Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer.
Standard first-line therapy for metastatic, squamous non-small-cell lung cancer (NSCLC) is platinum-based chemotherapy or pembrolizumab (for patients with programmed death ligand 1 [PD-L1] expression on ≥50% of tumor cells). More recently, pembrolizumab plus chemotherapy was shown to significantly prolong overall survival among patients with nonsquamous NSCLC. In this double-blind, phase 3 trial, we randomly assigned, in a 1:1 ratio, 559 patients with untreated metastatic, squamous NSCLC to receive 200 mg of pembrolizumab or saline placebo for up to 35 cycles; all the patients also received carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel for the first 4 cycles. Primary end points were overall survival and progression-free survival. After a median follow-up of 7.8 months, the median overall survival was 15.9 months (95% confidence interval [CI], 13.2 to not reached) in the pembrolizumab-combination group and 11.3 months (95% CI, 9.5 to 14.8) in the placebo-combination group (hazard ratio for death, 0.64; 95% CI, 0.49 to 0.85; P<0.001). The overall survival benefit was consistent regardless of the level of PD-L1 expression. The median progression-free survival was 6.4 months (95% CI, 6.2 to 8.3) in the pembrolizumab-combination group and 4.8 months (95% CI, 4.3 to 5.7) in the placebo-combination group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.45 to 0.70; P<0.001). Adverse events of grade 3 or higher occurred in 69.8% of the patients in the pembrolizumab-combination group and in 68.2% of the patients in the placebo-combination group. Discontinuation of treatment because of adverse events was more frequent in the pembrolizumab-combination group than in the placebo-combination group (13.3% vs. 6.4%). In patients with previously untreated metastatic, squamous NSCLC, the addition of pembrolizumab to chemotherapy with carboplatin plus paclitaxel or nab-paclitaxel resulted in significantly longer overall survival and progression-free survival than chemotherapy alone. (Funded by Merck Sharp & Dohme; KEYNOTE-407 ClinicalTrials.gov number, NCT02775435 .).


A STUDY OF THE SPINAL CORD BY NISSL'S METHOD IN TYPHOID FEVER AND IN EXPERIMENTAL INFECTION WITH THE TYPHOID BACILLUS.
(1) The application of the Nissl method to the study of the motor cells of the spinal cord, and the nerve cells of the dorsal root ganglia in typhoid fever, shows that these cells regularly suffer pathological changes in the course of the infection. (2) The alterations in the motor cells are more constant and of a severer grade than are those in the cells of the sensory ganglia. The more characteristic changes consist of disintegration, solution and destruction of the chromatic substance of the cell starting from the axone hillock and proceeding toward the nucleus. Coincidently the nuclei of the affected cells seek the periphery. Alterations are also suffered by the nucleus and nucleolus. (3) While this central form of ehromatolysis is the prevailing type of pathological change, disintegration, etc., of the Nissl bodies situated in the periphery of the cell and in the dendrites is also observed (peripheral chromatolysis). (4) In experimental infection with typhoid bacilli in rabbits a similar series of lesions in the corresponding nerve cells in the spinal cord and ganglia is encountered. (5) The main or central type of lesions discovered is identical with that found in man and animals after section, destruction, or even slight injury of the peripheral nerves. (6) The examination of the peripheral nerves arising from the lumbar segment of the cord (the site in man and rabbit of the most profound changes) in rabbits inoculated with typhoid bacilli showed well-marked evidences of parenchymatous degeneration. (7> It is probable that lesions of the peripheral nerves in typhoid fever in human beings are common and that the post-typhoid hyper sthesias and paralyses are due to this cause. (8) Restitution of the chromatic granules may take place in the affected nerve cells, the new formation beginning about the nucleus and extending through the protoplasm.


Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck.
Patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after platinum chemotherapy have a very poor prognosis and limited therapeutic options. Nivolumab, an anti-programmed death 1 (PD-1) monoclonal antibody, was assessed as treatment for this condition. In this randomized, open-label, phase 3 trial, we assigned, in a 2:1 ratio, 361 patients with recurrent squamous-cell carcinoma of the head and neck whose disease had progressed within 6 months after platinum-based chemotherapy to receive nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks or standard, single-agent systemic therapy (methotrexate, docetaxel, or cetuximab). The primary end point was overall survival. Additional end points included progression-free survival, rate of objective response, safety, and patient-reported quality of life. The median overall survival was 7.5 months (95% confidence interval [CI], 5.5 to 9.1) in the nivolumab group versus 5.1 months (95% CI, 4.0 to 6.0) in the group that received standard therapy. Overall survival was significantly longer with nivolumab than with standard therapy (hazard ratio for death, 0.70; 97.73% CI, 0.51 to 0.96; P=0.01), and the estimates of the 1-year survival rate were approximately 19 percentage points higher with nivolumab than with standard therapy (36.0% vs. 16.6%). The median progression-free survival was 2.0 months (95% CI, 1.9 to 2.1) with nivolumab versus 2.3 months (95% CI, 1.9 to 3.1) with standard therapy (hazard ratio for disease progression or death, 0.89; 95% CI, 0.70 to 1.13; P=0.32). The rate of progression-free survival at 6 months was 19.7% with nivolumab versus 9.9% with standard therapy. The response rate was 13.3% in the nivolumab group versus 5.8% in the standard-therapy group. Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of the patients in the nivolumab group versus 35.1% of those in the standard-therapy group. Physical, role, and social functioning was stable in the nivolumab group, whereas it was meaningfully worse in the standard-therapy group. Among patients with platinum-refractory, recurrent squamous-cell carcinoma of the head and neck, treatment with nivolumab resulted in longer overall survival than treatment with standard, single-agent therapy. (Funded by Bristol-Myers Squibb; CheckMate 141 ClinicalTrials.gov number, NCT02105636 .).


Visual acuity development of children with infantile nystagmus syndrome.
Infantile nystagmus syndrome (INS) can be idiopathic or associated with ocular or systemic disease. The ocular oscillation of INS directly contributes to loss of visual acuity. In this study, visual acuity development in patients with INS was examined. Children with INS were classified as having idiopathic INS (n = 84) or INS with an associated sensory deficit: INS and albinism (n = 71), bilateral optic nerve hypoplasia (ONH; n = 23), or congenital retinal disorder (n = 36). Visual acuity was assessed with Teller cards and/or optotypes, and the data were analyzed for three age groups (<24 months, 24-48 months, and >48 months). Patients with idiopathic INS showed mildly reduced visual acuity early in life and gradual maturation with age that paralleled a normative curve. Patients with albinism also showed a mild visual deficit early in life but failed to keep pace with the normative curve, showing a gradual increase in visual acuity deficit. Patients with ONH and congenital retinal disorders exhibited more severe visual acuity deficits during infancy. The ONH group displayed slow improvement of visual acuity with a plateau at 24 months through >48 months, with a small increase in visual acuity deficit. The congenital retinal disorder group had no significant change in visual acuity across age and had a rapid increase in visual acuity deficit. The pattern of visual acuity development differs among children with INS, depending on the presence or absence of associated sensory system deficits. Careful characterization of visual system differences in patients with INS is important if visual acuity is an outcome in clinical trials.


Endoscopic and surgical therapy for intrahepatic cholangiocarcinoma in the united states: a population-based study.
Intrahepatic cholangiocarcinoma (ICC) is a highly fatal disease with limited therapeutic options. The determinants, trends, and outcomes of different therapies for ICC are largely unknown in the United States. Using data from the Surveillance, Epidemiology, and End-Results-(SEER) Medicare database, we compared ICC patients receiving different therapies between 1992 and 1999. Univariate and multivariate analyses were performed and adjusted odds ratios (AORs) were calculated. Hazard ratios were calculated for the survival analysis. Eight hundred sixty-two cases were included. The mean age at diagnosis was 77.9 years (SD=7.1). Only 6.3% received surgical resection, 65.5% received palliative interventions (16.1% surgical, 44.0% endoscopic), 24.4% received only chemo or radiation therapy whereas 3.8% did not receive any treatment. The median survival was 708 days [95% confidence interval (CI): 458-945] for surgical resection, 227 days (95% CI: 182-294) for surgical palliation, and 123 days (95% CI: 108-148) for endoscopic palliation. Patients receiving surgical resection were younger (AOR=5.6, 95% CI: 2.9-11.1), more likely to be diagnosed later in the study period (AOR=2.2, 95% CI: 1.1-4.2), and had better mortality (hazard ratio=0.3, 95% CI: 0.2-0.4). Patients receiving surgical palliation were younger (AOR=1.6, 95% CI: 1.1-2.3), more likely to be diagnosed in the early time period (AOR=1.5, 95% CI: 1.1-2.2), and had similar mortality to those receiving endoscopic palliation. Only a minority of patients with ICC receives potentially curative therapy. Young age is the strongest predictor of receiving potentially curative treatment. Older patients and those diagnosed in recent time periods are more likely to receive endoscopic palliation. Surgical resection was associated with improved survival. There was no difference in survival between surgical and endoscopic palliation.


Retinal detachment surgery in Western Australia (2000-2013): a whole-population study.
To determine the background incidence rate of retinal detachment (RD) in Western Australia (WA) between 2000 and 2013, identify sociodemographic features associated with increased risk of incident RD and examine trends in surgical repair technique. A whole-population retrospective observational study of all people in WA was carried out using linked hospital inpatient records. Cases of RD were identified using a combination of International Classification of Diseases, Ninth revision, Clinical Modification (ICD-9-CM) and ICD-10-AM (Australian modification) diagnosis and procedure codes from routinely collected hospital inpatient data provided by the WA Data Linkage Branch. A Poisson regression model was used to examine the influence of age group, gender, season and year of surgery on RD incidence rates. Age-standardised and sex-standardised incidence of first-eye RD and incidence rate ratio (IRR) of first-eye RD associated with age, sex and season. Counts of RD repair according to surgical technique. There were 4376 first-eye RD between 2000 and 2013. Age-standardised incidence ranged between 12.78 and 16.20 cases per 1 00 000 person-years. After adjusting for age, year and season, males had a higher risk than females for incident detachment (IRR 1.82, 95% CI (CI) 1.71 to 1.93), as did those aged 60-79 years (IRR 33.26, 95% CI 27.60 to 40.08) compared with those aged less than 20 years. RD repair with vitrectomy alone increased by 59% over the study period. The incidence of first-eye RD remained stable between 2000 and 2013. The risk was higher in males and with older age.


