Articles de revues sur le sujet « R. J. La Varis Limited »

The Heider balance (HB) is investigated in a fully connected graph of N nodes. The links are described by a real symmetric array r (i, j), i, j =1, …, N. In a social group, nodes represent group members and links represent relations between them, positive (friendly) or negative (hostile). At the balanced state, r (i, j) r (j, k) r (k, i) > 0 for all the triads (i, j, k). As follows from the structure theorem of Cartwright and Harary, at this state the group is divided into two subgroups, with friendly internal relations and hostile relations between the subgroups. Here the system dynamics is proposed to be determined by a set of differential equations, [Formula: see text]. The form of equations guarantees that once HB is reached, it persists. Also, for N =3 the dynamics reproduces properly the tendency of the system to the balanced state. The equations are solved numerically. Initially, r (i, j) are random numbers distributed around zero with a symmetric uniform distribution of unit width. Calculations up to N =500 show that HB is always reached. Time τ(N) to get the balanced state varies with the system size N as N-1/2. The spectrum of relations, initially narrow, gets very wide near HB. This means that the relations are strongly polarized. In our calculations, the relations are limited to a given range around zero. With this limitation, our results can be helpful in an interpretation of some statistical data.

The symbiotic star R Aqr is part of a small sample of binary AGB stars observed with the Atacama Large Millimeter/submillimeter Array (ALMA). The sample stars are: R Aqr, Mira, W Aql, and π1 Gru. The sample covers a range in binary separation and wind properties, where R Aqr is the source with the smallest separation. The R Aqr binary pair consists of an M-type AGB star and a white dwarf at a separation of 45 mas, equivalent to about 10 AU at 218 pc. The aim of the ALMA study is to investigate the dependence of the wind shaping on the binary separation and to provide constraints for hydrodynamical binary interaction models. R Aqr is particularly interesting as the source with the smallest separation and a complex circumstellar environment that is strongly affected by the interaction between the two stars and by the high-energy radiation resulting from this interaction and from the hot white dwarf companion. The CO(J = 3 →2) line emission has been observed with ALMA at ~0.5′′ spatial resolution. The CO envelope around the binary pair is marginally resolved, showing what appears to be a rather complex distribution. The outer radius of the CO emitting region is estimated from the data and found to be about a factor of 10 larger than previously thought. This implies an average mass-loss rate during the past ~100 yr of Ṁ ≈ 2×10−7 M⊙ yr−1, a factor of 45 less than previous estimates. The channel maps are presented and the molecular gas distribution is discussed and set into the context of what was previously known about the system from multiwavelength observations. Additional molecular line emission detected within the bandwidth covered by the ALMA observations is also presented. Because of the limited extent of the emission, firm conclusions about the dynamical evolution of the system will have to wait for higher spatial resolution observations. However, the data presented here support the assumption that the mass-loss rate from the Mira star strongly varies and is focused on the orbital plane.

Owls use interaural time differences (ITDs) to locate a sound source. They compute ITD in a specialized neural circuit that consists of axonal delay lines from the cochlear nucleus magnocellularis (NM) and coincidence detectors in the nucleus laminaris (NL). Recent physiological recordings have shown that tonal stimuli induce oscillatory membrane potentials in NL neurons (Funabiki K, Ashida G, Konishi M. J Neurosci 31: 15245–15256, 2011). The amplitude of these oscillations varies with ITD and is strongly correlated to the firing rate. The oscillation, termed the sound analog potential, has the same frequency as the stimulus tone and is presumed to originate from phase-locked synaptic inputs from NM fibers. To investigate how these oscillatory membrane potentials are generated, we applied recently developed signal-to-noise ratio (SNR) analysis techniques (Kuokkanen PT, Wagner H, Ashida G, Carr CE, Kempter R. J Neurophysiol 104: 2274–2290, 2010) to the intracellular waveforms obtained in vivo. Our theoretical prediction of the band-limited SNRs agreed with experimental data for mid- to high-frequency (>2 kHz) NL neurons. For low-frequency (≤2 kHz) NL neurons, however, measured SNRs were lower than theoretical predictions. These results suggest that the number of independent NM fibers converging onto each NL neuron and/or the population-averaged degree of phase-locking of the NM fibers could be significantly smaller in the low-frequency NL region than estimated for higher best-frequency NL.

ABSTRACT The hybrid operating room can be defined as the combination of imaging system and operating table installed in an operating theater room for, e.g. use of an angiography imaging system and operation table in an operation theatre or use of an operating table in angiography room. Shorter patient recovery time, decreased length of stay, streamlined care delivery, improvement in cross-specialty communication, minimized risk for communication-related errors across clinical specialties and lower overall cost of care are some of the advantages of the hybrid operating room. Although no/limited data exists in the literature, the potential disadvantages of hybrid operating suite are cost, infection, prolonged anesthesia and radiation exposure. The primary components of a hybrid operating suite are an imaging system and imaging compatible operation table. Area required for hybrid operating suite varies from 80 to 150 m2. The most common configuration of hybrid operating suite includes a flat panel angiographic X-ray imaging system and surgical equipment for cardiac surgery. How to cite this article Siddharth V, Kant S, Chandrashekhar R, Gupta SK. Planning Premises and Design Considerations for Hybrid Operating Room. Int J Res Foundation Hosp Healthc Adm 2014;2(1):50-56.

We interpret at a molecular level an extraordinary response in the transient kinetics of the phosphointermediate of Na(+)-K(+)-ATPase (I. Klodos, R. L. Post, and B. Forbush III. J. Biol. Chem. 269: 1734-1743, 1994). The phosphointermediate comprises two principal states. The partition between these states varies with salt concentration. A jump in salt concentration changes the partition of some of the molecules more rapidly than they interconvert in a steady state at constant salt concentration. We propose that interconversion is limited by free volume in the lipid of the surrounding membrane. This lipid is partitioned into phases that vary with salt concentration. Free volume is larger at the interface between these phases than within the phases themselves. Na(+)-K(+)-ATPase molecules are distributed at random in the membrane. When the phase boundary moves in response to a jump in salt concentration, it crosses some Na+ -K+ -ATPase molecules, which transiently experience an increase in free volume of the surrounding lipid. Thus their phosphointermediate states equilibrate more rapidly than at a constant salt concentration. Functional and structural heterogeneity of Na(+)-K(+)-ATPase molecules is discussed.

Calcium (Ca) dynamics are incorporated into a mathematical model of the principal cell in the cortical collecting tubule developed earlier in Strieter et al. (1992a. Am. J Physiol. 263:F1063-1075). The Ca components are modeled after the Othmer-Tang model for IP(3)-sensitive calcium channels (1993, in Experimental and Theoretical Advances in Biological Pattern Formation, 295-319). There are IP(3)-sensitive Ca channels and ATP-driven pumps on the membrane of the endoplasmic reticulum. Calcium enters the cell passively down its electrochemical gradient. A Ca pump and Na/Ca exchange in the basolateral membrane are responsible for the extrusion of cytoplasmic calcium. Na/Ca exchange can also operate in reverse mode to transport Ca into the cell. Regulatory effects of cytoplasmic Ca on the apical Na channels are modeled after experimental data that indicate apical Na permeability varies inversely with cytoplasmic Ca concentration. Numerical results on changes in intracellular Ca caused by decreasing NaCl in the bath and the lumen are similar to those from experiments in Bourdeau and Lau (1990. Am. J Physiol. 258:F1497-1503). This match of simulation and experiment requires the synergistic action of the Na/Ca exchanger and the Ca regulated apical Na permeability. In a homogeneous medium, cytoplasmic Ca becomes oscillatory when extracellular Na is severely decreased, as observed in experiments of cultured principal cells (Koster, H., C. van Os and R. Bindels. 1993. Kidney Int.43:828-836). This essentially pathological situation arises because the hyperpolarization of membrane potential caused by Na-free medium increases Ca influx into the cell, while the Na/Ca exchanger is inactivated by the low extracellular Na and can no longer move Ca out of the cell effectively. The raising of the total amount of intracellular Ca induces oscillatory Ca movement between the cytoplasm and the endoplasmic reticulum. Ca homeostasis is investigated under the condition of severe extracellular Ca variations. As extracellular Ca is decreased, Ca regulation is greatly impaired if Ca does not regulate apical ionic transport. The simulations indicate that the Na/Ca exchanger alone has only limited regulatory capacity. The Ca regulated apical sodium or potassium permeability are essential for regulation of cytoplasmic Ca in the principal cell of the cortical collecting tubule.

Abstract Background: BCL2, a key regulator of apoptosis, is aberrantly expressed in many hematologic malignancies, which can lead to pathologic cancer cell survival. BCL2 inhibitors have been shown to be safe and effective, resulting in their approval for the treatment of pts with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and acute myeloid leukemia. Treatment with the currently approved BCL2 inhibitor, venetoclax, can be limited by common gastrointestinal toxicities, neutropenia, and the emergence of specific BCL2 mutations around the BH3-binding groove causing resistance. BGB-11417 was developed as a potent and highly selective inhibitor of BCL2. It has shown antitumor activity superior to venetoclax in human acute lymphoblastic leukemia, mantle cell lymphoma (MCL), and diffuse large B-cell lymphoma (DLBCL) xenograft models (Hu, AACR 3077). BGB-11417 also has a favorable pharmacokinetic profile with excellent bioavailability and selectivity for BCL2 at concentration <1nM. Toxicology studies have shown a broad therapeutic index and tolerable safety profile. The combination of a BCL2 inhibitor and a BTK inhibitor is tolerable with synergistic activity in CLL and MCL pts (Hillmen, J Clin Oncol 2019;37(30):2722-9; Jain, N Engl J Med 2019;30;380(22):2095-103; Siddiqi, ASH 2020 S158; Tam, N Engl J Med 2018; 378:1211-23). Zanubrutinib is a next-generation BTK inhibitor that has shown excellent activity and favorable toxicity in pts with CLL/SLL (Hillmen, EHA 2021 LB1900) and MCL (Tam, Blood Adv 2021;5(12):2577-85); with approval for treatment in MCL. Here we report preliminary results of the BGB-11417-101 trial (NCT04277637) in pts with non-Hodgkin lymphoma (NHL) or CLL/SLL treated with BGB-11417 monotherapy or in combination with zanubrutinib. Methods: BGB-11417-101 is a phase 1, open label, multicenter, dose-escalation and expansion study. Pts with NHL or CLL/SLL are treated with BGB-11417 as monotherapy or in combination with zanubrutinib. For dose escalation, pts with R/R B-cell malignancies are enrolled in 1 of 5 potential dose levels of BGB-11417 (40, 80, 160, 320, or 640 mg once daily). All pts utilize a ramp-up to intended target dose that varies by disease type. Pts in the combination therapy arm receive zanubrutinib 320 mg daily beginning 8-12 weeks before BGB-11417 is introduced. Adverse events (AEs) are reported per Common Terminology Criteria for AEs v5.0. Dose-limiting toxicity (DLT; assessed from ramp-up through day 21 at intended daily dose), evaluated by Bayesian logistic regression model, will be used to determine the maximum tolerated dose (MTD). Results: As of 24 May 2021 (data cutoff) 19 pts had been treated; 14 pts with monotherapy (NHL: n=11; CLL/SLL: n=3) and 5 pts with combination (all CLL; 3 pts were still on zanubrutinib pretreatment; 2 had started combination treatment). Median age was 72 y (range, 50-86); median follow-up was 1.9 mo (range, 0.7-12.4); all pts were R/R with a median of 2 prior regimens (range, 1-4). No DLTs were observed in pts with NHL receiving BGB-11417 monotherapy (n=11) up to the 160 mg dose level. AEs across all dose levels occurring in ≥2 pts (monotherapy) or ≥1 pt (combination) are listed in Table 1. A total of 5 pts discontinued treatment (all NHL) due to disease progression (n=4; 2 at 40 mg, 2 at 80 mg) or lack of efficacy (n=1 at 40 mg). No pt discontinued due to AEs. Laboratory tumor lysis syndrome was observed in 1 pt with CLL and high tumor burden (resolved with no sequelae). Initial efficacy after 3-month restaging in pts with CLL/SLL demonstrated 1 partial response (monotherapy arm) at the first dose level tested. All pts with CLL/SLL who have completed ramp-up (n=2, both monotherapy) normalized absolute lymphocyte count (ALC). Marked decreases in ALC were observed in pts with CLL at doses as low as 1 mg (Figure 1). Conclusion: Preliminary results suggest that BGB-11417 monotherapy is tolerable in pts with R/R NHL at the tested dose levels. Further assessment of safety and efficacy of BGB-11417 +/- zanubrutinib in CLL/SLL and NHL will be presented at the meeting, and evaluation in patients with treatment naïve CLL/SLL, R/R MCL, and R/R WM is planned. Figure 1 Figure 1. Disclosures Tam: AbbVie: Consultancy, Honoraria, Research Funding; BeiGene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria; Loxo: Consultancy; Novartis: Honoraria; Pharmacyclics: Honoraria. Verner: Janssen-Cilag Pty Ltd: Research Funding. Lasica: Celgene: Other: Travel, Accommodations, Expenses; Janssen: Other: Education. Arbelaez: Amgen: Other: Travel, Accommodations, Expenses. Browett: AbbVie: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Soumerai: BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy, Research Funding; AbbVie: Consultancy; GlaxoSmithKline: Research Funding; BostonGene: Research Funding; BMS: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Hilger: BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Fang: BeiGene (Shanghai) Co, Ltd.: Current Employment, Current equity holder in publicly-traded company. Huang: BeiGene: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses; Protara Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Simpson: Janssen: Research Funding; GSK: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; MSD: Research Funding; Roche: Research Funding; Celgene: Research Funding; Amgen: Research Funding; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; BeiGene: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Opat: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GIlead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Monash Health: Current Employment; BeiGene: Research Funding; Sandoz: Research Funding. Cheah: Ascentage Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Lilly: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Zanubrutinib is an investigational agent and has not been approved for NHL or CLL/SLL in the US

