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Summary: Background: The quantitative HepQuant SHUNT test of liver function and physiology generates a disease severity index (DSI) that correlates with risk for clinical complications, such as large oesophageal varices (LEVs). A derivative test, HepQuant DuO, generates an equivalent DSI and simplifies testing by requiring only oral administration of the test solution and two blood samples at 20 and 60 min. Aims: Since the DSIs measured from DuO and SHUNT are equivalent, we compared the diagnostic performance for large oesophageal varices (LEVs) between the DSIs measured from DuO and SHUNT tests. Methods: This study combined the data from two prospectively conducted US studies: HALT‐C and SHUNT‐V. A total of 455 subjects underwent both the SHUNT test and esophagogastroduodenoscopy (EGD). Results: DSI scores correlated with the probability of LEVs (p < 0.001) and demonstrated a stepwise increase from healthy lean controls without liver disease to subjects with chronic liver disease and no, small or large varices. Furthermore, a cutoff of DSI ≤ 18.3 from DuO had a sensitivity of 0.98 (missing only one case) and, if applied to the endoscopy (EGD) decision, would have prevented 188 EGDs (41.3%). The AUROC for DSI from DuO did not differ from that of the reference SHUNT test method (0.82 versus 0.81, p = 0.3500). Conclusions: DSI from HepQuant DuO links liver function and physiology to the risk of LEVs across a wide spectrum of patient characteristics, disease aetiologies and liver disease severity. DuO is minimally invasive, easy to administer, quantitative and may aid the decision to avoid or perform EGD for LEVs. [ABSTRACT FROM AUTHOR]

We prove limit laws for the number of occurrences of a pattern on the fringe of a ranked tree-child network which is picked uniformly at random. Our results extend the limit law for cherries proved by Bienvenu et al. (Random Struct. Algoritm. 60 (2022), no. 4, 653–689). For patterns of height 1 and 2, we show that they either occur frequently (mean is asymptotically linear and limit law is normal) or sporadically (mean is asymptotically constant and limit law is Poisson) or not all (mean tends to 0 and limit law is degenerate). We expect that these are the only possible limit laws for any fringe pattern. [ABSTRACT FROM AUTHOR]

Objectives: The prognostic relevance of metabolic tumor volume (MTV) having recently been demonstrated in patients with early‐stage favorable and advanced‐stage Hodgkin lymphoma. The current study aimed to assess the potential prognostic value of 18F‐fluorodeoxyglucose (FDG) positron emission tomography (PET) in early‐stage unfavorable Hodgkin lymphoma patients treated within the German Hodgkin Study Group HD17 trial. Methods: 18F‐FDG PET/CT images were available for MTV analysis in 154 cases. We used three different threshold methods (SUV2.5, SUV4.0, and SUV41%) to calculate MTV. Receiver‐operating‐characteristic analysis was performed to describe the value of these parameters in predicting an adequate therapy response. Therapy response was evaluated as PET negativity after 2 cycles of eBEACOPP followed by 2 cycles of ABVD. Results: All three threshold methods analyzed for MTV showed a positive correlation with the PET response after chemotherapy. Areas under the curve (AUC) were 0.70 (95% CI 0.53–0.87) and 0.65 (0.50–0.80) using the fixed thresholds of SUV4.0 and SUV2.5, respectively, for MTV‐ calculation. The calculation of MTV using a relative threshold of SUV41% showed an AUC of 0.63 (0.47–0.79). Conclusions: MTV does have predictive value after chemotherapy in early‐stage unfavorable Hodgkin lymphoma, particularly when the fixed threshold of SUV4.0 is used for MTV calculation. Trial registration: ClinicalTrials.gov NCT01356680. [ABSTRACT FROM AUTHOR]

Objectives: Patients with classical Hodgkin lymphoma (cHL) relapsing after second‐line therapy have a dismal prognosis and novel approaches are required for this patient group. Based on promising (pre‐)clinical data and the favourable toxicity profile, we performed a phase II clinical trial with the JAK inhibitor ruxolitinib in patients with relapsed or refractory cHL (r/r cHL). Methods: Patients ≥18 years with histologically confirmed r/r cHL who failed second‐line treatment were included. Ruxolitinib was given orally at a dose of 25 mg twice daily in continuous 28‐day cycles until progression or unacceptable toxicity. Primary endpoint was the PET/CT‐based overall response rate (ORR; complete response (CR) or partial response (PR)) after 2 cycles; secondary endpoints included progression‐free (PFS) and overall survival (OS) as well as feasibility. The Jericho Trial adopted a 2‐stage phase 2 design (Simon 1989). Results: Among the 12 included patients in stage 1, 2 had a PR, 3 had a stable disease (SD) and 6 had progressive disease (PD) after two treatment cycles (ORR: 2/12 evaluable patients, 16.7%). Median PFS was 3.6 months, the 1‐year OS estimate was 50.6% (median not reached). The toxicity profile was favourable with only one grade IV adverse event (7.1%) reported. Conclusion: Ruxolitinib exhibited a favourable side effect profile but modest activity in r/r cHL. Although the formal stopping criterion after stage 1 was not met, the trial did not continue to stage 2 due to the low response and PFS rates observed in stage 1. [ABSTRACT FROM AUTHOR]

