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Cancer of unknown primary (CUP) is a syndrome defined by clinical absence of a primary cancer after standardised investigations. Gene expression profiling (GEP) and DNA sequencing have been used to predict primary tissue of origin (TOO) in CUP and find molecularly guided treatments; however, a detailed comparison of the diagnostic yield from these two tests has not been described. Here, we compared the diagnostic utility of RNA and DNA tests in 215 CUP patients (82% received both tests) in a prospective Australian study. Based on retrospective assessment of clinicopathological data, 77% (166/215) of CUPs had insufficient evidence to support TOO diagnosis (clinicopathology unresolved). The remainder had either a latent primary diagnosis (10%) or clinicopathological evidence to support a likely TOO diagnosis (13%) (clinicopathology resolved). We applied a microarray (CUPGuide) or custom NanoString 18-class GEP test to 191 CUPs with an accuracy of 91.5% in known metastatic cancers for high-medium confidence predictions. Classification performance was similar in clinicopathology-resolved CUPs - 80% had high-medium predictions and 94% were concordant with pathology. Notably, only 56% of the clinicopathology-unresolved CUPs had high-medium confidence GEP predictions. Diagnostic DNA features were interrogated in 201 CUP tumours guided by the cancer type specificity of mutations observed across 22 cancer types from the AACR Project GENIE database (77,058 tumours) as well as mutational signatures (e.g. smoking). Among the clinicopathology-unresolved CUPs, mutations and mutational signatures provided additional diagnostic evidence in 31% of cases. GEP classification was useful in only 13% of cases and oncoviral detection in 4%. Among CUPs where genomics informed TOO, lung and biliary cancers were the most frequently identified types, while kidney tumours were another identifiable subset. In conclusion, DNA and RNA profiling supported an unconfirmed TOO diagnosis in one-third of CUPs otherwise unresolved by clinicopathology assessment alone. DNA mutation profiling was the more diagnostically informative assay. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and debilitating disease with limited therapeutic options. The aim of this clinical study was to evaluate the safety, efficacy and pharmacokinetics of a novel regimen comprised of metronomic oxaliplatin (O), chronomodulated capecitabine (X) and UGT1A1 genotype-guided dosing of irinotecan (IRI) [OXIRI] as well as its immunomodulatory effects. Thirty-six patients were enrolled into either dose-escalation or expansion cohorts. In the dose escalation phase, capecitabine doses (2000, 2650, 3500 and 4500 mg/day) were administered at midnight on days 1 to 14 while oxaliplatin and irinotecan were intravenously infused at fixed doses of 50 and 75 mg/m

In this paper we study, using a stylized analytical model, an entrepreneur's design of the optimal product menu for crowdfunding together with the optimal choice of the funding target. We find that in contrast to prior literature on crowdfunding, downward quality distortion of the low-quality product in the entrepreneur's product menu under crowdfunding can be higher, lesser or even non-existent than that under traditional selling. We also show that crowdfunding as an alternative to traditional selling is only attractive in the presence of a non-zero fixed cost. Our findings provide important implications for entrepreneurs in optimizing their crowdfunding project design.

Background: Patient frailty amongst patients with nonvalvular atrial fibrillation (NVAF) is associated with adverse health outcomes and increased risk of mortality. Additional evidence is needed to evaluate effective and safe NVAF treatment in this patient population. Objectives: This subgroup analysis of the ARISTOPHANES study compared the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) amongst frail NVAF patients prescribed nonvitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods: This comparative retrospective observational study of frail, older NVAF patients who initiated apixaban, dabigatran, rivaroxaban or warfarin from 01JAN2013-30SEP2015 was conducted using Medicare and 3 US commercial claims databases. To compare each drug, 6 propensity score-matched (PSM) cohorts were created. Patient cohorts were pooled from 4 databases after PSM. Cox models were used to estimate hazard ratios (HR) of S/SE and MB. Results: Amongst NVAF patients, 34% (N = 150 487) met frailty criteria. Apixaban and rivaroxaban were associated with a lower risk of S/SE vs warfarin (apixaban: HR: 0.61, 95% CI: 0.55–0.69; rivaroxaban: HR: 0.79, 95% CI: 0.72–0.87). For MB, apixaban (HR: 0.62, 95% CI: 0.57–0.66) and dabigatran (HR: 0.79, 95% CI: 0.70–0.89) were associated with a lower risk and rivaroxaban (HR: 1.14, 95% CI: 1.08–1.21) was associated with a higher risk vs warfarin. Conclusion: Amongst this cohort of frail NVAF patients, NOACs were associated with varying rates of stroke/SE and MB compared with warfarin. Due to the lack of real-world data regarding OAC treatment in frail patients, these results may inform clinical practice in the treatment of this patient population.