Abstract The variability of clinical phenotype in patients with severe hemophilia A (factor VIII activity < 1%) has been well established, currently and in the era prior to wide-spread prophylaxis. The introduction of prophylaxis as a treatment modifier of the natural history of severe hemophilia A has led to the introduction of composite scores to assist in the assessment of disease severity. Perhaps the most prominent of these is that proposed by Schulman et al (J Thromb Haem 2008;6(7):1113-21) which utilizes three domains of phenotypic presentation to characterize a patient's clinical phenotype, acute (annualized bleeding rate), chronic (joint status), and treatment intensity (normalized factor usage). However, the biologic mechanisms driving this variability in clinical phenotype continue to remain largely uncertain. Procoagulant platelet potential is an individual's ability to generate procoagulant platelets in response to a standard concentration of agonist. This response, which generates platelets capable of intensely supporting coagulation, tends to remain relatively constant and varies substantially between individuals. A few small case-control studies have investigated the role of procoagulant platelet potential or platelet-supported thrombin generation in mediating the phenotypic variability with discordant results. The relationship of procoagulant platelet potential and platelet-supported thrombin generation to phenotypic severity was investigated in a single-center cohort of 92 pediatric and adult severe hemophilia A patients without active inhibitors. Procoagulant platelet potential (defined as the ratio of procoagulant platelets / all activated platelets following stimulation with thrombin (0.5 units/mL) and convulxin (250 ng/mL)) and the expression of other platelet activation markers, including P-selectin (granule release) and PAC-1 (integrin activation) were investigated in washed platelets. Platelet-dependent thrombin generation was investigated in a limited cohort (45) of these patients. Phenotypic data was collected in regard to reported bleeding events over the past 5 years, joint health using the hemophilia joint health score, intensity of factor therapy, and therapeutic intent (prophylaxis or on-demand). Correlations were assessed as continuous variables using regression analysis with p <0.05 deemed significant. Procoagulant platelet potential was inversely correlated with both acute (annualized bleeding rate) (r = -0.47, p = 0.0006) and chronic measures (joint score) (r = -0.38, p = 0.0001) of phenotypic severity. In contrast, when platelet-dependent thrombin generation or other markers of thrombin or GPVI-dependent platelet activation potential were assessed i.e. P-selectin expression or PAC-1, no correlation was identified with either acute or chronic measures of phenotypic severity or with the HSS composite score. Surprisingly, when the composite score of HSS as defined by Schulman (acute + chronic + factor utilization) was utilized to assess a potential relationship this correlation was not observed. Further analysis revealed that this lack of correlation was due to the fact that therapeutic intensity (factor utilization) was directlycorrelated with procoagulant platelet potential (r = 0.54, p = 0.0006). Here we have identified a potentially critical role for procoagulant platelets as biologic modifiers of hemophilia A. Furthermore, we have identified a risk associated with the use of a composite score in assessing disease severity in hemophilia. Utilization of a composite score as the sole measure would have missed the significant effects noted in each of the individual domains. Procoagulant platelets both support thrombin generation and inflammatory cell recruitment. Thus, one potential hypothesis for these opposing effects on the domains of the composite score is that increased procoagulant platelet formation supports stable hemostatic plug formation (reduced bleeding rate) or increases inflammatory presentation resulting in therapy intensification or both. Finally, our results here point towards new tools and pathways for risk stratification and therapeutic modulation in patients with hemophilia A based on assessment of procoagulant platelet potential. Disclosures Jobe: Shire: Consultancy; Octapharma: Consultancy; CSL: Consultancy.

Abstract Introduction: Current SARS-CoV-2 vaccines are effective at preventing COVID-19 or limiting disease severity in healthy individuals, but effectiveness is lower among patients with cancer or immunosuppression. Vaccine effectiveness wanes with time and varies by vaccine type. Moreover, current vaccines are based on the ancestral SARS-CoV-2 spike protein sequence and emerging viral variants evade vaccine induced immunity. Booster doses partially overcome these issues, but there are limited clinical data on the durability of protection afforded by boosters – especially against SARS-CoV-2 variants.Methods: Here we describe a mechanistic mathematical model for vaccination-induced immunity and use it to predict vaccine effectiveness taking into account current and possible future viral, host and vaccine characteristics. Crucially, this allows predictions over time frames currently not reported in the clinical literature. The model incorporates the infection of lung epithelium by SARS-CoV-2, the response of innate and adaptive immune cells to infection, the production of pro-and anti-inflammatory cytokines, the activation of the coagulation cascade, as well as the effects of cancer cells on the lung and on the immune response. The model further accounts for the interactions between the virus, the immune cells and the tumor cells as well as for vaccination-induced immunity.Results: Model predictions were validated with clinical data. The model predicts that for healthy individuals vaccinated and boosted with mRNA-1273, BNT-162b2a, and Ad26.COV2.S, robust immunogenicity against the ancestral and delta variant extends beyond a year. Immunogenicity is also enhanced following booster vaccination in patients with cancer on various anti-cancer therapies, including immunotherapy, and for patients without cancer on immunosuppressive agents.Conclusion: Our model predicts that ³1 booster doses will be required for these individuals to maintain protective immunity. Furthermore, for immunosuppressed individuals, simulated new SARS-CoV2 variants with enhanced ability to bind to target cells, faster replication or reduced immunogenicity could lead to breakthrough infections even after a single booster dose. Modelling data such as these may be used to anticipate and plan for future vaccination needs. Citation Format: Chrysovalantis Voutouri, Corey C Hardin, Vivek Naranbhai, Mohammad R. Nikmaneshi, Melin J. Khandekar, Justin F Gainor, Triantafyllos Stylianopoulos, Lance L. Munn, Rakesh K. Jain. Mechanistic model for booster doses effectiveness in healthy, cancer and immunosuppressed patients infected with SARS-CoV-2 [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy; 2022 Oct 21-24; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2022;10(12 Suppl):Abstract nr A64.

BackgroundAnti-transcriptional intermediary factor 1γ (anti-TIF 1γ) antibody is robustly linked with cancer-associated dermatomyositis (DM) in adults, but its specificity varies widely between series. TIF 1γ can act either as a tumor promoter or suppressor and may behave as an autoantigen.ObjectivesInvestigate the association between anti-TIF 1γ antibody positivity and development of neoplasia.MethodsA retrospective chart review was conducted among patients with positive anti-TIF 1γ antibodies detected by immunoblot from March 2019 to December 2021 in three tertiary hospitals. Demographic variables, creatine kinase (CK) values, other autoantibodies, associated autoimmune diseases (AIDs) and existence or not of a cancer diagnosis were analyzed. To rule out malignancy, patients had to present a PET-CT scan without pathological findings or a chest CT scan, a gynecological study and a digestive study without alterations. A descriptive statistical analysis was performed.Results29 patients with anti-TIF 1γ antibodies were analyzed, 82.7% women, with a mean age of 61 years (31-96 years).The reason for requesting this antibody was: clinical features suggestive of DM in 10 patients (34.5%), muscle weakness in 9 (31%), interstitial lung disease (ILD) in 5 (17.2%), persistent CK elevation in 3 (10.3%), constitutional syndrome in 1 (3.5%) and antiphospholipid syndrome in 1 patient (3.5%). The mean time from symptoms onset to the detection of anti-TIF 1γ was 14 months (0-60 months).10 patients (34.5%) had a diagnosis of DM; 4 patients (13.8%) systemic lupus erythematosus (SLE); one (3.5%) had a SLE/DM overlap syndrome; one patient (3.5%) subacute cutaneous lupus; one (3.5%) was diagnosed with diffuse systemic sclerosis; one patient (3.5%) limited systemic sclerosis; one patient (3.5%) antiphospholipid syndrome; one patient (3.5%) HLA-B27+ spondyloarthritis and 9 patients (31%) had no associated AIS.5 patients (17.2%) showed ILD with different patterns: UIP (n=2), NSIP (n=2) and COP (n=1). Only 9 patients (31%) had elevated CK levels at the time of antibody determination.10 patients (34.5%) were diagnosed with cancer: lung adenocarcinoma (n=2), small cell lung carcinoma (n=2), breast carcinoma (n=2), hepatocarcinoma (n=1), cervical cancer (n=1), ovarian carcinoma (n=1) and gallbladder adenocarcinoma (n=1). Of those, 7 patients (70%) had elevated CK levels and 6 (60%) had a diagnosis of DM. None of the patients diagnosed with cancer had ILD.In 4 patients (40%), the diagnosis of cancer was simultaneous with the diagnosis of anti-TIF 1γ antibodies; in 4 (40%), the diagnosis of the tumor preceded the finding of the antibodies; in the other 2 (20%), the finding of the antibodies preceded that of the tumor. 30-month survival after cancer diagnosis was 10%.In 17 patients (58.6%) no malignancy has been found so far in the annual cancer screening. In two patients (6.9%) no cancer screening was performed.ConclusionIn our study, 60% of patients with DM and anti-TIF 1γ presented neoplasia, a prevalence similar to that established in other series (60-80%). Furthermore, 21% of patients with antibodies and without DM were diagnosed with cancer, suggesting that anti-TIF 1γ antibodies could also be associated with neoplasia in patients without DM. Patients with ILD did not present cancer, supporting the observation of previous studies in which the presence of ILD is a marker of low risk for neoplasia in patients with DM. HyperCKemia might predict the association with neoplasia in patients with anti-TIF 1γ antibodies.References[1]De Vooght J, Vulsteke JB, De Haes P, Bossuyt X, Lories R, De Langhe E. Anti-TIF1-γ autoantibodies: warning lights of a tumour autoantigen. Rheumatology. 2020 Mar 1;59(3):469-477[2]Shimizu K, Kobayashi T, Kano M, Hamaguchi Y, Takehara K, Matsushita T. Anti-transcriptional intermediary factor 1-γ antibody as a biomarker in patients with dermatomyositis. J Dermatol. 2020 Jan;47(1):64-68[3]Masiak A, Kulczycka J, Czuszyńska Z, Zdrojewski Z. Clinical characteristics of patients with anti-TIF1-γ antibodies. Reumatologia. 2016;54(1):14-8Disclosure of InterestsNone declared