Overall, 33 patients (52%) continued treatment beyond investigator assessed PD and a total of 16 patients received additional concomitant radiotherapy and/or chemotherapy. The majority of patients experiencing PD during or after anti-PD1 treatment received additional therapies (21/37, 57%). Outcomes of anti-programmed death 1 treatment for relapsed/refractory Hodgkin lymphoma: A German Hodgkin Study Group multicentre real-world analysis. [Extracted from the article]

Value of bone marrow biopsy in Hodgkin lymphoma patients staged by FDG PET: results from the German Hodgkin Study Group trials HD16, HD17, and HD18. Keywords: bone marrow involvement; Hodgkin lymphoma; intensive chemotherapy; positron emission tomography; prognosis EN bone marrow involvement Hodgkin lymphoma intensive chemotherapy positron emission tomography prognosis e5 e8 4 03/30/22 20220401 NES 220401 Newly diagnosed advanced-stage Hodgkin lymphoma (HL) has become a curable malignancy in the vast majority of patients.1,2 With response-adapted treatment comprising four or six cycles of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) in escalated dose (eBEACOPP), outstanding cure rates are achieved through a comparatively short and safe treatment approach.3,4 Around 5 to 15% of HL patients present with bone marrow (BM) involvement, as assessed by conventional biopsy.5-7 According to the Ann Arbor classification, BM involvement reflects a high tumour burden and therefore defines stage IV disease.8 Positron emission tomography (PET) using SP 18 sp F-fluoro-2-deoxy-d-glucose (FDG) has demonstrated superior sensitivity compared to BM biopsy.9-11 In paediatric advanced HL, only individuals showing three or more BM lesions were assumed to be at higher risk for progression or relapse.12 Yet, there are insufficient data available to establish whether this also holds true for adult patients receiving intensive first-line treatment. PET imaging was shown to identify BM lesions at a higher sensitivity than biopsy of the iliac bone and has become part of diagnostic work-up in most countries.15 Current study protocols no longer recommend BM biopsy in PET-negative individuals. [Extracted from the article]

Summary: Reinduction chemotherapy followed by high‐dose chemotherapy and autologous stem cell transplant (HDCT + ASCT) is second‐line standard of care for transplant‐eligible patients with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) but has a high failure rate. Because response to reinduction is predictive of the outcome after HDCT + ASCT, we aimed to improve the standard dexamethasone, high‐dose cytarabine and cisplatinum (DHAP) reinduction regimen by addition of the oral mammalian target of rapamycin inhibitor everolimus (everDHAP). Transplant‐eligible patients aged 18–60 years with histologically confirmed r/r cHL were included in this experimental phase I/II trial. Everolimus (10 mg/day, determined in phase‐I‐part) was administered on day 0–13 of each DHAP cycle. From July 2014 to March 2018, 50 patients were recruited to the phase II everDHAP group; two were not evaluable, three discontinued due to toxicity. Randomization to a placebo group stopped in October 2015 due to poor recruitment after nine patients. The primary end‐point of computed tomography (CT)‐based complete remission (CR) after two cycles of everDHAP was expected to be ≥40%. With a CT‐based CR rate of 27% (n = 12/45) after two cycles of everDHAP the trial did not meet the primary end‐point. Adding everolimus to DHAP is thus feasible; however, the everDHAP regimen failed to show an improved efficacy. [ABSTRACT FROM AUTHOR]

Summary: High programmed cell death 1 ligand 1 (PD‐L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin‐ and Reed–Sternberg cells (HRSC) have been shown to be associated with favourable response to anti‐PD‐1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD‐L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti‐PD‐1‐based first‐line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced‐stage or r/r cHL. All but two cases (97%) showed PD‐L1 expression by the tumour cells in variable amounts. While MHC‐I was rarely expressed in >50% of HRSC, MHC‐II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD‐L1 and MHC‐I/II expression on early response to the highly effective anti‐PD‐1‐based NIVAHL first‐line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti‐PD‐1 first‐line cHL treatment. [ABSTRACT FROM AUTHOR]

