Organocatalytic enantioselective oxa-Piancatelli rearrangement.

The first highly enantioselective oxa-Piancatelli rearrangement has been developed. This process which is catalyzed by a chiral BINOL-derived phosphoric acid rearranges a wide range of furylcarbinols into densely substituted γ-hydroxy cyclopentenones in high yield with excellent diastereo- and enantioselectivities (up to 99 : 1 er). This reaction exhibits a high functional group tolerance and was applied to complex bioactive molecules as well. The products were further manipulated into value-added molecular scaffolds further highlighting their versatility and synthetic utility.

Pancreatic Cystic Lesions on MRI: What Is The Likelihood of a Present or Future Diagnosis of Pancreatic Carcinoma?

BACKGROUND: Pancreatic cystic lesions (PCLs) are followed for years due to older and likely biased works demonstrating a strong association with pancreatic carcinoma; more recent data are needed clarifying this relationship. PURPOSE: To determine the association between PCLs on MRI and a synchronous or future diagnosis of pancreatic carcinoma. STUDY TYPE: Single-center retrospective cohort. POPULATION: A total of 192 patients (111 female, 58%) with median age 66 years (range 26-87 years) with PCLs on abdominal MRI from 2011 to 2016. FIELD STRENGTH/SEQUENCES: 1.5 T and 3 T, including T2 WI, T1 WI, diffusion weighted imaging and contrast-enhanced T1 WI. ASSESSMENT: Each PCL was reviewed independently by 2 of 10 fellowship-trained abdominal radiologists. Fukuoka guideline worrisome features and high-risk stigmata were evaluated. Follow-up imaging and clinical notes were reviewed within a system that captures pancreatic carcinoma for the region, for a median follow-up of 67 months (interquartile range: 43-88 months). STATISTICAL TESTS: Pancreatic carcinoma prevalence and incidence rate for future carcinoma with 95% confidence intervals (95% CI). Fisher exact test, logistic regression with odds ratios (OR) and the Wilcoxon rank-sum test were used to assess PCL morphologic features with the Kolmogorov-Smirnov test used to assess for normality. P < 0.05 defined statistical significance. RESULTS: The prevalence of pancreatic carcinoma on initial MRI showing a PCL was 2.4% (95% CI: 0.9%, 5.2%). Thickened/enhancing cyst wall was associated with pancreatic carcinoma, OR 52 (95% CI: 4.5, 1203). Of 189 patients with a PCL but without pancreatic carcinoma at the time of initial MRI, one developed high-grade dysplasia and none developed invasive carcinoma for an incidence rate of 0.97 (95% CI: 0.02, 5.43) and 0 (95% CI: 0, 3.59) cases per 1000 person-years, respectively. DATA CONCLUSION: A low percentage of patients with a PCL on MRI had a pancreatic carcinoma at the time of initial evaluation and none developed carcinoma over a median 67 months of follow-up. EVIDENCE LEVEL: 3 TECHNICAL EFFICACY: 5.

Hydroxy-directed iridium-catalyzed enantioselective formal ß-C(sp2)-H allylic alkylation of α,ß-unsaturated carbonyls.

Hydroxy-directed iridium-catalyzed enantioselective formal ß-C(sp2)-H allylic alkylation of kojic acid and structurally related α,ß-unsaturated carbonyl compounds is developed. This reaction, catalyzed by an Ir(i)/(P,olefin) complex, utilizes the nucleophilic character of α-hydroxy α,ß-unsaturated carbonyls, to introduce an allyl group at its ß-position in a branched-selective manner in good to excellent yield with uniformly high enantioselectivity (up to >99.9 : 0.1 er). To the best of our knowledge, this report represents the first example of the use of kojic acid in a transition metal catalyzed highly enantioselective transformation.

Mechanism and Origin of Remote Stereocontrol in the Organocatalytic Enantioselective Formal C(sp2)-H Alkylation Using Nitroalkanes as Alkylating Agents.

Experimental 13C kinetic isotope effects (KIEs) and density functional theory (DFT) calculations are used to evaluate the mechanism and origin of enantioselectivity in the formal C(sp2)-H alkylative desymmetrization of cyclopentene-1,3-diones using nitroalkanes as the alkylating agent. An unusual combination of an inverse (∼0.980) and a normal (∼1.033) KIE is observed on the bond-forming carbon atoms of the cyclopentene-1,3-dione and nitroalkane, respectively. These data provide strong support for a mechanism involving reversible carbon-carbon bond formation followed by rate- and enantioselectivity-determining nitro group elimination. The theoretical free-energy profile and the predicted KIEs indicate that this elimination event occurs via an E1cB pathway. The origin of remote stereocontrol is evaluated by distortion-interaction and SAPT0 analyses of the E1cB transition states leading to both enantiomers.

