Synthesis of [1,4]Oxathiepino[5,6-b]quinolines via Base-Mediated Intramolecular Hydroalkoxylation

A base-mediated intramolecular hydroalkoxylation that was used to prepare a series of seven-membered S,O-heterocycles is described. 2-Thiopropargyl-3-hydroxymethyl quinolines were prepared starting from 2-mercaptoquinoline-3-carbaldehydes, via S-propargylation and reduction of a formyl group. Interestingly, 2-mercaptopropargyl-3-hydroxymethyl quinolines were converted into the corresponding oxathiepinoquinolines in the presence of t-BuOK. It is proposed that the S-propargyl moiety, in the presence of base, is converted into its allenyl isomer; subsequent addition of a hydroxyl group to the terminal double bond yields the 3-methyl-5H-[1,4]oxathiepino[5,6-b]quinoline in good to high yield. Notably, the procedure is adaptable to the conversion of N-propargyl indole-2-methanol into the corresponding intramolecular hydroalkoxylation product.

The Effectiveness in Activating M-Type K+ Current Produced by Solifenacin ([(3R)-1-azabicyclo[2.2.2]octan-3-yl] (1S)-1-phenyl-3,4-dihydro-1H-isoquinoline-2-carboxylate): Independent of Its Antimuscarinic Action

Solifenacin (Vesicare®, SOL), known to be a member of isoquinolines, is a muscarinic antagonist that has anticholinergic effect, and it has been beneficial in treating urinary incontinence and neurogenic detrusor overactivity. However, the information regarding the effects of SOL on membrane ionic currents is largely uncertain, despite its clinically wide use in patients with those disorders. In this study, the whole-cell current recordings revealed that upon membrane depolarization in pituitary GH3 cells, the exposure to SOL concentration-dependently increased the amplitude of M-type K+ current (IK(M)) with effective EC50 value of 0.34 μM. The activation time constant of IK(M) was concurrently shortened in the SOL presence, hence yielding the KD value of 0.55 μM based on minimal reaction scheme. As cells were exposed to SOL, the steady-state activation curve of IK(M) was shifted along the voltage axis to the left with no change in the gating charge of the current. Upon an isosceles-triangular ramp pulse, the hysteretic area of IK(M) was increased by adding SOL. As cells were continually exposed to SOL, further application of acetylcholine (1 μM) failed to modify SOL-stimulated IK(M); however, subsequent addition of thyrotropin releasing hormone (TRH, 1 μM) was able to counteract SOL-induced increase in IK(M) amplitude. In cell-attached single-channel current recordings, bath addition of SOL led to an increase in the activity of M-type K+ (KM) channels with no change in the single channel conductance; the mean open time of the channel became lengthened. In whole-cell current-clamp recordings, the SOL application reduced the firing of action potentials (APs) in GH3 cells; however, either subsequent addition of TRH or linopirdine was able to reverse SOL-mediated decrease in AP firing. In hippocampal mHippoE-14 neurons, the IK(M) was also stimulated by adding SOL. Altogether, findings from this study disclosed for the first time the effectiveness of SOL in interacting with KM channels and hence in stimulating IK(M) in electrically excitable cells, and this noticeable action appears to be independent of its antagonistic activity on the canonical binding to muscarinic receptors expressed in GH3 or mHippoE-14 cells.

Electrochemical Benzylic C-H Functionalization with Isocyanides

We report the challenging direct carbamoylation or cyanation of benzylic C(sp3)-H bonds with an isocyanide via an electrochemical process giving rise to structures which are encountered in several biologically relevant compounds and drugs. This transformation proceeds in mild conditions without the need of external oxidant and avoids the necessity to start from a prefunctionalized benzylic substrate or the deployment of the cation pool method. Anodic oxidation of the benzylic position and subsequent addition of the isocyanide leads to the formation of a C-C bond and to a nitrilium cation which hydrolysis leads to alpha-aryl acetamide derivatives, while elimination of a t-butyl cation delivers alpha-aryl acetonitrile derivatives.

