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Background: Arthroscopic treatment of hip labral tears has increased significantly in recent years. There is limited evidence comparing nonoperative management to arthroscopic treatment. The purpose of this study is to evaluate the progression to total hip arthroplasty (THA), as well as the cost associated with arthroscopic management of labral tears compared to nonoperative treatment., Methods: The Humana claims database was queried from 2007 through 2016. International Classification of Diseases and Current Procedural Terminology codes were used to identify patients with hip labral tears and hip arthroscopy and THA procedures. Two cohorts were created: a nonoperative group and an operative group. Following propensity score matching, the rate of conversion and time to THA conversion were calculated. Cost was calculated using the total cost reimbursed for encounters within 6 months. Continuous variables were analyzed using Student t-test and Mann-Whitney test, and categorical variables were analyzed using chi-square test., Results: After propensity matching, 864 patients were included in the analysis. The conversion rate to THA in the operative group (6.7%) and the nonoperative group (5.3%) was not statistically different (P = .391). The operative group had a longer time to THA (21.5 ± 16.8 months) than the nonoperative group (15.9 ± 19.5 months; P = .044). The cost for the operative group was significantly higher ($14,266.55 ± $7187.96) compared to the nonoperative group ($2941.96 ± $2664.00; P < .001)., Conclusion: This study did not find a difference in the rate of conversion to THA for operative vs nonoperative groups. Time to THA in the operative group was longer, however, at the expense of higher costs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Ruxolitinib (Rux), a Jak1/2 inhibitor, results in reduced spleen size and improvement in constitutional symptoms in the majority of patients with myelofibrosis (MF). Therefore Rux, when given prior to hematopoietic cell transplantation (HCT) in patients with MF was hypothesized to improve engraftment, decrease incidence and severity of graft-versus-host disease, and lower non-relapse mortality (NRM). We conducted a phase II prospective trial to assess the effects of pre-HCT Rux on post-HCT outcomes in patients with MF. The primary endpoint was 2-year overall survival. To date, 28 patients (median age 56 years) have been transplanted. The median time on Rux pre-HCT was 7 months. Twenty-three patients received myeloablative and five reduced intensity conditioning. Donors included 14 HLA-matched siblings, 11 matched unrelated, 1 allele mismatched unrelated, and 3 umbilical cord blood. There have been no episodes of cytokine release syndrome and all patients achieved sustained engraftment. Two patients died from NRM and two patients relapsed. With a median follow-up of 13 months, overall survival is 93% (95% CI: 0.73, 0.98) at 1 year and 86% (95% CI: 0.61, 0.96) at 2 years post-HCT. This study demonstrates that pre-HCT Rux is well tolerated and suggests that pre-HCT Rux may improve post-HCT outcome.

A major chemical challenge facing implementation of 225 Ac in targeted alpha therapy-an emerging technology that has potential for treatment of disease-is identifying an 225 Ac chelator that is compatible with in vivo applications. It is unclear how to tailor a chelator for Ac binding because Ac coordination chemistry is poorly defined. Most Ac chemistry is inferred from radiochemical experiments carried out on microscopic scales. Of the few Ac compounds that have been characterized spectroscopically, success has only been reported for simple inorganic ligands. Toward advancing understanding in Ac chelation chemistry, we have developed a method for characterizing Ac complexes that contain highly complex chelating agents using small quantities (μg) of 227 Ac. We successfully characterized the chelation of Ac 3+ by DOTP 8- using EXAFS, NMR, and DFT techniques. To develop confidence and credibility in the Ac results, comparisons with +3 cations (Am, Cm, and La) that could be handled on the mg scale were carried out. We discovered that all M 3+ cations (M = Ac, Am, Cm, La) were completely encapsulated within the binding pocket of the DOTP 8- macrocycle. The computational results highlighted the stability of the M(DOTP) 5- complexes.