Summary: We retrospectively investigated histopathological growth patterns in individuals with advanced nodular lymphocyte‐predominant Hodgkin lymphoma (NLPHL) treated within the randomized HD18 study. In all, 35/60 patients (58%) presented with atypical growth patterns. Patients with atypical growth patterns more often had stage IV disease (P = 0·0354) and splenic involvement (P = 0·0048) than patients with typical growth patterns; a positive positron emission tomography after two cycles of chemotherapy (PET‐2) tended to be more common (P = 0·1078). Five‐year progression‐free survival [hazard ratio (HR) = 0·86; 95% confidence interval (CI) = 0·49–1·47] and overall survival (HR = 0·85; 95% CI = 0·49–1·51) did not differ between the groups after study treatment with PET‐2‐guided escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone). Thus, advanced NLPHL is often associated with atypical growth patterns but their prognostic impact is compensated by PET‐2‐guided escalated BEACOPP. [ABSTRACT FROM AUTHOR]

The substrate scope of the asymmetric allylation with zinc organyls catalyzed by 3,3‐bis(2,4,6‐triisopropylphenyl)‐1,1‐binaphthyl‐2,2‐diyl hydrogenphosphate (TRIP) has been extended to non‐cyclic ester organozinc reagents and ketones. Tertiary chiral alcohols are obtained with ee's up to 94% and two stereogenic centers can be created. Compared to the previous lactone reagent the stereopreference switches almost completely, proving the fact that the nature of the organometallic compound is of immense importance for the asymmetry of the product. [ABSTRACT FROM AUTHOR]

We give a detailed asymptotic analysis of the profiles of random symmetric digital search trees, which are in close connection with the performance of the search complexity of random queries in such trees. While the expected profiles have been analyzed for several decades, the analysis of the variance turns out to be very difficult and challenging, and requires the combination of several different analytic techniques, including Mellin and Laplace transforms, analytic de‐Poissonization, and Laplace convolutions. Our results imply concentration of the profiles in the range where the mean tends to infinity. Moreover, we also obtain a two‐point concentration for the distributions of the height and the saturation level. [ABSTRACT FROM AUTHOR]

Summary: Data on non‐Hodgkin lymphoma (NHL) after classical Hodgkin lymphoma (cHL) are scarce. We therefore performed a retrospective analysis comprising 11·841 cHL patients who had first‐line treatment within the randomized German Hodgkin Study Group (GHSG) HD7–HD15 studies. After a median follow‐up of 106 months, 175 patients (1·5%) had developed NHL. The median time to NHL was 44 months, the median age at NHL diagnosis was 54 years. The five‐year event‐free survival and overall survival estimates from the diagnosis of NHL were 36·9% and 44·2%, respectively. Thus, NHL after cHL is a rare event primarily affecting older individuals and often resulting in the patient´s death. [ABSTRACT FROM AUTHOR]

The asymmetric amination of secondary racemic allylic alcohols bears several challenges like the reactivity of the bi‐functional substrate/product as well as of the α,β‐unsaturated ketone intermediate in an oxidation‐reductive amination sequence. Heading for a biocatalytic amination cascade with a minimal number of enzymes, an oxidation step was implemented relying on a single PQQ‐dependent dehydrogenase with low enantioselectivity. This enzyme allowed the oxidation of both enantiomers at the expense of iron(III) as oxidant. The stereoselective amination of the α,β‐unsaturated ketone intermediate was achieved with transaminases using 1‐phenylethylamine as formal reducing agent as well as nitrogen source. Choosing an appropriate transaminase, either the (R)‐ or (S)‐enantiomer was obtained in optically pure form (>98 % ee). The enantio‐convergent amination of the racemic allylic alcohols to one single allylic amine enantiomer was achieved in one pot in a sequential cascade. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) infections are more common among US veterans receiving care through Veterans Affairs (VA) Medical Centers than among the general population. Historically, HCV therapies had lower efficacy rates in VA patients, possibly due to common comorbidities such as psychiatric disorders and substance abuse. The direct‐acting antivirals ombitasvir/paritaprevir/ritonavir and dasabuvir (OBV/PTV/r+DSV)±ribavirin (RBV) are approved in the US for HCV genotype 1 (GT1)‐infected adults with or without cirrhosis. This study prospectively evaluated the safety and efficacy of OBV/PTV/r+DSV±RBV in VA patients with HCV GT1 infection. TOPAZ‐VA was a phase 3b, open‐label trial. Adult US veterans with HCV GT1 infection, without cirrhosis or with compensated cirrhosis, were eligible for enrollment. Patients with GT1a infection received OBV/PTV/r +DSV+RBV for 12 weeks or 24 weeks (for those with cirrhosis); GT1b‐infected patients without cirrhosis received OBV/PTV/r +DSV for 12 weeks; those with cirrhosis received OBV/PTV/r +DSV with RBV. The primary endpoint was sustained virologic response at posttreatment week 12 (SVR12); safety was also assessed. Ninety‐nine patients were enrolled at 10 sites from May through November 2015. The majority were male (96%), white (60%), and with GT1a infection (68%); 49% reported ongoing psychiatric disorders. Overall, 94% (93/99) achieved SVR12; three patients had a virologic failure. The most common AEs were fatigue (28%), headache (20%), and nausea (15%); six patients discontinued treatment due to AEs. In US veterans with HCV GT1 infection, OBV/PTV/r +DSV±RBV yielded a 94% overall SVR12 rate and was well tolerated. The presence of psychiatric disorders and/or injection drug use did not impact efficacy. Highlights: Chronic hepatitis C virus (HCV) infection occurs at a higher prevalence in the VA Health System than in the general population.These patients are also at a higher risk of psychiatric disorders and substance abuse, which were historically risk factors for successful treatment of HCV.We treated 99 patients in the VA Health System with ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin for 12 to 24 weeks.Sustained virologic response was achieved in 93 of 99 patients, with safety and tolerability comparable to the general population.The presence of psychiatric or substance abuse disorders did not impact treatment success. [ABSTRACT FROM AUTHOR]