Trends of Anti-Vascular Endothelial Growth Factor Use in Ophthalmology Among Privately Insured and Medicare Advantage Patients.
To characterize the first 10 years of intravitreal anti-vascular endothelial growth factor (VEGF) medication use for ophthalmic disease, including bevacizumab, ranibizumab, and aflibercept. A retrospective cohort study using administrative claims data from January 1, 2006 to December 31, 2015. Total of 124 835 patients 18 years of age or over in the United States. OptumLabs Data Warehouse, which includes administrative claims data for over 100 million commercially insured and Medicare Advantage individuals, was used to identify patients receiving intravitreal anti-VEGF injections based on Current Procedural Terminology codes. Total and annual numbers of intravitreal anti-VEGF injections, as well as injections per 1000 enrolled patients per general category of ophthalmic disease, overall and for each available medication. There were 959 945 anti-VEGF injections among 124 835 patients from 2006 to 2015. Among all injections, 64.6% were of bevacizumab, 22.0% ranibizumab, and 13.4% aflibercept; 62.7% were performed to treat age-related macular degeneration (AMD), 16.1% to treat diabetic retinal diseases (including 0.9% of all injections that were for proliferative diabetic retinopathy), 8.3% to treat retinal vein occlusions, and 12.9% for all other uses. Use of bevacizumab and ranibizumab for AMD plateaued as of 2011/2012 and decreased thereafter (in 2006, 58.8 and 35.3 injections/1000 AMD patients, respectively; in 2015, 294.4 and 100.7 injections/1000), whereas use of aflibercept increased (1.1 injections/1000 AMD patients in 2011 to 183.0 injections/1000 in 2015). Bevacizumab use increased each year for diabetic retinal disease (2.4 injections/1000 patients with diabetic retinal disease in 2009 to 13.6 per 1000 in 2015) while that of ranibizumab initially increased significantly and then declined after 2014 (0.1 in 2009 to 4.0 in 2015). Aflibercept use increased each year in patients with diabetic retinal diseases and retinal vein occlusions (both <0.1 per 1000 retinal vein occlusion patients in 2011, 5.6 and 140.2 in 2015). Intravitreal injections of anti-VEGF medications increased annually from 2006 to 2015. Bevacizumab was the most common medication used, despite its lacking U.S. Food and Drug Administration approval to treat ophthalmic disease, and AMD was the most common condition treated. Ranibizumab use declined after 2014 while both the absolute and relative use of bevacizumab and aflibercept increased.


Serological, molecular and hematological diagnosis in horses with clinical suspicion of equine piroplasmosis: Pooling strengths.
Equine piroplasmosis (EP) is a tick-borne protozoan disease caused by Theileria equi and/or Babesia caballi. Clinical signs (fever, pale mucosal membranes, jaundice), anemia and hyperbilirubinemia have been associated with the disease. EP is widespread, has a significant economic impact on the equine industry and remains endemic in Spain. This study was carried out with samples belonging to 140 horses residing in Spain and showing common clinical signs of EP. A blood smear microscopic examination and a comparison between the different results obtained by competitive Enzyme-Linked Immunosorbent Assay (cELISA), real-time Polymerase Chain Reaction (PCR) and hematological and biochemical (direct and total bilirubin) screening were conducted. EP positivity rates by cELISA and PCR were 50.7% and 42.9%, respectively, whereas only 9% of the horses were positive in the microscopic analysis. A significantly higher number of B. caballi-positive horses were detected by cELISA than PCR, and Kappa value was higher for T. equi (k = 0.575) than for B. caballi (k = 0.401). For the first time, an association between a high ELISA inhibition percentage (IP) and a positive PCR result for B. caballi was determined. Although most authors have described T. equi as more pathogenic than B. caballi, we found that horses parasitized by B. caballi showed a more severe hemolytic anemia, whereas T. equi infections were mostly associated with leukocytosis. The hemogram and clinical chemistry could guide the veterinary surgeon towards the diagnosis of T. equi or B. caballi since horses showed a significant leukocytosis or anemia and hyperbilirubinemia, respectively; however PCR would be the test of choice in order to confirm the diagnosis. Information about the importance of a correct diagnosis of EP using a combination of techniques is essential in order to allow the early detection of cases and prevent the spread of the disease, as well as to avoid the common practice of treating horses without a laboratory diagnosis.


Off-axis holographic lens spectrum-splitting photovoltaic system for direct and diffuse solar energy conversion.
This paper describes a high-efficiency, spectrum-splitting photovoltaic module that uses an off-axis volume holographic lens to focus and disperse incident solar illumination to a rectangular shaped high-bandgap indium gallium phosphide cell surrounded by strips of silicon cells. The holographic lens design allows efficient collection of both direct and diffuse illumination to maximize energy yield. We modeled the volume diffraction characteristics using rigorous coupled-wave analysis, and simulated system performance using nonsequential ray tracing and PV cell data from the literature. Under AM 1.5 illumination conditions the simulated module obtained a 30.6% conversion efficiency. This efficiency is a 19.7% relative improvement compared to the more efficient cell in the system (silicon). The module was also simulated under a typical meteorological year of direct and diffuse irradiance in Tucson, Arizona, and Seattle, Washington. Compared to a flat panel silicon module, the holographic spectrum splitting module obtained a relative improvement in energy yield of 17.1% in Tucson and 14.0% in Seattle. An experimental proof-of-concept volume holographic lens was also fabricated in dichromated gelatin to verify the main characteristics of the system. The lens obtained an average first-order diffraction efficiency of 85.4% across the aperture at 532 nm.


Ab initio molar volumes and Gaussian radii.
Ab initio molar volumes are calculated and used to derive radii for ions and neutral molecules using a spatially diffuse model of the electron distribution with Gaussian spread. The Gaussian radii obtained can be used for computation of nonelectrostatic ion-ion dispersion forces that underlie Hofmeister specific ion effects. Equivalent hard-sphere radii are also derived, and these are in reasonable agreement with crystalline ionic radii. The Born electrostatic self-energy is derived for a Gaussian model of the electronic charge distribution. It is shown that the ionic volumes used in electrostatic calculations of strongly hydrated cosmotropic ions ought best to include the first hydration shell. Ionic volumes for weakly hydrated chaotropic metal cations should exclude electron overlap (in electrostatic calculations). Spherical radii are calculated as well as nonisotropic ellipsoidal radii for nonspherical ions, via their nonisotropic static polarizability tensors.


Trends in treatment costs for localized prostate cancer: the healthy screenee effect.
We sought to obtain estimates of trends in initial treatment costs during the prostate-specific antigen (PSA) era that account for the changing patient case-mix associated with screening. We used reimbursement claims for Medicare-eligible subjects diagnosed with nonmetastatic prostate cancer between 1991 and 1999. Patients were grouped by initial treatment, with 17,846 receiving radical prostatectomy (RP), 25,933 receiving external beam radiotherapy (XRT), and 4525 receiving brachytherapy (BT). Cancer-attributable costs were computed by subtracting noncancer costs from total Medicare reimbursements among newly diagnosed cancer patients. Noncancer costs were estimated in 2 ways: (1) average costs among age-matched, cancer-free control subjects (control method) and (2) projections based on claims from subjects before diagnosis (prediagnosis method). Adjusted annual percent change in cancer-attributable costs was calculated using multivariate generalized linear models. Noncancer costs increased at a much lower rate among men prior to diagnosis (3.8% annually) than among the general Medicare population (10.9%). The 2 approaches yielded different results; RP costs declined by 2.4% annually (prediagnosis method) versus 6.2% (control method); XRT costs declined by 1.5% versus 5.8%; and BT costs declined by 4.1% versus 8.3%. Because of self-selection of PSA screening, men diagnosed with prostate cancer today are now healthier overall than men in the general population and are considerably healthier than men diagnosed previously. Estimates of cancer-attributable costs that do not account for this healthy selection effect are likely to be biased. Declines in cancer-attributable treatment costs are evident even after accounting for a healthy screenee effect, suggesting that there has been a real reduction in cancer treatment costs.


On the discovery of new potent human farnesyltransferase inhibitors: emerging pyroglutamic derivatives.
In the current context of lack of emergence of innovative human farnesyltransferase inhibitors families, and given all new therapeutic perspectives that open up for such molecules in rare diseases (e.g. Hutchinson-Gilford progeria syndrome), and in delta hepatitis, cardiovascular or neuroinflammatory diseases, we have just discovered a new series of powerful inhibitors. These molecules are pyroglutamic acid derivatives, and were evaluated on human farnesyltransferase in vitro then modeled in silico on the active site of the protein. Three main points of the pyroglutamic acid cycle have undergone chemical modulations pyroglutamides in position 5 (compounds 7a-h), constrained bicyclic analogues of pyrroloimidazoledione type (compounds 1a-h), modulation of the position 3 (compounds 2-5 and 8), and allowed the first SAR in the field. Five derivatives in the current work have IC50 values in the small nanomolar range (2-5 nM). These new lead compounds open the way for the next generation of farnesyltransferase inhibitors.


Lateral transfers of large DNA fragments spread functional genes among grasses.
A fundamental tenet of multicellular eukaryotic evolution is that vertical inheritance is paramount, with natural selection acting on genetic variants transferred from parents to offspring. This lineal process means that an organism's adaptive potential can be restricted by its evolutionary history, the amount of standing genetic variation, and its mutation rate. Lateral gene transfer (LGT) theoretically provides a mechanism to bypass many of these limitations, but the evolutionary importance and frequency of this process in multicellular eukaryotes, such as plants, remains debated. We address this issue by assembling a chromosome-level genome for the grass Alloteropsis semialata, a species surmised to exhibit two LGTs, and screen it for other grass-to-grass LGTs using genomic data from 146 other grass species. Through stringent phylogenomic analyses, we discovered 57 additional LGTs in the A. semialata nuclear genome, involving at least nine different donor species. The LGTs are clustered in 23 laterally acquired genomic fragments that are up to 170 kb long and have accumulated during the diversification of Alloteropsis. The majority of the 59 LGTs in A. semialata are expressed, and we show that they have added functions to the recipient genome. Functional LGTs were further detected in the genomes of five other grass species, demonstrating that this process is likely widespread in this globally important group of plants. LGT therefore appears to represent a potent evolutionary force capable of spreading functional genes among distantly related grass species.


