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SUMMARYNon-steroidal anti-inflammatory drugs (NSAIDs) may inhibit antibody production by peripheral blood mononuclear cells; one consequence of this could be decreased effectiveness of vaccines in NSAID users. Because many older adults use low-dose aspirin for primary or secondary prevention of coronary events, any inhibitory effect of aspirin on vaccine immune response could reduce the benefits of vaccination programmes in older adults. We tested whether immune response to vaccination differed between users vs. non-users of low-dose aspirin, using data from four randomized trials of monovalent 2009 pandemic influenza A(H1N1) vaccine. Geometric mean haemagglutination inhibition antibody titres were not significantly lower in low-dose aspirin users compared to non-users. Our results provide reassurance that influenza vaccination effectiveness is probably not reduced in older adults taking chronic low-dose aspirin.

Background Poor outcomes occur when patients with serious infections receive antibiotics to which the organisms are resistant. Methods Decision trees simulated in-hospital mortality, costs, incremental cost-effectiveness ratio per life year saved, and carbapenem resistance according to 3 empirical antibiotic strategies among adults hospitalized for community-acquired (CA) upper urinary tract infections (UTIs): ceftriaxone (CRO) plus gentamicin (GM) in the intensive care unit (ICU), imipenem (IMP), and individualized choice (IMP or CRO) based on clinical risk factors for CA- extended-spectrum β -lactamase (ESBL). Results The estimated prevalence of CA-ESBL on admission was 5% (range, 1.3%-17.6%); 3% and 97% were admitted to the ICU and medical ward (MW), respectively. In the ICU, CRO plus GM was dominated; IMP was cost-effective (incremental cost-effectiveness ratio: €4,400 per life year saved compared with individualized choice). In the MW, IMP had no impact on mortality and was less costly (−€142 per patient vs CRO, −€38 vs individualized choice). The dominance of IMP was consistent in sensitivity analyses. Compared with CRO, colonization by carbapenem-resistant pathogens increased by an odds ratio of 4.5 in the IMP strategy. Conclusion Among the ICU patients, empirical IMP therapy reduces mortality at an acceptable cost. Among MW patients, individualized choice or CRO is preferred to limit carbapenem resistance at a reasonable cost.

BACKGROUND For patients with low-risk prostate cancer (PCa), active surveillance (AS) may produce oncologic outcomes comparable to those achieved with radical prostatectomy (RP). Health-related quality-of-life (HRQoL) outcomes are important to consider, yet few studies have examined HRQoL among patients with PCa who were managed with AS. In this study, the authors compared longitudinal HRQoL in a prospective, racially diverse, and contemporary cohort of patients who underwent RP or AS for low-risk PCa. METHODS Beginning in 2007, HRQoL data from validated questionnaires (the Expanded Prostate Cancer Index Composite and the 36-item RAND Medical Outcomes Study short-form survey) were collected by the Center for Prostate Disease Research in a multicenter national database. Patients aged ≤75 years who were diagnosed with low-risk PCa and elected RP or AS for initial disease management were followed for 3 years. Mean scores were estimated using generalized estimating equations adjusting for baseline HRQoL, demographic characteristics, and clinical patient characteristics. RESULTS Of the patients with low-risk PCa, 228 underwent RP, and 77 underwent AS. Multivariable analysis revealed that patients in the RP group had significantly worse sexual function, sexual bother, and urinary function at all time points compared with patients in the AS group. Differences in mental health between groups were below the threshold for clinical significance at 1 year. CONCLUSIONS In this study, no differences in mental health outcomes were observed, but urinary and sexual HRQoL were worse for patients who underwent RP compared with those who underwent AS for up to 3 years. These data offer support for the management of low-risk PCa with AS as a means for postponing the morbidity associated with RP without concomitant declines in mental health. Cancer 2015;121:2465–2473. © 2015 American Cancer Society.

Summary Background Once daily regimens are preferred for HIV-1 treatment, to facilitate adherence and improve quality of life. We compared a new once daily formulation of raltegravir to the currently marketed twice daily formulation. Methods In this randomised, double-blind, parallel-group, phase 3, non-inferiority study, we enrolled participants aged 18 years or older with HIV-1 RNA of 1000 or more copies per mL and no previous antiretroviral treatment at 139 sites worldwide. We randomly assigned participants (2:1) via an interactive voice and web response system to raltegravir 1200 mg (two 600 mg tablets) orally once daily or raltegravir 400 mg (one tablet) orally twice daily, each with tenofovir disoproxil fumarate and emtricitabine orally once daily, for up to 96 weeks. A computer-generated allocation schedule stratified randomisation by screening HIV-1 RNA value and co-infection with hepatitis B or C. Participants, sponsor personnel, investigators, and study site personnel involved in the treatment or evaluation of the participants were unaware of the treatment group assignments. The primary endpoint was the proportion of participants with HIV-1 RNA less than 40 copies per mL at week 48 assessed with the US Food and Drug Administration Snapshot algorithm. Non-inferiority was concluded if the lower bound of the two-sided 95% CI was greater than −10%. We assessed efficacy and safety in all participants who received one dose or more of study treatment. This study is registered with ClinicalTrials.gov, number NCT02131233. Findings Between May 26, 2014, and Dec 5, 2014, 802 participants were enrolled and randomly assigned, 533 to once daily treatment and 269 to twice daily; 797 received study therapy, 531 once daily and 266 twice daily. At week 48, 472 (89%) of 531 once daily recipients and 235 (88%) of 266 twice daily recipients achieved HIV-1 RNA less than 40 copies per mL (treatment difference 0·5%, 95% CI −4·2 to 5·2). Drug-related adverse events occurred in 130 (24%) of 531 participants in the once daily group (one of which was serious; none led to treatment discontinuation) and 68 (26%) of 266 participants in the twice daily group (two of which were serious; two led to treatment discontinuation). The most common drug-related adverse events were nausea (39 [7%] vs 18 [7%]), headache (16 [3%] vs 12 [5%]), and dizziness (12 [2%] vs eight [3%]). No treatment-related deaths were reported. Interpretation A once daily raltegravir 1200 mg regimen was non-inferior compared with raltegravir 400 mg twice daily for initial treatment of HIV-1 infection. These results support the use of raltegravir 1200 mg once daily for first-line therapy. Funding Merck & Co, Inc.