DCs are crucial for sensing pathogens and triggering immune response. Upon activation by pathogen-associated molecular pattern (PAMP) ligands, GM-CSF myeloid DCs (GM-DCs) secrete several cytokines, including IL-2. DC IL-2 has been shown to be important for innate and adaptive immune responses; however, IL-2 importance in DC physiology has never been demonstrated. Here, we show that autocrine IL-2 signaling is functional in murine GM-DCs in an early time window after PAMPs stimulation. IL-2 signaling selectively activates the JAK/STAT5 pathway by assembling holo-receptor complexes at the cell surface. Using the sensitivity of targeted mass spectrometry, we show conclusively that GM-DCs express CD122, the IL-2 receptor β-chain, at steady state. In myeloid DCs, this cytokine pathway inhibits survival of PAMP-matured GM-DCs which is crucial for maintaining immune tolerance and preventing autoimmunity. Our findings suggest that immune regulation by this novel autocrine signaling pathway can potentially be used in DC immunotherapy.

2-(Ethoxycarbonylmethoxy)-5-(arylazo)benzaldehydes 1-4 and their oximes 5-8 were synthesized and characterized by IR, (1)H and (13)C NMR spectroscopy. The favoured conformations of aldehydes 1-4 and oximes 5-8 were predicted theoretically. Selected geometrical parameters and charges were derived from optimized structures. IR, (1)H and (13)C NMR data were also computed using Gaussian-03 package and compared with the observed values. (15)N and (17)O chemical shifts were also determined theoretically.

Background: Left atrium (LA) remodeling has a crucial adverse impact on outcome and prognosis in mitral stenosis. Few studies have reported the effect of balloon mitral valvuloplasty (BMV) on LA volume. The aim of this study was to assess the evolution of LA volume immediately and 1 month after successful BMV in patients in sinus rhythm. Methods: Thirty-three consecutive patients (70% women; age 31 ± 8 years; range 19–45) with moderate to severe mitral stenosis (mitral valve area ≤1.5 cm2) who underwent successful BMV were included prospectively. Using two-dimensional echocardiography, and according to the prolate ellipse method, LA volume and LA volume indexed to body surface area were determined before BMV, and 24 hours and 1 month after BMV. Tricuspid and pulmonary regurgitation jets were recorded systematically using continuous-wave Doppler. Pulmonary artery–right ventricular (PA–RV) gradients, reflecting pulmonary pressures, and pulmonary vascular resistance were measured. Results: Mitral valve area increased from 0.88 ± 0.16 to 1.55 ± 0.26 cm2 (P < 0.0001). Mean mitral valve gradient (MVG) decreased from 16 ± 6 to 6 ± 2 mmHg (P < 0.0001) immediately after BMV. Indexed LA volume fell from 56 ± 14 to 48 ± 12 mL/m2 (P = 0.0002) immediately after BMV and to 45 ± 13 mL/m2 at 1 month (P < 0.0001). Only patients with a median LA volume ≥55 mL/m2 before BMV had a significant reduction in LA volume (P = 0.0001). Decrease in LA volume was correlated with decreases in PA–RV peak diastolic gradient (r = 0.45, P = 0.008) and MVG (r = 0.35, P = 0.04). Conclusion: In patients with mitral stenosis in sinus rhythm, successful BMV results in an immediate decrease in LA volume. This reduction, maximal immediately after BMV, correlates with decreases in MVG and PA–RV peak diastolic gradient, and is significant only when LA volume before BMV is severely enlarged. (Echocardiography 2011;28:154-160)