Enantioselective [6 + 2]-Cycloaddition of Transient 3-Methide-3H-pyrroles with 2-Vinylindoles under Chiral Brønsted Acid Catalysis.

An organocatalytic, highly diastereo- and enantioselective [6 + 2]-cycloaddition of 3-methide-3H-pyrroles with 2-vinylindoles has been developed. This BINOL phosphoric acid-catalyzed reaction utilizes pyrrole-3-carbinols as precursors for the in situ generation of 3-methide-3H-pyrroles to access densely substituted cyclopenta[b]pyrroles bearing three contiguous stereogenic centers as single diastereomers in good yields with excellent enantioselectivity.

Iridium-catalyzed enantioselective olefinic C(sp2)-H allylic alkylation.

The first iridium-catalyzed enantioselective olefinic C(sp2)-H allylic alkylation is developed in cooperation with Lewis base catalysis. This reaction, catalyzed by cinchonidine and an in situ generated cyclometalated Ir(i)/phosphoramidite complex, makes use of the latent enolate character of an α,ß-unsaturated carbonyl compound, namely coumalate ester, to introduce an allyl group at its α-position in a branched-selective manner in moderate to good yield with good to excellent enantioselectivities (up to 98 : 2 er).

Correction: Iridium-catalyzed enantioselective olefinic C(sp2)-H allylic alkylation.

[This corrects the article DOI: 10.1039/D0SC06208A.].

Influence of gender on cytokine induced depression and treatment: Gender aspects of IFN-α-induced depression.

BACKGROUND: Cytokine treatment with Interferon-alpha (IFN-α) represents a clinical model of immune associated depression, but it remains unclear if it is of the same entity as major depressive disorder (MDD). The study focuses on possible gender differences in IFN-α induced depression and effects of a pre-emptive antidepressant treatment. METHODS: Data from 181 patients with chronic hepatitis C infection (cHC) without history of mental illnesses undergoing treatment with IFN-α 2a and ribavirin were re-analyzed for gender effects. Patients with a pre-emptive antidepressant therapy with Escitalopram (n = 90, verum group) to prevent IFN-induced depression were compared to patients who received placebo (n = 91). Depressive symptoms before and during HCV-treatment were assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Depression Inventory (BDI) and the Hamilton Anxiety Rating Scale. RESULTS: We found significant differences regarding the incidence and severity of depressive symptoms between men and women for patients without antidepressant pre-treatment (placebo group). Significantly more women without pre-emptive antidepressant therapy suffered from clinically relevant depression (MADRS values ≥ 13, p = 0.041) and self-rated depressive symptoms (BDI ≥ 17, p = 0.024). Antidepressant pre-treatment showed comparable effects regarding the reduction of incidence and severity of depression in both women and men. CONCLUSIONS: Compared to MDD, IFN-alpha-induced depression in patients with cHC is also characterized by gender differences with an increased risk for women but no gender difference regarding the effects of an antidepressant pre-treatment is found. Our data strengthens the hypothesis that Interferon-induced depression serves as a clinical model for immune related depressive disorders.

Construction of a demand and capacity model for intensive care and hospital ward beds, and mortality from COVID-19.

BACKGROUND: This paper describes a model for estimating COVID-19 related excess deaths that are a direct consequence of insufficient hospital ward bed and intensive care unit (ICU) capacity. METHODS: Compartmental models were used to estimate deaths under different combinations of ICU and ward care required and received in England up to late April 2021. Model parameters were sourced from publicly available government information and organisations collating COVID-19 data. A sub-model was used to estimate the mortality scalars that represent increased mortality due to insufficient ICU or general ward bed capacity. Three illustrative scenarios for admissions numbers, 'Optimistic', 'Middling' and 'Pessimistic', were modelled and compared with the subsequent observations to the 3rd February. RESULTS: The key output was the demand and capacity model described. There were no excess deaths from a lack of capacity in the 'Optimistic' scenario. Several of the 'Middling' scenario applications resulted in excess deaths-up to 597 deaths (0.6% increase) with a 20% reduction compared to best estimate ICU capacity. All the 'Pessimistic' scenario applications resulted in excess deaths, ranging from 49,178 (17.0% increase) for a 20% increase in ward bed availability, to 103,735 (35.8% increase) for a 20% shortfall in ward bed availability. These scenarios took no account of the emergence of the new, more transmissible, variant of concern (b.1.1.7). CONCLUSIONS: Mortality is increased when hospital demand exceeds available capacity. No excess deaths from breaching capacity would be expected under the 'Optimistic' scenario. The 'Middling' scenario could result in some excess deaths-up to a 0.7% increase relative to the total number of deaths. The 'Pessimistic' scenario would have resulted in significant excess deaths. Our sensitivity analysis indicated a range between 49,178 (17% increase) and 103,735 (35.8% increase). Given the new variant, the pessimistic scenario appeared increasingly likely and could have resulted in a substantial increase in the number of COVID-19 deaths. In the event, it would appear that capacity was not breached at any stage at a national level with no excess deaths. it will remain unclear if minor local capacity breaches resulted in any small number of excess deaths.