Ruminant animals have a symbiotic relationship with the microorganisms in their rumens. In this relationship, rumen microbes efficiently degrade complex plant-derived compounds into smaller digestible compounds, a process that is very likely associated with host animal feed efficiency. The resulting simpler metabolites can then be absorbed by the host and converted into other compounds by host enzymes. We used a microbial community metabolic network inferred from shotgun metagenomics data to assess how this metabolic system differs between animals that are able to turn ingested feedstuffs into body mass with high efficiency and those that are not. We conducted shotgun sequencing of microbial DNA from the rumen contents of 16 sheep that differed in their residual feed intake (RFI), a measure of feed efficiency. Metagenomic reads from each sheep were mapped onto a database-derived microbial metabolic network, which was linked to the sheep metabolic network by interface metabolites (metabolites transferred from microbes to host). No single enzyme was identified as being significantly different in abundance between the low and high RFI animals (P > 0.05, Wilcoxon test). However, when we analyzed the metabolic network as a whole, we found several differences between efficient and inefficient animals. Microbes from low RFI (efficient) animals use a suite of enzymes closer in network space to the host’s reactions than those of the high RFI (inefficient) animals. Similarly, low RFI animals have microbial metabolic networks that, on average, contain reactions using shorter carbon chains than do those of high RFI animals, potentially allowing the host animals to extract metabolites more efficiently. Finally, the efficient animals possess community networks with greater Shannon diversity among their enzymes than do inefficient ones. Thus, our system approach to the ruminal microbiome identified differences attributable to feed efficiency in the structure of the microbes’ community metabolic network that were undetected at the level of individual microbial taxa or reactions.

Shared decision making (SDM) is widely encouraged by both the American Urological Association and Choosing Wisely for prostate cancer screening. Implementation of SDM is challenging secondary to time constraints and competing patient priorities. One strategy to mitigate the difficulties in implementing SDM is to utilize a decision aid (DA). Here we evaluate whether a DA improves a patient's prostate cancer knowledge and affects prostate-specific antigen (PSA) screening rates.Patients were randomized to usual care (UC), DA, or DA + SDM. Perception of quality of care was measured using the Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey. Outcomes were stratified by long term provider relationship (LTPR,3 years) versus short term provider relationship (STPR,3 years). Knowledge of prostate cancer screening and the decision regarding screening were assessed. Groups were compared using ANOVA and logistic regression models.A total of 329 patients were randomized. Patients in the DA + SDM arm were significantly more likely to report discussing the implication of screening (33% DA + SDM, 22% UC, 16% DA, p = 0.0292) and answered significantly more knowledge questions correctly compared to the UC arm (5.03 versus 4.46, p = 0.046). However, those in the DA arm were significantly less likely to report that they always felt encouraged to discuss all health concerns (72% DA, 78% DA + SDM, 87% UC, p = 0.0285). Interestingly, STPR patients in the DA arm were significantly more likely to undergo PSA-based prostate cancer screening (41%) than the UC arm (8%, p = 0.019). This effect was not observed in the LTPR group.Providing patients a DA without a personal interaction resulted in a greater chance of undergoing PSA-based screening without improving knowledge about screening or understanding of the consequences of this decision. This effect was exacerbated by a shorter term provider relationship. With complex issues such as the decision to pursue PSA-based prostate cancer screening, tools cannot substitute for direct interaction with a trusted provider.

Several new antibiotics (ceftaroline, ceftobiprole, omadacycline, solithromycine and delafloxacin) have recently been developed. Their place in the management of community acute pneumonia (CAP) needs to be clarified.Because multiresistant bacteria are infrequently involved in CAP, usual regimens using third generation cephalosporins, fluoroquinolones or macrolides, alone or in combination, are effective in the overwhelming majority of cases. Several studies have highlighted the non-inferiority of the new molecules regarding their clinical efficacy compared to usual regimens. The use of these new antibiotics could reduce the treatment duration of CAP and in some cases avoid combined therapy. These antibiotics do not offer real benefits in terms of spectrum of activity compared to the current recommended treatment. The anti-toxin effect of ceftaroline and the anti-inflammatory properties of solithromycin could potentially justify their prescription over molecules currently used.Results are still pending regarding the efficacy and any possible advantages of these new molecules, and also the emergence of drug resistant bacteria. Although these drugs share some advantages, they should not be selected over antibiotics usually prescribed for the treatment of CAP.

