/Cf-9 RAPIDLY ELICITED gene ACRE189 as essential for the Cf-9- and Cf-4-mediated hypersensitive response (HR) in Nicotiana benthamiana. We report a role for ACRE189 in disease resistance in tomato (Solanum lycopersicum) and tobacco (Nicotiana tabacum). ACRE189 (herein renamed Avr9/Cf-9-INDUCED F-BOX1 [ACIF1]) encodes an F-box protein with a Leu-rich-repeat domain. ACIF1 is widely conserved and is closely related to F-box proteins regulating plant hormone signaling. Silencing of tobacco ACIF1 suppressed the HR triggered by various elicitors (Avr9, Avr4, AvrPto, Inf1, and the P50 helicase of Tobacco mosaic virus [TMV]). ACIF1 is recruited to SCF complexes (a class of ubiquitin E3 ligases), and the expression of ACIF1 F-box mutants in tobacco compromises the HR similarly to ACIF1 silencing. ACIF1 affects N gene-mediated responses to TMV infection, including lesion formation and salicylic acid accumulation. Loss of ACIF1 function also reduced confluent cell death induced by Pseudomonas syringae pv tabaci. ACIF1 silencing in Cf9 tomato attenuated the Cf-9-dependent HR but not Cf-9 resistance to Cladosporium fulvum. Resistance conferred by the Cf-9 homolog Cf-9B, however, was compromised in ACIF1-silenced tomato. Analysis of public expression profiling data suggests that Arabidopsis thaliana homologs of ACIF1 (VFBs) regulate defense responses via methyl jasmonate- and abscisic acid-responsive genes. Together, these findings support a role of ACIF1/VFBs in plant defense responses.


Partial rupture of a locked patch of the Sumatra megathrust during the 2007 earthquake sequence.
The great Sumatra-Andaman earthquake and tsunami of 2004 was a dramatic reminder of the importance of understanding the seismic and tsunami hazards of subduction zones. In March 2005, the Sunda megathrust ruptured again, producing an event of moment magnitude (M(w)) 8.6 south of the 2004 rupture area, which was the site of a similar event in 1861 (ref. 6). Concern was then focused on the Mentawai area, where large earthquakes had occurred in 1797 (M(w) = 8.8) and 1833 (M(w) = 9.0). Two earthquakes, one of M(w) = 8.4 and, twelve hours later, one of M(w) = 7.9, indeed occurred there on 12 September 2007. Here we show that these earthquakes ruptured only a fraction of the area ruptured in 1833 and consist of distinct asperities within a patch of the megathrust that had remained locked in the interseismic period. This indicates that the same portion of a megathrust can rupture in different patterns depending on whether asperities break as isolated seismic events or cooperate to produce a larger rupture. This variability probably arises from the influence of non-permanent barriers, zones with locally lower pre-stress due to the past earthquakes. The stress state of the portion of the Sunda megathrust that had ruptured in 1833 and 1797 was probably not adequate for the development of a single large rupture in 2007. The moment released in 2007 amounts to only a fraction both of that released in 1833 and of the deficit of moment that had accumulated as a result of interseismic strain since 1833. The potential for a large megathrust event in the Mentawai area thus remains large.


BioBanking as the central tool for translational medicine CTM issue 2013.
THE IMPACT OF MAPPING THE HUMAN PROTEOME: Globally, the health care organizations are under resource and cost constrains due to the increasing number of patients that are due to a fast increase of the 65+ age group requiring extensive medical hospitalization and treatments. Hospitals worldwide strive to seek the best cure for patients, suffering from various diseases. A consequence of these global changes, of healthy populations in relation to patients forms the basis for the build of large and centralized biobank facilities, with strategies where the search for an understanding of diseases at a molecular level is at heart. The efforts made lies within large governmental resource allocations where patient centers are collecting samples from clinical study participants in order to try to discover universal expression patterns and molecular signatures of disease and disease stages. Most developments in this area are aimed towards the discovery, and understanding diagnosis implementations. By providing the right treatment alternatives for patients care, at the right time point i.e., at a given disease stage development becomes a major goal where pharmaceutical industry, academia and the health care sector joins forces in large clinical epidemiological, population-, and disease based studies. This becomes a clear strategic link to the enhancement and prospects for personalized medicines and target directed diagnosis developments (Companion Diagnostics), which require coordinated efforts across a wide range of disciplines. Currently, companion diagnostics is at the core of the personalized medicine paradigm shift. It will identify patients who are most likely to benefit from a particular therapeutic product, as well as identify patients likely to be at increased risk for serious adverse reactions as a result of treatment with a particular therapeutic agent. It is predicted that more than half of all new drugs will require a companion diagnostic, which opens up for an endeavor for Proteomics research implementations.


Chaperonin-Based Biolayer Interferometry To Assess the Kinetic Stability of Metastable, Aggregation-Prone Proteins.
Stabilizing the folded state of metastable and/or aggregation-prone proteins through exogenous ligand binding is an appealing strategy for decreasing disease pathologies caused by protein folding defects or deleterious kinetic transitions. Current methods of examining binding of a ligand to these marginally stable native states are limited because protein aggregation typically interferes with analysis. Here, we describe a rapid method for assessing the kinetic stability of folded proteins and monitoring the effects of ligand stabilization for both intrinsically stable proteins (monomers, oligomers, and multidomain proteins) and metastable proteins (e.g., low Tm) that uses a new GroEL chaperonin-based biolayer interferometry (BLI) denaturant pulse platform. A kinetically controlled denaturation isotherm is generated by exposing a target protein, immobilized on a BLI biosensor, to increasing denaturant concentrations (urea or GuHCl) in a pulsatile manner to induce partial or complete unfolding of the attached protein population. Following the rapid removal of the denaturant, the extent of hydrophobic unfolded/partially folded species that remains is detected by an increased level of GroEL binding. Because this kinetic denaturant pulse is brief, the amplitude of binding of GroEL to the immobilized protein depends on the duration of the exposure to the denaturant, the concentration of the denaturant, wash times, and the underlying protein unfolding-refolding kinetics; fixing all other parameters and plotting the GroEL binding amplitude versus denaturant pulse concentration result in a kinetically controlled denaturation isotherm. When folding osmolytes or stabilizing ligands are added to the immobilized target proteins before and during the denaturant pulse, the diminished population of unfolded/partially folded protein manifests as a decreased level of GroEL binding and/or a marked shift in these kinetically controlled denaturation profiles to higher denaturant concentrations. This particular platform approach can be used to identify small molecules and/or solution conditions that can stabilize or destabilize thermally stable proteins, multidomain proteins, oligomeric proteins, and, most importantly, aggregation-prone metastable proteins.