Valuing ecosystem services in terms of ecological risks and returns.
The economic valuation of ecosystem services is a key policy tool in stemming losses of biological diversity. It is proposed that the loss of ecosystem function and the biological resources within ecosystems is due in part to the failure of markets to recognize the benefits humans derive from ecosystems. Placing monetary values on ecosystem services is often suggested as a necessary step in correcting such market failures. We consider the effects of valuing different types of ecosystem services within an economic framework. We argue that provisioning and regulating ecosystem services are generally produced and consumed in ways that make them amenable to economic valuation. The values associated with cultural ecosystem services lie outside the domain of economic valuation, but their worth may be expressed through noneconomic, deliberative forms of valuation. We argue that supporting ecosystem services are not of direct value and that the losses of such services can be expressed in terms of the effects of their loss on the risk to the provision of the directly valued ecosystem services they support. We propose a heuristic framework that considers the relations between ecological risks and returns in the provision of ecosystem services. The proposed ecosystem-service valuation framework, which allows the expression of the value of all types of ecosystem services, calls for a shift from static, purely monetary valuation toward the consideration of trade-offs between the current flow of benefits from ecosystems and the ability of those ecosystems to provide future flows.


Tubular sclerosis rather than the smear layer impedes dye penetration into the dentine of endodontically instrumented root canals.
To evaluate the effect of different root canal irrigating regimes on dentine penetration of Patent Blue dye. Eighty extracted single-rooted human mandibular premolar teeth with narrow root canals were prepared using ProFile instruments. After each instrument, canals were irrigated with 1% sodium hypochlorite. Subsequently, teeth were randomly assigned to receive a 10 mL rinse of aqueous 17% (w/v) ethylenediaminetetraacetic acid or tap water for 2 or 10 min, followed by a final rinse with a 2% Patent Blue dye solution for 2 or 10 min (eight groups, n = 10 teeth per group). Teeth were then horizontally sectioned 3, 6 and 9 mm from the apex. Sections were digitally photographed and dye penetration was calculated as percentage of total dentine area using NIH Image J. Values were compared using one-way anova and Bonferroni correction with the alpha-type error set at <0.05. Representative tooth sections from all groups were further analysed using scanning electron microscopy. No significant impact of irrigating protocols on dye penetration was found. Dye penetration was significantly (P < 0.001) greater in the coronal than middle, and in middle than in apical root thirds. When observed microscopically, irrigant penetration was independent of the presence of a smear layer, but was rather a function of tubular sclerosis. Tubular sclerosis, a physiological phenomenon that starts in the third decade of life in the apical root region and advances coronally with age, was the main factor influencing penetrability of root dentine.


Results of a prospective multicenter controlled study comparing surgical outcomes of microscopic versus fully endoscopic transsphenoidal surgery for nonfunctioning pituitary adenomas: the Transsphenoidal Extent of Resection (TRANSSPHER) Study.
Many surgeons have adopted fully endoscopic over microscopic transsphenoidal surgery for nonfunctioning pituitary tumors, although no high-quality evidence demonstrates superior patient outcomes with endoscopic surgery. The goal of this analysis was to compare these techniques in a prospective multicenter controlled study. Extent of tumor resection was compared after endoscopic or microscopic transsphenoidal surgery in adults with nonfunctioning adenomas. The primary end point was gross-total tumor resection determined by postoperative MRI. Secondary end points included volumetric extent of tumor resection, pituitary hormone outcomes, and standard quality measures. Seven pituitary centers and 15 surgeons participated in the study. Of the 530 patients screened, 260 were enrolled (82 who underwent microscopic procedures, 177 who underwent endoscopic procedures, and 1 who cancelled surgery) between February 2015 and June 2017. Surgeons who used the microscopic technique were more experienced than the surgeons who used the endoscopic technique in terms of years in practice and number of transsphenoidal surgeries performed (p < 0.001). Gross-total resection was achieved in 80.0% (60/75) of microscopic surgery patients and 83.7% (139/166) of endoscopic surgery patients (p = 0.47, OR 0.8, 95% CI 0.4-1.6). Volumetric extent of resection, length of stay, surgery-related deaths, and unplanned readmission rates were similar between groups (p > 0.2). New hormone deficiency was present at 6 months in 28.4% (19/67) of the microscopic surgery patients and 9.7% (14/145) of the endoscopic surgery patients (p < 0.001, OR 3.7, 95% CI 1.7-7.7). Microscopic surgery cases were significantly shorter in duration than endoscopic surgery cases (p < 0.001). Experienced surgeons who performed microscopic surgery and less experienced surgeons who performed endoscopic surgery achieved similar extents of tumor resection and quality outcomes in patients with nonfunctioning pituitary adenomas. The endoscopic technique may be associated with lower rates of postoperative pituitary gland dysfunction. This study generally supports the transition to endoscopic pituitary surgery when the procedure is performed by proficient surgeons, although both techniques yield overall acceptable surgical outcomes.■ CLASSIFICATION OF EVIDENCE Type of question: therapeutic; study design: prospective cohort trial; evidence: class III.Clinical trial registration no.: NCT02357498 (clinicaltrials.gov).


Matrix-based fertilizers reduce nutrient and bacterial leaching after manure application in a greenhouse column study.
We tested the efficacy of matrix-based fertilizers (MBFs) to reduce Escherichia coli and Enterococcus spp., NH(4), NO(3), dissolved reactive phosphorus (DRP), and total phosphorus (TP) in leachate and soil after dairy manure application in greenhouse column studies. The MBFs are composed of inorganic N and P in compounds that are relatively loosely bound (MBF8) to more tightly bound (MBF9) mixtures using combinations of starch, cellulose, lignin, Al(2)(SO(4))(3)18H(2)O, and/or Fe(2)(SO(4))(3)3H(2)O to create a matrix that slowly releases the nutrients. One day after the first dairy manure application, E. coli numbers were greater in leachate from control columns than in leachate from columns receiving MBFs. After three dairy manure applications, E. coli and Enterococcus spp. numbers in leachates were not consistently different between controls and columns receiving MBFs. When MBF8 was applied to the soil, the total amount of DRP, TP, NH(4), and NO(3) in leachate was lower than in the control columns. Bermudagrass receiving MBFs had greater shoot, root, and total biomass than grass growing in the control columns. Grass shoot, root, and total biomass did not differ among columns receiving MBFs. Nitrogen and phosphorus bound to the Al(2)(SO(4))(3)18H(2)O or Fe(2)(SO(4))(3)3H(2)O-lignin-cellulose matrix become gradually available to plants over the growing season. The MBF8 and MBF9 formulations do not depend on organic or inorganic coatings to reduce N and P leaching and have the potential with further testing and development to provide an effective method to reduce N and P leaching from soils treated with animal waste.


Immigration, acculturation, and preferred help-seeking sources for depression: comparison of five ethnic groups.
Immigrants are more likely than the majority population to have unmet needs for public mental health services. This study aims to understand potential ethnic differences in preferred help-seeking sources for depression in Norway, and how such preferences relate to acculturation orientation. A convenience sample of immigrants from Russia (n = 164), Poland (n = 127), Pakistan (n = 128), and Somalia (n = 114), and Norwegian students (n = 250) completed a survey. The sample was recruited from social media platforms, emails, and direct contact. The survey consisted of a vignette describing a moderately depressed person. Respondents were asked to provide advice to the person by completing a modified version of the General Help-Seeking Questionnaire. The immigrant sample also responded to questions about acculturation orientation using the Vancouver Index of Acculturation Scale. Significant differences were found in the endorsement of traditional (e.g., religious leader), informal (e.g., family), and semiformal (e.g., internet forum) help-sources between immigrant groups, and between immigrant groups and the Norwegian respondent group. Immigrants from Pakistan and Somalia endorsed traditional help sources to a greater extent than immigrants from Russia and Poland, and the Norwegian student sample. There were no ethnic differences in endorsement of formal mental help sources (e.g., a medical doctor). Maintenance of the culture of origin as the acculturation orientation was associated with preferences for traditional and informal help sources, while the adoption of mainstream culture was associated with semiformal and formal help-seeking sources. Ethnic differences in help-seeking sources need to be considered when designing and implementing mental health services.


Sleep Disturbance in Individuals at Clinical High Risk for Psychosis.
Disturbed sleep is a common feature of psychotic disorders that is also present in the clinical high risk (CHR) state. Evidence suggests a potential role of sleep disturbance in symptom progression, yet the interrelationship between sleep and CHR symptoms remains to be determined. To address this knowledge gap, we examined the association between disturbed sleep and CHR symptoms over time. Data were obtained from the North American Prodrome Longitudinal Study (NAPLS)-3 consortium, including 688 CHR individuals and 94 controls (mean age 18.25, 46% female) for whom sleep was tracked prospectively for 8 months. We used Cox regression analyses to investigate whether sleep disturbances predicted conversion to psychosis up to >2 years later. With regressions and cross-lagged panel models, we analyzed longitudinal and bidirectional associations between sleep (the Pittsburgh Sleep Quality Index in conjunction with additional sleep items) and CHR symptoms. We also investigated the independent contribution of individual sleep characteristics on CHR symptom domains separately and explored whether cognitive impairments, stress, depression, and psychotropic medication affected the associations. Disturbed sleep at baseline did not predict conversion to psychosis. However, sleep disturbance was strongly correlated with heightened CHR symptoms over time. Depression accounted for half of the association between sleep and symptoms. Importantly, sleep was a significant predictor of CHR symptoms but not vice versa, although bidirectional effect sizes were similar. The critical role of sleep disturbance in CHR symptom changes suggests that sleep may be a promising intervention target to moderate outcome in the CHR state.


Familial hyperlipidemia in stroke in the young.
Serum cholesterol, low density lipoproteins (LDL), very low density lipoproteins (VLDL) and chylomicron levels were studied in 25 young patients (age 40 years or less) of non-embolic ischemic stroke of unknown aetiology. Fifteen patients were males and 10 were females. The prevalence of hyperlipidemia was found to be 60%. Frederickson's type IIb hyperlipoproteinemia was the commonest (32%) abnormal pattern observed, followed by type IIa (12%), type IV (12%) and type V (4%). Family studies were carried out in all the 25 index patients (15 hyperlipidemic and 10 normolipidemic). Familial hyperlipidemia (i.e. 2 or more hyperlipidemic members in the same family) was found in 9 of the 15 hyperlipidemic index patients and in none of the normolipidemic index patients. The common pattern was found to be that of familial combined hyperlipidemia. The study indicates that screening the family members of hyperlipidemic young patients of non-embolic ischemic stroke may delineate a group of high risk individuals for possible primary prevention before they develop the disease.