Background: Grazing mammals rely on their ruminal microbial symbionts to convert plant structural biomass into metabolites they can assimilate. To explore how this complex metabolic system adapts to the host animal's diet, we inferred a microbiome-level metabolic network from shotgun metagenomic data. Results: Using comparative genomics, we then linked this microbial network to that of the host animal using a set of interface metabolites likely to be transferred to the host. When the host sheep were fed a grain-based diet, the induced microbial metabolic network showed several critical differences from those seen on the evolved forage-based diet. Grain-based (e.g., concentrate) diets tend to be dominated by a smaller set of reactions that employ metabolites that are nearer in network space to the host's metabolism. In addition, these reactions are more central in the network and employ substrates with shorter carbon backbones. Despite this apparent lower complexity, the concentrate-associated metabolic networks are actually more dissimilar from each other than are those of forage-fed animals. Because both groups of animals were initially fed on a forage diet, we propose that the diet switch drove the appearance of a number of different microbial networks, including a degenerate network characterized by an inefficient use of dietary nutrients. We used network simulations to show that such disparate networks are not an unexpected result of a diet shift. Conclusion: We argue that network approaches, particularly those that link the microbial network with that of the host, illuminate aspects of the structure of the microbiome not seen from a strictly taxonomic perspective. In particular, different diets induce predictable and significant differences in the enzymes used by the microbiome. Nonetheless, there are clearly a number of microbiomes of differing structure that show similar functional properties. Changes such as a diet shift uncover more of this type of diversity. USDA National Research Initiative (NRI) grant [2011-68006-30185]; National Science FoundationNational Science Foundation (NSF) [NSF-CCF-1421765, NSF-DBI-1358997] This project was supported USDA National Research Initiative (NRI) grant # 2011-68006-30185 (MJE, RRC, KJA, WRL, KMC, GCC) and National Science Foundation grants NSF-CCF-1421765 (HT, GCC) and NSF-DBI-1358997 (MB, HJL, KB, TM, GCC). Public domain – authored by a U.S. government employee

Perovskite solar cells now compete with their inorganic counterparts in terms of power conversion efficiency, not least because of their small open-circuit voltage (V-OC) losses. A key to surpass traditional thin-film solar cells is the fill factor (FF). Therefore, more insights into the physical mechanisms that define the bias dependence of the photocurrent are urgently required. In this work, we studied charge extraction and recombination in efficient triple cation perovskite solar cells with undoped organic electron/hole transport layers (ETL/HTL). Using integral time of flight we identify the transit time through the HTL as the key figure of merit for maximizing the fill factor (FF) and efficiency. Complementarily, intensity dependent photocurrent and V-OC measurements elucidate the role of the HTL on the bias dependence of non-radiative and transport-related loss channels. We show that charge transport losses can be completely avoided under certain conditions, yielding devices with FFs of up to 84%. Optimized cells exhibit power conversion efficiencies of above 20% for 6 mm(2) sized pixels and 18.9% for a device area of 1 cm(2). These are record efficiencies for hybrid perovskite devices with dopant-free transport layers, highlighting the potential of this device technology to avoid charge-transport limitations and to approach the Shockley-Queisser limit.

Although the primary protein sequence of ubiquitin (Ub) is extremely stable over evolutionary time, it is highly tolerant to mutation during selection experiments performed in the laboratory. We have proposed that this discrepancy results from the difference between fitness under laboratory culture conditions and the selective pressures in changing environments over evolutionary time scales. Building on our previous work (Mavor et al 2016), we used deep mutational scanning to determine how twelve new chemicals (3-Amino-1,2,4-triazole, 5-fluorocytosine, Amphotericin B, CaCl2, Cerulenin, Cobalt Acetate, Menadione, Nickel Chloride, p-fluorophenylalanine, Rapamycin, Tamoxifen, and Tunicamycin) reveal novel mutational sensitivities of ubiquitin residues. We found sensitization of Lys63 in eight new conditions. In total, our experiments have uncovered a sensitizing condition for every position in Ub except Ser57 and Gln62. By determining the Ubiquitin fitness landscape under different chemical constraints, our work helps to resolve the inconsistencies between deep mutational scanning experiments and sequence conservation over evolutionary timescales.Builds onMavor D, Barlow KA, Thompson S, Barad BA, Bonny AR, Cario CL, Gaskins G, Liu Z, Deming L, Axen SD, Caceres E, Chen W, Cuesta A, Gate R, Green EM, Hulce KR, Ji W, Kenner LR, Mensa B, Morinishi LS, Moss SM, Mravic M, Muir RK, Niekamp S, Nnadi CI, Palovcak E, Poss EM, Ross TD, Salcedo E, See S, Subramaniam M, Wong AW, Li J, Thorn KS, Conchúir SÓ, Roscoe BP, Chow ED, DeRisi JL, Kortemme T, Bolon DN, Fraser JS. Determination of Ubiquitin Fitness Landscapes Under Different Chemical Stresses in a Classroom Setting. eLife. 2016.Impact StatementWe organized a project-based course that used deep mutational scanning in multiple chemical conditions to resolve the inconsistencies between tolerance to mutations in laboratory conditions and sequence conservation over evolutionary timescales.