Racial, Ethnic, and Socioeconomic Factors Result in Disparities in Outcome Among Children with Acute Lymphoblastic Leukemia Not Fully Attenuated By Disease Prognosticators: A Children's Oncology Group (COG) Study

Introduction: Health disparities are major issue for racial, ethnic, and socioeconomically disadvantaged groups. Though outcomes in childhood acute lymphoblastic leukemia (ALL) have steadily improved, identifying persistent disparities is critical. Prior studies evaluating ALL outcomes by race or ethnicity have noted narrowing disparities or that residual disparities are secondary to differences in leukemia biology or socioeconomic status (SES). We aimed to identify persistent inequities by race/ethnicity and SES in childhood ALL in the largest cohort ever assembled for this purpose. Methods: We identified a cohort of newly-diagnosed patients with ALL, age 0-30.99 years who were enrolled on COG trials between 2004-2019. Race/ethnicity was categorized as non-Hispanic white vs. Hispanic vs. non-Hispanic Black vs. non-Hispanic Asian vs. Non-Hispanic other. SES was proxied by insurance status: United States (US) Medicaid (public health insurance for low-income individuals) vs. US other (predominantly private insurance) vs. non-US patients (mainly jurisdictions with universal health insurance). Event-free and overall survival (EFS, OS) were compared across race/ethnicity and SES. The relative contribution of disease prognosticators (age, sex, white blood cell count, lineage, central nervous system status, cytogenetics, end Induction minimal residual disease) was examined with Cox proportional hazard multivariable models of different combinations of the three constructs of interest (race/ethnicity, SES, disease prognosticators) and examining hazard ratio (HR) attenuation between models. Results: The study cohort included 24,979 children, adolescents, and young adults with ALL. Non-Hispanic White patients were 13,872 (65.6%) of the cohort, followed by 4,354 (20.6%) Hispanic patients and 1,517 (7.2%) non-Hispanic Black patients. Those insured with US Medicaid were 6,944 (27.8%). Five-year EFS (Table 1) was 87.4%±0.3% among non-Hispanic White patients vs. 82.8%±0.6% [HR 1.37, 95 th confidence interval (95CI) 1.26-1.49; p<0.0001] among Hispanic patients and 81.9%±1.2% (HR 1.45, 95CI 1.28-1.56; p<0.0001) among non-Hispanic Black patients. Outcomes for non-Hispanic Asian patients were similar to those of non-Hispanic White patients. US patients on Medicaid had inferior 5-year EFS as compared to other US patients (83.2%±0.5% vs. 86.3%±0.3%, HR 1.21, 95CI 1.12-1.30; p<0.0001) while non-US patients had the best outcomes (5-year EFS 89.0%±0.7%, HR 0.78, 95CI 0.71-0.88; p<0.0001). There was substantial imbalance in traditional disease prognosticators (e.g. T-cell lineage) across both race/ethnicity and SES, and of race/ethnicity by SES. For example, T-lineage ALL accounted for 17.6%, 9.4%, and 6.6% of Non-Hispanic Black, Non-Hispanic White, and Hispanic patients respectively (p<0.0001). Table 2 shows the multivariable models and illustrates different patterns of HR adjustment among specific racial/ethnic and SES groups. Inferior EFS among Hispanic patients was substantially attenuated by the addition of disease prognosticators (HR decreased from 1.37 to 1.17) and further (but not fully) attenuated by the subsequent addition of SES (HR 1.11). In contrast, the increased risk among non-Hispanic Black children was minimally attenuated by both the addition of disease prognosticators and subsequent addition of SES (HR 1.45 to 1.38 to 1.32). Similarly, while the superior EFS of non-US insured patients was substantially attenuated by the addition of race/ethnicity and disease prognosticators (HR 0.79 to 0.94), increased risk among US Medicaid patients was minimally attenuated by the addition of race/ethnicity or disease prognosticators (HR 1.21 to 1.16). OS disparities followed similar patterns but were consistently worse than in EFS, particularly among patients grouped as non-Hispanic other. Conclusions: Substantial disparities in survival outcomes persist by race/ethnicity and SES in the modern era. Our findings suggest that reasons for these disparities vary between specific disadvantaged groups. Additional work is required to identify specific drivers of survival disparities that may be mitigated by targeted interventions. Figure 1 Figure 1. Disclosures Gupta: Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees. Teachey: NeoImmune Tech: Research Funding; Sobi: Consultancy; BEAM Therapeutics: Consultancy, Research Funding; Janssen: Consultancy. Zweidler-McKay: ImmunoGen: Current Employment. Loh: MediSix therapeutics: Membership on an entity's Board of Directors or advisory committees.