Non‐take‐up of means tested benefits is a widespread phenomenon in European welfare states. The paper assesses whether the reform that replaced the monetary social assistance benefit by the minimum income benefit in Austria in 2010/11 has succeeded in increasing take up rates. We use EU‐SILC register data together with the tax‐benefit microsimulation model EUROMOD/SORESI. The results show that the reform led to a significant decrease of non‐take‐up from 53 to 30% in terms of the number of households and from 51 to 30% in terms of expenditure. Following the three‐t's (threshold, trigger, and trade‐off) introduced by Van Oorschot, estimates of a two‐stage Heckman selection model as well as expert interviews indicate that the taken measures include both threshold and trade‐off characteristics. Elements such as the higher degree of anonymity within the claiming process, the provision of health insurance, binding minimum standards, the limitation of the maintenance obligations, new regulations related to the liquidation of wealth, as well as the general coverage of the benefit reform in the media and in public discussions led to an improved access to the benefit. [ABSTRACT FROM AUTHOR]

Alcohol use disorder (AUD) screening is important but focused training with using AUDIT‐10 with counselling/mental health (MH) referral may be needed. We aimed to compare the effect of training on AUD screening/intervention in hepatology clinics in pre vs post‐training phases of a quality‐improvement initiative. Pre‐training encounters were evaluated for inquiry into AUD, AUDIT‐10 and MH referrals. Dedicated AUD‐related training was provided to hepatology providers and analyses repeated post‐training. Pre‐training (n = 378) and post‐training patients(n = 318) had similar demographics and disease characteristics. Post‐training there was higher inquiry about alcohol(92% vs 80%, P <.0001), counselling (82% vs 68%, P <.0001). This led to higher diagnosis of drinkers (49% vs 31%, P <.0001) of whom higher proportion had AUDIT‐10 administered(91% vs 34%, P <.0001) and referred to MH(29% vs 8%, P <.0001). On regression presumed alcohol‐related aetiology, younger age and post‐training period were associated with AUDIT‐10 administration. AUD‐focused training significantly improves rates of screening and MH referral for problem drinking in a hepatology clinic population. [ABSTRACT FROM AUTHOR]

Background & Aims: Gut microbiota are affected by diet and ethnicity, which impacts cognition and hospitalizations in cirrhosis. Aim: Study interactions of diet with microbiota and impact on hospitalizations and cognition in American and Mexican cohorts. Methods: Controls and age‐balanced patients with compensated/decompensated cirrhosis were included and followed for 90‐day hospitalizations. A subset underwent minimal hepatic encephalopathy (MHE) testing. Parameters such as dietary, salivary and faecal microbiota (diversity, taxa analysis, cirrhosis dysbiosis ratio CDR:high = good) between/within countries were analysed. Regression analyses for hospitalizations and MHE were performed. Results: In all, 275 age‐balanced subjects (133 US [40 Control, 50 Compensated, 43 Decompensated] and 142 Mexican [41 Control, 49 Compensated, 52 Decompensated]) were enrolled. MELD/cirrhosis severity was comparable. Diet showed lower protein and animal fat intake in all decompensated patients, but this was worse in Mexico. Diversity was lower in stool and saliva in decompensated patients, and worse in Mexican cohorts. Prevotellaceae were lower in decompensated cirrhosis, particularly those with lower animal fat/protein consumption across countries. Hospitalizations were higher in Mexico vs the USA (26% vs 14%, P =.04). On regression, Prevotellaceae, Ruminococcaceae and Lachnospiraceae lowered hospitalization risk independent of MELD and ascites. MHE testing was performed in 120 (60/country and 20/subgroup) subjects and MHE rate was similar. MELD and decompensation increased while CDR and Prevotellaceae decreased the risk of MHE. Conclusions: Changes in diet and microbiota, especially related to animal fat and protein intake and Prevotellaceae, are associated with MHE and hospitalizations in Mexican patients with cirrhosis compared to an American cohort. Nutritional counselling to increase protein intake in cirrhosis could help prevent these hospitalizations. [ABSTRACT FROM AUTHOR]

