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Osimertinib, an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), potently and selectively inhibits EGFR-TKI-sensitizing and EGFR T790M resistance mutations. In the Phase III FLAURA study (NCT02296125), first-line osimertinib improved outcomes vs comparator EGFR-TKIs in EGFRm advanced non-small cell lung cancer. This analysis identifies acquired resistance mechanisms to first-line osimertinib. Next-generation sequencing assesses circulating-tumor DNA from paired plasma samples (baseline and disease progression/treatment discontinuation) in patients with baseline EGFRm. No EGFR T790M-mediated acquired resistance are observed; most frequent resistance mechanisms are MET amplification (n = 17; 16%) and EGFR C797S mutations (n = 7; 6%). Future research investigating non-genetic acquired resistance mechanisms is warranted.

Supplemental material, sj-pdf-3-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Supplemental material, sj-pdf-3-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Supplemental material, sj-pdf-2-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Supplemental material, sj-pdf-4-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Supplemental material, sj-pdf-2-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Supplemental material, sj-docx-1-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Supplemental material, sj-pdf-4-cjk-10.1177_20543581231168088 for Perspectives of Pediatric Nephrologists, Intensivists and Nurses Regarding AKI Management and Expected Outcomes by Adrian Che, David D’Arienzo, Allison Dart, Cherry Mammen, Susan Samuel, Todd Alexander, Catherine Morgan, Tom Blydt-Hansen, Patricia Fontela, Gonzalo Garcia Guerra, Rahul Chanchlani, Stella Wang, Vedran Cockovski, Natasha Jawa, Jasmine Lee, Sophia Nunes, Stephanie Reynaud and Michael Zappitelli in Canadian Journal of Kidney Health and Disease

Savolitinib, an oral, potent, and highly selective MET-TKI, in combination with osimertinib, a 3rd-generation, irreversible, oral EGFR-TKI, may overcome common acquired MET-driven resistance following osimertinib treatment. The ongoing Ph2 SAVANNAH (NCT03778229) study is investigating this combination in pts with EGFRm NSCLC who have MET overexpression and/or amplification upon progressive disease (PD) post-osimertinib. Using plasma EGFRm as an estimate of tumor burden, we report exploratory analyses of progression-free survival (PFS) by plasma EGFRm clearance during treatment at Day (D) 22. Additionally, agreement between tissue (IHC/FISH) and plasma (NGS) testing for detecting MET overexpression and/or amplification is reported. Following central MET testing on tumor tissue collected upon PD post-osimertinib, eligible pts received oral savolitinib (300 or 600 mg QD, or 300 mg BID) + oral osimertinib 80 mg QD. MET overexpression was assessed by IHC (3+ staining in ≥50% of tumor cells [IHC50+]) and amplification by FISH (MET copy number ≥5 and/or MET:CEP7 ratio ≥2 [FISH5+]). Here, PFS analysis was performed in subgroups identified by exploratory higher biomarker cut-off levels of 3+ staining in ≥90% tumor cells (IHC90+) and/or MET copy number ≥10 (FISH10+). Plasma EGFRm (Ex19del/L858R only) analysis was conducted by ddPCR at D1 and every week thereafter for 4 weeks and at week 6. Plasma EGFRm clearance was defined as undetected EGFRm ctDNA at D22, where it was detected at D1. Baseline (BL) MET amplifications were determined via ctDNA NGS at D1. Agreement analysis was performed (DCO 27Aug2021). This analysis included 192 pts who received savolitinib 300 mg QD + osimertinib and had ≥2 post-BL RECIST scans. Of those with valid tissue FISH and IHC results and evaluable ctDNA at D1 (88% [169/192]), 124 pts had detectable plasma EGFRm. Plasma EGFRm clearance was assessed in 103 pts with detectable D1 plasma EGFRm who also had evaluable ctDNA at D22. Clearance was observed more frequently in pts with IHC90+ or FISH10+ tumors (42% [28/66]) than those with IHC90- and FISH10- tumors (16% [6/37]). Median PFS (95% CI) with vs without clearance was 11.0 (7.4, 13.0) vs 4.1 (2.7, 5.5) months in pts with IHC90+ or FISH10+ tumors. Agreement between tissue FISH and plasma NGS was assessed in 72 evaluable pts. Overall, 21 (29%) pts had MET FISH10+ tumors and 14 (19%) had plasma NGS focal MET amplification, with 11 being positive by both methods (positive percent agreement [PA]: 52%, negative PA: 94%, overall PA: 67%). Plasma EGFRm clearance was observed after 3 wks of savolitinib + osimertinib, particularly in pts with MET IHC90+ or FISH10+ tumors and was associated with improved PFS. Limited positive agreement between tissue- and BL plasma-based testing suggests IHC/FISH may be able to identify more pts likely to benefit from savolitinib + osimertinib. Citation Format: Ryan James Hartmaier, Aleksandra Markovets, Wanning Xu, Agata Baczynska, Alexander Todd, Myung-Ju Ahn. Baseline and on-treatment plasma-based genomics as a predictor of outcome in SAVANNAH: Savolitinib + osimertinib in EGFRm MET overexpressed/amplified NSCLC post-osimertinib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB294.