Synopsis of the Genus Pentacalia (Compositae, Senecioneae) in Bolivia

The Neotropical genus Pentacalia Cass. (Compositae, Senecioneae) is distributed from southern Mexico to northwestern Argentina, plus two disjunct species that thrive in Brazil. Most species diversity occurs in the montane forests of Colombia, Ecuador, and Peru. It comprises scandent woody plants characterized by displaying alternate leaves (opposite in three species), involucres with supplementary bracts, usually yellow ray florets (when present), sagittate to caudate anther bases, and truncate to obtuse style branches with a crown of sweeping trichomes (sometimes with a tuft of longer trichomes, but not strictly penicillate). The Bolivian species were revised for the first time by Cabrera (1985), who treated the group under Senecio L. sect. Streptothamni Greenm. Because of the subsequent addition of new species and the need of taxonomic arrangements, an updated synopsis of the genus recognizing 18 species is presented. The names P. brittoniana (Hieron.) Cuatrec. and P. miguelii (Cuatrec.) Cuatrec. are synonymized with P. psidiifolia (Rusby) Cuatrec., as well as P. inquisiviensis H. Rob. & Cuatrec. with P. cardenasii (Cuatrec.) Cuatrec. and P. sailapatensis (Cuatrec.) Cuatrec. with P. urubambensis (Cabrera) Cuatrec. Seven names are lectotypified and an epitype is designated for the name P. zongoensis (Cabrera) J. Calvo. The new species P. viburnifolia J. Calvo & A. Fuentes is described. Revised nomenclature, succinct descriptions, taxonomic discussions, lists of specimens examined, and distribution maps are provided for all accepted species, in addition to an identification key. Pictures of living plants are also presented for eight species.

Effects of High Salinity on Alginate Fouling during Ultrafiltration of High-Salinity Organic Synthetic Wastewater

Ultrafiltration is widely employed in treating high-salinity organic wastewater for the purpose of retaining particulates, microbes and macromolecules etc. In general, high-salinity wastewater contains diverse types of saline ions at fairly high concentration, which may significantly change foulant properties and subsequent fouling propensity during ultrafiltration. This study filled a knowledge gap by investigating polysaccharide fouling formation affected by various high saline environments, where 2 mol/L Na+ and 0.5-1.0 mol/L Ca2+/Al3+ were employed and the synergistic influences of Na+-Ca2+ and Na+-Al3+ were further unveiled. The results demonstrated that the synergistic influence of Na+-Ca2+ strikingly enlarged the alginate size due to the bridging effects of Ca2+ via binding with carboxyl groups in alginate chains. As compared with pure alginate, the involvement of Na+ aggravated alginate fouling formation, while the subsequent addition of Ca2+ or Al3+ on the basis of Na+ mitigated fouling development. The coexistence of Na+-Ca2+ led to alginate fouling formed mostly in a loose and reversible pattern, accompanied by significant cracks appearing on the cake layer. In contrast, the fouling layer formed by alginate-Na+-Al3+ seemed to be much denser, leading to severer irreversible fouling formation. Notably, the membrane rejection under various high salinity conditions was seriously weakened. Consequently, the current study offered in-depth insights into the development of polysaccharide-associated fouling during ultrafiltration of high-salinity organic wastewater.

Subglacial erosion has the potential to sustain microbial processes in Subglacial Lake Whillans, Antarctica

Subglacial Lake Whillans lies below around 800 m of Antarctic ice and is isolated from fresh sources of photosynthetic organic matter to sustain life. The diverse microbial ecosystems within the lake and underlying sediments are therefore dependent on a combination of relict, overridden, marine-derived organic matter and mineral-derived energy. Here, we conduct experiments to replicate subglacial erosion involving both gentle and high-energy crushing of Subglacial Lake Whillans sediments and the subsequent addition of anoxic water. We find that substantial quantities of reduced species, including hydrogen, methane, acetate and ammonium and oxidised species such as hydrogen peroxide, sulfate and carbon dioxide are released. We propose that the concomitant presence of both hydrogen and hydrogen peroxide, alongside high concentrations of mineral surface radicals, suggests that the splitting of water on freshly abraded mineral surfaces increases the concentrations of redox pairs from rock-water reactions and could provide a mechanism to augment the energy available to microbial ecosystems.