Involvement of p38 in signal switching from autophagy to apoptosis via the PERK/eIF2α/ATF4 axis in selenite-treated NB4 cells.
Selenite has emerged as an optional chemotherapeutic agent for hematological malignancies. Autophagy and apoptosis are both engaged in selenite-induced cell death. In a previous report, we have identified heat shock protein 90 (Hsp90) as a critical modulator of the balance between autophagy and apoptosis in selenite-treated leukemia cells. However, the mechanisms by which selenite mediates the crosstalk between autophagy and apoptosis remain largely unknown. Herein, we demonstrate that the endoplasmic reticulum (ER) stress-related PERK/eIF2α/ATF4 pathway and p38 are core modules for the selenite-induced switch to apoptosis from autophagy. We found that selenite activated PERK and eIF2α/ATF4 downstream to promote apoptosis. During this progression, p38 was dissociated from PERK-inhibiting Hsp90 and became autophosphorylated. Then, activated p38 further enhanced the docking of activating transcription factor 4 (ATF4) onto the CHOP (CCAAT/enhancer-binding protein homologous protein) promoter via eIF2α to enhance apoptosis. We also found that activated p38 suppressed the phosphorylation of eIF4E that directed ATF4 to bind to the MAP1LC3B (microtubule-associated protein 1 light chain 3B) promoter. Because of the deactivation of eIF4E, the association of ATF4 with the MAP1LC3B promoter was inhibited, and autophagy was compromised. Intriguingly, p53 played important roles in mediating the p38-mediated regulation of eIF2α and eIF4E. When activated by p38, p53 induced the phosphorylation of eIF2α and the dephosphorylation of eIF4E, particularly in the nucleus where the ATF4 transcription factor was modulated, ultimately resulting in differential expression of CHOP and LC3. Moreover, selenite exhibited potent antitumor effects in vivo. In an NB4 cell xenograft model, selenite induced apoptosis and hampered autophagy. In addition, related signaling proteins demonstrated similar changes to those observed in vitro. These data suggest that selenite may be a candidate drug for leukemia therapy.


Calloused hands, shorter life? Occupation and older-age survival in Mexico.
Inequalities in mortality are often attributed to socioeconomic differences in education level, income, and wealth. Low socioeconomic status (SES) is generally related to worse health and survival across the life course. Yet, disadvantaged people are also more likely to hold jobs requiring heavy physical labor, repetitive movement, ergonomic strain, and safety hazards. We examine the link between primary lifetime occupation, together with education and net worth, on survival among older adults in Mexico. We use data from four waves (2001, 2003, 2012, and 2015) of the Mexican Health and Aging Study (MHAS). We estimate age-specific mortality rates for ages 50 and over using a hazards model based on a two-parameter Gompertz function. Primary lifetime occupations have a stronger association with survival for women than men. Women with higher socioeconomic status have significantly lower mortality rates than lower status women, whether SES is assessed in terms of schooling, wealth, or occupation. Occupational categories are not jointly related to survival among men, even without controls for education and wealth. There are significant survival differences by wealth among men, but no disparities in mortality by education. Consistent with recent studies of the Mexican population, we fail to find the expected gradient in the association between some measures of SES and better survival among men. Our estimates extend this anomalous pattern among Mexican men to another dimension of SES, occupation. SES differentials in mortality are substantially larger for Mexican women, highlighting an important gender disparity.


Investigation of gene dosage imbalances in patients with Noonan syndrome using multiplex ligation-dependent probe amplification analysis.
The RAS-MAPK syndromes are a group of clinically and genetically related disorders caused by dysregulation of the RAS-MAPK pathway. A member of this group of disorders, Noonan syndrome (NS), is associated with several different genes within the RAS-MAPK pathway. To date, mutations in PTPN11, SOS1, KRAS, RAF1 and SHOC2 are known to cause NS and a small group of patients harbour mutations in BRAF, MEK1 or NRAS. The majority of the mutations are predicted to cause an up-regulation of the pathway; hence they are gain-of-function mutations. Despite recent advances in gene identification in NS, the genetic aetiology is still unknown in about 1/4 of patients. To investigate the contribution of gene dosage imbalances of RAS-MAPK-related genes to the pathogenesis of NS, a multiplex ligation-dependent probe amplification (MLPA) assay was developed. Two probe sets were designed for seven RAS-MAPK-syndrome-related candidate genes: PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2. The probe sets were validated in 15 healthy control individuals and in glioma tumour cell lines. Subsequently, 44 NS patients negative for mutations in known NS-associated genes were screened using the two probe sets. The MLPA results for the patients revealed no gene dosage imbalances. In conclusion, the present results exclude copy number variation of PTPN11, SOS1, RAF1, KRAS, BRAF, MEK1 and MEK2 as a common pathogenic mechanism of NS. The validated and optimised RAS-MAPK probe sets presented here enable rapid high throughput screening of further patients with RAS-MAPK syndromes.