Abstract Abstract 3664 Background: Positron Emission Tomography scans performed during chemotherapy (Interim-PET) have been used prognostically in patients with Diffuse Large B-cell Lymphoma (DLBCL) and as a tool in response-adapted therapy trials. However, evidence on the predictive role of interim-PET in DLBCL has been limited by study heterogeneity in lymphoma subtypes and treatment regimens. Although earlier studies reported positive interim-PET predicted poorer outcome, a systematic review (Terasawa et al. J Clin Oncol 2009; 27(11):1906–14) could not draw reliable conclusions due to heterogeneity. Recent studies, which maintained a homogeneous patient group with regards to lymphoma subtype (DLBCL) and treatment (Rituximab-CHOP), showed conflicting results (Vitolo et al, Blood 2010; 116: Abs. 2819. Yang et al, Blood 2010; 116: 1799. Gonzalez-Barca et al Blood 2010; 116: Abs. 2793.) Aim: To evaluate the prognostic value of interim-PET in DLBCL patients receiving R-CHOP, without the confounding effect of therapy change based on interim-PET result. We seek to improve our prognostic ability by combining the International Prognostic Index (IPI) with Interim-PET results. Methods: We reviewed retrospectively consecutive DLBCL patients treated with R-CHOP as frontline therapy from 2005 to 2010 at a single institution. Interim-PET images were re-examined by a nuclear medicine physician blinded to the IPI and clinical outcomes. The PET results were classified as Negative or Positive, based on qualitative assessment of the relative intensity of FDG uptake of the area of disease compared to the adjacent mediastinal blood pool or aorta/IVC. Interim-PET was categorised as positive if the uptake was more than mildly above the blood pool intensity. One hundred patients commenced R-CHOP (14 or 21) therapy for DLBCL; 24 patients did not receive interim-PET for logistics reasons and were excluded. Progression free survival (PFS) and overall survival (OS) were analysed by the Cox proportional hazards model and prognostic accuracy was assessed using Harrell's C statistics. Results: In 76 patients analysed, the median age was 61 years (range 16–87); 59% were males. The IPI distribution was: IPI 0 (n=10), 1 (19), 2 (21), 3 (13), 4 (12), 5 (1). The median time of the interim-PET was after cycle 3. Eleven patients (14%) were positive and 65 patients (86%) were negative at Interim-PET. With a median follow-up of 32.5 months, 2-year OS and 2-year PFS (figures 1 and 2) were 70.8% and 60.0% respectively in the PET-negative group, 36.4% and 36.4% for the PET-positive group (log-rank p-value 0.003 for OS, 0.011 for PFS). Correlation analysis showed that the IPI and Interim-PET were minimally associated (rho=0.0873) and were both independent prognostic factors for survival. Cox regression analysis showed that interim PET and IPI were both significant indicators of PFS (p < 0.001 and p=0.002 respectively). The PET result makes a significant contribution to prognostication if IPI is greater than 2 (p<0.0001) and we found the contribution to vary by IPI when the score was greater than 2 (data not shown). In isolation, the prognostic accuracy of a negative PET result is poor (C = 0.63) as it is for IPI (C = 0.75), but when the two indicators are combined the predictive accuracy is improved (C = 0.81). A nomogram utilising the IPI and interim-PET results in the prediction of the 24 month relapse-free survival was created (Figure 3). Conclusion: In our hands, IPI and PET provide independent prognostic information; we found interim PET to have a negative predictive value that varies according to the IPI at diagnosis. By combining the two, a more powerful predictive model may be created as a nomogram. This should be readily testable in larger patient populations where PET data is available, and then ideally prospectively in randomised clinical trials. Example of using the Sir Charles Gairdner Hospital Nomogram: a patient with an IPI of 2 will receive a score of 33; if their interim-PET result is positive, this will produce a score of 70, resulting in a total score of 103. On the lower 2 panels, a total of 103 points is estimated to give rise to a 40% probability of Relapse-free survival at 24 months. Disclosures: No relevant conflicts of interest to declare.

This paper examines one of the literary techniques in J. R.R. Tolkien’s novel The Lord of the Rings that creates “the depth effect”: texts’ insertion. The article’s author analyzes an insert text from the second part of the prologue (“The Herblore of the Shire”) and its integration in the main plot of the novel, and also looks into interchanges between the main text and insert ones, and Meriadoc’s role as one of the secondary narrators. The Lord of the Rings is full of insert texts of various genres and “The Herblore of the Shire” is merely one of them, but it shows that such texts are not isolated and not limited to single occasions. Throughout the novel they serve as quotations that link different plot episodes and organize them around the image of the secondary narrator. According to Tolkien’s creative position that he repeatedly stated in his letters, we can say that he carefully contemplated the ways of involving his reader in his fantastic world; that is why it is important to describe narrative and compositional techniques of the novel that served the author’s purpose.

Introduction: The overall survival of children with ALL (Acute Lymphoblastic Leukemia) has improved markedly over the last decade, yet relapse occurs in about 20% of patients. The spread of leukemic blasts to the Central Nervous System (CNS) and increased resistance to therapy due to cell adherence within the Bone Marrow (BM) or CNS constitutes major challenges to treatment. For these reasons, adhesion molecules governing the homing and adhesion of leukemic cells are perceived to be of extraordinary importance, both as potential biomarkers and therapeutic targets. Integrins constitute a large family of heterodimeric receptors composed of alpha and beta subunits, which play important roles during homing and migration of normal leucocytes by facilitating adhesion to both stromal cells and components of the extracellular matrix. Increased expression of CD49d (integrin subunit α4) is a marker for adverse prognosis in ALL and recently, CD49f (integrin subunit α6) was shown to facilitate metastasis of ALL xenografts to the central nervous system in mice (Yao H et al., Nature 2018). Methods Previous studies of integrins in BCP-ALL have focused on individual alpha integrins in xenograft models and were based on limited numbers of clinical samples. The present study was based on a large number of Danish pediatric BCP-ALL patients stratified between 2012-2018 using Minimal Residual Disease (MRD) according to the Nordic NOPHO-2008 protocol (Toft N et al., Eur J Haematol 2013). Diagnostic BM samples were subjected to flowcytometric analysis (FCM) of CD49f (n=246) and CD49d (n=135), using a backbone of lineage-specific B-cell markers (CD45, CD10, CD19, CD20). Leukemic blasts were detected in Cerebrospinal Fluid (CSF) using high-sensitivity FCM and the following markers CD45, CD10, CD19, CD20, CD34 and CD38 (n = 246, with matching BM and CSF samples). Results Our data provided us with a unique possibility to identify the role of CD49d and CD49f with respect to minimal residual disease (MRD) at the end of induction therapy (day 29), which is considered the most important prognostic factor in paediatric lymphoblastic leukemia. We found that CD49f was more highly expressed in patients with MRD ≥ 0,1% at day 29 than patients with MRD < 0,1% (p = 0,01), whereas no difference was seen with respect to CD49d. We also investigated the correlation between white blood cell (WBC) and surface expression of CD49d and CD49f in diagnostic BM blasts with respect to different cytogenetic subtypes. A Kruskall-Wallis test showed that the expression varies according to genetic subtypes (p‹0.0001). We found that the expression of CD49d was highest among the high hyperdiploid and iAMP21 (intrachromosomal amplification of chromosome 21) patients, whereas the expression of CD49f was highest among the t12,21 and iAMP21 patients. Notably, the expression of CD49f was inversely correlated to WBC (r=0,17, p=0.01), which was most pronounced among the patients in the B-other cytogenetic subgroup defined as leukaemia that could not be classified into the existing cytogenetic groups (r=0,42, P‹0.0001). In case of strong adherence to BM, lower levels of leukemic blasts might be expected in circulation resulting in high MRD but low WBC. Therefore, both MRD and WBC data are consistent with a prominent adhesive role of CD49f within BM. In contrast, we found significantly lower CD49f surface expression in diagnostic BM samples in patients with leukemic blasts within CSF (p=0.0297). Conclusions: Recently, Yao et al. (2018) showed that ALL cells in circulation are unable to breach the blood-brain barrier in mice and instead employ CD49f (integrin α6) to migrate into the CNS along vessels that connect vertebral or calvarial bone marrow and the subarachnoid space. Potentially, this mechanism could account for cases of ALL relapse within CNS. Our work shows a strong association between high MRD and the expression of CD49f which is a function that would have been anticipated for CD49d due to previous works with ALL and CLL. Furthermore, we found significantly lower CD49f surface expression in leukemic blasts within the BM in patients with CSF involvement and therefore no support for the recently proposed role of CD49f in facilitating the spread of leukemic cells to the CNS. Disclosures No relevant conflicts of interest to declare.

The evaluation of J-integral from experimental data requires the ηpl and γ functions. However, these functions are available for limited geometry in the literature. In this paper, limit-load-based general expressions of ηpl and γ functions have been derived. These general expressions are then utilized to derive the ηpl and γ functions for through-wall circumferentially/axially cracked elbows under in-plane bending moment which are not available in the literature. The functions are then applied to generate J-R curves from fracture experiments of elbows. Finite element analyses of the tested elbows are also described in the paper.