On Biophysical Properties and Sensitivity to Gap Junction Blockers of Connexin 39 Hemichannels Expressed in HeLa Cells.
Although connexins (Cxs) are broadly expressed by cells of mammalian organisms, Cx39 has a very restricted pattern of expression and the biophysical properties of Cx39-based channels [hemichannels (HCs) and gap junction channels (GJCs)] remain largely unknown. Here, we used HeLa cells transfected with Cx39 (HeLa-Cx39 cells) in which intercellular electrical coupling was not detected, indicating the absence of GJCs. However, functional HCs were found on the surface of cells exposed to conditions known to increase the open probability of other Cx HCs (e.g., extracellular divalent cationic-free solution (DCFS), extracellular alkaline pH, mechanical stimulus and depolarization to positive membrane potentials). Cx39 HCs were blocked by some traditional Cx HC blockers, but not by others or a pannexin1 channel blocker. HeLa-Cx39 cells showed similar resting membrane potentials (RMPs) to those of parental cells, and exposure to DCFS reduced RMPs in Cx39 transfectants, but not in parental cells. Under these conditions, unitary events of ~75 pS were frequent in HeLa-Cx39 cells and absent in parental cells. Real-time cellular uptake experiments of dyes with different physicochemical features, as well as the application of a machine-learning approach revealed that Cx39 HCs are preferentially permeable to molecules characterized by six categories of descriptors, namely: (1) electronegativity, (2) ionization potential, (3) polarizability, (4) size and geometry, (5) topological flexibility and (6) valence. However, Cx39 HCs opened by mechanical stimulation or alkaline pH were impermeable to Ca2+. Molecular modeling of Cx39-based channels suggest that a constriction present at the intracellular portion of the para helix region co-localizes with an electronegative patch, imposing an energetic and steric barrier, which in the case of GJCs may hinder channel function. Results reported here demonstrate that Cx39 form HCs and add to our understanding of the functional roles of Cx39 HCs under physiological and pathological conditions in cells that express them.


Function from structure? The crystal structure of human phosphatidylethanolamine-binding protein suggests a role in membrane signal transduction.
Proteins belonging to the phosphatidylethanolamine-binding protein (PEBP) family are highly conserved throughout nature and have no significant sequence homology with other proteins of known structure or function. A variety of biological roles have previously been described for members of this family, including lipid binding, roles as odorant effector molecules or opioids, interaction with the cell-signalling machinery, regulation of flowering plant stem architecture, and a function as a precursor protein of a bioactive brain neuropeptide. To date, no experimentally derived structural information has been available for this protein family. In this study we have used X-ray crystallography to determine the three-dimensional structure of human PEBP (hPEBP), in an attempt to clarify the biological role of this unique protein family. The crystal structures of two forms of hPEBP have been determined: one in the native state (at 2.05 A resolution) and one in complex with cacodylate (at 1.75 A resolution). The crystal structures reveal that hPEBP adopts a novel protein topology, dominated by the presence of a large central beta sheet, and is expected to represent the archaetypal fold for this family of proteins. Two potential functional sites have been identified from the structure: a putative ligand-binding site and a coupled cleavage site. hPEBP forms a dimer in the crystal with a distinctive dipole moment that may orient the oligomer for membrane binding. The crystal structure of hPEBP suggests that the ligand-binding site could accommodate the phosphate head groups of membrane lipids, therefore allowing the protein to adhere to the inner leaf of bilipid membranes where it would be ideally positioned to relay signals from the membrane to the cytoplasm. The structure also suggests that ligand binding may lead to coordinated release of the N-terminal region of the protein to form the hippocampal neurostimulatory peptide, which is known to be active in the development of the hippocampus. These studies are consistent with a primary biological role for hPEBP as a transducer of signals from the interior membrane surface.


On the stability of sequences inserted into viral genomes.
Viruses are widely used as vectors for heterologous gene expression in cultured cells or natural hosts, and therefore a large number of viruses with exogenous sequences inserted into their genomes have been engineered. Many of these engineered viruses are viable and express heterologous proteins at high levels, but the inserted sequences often prove to be unstable over time and are rapidly lost, limiting heterologous protein expression. Although virologists are aware that inserted sequences can be unstable, processes leading to insert instability are rarely considered from an evolutionary perspective. Here, we review experimental work on the stability of inserted sequences over a broad range of viruses, and we present some theoretical considerations concerning insert stability. Different virus genome organizations strongly impact insert stability, and factors such as the position of insertion can have a strong effect. In addition, we argue that insert stability not only depends on the characteristics of a particular genome, but that it will also depend on the host environment and the demography of a virus population. The interplay between all factors affecting stability is complex, which makes it challenging to develop a general model to predict the stability of genomic insertions. We highlight key questions and future directions, finding that insert stability is a surprisingly complex problem and that there is need for mechanism-based, predictive models. Combining theoretical models with experimental tests for stability under varying conditions can lead to improved engineering of viral modified genomes, which is a valuable tool for understanding genome evolution as well as for biotechnological applications, such as gene therapy.


Treating disordered speech and voice in Parkinson's disease online: a randomized controlled non-inferiority trial.
Telerehabilitation may be a feasible solution to the current problems faced by people with Parkinson's disease in accessing speech pathology services. To investigate the validity and reliability of online delivery of the Lee Silverman Voice Treatment (LSVT®) for the speech and voice disorder associated with Parkinson's disease. Thirty-four participants with Parkinson's disease and mild-to-moderate hypokinetic dysarthria took part in the randomized controlled non-inferiority laboratory trial and received the LSVT® in either the online or the face-to-face environment. Online sessions were conducted via two personal computer-based videoconferencing systems with real-time and store-and-forward capabilities operating on a 128 kbit/s Internet connection. Participants were assessed pre- and post-treatment on acoustic measures of mean vocal sound pressure level, phonation time, maximum fundamental frequency range, and perceptual measures of voice, articulatory precision and speech intelligibility. Non-inferiority of the online LSVT® modality was confirmed for the primary outcome measure of mean change in sound pressure level on a monologue task. Additionally, non-significant main effects for the LSVT® environment, dysarthria severity, and interaction effects were obtained for all outcomes measures. Significant improvements following the LSVT® were also noted on the majority of measures. The LSVT® was successfully delivered online, although some networking difficulties were encountered on a few occasions. High participant satisfaction was reported overall. Online treatment for hypokinetic dysarthria associated with Parkinson's disease appears to be clinically valid and reliable. Suggestions for future research are outlined.


Conventional versus automated measurement of blood pressure in the office (CAMBO) trial.
Effective strategies to identify office-induced hypertension in routine clinical practice are required to improve diagnosis and management of hypertension. To compare the quality and accuracy of automated office blood pressure (AOBP) measurement using the BpTRU device with manual office blood pressure (MOBP) in routine clinical practice using awake ambulatory blood pressure (AABP) as the gold standard. Primary care practices in Eastern Canada were allocated by cluster randomization to use of AOBP (36 practices, 52 physicians) or to MOBP (31 practices, 36 physicians) in patients with systolic hypertension. The last routine MOBP reading pre-enrolment was compared to the blood pressure (BP) at the first visit after enrollment and after 2 years of follow-up. The primary outcome measure was the mean difference between the AABP and MOBP versus AOBP. The mean (95% confidence interval) decrease in systolic BP from pre- to post-enrollment was greater (P < 0.001) at the first visit in the 252 AOBP patients [-14.3 (-16.6, -12.0)] compared to the 209 MOBP patients [-8.0 (-2.2, -5.8)]. At Year 2, AOBP decreased by -16.3 (-18.6, -14.1) compared to a decrease in MOBP of -12.4 (-14.7, -10.1) (P = 0.02). The mean difference between systolic AABP and MOBP at the first post-enrollment office visit [-7.3 (-9.7, -4.9)] was greater (P < 0.001) than the difference for AOBP [-1.8 (-4.0, 0.4)]. At Year 2, these differences were -5.2 (-7.5, -3.0) for MOBP and -2.8 (-4.9, -0.7) for AOBP (P = 0.13). AOBP virtually eliminated office-induced hypertension. The decrease in MOBP was attributed to participation in a research study and not to any specific intervention.


Phosphorylation on threonine-18 of the regulatory light chain dissociates the ATPase and motor properties of smooth muscle myosin II.
We cloned the full-length cDNA for the cytoplasmic myosin II regulatory light chain (RLC) from a stage 1-2 Xenopus oocyte library. The Xenopus RLC is 94% identical to the chicken smooth muscle myosin RLC. All of the protein kinase C and myosin light chain kinase phosphorylation sites are conserved. Using trifluoperazine [Trybus, K. M., Waller, G. S., & Chatman, T. A. (1994) J. Cell Biol. 124, 963-969], we removed the RLC of smooth muscle myosin and replaced it with recombinant Xenopus RLCs. The wild-type Xenopus RLC substitutes for the gizzard RLC in actin-activated ATPase and in vitro motility assays. We made alanine substitutions of the two residues phosphorylated by myosin light chain kinase, Ser-19 and Thr-18. All of the myosin hybrids, regardless of their mutations or phosphorylation, have similar K+EDTA ATPase activities. As expected, the T18A, S19A hybrid had no actin-activated ATPase, whereas the T18A hybrid phosphorylated on Ser-19 had an actin-activated ATPase similar to that of wild-type hybrids phosphorylated only on Ser-19. The actin-activated ATPase of myosin phosphorylated only on Thr-18 is approximately 15-fold lower than that of myosin phosphorylated on Ser-19. Phosphorylation of either Ser-19 or Thr-18 permits the formation of filaments. Remarkably, in the gliding filament assay, myosin phosphorylated only on Thr-18 moves actin filaments at velocities similar to myosin phosphorylated on Ser-19 or both Thr-18 and Ser-19.


New Cost-Effectiveness Methods to Determine Value-Based Prices for Potential Cures: What Are the Options?
Evaluating different approaches to assessing the clinical effectiveness and value of potential cures will be essential to arm the policymaker, payer, and manufacturer communities with a platform that can reward innovation while supporting a sustainable health insurance system. Potential cures will accentuate concerns about substantial uncertainty in long-term outcomes. They will also focus attention on whether broader elements of value need to be incorporated and whether specific social values have a special place in evaluations of potential cures. In addition, the large magnitudes of potential health gain and cost offsets may require new methods before translation into value-based price recommendations. This article analyzes the challenges and presents several options to modify the conduct and presentation of cost-effectiveness analyses to ensure they provide policy-relevant assessments of the value of potential cures.