This study was designed to examine the roles of emotional reactivity, self-regulation, and pubertal timing in prosocial behaviors during adolescence. Participants were 850 sixth graders (50% female, Mean age = 11.03, SD = .17) who were followed up at age 15. In hierarchical regression models, measures of emotional reactivity, self-regulation, pubertal timing and their interactions were used to predict (concurrently and over time) adolescents’ prosocial behaviors in the home and with peers. Overall, the findings provide evidence for pubertal and temperament based predictors of prosocial behaviors expressed in different contexts. Self-regulation was positively related to both forms of prosocial behavior, concurrently and longitudinally. Emotional reactivity showed moderately consistent effects, showing negative concurrent relations to prosocial behavior with peers and negative longitudinal relations (four years later) to prosocial behavior at home. Some curvilinear effects of temperament on prosocial behaviors were also found. Effects of pubertal timing were found to interact with gender, such that boys who were early maturers showed the highest levels of prosocial behavior at home concurrently. Discussion focuses on the role of temperament-based mechanisms in the expression of prosocial behaviors in different contexts in adolescence.

Perovskite solar cells with all-organic transport layers exhibit efficiencies rivaling their counterparts that employ inorganic transport layers, while avoiding high-temperature processing. Herein, it is investigated how the choice of the fullerene derivative employed in the electron-transporting layer of inverted perovskite cells affects the open-circuit voltage (V

Solar cells made from inorganic amp; 8722;organic perovskites have gradually approached market requirements as their efficiency and stability have improved tremendously in recent years. Planar low temperature processed perovskite solar cells are advantageous for possible large scale production but are more prone to exhibiting photocurrent hysteresis, especially in the regular n amp; 8722;i amp; 8722;p structure. Here, a systematic characterization of different electron selective contacts with a variety of chemical and electrical properties in planar n amp; 8722;i amp; 8722;p devices processed below 180 C is presented. The inorganic metal oxides TiO2 and SnO2, the organic fullerene derivatives C60, PCBM, and ICMA, as well as double layers with a metal oxide PCBM structure are used as electron transport materials ETMs . Perovskite layers deposited atop the different ETMs with the herein applied fabrication method show a similar morphology according to scanning electron microscopy. Further, surface photovoltage spectroscopy measurements indicate comparable perovskite absorber qualities on all ETMs, except TiO2, which shows a more prominent influence of defect states. Transient photoluminescence studies together with current amp; 8722;voltage scans over a broad range of scan speeds reveal faster charge extraction, less pronounced hysteresis effects, and higher efficiencies for devices with fullerene compared to those with metal oxide ETMs. Beyond this, only ouble layer ETM structures substantially diminish hysteresis effects for all performed scan speeds and strongly enhance the power conversion efficiency up to a champion stabilized value of 18.0 . The results indicate reduced recombination losses for a double layer TiO2 PCBM contact design First, a reduction of shunt paths through the fullerene to the ITO layer. Second, an improved hole blocking by the wide band gap metal oxide. Third, decreased transport losses due to an energetically more favorable contact, as implied by photoelectron spectroscopy measurements. The herein demonstrated improvements of multilayer selective contacts may serve as a general design guideline for perovskite solar cells

Use of intermittent androgen-deprivation therapy (IADT) in patients with prostate cancer has been evaluated in several studies, in an attempt to delay the development of castration resistance and reduce side-effects associated with ADT. However it is still not clear whether survival is adversely affected in patients treated with IADT. In this review, we explore the available data in an attempt to identify the most suitable candidate patients for IADT, and discuss factors that may inform appropriate patient stratification. ADT is first-line treatment for advanced/metastatic prostate cancer and is also recommended for use with definitive radiotherapy for high-risk localised prostate cancer. The changes in hormone levels induced by ADT can lead to short- and long-term side-effects which, although treatable in most cases, can significantly reduce the tolerability of ADT treatment. IADT has been investigated in several phase II and phase III studies in patients with locally advanced or metastatic prostate cancer, in an attempt to delay time to tumour progression and reduce the side-effect burden of ADT. In selected patient groups IADT is no less effective than continuous ADT, ameliorating the impact of ADT-related side-effects, and, to a degree, their impact on patient health-related quality of life (HRQL). Further comparative study is required, particularly in relation to HRQL and long-term complications associated with ADT.