Enantioselective Direct Vinylogous Allylic Alkylation of 4-Methylquinolones under Iridium Catalysis.

The first enantioselective vinylogous allylic alkylation of 4-methylquinolones has been developed. This iridium-catalyzed reaction introduces an allyl group at the γ-position of 4-methyl-2-quinolones with exclusive branched selectivity and an excellent level of enantioselectivity. This in turn allows for the enantioselective synthesis of γ-allylquinolines and related nitrogenous heterocycles. This is the first application of 4-methylquinolones in an enantioselective transformation.

Iridium-catalyzed enantioselective direct vinylogous allylic alkylation of coumarins.

The first iridium-catalyzed enantioselective vinylogous allylic alkylation of coumarins is presented. Using easily accessible linear allylic carbonates as the allylic electrophile, this reaction installs unfunctionalized allyl groups at the γ-position of 4-methylcoumarins in an exclusively branched-selective manner generally in high yields with an excellent level of enantioselectivity (up to 99 : 1 er).

Catalytic Enantioselective Desymmetrization of Norbornenoquinones via C(sp2)-H Alkylation.

The enantioselective Diels-Alder (DA) reaction with monosubstituted p-benzoquinones is an unmet challenge. A new approach for the enantioselective synthesis of monosubstituted quinone-DA adducts is presented based on C(sp2)-H alkylative desymmetrization of meso-DA adducts. Catalyzed by a tertiary amino-thiourea derivative, this reaction utilizes nitroalkanes as the alkylating agents and generates densely functionalized products bearing at least four contiguous stereogenic centers remote from the reaction site with excellent enantioselectivities.

Enantioselective Formal C(sp2 )-H Vinylation.

An enantioselective formal C(sp2 )-H vinylation of prochiral 2,2-disubstituted cyclopentene-1,3-dione is presented. This vinylative desymmetrization is realized by using a two-step procedure that consists of a catalytic enantioselective vinylogous Michael addition of deconjugated butenolides to cyclopentene-1,3-dione and a base-mediated decarboxylation. The overall process utilizes deconjugated butenolides as the source of the highly substituted vinyl unit. Five-membered carbocycles containing a remote all-carbon quaternary stereogenic center are obtained in good yields and with good to high enantioselectivities.

Pilomatricoma perforante que se presenta como una úlcera en el hélix del pabellón auricular / Perforating pilomatricoma presenting as an ulcer in the helix of the pinna

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Sadness and mild cognitive impairment as predictors for interferon-alpha-induced depression in patients with hepatitis C.

BACKGROUND: Antiviral therapy with interferon-alpha (IFN-α) for hepatitis C virus (HCV) infection is associated with increased risk for depression. AIMS: To identify clinical predictors for IFN-α-induced depression during antiviral therapy for HCV infection. METHOD: Depression (defined with the Montgomery-Åsberg Depression Rating Scale (MADRS)) was evaluated before and during antiviral treatment in 91 people with chronic HCV infection without a history of psychiatric disorders. Cognitive function was evaluated using the Trail Making Test A/B (TMT A/B). (Trial registration at ClinicalTrials.gov: NCT00136318.) RESULTS: Depression during antiviral therapy was significantly associated with a baseline MADRS score of 3 or higher (P = 0.006). In total, 89% (n = 16) of patients who had a baseline score >0 for the single item sadness developed depression. Poor baseline performance in the TMT A (P = 0.027) and TMT B (P = 0.033) was predictive for severe depression. CONCLUSIONS: Pre-treatment screening for subthreshold depressive and cognitive symptoms will help to identify those at risk for IFN-α-associated depression among patients with chronic hepatitis C.

Management of mental health problems prior to and during treatment of hepatitis C virus infection in patients with drug addiction.

Psychiatric comorbidity is a common problem in patients with substance use disorders. Patients with psychiatric diseases and/or substance abuse have an increased risk for hepatitis C virus (HCV) infection. Furthermore, psychiatric problems occur frequently during antiviral treatment and may be associated with the use of interferon alpha (IFN-α) but also with the primary psychiatric condition. As a consequence, substance abuse and/or acute psychiatric problems are still important reasons for nontreatment of chronic HCV infection. However, prospective and controlled data from recent years showed that if an interdisciplinary treatment is provided, patients with substance use disorders and/or psychiatric diseases do not differ regarding sustained virologic response or IFN-α-associated complications such as depression when compared with controls. Moreover, depression as the most important acute IFN-α-associated psychiatric adverse event can be acutely treated or even prevented by antidepressant pretreatment. Other, more rare but severe complications such as mania, psychotic symptoms, or delirium need individual psychiatric interventions.