Evidence for a structural motif in toxins and interleukin-2 that may be responsible for binding to endothelial cells and initiating vascular leak syndrome.
The dose-limiting toxicity of interleukin-2 (IL-2) and immunotoxin (IT) therapy in humans is vascular leak syndrome (VLS). VLS has a complex etiology involving damage to vascular endothelial cells (ECs), extravasation of fluids and proteins, interstitial edema, and organ failure. IL-2 and ITs prepared with the catalytic A chain of the plant toxin, ricin (RTA), and other toxins, damage human ECs in vitro and in vivo. Damage to ECs may initiate VLS; if this damage could be avoided without losing the efficacy of ITs or IL-2, larger doses could be administered. In this paper, we provide evidence that a three amino acid sequence motif, (x)D(y), in toxins and IL-2 damages ECs. Thus, when peptides from RTA or IL-2 containing this sequence motif are coupled to mouse IgG, they bind to and damage ECs both in vitro and, in the case of RTA, in vivo. In contrast, the same peptides with a deleted or mutated sequence do not. Furthermore, the peptide from RTA attached to mouse IgG can block the binding of intact RTA to ECs in vitro and vice versa. In addition, RTA, a fragment of Pseudomonas exotoxin A (PE38-lys), and fibronectin also block the binding of the mouse IgG-RTA peptide to ECs, suggesting that an (x)D(y) motif is exposed on all three molecules. Our results suggest that deletions or mutations in this sequence or the use of nondamaging blocking peptides may increase the therapeutic index of both IL-2, as well as ITs prepared with a variety of plant or bacterial toxins.


Dimerization Efficiency of Canine Distemper Virus Matrix Protein Regulates Membrane-Budding Activity.
Paramyxoviruses rely on the matrix (M) protein to orchestrate viral assembly and budding at the plasma membrane. Although the mechanistic details remain largely unknown, structural data suggested that M dimers and/or higher-order oligomers may facilitate membrane budding. To gain functional insights, we employed a structure-guided mutagenesis approach to investigate the role of canine distemper virus (CDV) M protein self-assembly in membrane-budding activity. Three six-alanine-block (6A-block) mutants with mutations located at strategic oligomeric positions were initially designed. While the first one includes residues potentially residing at the protomer-protomer interface, the other two display amino acids located within two distal surface-exposed α-helices proposed to be involved in dimer-dimer contacts. We further focused on the core of the dimeric interface by mutating asparagine 138 (N138) to several nonconservative amino acids. Cellular localization combined with dimerization and coimmunopurification assays, performed under various denaturing conditions, revealed that all 6A-block mutants were impaired in self-assembly and cell periphery accumulation. These phenotypes correlated with deficiencies in relocating CDV nucleocapsid proteins to the cell periphery and in virus-like particle (VLP) production. Conversely, all M-N138 mutants remained capable of self-assembly, though to various extents, which correlated with proper accumulation and redistribution of nucleocapsid proteins at the plasma membrane. However, membrane deformation and VLP assays indicated that the M-N138 variants exhibiting the most reduced dimerization propensity were also defective in triggering membrane remodeling and budding, despite proper plasma membrane accumulation. Overall, our data provide mechanistic evidence that the efficiency of CDV M dimerization/oligomerization governs both cell periphery localization and membrane-budding activity.IMPORTANCE Despite the availability of effective vaccines, both measles virus (MeV) and canine distemper virus (CDV) still lead to significant human and animal mortality worldwide. It is assumed that postexposure prophylaxis with specific antiviral compounds may synergize with vaccination campaigns to better control ongoing epidemics. Targeting the matrix (M) protein of MeV/CDV is attractive, because M coordinates viral assembly and egress through interaction with multiple cellular and viral components. However, the lack of basic molecular knowledge of how M orchestrates these functions precludes the rational design of antivirals. Here we combined structure-guided mutagenesis with cellular, biochemical, and functional assays to investigate a potential correlation between CDV M self-assembly and virus-like particle (VLP) formation. Altogether, our findings provide evidence that stable M dimers at the cell periphery are required to productively trigger VLPs. Such stabilized M dimeric units may facilitate further assembly into robust higher-order oligomers necessary to promote plasma membrane-budding activity.


BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1.
DNA damage response (DDR) and the centrosome cycle are 2 of the most critical cellular processes affecting the genome stability in animal cells. Yet the cross-talks between DDR and the centrosome are poorly understood. Here we showed that deficiency of the breast cancer 1, early onset gene (BRCA1) induces centrosome amplification in non-stressed cells as previously reported while attenuating DNA damage-induced centrosome amplification (DDICA) in cells experiencing prolonged genotoxic stress. Mechanistically, the function of BRCA1 in promoting DDICA is through binding and recruiting polo-like kinase 1 (PLK1) to the centrosome. In a recent study, we showed that FancJ also suppresses centrosome amplification in non-stressed cells while promoting DDICA in both hydroxyurea and mitomycin C treated cells. FancJ is a key component of the BRCA1 B-complex. Here, we further demonstrated that, in coordination with BRCA1, FancJ promotes DDICA by recruiting both BRCA1 and PLK1 to the centrosome in the DNA damaged cells. Thus, we have uncovered a novel role of BRCA1 and FancJ in the regulation of DDICA. Dysregulation of DDR or centrosome cycle leads to aneuploidy, which is frequently seen in both solid and hematological cancers. BRCA1 and FancJ are known tumor suppressors and have well-recognized functions in DNA damage checkpoint and DNA repair. Together with our recent findings, we demonstrated here that BRCA1 and FancJ also play an important role in centrosome cycle especially in DDICA. DDICA is thought to be an alternative fail-safe mechanism to prevent cells experiencing severe DNA damage from becoming carcinogenic. Therefore, BRCA1 and FancJ are potential liaisons linking early DDR with the DDICA. We propose that together with their functions in DDR, the role of BRCA1 and FancJ in the activation of DDICA is also crucial for their tumor suppression functions in vivo.


Low-dose ketamine improves pain relief in patients receiving intravenous opioids for acute pain in the emergency department: results of a randomized, double-blind, clinical trial.
Low-dose ketamine has been used perioperatively for pain control and may be a useful adjunct to intravenous (IV) opioids in the control of acute pain in the emergency department (ED). The aim of this study was to determine the effectiveness of low-dose ketamine as an adjunct to morphine versus standard care with morphine alone for the treatment of acute moderate to severe pain among ED patients. A double-blind, randomized, placebo-controlled trial with three study groups was conducted at a large, urban academic ED over a 10-month period. Eligible patients were 18 to 65 years old with acute moderate to severe pain (score of at least 5 out of 10 on the numerical pain rating scale [NRS] and pain duration < 7 days) who were deemed by their treating physician to require IV opioids. The three study groups were: 1) morphine and normal saline placebo (standard care group), 2) morphine and 0.15 mg/kg ketamine (group 1), or 3) morphine and 0.3 mg/kg ketamine (group 2). Participants were assessed at 30, 60, and 120 minutes after study medication administration and received rescue analgesia as needed to target a 50% reduction in pain. The primary outcome measure of pain relief, or pain intensity reduction, was derived using the NRS and calculated as the summed pain-intensity (SPID) difference over 2 hours. The amount and timing of rescue opioid analgesia was evaluated as a secondary outcome. The occurrence of adverse events was also measured. Sixty patients were enrolled (n = 20 in each group). There were no differences between study groups with respect to age, sex, race/ethnicity, preenrollment analgesia, or baseline NRS. Over the 2-hour poststudy medication administration period, the SPIDs were higher (greater pain relief) for the ketamine study groups than the control group (standard care 4.0, interquartile range [IQR] = 1.8 to 6.5; group 1 7.0, IQR = 4.3 to 10.8; and group 2 7.8, IQR = 4.8 to 12.8; p < 0.02). The SPIDs for the ketamine groups were similar (p < 0.46). When compared to standard care, group 2 sustained the reduction in pain intensity up to 2 hours, whereas group 1 was similar to standard care by 2 hours. Similar numbers of patients received rescue analgesia: standard care group, seven of 20, 35%; group 1, four of 20, 20%; and group 2, four of 20, 20% (p = 0.48). Among those receiving rescue analgesia, those in the standard care group received analgesia sooner than either low-dose ketamine group, on average. More participants in the low-dose ketamine groups reported dysphoria and dizziness. Low-dose ketamine is a viable analgesic adjunct to morphine for the treatment of moderate to severe acute pain. Dosing of 0.3 mg/kg is possibly more effective than 0.15 mg/kg, but may be associated with minor adverse events. Future studies should evaluate additional outcomes, optimum dosing, and use in specific populations.


The EHA Research Roadmap: Immune-based Therapies for Hematological Malignancies.
In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1-2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European Hematology Research. the 11 EHA Research Roadmap sections include normal hematopoiesis; malignant lymphoid diseases; malignant myeloid diseases; anemias and related diseases; platelet disorders; blood coagulation and hemostatic disorders; transfusion medicine; infections in hematology; hematopoietic stem cell transplantation; CAR-T and Other cell-based immune therapies; and gene therapy.


Aggregation behavior and size of lipopolysaccharide from Escherichia coli O55:B5.
Dynamic light scattering, steady-state fluorescence, NMR diffusometry and cryo-TEM have been used to gain more insight into the aggregation behaviour of LPS from Escherichia coli O55:B5. Knowledge of this behaviour of the amphiphilic LPS molecule is in many cases of importance for the design of experiments and interpretation of results when using LPS in solution. The aim of this work was to study the aggregation and determine the aggregate size of E. coli O55:B5. The mean hydrodynamic radius of the LPS aggregates was determined by NMR diffusometry and dynamic light scattering to 14 and 26 nm, respectively. The cryo-TEM technique revealed predominantly spherical aggregates of 9-19 nm. We wish to report 10 microg/ml as the aggregation start for LPS E. coli O55:B5 in PBS buffer, pH 7.2. We suggest that the aggregation is a continuous process that starts at 10 microg/ml and proceeds up to 300 microg/ml.