ZusammenfassungEinleitung: Die Ergebnisse der HALT-Prostatakarzinom-Studie (1) zeigten, dass Denosumab bei Prostatakarzinompatienten unter hormonablativer Therapie (HALT) die Knochenmineraldichte (BMD) gegenüber Placebo an allen Messorten signifikant erhöhte und die Inzidenz vertebraler Frakturen nach 36 Monaten signifikant um 62 % senkte. Keine Unterschiede wurden hinsichtlich der Zeit bis zur ersten klinischen Fraktur (jegliche nonvertebrale oder klinisch vertebrale Fraktur) beobachtet. In einer Post-hoc-Analyse wurde nun überprüft, ob Denosumab auch bei Patienten mit normaler bis osteopenischer Knochendichte das Risiko für neue vertebrale Frakturen reduziert.Methoden: Hierzu wurde bei allen Teilnehmern der HALT-Studie (n = 1468) mit einem BMD-T-Score > –2,5 an Lendenwirbelsäule (LWS), Gesamthüfte und Schenkelhals sowie auswertbarem Frakturstatus die Inzidenz neuer vertebraler Frakturen nach 36 Mona-ten unter Behandlung mit Denosumab vs. Placebo ermittelt.Ergebnisse: Zu Studienbeginn wiesen 1174 bzw. 80 % der Studienteilnehmer einen BMDT-Score > –2,5 an allen drei Messorten auf. 1087 bzw. 74 % der Studienteilnehmer erfüllten die Kriterien für die Frakturauswertung. In dieser Subgruppe reduzierte Denosumab das Risiko für vertebrale Frakturen nach 36 Mona-ten gegenüber Placebo signifikant um 61 % (Placebo: 2,8 %; Denosumab: 1,1 %; p = 0,0386). Weitere Frakturendpunkte wurden nicht untersucht.Fazit: Denosumab reduzierte das Risiko für vertebrale Frakturen bei Patienten der HALT-Studie mit normaler und osteopenischer Knochendichte in ähnlichem Ausmaß wie im Gesamtkollektiv.

Pallation of end-stage melanoma and breast cancer patients is a challenge. Despite the generally successful use of electrochemotherapy (ECT) in these patients, response rates can still be improved. Previous studies demonstrated the anticancer potential of nano-second PEFs (nsPEFs), which are able to induce apoptosis [1] or nanopore formation when using different settings [2]. Likewise, the anticancer capacity of cold physical plasma has been demonstrated in various studies in cell lines and in xenograft tumors in mice [3-7]. The apoptotic effect of cold plasmas is mediated by a variety of reactive species being released onto the cells, where the species trigger redox signaling, and subsequent cell death in some instances [8, 9]. By contrast, PEFs act by a mechanism much less dependent on the newly generated reactive species. Our idea was to combine both treatments to improve palliative cancer treatment in the future. Malignant suspension cell lines were tested to investigate the proof of concept of additive or possible even synergistic cytotoxic effects. Plasma treatment time (kINPen) and PEF intensity as well as pulse length were varied to retrieve sublethal dosage regimens for each treatment. The sequence of combination (first plasma, then PEF or vice versa) was also modulated. To investigate the mode of action of both therapies, a number of cellular parameters were investigated. This included oxidation at cytosolic and membrane compartments, thiol content, mitochondrial depolarization, caspase activation and phosphatidylserine exposure, metabolic activity, cell membrane permeabilization, cell growth and morphology, and protection by antioxidants. Furthermore, we identified a synergistic effect of plasma and PEFs using tumorigenic adherent cells in preliminary tests.

Today s perovskite solar cells PSCs are limited mainly by their open amp; 8208;circuit voltage VOC due to nonradiative recombination. Therefore, a comprehensive understanding of the relevant recombination pathways is needed. Here, intensity amp; 8208;dependent measurements of the quasi amp; 8208;Fermi level splitting QFLS and of the VOC on the very same devices, including pin amp; 8208;type PSCs with efficiencies above 20 , are performed. It is found that the QFLS in the perovskite lies significantly below its radiative limit for all intensities but also that the VOC is generally lower than the QFLS, violating one main assumption of the Shockley amp; 8208;Queisser theory. This has far amp; 8208;reaching implications for the applicability of some well amp; 8208;established techniques, which use the VOC as a measure of the carrier densities in the absorber. By performing drift amp; 8208;diffusion simulations, the intensity dependence of the QFLS, the QFLS amp; 8208;VOC offset and the ideality factor are consistently explained by trap amp; 8208;assisted recombination and energetic misalignment at the interfaces. Additionally, it is found that the saturation of the VOC at high intensities is caused by insufficient contact selectivity while heating effects are of minor importance. It is concluded that the analysis of the VOC does not provide reliable conclusions of the recombination pathways and that the knowledge of the QFLS amp; 8208;VOC relation is of great importance

Recently, significant technological innovations have enabled the measurement of both X-ray and electron diffraction from protein microcrystals. These new microcrystallography experiments are useful when large crystals cannot be obtained, but also in other cases, such as when large crystals suffer from long-range disorder, or when uniform perturbations need to be applied rapidly to the entire crystal volume. Optimizing the preparation of protein microcrystals for this new class of experiments presents new challenges for crystallographers, who have traditionally sought to grow large, single crystals. To better understand these new challenges, we optimized the production of microcrystalline samples of cyclophilin A (CypA), starting from conditions that produced millimeter scale crystals. Next, we used these microcrystals to determine CypA structures by serial femtosecond crystallography (SFX) at two XFEL lightsources, and by microcrystal electron diffraction (microED) in an electron cryomicroscope. Here, I will present our optimization strategy for protein microcrystallization, and compare the results of X-ray and electron microcrystallography experiments with CypA. I will focus on the unique caveats of sample delivery for each method, and compare the resulting structures. The goal will be to provide insight into which microcrystallography experiment is most appropriate for which types of samples, and to share our experience with sample preparation and delivery for each type of experiment.