Hormonal Treatment and Cardiovascular Risk Profile in Transgender Adolescents

BACKGROUND AND OBJECTIVES The effects of endocrinological treatment on cardiovascular risk profile in transgender adolescents are unknown. In this retrospective cohort study, we aim to investigate these effects and assess obesity and dyslipidemia prevalence in transgender adolescents at 22 years compared with peers. METHODS Changes in BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), glucose, homeostatic model assessment for insulin resistance (HOMA-IR), and lipid values during treatment, along with the prevalence of obesity and dyslipidemia at 22 years, were recorded in 71 transwomen and 121 transmen who started gonadotropin-releasing hormone agonists in their adolescence (15 years), with a subsequent addition of sex hormones (17 years). RESULTS In transwomen, changes in BMI (+3.0; 95% confidence interval [CI] 1.6 to 4.4), SBP (–2 mmHg; 95% CI –7 to 3), DBP (+10 mmHg; 95% CI 7 to 14), glucose (0.0 mmol/L; 95% CI –0.2 to 0.2), HOMA-IR (+0.6; 95% CI –0.6 to 1.9), and lipid values were similar or more favorable compared with peers. The same was true for transmen regarding changes in BMI (+2.3; 95% CI 1.7 to 2.9), SBP (+7 mmHg; 95% CI 3 to 10), DBP (+7 mmHg; 95% CI 5 to 10), glucose (+0.1 mmol/L; 95% CI –0.1 to 0.3), HOMA-IR (–0.2; 95% CI –0.8 to 0.3), and lipid values. At age 22, obesity prevalence was 9.9% in transwomen, 6.6% in transmen, 2.2% in ciswomen, and 3.0% in cismen. CONCLUSIONS Generally, endocrinological treatment in transgender adolescents is safe regarding cardiovascular risk. Because obesity is more prevalent in transgender adolescents compared with peers, body weight management should be important during the medical trajectory.

Reduced blood product utilization via implementation of an anemia clinic and consult service in a large health system hospital.

e18654 Background: An Anemia Clinic program was started Sept. 2016 as part of system wide implementation of Patient Blood Management (PBM) initiated in 2015. Methods: The Anemia Clinic accepted referrals for non-cancer anemia, predominantly preoperative cardiovascular surgery (CVS) Pts. Hgb thresholds were <13 g/dL in men and <12 g/dL in women. Non-anemia cytopenias triggered Hematology referral. All Pts were screened for iron, B12, folate, and reticulocyte. Nutrient deficiencies were supplemented. Pts with CKD or chronic disease were considered for erythropoiesis stimulating agents. Results: PBM implementation resulted in a drop in packed red blood cell (PRBC) usage (Table). Of CVS Pts pre-operatively anemic in 2020, 181 were referred to the Anemia Clinic and 259 were not. The percentage of Pts who received PRBCs after Anemia Clinic referral was not statistically different from those who were not referred (52.5% vs. 43.6% Chi-Square p=0.07). Of preoperatively anemic Pts who were transfused in 2020, an average of 1.49 PRBCs were used in the referred group vs. an average of 2.12 PRBCs in those in the not referred group (Poisson Means p=0.0009). Length of stay (LOS) which was a median 9d ( P25=6d, P75=16d) in the referred group vs a median 10d ( P25=6d, P75=16d) in the non-referred group was not statistically different between groups (Smirnov p=0.99). LOS analyses of observed-to-expected (O/E) ratios used the Premier Healthcare Providers Alliance Database (PHD) which contains data on approximately 45% of US hospital discharges. For 2020 through Nov. the referred group had an O/E = 0.89 (observed LOS μgeo = 9.97 days, expected LOS μgeo = 11.17 days, N=159). The not referred group had an O/E = 0.94 (observed LOS μgeo = 10.14 days, expected LOS μgeo = 10.83 days, N=232). Conclusions: PBM decreased PRBC use through systematization of best practices during the initial year. Subsequent addition of Anemia Clinic services did not decrease PRBC use further at first but appears to have contributed to this past year’s decrease. There is a trend toward shorter LOS for patients referred to Anemia Clinic but it is not statistically significant. Our methods improved nutrient deficiency identification which may improve both later health outcomes not detected here and access to treatment for hematologic malignancies.[Table: see text]

Three addend addition: Who goes out of order and why?

Single-digit, three addend sums of the type a + b + c offer a rich opportunity to directly observe the range of strategies that different participants may use because they afford the possibility of measuring a partial sum (i.e., a + b or a + c or b + c). For example, while computing the sum 9 + 7 + 1, do participants go in order by first adding 9 + 7 and then adding 1, or do they incur the cost of going out of order by adding 9 + 1 in order to obtain the partial sum of 10, which makes the subsequent addition of 7 less effortful? Informed by findings in simple and complex arithmetic, we investigated the problem types and participant characteristics that can predict out of order switching behavior in such three-addend sums. To test our hypotheses, we tasked participants, first in an online study, and then in an in-person study to complete 120 single-digit, three addend problems. We found that participants switched the order of addition to prioritize efficiency gains in contexts in which the partial sum addends were small or equal to each other, or when doing so led to a partial sum of 10, or led to a partial sum that is equal to the third remaining integer. Response latency data confirmed that participants were deriving efficiencies in the manner we expected. Related to individual differences, our findings showed that participants with higher levels of math education were most likely to seek efficiency benefits whenever they were on offer.