Association of smoking behavior among Chinese expectant fathers and smoking abstinence after their partner becomes pregnant: a cross-sectional study.
Exposure to secondhand smoke (SHS) during pregnancy can cause pregnancy complications and adverse birth outcomes. About 40% of Chinese expectant fathers are smokers and they rarely attempt to quit smoking. There is a paucity of effective smoking cessation services targeting this population. In this study, we assessed the smoking behavior of Chinese expectant fathers and examined its association with smoking abstinence after their partner became pregnant, which is an essential prerequisite for designing effective smoking cessation interventions. We conducted a cross-sectional survey in the obstetrics and gynecology clinic of three tertiary hospitals in China. Expectant fathers who smoked at least one cigarette per day for 1 month within the past 12 months were invited to participate in this study. The participants were asked to complete a structured questionnaire that assessed their smoking behaviors before and after their partner became pregnant. From December 2017 to March 2018, we recruited a total of 466 eligible expectant fathers, among whom 323 (69.3%) were identified as current smokers and 143 (30.7%) were ex-smokers. Using lasso regression, 19 features were selected from among 27 independent variables. The results of the selected multivariable logistic regression model showed that knowledge about the health hazards of smoking among smokers (odds ratio (OR) 1.39; 95% confidence interval (CI) 1.24 to 1.58; p < 0.001), knowledge about the health hazards of SHS to pregnant women (OR 1.46; 95% CI 1.09 to 1.97; p < 0.001), knowledge about harm to the fetus and newborn (OR 1.58; 95% CI 1.25 to 2.03; p < 0.001), and being a first-time expectant father (OR 2.08; 95% CI 1.02 to 3.85; p = 0.046) were significantly positively associated with smoking abstinence among expectant fathers after their partner became pregnant. Significantly negative associations were found for severe dysfunctionality in terms of family support (OR 0.48; 95% CI 0.24 to 0.95; p = 0.036) and smoking only outside the home (OR 0.81; 95% CI 0.26 to 0.98; p < 0.001). In this study, we identified several factors associated with smoking abstinence among expectant fathers after their partner became pregnant. These findings can guide the development of effective interventions targeting expectant fathers, to help them quit smoking.


Increase in brain-derived neurotrophic factor expression in early crack cocaine withdrawal.
Recent reports suggest that brain-derived neurotrophic factor (BDNF) could be a biomarker for relapse, drug craving and withdrawal severity. In particular, elevated BDNF levels among former cocaine users have been associated with higher rates of relapse in 90 d. However, no data are available on BDNF levels at baseline and during crack cocaine withdrawal. This study evaluated BDNF among crack cocaine users during inpatient treatment, before and after withdrawal, vs. healthy controls. Clinical correlates with changes in BDNF levels were also assessed. Serum BDNF was evaluated in 49 male crack users on the first and last days of hospitalization and in 97 healthy controls. Serum BDNF was assayed using a sandwich ELISA kit. BDNF levels were significantly lower upon admission when compared to controls, even after adjustment for age, length of inpatient treatment, number of crack rocks used in the last 30 d, years of crack use and interaction between the latter two variables. At discharge, BDNF levels between patients and controls were similar. Number of crack rocks used in the last 30 d and years of crack use were inversely correlated with the outcome. Our findings show that BDNF levels increase during early crack cocaine withdrawal, at an inverse correlation with number of crack rocks used in the last 30 d and years of crack use.


MicroRNA expression profile in primary lung cancer cells lines obtained by endobronchial ultrasound transbronchial needle aspiration.
Novel cancer biomarkers like microRNA (miRNA) are promising tools to gain a better understanding of lung cancer pathology and yield important information to guide therapy. In recent years, new less invasive methods for the diagnosis and staging of NSCLC have become key tools in thoracic oncology and the worldwide spread of endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA). However, appropriate specimen handling is mandatory to achieve adequate results and reproducibility. The aim of this single centre prospective study was to evaluate the feasibility of a complete miRNA expression profile in fresh NSCLC cell lines obtained by EBUS-TBNA. Patients with proven NSCLC underwent EBUS-TBNA for the diagnosis of suspect lymph node metastasis, and cytological specimens were collected for epithelial cell culture and miRNA expression analysis. To validate the miRNA expression profile, we compared the results from EBUS-TBNA NSCLC specimens with those obtained from formalin-fixed paraffin-embedded (FFPE) mediastinoscopy specimens. Analysis of the miRNA expression profiles of three independent EBUS-TBNA-derived primary cell lines allowed the screening of 377 different human miRNAs. One hundred and fifty miRNAs were detected in all cell lines. Analysis of the miRNA expression profile in mediastinoscopy specimens showed a strong similarity in the clusters analysed. The miRNA expression profile is feasible and reliable in EBUS-TBNA specimens. Validation of this protocol in fresh cytological specimens represents an effective and reproducible method to correlate translational and clinical research.


Immuno-capture of extracellular vesicles for individual multi-modal characterization using AFM, SEM and Raman spectroscopy.
Tumor-derived extracellular vesicles (tdEVs) are promising blood biomarkers for cancer disease management. However, blood is a highly complex fluid that contains multiple objects in the same size range as tdEVs (30 nm-1 μm), which obscures an unimpeded analysis of tdEVs. Here, we report a multi-modal analysis platform for the specific capture of tdEVs on antibody-functionalized stainless steel substrates, followed by their analysis using SEM, Raman spectroscopy and AFM, at the single EV level in terms of size and size distribution, and chemical fingerprint. After covalent attachment of anti-EpCAM (epithelial cell adhesion molecule) antibodies on stainless steel substrates, EV samples derived from a prostate cancer cell line (LnCAP) were flushed into a microfluidic device assembled with this stainless steel substrate for capture. To track the captured objects between the different analytical instruments and subsequent correlative analysis, navigation markers were fabricated onto the substrate from a cyanoacrylate glue. Specific capture of tdEVs on the antibody-functionalized surface was demonstrated using SEM, AFM and Raman imaging, with excellent correlation between the data acquired by the individual techniques. The particle distribution was visualized with SEM. Furthermore, a characteristic lipid-protein band at 2850-2950 cm-1 was observed with Raman spectroscopy, and with AFM the size distribution and surface density of the captured EVs was assessed. Finally, correlation of SEM and Raman images enabled discrimination of tdEVs from cyanoacrylate glue particles, highlighting the capability of this multi-modal analysis platform for distinguishing tdEVs from contamination. The trans-instrumental compatibility of the stainless steel substrate and the possibility to spatially correlate the images of the different modalities with the help of the navigation markers open new avenues to a wide spectrum of combinations of different analytical and imaging techniques for the study of more complex EV samples.


Binding of sulphatide to recombinant haemagglutinin of influenza A virus produced by a baculovirus protein expression system.
Association of sulphatide with influenza A virus (IAV) haemagglutinin (HA) delivered to the cell surface promotes progeny virus production. However, it is not known whether there is direct binding of HA to sulphatide. In this study, we found that recombinant HA, which was produced by a baculovirus protein expression system from the HA gene of A/duck/HK/313/4/78 (H5N3), bound to sulphatide in a dose-dependent manner and that the binding was inhibited by a specific antibody. Our results indicate that the recombinant HA is useful for elucidation of the binding domain of HA with sulphatide and for the development of new anti-IAV agents.


Malignant pleural mesothelioma: staging systems.
Malignant pleural mesothelioma has a very specific growth pattern invading the pleural surfaces and neighboring structures. For this reason precise estimation of tumor volume and description of local extension are particularly difficult. Different staging systems have been introduced, and the most widely used are discussed. Restaging of mesothelioma after induction therapy is even more complicated and still controversial. The recently described, modified response evaluation criteria in solid tumors (RECIST) criteria are presently the most accurate for response evaluation.


Serum levels of shed Her2/neu protein in men with prostate cancer correlate with disease progression.
We determined the association between serum levels of shed Her-2/neu protein and disease progression in men with prostate cancer. Serum from 279 patients enrolled in a prospective serum bank and database at New York University Medical Center was analyzed using the Food and Drug Administration approved Immuno-1 Her-2/neu assay. Patients were classified by the Prostate-Specific Antigen Working Group model into 5 groups, namely group 1-no evidence of cancer in 60, group 2-clinically localized disease in 67, group 3-prostate specific antigen increasing after therapy and no clinical metastases in 77, group 4-clinical metastases and castration sensitivity in 42, and group 5-clinical metastases and castration resistance in 33. A cutoff of 14 ng/ml for normal serum Her-2/neu was established based on the 95th order statistic in group 1. Of 279 patients 37 (13.3%) had increased serum Her-2/neu, that is 5%, 11.9%, 10.4%, 16.7% and 33.3% in groups 1 to 5, respectively. There was a significant difference between patients with (groups 4 and 5) and without (groups 2 and 3) clinical metastases (p = 0.006). In group 5 patients serum Her-2/neu was significantly higher than in group 2 patients (p <0.02). The risk of cause specific death increased significantly with each unit increase in serum Her-2/neu (p <0.001). Increased serum Her-2/neu correlates with the presence of metastatic disease and it may indicate an increased risk of death in patients with castrate, metastatic prostate cancer. The detection of serum Her-2/neu is a minimally invasive alternative to tumor sampling for identifying potential candidates for anti-Her-2/neu treatment strategies. Further studies are needed to optimize this assay for application in the clinical setting.


Bending the curve of terrestrial biodiversity needs an integrated strategy.
Increased efforts are required to prevent further losses to terrestrial biodiversity and the ecosystem services that it provides1,2. Ambitious targets have been proposed, such as reversing the declining trends in biodiversity3; however, just feeding the growing human population will make this a challenge4. Here we use an ensemble of land-use and biodiversity models to assess whether-and how-humanity can reverse the declines in terrestrial biodiversity caused by habitat conversion, which is a major threat to biodiversity5. We show that immediate efforts, consistent with the broader sustainability agenda but of unprecedented ambition and coordination, could enable the provision of food for the growing human population while reversing the global terrestrial biodiversity trends caused by habitat conversion. If we decide to increase the extent of land under conservation management, restore degraded land and generalize landscape-level conservation planning, biodiversity trends from habitat conversion could become positive by the mid-twenty-first century on average across models (confidence interval, 2042-2061), but this was not the case for all models. Food prices could increase and, on average across models, almost half (confidence interval, 34-50%) of the future biodiversity losses could not be avoided. However, additionally tackling the drivers of land-use change could avoid conflict with affordable food provision and reduces the environmental effects of the food-provision system. Through further sustainable intensification and trade, reduced food waste and more plant-based human diets, more than two thirds of future biodiversity losses are avoided and the biodiversity trends from habitat conversion are reversed by 2050 for almost all of the models. Although limiting further loss will remain challenging in several biodiversity-rich regions, and other threats-such as climate change-must be addressed to truly reverse the declines in biodiversity, our results show that ambitious conservation efforts and food system transformation are central to an effective post-2020 biodiversity strategy.