Background: A major contributor to the black-white mortality gap in endometrial cancer (EC) is late stage at diagnosis for black women, which may be driven by delays in diagnosis both prior to and after symptom disclosure. Methods: For phase 1, black women with EC were recruited through oncology clinics and a local cancer support group. In-depth interviews were conducted focused on experiences of menopause, postmenopausal bleeding (PMB), and symptom disclosure, and transcripts coded using directed content analysis. For phase 2, EC cases from 2001–2015 were identified in SEER-Medicare. Location, provider type, and dates of symptom report and diagnosis were defined by claims data. The diagnostic interval was then calculated and step-wise multivariate modeling used to determine factors associated with time to diagnosis. Results: Phase 1 included 11 black women from 4 states (WA, LA, GA, CA), ages 47–70, stages 1––3 at diagnosis, for a total of 147 pages of transcribed interviews. Most were insured, with access to routine medical care. Common themes were a lack of knowledge of normal vs abnormal menopausal symptoms and silencing about bleeding among friends and family. The predominant interpretation of PMB was a resumption of normal menstruation, leading to significant delay in symptom disclosure. Reporting to an MD was largely driven by increased severity of bleeding or the onset of pain. Phase 2 included 3,363 EC cases, with 293 (8%) black women. The median diagnostic interval was 28 days (IQR: 8–110 days). After adjusting for age, region, gynecologic history and other presenting symptoms, provider differences were noted with shorter time for ER MDs (84%; PP=.05) vs OBGYN. Characterization of bleeding as ‘abnormal’ rather than ‘postmenopausal’ prolonged time to diagnosis by 60% (PP=.017). Step-wise modeling showed that this association was explained by differences in diagnostic work-up: Compared to those with a biopsy within 7 days of presentation, women who had an ultrasound or no procedures had longer intervals (42% and 99%, respectively) to diagnosis (PConclusion: Among black women with access to medical care, there are modifiable factors that contribute to delays in diagnosis of EC both prior to and after symptom disclosure to a physician. This is the first study to identify targets for intervention to reduce the mortality rate in this high-risk group.

Mononuclear iron complexes in which the iron(III) ion is coordinated by a pentadentate Schiff base ligand L5 with two phenolate, two imino and one amino group can exhibit a spin crossover. In this contribution experimental results are presented for complexes with cyanate and thiocyanate as co-ligands. Furthermore, theoretical results of quantum chemical calculations of energies and entropies for the low-spin and high-spin state are shown and compared with Mossbauer results. We also demonstrate how the ligand field of the monodentate co-ligand influences the spin crossover energies and entropies in [FeIIIL5NCY] complexes.

Background Advanced stage at diagnosis is an independent, unexplained contributor to racial disparity in endometrial cancer. Objective We sought to investigate whether, prior to diagnosis, provider recognition of the cardinal symptom of endometrial cancer, postmenopausal bleeding, differs by patient race. Study Design Black and White women diagnosed with endometrial cancer (2001 through 2011) from Surveillance, Epidemiology, and End Results–Medicare who had at least 2 years of claims prior to diagnosis were identified. Bleeding diagnoses along with procedures done prior to diagnosis were captured via claims data. Multinomial logistic regression was used to evaluate the association of race with diagnostic workup and multivariate models built to determine the association of appropriate diagnostic procedures with stage at diagnosis. Results In all, 4354 White and 537 Black women diagnosed with endometrial cancer were included. Compared to White women, Black women were less likely to have guideline-concordant care: postmenopausal bleeding and appropriate diagnostic evaluation (70% vs 79%, P Conclusion The lack of recognition and evaluation of postmenopausal bleeding is associated with advanced stage at diagnosis in endometrial cancer. Older Black women are at highest risk for the most aggressive histology types, yet they are less likely to have guideline-concordant evaluation of vaginal bleeding. Efforts aimed at improving recognition–among patients and providers–of postmenopausal bleeding in Black women could substantially reduce disparities in endometrial cancer.

This study reports on the prevalence of bullying victimization at school and work among college freshmen, and the relationships between victimization and changes in alcohol consumption and alcohol problems. Web survey data at two points in time from a sample of 2118 freshmen from eight colleges and universities in the Midwestern United States indicated that 43% of students experienced bullying at school, and 33% of students experienced bullying at work. Bullying, particularly at school, consistently predicted alcohol consumption and problematic drinking, controlling for baseline drinking and other school and work stressors.

Objective To show non-inferiority of levetiracetam to sulthiame with respect to efficacy, tolerability and safety in benign epilepsy with centrotemporal spikes in a prospective, double-blinded randomized controlled trial. Methods A sample size of 60 subjects (treatment group) was calculated to show reliable statistical results for non-inferiority. A total of 44 patients could be randomly allocated to either (LEV or STM) treatment group. Explorative data analysis was performed to investigate differences in the number of treatment failure events (occurrence of a seizure during the observation period of 6 months) and total dropouts. In addition, information of the occurrence of adverse events was collected. Results 43 patients were analyzed. One patient had to be excluded due to protocol violation. Treatment failure events occurred in four patients (19.0%) in the LEV treatment group and in two patients (9.1%) in the STM treatment group, respectively, (p = 0.412). The number of dropouts due to adverse reactions was five in the LEV treatment group and one in STM treatment group (23.8% vs. 4.5%, respectively, p = 0.095). Severe adverse events occurred in patients treated with LEV (n = 2, 9.5%). The total number of dropouts due to either seizure recurrence or adverse events was significantly higher in the LEV group (n = 9, 42.9%) compared to the STM group (n = 3, 13.6%, p = 0.03). Interpretation The study results concerning non-inferiority were not conclusive, as the calculated sample size was not reached to support sufficient statistical power due to limited recruitment in a 26 months period. The rates of seizure free patients were [relatively] high in both groups. However, the results indicate that termination of drug treatment due to seizure recurrence or adverse events occurred more frequently in the LEV group compared to STM. Behavioral disturbances were the most common adverse event causing study termination.