Regioselective hydroxylation on inactivated C−H bonds is among the dream reactions of organic chemists. Cytochrome P450 enzymes (CYPs) perform this reaction in general with high regio‐ and stereoselectivity (e. g. for steroids as substrates). Furthermore, enzyme engineering may allow to tune the properties of the enzyme. Regioselective hydroxylation of shorter or linear molecules (fatty acids), however, remains challenging even with this enzyme class, due to the high similarity of the substrate's backbone carbons and their conformational flexibility. CYPs hydroxylating fatty acids selectively in the chemically more distinct α‐ or ω‐ position are well described. In contrast, selective in‐chain hydroxylation of fatty acids lacks precedence. The peroxygenase CYP152A1 (P450Bsβ) is a family member that displays fatty acid hydroxylation at both, the α‐ and β‐position, with preference for the α‐position. Herein we report the influence of hydrophobic active site residues on the hydroxylation pattern of this enzyme. By site directed mutagenesis and combination of the libraries, double and triple mutation variants were identified, which hydroxylated decanoic acid (C10) with improved regio‐selectivity in the β‐position. Variants were identified with a 10‐fold increase of the β‐regioselectivity (expressed as α/β‐ratio) compared to the wild type. In total 103 variants of CYP152A1 (P450Bsβ) were investigated. [ABSTRACT FROM AUTHOR]

Background & Aims: Nonalcoholic steatohepatitis (NASH) is a chronic and severe form of nonalcoholic fatty liver disease that can progress to cirrhosis and hepatocellular carcinoma and is a risk factor for cardiovascular disease. Although NASH has no approved treatments, obeticholic acid (OCA), a synthetic bile acid and farnesoid X receptor (FXR) agonist, was shown to improve histological features of NASH and fibrosis. Considering that FXR activation influences plasma lipoprotein concentrations, the Combination OCA aNd sTatins for monitoRing Of Lipids (CONTROL) study evaluated how statins can regulate lipoprotein metabolism with OCA treatment in patients with NASH. Methods: This randomized, double‐blind, placebo‐controlled, phase 2 study began with a 5‐week screening/statin washout; 84 patients with NASH were randomly assigned (1:1:1:1) to receive placebo or 5 mg, 10 mg or 25 mg OCA once daily during the 16‐week double‐blind phase. Concurrent once daily atorvastatin (10 mg/days) was initiated at Week 4 with subsequent titration. Enrolled patients had biopsy‐confirmed diagnosis of NASH with no evidence of hepatic decompensation. Plasma was collected to analyse lipoprotein parameters. Results: At Week 4, all OCA groups had an increase from baseline in mean low‐density lipoprotein cholesterol (LDLc) and mean LDL particle concentration (LDLpc), mostly owing to large, less atherogenic LDLc particles. Atorvastatin 10 mg decreased LDLc and LDLpc levels below baseline in all OCA groups by Week 8; higher doses did not provide additional clinical benefits. Conclusions: The CONTROL study showed that OCA‐induced increases in LDLc in patients with NASH were mitigated with atorvastatin. The combination of OCA and atorvastatin was generally safe and well tolerated (NCT02633956). [ABSTRACT FROM AUTHOR]

Podophyllotoxin is probably the most prominent representative of lignan natural products. Deoxy‐, epi‐, and podophyllotoxin, which are all precursors to frequently used chemotherapeutic agents, were prepared by a stereodivergent biotransformation and a biocatalytic kinetic resolution of the corresponding dibenzylbutyrolactones with the same 2‐oxoglutarate‐dependent dioxygenase. The reaction can be conducted on 2 g scale, and the enzyme allows tailoring of the initial, "natural" structure and thus transforms various non‐natural derivatives. Depending on the substitution pattern, the enzyme performs an oxidative C−C bond formation by C−H activation or hydroxylation at the benzylic position prone to ring closure. [ABSTRACT FROM AUTHOR]