Urinary angiostatin--a novel putative marker of renal pathology chronicity in lupus nephritis.
There is a critical need to identify biomarkers for Systemic Lupus Erythematosus (SLE) which has a high prevalence of renal failure. When urine from patients with lupus nephritis was recently screened for the levels of ∼280 molecules using an exploratory array-based proteomic platform, elevated angiostatin levels were noted. Angiostatin is a bioactive fragment of plasminogen, and has been known to have modulatory function in angiogenesis and inflammation. The significant elevation in urinary angiostatin was next validated in an independent cohort of SLE patients (n = 100) using ELISA. Among patients with SLE, urine angiostatin was significantly increased in active SLE compared with inactive SLE, correlating well with the SLEDAI disease activity index and SLICC renal activity score (r = 0.66, p < 0.0001). ROC curve analysis further confirmed that urinary angiostatin had the capacity to discriminate patients with active SLE from those with inactive disease. Patients with Class IV lupus nephritis exhibited the highest levels of urinary angiostatin. Immunohistochemistry staining localized angiostatin expression to the renal tubular cells in these patients. Finally, when paired urine-kidney samples procured concurrently from patients with LN were next examined, urine angiostatin levels correlated strongly with the renal pathology chronicity index, but not with the activity index. Given that Class IV lupus nephritis and renal pathology chronicity changes forebode poor renal and patient survival, urinary angiostatin emerges as a novel noninvasive marker of renal disease in SLE. Longitudinal studies are in progress to further assess the disease-predictive potential of urinary angiostatin.


Meaning of tumor protein 53-induced nuclear protein 1 in the molecular mechanism of gemcitabine sensitivity.
Stress proteins of the pancreas, such as tumor protein 53-induced nuclear protein 1 (TP53INP1), are important factors in the invasion and metastasis of pancreatic cancer. TP53INP1 is a pro-apoptotic factor and is transcriptionally regulated in p53-dependent and -independent manners. A previous study proved that gemcitabine induces TP53INP1 expression in pancreatic cancer cells and the pancreatic cancer cell line (PANC-1). The present study aimed to clarify the association between TP53INP1 and gemcitabine sensitivity. The expression of TP53INP1 and its related factors, such as cell growth and cell cycle status in TP53INP1-knockout mouse embryonic fibroblasts [TP53INP1-/--mouse embryonic fibroblasts (MEFs)] to those in wild-type counterparts (TP53INP1+/+-MEFs) were compared. Flow cytometric analysis demonstrated no difference of the checkpoint function in TP53INP1-/--MEFs and TP53INP1+/+-MEFs when exposed to 10 ng/ml of gemcitabine. No significant difference was found in the level of p53 expression in the cell types, although the base level and gemcitabine-induced expression of p21 were significantly decreased in TP53INP1-/--MEFs, compared to those in wild-type counterparts. Results showed that gemcitabine induced the p21 expression in TP53INP1+/+-MEFs, although not in TP53INP1-/--MEFs. However, their respective cell-cycle checkpoints were not different. Therefore, TP53INP1 was found to be associated with drug sensitivity through control of the cell cycle.


Rad51/Dmc1 paralogs and mediators oppose DNA helicases to limit hybrid DNA formation and promote crossovers during meiotic recombination.
During meiosis programmed DNA double-strand breaks (DSBs) are repaired by homologous recombination using the sister chromatid or the homologous chromosome (homolog) as a template. This repair results in crossover (CO) and non-crossover (NCO) recombinants. Only CO formation between homologs provides the physical linkages guiding correct chromosome segregation, which are essential to produce healthy gametes. The factors that determine the CO/NCO decision are still poorly understood. Using Schizosaccharomyces pombe as a model we show that the Rad51/Dmc1-paralog complexes Rad55-Rad57 and Rdl1-Rlp1-Sws1 together with Swi5-Sfr1 play a major role in antagonizing both the FANCM-family DNA helicase/translocase Fml1 and the RecQ-type DNA helicase Rqh1 to limit hybrid DNA formation and promote Mus81-Eme1-dependent COs. A common attribute of these protein complexes is an ability to stabilize the Rad51/Dmc1 nucleoprotein filament, and we propose that it is this property that imposes constraints on which enzymes gain access to the recombination intermediate, thereby controlling the manner in which it is processed and resolved.


Role of ubiquitin-proteasome degradation pathway in biogenesis efficiency of {beta}-cell ATP-sensitive potassium channels.
ATP-sensitive potassium (K(ATP)) channels of pancreatic beta-cells mediate glucose-induced insulin secretion by linking glucose metabolism to membrane excitability. The number of plasma membrane K(ATP) channels determines the sensitivity of beta-cells to glucose stimulation. The K(ATP) channel is formed in the endoplasmic reticulum (ER) on coassembly of four inwardly rectifying potassium channel Kir6.2 subunits and four sulfonylurea receptor 1 (SUR1) subunits. Little is known about the cellular events that govern the channel's biogenesis efficiency and expression. Recent studies have implicated the ubiquitin-proteasome pathway in modulating surface expression of several ion channels. In this work, we investigated whether the ubiquitin-proteasome pathway plays a role in the biogenesis efficiency and surface expression of K(ATP) channels. We provide evidence that, when expressed in COS cells, both Kir6.2 and SUR1 undergo ER-associated degradation via the ubiquitin-proteasome system. Moreover, treatment of cells with proteasome inhibitors MG132 or lactacystin leads to increased surface expression of K(ATP) channels by increasing the efficiency of channel biogenesis. Importantly, inhibition of proteasome function in a pancreatic beta-cell line, INS-1, that express endogenous K(ATP) channels also results in increased channel number at the cell surface, as assessed by surface biotinylation and whole cell patch-clamp recordings. Our results support a role of the ubiquitin-proteasome pathway in the biogenesis efficiency and surface expression of beta-cell K(ATP) channels.


Influences of Host Community Characteristics on Borrelia burgdorferi Infection Prevalence in Blacklegged Ticks.
Lyme disease is a major vector-borne bacterial disease in the USA. The disease is caused by Borrelia burgdorferi, and transmitted among hosts and humans, primarily by blacklegged ticks (Ixodes scapularis). The ~25 B. burgdorferi genotypes, based on genotypic variation of their outer surface protein C (ospC), can be phenotypically separated as strains that primarily cause human diseases-human invasive strains (HIS)-or those that rarely do. Additionally, the genotypes are non-randomly associated with host species. The goal of this study was to examine the extent to which phenotypic outcomes of B. burgdorferi could be explained by the host communities fed upon by blacklegged ticks. In 2006 and 2009, we determined the host community composition based on abundance estimates of the vertebrate hosts, and collected host-seeking nymphal ticks in 2007 and 2010 to determine the ospC genotypes within infected ticks. We regressed instances of B. burgdorferi phenotypes on site-specific characteristics of host communities by constructing Bayesian hierarchical models that properly handled missing data. The models provided quantitative support for the relevance of host composition on Lyme disease risk pertaining to B. burgdorferi prevalence (i.e. overall nymphal infection prevalence, or NIPAll) and HIS prevalence among the infected ticks (NIPHIS). In each year, NIPAll and NIPHIS was found to be associated with host relative abundances and diversity. For mice and chipmunks, the association with NIPAll was positive, but tended to be negative with NIPHIS in both years. However, the direction of association between shrew relative abundance with NIPAll or NIPHIS differed across the two years. And, diversity (H') had a negative association with NIPAll, but positive association with NIPHIS in both years. Our analyses highlight that the relationships between the relative abundances of three primary hosts and the community diversity with NIPAll, and NIPHIS, are variable in time and space, and that disease risk inference, based on the role of host community, changes when we examine risk overall or at the phenotypic level. Our discussion focuses on the observed relationships between prevalence and host community characteristics and how they substantiate the ecological understanding of phenotypic Lyme disease risk.


Inverse association between central obesity and arterial stiffness in Korean subjects with metabolic syndrome: a cross-sectional cohort study.
Metabolic syndrome (MetS) is associated with increased risks of diabetes and atherosclerotic cardiovascular disease. Whether central obesity (CeO) is a prerequisite for the diagnosis of MetS in the International Diabetes Federation (IDF) definition is a substantial issue because it may influence the clinical value of MetS for predicting subclinical atherosclerosis. We investigated the relation between MetS, as defined by the National Cholesterol Education Program-Adult Treatment Panel (NCEP-ATP) III criteria, and arterial stiffness according to CeO status in 2,560 healthy Korean subjects who participated in a community-based cohort study. Arterial stiffness was measured using brachial-ankle pulse wave velocity (baPWV). The prevalence of MetS was 37%; 84% of MetS subjects had CeO. The prevalence of diabetes was significantly higher in MetS subjects than in non-MetS subjects (30 vs. 8%, p <0.001). The number of MetS components was significantly correlated with baPWV (r = 0.311, p <0.001). In a subgroup analysis of MetS subjects, the prevalence of diabetes was not significantly different in MetS subjects with and without CeO. MetS subjects without CeO had significantly higher baPWV than those with CeO (1654 ± 315 vs. 1578 ± 270 cm/s, p = 0.002). Multiple regression models revealed that waist circumference was independently associated with decreased baPWV in MetS subjects. Despite the significant correlation between the number of MetS components and arterial stiffness, there appeared to be an inverse association between CeO and arterial stiffness in MetS subjects. In contrast to the IDF definition, our findings suggest that CeO is not crucial for the diagnosis of MetS in otherwise healthy Koreans having multiple metabolic risk factors with respect to subclinical atherosclerosis reflected in arterial stiffness.


Caspase-3-mediated cleavage of ROCK I induces MLC phosphorylation and apoptotic membrane blebbing.
Increased phosphorylation of myosin light chain (MLC) is necessary for the dynamic membrane blebbing that is observed at the onset of apoptosis. Here we identify ROCK I, an effector of the small GTPase Rho, as a new substrate for caspases. ROCK I is cleaved by caspase-3 at a conserved DETD1113/G sequence and its carboxy-terminal inhibitory domain is removed, resulting in deregulated and constitutive kinase activity. ROCK proteins are known to regulate MLC-phosphorylation, and apoptotic cells exhibit a gradual increase in levels of phosphorylated MLC concomitant with ROCK I cleavage. This phosphorylation, as well as membrane blebbing, is abrogated by inhibition of caspases or ROCK proteins, but both processes are independent of Rho activity. We also show that expression of active truncated ROCK I induces cell blebbing. Thus, activation of ROCK I by caspase-3 seems to be responsible for bleb formation in apoptotic cells.


