Rhodium complexes bearing tetradentate diamine-bis(phenolate) ligands

Using tetradentate, dianionic ligands, several new rhodium complexes have been prepared. Some of these diamine-bis(phenolate) compounds, are active for C–H activation of benzene. These complexes are air and thermally stable. All four complexes were characterized by X-ray diffraction

Mechanism of efficient anti-Markovnikov olefin hydroarylation catalyzed by homogeneous Ir(III) complexes

The mechanism of the hydroarylation reaction between unactivated olefins (ethylene, propylene, and styrene) and benzene catalyzed by [(R)Ir(μ-acac-O,O,C^3)-(acac-O,O)_2]_2 and [R-Ir(acac-O,O)_2(L)] (R = acetylacetonato, CH_3, CH_2CH_3, Ph, or CH_2CH_2Ph, and L = H_2O or pyridine) Ir(III) complexes was studied by experimental methods. The system is selective for generating the anti-Markovnikov product of linear alkylarenes (61 : 39 for benzene + propylene and 98 : 2 for benzene + styrene). The reaction mechanism was found to follow a rate law with first-order dependence on benzene and catalyst, but a non-linear dependence on olefin. ^(13)C-labelling studies with CH_3^(13)CH_2-Ir-Py showed that reversible β-hydride elimination is facile, but unproductive, giving exclusively saturated alkylarene products. The migration of the ^(13)C-label from the α to β-positions was found to be slower than the C–H activation of benzene (and thus formation of ethane and Ph-d_5-Ir-Py). Kinetic analysis under steady state conditions gave a ratio of the rate constants for CH activation and β-hydride elimination (k_(CH): k_β) of 0.5. The comparable magnitude of these rates suggests a common rate determining transition state/intermediate, which has been shown previously with B3LYP density functional theory (DFT) calculations. Overall, the mechanism of hydroarylation proceeds through a series of pre-equilibrium dissociative steps involving rupture of the dinuclear species or the loss of L from Ph-Ir-L to the solvento, 16-electron species, Ph-Ir(acac-O,O)_2-Sol (where Sol refers to coordinated solvent). This species then undergoes trans to cis isomerization of the acetylacetonato ligand to yield the pseudo octahedral species cis-Ph-Ir-Sol, which is followed by olefin insertion (the regioselective and rate determining step), and then activation of the C–H bond of an incoming benzene to generate the product and regenerate the catalyst

Planned delivery or expectant management for late preterm pre-eclampsia in low-income and middle-income countries (CRADLE-4): a multicentre, open-label, randomised controlled trial

Background: Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks’ gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. / Methods: In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks’ gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. / Findings: Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference –3·39%, 90% CI –8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. / Interpretation: Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks’ gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. / Funding: UK Medical Research Council and Indian Department of Biotechnology

Daratumumab, Cyclophosphamide, Bortezomib, Lenalidomide, and Dexamethasone as Induction and Extended Consolidation Improves Outcome in Ultra-High-Risk Multiple Myeloma

Purpose: The multicenter OPTIMUM (MUKnine) phase II trial investigated daratumumab, low-dose cyclophosphamide, lenalidomide, bortezomib, and dexamethasone (Dara-CVRd) before and after autologous stem-cell transplant (ASCT) in newly diagnosed patients with molecularly defined ultra–high-risk (UHiR) multiple myeloma (NDMM) or plasma cell leukemia (PCL). To provide clinical context, progression-free survival (PFS) and overall survival (OS) were referenced to contemporaneous outcomes seen in patients with UHiR NDMM treated in the recent Myeloma XI (MyeXI) trial.Methods: Transplant-eligible all-comers NDMM patients were profiled for UHiR disease, defined by presence of ≥2 genetic risk markers t(4;14)/t(14;16)/t(14;20), del(1p), gain(1q), and del(17p), and/or SKY92 gene expression risk signature. Patients with UHiR MM/PCL were offered treatment with Dara-CVRd induction, V-augmented ASCT, extended Dara-VR(d) consolidation, and Dara-R maintenance. UHiR patients treated in MyeXI with carfilzomib, lenalidomide, dexamethasone, and cyclophosphamide, or lenalidomide, dexamethasone, and cyclophosphamide, ASCT, and R maintenance or observation were identified by mirrored molecular screening. OPTIMUM PFS at 18 months (PFS18m) was compared against MyeXI using a Bayesian framework, and patients were followed up to the end of consolidation for PFS and OS.Results: Of 412 screened NDMM OPTIMUM patients, 103 were identified as UHiR or PCL and subsequently treated on trial with Dara-CVRd; 117 MyeXI patients identified as UHiR formed the external comparator arm, with comparable clinical and molecular characteristics to OPTIMUM. Comparison of PFS18m per Bayesian framework resulted in a 99.5% chance of OPTIMUM being superior to MyeXI. At 30 months' follow-up, PFS was 77% for OPTIMUM versus 39.8% for MyeXI, and OS 83.5% versus 73.5%, respectively. Extended post-ASCT Dara-VRd consolidation therapy was highly deliverable, with limited toxicity.Conclusion: Our results suggest that Dara-CVRd induction and extended post-ASCT Dara-VRd consolidation markedly improve PFS for UHiR NDMM patients over conventional management, supporting further evaluation of this strategy.</p

Treatment of Cancer‐Associated Venous Thromboembolism: 12‐month outcomes of the placebo versus rivaroxaban randomisation of the SELECT‐D Trial. (SELECT‐D: 12m)