Supplemental material, sj-docx-1-cjk-10.1177_20543581211033405 for Training Programs for Fundamental and Clinician-Scientists: Balanced Outcomes for Graduates by Gender by Christie Rampersad, Todd Alexander, Elisabeth Fowler, Sunny Hartwig, Adeera Levin, Norman D. Rosenblum, Susan Samuel, Chris Wiebe and Julie Ho in Canadian Journal of Kidney Health and Disease

Large uncertainty remains in future projections of tropical precipitation change under global warming. A simplified method for diagnosing tropical precipitation change is tested here on present-day El Niño–Southern Oscillation (ENSO) precipitation shifts. This method, based on the weak temperature gradient approximation, assumes precipitation is associated with local surface relative humidity (RH) and surface air temperature (SAT), relative to the tropical mean. Observed and simulated changes in RH and SAT are subsequently used to diagnose changes in precipitation. Present-day ENSO precipitation shifts are successfully diagnosed using observations (correlationr= 0.69) and an ensemble of atmosphere-only (0.51 ≤r≤ 0.8) and coupled (0.5 ≤r≤ 0.87) climate model simulations. RH (r= 0.56) is much more influential than SAT (r= 0.27) in determining ENSO precipitation shifts for observations and climate model simulations over both land and ocean. Using intermodel differences, a significant relationship is demonstrated between method performance over ocean for present-day ENSO and projected global warming (r= 0.68). As a caveat, the authors note that mechanisms leading to ENSO-related precipitation changes are not a direct analog for global warming–related precipitation changes. The diagnosis method presented here demonstrates plausible mechanisms that relate changes in precipitation, RH, and SAT under different climate perturbations. Therefore, uncertainty in future tropical precipitation changes may be linked with uncertainty in future RH and SAT changes.

This paper presents an investigation of the robustness of correlations between characteristics of Arctic summer cyclones and September Arctic sea ice extent. A cyclone identification and tracking algorithm is run for output from 100-year coupled climate model simulations at two resolutions and for 30 years of reanalysis data, using two different tracking variables (mean sea-level pressure, MSLP; and 850 hPa vorticity) for identification of the cyclones. The influence of the tracking variable, the spatial resolution of the model, and spatial and temporal sampling on the correlations is then explored. We conclude that the correlations obtained depend on all of these factors and that care should be taken when interpreting the results of such analyses. Previous studies of this type have used around 30 years of reanalysis and observational data, analysed with a single tracking variable. Our results therefore cast some doubt on the conclusions drawn in those studies.

A rise in global mean sea level is a robust feature of projected anthropogenic climate change using state-of-the-art atmosphere-ocean general circulation models (AOGCMs). However, there is considerable disagreement over the more policy-relevant regional patterns of sea level rise. The Flux-Anomaly-Forced Model Intercomparison Project (FAFMIP) aims to improve our understanding of the mechanisms controlling regional and dynamic sea level change. In FAFMIP, identical air-sea buoyancy and momentum flux perturbations are applied to an ensemble of different AOGCMs, to sample the uncertainty associated with model structure and physical processes. Our novel implementation applies FAFMIP perturbations to an ensemble of OGCMs. This framework enables an estimate of the unknown atmosphere-ocean feedbacks, by comparing the coupled and ocean-only response to surface flux perturbations.Comparing the response to idealised FAFMIP forcing with more realistic, increasing CO2 forcing, much of the spread in regional sea level projections for the North Atlantic and Southern Ocean arises from ocean model structural differences. Ocean-only simulations indicate that only a small proportion of this spread is due to differences in the atmosphere-ocean feedback. Novel tendency diagnostics indicate the relative effect of resolved advection, parametrised eddies, and dianeutral mixing on regional and dynamic sea level change. This study helps to reduce uncertainty in regional sea level projections by refining our estimates of atmosphere-ocean feedbacks and developing our understanding of the physical processes controlling sea level change.

Duodenum inversum (DI), also known as inverted duodenum or duodenum reflexum, is a congenital malformation in which the third portion of the duodenum, instead of continuing leftward to the ligament of Treitz, reverses direction and travels in a superior, posterior track prior to crossing the midline above the pancreas. We present a case of a 62-year-old woman presenting with chronic nausea and vomiting, subsequently found to have DI.