Skeletal muscle grafts applied to the heart. A word of caution.
Latissimus dorsi pedicle grafts (LDPGs) were wrapped around the heart in eight dogs. In four dogs, the LDPGs were stimulated chronically; the remaining four dogs served as unstimulated controls. Right-sided cardiac filling pressures were normal in all dogs when measured 4 months after graft application. Mean tension generated by the viable LDPGs was 153 +/- 49.9 g. LDPGs contracting in synchrony with the heart did not increase cardiac output. In one dog, the aortic pressure changed from 140/100 to 155/85 mm Hg during synchronous contraction of the LDPG. Three dogs were placed on cardiopulmonary bypass, and their hearts were placed in fibrillation. The LDPGs were then stimulated at a burst frequency of 85 Hz and contracted vigorously. Under these conditions, the left ventricular pressure increased by an average of 15 mm Hg with each LDPG contraction; however, the mean aortic pressure was virtually unchanged. Left ventricular and aortic pressures of 125/20 and 125/65 mm Hg, respectively, could be obtained with manual compression of the fibrillating heart. This study indicates that although LDPGs can be made to contract chronically and in synchrony with the heart, they do not necessarily augment left ventricular performance.


The risk of all-cause and cause-specific mortality in people prescribed mirtazapine: an active comparator cohort study using electronic health records.
Studies have reported an increased risk of mortality among people prescribed mirtazapine compared to other antidepressants. The study aimed to compare all-cause and cause-specific mortality between adults prescribed mirtazapine or other second-line antidepressants. This cohort study used English primary care electronic medical records, hospital admission records, and mortality data from the Clinical Practice Research Datalink (CPRD), for the period 01 January 2005 to 30 November 2018. It included people aged 18-99 years with depression first prescribed a selective serotonin reuptake inhibitor (SSRI) and then prescribed mirtazapine (5081), a different SSRI (15,032), amitriptyline (3905), or venlafaxine (1580). Follow-up was from starting to stopping the second antidepressant, with a 6-month wash-out window, censoring at the end of CPRD follow-up or 30 November 2018. Age-sex standardised rates of all-cause mortality and death due to circulatory system disease, cancer, or respiratory system disease were calculated. Survival analyses were performed, accounting for baseline characteristics using inverse probability of treatment weighting. The cohort contained 25,598 people (median age 41 years). The mirtazapine group had the highest standardised mortality rate, with an additional 7.8 (95% confidence interval (CI) 5.9-9.7) deaths/1000 person-years compared to the SSRI group. Within 2 years of follow-up, the risk of all-cause mortality was statistically significantly higher in the mirtazapine group than in the SSRI group (weighted hazard ratio (HR) 1.62, 95% CI 1.28-2.06). No significant difference was found between the mirtazapine group and the amitriptyline (HR 1.18, 95% CI 0.85-1.63) or venlafaxine (HR 1.11, 95% CI 0.60-2.05) groups. After 2 years, the risk was significantly higher in the mirtazapine group compared to the SSRI (HR 1.51, 95% CI 1.04-2.19), amitriptyline (HR 2.59, 95% CI 1.38-4.86), and venlafaxine (HR 2.35, 95% CI 1.02-5.44) groups. The risks of death due to cancer (HR 1.74, 95% CI 1.06-2.85) and respiratory system disease (HR 1.72, 95% CI 1.07-2.77) were significantly higher in the mirtazapine than in the SSRI group. Mortality was higher in people prescribed mirtazapine than people prescribed a second SSRI, possibly reflecting residual differences in other risk factors between the groups. Identifying these potential health risks when prescribing mirtazapine may help reduce the risk of mortality.


Cemented femoral fixation: the North Atlantic divide.
There is a North Atlantic divide, with cementless femoral stems being used more frequently in the USA and cemented stems being used more frequently in many countries in Europe. This is primarily because different cemented stems have been used on different sides of the Atlantic and the results of the cemented stems in the US have often been poor, whereas the results of the stems used in Europe have been good. In the National registers in Europe, cemented stems have tended to achieve better results than cementless.


Vibrio metoecus sp. nov., a close relative of Vibrio cholerae isolated from coastal brackish ponds and clinical specimens.
A Gram-staining-negative, curved-rod-shaped bacterium with close resemblance to Vibrio cholerae, the aetiological agent of cholera, was isolated over the course of several years from coastal brackish water (17 strains) and from clinical cases (two strains) in the United States. 16S rRNA gene identity with V. cholerae exceeded 98 % yet an average nucleotide identity based on genome data of around 86 % and multi locus sequence analysis of six housekeeping genes (mdh, adk, gyrB, recA, pgi and rpoB) clearly delineated these isolates as a distinct genotypic cluster within the V. cholerae-V. mimicus clade. Most standard identification techniques do not differentiate this cluster of isolates from V. cholerae. Only amplification of the ompW gene using V. cholerae-specific primers and a negative Voges-Proskauer test showed a difference between the two clusters. Additionally, all isolated strains differed phenotypically from V. cholerae in their ability to utilize N-acetyl-d-galactosamine and d-glucuronic acid as sole carbon sources. Furthermore, they were generally unable to infect the slime mould Dictyostelium discoideum, a widespread ability in V. cholerae. Based on these clear phenotypic differences that are not necessarily apparent in standard tests as well as average nucleotide identity and phylogeny of protein-coding genes, we propose the existence of a novel species, Vibrio metoecus sp. nov. with the type strain OP3H(T) ( = LMG 27764(T) = CIP 110643(T)). Due to its close resemblance to V. cholerae and the increasing number of strains isolated over the past several years, we suggest that V. metoecus sp. nov. is a relatively common species of the genus Vibrio, isolates of which have been identified as atypical isolates of V. cholerae in the past. Its isolation from clinical samples also indicates that strains of this species, like V. cholerae, are opportunistic pathogens.