Introdução: As alterações vasculares são anomalias de desenvolvimento dos vasos que proporcionam acúmulo de sangue e são de etiologia desconhecida. Fazem parte deste grupo de lesões as malformações arteriovenosas, hemangiomas, linfoangiomas e varicosidades. Embora não raras, as lesões vasculares que ocorrem nos lábios, por vezes, interferem na estética e apresentam dificuldades quanto ao seu diagnóstico e tratamento. Objetivo: Descrever um caso clínico realizado com laser de diodo de alta potência para a fotocoagulação de uma lesão vascular, abordando suas vantagens e limitações em comparação ao tratamento cirúrgico. Material e Método: O procedimento foi realizado em um paciente de 53 anos, sexo feminino, branca, com queixa de aparecimento de uma bolha de sangue no lábio com evolução de aproximadamente oito anos. Ao exame físico intraoral, observou-se nódulo em vermelhão do lábio inferior, do lado direito, próxima à comissura labial, medindo aproximadamente 1,0 cm de diâmetro, de base séssil, superfície lisa, limites bem definidos, coloração violácea, consistência macia e sem sintomatologia dolorosa à palpação. Após a diascopia e diagnóstico clínico de lesão vascular, optou-se pela fotocoalulação com laser de diodo de alta potência. Resultados: Houve regressão total da lesão, após uma única aplicação, sem complicações trans e pós-operatórias, sem sangramento durante a cirurgia, o que proporcionou melhor visão do campo operatório e resultou em um procedimento minimamente invasivo. A paciente encontra-se em proservação, sem recidiva da lesão. Conclusão: A fotocoagulação pode ser considerada como uma alternativa segura e eficiente para o tratamento de lesões vasculares. Descritores: Lesões do Sistema Vascular; Fotocoagulação; Laser; Mucosa Bucal. 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The demand for electronic devices with high storage capacities and long-lasting batteries has motivated the development of new battery systems. Metal-air and semiconductor-air batteries are particularly interesting due to their high capacity densities due to the use of air for the cathode reaction. The Si-air battery was introduced as a battery system that operated with a room-temperature ionic liquid or KOH as the electrolyte.[1,2] However, the practical capacity density is reduced to a fraction of the theoretical value in liquid electrolytes, and the passivation of the silicon anode in aqueous electrolytes is a major challenge.[3,4] Increasing the surface area of the Si electrode can reduce the local reaction rate and enable the dissolution of the reaction products, but it also increases the overall corrosion rate. A threshold temperature and the addition of fresh electrolyte solution can also extend the discharge duration.[3,5] Silicon-air batteries have the potential to become the next generation of batteries, as they are made from non-critical raw materials and have a high theoretical capacity. However, silicon-air batteries using alkaline electrolytes suffer from early passivation and termination of discharge. To understand this process, we investigated the correlation between dissolved silicon in the electrolyte and the discharge duration until passivation. Our findings revealed that silicate enrichment in the electrolyte reduces the flow of reaction products away from the silicon surface, leading to rapid oxidation and passivation of the surface.[6] We utilized various techniques, including electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM), to investigate this phenomenon further. Our results showed that the silicate concentration in the electrolyte plays a crucial role in determining the performance of silicon-air batteries. A lower concentration of silicates in the electrolyte leads to sustained discharge, while a higher concentration results in early passivation and termination of discharge. In conclusion, our investigation highlights the critical role of silicates in the performance of silicon-air batteries utilizing alkaline solutions. Our findings suggest that controlling the concentration of silicates in the electrolyte is crucial to ensure the sustained discharge of these batteries. This study provides essential insights into the mechanisms governing the passivation of silicon surfaces in alkaline electrolytes, which will aid in the development of more efficient and sustainable energy storage solutions. [1] G. Cohn, D. Starosvetsky, R. Hagiwara, D. D. Macdonald, Y. Ein-Eli, Electrochem. commun. 2009, 11, 1916–1918. [2] X. Zhong, H. Zhang, Y. Liu, J. Bai, L. Liao, Y. Huang, X. Duan, ChemSusChem 2012, 5, 177–180. [3] Y. E. Durmus, Ö. Aslanbas, S. Kayser, H. Tempel, F. Hausen, L. G. J. G. J. de Haart, J. Granwehr, Y. Ein-Eli, R.-A. A. Eichel, H. Kungl, Electrochim. Acta 2017, 225, 215–224. [4] Y. E. Durmus, S. Jakobi, T. Beuse, Ö. Aslanbas, H. Tempel, F. Hausen, L. G. J. de Haart, Y. Ein-Eli, R.-A. Eichel, H. Kungl, J. Electrochem. Soc. 2017, 164, A2310–A2320. [5] S. Sarwar, M. Kim, G. Baek, I. Oh, H. Lee, Bull. Korean Chem. Soc. 2016, 37, 997–1003. [6] R. Schalinski, S. L. Schweizer, R. B. Wehrspohn, ChemSusChem 2023, DOI 10.1002/cssc.202300077.

This study aims to develop a 'learning module' identification of material content based on research and local wisdom. This module is a refinement of the Material Physics module. This course is an option; therefore the content tends towards the development of talent and interest to motivate the Master's degree. During this study more based on literature studies, the means are very limited. As a result, many curiosity and student awareness can not be missed because learning through research is very limited. The development of research-based modules and local wisdom can support the needs of students to conduct research. The research method used in this research is R & D research using Borg & Gall development model including product analysis, development, expert validation and revision, small field trial phase, large scale field trial and final product result. Learning module on subject matter identification of research-based materials and local wisdom as a product of development.

This research aims to develop an electronic module based on Canva to enhance environmental awareness among seventh-grade students. The module development process utilized the Research and Development (R&D) approach with the Borg and Gall development model. The development steps include field studies, planning, initial product development, limited testing, product revision, extensive testing, effectiveness evaluation, and final product revision. The E-JASBIO module contains materials on environmental pollution, presented in an engaging format with the integration of Quranic verses. The validation results from experts indicate a high level of suitability, with media experts rating it at 81%, material experts at 92%, and language experts at 88%. Field testing involving limited participants showed positive responses from teachers (78%) and students (80%), indicating the module's effectiveness. In conclusion, the E-JASBIO module is deemed highly suitable and effective in enhancing environmental awareness among seventh-grade students, with its engaging content and integration of multimedia elements contributing to its success.

X-Linked Protocadherin 19 Mutations Cause Female-Limited Epilepsy and Cognitive Impairment. Dibbens LM, Tarpey PS, Hynes K, Bayly MA, Scheffer IE, Smith R, Bomar J, Sutton E, Vandeleur L, Shoubridge C, Edkins S, Turner SJ, Stevens C, O'Meara S, Tofts C, Barthorpe S, Buck G, Cole J, Halliday K, Jones D, Lee R, Madison M, Mironenko T, Varian J, West S, Widaa S, Wray P, Teague J, Dicks E, Butler A, Menzies A, Jenkinson A, Shepherd R, Gusella JF, Afawi Z, Mazarib A, Neufeld MY, Kivity S, Lev D, Lerman-Sagie T, Korczyn AD, Derry CP, Sutherland GR, Friend K, Shaw M, Corbett M, Kim HG, Geschwind DH, Thomas P, Haan E, Ryan S, McKee S, Berkovic SF, Futreal PA, Stratton MR, Mulley JC, Gecz J. Nat Genetics 2008;40(6):776–781. Epilepsy and mental retardation limited to females (EFMR) is a disorder with an X-linked mode of inheritance and an unusual expression pattern. Disorders arising from mutations on the X chromosome are typically characterized by affected males and unaffected carrier females. In contrast, EFMR spares transmitting males and affects only carrier females. Aided by systematic resequencing of 737 X chromosome genes, we identified different protocadherin 19 ( PCDH19) gene mutations in seven families with EFMR. Five mutations resulted in the introduction of a premature termination codon. Study of two of these demonstrated nonsense-mediated decay of PCDH19 mRNA. The two missense mutations were predicted to affect adhesiveness of PCDH19 through impaired calcium binding. PCDH19 is expressed in developing brains of human and mouse and is the first member of the cadherin superfamily to be directly implicated in epilepsy or mental retardation.

