The External Genitalia Score (EGS): A European Multicenter Validation Study

CONTEXT: Standardized description of external genitalia is needed in the assessment of children with atypical genitalia. OBJECTIVES: To validate the External Genitalia Score (EGS), to present reference values for preterm and term babies up to 24 months and correlate obtained scores with anogenital distances (AGDs). DESIGN, SETTING: A European multicenter (n = 8) validation study was conducted from July 2016 to July 2018. PATIENTS AND METHODS: EGS is based on the external masculinization score but uses a gradual scale from female to male (range, 0-12) and terminology appropriate for both sexes. The reliability of EGS and AGDs was determined by the interclass correlation coefficient (ICC). Cross-sectional data were obtained in 686 term babies (0-24 months) and 181 preterm babies, and 111 babies with atypical genitalia. RESULTS: The ICC of EGS in typical and atypical genitalia is excellent and good, respectively. Median EGS (10th to 90th centile) in males < 28 weeks gestation is 10 (8.6-11.5); in males 28-32 weeks 11.5 (9.2-12); in males 33-36 weeks 11.5 (10.5-12) and in full-term males 12 (10.5-12). In all female babies, EGS is 0 (0-0). The mean (SD) lower/upper AGD ratio (AGDl/u) is 0.45 (0.1), with significant difference between AGDl/u in males 0.49 (0.1) and females 0.39 (0.1) and intermediate values in differences of sex development (DSDs) 0.43 (0.1). The AGDl/u correlates with EGS in males with typical genitalia and in atypical genitalia. CONCLUSIONS: EGS is a reliable and valid tool to describe external genitalia in premature and term babies up to 24 months. EGS correlates with AGDl/u in males. It facilitates standardized assessment, clinical decision-making and multicenter research

Long working hours and risk of coronary heart disease and stroke : a systematic review and meta-analysis of published and unpublished data for 603 838 individuals

Background Long working hours might increase the risk of cardiovascular disease, but prospective evidence is scarce, imprecise, and mostly limited to coronary heart disease. We aimed to assess long working hours as a risk factor for incident coronary heart disease and stroke. Methods We identified published studies through a systematic review of PubMed and Embase from inception to Aug 20, 2014. We obtained unpublished data for 20 cohort studies from the Individual-Participant-Data Meta-analysis in Working Populations (IPD-Work) Consortium and open-access data archives. We used cumulative random-effects meta-analysis to combine effect estimates from published and unpublished data. Findings We included 25 studies from 24 cohorts in Europe, the USA, and Australia. The meta-analysis of coronary heart disease comprised data for 603 838 men and women who were free from coronary heart disease at baseline; the meta-analysis of stroke comprised data for 528 908 men and women who were free from stroke at baseline. Follow-up for coronary heart disease was 5.1 million person-years (mean 8.5 years), in which 4768 events were recorded, and for stroke was 3.8 million person-years (mean 7.2 years), in which 1722 events were recorded. In cumulative meta-analysis adjusted for age, sex, and socioeconomic status, compared with standard hours (35-40 h per week), working long hours (>= 55 h per week) was associated with an increase in risk of incident coronary heart disease (relative risk [RR] 1.13, 95% CI 1.02-1.26; p=0.02) and incident stroke (1.33, 1.11-1.61; p=0.002). The excess risk of stroke remained unchanged in analyses that addressed reverse causation, multivariable adjustments for other risk factors, and different methods of stroke ascertainment (range of RR estimates 1.30-1.42). We recorded a dose-response association for stroke, with RR estimates of 1.10 (95% CI 0.94-1.28; p=0.24) for 41-48 working hours, 1.27 (1.03-1.56; p=0.03) for 49-54 working hours, and 1.33 (1.11-1.61; p=0.002) for 55 working hours or more per week compared with standard working hours (p(trend) Interpretation Employees who work long hours have a higher risk of stroke than those working standard hours; the association with coronary heart disease is weaker. These findings suggest that more attention should be paid to the management of vascular risk factors in individuals who work long hours. Copyright (C) Kivimaki et al. Open Access article distributed under the terms of CC BY.Peer reviewe

Palladium Catalyzed Carbonylative Heck Reaction Affording Monoprotected 1,3-Ketoaldehydes