Radiolabelling diverse positron emission tomography (PET) tracers using a single digital microfluidic reactor chip.
Radiotracer synthesis is an ideal application for microfluidics because only nanogram quantities are needed for positron emission tomography (PET) imaging. Thousands of radiotracers have been developed in research settings but only a few are readily available, severely limiting the biological problems that can be studied in vivo via PET. We report the development of an electrowetting-on-dielectric (EWOD) digital microfluidic chip that can synthesize a variety of (18)F-labeled tracers targeting a range of biological processes by confirming complete syntheses of four radiotracers: a sugar, a DNA nucleoside, a protein labelling compound, and a neurotransmitter. The chip employs concentric multifunctional electrodes that are used for heating, temperature sensing, and EWOD actuation. All of the key synthesis steps for each of the four (18)F-labeled tracers are demonstrated and characterized with the chip: concentration of fluoride ion, solvent exchange, and chemical reactions. The obtained fluorination efficiencies of 90-95% are comparable to, or greater than, those achieved by conventional approaches.


Superconducting vortices in CeCoIn5: toward the Pauli-limiting field.
Many superconducting materials allow the penetration of magnetic fields in a mixed state in which the superfluid is threaded by a regular lattice of Abrikosov vortices, each carrying one quantum of magnetic flux. The phenomenological Ginzburg-Landau theory, based on the concept of characteristic length scales, has generally provided a good description of the Abrikosov vortex lattice state. We conducted neutron-scattering measurements of the vortex lattice form factor in the heavy-fermion superconductor cerium-cobalt-indium (CeCoIn5) and found that this form factor increases with increasing field-opposite to the expectations within the Abrikosov-Ginzburg-Landau paradigm. We propose that the anomalous field dependence of the form factor arises from Pauli paramagnetic effects around the vortex cores and from the proximity of the superconducting state to a quantum critical point.


Diarrhoea morbidity and mortality in older children, adolescents, and adults.
Diarrhoea is a leading cause of morbidity and mortality yet diarrhoea specific incidence and mortality rates for older children, adolescents, and adults have not been systematically calculated for many countries. We conducted a systematic literature review to generate regional incidence rates by age and to summarize diarrhoea specific mortality rates for regions of the world with inadequate vital registration data. Diarrhoea morbidity rates range from 29.9 episodes/100 person-years for adults in the South East Asian region to 88.4 episodes/100 person-years in older children in the Eastern Mediterranean region and have remained unchanged in the last 30 years. Diarrhoea mortality rates decline as the child ages and remain relatively constant during adulthood. These data are critical for improving estimates worldwide and further highlight the need for improved diarrhoea specific morbidity and mortality data in these age groups.


Childhood origins of adult health: a basis for life-course health policy.
Many common chronic and mental disorders have modifiable precursors that arise during childhood. The life-course model of how health is produced provides a scientific basis for understanding the continuity between child and adult health. Life-course health policy seeks to promote the well-being of the young, both because of its intrinsic value and because doing so will improve the health of the population at all ages. It mandates increased attention to the promotion of biopsychosocial adaptability and other approaches to preventing the precursors to future disorders. Finally, it requires health policies to foster positive long-term outcomes focused on the individual, family, and community.


Accuracy of a Novel Histoplasmosis Enzyme Immunoassay to Evaluate Suspicious Lung Nodules.
Granulomas caused by infectious lung diseases present as indeterminate pulmonary nodules (IPNs) on radiography. Newly available serum enzyme immunoassay (EIA) for histoplasmosis has not been studied for the evaluation of IPNs. We investigated serum biomarkers of histoplasmosis antibodies as an indication of benign disease in IPNs from a highly endemic region. A total of 152 serum samples from patients presenting with pulmonary nodules ≤30 mm in maximum diameter were analyzed for histoplasmosis antibodies by immunodiffusion and EIA IgG and IgM tests. Serology and FDG-PET/CT scan diagnostic test characteristics were estimated and compared. Cancer prevalence was 55% (n = 83). Thirty-nine (26%) individuals were positive for IgG histoplasmosis antibodies. Twelve samples were IgM antibody positive. Immunodiffusion serology was similar to IgM antibody results with 13 positive tests. Diagnostic likelihood ratios for benign disease were 0.62, 0.33, and 0.28 for FDG-PET/CT, IgG, and IgM antibodies, respectively. When both IgG and IgM were positive (n = 8), no nodules were cancerous and six were FDG-PET/CT avid. A positive EIA test for both IgM and IgG strongly suggested histoplasmosis etiology and benign granuloma for 12% of benign nodules arising from a highly endemic region. Presence of either IgG or IgM histoplasma antibodies was associated with benign disease. The EIA test was more sensitive in assessing histoplasma exposure than immunodiffusion serology. A new CLIA-certified histoplasmosis antibody EIA test measures histoplasmosis exposure, offers a possible alternative clinical diagnosis for benign IPNs, and may improve IPN evaluation while avoiding harmful invasive biopsies.