There are different apprehensions regarding the contemporary assessment system. Often, I listen to my colleagues saying that multiple-choice questions are seen as easier to score. Why can’t all assessments be multiple-choice tests? Some others would say, whether the tests given reflect what students will need to know as competent professionals? What evidence can be collected to make sure that test content is relevant? Others come up with concerns that there is a perception amongst students that some examiners are harsher than others and some tasks are easier than others. What can be done to evaluate whether this is the case? Sometimes, the students come up with queries that they are concerned about being observed when interacting with patients. They are not sure why this is needed. What rationale is there for using workplace-based assessment? Some of the students worry if the pass marks for the assessments are ‘correct’, and what is the evidence for the cut-off scores? All these questions are important, and I would deliberate upon them with evidence from the literature. Deliberating on the first query of using multiple-choice questions for everything, we know that assessment of a medical student is a complex process as there are multiple domains of learning such as cognition, skills, and behaviors (Norcini and McKinley, 2007)(Boulet and Raymond, 2018). Each of the domains further has multiple levels from simple to complex tasks (Norcini and McKinley, 2007). For example, the cognition is further divided into six levels, starting from recall (Cognition level 1 or C1) up to creativity (Cognition level 6 or C6) (Norcini and McKinley, 2007). Similarly, the skills and behaviors also have levels starting from observation up to performance and practice (Norcini and McKinley, 2007). Moreover, there are different competencies within each domain that further complicates our task as an assessor to appropriately assess a student (Boulet and Raymond, 2018). For instance, within the cognitive domain, it is not just making the learning objectives based on Bloom’s Taxonomy that would simplify our task because the literature suggests that individuals have different thinking mechanisms, such as fast and slow thinking to perform a task (Kahneman, 2011). We as educationalists do not know what sort of cognitive mechanism have we triggered through our exam items (Swanson and Case, 1998). Multiple Choice Questions is one of the assessment instruments to measure competencies related to the cognitive domain. This means that we cannot use multiple-choice questions to measure the skills and behaviors domains, so clearly multiple-choice questions cannot assess all domains of learning (Vleuten et al, 2010). Within the cognitive domain, there are multiple levels and different ways of thinking mechanisms (Kahneman, 2011). Each assessment instrument has its strength and limitations. Multiple-choice questions may be able to assess a few of the competencies, also with some added benefits in terms of marking but there always are limitations. The multiple-choice question is no different when it comes to the strengths and limitations profile of an assessment instrument (Swanson and Case, 1998). There are certain competencies that can be easily assessed using multiple-choice questions (Swanson and Case, 1998). For example, content that requires recall, application, and analysis can be assessed with the help of multiple-choice questions. However, creativity or synthesis which is cognition level six (C6) as per Blooms’ Taxonomy, cannot be assessed with closed-ended questions such as a multiple-choice question. This means that we need some additional assessment instruments to measure the higher levels of cognition within the cognitive domain. For example, asking students to explore an open-ended question as a research project can assess the higher levels of cognition because the students would be gathering information from different sources of literature, and then synthesizing it to answer the question. It is reported that marking and reading the essay questions would be time-consuming for the teachers (McLean and Gale, 2018). Hence, the teacher to student’s ratio in assessing the higher levels of cognition needs to be monitored so that teachers or assessors can give appropriate time to assess the higher levels of cognition of their students. Hence, we have to use other forms of assessment instruments along with multiple-choice questions to assess the cognitive domain. This will help to assess the different levels of cognition and will also incite the different thinking mechanisms. Regarding the concerns, whether the tests given reflect what students will need to know as competent professionals? What evidence can be collected to make sure that test content is relevant? It is one of an important issue for medical education and assessment directors whether the tests that they are taking are reflective of the students being competent practitioners? It is also quite challenging as some of the competencies such as professionalism or professional identity formation are difficult to be measured quantitatively with the traditional assessment instruments (Cruess, Cruess, & Steinert, 2016). Moreover, there is also a question if all the competencies that are required for a medical graduate can be assessed with the assessment instruments presently available? Hence, we as educationalists have to provide evidence for the assessment of required competencies and relevant content. One of the ways that we can opt is to carefully align the required content with their relevant assessment instruments. This can be done with the help of assessment blueprints, or also known as the table of specifications in some of the literature (Norcini and McKinley, 2013). An assessment blueprint enables us to demonstrate our planned curriculum, that is, what are our planned objectives, and how are we going to teach and assess them (Boulet and Raymond, 2018). We can also use the validity construct in addition to the assessment blueprints to provide evidence for testing the relevant content. Validity means that the test is able to measure what it is supposed to measure (Boulet and Raymond, 2018). There are different types of validity but one of the validity that is required in this situation to establish the appropriateness of the content is the Content Validity. Content validity is established by a number of subject experts who comment on the appropriateness and relevance of the content (Lawshe, 1975). The third method by which the relevance of content can be established is through standard-setting. A standard is a single cut-off score to qualitatively declare a student competent or incompetent based on the judgment of subject experts (Norcini and McKinley, 2013). There are different ways of standard-setting for example Angoff, Ebel, Borderline method, etc. (Norcini and McKinley, 2013). Although the main purpose is the establishment and decides the cut-off score during the process, the experts also debate on the appropriateness and relevance of the content. This means that the standard-setting methods also have validity procedures that are in-built in their process of establishing the cut-off score. These are some of the methods by which we can provide evidence of the relevance of the content that is required to produce a competent practitioner. The next issue is the perception amongst students that some examiners are harsher than others and some tasks are easier than others. Both these observations have quite a lot of truth in them and can be evaluated following the contemporary medical education evaluation techniques. The first issue reported is that some examiners are harsher than others. In terms of assessment, it has been reported in the literature as ‘hawk dove effect’ (McManus et al, 2006, Murphy et al, 2009). There are different reasons identified in the literature for some of the examiners to be more stringent than others such as age, ethnic background, behavioral reasons, educational background, and experience in a number of years (McManus et al, 2006). Specifically, those examiners who are from ethnic minorities and have more experience show more stringency (McManus et al, 2006). Interestingly, it has been reported elsewhere how the glucose levels affect the decision making of the pass-fail judgments (Kahneman, 2011). There are psychometric methods reported in the literature, such as Rasch modeling that can help determine the ‘hawk dove effect’ of different examiners, and whether it is too extreme or within a zone of normal deviation (McManus et al, 2006, Murphy, et al, 2009). Moreover, the literature also suggests ways to minimize the hawk-dove effect by identifying and paring such examiners so the strictness of one can be compensated by the leniency of the other examiner (McManus et al, 2006). The other issue in this situation is that the students find some tasks easier than others. This is dependent on the complexity of tasks and also on the competence level of students. For example, a medical student may achieve independent measuring of blood pressure in his/her first year but even a consultant surgeon may not be able to perform complex surgery such as a Whipple procedure. This means that while developing tasks we as educationalists have to consider both the competence level of our students and the complexity of the tasks. One way to theoretically understand it is by taking help from the cognitive load theory (Merrienboer 2013). The cognitive load theory suggests that there are three types of cognitive loads; namely, the Intrinsic, Extraneous, and Germane loads (Merrienboer 2013). The intrinsic load is associated with the complexity of the task. The extraneous load is added to the working memory of students due to a teacher who does not plan his/her teaching session as per students' needs (Merrienboer 2013). The third load is the germane or the good load that helps the student to understand the task and is added by using teaching methods that helps students understand the task (Merrienboer 2013). The teachers can use different instructional designs such as the 4CID model to plan their teaching session of the complex tasks (Merrienboer 2013). One of the ways to understand the difficulty of the task can be to pilot test the task with few students or junior colleagues. Another way to determine the complexity of the task can be through standard-setting methods where a cut-off score is established after the experts discuss each task and determine its cut-off score based on their judgments (Norcini and McKinley, 2013). However, it is important that the experts who have been called for setting standards have relevant experience so as to make credible judgments (Norcini and McKinley, 2013). A third way to evaluate the complexity of tasks is by applying the post-exam item analysis techniques. The difficulty of the task is evaluated after the performance of students in the exam. Each item’s difficulty in the exam can be measured. The items can be placed from extremely easy (100% students correctly answered the item) to extremely difficult (100% students failed on that specific item). The item analysis enables the teachers to determine which tasks were easier in exams as compared to more difficult tasks. Another concern that comes from students is about their observation when interacting with patients. Health professions training programs require the interaction of students with patients. The student-patient interaction is not very often in initial years of student’s training due to the issues of patient safety, and due to the heavy workload on clinical faculty. However, with the passage of time in the training program, these student patient interactions increase. There is also a strong theoretical basis for better learning when the students are put in a context or a given situation (Wenger, 1998). For example, infection control can be taught through a lecture however the learning can be more effective if the students practically learn it in an operation theatre. Moreover, the undergraduate students or foundation year house job doctors are yet not competent enough to practice independently and require supervision for the obvious reasons of patient safety. Although, some of the students may not like being observed it is one of the requirements for their training. The examiners observing them can give them constructive feedback to further improve their performance (Etheridge and Boursicot, 2013). Feedback is one of the essential components of workplace-based assessments, and it is suggested in the literature that the time for feedback to the student should be almost equal to one-third of the procedure or task time (Etheridge and Boursicot, 2013), that is, for a fifteen minutes tasks, there should be at least five minutes for the feedback hence having a total of twenty minutes time on the whole. Further, it is important for the examiners and senior colleagues to establish trust in the competence of their students or trainees. The ‘trust’ is one of the behavioral constructs that also starts initially with an observation (Etheridge and Boursicot, 2013). Hence, observation of students or house officers by senior colleagues or teachers during clinical encounters is important to establish trust in student’s competence levels. Additionally, in the workplace, there are different skills that are required by the students to demonstrate, and each skill is quite different to others. There are different workplace-based assessment instruments and each of them assesses only certain aspects of student’s performance during clinical practice. For instance, the Mini Clinical Evaluation Exercise (Mini-CEX) can primarily assess the history taking and physical examination skills of students (Etheridge and Boursicot, 2013). Similarly, the Directly Observed Procedural Skills (DOPS) is required to assess the technical and procedural skills of students (Etheridge and Boursicot, 2013). More so, the Case-based Discussion (CBD) is required to assess clinical reasoning skills, decision-making skills, ethics, and professionalism (Etheridge and Boursicot, 2013). Further, multi-source feedback (MSF) or 360-degree assessment collects feedback about a student on their performance from multiple sources such as patients, senior and junior colleagues, nursing staff, and administrative staff (Etheridge and Boursicot, 2013). All these workplace-based assessments require observation of students so they can be given appropriate feedback on their technical and nontechnical skills (Etheridge and Boursicot, 2013). Hence, clinical encounters at the workplace are quite complex and require training of students from different aspects to fully train them that cannot be accomplished without observation. Some students also worry whether the pass marks for the assessments are ‘correct’, and what is the evidence for the cut-off score in their exams? A standard is a single cut-off score that determines the competence of a student in a particular exam (Norcini and McKinley, 2013). The cut-off score is decided by experts who make a qualitative judgment (Norcini and McKinley, 2013). The purpose is not to establish an absolute truth but to demonstrate the creditability of pass-fail decisions in an exam (Norcini and McKinley, 2013). There are certain variables related to standard setters that may affect the creditability of the standard-setting process; such as age, gender, ethnicity, their understanding of the learners, their educational qualification, and their place of work. Moreover, the definition of competence varies with time, place and person (Norcini and McKinley, 2013). Hence, it is important that the standard setters must know the learners and the competence level expected from them and the standard setters must be called from different places. This is one of the first requirements to have the profile of the standard setters to establish their credibility. Moreover, the selection of the method of standard setting is important, and how familiar are the standard setters with the method of standard-setting. There are many standard-setting methods for different assessment instruments and types of exams (Norcini and McKinley, 2013). It is essential to use the appropriate standard-setting method, and also to train the standard setters on that method of standard setting so they know the procedure. The training can be done by providing them certain data to solve it following the steps of the standard-setting procedure. The record of these exercises is important and can be required at later stages to show the experience of the standard setters. Further, every standard-setter writes a cut-off score for each item (Norcini and McKinley, 2013). The mean score of all the standard setters is calculated to determine the cut-off score for each item (Norcini and McKinley, 2013). The total cut-off score is calculated by adding the pass marks of each individual item (Norcini and McKinley, 2013). The cut-off scores for items would also help in differentiating the hawks from doves, that is, those examiners who are quite strict from those who are lenient (McManus et al, 2006). Hence, it is important to keep the record of these cut-off scores of each item for future records and to have a balanced standard-setting team for future exams (Norcini and McKinley, 2013). Additionally, the meeting minutes is an important document to keep the record for the decisions made during the meeting. Lastly, the exam results and post-exam item analysis is an important document to see the performance of students on each item and to make comparisons with the standard-setting meeting (Norcini and McKinley, 2013). It would be important to document the items that behaved as predicted by the standard setters and those items that would show unexpected responses; for example, the majority of the borderline students either secured quite high marks than the cut-off score or vice versa (Norcini and McKinley, 2013). All the documents mentioned above would ensure the creditability of the standard-setting process and would also improve the quality of exam items. There are many other aspects that could not be discussed in this debate on the contemporary assessment system in medical education. Another area that needs deliberations is the futuristic assessment system and how it would address the limitations of the current system? Disclaimer: This work is derived from one of the assignments of the author submitted for his certificate from Keele University. -------------------------------------------------------------------------- References Boulet, J. and Raymond, M. (2018) ‘Blueprinting: Planning your tests. FAIMER-Keele Master’s in Health Professions Education: Accreditation and Assessment. Module 1, Unit 2.’, FAIMER Centre for Distance Learning, CenMEDIC. 6th edn. London, pp. 7–90. Cruess, R. L., Cruess, S. R., & Steinert, Y. (2016). ‘Amending Miller’s pyramid to include professional identity formation’. Acad Med, 91(2), pp. 180–185. Etheridge, L. and Boursicot, K. (2013) ‘Performance and workplace assessment’, in Dent, J. A. and Harden, R. M. (eds) A practical guide for medical teachers. 4th edn. London: Elsevier Limited. Kahneman, D. (2011) Thinking, fast and slow. New York: Farrar, Straus and Giroux. Lawshe, CH. (1975) A quantitative approach to content validity. Pers Psychol, 28(4), pp. 563–75. McLean, M. and Gale, R. (2018) Essays and short answer questions. FAIMER-Keele Master’s in Health Professions Education: Accreditation and Assessment. Module 1, Unit 5, 5th edition. FAIMER Centre for Distance Learning, CenMEDIC, London. McManus, IC. Thompson, M. and Mollon, J. (2006) ‘ Assessment of examiner leniency and stringency (‘hawk-dove effect’) in the MRCP(UK) clinical examination (PACES) using multi-facet Rasch modelling’ BMC Med Educ. 42(6) doi:10.1186/1472- 6920-6-42 Merrienboer, J.J.G. (2013) ‘Instructional Design’, in Dent, J. A. and Harden, R. M. (eds) A practical guide for medical teachers. 4th edn. London: Elsevier Limited. Murphy, JM. Seneviratne, R. Remers, O and Davis, M. (2009) ‘Hawks’ and ‘doves’: effect of feedback on grades awarded by supervisors of student selected components, Med Teach, 31(10), e484-e488, DOI: 10.3109/01421590903258670 Norcini, J. and McKinley, D. W. (2007) ‘Assessment methods in medical education’, Teaching and Teacher Education, 23(3), pp. 239–250. doi: 10.1016/j.tate.2006.12.021. Norcini, J. and Troncon, L. (2018) Foundations of assessment. FAIMER-Keele Master’s in Health Professions Education: Accreditation and Assessment. Module 1, Unit 1. 6th edn. London: FAIMER Centre for Distance Learning CenMEDIC. Norcini, J. and McKinley, D. W. (2013) ‘Standard Setting’, in Dent, J. A. and Harden, R. M. (eds) A practical guide for medical teachers. 4th edn. London: Elsevier Limited. Swanson, D. and Case, S. (1998) Constructing written test questions for the basic and clincial sciences. 3rd Ed. National Board of Medical Examiners. 3750 Market Street Philadelphia, PA 19104. Van Der Vleuten, C. Schuwirth, L. Scheele, F. Driessen, E. and Hodges, B. (2010) ‘The assessment of professional competence: building blocks for theory development’, Best Practice & Research Clinical Obstetrics and Gynecology, pp. 1-17. doi:10.1016/j. bpobgyn.2010.04.001 Wenger, E. (1998). Communities of practice: Learning, meaning, and identity. Cambridge university press.