The direct carbonylative palladium catalyzed synthesis of monoprotected 1,3-ketoaldehydes is reported starting from aryl iodides applying near stoichiometric amounts of carbon monoxide. Besides representing platforms for a variety of heterocyclic structures, these motives serve as viable precursors for the highly relevant aryl methyl ketones. The presented strategy can also be adapted for the facile and efficient incorporation of ¹³C-labeled carbon monoxide

Access to 2‑(Het)aryl and 2‑Styryl Benzoxazoles via Palladium-Catalyzed Aminocarbonylation of Aryl and Vinyl Bromides

A sequential one-pot procedure for the synthesis of either 2-(hetero)­aryl or 2-styryl benzoxazoles is reported, starting from aryl and vinyl bromides, respectively, involving an initial aminocarbonylation with 2-aminophenols as nucleophiles followed by an acid mediated ring closure to generate the heterocycle. The methodology displays a broad substrate scope in moderate to excellent yields and can be exploited for ¹³C-isotope labeling. Finally, this carbonylative protocol was applied to the synthesis of a potential Alzheimer’s plaque binder and a selective PPAR antagonist including site-specific labeling with ¹³C-carbon monoxide

An Efficient Method for the Preparation of Tertiary Esters by Palladium-Catalyzed Alkoxycarbonylation of Aryl Bromides

The palladium-catalyzed alkoxycarbonylation of aryl bromides is described for the efficient preparation of tertiary esters. The protocol proved compatible with a wide variety of functionalized (hetero)aromatic bromides, as well as several different sterically hindered tertiary alcohols, affording the alkoxycarbonylated products in high yields. Finally, the formation of aromatic trityl esters is discussed

A High Mobility Reactor Unit for R&D Continuous Flow Transfer Hydrogenations

A suitcase sized mobile reactor unit (MRU) weighing in at less than 10 kg was designed for laboratory scale transfer hydrogenations in continuous flow. Simple cyclohexene and a cosolvent in combination with a palladium-on-charcoal packed bed reactor provided a setup with isolation of nearly all products without the need for further purification. Several functional groups including olefins, triple bonds, nitro-groups, carbonyls, and so forth were effectively reduced with retention times as low as 2 min. Additionally, standard protection groups such as Cbz, benzyl, and allyl ether or esters were removed in high yields. To prove the flexibility of the setup an example of the Mizoroki–Heck reaction was also performed on the MRU. Finally, two scale-up transfer hydrogenation experiments were performed affording isolation of the desired target compounds in 0.5 and 0.8 mol scales with less than 4 h of continuous operation on the MRU

Improved Safety during Transfer of Pyrophoric <i>tert</i>-Butyllithium from Flasks with Protective Seals

A simple setup has been devised to facilitate safer transfer of air-sensitive and pyrophoric reagents from Sure/Seal bottles in a fume hood setting. The setup is composed of three parts; a sealed transfer vial, a custom bottle cap for transfer vial alignment, and a metal clip. All of the needed parts are constructed from standard laboratory equipment and by 3D printing. Titration of <i>tert</i>-butyllithium was used as an example of safe transfer of a highly pyrophoric reagent, and an instructional video has been prepared

Silacarboxylic Acids as Efficient Carbon Monoxide Releasing Molecules: Synthesis and Application in Palladium-Catalyzed Carbonylation Reactions

Silacarboxylic acids have been demonstrated to be easy to handle, air-stable carbon monoxide precursors. Different silacarboxylic acids were synthesized from the corresponding chlorosilanes and carbon dioxide, and their decarbonylation, upon treatment with an array of activators, was evaluated. The release of CO from crystalline MePh₂SiCO₂H proved to be highly efficient, and it was successfully applied in a selection of palladium-catalyzed carbonylative couplings using near-stoichiometric quantities of carbon monoxide precursor. Finally, the synthesis of MePh₂Si¹³CO₂H and its application in carbonyl labeling of two bioactive compounds was demonstrated

Improved Safety during Transfer of Pyrophoric <i>tert</i>-Butyllithium from Flasks with Protective Seals

A simple setup has been devised to facilitate safer transfer of air-sensitive and pyrophoric reagents from Sure/Seal bottles in a fume hood setting. The setup is composed of three parts; a sealed transfer vial, a custom bottle cap for transfer vial alignment, and a metal clip. All of the needed parts are constructed from standard laboratory equipment and by 3D printing. Titration of <i>tert</i>-butyllithium was used as an example of safe transfer of a highly pyrophoric reagent, and an instructional video has been prepared