Selenium for preventing cancer.
This review is the third update of the Cochrane review "Selenium for preventing cancer". Selenium is a naturally occurring element with both nutritional and toxicological properties. Higher selenium exposure and selenium supplements have been suggested to protect against several types of cancer. To gather and present evidence needed to address two research questions:1. What is the aetiological relationship between selenium exposure and cancer risk in humans?2. Describe the efficacy of selenium supplementation for cancer prevention in humans. We updated electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 2), MEDLINE (Ovid, 2013 to January 2017, week 4), and Embase (2013 to 2017, week 6), as well as searches of clinical trial registries. We included randomised controlled trials (RCTs) and longitudinal observational studies that enrolled adult participants. We performed random-effects (RE) meta-analyses when two or more RCTs were available for a specific outcome. We conducted RE meta-analyses when five or more observational studies were available for a specific outcome. We assessed risk of bias in RCTs and in observational studies using Cochrane's risk assessment tool and the Newcastle-Ottawa Scale, respectively. We considered in the primary analysis data pooled from RCTs with low risk of bias. We assessed the certainty of evidence by using the GRADE approach. We included 83 studies in this updated review: two additional RCTs (10 in total) and a few additional trial reports for previously included studies. RCTs involved 27,232 participants allocated to either selenium supplements or placebo. For analyses of RCTs with low risk of bias, the summary risk ratio (RR) for any cancer incidence was 1.01 (95% confidence interval (CI) 0.93 to 1.10; 3 studies, 19,475 participants; high-certainty evidence). The RR for estimated cancer mortality was 1.02 (95% CI 0.80 to 1.30; 1 study, 17,444 participants). For the most frequently investigated site-specific cancers, investigators provided little evidence of any effect of selenium supplementation. Two RCTs with 19,009 participants indicated that colorectal cancer was unaffected by selenium administration (RR 0.99, 95% CI 0.69 to 1.43), as were non-melanoma skin cancer (RR 1.16, 95% CI 0.30 to 4.42; 2 studies, 2027 participants), lung cancer (RR 1.16, 95% CI 0.89 to 1.50; 2 studies, 19,009 participants), breast cancer (RR 2.04, 95% CI 0.44 to 9.55; 1 study, 802 participants), bladder cancer (RR 1.07, 95% CI 0.76 to 1.52; 2 studies, 19,009 participants), and prostate cancer (RR 1.01, 95% CI 0.90 to 1.14; 4 studies, 18,942 participants). Certainty of the evidence was high for all of these cancer sites, except for breast cancer, which was of moderate certainty owing to imprecision, and non-melanoma skin cancer, which we judged as moderate certainty owing to high heterogeneity. RCTs with low risk of bias suggested increased melanoma risk.Results for most outcomes were similar when we included all RCTs in the meta-analysis, regardless of risk of bias. Selenium supplementation did not reduce overall cancer incidence (RR 0.99, 95% CI 0.86 to 1.14; 5 studies, 21,860 participants) nor mortality (RR 0.81, 95% CI 0.49 to 1.32; 2 studies, 18,698 participants). Summary RRs for site-specific cancers showed limited changes compared with estimates from high-quality studies alone, except for liver cancer, for which results were reversed.In the largest trial, the Selenium and Vitamin E Cancer Trial, selenium supplementation increased risks of alopecia and dermatitis, and for participants with highest background selenium status, supplementation also increased risk of high-grade prostate cancer. RCTs showed a slightly increased risk of type 2 diabetes associated with supplementation. A hypothesis generated by the Nutritional Prevention of Cancer Trial - that individuals with low blood selenium levels could reduce their risk of cancer (particularly prostate cancer) by increasing selenium intake - has not been confirmed. As RCT participants have been overwhelmingly male (88%), we could not assess the potential influence of sex or gender.We included 15 additional observational cohort studies (70 in total; over 2,360,000 participants). We found that lower cancer incidence (summary odds ratio (OR) 0.72, 95% CI 0.55 to 0.93; 7 studies, 76,239 participants) and lower cancer mortality (OR 0.76, 95% CI 0.59 to 0.97; 7 studies, 183,863 participants) were associated with the highest category of selenium exposure compared with the lowest. Cancer incidence was lower in men (OR 0.72, 95% CI 0.46 to 1.14, 4 studies, 29,365 men) than in women (OR 0.90, 95% CI 0.45 to 1.77, 2 studies, 18,244 women). Data show a decrease in risk of site-specific cancers for stomach, colorectal, lung, breast, bladder, and prostate cancers. However, these studies have major weaknesses due to study design, exposure misclassification, and potential unmeasured confounding due to lifestyle or nutritional factors covarying with selenium exposure beyond those taken into account in multi-variable analyses. In addition, no evidence of a dose-response relation between selenium status and cancer risk emerged. Certainty of evidence was very low for each outcome. Some studies suggested that genetic factors might modify the relation between selenium and cancer risk - an issue that merits further investigation. Well-designed and well-conducted RCTs have shown no beneficial effect of selenium supplements in reducing cancer risk (high certainty of evidence). Some RCTs have raised concerns by reporting a higher incidence of high-grade prostate cancer and type 2 diabetes in participants with selenium supplementation. No clear evidence of an influence of baseline participant selenium status on outcomes has emerged in these studies.Observational longitudinal studies have shown an inverse association between selenium exposure and risk of some cancer types, but null and direct relations have also been reported, and no systematic pattern suggesting dose-response relations has emerged. These studies suffer from limitations inherent to the observational design, including exposure misclassification and unmeasured confounding.Overall, there is no evidence to suggest that increasing selenium intake through diet or supplementation prevents cancer in humans. However, more research is needed to assess whether selenium may modify the risk of cancer in individuals with a specific genetic background or nutritional status, and to investigate possible differential effects of various forms of selenium.


PCR-mediated gene replacement in Escherichia coli.
The hyper-recombinogenic properties of an E. coli strain in which the recBCD genes have been replaced by lambda red recombination functions were exploited in the development of a general PCR-mediated gene replacement scheme for Escherichia coli. Linear DNA substrates generated by recombinant PCR are introduced by electroporation into strains containing the recBCDDelta::red substitution. This technique allows for gene replacement in E. coli without prior cloning of the gene of interest. In addition, the counter-selectable marker sacB has been used to construct unmarked precise gene deletions without the need to form sacB-containing plasmid integrates. In other experiments, electroporation of recBCDDelta::red strains with high concentrations of linear DNA fragments (derived from plasmid digests) gave linear transformation rates approaching 1% of the survivors of electroporation. The placement of lambda red and gam at a locus in the chromosome other than recBCD (galK) resulted in a strain that was as hyper-rec as one containing the lambda red for recBCD substitution. The gene replacement technique described here has been used for the construction of deletion-substitution alleles of lacZ and sulA, as well as six genes important for general homologous recombination in E. coli. Three of these replacements were performed without prior cloning of the genes.