Background The SELECT‐D trial demonstrated reduction in recurrent venous thromboembolism (VTE) but increased bleeding with rivaroxaban compared to dalteparin for treatment of acute VTE in cancer patients, at 6 months. Uncertainty remains around optimal duration of anticoagulation. Objectives To assess VTE recurrence and bleeding, with anticoagulation or not, beyond 6 months Patients/Methods In SELECT‐D, after 6 months of trial treatment for VTE, patients with active cancer and residual deep vein thrombosis (RDVT) or index pulmonary embolism (PE) were eligible for randomisation to a further 6 months of rivaroxaban or placebo. Patients with no RDVT stopped anticoagulation. Primary outcome was VTE recurrence at 12 months. The second randomisation closed prematurely due to low recruitment when 92 of the planned 300 patients were recruited. Results 92 of 136 eligible patients were randomised to rivaroxaban or placebo. The cumulative VTE recurrence after 6 months from the second randomisation, was 14% with placebo and 4% with rivaroxaban (Hazard Ratio 0.32; 95% CI 0.06‐1.58). The major and clinically‐relevant non‐major bleeding rates were 0% and 0% with placebo; and 5% (95% CI 1‐18%) and 4% (95% CI 1‐17%) with rivaroxaban. In an exploratory analysis, 7 (15.2 %) of 46 placebo patients with RDVT or an index PE experienced recurrent VTE compared to none in the 35 patients in the RDVT‐negative cohort (P=0.03). Conclusion The SELECT‐D trial was underpowered to detect a statistically significant reduction in recurrent VTE with extended anticoagulation. The absence of RDVT and/or index PE, defined a population at low risk of recurrence

Rare missense variants in Tropomyosin-4 (TPM4) are associated with platelet dysfunction, cytoskeletal defects, and excessive bleeding

Background: A significant challenge is faced for the genetic diagnosis of inherited platelet disorders in which candidate genetic variants can be found in more than 100 bleeding, thrombotic, and platelet disorder genes, especially within families in which there are both normal and low platelet counts. Genetic variants of unknown clinical significance (VUS) are found in a significant proportion of such patients in which functional studies are required to prove pathogenicity. Objective: To identify the genetic cause in patients with a suspected platelet disorder and subsequently perform a detailed functional analysis of the candidate genetic variants found. Methods: Genetic and functional studies were undertaken in three patients in two unrelated families with a suspected platelet disorder and excessive bleeding. A targeted gene panel of previously known bleeding and platelet genes was used to identify plausible genetic variants. Deep platelet phenotyping was performed using platelet spreading analysis, transmission electron microscopy, immunofluorescence, and platelet function testing using lumiaggregometry and flow cytometry. Results: We report rare conserved missense variants (p.R182C and p.A183V) in TPM4 encoding tromomyosin-4 in 3 patients. Deep platelet phenotyping studies revealed similar platelet function defects across the 3 patients including reduced platelet secretion, and aggregation and spreading defects suggesting that TPM4 missense variants impact platelet function and show a disordered pattern of tropomyosin staining. Conclusions: Genetic and functional TPM4 defects are reported making TPM4 a diagnostic grade tier 1 gene and highlights the importance of including TPM4 in diagnostic genetic screening for patients with significant bleeding and undiagnosed platelet disorders, particularly for those with a normal platelet count

Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism

INTRODUCTION: Venous thromboembolism (VTE) in cancer patients is an increasingly frequent clinical problem. The overall impact of VTE on cancer patients can be considerable. Targeted patient selection by identifying patients with clinically significant recurrent VTE may have wider health economic benefits whilst reducing patient risk through over-treatment. In the UK, dalteparin is one licensed anticoagulant for the extended treatment and prevention of recurrence of VTE in cancer patients. Rivaroxaban is a highly selective direct Factor Xa inhibitor with oral bioavailability. AIM: To assess VTE recurrence in selected cancer patients at risk of recurrence of VTE treated with rivaroxaban or dalteparin. The secondary objectives include safety, acceptability, biomarker identification and health economics. MATERIALS AND METHODS: Select-d is a prospective, randomised, open label, multicentre pilot trial comparing dalteparin (200 IU/kg daily subcutaneously for 1 month and 150 IU/kg months 2-6); and rivaroxaban (15mg orally twice daily for 3 weeks and 20mg once daily for 6 months in total) for cancer patients with VTE - symptomatic and incidental pulmonary embolism (P)E or symptomatic lower limb proximal deep vein thrombosis (DVT) - with a second placebo-controlled randomisation (rivaroxaban vs placebo) comparing the duration of therapy (6 vs 12 months) in all patients with PE and those with a DVT who are residual vein thrombosis (RVT) positive. 70% of DVT patients are estimated to be RVT positive after initial treatment. 530 patients are being recruited toprovide reliable estimates of the primary outcome (VTE recurrence rates) to within the 95% confidence interval of 8% assuming VTE rates are 10% at six months. RESULTS: As of 1st December 2015, 264 patients have been recruited from 61 open sites across the UK. Preliminary data indicate that the majority of patients presented with solid tumours (98%), ranging from early or locally advanced (41%) to metastatic disease (57%), and primarily comprising colorectal, lung, and breast malignancies. Only a small number of select-d patients presented with haematological malignancies (2%), which included; leukaemia, myeloma and lymphoma. Over half of the select-d patients had an incidental PE (54%); the remainder had symptomatic PE or DVT (46%). The median number of hours on anticoagulation prior to starting select-d randomised treatment was 48 hours. CONCLUSIONS: select-d is the first randomised trial for treatment of VTE, investigating the direct oral anticoagulants vs a low molecular weight heparin in patients with cancer. The results will support optimal treatment for this key patient group and are eagerly awaited