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Summary: About 30% of all Hodgkin lymphoma (HL) patients are ≥60 years old. As lenalidomide has promising single agent activity in multiple relapsed HL, we replaced bleomycin in ABVD with lenalidomide in this phase‐I trial. Patients aged ≥60 years with early‐unfavourable‐ or advanced‐stage HL (Eastern Cooperative Oncology Group performance status ≤2, Cumulative Illness Rating Scale for Geriatrics score 0–7) received 4–8 cycles of AVD (doxorubicin, vinblastine, dacarbazine) and lenalidomide in escalation with overdose control. Dose‐limiting toxicities (DLTs) included thromboembolism ≥grade 2, severe haematological toxicity, neutropenic fever and prolonged therapy delay. Twenty‐five patients with a median age of 68 years were included, 68% had advanced‐stage HL. A pre‐defined stopping criterion for dose escalation after DLT evaluation of 20/24 patients suggested a recommended phase II dose (RPTD) of 20 mg. DLTs occurred in 10/24 evaluable patients, all treated with ≥20 mg, however, median relative dose intensity was 97% (interquartile range 49–104%). Grade 3 or higher toxicities occurred in all 22 patients at ≥20 mg lenalidomide but no treatment‐related deaths occurred. Overall response rate was 80% for all patients (20/25) and 86% (19/22) at ≥20 mg lenalidomide. Three‐year estimates for progression‐free survival and OS were 69·7% (95% CI: 50·3–89·1%) and 83·8% (95%‐CI: 69·3–98·4%), respectively. In conclusion, AVD with lenalidomide 20 mg is feasible and highly effective in older HL patients. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to assess the use and outcome of rehabilitation after total laryngectomy in Germany. Methods: We enrolled patients who were scheduled for total laryngectomy, approached them again after surgery, after 3 months and 1 year. Patients completed questionnaires and were interviewed. Results: Of 309 participants, 14% had not received any rehabilitation. Reasons for nonuse were primarily ongoing treatment and poor health. Users of rehabilitation had 4 times the odds of attaining any ability to speak compared to nonusers (odds ratio 3.8, P = .02). The main aim of rehabilitation from the perspective of the users was speech rehabilitation, mentioned by 71% before starting rehabilitation. This was also what most users (27%) found the most helpful part of rehabilitation. Conclusions: Patients are interested in attending rehabilitation. They especially want to improve their speech capacity, which indeed is better among users of rehabilitation than in those without. [ABSTRACT FROM AUTHOR]

Fluorination and trifluoromethylation are indispensable tools in the preparation of modern pharmaceuticals and APIs. Herein we present a concept for the introduction of a trifluoromethyl group into unprotected phenols employing catalytic copper(I) iodide and hydroquinone, tBuOOH, and the Langlois' reagent. The method proceeds under mild conditions and exhibits an extended substrate scope compared to the biocatalytic trifluoromethylation using laccase from Agaricus bisporus. Various functional groups such as aldehydes, esters, ethers, ketones and nitriles were tolerated. The hydroquinone‐mediated trifluoromethylation reaction allowed accessing trifluoromethylated phenols, which are cumbersome to prepare via previously known chemical methods. Cu and HQ can do: The presence of catalytic Cu and sub‐stoichiometric amounts of hydroquinone enables the direct radical trifluoromethylation of phenols, which are difficult to trifluoromethylate with other chemical methods. Instead of the anticipated radical quenching effect of hydroquinone, it led to a highly increased reaction rate and improved overall selectivity of the trifluoromethylation process. [ABSTRACT FROM AUTHOR]

The authors discuss imperialism in the role-paying games from the game developer BioWare. They mention the issue of imperialism disguised as adventure in video games, the "Mass Effect" and "Dragon Age" series of games, and the question of neoliberalism as presented in the games.

We study the joint asymptotic behavior of the space requirement and the total path length (either summing over all root-key distances or over all root-node distances) in random m-ary search trees. The covariance turns out to exhibit a change of asymptotic behavior: it is essentially linear when [ABSTRACT FROM AUTHOR]

We study asymmetric simple-current extensions of Gepner models in dimensions [ABSTRACT FROM AUTHOR]

Accurate clinical staging is crucial for adequate risk-adapted treatment in Hodgkin lymphoma ( HL) to prevent patients from under- or over-treatment. Within the latest German Hodgkin Study Group trial generation, diagnostic findings such as histopathology, computerized tomography imaging and clinical risk factors were re-evaluated by expert panels. Here, we retrospectively analysed 5965 patients and identified 399 in who major discordant findings changed their first-line treatment allocation. Histopathology review did not confirm the initial diagnosis of HL in 87 patients. Treatment allocation was revised in 312 of the remaining 5878 patients: 176 were assigned to a higher and 128 to a lower risk group, respectively; the correct treatment group remained unclear in 8 patients. Cases of revised treatment allocation accounted for 9·8%, 6·0%, 0·8%, and 14·8% of patients initially assigned to the HD13, HD14, HD15 trials and stage IA lymphocyte-predominant HL project, respectively. Most revisions were due to wrong application of clinical stage (20·5% of 312 patients with revised treatment group), histological subtype (9·0%) or the risk factors ≥3 involved areas (46·8%) or large mediastinal mass (9·3%). In conclusion, centralized review by experienced experts changed risk-adapted first-line treatment in a relevant proportion of HL patients. Quality control measures clearly improve the accuracy of treatment and should be implemented in clinical practice. [ABSTRACT FROM AUTHOR]