ABSTRACT Patients usually under-report symptoms of incontinence. Therefore, improved physician-patient communication is vital. Most urinary incontinence can be evaluated and treated after careful history and simple clinical assessment. Initial treatment, for both urge urinary incontinence and stress urinary incontinence, is lifestyle modification and pelvic floor muscle exercises. Urgency responds to bladder training and drug therapy with anticholinergic medication. Pharmacotherapy has a limited place in stress incontinence. How to cite this article Malhotra N, Garg R, Agrawal P, Rawat R. Urinary Incontinence: Revisited. J South Asian Feder Obst Gynae 2014;6(2):107-111.

This study aims to develop adobe flash learning media based on metacognitive abilities. The research method used is research and development (R&D) with the ADDIE model, which consists of 5 stages: Analysis, Design, Development, Implementation, and Evaluation.This research was conducted at SMA Negeri 1 Bantarkalong in the odd semester of the 2021/2022 academic year. Limited trials were carried out on five students of class XII MIPA 1, and field tests were carried out on class XII MIPA 2, which amounted to 21 people. The validation results of material and media experts stated that the adobe flash learning media based on metacognitive abilities was valid and could be used with some improvements.Based on the questionnaire responses, the limited trial students scored 191 in the "Good" category.At the same time, the results of the teacher's response questionnaire got a score of 132 in the "Very Good" class.Then the teaching activity observation sheet results obtained a teaching implementation score of 94% with the "Very Good" category. In addition, the results of the questionnaire responses from field test students scored 866 in the "Very Good" category.

We document a seemingly unique case of severe prosopagnosia, L. R., who suffered damage to his anterior and inferior right temporal lobe as a result of a motor vehicle accident. We systematically investigated each of three factors associated with expert face recognition: fine-level discrimination, holistic processing, and configural processing (Experiments 1-3). Surprisingly, L. R. shows preservation of all three of these processes; that is, his performance in these experiments is comparable to that of normal controls. However, L. R. is only able to apply these processes over a limited spatial extent to the fine-level detail within faces. Thus, when the location of a given change is unpredictable (Experiment 3), L. R. exhibits normal detection of features and spatial configurations only for the lower half of each face. Similarly, when required to divide his attention over multiple face features, L. R. is able to determine the identity of only a single feature (Experiment 4). We discuss these results in the context of forming a better understanding of prosopagnosia and the mechanisms used in face recognition and visual expertise. We conclude that these mechanisms are not “all-or-none”, but rather can be impaired incrementally, such that they may remain functional over a restricted spatial area. This conclusion is consistent with previous research suggesting that perceptual expertise is acquired in a spatially incremental manner [Gauthier, I., & Tarr, M. J. Unraveling mechanisms for expert object recognition: Bridging brain activity and behavior. Journal of Experimental Psychology: Human Perception & Performance, 28, 431-446, 2002].

ABSTRACT The esophageal perforation is the result of an iatrogenic cause, spontaneous cause or external trauma. The injury belonging to trauma can have different etiologies, such as the ones that are caused because of strange bodies or caustic substances. Within complications that can appear in esophageal perforation, we have the descending necrotizing mediastinitis, which is a mediastinal infection that starts in the oropharyngeal area. The spread of the infection through the anatomical spaces to the mediastinum can produce a mortality of 67%. How to cite this article Arízaga S, Rodas EB, Pino R, Reinoso J, Salamea JC. Descending Necrotizing Cervicomediastinitis Secondary to Esophageal Perforation: Management in a Hospital with Limited Resources. Panam J Trauma Crit Care Emerg Surg 2015;4(1):23-29.

Does visual working memory represent a fixed number of objects, or is capacity reduced as object complexity increases? We measured accuracy in detecting changes between sample and test displays and found that capacity estimates dropped as complexity increased. However, these apparent capacity reductions were strongly correlated with increases in sample-test similarity ( r = .97), raising the possibility that change detection was limited by errors in comparing the sample and test, rather than by the number of items that were maintained in working memory. Accordingly, when sample-test similarity was low, capacity estimates for even the most complex objects were equivalent to the estimate for the simplest objects ( r = .88), suggesting that visual working memory represents a fixed number of items regardless of complexity. Finally, a correlational analysis suggested a two-factor model of working memory ability, in which the number and resolution of representations in working memory correspond to distinct dimensions of memory ability.

This study aims to develop chemistry animation media of redox reactions. The study was conducted by using the approach of R & D by Borg & Gall including preliminary study, early product development, validation, limited testing, product revision, and the testing stage. To examine the effectiveness of media on students’ motivation and learning outcomes using the stages of classroom action research (CAR) was conducted at SMAN 4 Praya. Data of the study was collected through activity observation, questionnaires, and achievement test. Based on the result, it can be concluded that students’ cognitive achievement hasclassical completeness by 61% in cycle 1 and 78 % in cycle 2. The average of students’ motivation also improveby 69 in cycle 1 and by 75 in cycle 2 although both are included in the middle category.

Abstract Introduction In acute myeloid leukemia (AML) older age is independently associated with poor outcome, due to patient- and disease-related factors. Different genetic profiles characterize AML patients and their frequency varies according to age. Their identification can improve early risk stratification to select the most appropriate therapy, including alternative, not chemotherapy based, treatment modalities, such as hypomethylating and targeted agents (Döhner H et al., Blood 2017). We analyzed the clinical outcome of AML patients aged ≥60 years who were enrolled in the randomized multicentric trial NILG 02/06, and were deeply genetically characterized (Clinical Trials.gov Identifier: NCT00495287). Patients and Methods Five hundred seventy-four newly diagnosed AML patients were enrolled into the study and 168 were aged ≥60 years; all patients were randomized to receive conventional induction chemotherapy with idarubicin, cytarabine and etoposide (ICE) or sequential high-dose cytarabine and idarubicin (sHD), followed by consolidation courses with high dose cytarabine (Bassan R et al., annual congress EHA. Jun 9, 2016, abstr S485). Genetic characterization at diagnosis was obtained by conventional cytogenetics and RT-PCR for 145 and 168 patients, respectively, while Next Generation Sequencing was performed for 51 patients with normal karyotype. Patients were re-classified as per the 2017 European Leukemia Net (ELN) guidelines (Döhner H et al., Blood 2017). A myelodysplastic/myeloproliferative (MDS/MPN) related genetic signature was defined according to cytogenetic WHO criteria and/or molecular abnormalities known to be associated with MDS/MPN (Bullinger L et al., J Clin Oncol 2017) and used for outcome correlation. Results The characteristics of patients are summarized in Table 1. According to the ELN risk stratification, patients were classified as favorable, intermediate or adverse risk (23%, 38% and 39% of patients, respectively). A genetic MDS/MPN signature was demonstrated in 42% of patients (63/149), which was a higher proportion compared to that of patients with a clinical diagnosis of an antecedent MDS/MPN (19% of patients, 32/168). No significant difference was observed between the induction regimens regarding the achievement of complete remission (CR) (71% for sHD and 61% for ICE, P=0.23) and early death rate (12% and 10.6%, P=0.96). After achieving CR, a median of 2 consolidation courses was administered (range 1-5) within both treatment arms. A limited proportion of patients with high-risk genetic or clinical features (14%) had the opportunity to undergo an allogeneic hematopoietic stem cell transplant (alloHSCT), the majority of them (63%) receiving a reduced intensity conditioning. By intention to treat, 5-years overall survival (OS) and disease- free survival (DFS) on the whole study population were 29% and 32% respectively, without significant differences between the remission induction treatment (for sHD and ICE, OS: 29% and 28%, P=0.88; DFS: 34% and 29%, P=0.90). According to the ELN risk stratification, 5-years OS was 68%, 25% and 7% for favorable, intermediate and adverse groups (P<0.0001), while 3-years DFS was 73%, 28% and 13% (P<0.0001) (Figure 1A). According to the presence or absence of a MDS/MPN signature at diagnosis, 5-years OS was 11% vs 41% (P=0.0001) while 3-years DFS was 12% vs 49% (P<0.0001) (Figure 1B). AlloHSCT was associated with a significant benefit in terms of 5-years OS (57% vs 25%, P=0.0162) and DFS (53% vs 26%, P=0.0363) (Figure 1C). As expected, age had also an impact, with patients aged 60-64 years performing better than patients aged ≥65 years (5-years OS 38% vs 13%, P=0.003; 5-years DFS 43% vs 10%, P=0.002). Conclusions Older AML patients with favorable risk features according to ELN benefit from standard chemotherapy. The definition of an adverse genetic risk profile and particularly of a MDS/MPN signature is crucial to identify patients who have a very dismal outcome. These patients should be considered for alternative, innovative treatment options. In high-risk, ≥60 years old AML patients with a good performance status, alloHSCT significantly improves both OS and DFS and should always be considered as the most effective post consolidation treatment. Disclosures Cattaneo: GILEAD: Other: Advisory Board. Cortelezzi:janssen: Consultancy; novartis: Consultancy; abbvie: Consultancy; roche: Consultancy. Rambaldi:Italfarmaco: Consultancy; Omeros: Consultancy; Roche: Consultancy; Amgen Inc.: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Celgene: Consultancy.

Study Objective. To validate the utility of a previously reported 3‐point limited sampling model (LSM) for determining etoposide area under the curve to infinity (AUC∞).Design. Secondary analysis of data from two clinical trials of etoposide.Setting. University medical center clinical research center.Patients. Thirty‐four patients with different malignancies.Interventions. Etoposide was administered as a 2‐hour infusion to 34 patients. Serial plasma samples were drawn over 24 hours after the infusion and analyzed for etoposide by high‐performance liquid chromatography.Measurements and Main Results. The 3‐point LSM AUC was compared with a 14‐point actual AUC calculated by the linear trapezoidal rule. Actual and predicted AUC∞ by the LSM were highly correlated (r=0.97, p<0.0001). The LSM predictions had a mean absolute error of 10.9% (95% CI −14.1, −5.3) and a mean error of −9.7% (95% CI 6.9, 14.9). Nine patients with poor AUC∞ estimations by the LSM (error > 12%) tended to have abnormally low or high peak concentrations.Conclusion. Our findings suggest the development of more robust LSM using other techniques, such as pharmacostatistical models, that can accommodate a greater degree of pharmacokinetic variability. (Pharmacotherapy 1997;17(5):887–890)

Abstract We report the discovery of two short-period massive giant planets from NASA’s Transiting Exoplanet Survey Satellite (TESS). Both systems, TOI-558 (TIC 207110080) and TOI-559 (TIC 209459275), were identified from the 30 minute cadence full-frame images and confirmed using ground-based photometric and spectroscopic follow-up observations from TESS’s follow-up observing program working group. We find that TOI-558 b, which transits an F-dwarf (M * = 1.349 − 0.065 + 0.064 M ⊙, R * = 1.496 − 0.040 + 0.042 R ⊙, T eff = 6466 − 93 + 95 K, age 1.79 − 0.73 + 0.91 Gyr) with an orbital period of 14.574 days, has a mass of 3.61 ± 0.15 M J, a radius of 1.086 − 0.038 + 0.041 R J, and an eccentric (e = 0.300 − 0.020 + 0.022 ) orbit. TOI-559 b transits a G dwarf (M * = 1.026 ± 0.057 M ⊙, R * = 1.233 − 0.026 + 0.028 R ⊙, T eff = 5925 − 76 + 85 K, age 6.8 − 2.0 + 2.5 Gyr) in an eccentric (e = 0.151 ± 0.011) 6.984 days orbit with a mass of 6.01 − 0.23 + 0.24 M J and a radius of 1.091 − 0.025 + 0.028 R J. Our spectroscopic follow up also reveals a long-term radial velocity trend for TOI-559, indicating a long-period companion. The statistically significant orbital eccentricity measured for each system suggests that these planets migrated to their current location through dynamical interactions. Interestingly, both planets are also massive (>3 M J), adding to the population of massive giant planets identified by TESS. Prompted by these new detections of high-mass planets, we analyzed the known mass distribution of hot and warm Jupiters but find no significant evidence for multiple populations. TESS should provide a near magnitude-limited sample of transiting hot Jupiters, allowing for future detailed population studies.