Escitalopram for the prevention of peginterferon-α2a-associated depression in hepatitis C virus-infected patients without previous psychiatric disease: a randomized trial.

BACKGROUND: Depression is a major complication during treatment of chronic hepatitis C virus (HCV) infection with interferon-α (IFN-α). It is unclear whether antidepressants can prevent IFN-induced depression in patients without psychiatric risk factors. OBJECTIVE: To examine whether preemptive antidepressant treatment with escitalopram can decrease the incidence or severity of depression associated with pegylated IFN-α in HCV-infected patients without a history of psychiatric disorders. DESIGN: Randomized, multicenter, double-blind, prospective, placebo-controlled, parallel-group trial. (ClinicalTrials.gov registration number: NCT00136318) SETTING: 10 university and 11 academic hospitals in Germany. PATIENTS: 181 HCV-infected patients with no history of psychiatric disorders enrolled between August 2004 and December 2008. INTERVENTION: Escitalopram, 10 mg/d (n = 90), or placebo (n = 91) administered 2 weeks before and for 24 to 48 weeks during antiviral therapy. MEASUREMENTS: The primary end point was the incidence of depression, defined as a Montgomery-Asberg Depression Rating Scale (MADRS) score of 13 or higher. Secondary end points were time to depression, incidence of major depression according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, quality of life, sustained virologic response, tolerability, and safety. RESULTS: 32% (95% CI, 21% to 43%) of the patients in the escitalopram group developed a MADRS score of 13 or higher compared with 59% (CI, 48% to 69%) in the placebo group (absolute difference, 27 percentage points [CI, 12 to 42 percentage points]; P < 0.001). Major depression was diagnosed in 8% of the patients in the escitalopram group and 19% in the placebo group (absolute risk difference, 11 percentage points [CI, 5 to 15 percentage points]; P = 0.031). Tolerability and safety parameters did not differ between the groups. In the escitalopram group, 56% (CI, 46% to 66%) of patients achieved a sustained virologic response compared with 46% (CI, 37% to 57%) in the placebo group (P = 0.21). LIMITATIONS: Results might not be generalizable to patients with previous psychiatric disease. Some patients withdrew or developed temporary elevated MADRS scores after randomization but before the study medication was started. CONCLUSION: Prophylactic antidepressant treatment with escitalopram was effective in reducing the incidence and severity of IFN-associated depression in HCV-infected patients without previous psychiatric disease. PRIMARY FUNDING SOURCE: Roche Pharma and Lundbeck.

Dynamic chromosomal rearrangements in Hodgkin's lymphoma are due to ongoing three-dimensional nuclear remodeling and breakage-bridge-fusion cycles.

BACKGROUND: Hodgkin's lymphoma is characterized by the presence of mono-nucleated Hodgkin cells and bi- to multi-nucleated Reed-Sternberg cells. We have recently shown telomere dysfunction and aberrant synchronous/asynchronous cell divisions during the transition of Hodgkin cells to Reed-Sternberg cells.1 DESIGN AND METHODS: To determine whether overall changes in nuclear architecture affect genomic instability during the transition of Hodgkin cells to Reed-Sternberg cells, we investigated the nuclear organization of chromosomes in these cells. RESULTS: Three-dimensional fluorescent in situ hybridization revealed irregular nuclear positioning of individual chromosomes in Hodgkin cells and, more so, in Reed-Sternberg cells. We characterized an increasingly unequal distribution of chromosomes as mono-nucleated cells became multi-nucleated cells, some of which also contained chromosome-poor 'ghost' cell nuclei. Measurements of nuclear chromosome positions suggested chromosome overlaps in both types of cells. Spectral karyotyping then revealed both aneuploidy and complex chromosomal rearrangements: multiple breakage-bridge-fusion cycles were at the origin of the multiple rearranged chromosomes. This conclusion was challenged by super resolution three-dimensional structured illumination imaging of Hodgkin and Reed-Sternberg nuclei. Three-dimensional super resolution microscopy data documented inter-nuclear DNA bridges in multi-nucleated cells but not in mono-nucleated cells. These bridges consisted of chromatids and chromosomes shared by two Reed-Sternberg nuclei. The complexity of chromosomal rearrangements increased as Hodgkin cells developed into multi-nucleated cells, thus indicating tumor progression and evolution in Hodgkin's lymphoma, with Reed-Sternberg cells representing the highest complexity in chromosomal rearrangements in this disease. CONCLUSIONS: This is the first study to demonstrate nuclear remodeling and associated genomic instability leading to the generation of Reed-Sternberg cells of Hodgkin's lymphoma. We defined nuclear remodeling as a key feature of Hodgkin's lymphoma, highlighting the relevance of nuclear architecture in cancer.