Regulation of leading edge microtubule and actin dynamics downstream of Rac1.
Actin in migrating cells is regulated by Rho GTPases. However, Rho proteins might also affect microtubules (MTs). Here, we used time-lapse microscopy of PtK1 cells to examine MT regulation downstream of Rac1. In these cells, "pioneer" MTs growing into leading-edge protrusions exhibited a decreased catastrophe frequency and an increased time in growth as compared with MTs further from the leading edge. Constitutively active Rac1(Q61L) promoted pioneer behavior in most MTs, whereas dominant-negative Rac1(T17N) eliminated pioneer MTs, indicating that Rac1 is a regulator of MT dynamics in vivo. Rac1(Q61L) also enhanced MT turnover through stimulation of MT retrograde flow and breakage. Inhibition of p21-activated kinases (Paks), downstream effectors of Rac1, inhibited Rac1(Q61L)-induced MT growth and retrograde flow. In addition, Rac1(Q61L) promoted lamellipodial actin polymerization and Pak-dependent retrograde flow. Together, these results indicate coordinated regulation of the two cytoskeletal systems in the leading edge of migrating cells.


Speckle-contrast monitoring of tissue thermal modification.
Measurements of the contrast value of time-averaged speckle-modulated images of cartilage tissue are used to study tissue thermal modification in the case of laser-light treatment. This modification is related to thermally induced internal stress relaxation in the matrix of the treated tissue. The specific feature of the evolution of time-averaged speckle contrast with a change in the current temperature of modified collagen tissue is the typical looplike form of the contrast-temperature dependencies associated with irreversible changes in tissue structure and correlated with changes in the tissue diffuse transmittance and the tissue internal stress mentioned by other researchers.


Management and monitoring recommendations for the use of eliglustat in adults with type 1 Gaucher disease in Europe.
In Gaucher disease, diminished activity of the lysosomal enzyme, acid β-glucosidase, leads to accumulation of glucosylceramides and related substrates, primarily in the spleen, liver, and bone marrow. Eliglustat is an oral substrate reduction therapy approved in the European Union and the United States as a first-line treatment for adults with type 1 Gaucher disease who have compatible CYP2D6 metabolism phenotypes. A European Advisory Council of experts in Gaucher disease describes the characteristics of eliglustat that are distinct from enzyme augmentation therapy (the standard of care) and miglustat (the other approved substrate reduction therapy) and recommends investigations and monitoring for patients on eliglustat therapy within the context of current recommendations for Gaucher disease management. Eliglustat is a selective, potent inhibitor of glucosylceramide synthase, the enzyme responsible for biosynthesis of glucosylceramides which accumulate in Gaucher disease. Extensive metabolism of eliglustat by CYP2D6, and, to a lesser extent, CYP3A of the cytochrome P450 pathway, necessitates careful consideration of the patient's CYP2D6 metaboliser status and use of concomitant medications which share metabolism by these pathways. Guidance on specific assessments and monitoring required for eliglustat therapy, including an algorithm to determine eligibility for eliglustat, are provided. As a first-line therapy for type 1 Gaucher disease, eliglustat offers eligible patients a daily oral therapy alternative to biweekly infusions of enzyme therapy. Physicians will need to carefully assess individual Gaucher patients to determine their appropriateness for eliglustat therapy. The therapeutic response to eliglustat and use of concomitant medications will require long-term monitoring.


Clamping techniques and protecting strategies in liver surgery.
The use of vascular occlusion during liver resection is still a matter of debate. The aim of this review was to assess the advantages and disadvantages of portal triad occlusion as a protective strategy during elective liver resection and liver transplantation. Newer strategies such as pharmacological preconditioning are also discussed. A systematic literature search was conducted to detect randomized controlled trials assessing the effectiveness and safety of portal triad clamping, ischaemic preconditioning and pharmacological preconditioning during liver surgery. Vascular clamping cannot be systematically recommended. When used, portal triad clamping is associated with a tendency towards reduced blood loss and blood transfusion without having an impact on morbidity. Intermittent clamping appears to be better tolerated than continuous clamping, especially in patients with chronic liver disease. Ischaemic preconditioning before continuous portal triad clamping reduces reperfusion injury after warm ischaemia, particularly in steatotic patients. Ischaemic preconditioning has unclear effects in transplantation and there is currently no evidence to support or refute the use of ischaemic preconditioning in the donor. There are emerging alternative conditioning strategies, including the use of volatile anaesthetics, which may provide new and easily applicable therapeutic options to protect the liver.


Mechanism of water oxidation by non-heme iron catalysts when driven with sodium periodate.
Iron tris(2-methylpyridyl)amine (TPA) and iron 1-(bis(2-methylpyridyl)amino)-2-methyl-2-propanoate (BPyA) salts are characterized as water oxidation catalysts (WOCs) using sodium periodate. Under the conditions used, these complexes serve as homogeneous WOCs as demonstrated via kinetic analysis and dynamic light scattering (DLS). The Fe(BPyA) salt serves as both a mononuclear and dinuclear catalyst, with the mononuclear form showing higher catalytic activity. Based on the H/D kinetic isotope effect and pH dependence, the rate determining step (RDS) in water oxidation (WO) by Fe(BPyA) is nucleophilic attack by water during O-O bond formation. In contrast, Fe(TPA) shows complex kinetic behavior due to the formation of multiple oxidation states of the complex in solution, each of which exhibits catalytic activity for WO. The RDS in WO by Fe(TPA) follows an equilibrium established between monomeric and dimeric forms of the catalyst. Under acidic conditions formation of the monomer is favored, which leads to an increase in the WO rate.