Impact of Acarbose on Incident Diabetes and Regression to Normoglycemia in People With Coronary Heart Disease and Impaired Glucose Tolerance: Insights From the ACE Trial.
We examined the impact of acarbose, an α-glucosidase inhibitor, on incident diabetes and regression to normoglycemia in 6,522 Acarbose Cardiovascular Evaluation (ACE) trial participants in China who had impaired glucose tolerance (IGT) and coronary heart disease (CHD). Participants were randomly assigned to acarbose or placebo and followed with four monthly fasting plasma glucose (FPG) tests and annual oral glucose tolerance tests. Incident diabetes was defined as two successive diagnostic FPG levels ≥7 mmol/L or 2-h plasma glucose (PG) levels ≥11.1 mmol/L while taking study medication or a masked adjudicated confirmation of this diagnosis. Regression to normoglycemia was defined as FPG <6.1 mmol/L and 2-h PG <7.8 mmol/L. Intention-to-treat and on-treatment analyses were conducted using Poisson regression models, overall and for subgroups (age, sex, CHD type, HbA1c, FPG, 2-h PG, BMI, estimated glomerular filtration rate, for IGT alone, for IGT + impaired fasting glucose, and for use of thiazides, ACE inhibitors [ACEis]/angiotensin receptor blockers [ARBs], β-blockers, calcium channel blockers, or statins). Incident diabetes was less frequent with acarbose compared with placebo (3.2 and 3.8 per 100 person-years, respectively; rate ratio 0.82 [95% CI 0.71, 0.94], P = 0.005), with no evidence of differential effects within the predefined subgroups after accounting for multiple testing. Regression to normoglycemia occurred more frequently in those randomized to acarbose compared with placebo (16.3 and 14.1 per 100 person-years, respectively; 1.16 [1.08, 1.25], P < 0.0001). This effect was greater in participants not taking an ACEi or ARB (1.36 [1.21, 1.53], P interaction = 0.0006). The likelihood of remaining in normoglycemic regression did not differ between the acarbose and placebo groups (P = 0.41). Acarbose reduced the incidence of diabetes and promoted regression to normoglycemia in Chinese people with IGT and CHD.


Antipseudomonal monotherapy or combination therapy for older adults with community-onset pneumonia and multidrug-resistant risk factors: a retrospective cohort study.
Infectious Diseases Society of America guidelines recommend empiric antipseudomonal combination therapy when Pseudomonas is suspected. However, combination antipseudomonal therapy is controversial. This study compares all-cause 30-day mortality in older patients who received antipseudomonal monotherapy (PMT) or antipseudomonal combination therapy (PCT) for the treatment of community-onset pneumonia. This population-based, retrospective cohort study used data from over 150 Veterans Health Administration hospitals. Patients were classified as being at low, medium, or high risk of drug-resistant pathogens. In total, 31,027 patients were assigned to PCT or PMT treatment arms based on antibiotics received in the first 48 hours of hospital admission. The unadjusted 30-day mortality difference between PCT and PMT was most pronounced in the low-risk group (18% vs 8%), followed by the medium-risk group (24% vs 18%) and then the high-risk group (39% vs 33%). PCT was associated with higher 30-day mortality than PMT overall (adjusted odds ratio [aOR], 1.54; 95% confidence interval [CI], 1.43-1.66) in all 3 risk groups: low (aOR, 1.69; 95% CI, 1.50-1.89), medium (aOR, 1.30; 95% CI, 1.14-1.48), and high (aOR, 1.21; 95% CI, 1.04-1.40). Older adults who received combination antipseudomonal therapy for community-onset pneumonia fared worse than those who received monotherapy. Empiric combination antipseudomonal therapy should not be routinely offered to all patients suspected of having pseudomonal pneumonia.


Seven challenges for model-driven data collection in experimental and observational studies.
Infectious disease models are both concise statements of hypotheses and powerful techniques for creating tools from hypotheses and theories. As such, they have tremendous potential for guiding data collection in experimental and observational studies, leading to more efficient testing of hypotheses and more robust study designs. In numerous instances, infectious disease models have played a key role in informing data collection, including the Garki project studying malaria, the response to the 2009 pandemic of H1N1 influenza in the United Kingdom and studies of T-cell immunodynamics in mammals. However, such synergies remain the exception rather than the rule; and a close marriage of dynamic modeling and empirical data collection is far from the norm in infectious disease research. Overcoming the challenges to using models to inform data collection has the potential to accelerate innovation and to improve practice in how we deal with infectious disease threats.


Accelerating preschoolers' early literacy development through classroom-based teacher-child storybook reading and explicit print referencing.
This study examined the impact of teacher use of a print referencing style during classroom-based storybook reading sessions conducted over an academic year. Impacts on preschoolers' early literacy development were examined, focusing specifically on the domain of print knowledge. This randomized, controlled trial examined the effects of a print referencing style on 106 preschool children attending 23 classrooms serving disadvantaged preschoolers. Following random assignment, teachers in 14 classrooms used a print referencing style during 120 large-group storybook reading sessions during a 30-week period. Teachers in 9 comparison classrooms read at the same frequency and with the same storybooks but used their normal style of reading. Children whose teachers used a print referencing style showed larger gains on 3 standardized measures of print knowledge: print concept knowledge, alphabet knowledge, and name writing, with medium-sized effects. The convergence of the present findings with those of previous efficacy studies indicates that print referencing intervention can be used confidently as an approach for facilitating print knowledge in preschool-age children. Speech-language pathologists can serve an important role in supporting preschool educators as they use this evidence-based technique with pupils in their classrooms.


Scar1 and the related Wiskott-Aldrich syndrome protein, WASP, regulate the actin cytoskeleton through the Arp2/3 complex.
The actin-related proteins Arp2 and Arp3 are part of a seven-protein complex which is localized in the lamellipodia of a variety of cell types, and in actin-rich spots of unknown function. The Arp2/3 complex enhances actin nucleation and causes branching and crosslinking of actin filaments in vitro; in vivo it is thought to drive the formation of lamellipodia and to be a control center for actin-based motility. The Wiskott-Aldrich syndrome protein, WASP, is an adaptor protein implicated in the transmission of signals from tyrosine kinase receptors and small GTPases to the actin cytoskeleton. Scar1 is a member of a new family of proteins related to WASP, and it may also have a role in regulating the actin cytoskeleton. Scar1 is the human homologue of Dictyostelium Scar1, which is thought to connect G-protein-coupled receptors to the actin cytoskeleton. The mammalian Scar family contains at least four members. We have examined the relationships between WASP, Scar1, and the Arp2/3 complex. We have identified WASP and its relative Scar1 as proteins that interact with the Arp2/3 complex. We have used deletion analysis to show that both WASP and Scar1 interact with the p21 subunit of the Arp2/3 complex through their carboxyl termini. Overexpression of carboxy-terminal fragments of Scar1 or WASP in cells caused a disruption in the localization of the Arp2/3 complex and, concomitantly, induced a complete loss of lamellipodia and actin spots. The induction of lamellipodia by platelet-derived growth factor was also suppressed by overexpression of the fragment of Scar1 that binds to the Arp2/3 complex. We have identified a conserved sequence domain in proteins of the WASP family that binds to the Arp2/3 complex. Overexpression of this domain in cells disrupts the localization of the Arp2/3 complex and inhibits lamellipodia formation. Our data suggest that WASP-related proteins may regulate the actin cytoskeleton through the Arp2/3 complex.


Overexpression of human TRK proto-oncogene into mouse cells using an inducible vector system.
The TRK proto-oncogene encodes a tyrosine kinase receptor for an, as yet, unidentified ligand. In order to help the identification of this ligand, we have constructed an expression vector capable of overexpressing the TRK protein in an inducible fashion. We report here the characterization of the TRK proto-oncogene products obtained from this expression vector.


Short-term outcome in trial entrants and trial eligible patients.
Of 253 patients from nine medical centres identified with first episodes of schizophrenic illness, 17 did not achieve discharge during the period of trial recruitment. 120 entered a randomised controlled trial of neuroleptic medication and were followed-up, as were 116 who were eligible for the trial but did not enter it. Overall, 60% of the sample had relapsed within two years of discharge; age, sex, ethnic origin, duration of admission, social withdrawal before admission, and type of onset of illness were not significantly related to relapse. Relapse rates were lower on active trial or standard medication than placebo, but however assessed, outcome at this early stage was poor for many patients.


Prox1 and FOXC2 act as regulators of lymphangiogenesis and angiogenesis in oral squamous cell carcinoma.
Prospero homeobox 1 (Prox1) and forkhead box (FOX) C2 regulate angiogenesis and/or lymphangiogenesis. However, the detailed role and function of Prox1 and FOXC2 in cancer remains controversial. In the present study, we examined the expression of Prox1 and FOXC2 proteins in specimens from 163 cases with oral squamous cell carcinoma (OSCC). Furthermore, the role of Prox1 and FOXC2 in cancer cell growth and invasion was evaluated in cultured OSCC cells. Prox1 expression was significantly associated with local progression of the tumor (P = 0.0023), clinical stage (P<0.0001), lymphovessel density (LVD) (P<0.0001), nodal metastasis (P<0.0001), and worse prognosis (P<0.0001). Immunoreactivity of FOXC2 was strongly correlated with microvessel density (MVD) (P<0.0001) and poor prognosis (P = 0.0076). In vitro analysis demonstrated that Prox1 regulates cell growth, proliferation, invasion, and lymphangiogenesis by activating vascular endothelial growth factor (VEGF)-C expression. Furthermore, FOXC2 enhanced the expression level of Prox1 and promoted angiogenesis by enhancement of VEGF-A expression. Our results suggested that Prox1 and FOXC2 play key roles in OSCC progression and that further studies focusing on these proteins may yield useful insights for diagnosis and therapy of OSCC.


Ethics in sports medicine.
Physicians have struggled with the medical ramifications of athletic competition since ancient Greece, where rational medicine and organized athletics originated. Historically, the relationship between sport and medicine was adversarial because of conflicts between health and sport. However, modern sports medicine has emerged with the goal of improving performance and preventing injury, and the concept of the "team physician" has become an integral part of athletic culture. With this distinction come unique ethical challenges because the customary ethical norms for most forms of clinical practice, such as confidentiality and patient autonomy, cannot be translated easily into sports medicine. The particular areas of medical ethics that present unique challenges in sports medicine are informed consent, third parties, advertising, confidentiality, drug use, and innovative technology. Unfortunately, there is no widely accepted code of sports medicine ethics that adequately addresses these issues.