Die Androgendeprivation ist ein wesentlicher Bestandteil der Behandlung fortgeschrittener Prostatakarzinome. In zahlreichen prospektiv randomisierten Studien wurde der Frage nachgegangen, ob zeitweise Unterbrechungen des Androgenentzugs die Entwicklung einer Kas­trationsresistenz hinauszogern und gleichzeitig die Lebensqualitat der Patienten verbessern kann. Ein Herauszogern der Kastrationsresistenz durch intermittierende Androgendeprivation (IAD) wurde in keiner Phase-III-Studie belegt. Die Uberlebensdaten der bisherigen Phase-III-Studien zeigten mit Ausnahme einer Untersuchung zumindestens keinen Uberlebensnachteil. Die Daten zur Lebensqualitat sind uneinheitlich mit einem Trend zur Verbesserung unter IAD. Dass die IAD fester Bestandteil der Behandlungspraxis ist, spiegelt sich sowohl in der deutschen als auch in der europaischen Leitlinie wider. In dieser Ubersichtsarbeit soll ein Leitfaden fur eine individualisierte Behandlung auf der Basis der aktuell publizierten Studien vorgestellt werden.

Das maligne Melanom (MM) ist ein Hauttumor, dessen Inzidenz in Mitteleuropa beangstigend ansteigt. Das MM ist zwar durch eine gute Zuganglichkeit an der Korperoberflache gekennzeichnet, aber auch durch eine fruhzeitige Metastasierung. Durch das Melanom-Screening-Programm in Deutschland werden zunehmend haufig im ambulanten Bereich Navi und Melanome in Lokalanasthesie entfernt. Nur durch Fruherkennung und komplette Exzision des Tumors ist mit hoher Wahrscheinlichkeit eine Heilung zu erzielen. In der Allgemeinchirurgie kommen die Patienten mit der Frage der Nachexzision, Entnahme von Wachterlymphknotenbiopsie (WLKB) und regionaler Lymphknotendissektion oder zur Resektion von Fernmetastasen zur Vorstellung. Entscheidend ist die genaue histologische Aufarbeitung und Beschreibung des primaren Exzidats. Betragt die Tiefenausdehnung mehr als einen Millimeter, ist eine Wachterlymphknotenbiopsie indiziert, von der dann das weitere Vorgehen und die Prognose abhangen. Da systemische Therapieformen verhaltnismasig schlechte Ansprechraten aufweisen, hat die u. U. auch wiederholte operative Therapie von regionalen oder Fernmetastasen in Zusammenarbeit zwischen Dermatoonkologie und Chirurgie einen hohen Stellenwert.

Background Blood products are a limited resource particularly in a rural setting and their appropriate use is important to maintain patient safety and minimise costs. Objective To assess the appropriateness of transfusion practices in a rural hospital. Design/Data Sources A retrospective medical record audit of packed red blood cell (PRBC) use. Setting A rural hospital 300 km northwest of Melbourne. Participants All patients in Wimmera Base Hospital who had a PRBC crossmatch request from October 2010 to March 2011 inclusive. Main outcome measures Proportion of appropriate transfusions and crossmatch to transfusion ratios. Results A total of 257 patients and 657 PRBC units were cross-matched during the study period. Of these patients, 28.4% had pre-procedure (elective) cross-matches. Of the elective cross-matches, 27.4% were inappropriate, compared with 16.1% of emergency cross-matches. The cross-match to transfusion ratio (C:T) was 1.59 for emergency requests and 5.96 for elective requests. The C:T ratio was high in the surgical and obstetrics and gynaecology departments. 16.3% of all transfusions were single-unit transfusions. Conclusions Emergency requests were predominantly appropriate but a significant proportion of elective requests were inappropriate, suggesting changes in elective crossmatch request protocols, and increased education regarding ordering blood in a rural setting.