During the last decade the use of ω-transaminases has been identified as a very powerful method for the preparation of optically pure amines from the corresponding ketones. Their immense potential for the preparation of chiral amines, together with their ease of use in combination with existing biocatalytic methods, have made these biocatalysts a competitor to any chemical methodology for (asymmetric) amination. An increasing number of examples, especially from industry, shows that this biocatalytic technology outmaneuvers existing chemical processes by its simple and flexible nature. In the last few years numerous publications and patents on synthetic routes, mainly to pharmaceuticals, involving ω-transaminases have been published. The review gives an overview of the application of ω-transaminases in organic synthesis with a focus on active pharmaceutical ingredients (APIs) and the developments during the last few years. [ABSTRACT FROM AUTHOR]

Insights into the mechanism of the unusual trans-hydrogenation of internal alkynes catalyzed by {Cp*Ru} complexes were gained by para-hydrogen (p-H2) induced polarization (PHIP) transfer NMR spectroscopy. It was found that the productive trans-reduction competes with a pathway in which both H atoms of H2 are delivered to a single alkyne C atom of the substrate while the second alkyne C atom is converted into a metal carbene. This ' geminal hydrogenation' mode seems unprecedented; it was independently confirmed by the isolation and structural characterization of a ruthenium carbene complex stabilized by secondary inter-ligand interactions. A detailed DFT study shows that the trans alkene and the carbene complex originate from a common metallacyclopropene intermediate. Furthermore, the computational analysis and the PHIP NMR data concur in that the metal carbene is the major gateway to olefin isomerization and over-reduction, which frequently interfere with regular alkyne trans-hydrogenation. [ABSTRACT FROM AUTHOR]

Amination of non-activated aliphatic fatty alcohols to the corresponding primary amines was achieved through a five-enzyme cascade reaction by coupling a long-chain alcohol oxidase from Aspergillus fumigatus (LCAO_Af) with a ω-transaminase from Chromobacterium violaceum (ω-TA_Cv). The alcohol was oxidized at the expense of molecular oxygen to yield the corresponding aldehyde, which was subsequently aminated by the PLP-dependent ω-TA to yield the final primary amine product. The overall cascade was optimized with respect to pH, O2 pressure, substrate concentration, decomposition of H2O2 (derived from alcohol oxidation), NADH regeneration, and biocatalyst ratio. The substrate scope of this concept was investigated under optimized conditions by using terminally functionalized C4-C11 fatty primary alcohols bearing halogen, alkyne, amino, hydroxy, thiol, and nitrile groups. [ABSTRACT FROM AUTHOR]

In a recent paper, Bindjeme and Fill obtained a surprisingly easy exact formula for the L2-distance of the (normalized) number of comparisons of Quicksort under the uniform model to its limit. Shortly afterwards, Neininger proved a central limit theorem for the error. As a consequence, he obtained the asymptotics of the L3-distance. In this short note, we use the moment transfer approach to re-prove Neininger's result. As a consequence, we obtain the asymptotics of the Lp-distance for all [ABSTRACT FROM AUTHOR]

We report on a 'green' method for the utilization of carbon dioxide as C1 unit for the regioselective synthesis of ( E)-cinnamic acids via regioselective enzymatic carboxylation of para-hydroxystyrenes. Phenolic acid decarboxylases from bacterial sources catalyzed the β-carboxylation of para-hydroxystyrene derivatives with excellent regio- and ( E/ Z)-stereoselectivity by exclusively acting at the β-carbon atom of the CC side chain to furnish the corresponding ( E)-cinnamic acid derivatives in up to 40% conversion at the expense of bicarbonate as carbon dioxide source. Studies on the substrate scope of this strategy are presented and a catalytic mechanism is proposed based on molecular modelling studies supported by mutagenesis of amino acid residues in the active site. [ABSTRACT FROM AUTHOR]

The important biochemical probe molecule brefeldin A ( 1) has served as an inspirational target in the past, but none of the many routes has actually delivered more than just a few milligrams of product, where documented. The approach described herein is clearly more efficient; it hinges upon the first implementation of ruthenium-catalyzed trans-hydrogenation in natural products total synthesis. Because this unorthodox reaction is selective for the triple bond and does not touch the transannular alkene or the lactone site of the cycloalkyne, it outperforms the classical Birch-type reduction that could not be applied at such a late stage. Other key steps en route to 1 comprise an iron-catalyzed reductive formation of a non-terminal alkyne, an asymmetric propiolate carbonyl addition mediated by a bulky amino alcohol, and a macrocyclization by ring-closing alkyne metathesis catalyzed by a molybdenum alkylidyne. [ABSTRACT FROM AUTHOR]