Osimertinib is a third-generation, irreversible tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR-TKI) that selectively inhibits both EGFR-TKI-sensitizing andIn this trial, we randomly assigned 556 patients with previously untreated advanced NSCLC with anThe median overall survival was 38.6 months (95% confidence interval [CI], 34.5 to 41.8) in the osimertinib group and 31.8 months (95% CI, 26.6 to 36.0) in the comparator group (hazard ratio for death, 0.80; 95.05% CI, 0.64 to 1.00; P = 0.046). At 3 years, 79 of 279 patients (28%) in the osimertinib group and 26 of 277 (9%) in the comparator group were continuing to receive a trial regimen; the median exposure was 20.7 months and 11.5 months, respectively. Adverse events of grade 3 or higher were reported in 42% of the patients in the osimertinib group and in 47% of those in the comparator group.Among patients with previously untreated advanced NSCLC with an

We theoretically consider binding of quasi‐2D charged excitons X− on isolated donor ions D+ located at various distances from the quantum well. We establish how many different singlet Xs− and triplet Xt− bound states a donor ion D+ can support in magnetic fields B > 5 T. We show that dark X− states acquire finite oscillator strengths and that shake‐up transitions become allowed in photoluminescence in the presence of the D+ ion.

Fiber optic polarization splitters are demonstrated in polarization-maintaining fiber, using polished-type fiber couplers having intermediate copper thin-film layers. The splitters operate to give four port-symmetric 19-dB polarization isolation with less than 1-dB TM coupling loss. The effects of asymmetric longitudinal displacements on the devices are considered, and positional asymmetry is used to realize higher perlormance 1 x 2 port devices, with up to 25 dB isolation and 0.5 dB loss.

5'-Deoxy-5'-iodo-2': 3'-O-isopropylideneuridine (I) when treated with silver acetate in methanol gives 2': 3'-O-isopropylideneuridine, and base-catalysed methanolysis leads to 2': 3'-O-isopropylidene-O 2 - methyl-uridine which is converted by methanolic ammonia into 2': 3'-isopropylidene-isocytidine (IV). Acid- hydrolysis of (IV)yields isocytidine. Analogous transformation are described with 2': 3'-di-O-acetyluridine derivatives.

Aus einer Diskussion uber den Abbau von Zuckerphosphaten wird gefolgert, das die durch Alkali bewirkte schnelle Zersetzung von Zuckerphosphaten mit freier reduzierender Gruppe in bestimmten Fallen auf Eliminierungs reaktionen und nicht auf einfache Hydrolyse zuruckzufuhren ist. – So wird Glucose-3-phosphat (I), fur das eine bequeme Synthese beschrieben wird, durch Alkali zu Glucometasaccharinsaure (IV) umgesetzt. In analoger Weise wird Ribose-3-phosphat in eine C5-Saccharinsaure umgewandelt.

Uridine.5’ pyrophosphate has been synthesized by condensing 2’:3’-iso-propylidene 5’-iodo-5’-deoxyuridine with silver tribenzyl pyrophosphate and subsequently removing the protecting groups. The product, isolated as its barium salt, is identical with the “uridine diphoshate” obtained as a break down product of the naturally occurring coenzyme UDPG. In course of the work described use has been made of the observation that lithium chloride removes two benzyl groups from fully esterified pyrophosphates.

Es wird ein Uberblick uber eigene Arbeiten auf dem Gebiet der Nucleoside, Nucleotide und Nuclein-sauren, insbesondere uber Darstellung und Eigenschaften organischer Phosphate, Pyrophosphate und Polyphosphate gegeben.

The seeds of Striga hermonthica will only germinate readily when they have been exposed to a chemical stimulant released from a potential host root, and the purpose of the investigation has been the examination of the chemical nature of the stimulant. Crude concentrates have been prepared by growing roots of intact seedlings of Sorghum vulgare in water to which charcoal has been added, removing the charcoal and then eluting it with 70% acetone. A residue is obtained which when redissolved in water promotes the germination of the parasite seed. It has been shown that the concentrate contains carbo­hydrates and particularly pentoses although aldopentoses appear to be absent. At the same time the effects on germination of a large variety of sugars has been tested and a relatively weak effect has been observed with certain samples of seed with D-fructose, D-fructose-1:6-diphosphate and with L-sorbose. The most powerful stimulation, however, has been given by D-xyloketose. This carbohydrate has given germination with all samples of seed with which it has been tested and at concentrations lower than with the crude concentrate. Maximum germination has been recorded with D-xyloketose at a concentration of 1 x 10 -6 mg./ml. and some stimulation at 1 x 10 -7 mg./ml. Fresh preparations of the concentrate and of D-xyloketose are also similar in the important respects that when stored at 5 to 15°C the activities of both disappear completely within 72 hr., and that they are both completely inactivated by heating at 60°C for 60 min. Thus it is highly probable that the stimulating action of the crude concentrate is due to a substance which is either similar to or identical with D-xyloketose.

Monoacetylation of 5'-O'-acetyluridine yields a crystalline diacetate, from which by phosphorylation with dibenzyl phosphorochloridate followed by removal of protecting groups uridylic acid a is obtained. The diacetate is shown to be 3': 5'-Di-O-acetyl-2'-O-toluene-p-sulphonyluridine → O 2 : 2'-cyclouridine → 3-β-D-arobofuranosyl. Uridylic acid a is, therefore,uridine-2' phosphate. 3-β-D-Arobofuranosyl-uracil is identical with spongouridine, a nucleoside occuring naturally in sponges.