The Effect of Incorrect Foot Placement on the Accuracy of Radiographic Measurements of the Hallux Valgus and Inter-Metatarsal Angles for Treating Hallux Valgus.
PURPOSE OF THE STUDY Accurate radiographic measurements are crucial in treating hallux valgus (HV). This three-dimensional deformity should not be evaluated from one joint on one plane. However, in practice, surgeons measure the deformity only on transverse dorsoplantar radiographs. We determined the amount of error associated with positioning the foot incorrectly on radiographs. MATERIAL AND METHODS To simulate incorrect positions of the foot in radiographic evaluation, we designed an angled device that can move in transverse and frontal plane. In four patients with symptomatic HV, we took weight-bearing radiographs of the involved foot in seven different positions. These 28 radiographs were given identifying but meaningless labels. On each radiograph, six surgeons blinded to the position of the radiograph measured the HV angle (HVA) and the inter-metatarsal angle (IMA) and state the treatment plan according to five treatment options were given to participants. RESULTS Inter-observer agreement was high for measurements of HVA and IMA in all positions (interclass correlation coefficients, 0.96 and 0.88, respectively). However, intra-observer agreement was poor for HVA (intra-observer agreement, 0.17) but good for IMA (intra-observer agreement, 0.64). According to the measurements in different positions, intra-observer treatment choices revealed moderate results (ICC: 0.524). Clinical Relevance Radiographic measurements are very important on the treatment decisions of hallux valgus. The foot position can influence the measurement accuracy and can cause incorrect decisions. In this study, we evaluated the impact of foot positions on measurements of hallux valgus angle and inter-metatarsal angle. Additionally, we evaluated the incorrect foot positioning on treatment decisions. Moreover, we analyzed intra-observer and inter-observer agreements of these angles in various positions. CONCLUSIONS We recommend that measurements of IMA are more reliable than those of HVA for managing hallux valgus in terms of false weight bearing radiographs taken in different positions. Positional changes during foot radiographs could lead clinicians to perform incorrect HVA and IMA measurements. This could change the treatment option. HVA measurements were more affected with foot positioning. It is important to take full weight bearing foot radiographs in correct technique. Key words: hallux valgus, radiology, data accuracy.


A health care chaplain's pastoral response to moral distress.
This article offers health care chaplains a pastoral response to moral distress experienced by health care professionals. The article offers a broad definition, explores its impact on health care professionals, and looks at various interventions to ameliorate its effects. The article goes on to clarify the concept of moral distress by differentiating it from the experience of moral dilemmas, and looking closer at the aspects of initial and reactive distress. After defining moral distress, the article explores two clinical models that create a better context to understand the phenomenon. Finally, the article proposes a pastoral response to moral distress from the integration of the five functions of pastoral care: "healing," "sustaining," "guiding," "reconciling," and "nurturing" based on the work of William Clebsch, Charles Jaekle, and Howard Clinebell. The author then applies the pastoral response to moral distress by illustrating the outcome of a scenario with a critical care nurse.


The Otago Exercise Program performed as group training versus home training in fall-prone older people: a randomized controlled Trial.
Exercise programs targeting muscle strength and balance can reduce falls. The study aimed to compare the Otago Exercise Program (OEP), originally designed as supervised home training (HT), with the same programme performed as GT, on functional balance and muscle strength, mobility, fall efficacy and self-reported health. A single-blind randomized controlled trial with assessments at baseline (T1), following the 12-week intervention (T2), and 3 months following intervention (T3), was performed. 125 people, mean age 82.5 (SD = 5.7) years, 73% women, referred to a Falls Outpatient Clinic, participated. 74% had fallen, and 37% had a fall-related hospital stay during the previous year. OEP supervised by physiotherapists was performed as GT twice weekly or as HT three times a week, for 12 weeks. Total exercise time was comparable between groups. The primary outcome was the Berg Balance Scale assessed at T2. From T1-T2, Berg Balance Scale improved significantly more in the GT group than in the HT group (mean group difference in change of 3.2 points, 95%CI = 0.7-5.8, p = 0.014). Of the secondary outcomes, the 30-second sit-to-stand test (p = 0.004), and physical health measured by the Short Form-36 (p = 0.004), improved significantly more for the GT group. Change in mobility measured by the Timed Up and Go test, mental health by the Short Form-36, and fall efficacy by the Fall Efficacy Scale International did not differ between groups. The 30-second sit-to-stand test and the Timed Up and Go, but not the Berg Balance Scale, was still better in the GT group at T3. In fall-prone home-dwelling older people, the OEP performed as GT is more effective for improving functional balance, muscle strength and physical health, but not fall efficacy and mental health than when performed as HT. The OEP provided as GT should be considered in this population.


Pragmatic Language Skills: A Comparison of Children With Cochlear Implants and Children Without Hearing Loss.
Pragmatic language ability refers to the ability to use language in a social context. It has been found to be correlated with success in general education for deaf and hard of hearing children. It is therefore of great importance to study why deaf and hard of hearing children often perform more poorly than their hearing peers on tests measuring pragmatic language ability. In the current study the Pragmatics Profile questionnaire from the CELF-IV battery was used to measure pragmatic language ability in children using cochlear implants (N = 14) and children without a hearing loss (N = 34). No significant difference was found between the children with cochlear implants (CI) and the children without hearing loss (HL) for the sum score of the pragmatics language measure. However, 35.71% of the children with CI performed below age norm, while only 5.89% of the children without HL performed below age norm. In addition, when dividing the sum score into three sub-measures: Rituals and Conversational skills (RCS), Asking for, Giving, and Responding to Information (AGRI), and Nonverbal Communication skills (NCS), significant differences between the groups were found for the NCS measure and a tendency for a difference was found for the RCS measure. In addition, all three sub-measures (NCS, AGRI, RCS) were correlated to verbal fluency in the children with CI, but not the children without HL.