The combination of two cofactor self-sufficient biocatalytic cascade modules allowed the successful transformation of cyclohexanol into the nylon-6 monomer 6-aminohexanoic acid at the expense of only oxygen and ammonia. A hitherto unprecedented carboxylic acid capping strategy was introduced to minimize the formation of the dead-end intermediate 6-hydroxyhexanoic acid. For this purpose, the precursor ε-caprolactone was converted in aqueous medium in the presence of methanol into the corresponding methyl ester instead of the acid. Hence, it was shown for the first time that esterases-specifically horse liver esterase-can perform the selective ring-opening of ε-caprolactone with a clear preference for methanol over water as the nucleophile. [ABSTRACT FROM AUTHOR]

Background Gaining a new voice is one of the major aims after total laryngectomy. The objective of this study was to describe the process and results of speech rehabilitation during the first year after surgery. Methods Speech intelligibility was measured 6 months ( n = 273) and 1 year ( n = 225) after total laryngectomy. Results Objective (23.4 to 47.5 points, p < .0001) and subjective (51.6 to 64.7 points, p < .0001) speech intelligibility improved between 6 months and 1 year after total laryngectomy. Patients who used tracheoesophageal puncture (TEP) had the best results in speech intelligibility 6 months and 1 year after total laryngectomy. In all, 12% of the patients who used TEP initially no longer used it 1 year later. Patients who had received rehabilitation had better objective speech intelligibility than those who did not. Conclusions Speech improves considerably between 6 months and 1 year after total laryngectomy. Nonattendance of rehabilitation is associated with a worse functional outcome in speech rehabilitation. Head Neck, 35: 1583-1590, 2013 [ABSTRACT FROM AUTHOR]

Asymmetric allylation of (hetero)aromatic aldehydes by a zinc(II)-allylbutyrolactone species catalyzed by a chiral BINOL-type phosphoric acid gave β-substituted α-methylenebutyrolactones in 68 to >99% ee and 52-91% isolated yield. DFT studies on the intermediate Zn2+-complex - crucial for chiral induction - suggest a six-membered ring intermediate, which allows the phosphoric acid moiety to activate the aldehyde. The methodology was applied to the synthesis of the antitumour natural product ( S)-(−)-hydroxymatairesinol. [ABSTRACT FROM AUTHOR]

Background It has often been argued that if patients' success with speech rehabilitation after laryngectomy is limited, it is the result of lacking motivation on their part. This project investigated the role of motivation in speech rehabilitation. Methods In a multicenter prospective cohort study, 141 laryngectomees were interviewed at the beginning of rehabilitation and 1 year after laryngectomy. Speech intelligibility was measured with a standardized test, and patients self-assessed their own motivation shortly after the surgery. Logistic regression, adjusted for several theory-based confounding factors, was used to assess the impact of motivation on speech intelligibility. Results Speech intelligibility 1 year after laryngectomy was not significantly associated with the level of motivation at the beginning of rehabilitation (odds ratio [OR], 1.3; 95% confidence interval [CI], 0.7-2.3; p = .43) after adjusting for the effect of potential confounders (implantation of a voice prosthesis, patient's cognitive abilities, frustration tolerance, physical functioning, and type of rehabilitation). Conclusions Motivation is not a strong predictor of speech intelligibility 1 year after laryngectomy. © 2012 Wiley Periodicals, Inc. Head Neck, 2012 [ABSTRACT FROM AUTHOR]

Various artificial network designs that involve biocatalysts were tested for the asymmetric amination of sec-alcohols to the corresponding α-chiral primary amines. The artificial systems tested involved three to five redox enzymes and were exemplary of a range of different sec-alcohol substrates. Alcohols were oxidised to the corresponding ketone by an alcohol dehydrogenase. The ketones were subsequently aminated by employing a ω-transaminase. Of special interest were redox-neutral designs in which the hydride abstracted in the oxidation step was reused in the amination step of the cascade. Under optimised conditions up to 91 % conversion of an alcohol to the amine was achieved. [ABSTRACT FROM AUTHOR]

( R)-Lasiodiplodin methyl ether, a precursor of the antileukemic agent lasiodiplodin, was synthesized through a seven-step linear sequence. Chirality was introduced through a sulfatase-based deracemization process, in which a functionalized ( rac)- sec-sulfate ester was enzymatically hydrolyzed with inversion of the stereocenter using an alkyl sulfatase. The remaining sulfate ester enantiomer was hydrolyzed with retention of configuration under acidic conditions, yielding the chiral key building block as the sole product in 93 % ee The total synthesis was completed through Negishi cross-coupling and ring-closing metathesis. [ABSTRACT FROM AUTHOR]