It is not known which kinetic step in the acto-myosin ATPase cycle limits contraction speed in unloaded muscles (V0). Huxley’s 1957 model [Huxley AF (1957) Prog Biophys Biophys Chem 7:255–318] predicts that V0 is limited by the rate that myosin detaches from actin. However, this does not explain why, as observed by Bárány [Bárány M (1967) J Gen Physiol 50(6, Suppl):197–218], V0 is linearly correlated with the maximal actin-activated ATPase rate (vmax), which is limited by the rate that myosin attaches strongly to actin. We have observed smooth muscle myosin filaments of different length and head number (N) moving over surface-attached F-actin in vitro. Fitting filament velocities (V) vs. N to a detachment-limited model using the myosin step size d = 8 nm gave an ADP release rate 8.5-fold faster and ton (myosin’s attached time) and r (duty ratio) ∼10-fold lower than previously reported. In contrast, these data were accurately fit to an attachment-limited model, V = N·v·d, over the range of N found in all muscle types. At nonphysiologically high N, V = L/ton rather than d/ton, where L is related to the length of myosin’s subfragment 2. The attachment-limited model also fit well to the [ATP] dependence of V for myosin-rod cofilaments at three fixed N. Previously published V0 vs. vmax values for 24 different muscles were accurately fit to the attachment-limited model using widely accepted values for r and N, giving d = 11.1 nm. Therefore, in contrast with Huxley’s model, we conclude that V0 is limited by the actin–myosin attachment rate.

Abstract Reilly, T. O. M., Fraser, H. M., Fryer, R. J., Clarke, J., and Greenstreet, S. P. R. 2014. Interpreting variation in fish-based food web indicators: the importance of “bottom-up limitation” and “top-down control” processes. – ICES Journal of Marine Science, 71: 406–416. Proposed indicators for the Marine Strategy Framework Directive (MSFD) food webs Descriptor focus on structural elements of food webs, and in particular on the abundance and productivity of top predators. However, the inferences that can be drawn from such indicators depend on whether or not the predators are “bottom-up limited” by the availability of their prey. Many seabird populations appear to be “bottom-up limited” so that variation in their reproductive success and/or abundance reflects changes in lower trophic levels. Here we find that gadoid fish predators off the Firth of Forth, southeast Scotland, do not appear to be “bottom-up limited” by the biomass of their main prey, 0-group sandeels; gadoid biomass and feeding performance was independent of sandeel biomass. Variability in food web indicators based on these gadoid predators seems to impart little insight into underlying processes occurring at lower trophic levels in the local food web. The implications of this in terms of how the currently proposed MSFD food web indicators should be used and interpreted are considered, and the ramifications in terms of setting targets representing good environmental status for both fish and seabird communities are discussed.

Context. The energy-limited atmospheric escape approach is widely used to estimate mass-loss rates for a broad range of planets that host hydrogen-dominated atmospheres as well as for performing atmospheric evolution calculations. Aims. We aim to study the applicability range of the energy-limited atmospheric escape approximation. Methods. We revise the energy-limited atmospheric escape formalism and the involved assumptions. We also compare the results of the energy-limited formalism with those of hydrodynamic simulations, employing a grid covering planets with masses, radii, and equilibrium temperatures ranging between 1 M⊕ and 39 M⊕, 1 R⊕ and 10 R⊕, and 300 and 2000 K, respectively. Results. Within the grid boundaries, we find that the energy-limited approximation gives a correct order of magnitude estimate for mass-loss rates for about 76% of the planets, but there can be departures from hydrodynamic simulations by up to two to three orders of magnitude in individual cases. Furthermore, we find that planets for which the mass-loss rates are correctly estimated by the energy-limited approximation to within one order of magnitude have intermediate gravitational potentials (≈2.5–5.5 ×108 J kg−1) as well as low-to-intermediate equilibrium temperatures and irradiation fluxes of extreme ultraviolet and X-ray radiation. However, for planets with low or high gravitational potentials, or high equilibrium temperatures and irradiation fluxes, the approximation fails in most cases. Conclusions. The energy-limited approximation should not be used for planetary evolution calculations that require computing mass-loss rates for planets that cover a broad parameter space. In this case, it is very likely that the energy-limited approximation would at times return mass-loss rates of up to several orders of magnitude above or below those predicted by hydrodynamic simulations. For planetary atmospheric evolution calculations, interpolation routines or approximations based on grids of hydrodynamic models should be used instead.

Metals and their alloys, except for a few intermetallics, are inherently ductile, i.e., plastic deformation precedes fracture in these materials. Therefore, resistance to fracture is directly related to the development of the plastic zone at the crack tip. Recent studies indicate that the fracture toughness of single crystals depends on the crystallographic orientation of the notch as well as the loading direction. In general, the dependence of crack propagation resistance on crystallographic orientation arises from the anisotropy of (i) elastic constants, (ii) plastic deformation (or slip), and (iii) the weakest fracture planes (e.g., cleavage planes). Because of the triaxial stress state at the notch tips, many slip systems that otherwise would not be activated during uniaxial testing become operational. The plastic zone formation in single crystals has been tackled theoretically by Rice and his co-workers [Rice, J. R., 1987, Mech. Mater. 6, pp. 317–335; Rice, J. R., and Saeedvafa, M., 1987, J. Mech. Phys. Solids 36, pp. 189–214; Saeedvafa, M., and Rice, J. R., 1988; ibid., 37, pp. 673–691; Rice, J. R., Hawk, D. E., Asaro, R. J., 1990, Int. J. Fract. 42, pp. 301–321; Saeedvafa, M., and Rice, J. R., 1992, Modell. Simul. Mater. Sci. Eng. 1, pp. 53–71] and only limited experimental work has been conducted in this area. The study of the stresses and strains in the vicinity of a fcc single-crystal notch tip is of relatively recent origin. We present experimental and numerical investigation of three-dimensional (3D) stress fields and evolution of slip sector boundaries near notches in fcc single-crystal PWA1480 tension test specimens and demonstrate that a 3D linear elastic finite element model, which includes the effect of material anisotropy, is shown to predict active slip planes and sectors accurately. The slip sector boundaries are shown to have complex curved shapes with several slip systems active simultaneously near the notch. Results are presented for surface and mid-plane of the specimens. The results demonstrate that accounting for 3D elastic anisotropy is very important for accurate prediction of slip activation near fcc single-crystal notches loaded in tension. Results from the study will help establish guidelines for fatigue damage near single-crystal notches.

This paper attempts to explain the process of institutional transition of post-communist countries applying conceptual framework proposed by D.C. North, J. J. Wallis, and B. R. Weingast. The first part of the article is devoted to outline the theory of North, Weingast, and Wallis. The second part the theory is used to analyze transformation processes in post-communist countries. An important conclusion of this paper is that cultural, religious and historical factors have crucial impact on formation of new coalitions of elites in the transitions countries. In the countries where Western values were present the transfer of the market and democratic formal institutions was easier. Also, the process of transformation was strongly influenced by external factors, especially the prospect of integration with the European Union, which encouraged elites to take action that benefited the opening of both political and economic markets. These observations suggest that, in general, the success of transformation in transition countries did not depend on the intentional actions of ruling elites.

ABSTRACT Fluorosis can cause enamel degeneration to varying extent depending on the fluoride levels prevalent in that particular area. It can range from slight mottling of enamel to severe degeneration leading to demineralization and resultant discoloration. In the latter case, treatment options are limited to bonding of the outer surface of teeth either with composite or porcelain. Clinical significance Porcelain laminates offer an excellent solution to enhance esthetics in a patient with fluorosis as it combines the advantage of being highly esthetic along with being conservative in its penetration to enamel. How to cite this article Williams C, Malhotra A, Taneja VK, Kiran R, Babu R. Enhancing White and Pink Esthetics using Porcelain Laminates in a Fluorosis Patient. J Contemp Dent Pract 2012;13(4):571-573.

ABSTRACT Patients usually under-report symptoms of incontinence. Therefore, improved physician-patient communication is vital. Most urinary incontinence can be evaluated and treated after careful history and simple clinical assessment. Initial treatment, for both urge urinary incontinence and stress urinary incontinence, is lifestyle modification and pelvic floor muscle exercises. Urgency responds to bladder training and drug therapy with anticholinergic medication. Pharmacotherapy has a limited place in stress incontinence. How to cite this article Malhotra J, Garg R, Kumari SS, Tandon A, Jain M, Malhotra N. Managing Vasomotor Symptoms in Menopausal Women. J South Asian Feder Menopause Soc 2014;2(2):87-90.

AbstractRecent epigraphic evidence from Cebel İres Dağı, Çineköy and Tell Šēh Hamad have provided further important additional documentation in Phoenician for a deity Kur(r)a. This article investigates the growing attestations for this deity in the first millennium sources, both cuneiform and alphabetic. In light of the growing occurrences of b'l kr, it proposes a reassessment of the enigmatic phrase b'l krntryš in the Phoenician text from Karatepe. The article also presents the limited second millennium data and evaluates the possible connections with the third millennium Eblaite deity Kura.L'évidence épigraphique récente de Cebel İres Dağı, Çineköy et Tell Šēh Hamad a fourni encore plus de documentation importante en phénicien pour une divinité nommée Kur(r)a. Cet article étudie les attestations croissantes pour cette divinité dans les sources cunéiformes et alphabétiques du premier millénaire av. J.-C. À la lumière des occurrences croissantes de b'l kr, cette étude propose une réévaluation de l'expression énigmatique b'l krntryš dans le texte phénicienne de Karatepe. L'article présente également les données limitées du deuxième millénaire et évalue les liens possibles avec la divinité éblaïte du troisième millénaire Kura.

ABSTRACTBackground:There is only limited knowledge of the development of the immune responses of the gut in very young infants after exposure to bacterial and food antigens at birth.Methods:In this study, 49 large intestinal biopsy specimens, which were judged to have normal morphology, were taken from 49 young infants. Eleven patients had Hirschsprung's disease (group 1) and 38 had miscellaneous conditions (group 2). The densities of T cells, their subsets expressing surface antigens CD8 and CD4, and T‐cell receptors α/β or γ/δ were measured, as well as densities of mononuclear and epithelial cells expressing HLA‐class II antigens.Results:T‐cell densities in groups 1 and 2 were similar. Patients with Hirschsprung's disease had significantly more HLA‐DR (p = 0.006) and HLA‐DP‐expressing cells (p = 0.003) in the lamina propria than did the patients in group 2. In group 1, HLA‐DR‐ (r = 0.58; p= 0.46) and HLA‐DP‐expressing cells (r = 0.66; p = 0.03) showed a significant positive regression with age in the lamina propria, whereas in group 2, HLA‐DR+ cells in the lamina propria showed marked(r = ‐0.9; p = 0.006) negative regression during the first 1.5 months of life. In contrast to results in previous reports, in the current results, HLA‐D region antigens were present in the epithelium in a considerable proportion (up to one fourth) of specimens from the large intestine in both groups. CD3+ (r = ‐0.59; p = 0.006) and CD4+ (r = ‐0.64; p = 0.002) cells showed a strong negative regression with age in the lamina propria during the first 2.5 months; and thereafter, there was a weak, insignificant rise in the numbers of these cells. The distribution of CD4+, CD8+, and TCR α/β orγ/δ T cells of the epithelium of the young infants did not differ significantly from that in the epithelium of adults.Conclusions:These results show that several significant changes occur in the mucosal immune system during the first few weeks of life.