A Phase II Study of Biweekly Cisplatin, Fixed-Dose-Rate Gemcitabine and Infusional 5-Fluorouracil in Patients With Metastatic Pancreatic and Biliary Cancers.
Combinations of gemcitabine, 5-fluorouracil (5-FU), and platinum have demonstrated improved outcomes compared with singlet chemotherapy in pancreatic and biliary cancers. This phase II study examined efficacy and safety of a novel schedule of cisplatin, fixed-dose-rate gemcitabine and infusional 5-FU. Patients with metastatic adenocarcinoma of the pancreas or biliary tract, previously untreated or having received 1 cytotoxic regimen for advanced disease, were treated with gemcitabine 1000 mg/m intravenously (IV) over 100 minutes, cisplatin 35 mg/m IV over 30 minutes, and 5-FU 2400 mg/m IV over 48 hours on day 1 of a 14-day cycle. Patients were treated until disease progression or for 12 cycles. After 12 cycles, patients with stable or responding disease could continue gemcitabine and 5-FU. The primary endpoint was objective response. Thirty-nine patients were treated: 8 with biliary cancer (all untreated) and 31 with pancreatic cancer (17 untreated, 14 previously treated). Best response in 25 untreated patients was partial response in 40%, stable disease in 40%, and progressive disease in 20%. In 14 previously treated pancreatic patients, best response was partial response in 7%, stable disease in 50%, and progressive disease in 43%. Median overall survival in untreated patients was 10.3 versus 4.9 months in previously treated patients. Adverse events were primarily uncomplicated hematologic toxicity, ≥grade 3 neutropenia (54%), anemia (21%), and thrombocytopenia (13%). Biweekly cisplatin, fixed-dose-rate gemcitabine, and infusional 5-FU demonstrated a high response rate and were well tolerated, encouraging further investigation of this regimen in metastatic pancreatic and biliary cancers.


Factors Affecting Sentinel Node Metastasis in Thin (T1) Cutaneous Melanomas: Development and External Validation of a Predictive Nomogram.
Thin melanomas (T1; ≤ 1 mm) constitute 70% of newly diagnosed cutaneous melanomas. Regional node metastasis determined by sentinel node biopsy (SNB) is an important prognostic factor for T1 melanoma. However, current melanoma guidelines do not provide clear indications on when to perform SNB in T1 disease and stress an individualized approach to SNB that considers all clinicopathologic risk factors. We aimed to identify determinants of sentinel node (SN) status for incorporation into an externally validated nomogram to better select patients with T1 disease for SNB. The development cohort comprised 3,666 patients with T1 disease consecutively treated at the Istituto Nazionale Tumori (Milan, Italy) between 2001 and 2018; 4,227 patients with T1 disease treated at 13 other European centers over the same period formed the validation cohort. A random forest procedure was applied to the development data set to select characteristics associated with SN status for inclusion in a multiple binary logistic model from which a nomogram was elaborated. Decision curve analyses assessed the clinical utility of the nomogram. Of patients in the development cohort, 1,635 underwent SNB; 108 patients (6.6%) were SN positive. By univariable analysis, age, growth phase, Breslow thickness, ulceration, mitotic rate, regression, and lymphovascular invasion were significantly associated with SN status. The random forest procedure selected 6 variables (not growth phase) for inclusion in the logistic model and nomogram. The nomogram proved well calibrated and had good discriminative ability in both cohorts. Decision curve analyses revealed the superior net benefit of the nomogram compared with each individual variable included in it as well as with variables suggested by current guidelines. We propose the nomogram as a decision aid in all patients with T1 melanoma being considered for SNB.


Discovery of Lorentz-violating type II Weyl fermions in LaAlGe.
In quantum field theory, Weyl fermions are relativistic particles that travel at the speed of light and strictly obey the celebrated Lorentz symmetry. Their low-energy condensed matter analogs are Weyl semimetals, which are conductors whose electronic excitations mimic the Weyl fermion equation of motion. Although the traditional (type I) emergent Weyl fermions observed in TaAs still approximately respect Lorentz symmetry, recently, the so-called type II Weyl semimetal has been proposed, where the emergent Weyl quasiparticles break the Lorentz symmetry so strongly that they cannot be smoothly connected to Lorentz symmetric Weyl particles. Despite some evidence of nontrivial surface states, the direct observation of the type II bulk Weyl fermions remains elusive. We present the direct observation of the type II Weyl fermions in crystalline solid lanthanum aluminum germanide (LaAlGe) based on our photoemission data alone, without reliance on band structure calculations. Moreover, our systematic data agree with the theoretical calculations, providing further support on our experimental results.


The diphtheria toxin channel-forming T domain translocates its own NH2-terminal region across planar bilayers.
The T domain of diphtheria toxin, which extends from residue 202 to 378, causes the translocation of the catalytic A fragment (residues 1-201) across endosomal membranes and also forms ion-conducting channels in planar phospholipid bilayers. The carboxy terminal 57-amino acid segment (322-378) in the T domain is all that is required to form these channels, but its ability to do so is greatly augmented by the portion of the T domain upstream from this. In this work, we show that in association with channel formation by the T domain, its NH2 terminus, as well as some or all of the adjacent hydrophilic 63 amino acid segment, cross the lipid bilayer. The phenomenon that enabled us to demonstrate that the NH2-terminal region of the T domain was translocated across the membrane was the rapid closure of channels at cis negative voltages when the T domain contained a histidine tag at its NH2 terminus. The inhibition of this effect by trans nickel, and by trans streptavidin when the histidine tag sequence was biotinylated, clearly established that the histidine tag was present on the trans side of the membrane. Furthermore, the inhibition of rapid channel closure by trans trypsin, combined with mutagenesis to localize the trypsin site, indicated that some portion of the 63 amino acid NH2-terminal segment of the T domain was also translocated to the trans side of the membrane. If the NH2 terminus was forced to remain on the cis side, by streptavidin binding to the biotinylated histidine tag sequence, channel formation was severely disrupted. Thus, normal channel formation by the T domain requires that its NH2 terminus be translocated across the membrane from the cis to the trans side, even though the NH2 terminus is >100 residues removed from the channel-forming part of the molecule.


Complement factor H Y402H polymorphism is not associated with late-onset Alzheimer's disease.
There is evidence to suggest a role for immune dysfunction in the pathogenesis of Alzheimer's disease, and it has previously been shown that blood plasma levels of the protein complement factor H, a member of the alternative complement pathway, was specifically elevated in people with late-onset Alzheimer's disease. We have genotyped the common complement factor H Y402H polymorphism in a large case-control cohort to investigate association with late-onset Alzheimer's disease susceptibility and find no evidence that this SNP is associated with disease risk. However, it remains possible that another variant in this gene may modify susceptibility for late-onset Alzheimer's disease.