Optimal feedback control of a fed-batch bioreactor may be implemented by regulating the feed rate or the feed concentration and either may be used to optimize the same performance index. The latter approach, however, offers several advantages. In two bioreactors operating to maximize the instantaneous product formation rate, one with feed rate and the other with feed concentration control, the same amount of nutrients are fed to both fermenters. At the end of fermentation the fermenter with feed concentration control produces higher antibiotic concentration in a lesser volume than the other. The feed rate strategy, however, is more tolerant of the errors in the model than its counterpart. Such robustness is because of the complex volume effects which are absent with feed concentration (the feed rate is constant). The feed concentration strategy uses more information described in the model and hence is more sensitive to the errors. When the volume dependence is removed by implementing the control in the mass variable forms instead of the commonly used concentration forms, the feed concentration strategy becomes more robust and consequently less sensitive to the modeling errors. An ability to implement the feed concentration structure in either the mass or the concentration forms allows for a choice between sensitivity and robustness. Higher sensitivity would be desirable during system identification studies where parameters are estimated from data, whereas higher robustness would be preferred during plant operation.

A 52-year-old woman presented with left ventricular (LV) dysfunction and incessant narrow complex tachycardia. Electrocardiogram and clinical picture were suggestive of a permanent form of junctional reciprocating tachycardia, but electrophysiology study showed the tachycardia to be a fast-slow form of atrioventricular nodal reentrant tachycardia (AVNRT). Slow pathway ablation terminated the tachycardia and the LV dysfunction resolved completely at follow-up. Fast-slow AVNRT has not been reported to present in incessant form, and the mechanism in this patient was absent retrograde fast pathway conduction resulting in easy initiation and maintenance of tachycardia.

A commonly held belief is that if people can benefit financially from enterprises that depend on nearby forests, reefs, and other natural habitats, then they will take action to conserve and sustainably use them. The Biodiversity Conservation Network brought together conservation and development organizations and local communities to systematically test this hypothesis across 39 conservation project sites in Asia and the Pacific. Each project implemented one or more community-based enterprises such as setting up an ecotourism lodge, distilling essential oils from wild plant roots, producing jams and jellies from forest fruits, harvesting timber, or collecting marine samples to test for pharmaceutical compounds. Each project team collected the biological, enterprise, and social data necessary to test the network's hypothesis. We present the results of this test. We found that a community-based enterprise strategy can lead to conservation, but only under limited conditions and never on its own. We summarize the specific conditions under which an enterprise strategy will and will not work in a decision chart that can be used by project managers to determine whether this strategy might make sense at their site. We also found that an enterprise strategy can be subsidized and still create a net gain that pays for conservation. Based on our experiences, we recommend developing “learning portfolios” that combine action and research to test other conservation strategies. Resumen: Una creencia comunmente difundida es que la gente se puede beneficiar financieramente de empresas que dependen de bosques, arrecifes, y otros habitats naturales cercanos y por lo tanto llevarian a cabo acciones para conservar y usarlos sostenidamente. La Red de Conservacion de la Biodiversidad junto a organizaciones de conservacion y desarrollo y a comunidades locales para probar sistematicamente esta hipotesis en 39 proyectos de conservacion en sitios de Asia y el Pacifico. Cada proyecto implemento una o mas empresas basadas en la comunidad, tales como el establecimiento de alojamiento para ecoturismo, destilacion de aceites esenciales a partir de raices de plantas silvestres, produccion de jaleas y mermeladas de frutas del bosque, tala de madera, o la colecta de muestras marinas para probar compuestos farmaceuticos. Cada equipo de trabajo colecto los datos biologicos, empresariales y sociales necesarios para probar la hipotesis de la red. Nosotros presentamos aqui los resultados de esta prueba. Encontramos que una estrategia de las empresas basadas en la comunidad puede conducir a la conservacion, pero solo bajo limitadas condiciones y nunca por si sola. Resumimos las condiciones especificas bajo las cuales una estrategia empresarial trabajaria o no en un diagrama de decisiones que puede ser usado por administradores para determinar si esta estrategia tendria sentido para su sitio. Tambien encontramos que una estrategia empresarial puede ser subsidiada y aun crear una ganancia neta que pague por la conservacion. En base a nuestras experiencias, recomendamos desarrollar “portafolios de aprendizaje” que combinen acciones e investigacion para probar otras estrategias de conservacion.