18033 Background: BI significantly decrease brain metastases (BM) and prolonged CNS relapse free (CRF) duration (J Neurooncol 2: 253, 1984). Studies of 5 CCRT protocols using chest irradiation with randomization to BI after 2–3 courses of chemotherapy showed that patients who had complete response (CR), partial response (PR), minor response (MR), or no change (NC) of the diseases with CCRT benefited from BI with significantly reduced BM, prolonged response (R) duration and time to progression (TTP). (Proc. ASCO 5: Abstract 728, 1986). The value of BI remains unclear. Methods: Re-evaluation of previously mentioned 5 CCRT protocols was done to determine the effects on S, duration of R, TTP, and CRF with evaluations at 75th percentiles. Results: Of 138 patients (59 BI+), there was no significant difference between BI+ and BI- in terms of characteristics and response to CCRT. The effects of BI on S, duration of R, TTP, and CRF are as above. Conclusions: 1) BI significantly improved the duration of R,TTP, and CRF; 2) Although no S benefit was found in standard evaluation, BI patients had 37 weeks S advantage at 75th percentiles; 3) Patients who had CR, PR, or MR had benefited from BI and the benefits were more when evaluated at 75th percentiles; 4) The standard study of duration curves should be modified to look at a higher percentiles if the proposed treatment had low responses; 5) Awaiting for the results of RTOG 0214, our information could possibly favor BI in these patients. [Table: see text] No significant financial relationships to disclose.

Modular Propagation of Epileptiform Activity: Evidence for an Inhibitory Veto in Neocortex. Trevelyan AJ, Sussillo D, Watson BO, Yuste R. J Neurosci 2006;26(48):12447–12455. What regulates the spread of activity through cortical circuits? We present here data indicating a pivotal role for a vetoing inhibition restraining modules of pyramidal neurons. We combined fast calcium imaging of network activity with whole-cell recordings to examine epileptiform propagation in mouse neocortical slices. Epileptiform activity was induced by washing Mg2+ ions out of the slice. Pyramidal cells receive barrages of inhibitory inputs in advance of the epileptiform wave. The inhibitory barrages are effectively nullified at low doses of picrotoxin (2.5–5 μM). When present, however, these inhibitory barrages occlude an intense excitatory synaptic drive that would normally exceed action potential threshold by approximately a factor of 10. Despite this level of excitation, the inhibitory barrages suppress firing, thereby limiting further neuronal recruitment to the ictal event. Pyramidal neurons are recruited to the epileptiform event once the inhibitory restraint fails and are recruited in spatially clustered populations (150–250 μm diameter). The recruitment of the cells within a given module is virtually simultaneous, and thus epileptiform events progress in intermittent (0.5–1 Hz) steps across the cortical network. We propose that the interneurons that supply the vetoing inhibition define these modular circuit territories. Feedforward Inhibition Contributes to the Control of Epileptiform Propagation Speed Trevelyan AJ, Sussillo D, Yuste R. J Neurosci 2007;27(13):3383–3387. It is still poorly understood how epileptiform events can recruit cortical circuits. Moreover, the speed of propagation of epileptiform discharges in vivo and in vitro can vary over several orders of magnitude (0.1–100 mm/s), a range difficult to explain by a single mechanism. We previously showed how epileptiform spread in neocortical slices is opposed by a powerful feedforward inhibition ahead of the ictal wave. When this feedforward inhibition is intact, epileptiform spreads very slowly (100 μm/s). We now investigate whether changes in this inhibitory restraint can also explain much faster propagation velocities. We made use of a very characteristic pattern of evolution of ictal activity in the zero magnesium (0 Mg2+) model of epilepsy. With each successive ictal event, the number of preictal inhibitory barrages dropped, and in parallel with this change, the propagation velocity increased. There was a highly significant correlation ( p < 0.001) between the two measures over a 1,000-fold range of velocities, indicating that feedforward inhibition was the prime determinant of the speed of epileptiform propagation. We propose that the speed of propagation is set by the extent of the recruitment steps, which in turn is set by how successfully the feedforward inhibitory restraint contains the excitatory drive. Thus, a single mechanism could account for the wide range of propagation velocities of epileptiform events observed in vitro and in vivo.

This study aims to develop a guided inquiry that is valid and effective so that it can shape and train students' habits of mind. This research is research and development (R & D) with steps; observation of potential problems, product design, design validation, limited scale trials, product design revisions, large-scale trials. Worksheet validation is done by 2 validators with 4.2 validation results with a valid category. The results of the study on the implementation test on 12 students showed the results of the N-Gain test of 0.73 with high categories and the habits of mind of students assessed through questionnaires had an average score of 74.5 in the good category. The results of the habits of mind observation of students showed an increase from the first meeting to the last meeting. Based on the results of the study it can be concluded that guided inquiry-oriented guided inquiry development is valid and effective to train and form the habits of mind of students. Research findings also indicate a positive correlation between habits of mind and student learning outcomes.

SummaryEpigastric impedance recording was used to measure gastric half‐emptying time (t1/2) of orange squash in 45 healthy infants and children. The relationship between age, body size, and composition and the impedance increase after gastric filling was investigated, together with the effects on half‐emptying time of adding fat, increasing viscosity, and increasing osmolality in the test meal. The mean t1/2 for orange squash was 13.5 min. The increase in impedance per unit volume ingested showed a significant inverse relationship with age (r = −0.62, p < 0.001), and with various anthropometric variables (r ranged from −0.48 to −0.80, p < 0.01). No relationship was observed between t1/2, and age, sex, body size, or composition. Addition of 1.25% triglyceride or a 600‐fold increase in viscosity of the test meal were both accompanied by a significant lengthening of t1/2 (p = 0.005 and p < 0.001, respectively), but t1/2 did not alter with a fourfold increase in test meal osmolality. The test was well tolerated by all subjects, but its usefulness is limited by susceptibility to movement artefact, and also the necessity to use simple, liquid test meals.

Abstract Korneliussen, R. J., Heggelund, Y., Eliassen, I. K., and Johansen, G. O. 2009. Acoustic species identification of schooling fish. – ICES Journal of Marine Science, 66: 1111–1118. The development of methods for the acoustic identification of fish is a long-term objective aimed at reducing uncertainty in acoustic-survey estimates. The relative frequency response r(f) measured simultaneously at several frequencies is one of the main acoustic features that characterize the targets, but the relationship between nearest neighbours, school morphology, and environmental and geographical data are also important characteristics in this context. The number of acoustic categories that can be separated with a high spatial resolution is limited by the stochastic nature of the measurements. Because the acoustic categorization of larger ensembles is more reliable than for single targets, spatial smoothing of the backscattering within the school boundaries before that process allows the separation of more categories than is possible with the raw, highly resolved data. Using the mean r(f) of an entire school gives even more reliable categorization, but determining whether or not the school is monospecific sets a new challenge. This problem is evaluated here. The methods are tested and verified. Identification of acoustic categories with similar acoustic properties is done for schooling fish, although the results have limited spatial resolution. The reliability of the categorization is further improved when knowledge of school morphology and geographical distribution of the species are taken into account.

Microfluidic electrochemical cells are increasingly being used as power sources for energizing portable electronic devices [1]. Of particular interest is the capillary-driven flow cells because they do not need any type of micropump to establish the flow. In a recent work [2], we developed a general, robust mathematical/numerical model for designing capillary-driven, paper-based, microfluidic flow cells. The model was validated against experimental data available for a novel single-use microfluidic flow cell of this nature called PowerPAD [3]. This flow cell is activated by a drop of water when poured on its sample pad. After dissolving the solid electrolytes stored below the sample pad, the liquid electrolytes produced this way infiltrate the porous electrodes before entering the cellulosic absorbent pad situated below the porous electrodes. Soon after entering the pad, they start flowing in the lateral direction until they are brought into direct contact with each other (at some point in time) so that the electrochemical reactions can take place at the electrodes. The two liquids then continue flowing co-laminarly until the pad becomes fully-saturated and the flow rate drops to zero. The experimental data reported by the inventors of the PowerPAD actually correspond to the fully-saturated case [3]. (Under these conditions the cell works like an ordinary battery when connected to an external load.) They demonstrated that, dependent on the thickness of the absorbent pad, the cell can generate electricity for roughly an hour. In [2], we showed that, for a given electrode, by modifying the microstructure of its absorbent pad (e.g., its porosity or pore-size) and/or its flow structure the runtime of the cell can be extended to roughly three hours so that it can be used for energizing certain portable electronic devices. However, there are other prospective applications in which the power might be needed for merely a few seconds [4]. Remote sensors used for measuring/reporting the pH of acid rains belong to this category. PowerPAD can be used for such short-lived applications, but the mathematical model presented in [2] has to be refined to simulate power generation during the dynamic infiltration process, which is the objective of the present work. As the first step, Darcy’s equation is solved numerically to find the bulk velocity from which the Reynolds number is obtained and used to calculate the mass-transfer coefficient. More importantly, the Richards equations is solved numerically to find the time-dependent saturation field, S(t), which is needed for calculating the mass-transfer coefficient during the infiltration process. Here, the empirical correlation proposed by Barton and Brushett [5] for the Sherwood number (Sh) is modified to incorporate a diffusion-limited term which varies linearly with the saturation field, S(x,y,t); that is: where Re is the Reynolds number and Sc is the Schmidt number. Figure 1a shows the two-dimensional model of PowerPAD used for the simulations, which were performed using the finite-element software package COMSOL; see [2] for the details. According to the imbibition results obtained for the 4h-PAD system [3], the cell is predicted to start generating electricity after t = 0.33 s; see Fig. 1b. The system, however, needs roughly t = 20 s to become fully-saturated. Figure 1c shows the polarization curves for the 4h-PAD system at discrete times, whereas Fig. 1d shows variation of the maximum power as a function of time, up to the fully-saturated time. In these figures the discrete times (5.2, 8, 12, and 20 s) correspond, respectively, to the flow rates 11, 4.5, 0.4, and 0.01 mm3/s. According to Fig. 1d, during the transient phase the maximum power is roughly 50% larger than that for the fully-saturated case. The higher power generation during this initial infiltration process is attributed to the bulk fluid flow through the porous electrodes implying that the mass-transfer coefficients are improved through Re and Sc. References: [1] O.A. Ibrahim, M. Navarro-Segarra, P. Sadeghi, N. Sabaté, J.P. Esquivel, and E. Kjeang, Chem. Rev., 122 (7) (2022) 7236–7266. [2] P. Sadeghi, and E. Kjeang, Computational modelling of paper-based capillary-driven microfluidic flow cells, J. of Power Sources, 548 (2022)232084. [3] J.P. Esquivel, P. Alday, O.A. Ibrahim, B. Fernández, E. Kjeang, and N. Sabaté, A metal-free and biotically degradable battery for portable single-use applications, Adv. Energy Mater., 7 (2017) 1700275-86. [4] C. Dincer, R. Bruch, E. Costa-Rama, M.T. Fernández-Abedul, A. Merkoçi, A. Manz, G.A. Urban, and F. Güder, Disposable sensors in diagnostics, food, and environmental, monitoring, Adv. Mater., 31 (2019)1-28. [5] J.L. Barton, and F.R. Brushett, A one-dimensional stack model for redox flow battery analysis and operation, Batteries, 5 (2019) 1-25. Figure 1