The primary purpose of the study was to evaluate whether a pericardiectomy (PERI) alters training- or myocardial infarction (MI)-induced left ventricular hypertrophy (LVH), chamber geometry, gene expression and/or running performance. Mice were randomized into 6 groups: naive control (CONT)-sedentary (Sed), CONT-trained (Tr), PERI-Sed, PERI-Tr, MI-Sed and MI-Tr. MI mice also received a pericardiectomy as part of the MI surgical procedure. 10 weeks of treadmill running resulted in enhanced running performance-to-exhaustion in all 3 trained groups (CONT-Tr, PERI-Tr, MI-Tr) compared to sedentary cohorts (P

At present, abiraterone acetate and enzalutamide are the most commonly used substances in the first-line treatment of asymptomatic or mildly symptomatic metastatic castration-resistant prostate carcinoma (mCRPC). Since the relevant pivotal trials have demonstrated comparable clinical efficacy for both substances, further factors should be considered for the choice of treatment. As mCRPC patients usually receive several lines of treatment, different adaptation and resistance mechanisms leading to treatment failure could be important. This is indicated by daily routine observations and some initial clinical studies on resistance and different sequences of therapy. However, until the clinical relevance has been confirmed, it is mostly adverse events and comorbidities that are taken into account for the choice of first-line therapy. Also potential interactions with comedications and patient preferences should be considered. In the first-line treatment of mCRPC, ongoing discussions not only centre around the choice of medication for first-line mCRPC therapy, but also around the point in time they are started. For abiraterone acetate, for example, there is confirmed evidence that patients may benefit from early use within the approved indication. If the clinical importance of the different resistance mechanisms and differences in efficacy of various sequences could be confirmed, this would be a strong argument for therapy decisions and should therefore be further analysed in prospective clinical studies.

A two-part latent growth mixture model was implemented in order to examine heterogeneity in the growth of sexual harassment (SH) victimization in college and university students, and the extent to which SH class membership explains substance use and mental health outcomes for certain groups of students. Demographic risk factors, mental health, and substance use were examined as they related to chronically experienced SH victimization. Incoming freshmen students (N = 2855; 58% female; 54% White) completed a survey at five time points. In addition to self-reporting gender, race, and sexual orientation, students completed measures of sexual harassment, anxiety, depression, binge drinking, and marijuana use. Overall, self-reported SH declined upon college entry, although levels rebounded by the third year of college. Results also supported a two-class solution (Infrequent and Chronic) for SH victimization. Being female, White, and a sexual minority were linked to being classified into the Chronic (relative to the Infrequent) SH class. In turn, Chronic SH class membership predicted greater anxiety, depression, and substance use, supporting a mediational model.

Sexual harassment on college campuses is a frequent occurrence and serious public health concern. Victims of sexual harassment are at risk for many possible negative health consequences. In addition, certain psychological distress symptoms and/or alcohol use may put individuals at increased risk of being victims of sexual harassment. Data from more than 2,000 college students in the Midwestern United States were used to examine reciprocal causal effects of the relations between (a) experiencing sexual harassment and alcohol use and (b) experiencing sexual harassment and psychological distress symptoms, specifically depression and anger/hostility. Analyses were conducted separately for sexual harassment which occurs at school and which occurs in college students' workplaces, and also separately for men and women. Results of cross-lagged panel models showed that there were reciprocal causal effects between sexual harassment and alcohol problems, depression, and anger. Discussion focuses on the overall patterns of results as well as the nuances within these findings.

Active surveillance is an important alternative to definitive therapy for men with low risk prostate cancer. However, the impact of active surveillance on health related quality of life compared to that in men without cancer remains unknown. In this study we evaluated health related quality of life outcomes in men on active surveillance compared to men followed after negative prostate needle biopsy.A prospective study was conducted on men who were enrolled into the Center for Prostate Disease Research Multicenter National Database and underwent prostate needle biopsy for suspicion of prostate cancer between 2007 and 2014. Health related quality of life was assessed at biopsy (baseline) and annually for up to 3 years using SF-36 and EPIC questionnaires. Health related quality of life scores were modeled using generalized estimating equations, adjusting for baseline health related quality of life, and demographic and clinical characteristics.Of the 1,204 men who met the initial eligibility criteria 420 had a negative prostate needle biopsy (noncancer comparison group). Among the 411 men diagnosed with low risk prostate cancer 89 were on active surveillance. Longitudinal analysis revealed that for most health related quality of life subscales there were no significant differences between the groups in adjusted health related quality of life score trends over time.In this study most health related quality of life outcomes in patients with low risk prostate cancer on active surveillance did not differ significantly from those of men without prostate cancer. A comparison group of men with a similar risk of prostate cancer detection is critical to clarify the psychological and physical impact of active surveillance.

Introduction Benign epilepsy with centrotemporal spikes (BECTS) is a common epilepsy syndrome in childhood. Besides the occurrence of seizures, mild cognitive impairments and behavioral problems affecting language skills, spatial perception, memory, executive function, and academic achievement might be present. There is no international consensus about the decision whether or not to treat affected children. The influence of treatment on cognitive functions is debated. Methods Patients diagnosed with BECTS were assessed in short term auditory memory, long-term verbal memory, intelligence and behavior using the “number recall” test from the Kaufman assessment battery for children, the “verbal learning memory test”, the “culture free intelligence test” and the “child behavior checklist” prior to a randomized controlled antiepileptic therapy and after a treatment period of 6 months with either sulthiame or levetiracetam. Results 43 of 44 randomized patients were analyzed. One patient had to be excluded due to protocol violation. Patients who completed the study showed a non-significant improvement in parent-reported behavioral problems under therapy. Cognitive skills were not affected. Conclusion The present data suggest that antiepileptic drug treatment of children with BECTS with either sulthiame or levetiracetam does not affect cognitive performance. Behavior improved in a subset of patients though not reaching statistical significance.