BACKGROUND Our aim was to study the feasibility of total intravenous anaesthesia with propofol in spontaneously breathing children undergoing ophthalmic procedures. METHODS Fifty-five children (aged 6 months to 5 years) were randomly allocated to receive either propofol bolus (until loss of eyelash reflex) followed by infusion [group P (n=29)] or halothane 3-4% for induction, followed by 1-2% in 70% nitrous oxide and oxygen via face mask [group H (n=28)]. Dose for induction and maintenance, intraoperative adverse events, time to recovery (on an Observer's Assessment of Alertness/Sedation Scale, 5 at each level) and duration of procedure were recorded. All children in both groups, were anaesthetized successfully. RESULTS 4.0 +/- 0.7 mg x kg(-1) and 5.1 +/- 1.0 mg x kg(-1) of propofol were required for loss of eyelash reflex and tolerance of the ophthalmic speculum, respectively. An infusion rate of 8.3 +/- 1.7 mg x kg(-1) x h(-1) was needed for maintenance of anaesthesia; 3.4 +/- 0.5%, 3.6 +/- 0.4% and 1.4 +/- 0.4% halothane was needed for induction, tolerance of the eye speculum and maintenance of anaesthesia, respectively. Induction and recovery were significantly faster with halothane compared with propofol [induction - 38.3 +/- 6.6 s (group H)/60.9 +/- 15.2 s (group P) (P < 0.001); recovery 12.8 +/- 4.6 min (group H)/27.0 +/- 23.3 min (group P) (P < 0.001)]. Apnoea, coughing and breath-holding were seen only in group H. Group P had significantly higher incidence of involuntary movements (minor degree) (n=6) (P < 0.01). CONCLUSIONS Propofol is a feasible option for paediatric diagnostic ophthalmic procedures with the advantage over halothane of providing complete access to the eye.

AlGaN is an important material for ultra-violet light emitters, photo detectors and high breakdown voltage switching devices. In this work, crack-free AlxGa1-xN (5% 70%) template. The structural quality of AlGaN layers is comparable to that of GaN layers grown on silicon(111). For Al0.16Ga0.84N, the FWHM of HR-XRD (0002) and (-1102) ω-scan is around 650 arc sec and 1200 arc sec respectively. Based on this high quality AlGaN buffer, a double heterostructure (DH) FET was demonstrated. The sheet resistance of DH-FET is 274 ± 4.7 Ω/□ and the uniformity value of 1.7% is also excellent. Some of the wafers have been processed. Devices with a gate length of 2 μm showed current density of 500 mA/mm and transconductance of more than 200 mS/mm. (© 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

We report on the fabrication of AlGaN/GaN double-insulator MOSHEMTs using SiO2 and SiN as the prime gate insulators. Both the dielectrics showed enhanced saturation current density and pinch-off voltage compared to conventional HEMTs. The SiO2/SiN/AlGaN/GaN MOSHEMTs exhibited a low current collapse and low leakage current compared to SiN MISHEMTs and unpassivated HEMTs. However, the SiN/SiO2/AlGaN/GaN MOSHEMTs exhibited a lower current collapse coupled with moderate leakage current compared to SiO2 MOSHEMTs and unpassivated HEMTs. The comparison of device dc characteristics of double-insulator MOSHEMTs with single-insulator MOSHEMTs revealed its superiority in reducing the problem of current collapse and leakage current simultaneously. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Metal–oxide–semiconductor high-electron-mobility transistors were demonstrated on AlGaN/GaN with electron beam (EB) evaporated ZrO2. The composition of the EB deposited ZrO2 thin films was confirmed using X-ray photoelectron spectroscopy (XPS). The fabricated ZrO2-based MOSHEMTs exhibited high positive gate voltage of operation up to +7 V with low gate leakage current. For a comparison, conventional high-electron-mobility transistors (HEMTs) were also fabricated with identical device dimensions. The maximum drain current densities of 1168 and 538 mA/mm were observed on MOSHEMTs and HEMTs, respectively. Low gate leakage current density of four orders of magnitude was observed on ZrO2-based MOSHEMTs when compared with the conventional HEMTs. The observation of high forward on-voltage with low gate leakage current density and high positive operational voltage reveals the importance of ZrO2 dielectric films for MOSHEMT devices. (© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)