Objectives: Laryngomalacia is an established cause of stridor and sleep-disordered breathing in children. However, the relationship between laryngomalacia and dysphagia has not been well characterized. The objectives of this study were to (1) describe the patient characteristics, symptoms, and prevalence of dysphagia in children with laryngomalacia and (2) examine the effectiveness of supraglottoplasty in improving feeding., Methods: This was a retrospective study of patients with laryngomalacia who underwent a modified barium swallow study (MBSS) at a tertiary academic pediatric medical center between March 1, 2014, and March 1, 2018. Patients were excluded if they did not undergo a MBSS. Comorbidities, airway and feedings symptoms, MBSS results, and surgical history were recorded from each patient's electronic medical record., Results: Forty-four children met inclusion/exclusion criteria. The median age at presentation was 96 days. There was a male predominance (66%). About one-third had a genetic or neuromuscular comorbidity. Most children had stridor (93%) and feeding difficulty (86%), while 50% had parent-reported poor weight gain. Fifty-seven percent of patients had evidence of penetration or aspiration on MBSS. All patients with a positive MBSS had dysphagia symptoms. Fifty-seven percent of patients underwent supraglottoplasty. Postoperatively, 92% reported improvement in dysphagia symptoms., Conclusion: Dysphagia is prevalent among a subset of children with laryngomalacia. Symptomatic children may benefit from a swallow evaluation to help determine the need for further intervention. Children who undergo supraglottoplasty for laryngomalacia have improved dysphagia at follow-up, though the amount of improvement directly attributable to surgery is unclear and warrants further investigation.

We report the small-scale synthesis, isolated yield, single-crystal X-ray structure, 1 H NMR solution spectroscopy /solid-state UV/Vis-nIR spectroscopy, and density functional theory (DFT)/ab initio wave function theory calculations on an Am 3+ organometallic complex, [Am(C 5 Me 4 H) 3 ] (1). This constitutes the first quantitative data on Am-C bonding in a molecular species., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

This work provides new routes for the conversion of U(iv) into U(vi) bis(imido) complexes and offers new information on the manner in which the U(vi) compounds form. Many compounds from the series described by the general formula U(NR) 2 (EPh) 2 (L) 2 (R = 2,6-diisopropylphenyl, tert-butyl; E = S, Se, Te; L = py, EPh) were synthesized via oxidation of an in situ generated U(iv) amido-imido species with Ph 2 E 2 . This synthetic sequence provides a general route into bis(imido) U(vi) chalcogenolate complexes, circumventing the need to perform problematic salt metathesis reactions on U(vi) iodides. Investigation into the speciation of the U(iv) complexes that form prior to oxidation found a significant dependence on the identity of the ancillary ligands, with t Bu 2 bpy forming the isolable imido-(bis)amido complex, U(NDipp)(NHDipp) 2 ( t Bu 2 bpy) 2 . Together, these data are consistent with the view that the bis(imido) U(vi) motif - much like the uranyl ion, UO 2 2+ - is a thermodynamic sink into which simple ligand frameworks are unable to prevent uranium from falling when in the presence of a suitable retinue of imido proligands.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired clonal hematopoietic cell disease characterized by the destruction of hematopoietic cells through activation of the complement system with manifestations that can be life-threatening including hemolysis, thrombosis, and marrow failure. Allogeneic hematopoietic cell transplantation (HCT) remains the sole cure for PNH, but eculizumab, a terminal complement inhibitor of C5, has been used to prevent complement-mediated hemolysis in patients with PNH since its approval by the Food and Drug Administration in 2007. We examined outcomes of HCT in patients with PNH to evaluate the effects of disease subtype, conditioning intensity, and eculizumab use either pre-HCT or post-HCT. Fifty-five patients with a diagnosis of PNH underwent at least 1 HCT, with 4 patients requiring a second HCT for graft failure. The median age at the time of first HCT was 30.0 years (range, 4.2 to 66.9 years). Seventeen patients (30.9%) had classical PNH, and the remaining 38 patients had PNH associated with another marrow disorder (aplastic anemia in 26 of the 38). Indications for HCT included pancytopenia in 47.3% of the patients, myeloid malignancy (myelodysplastic syndrome, myeloproliferative neoplasm, or acute myelogenous leukemia) in 21.8%, recurrent hemolysis in 20.0%, and thrombosis in 10.9%. Of the 55 first HCTs, 26 were performed with myeloablative conditioning, 27 were performed with reduced-intensity conditioning, and 2 sets of identical twins underwent HCT without any conditioning. Donor types included HLA-matched related in 38.2%, HLA-matched unrelated in 34.5%, single HLA-allele mismatched unrelated in 16.4%, umbilical cord blood in 5.5%, syngeneic in 3.6%, and HLA-haploidentical in 1.8%. The median duration of follow-up in surviving patients was 6.1 years (range, 2.1 to 46.1 years) after first HCT. The median time to neutrophil and platelet engraftment was 17 days and 19 days, respectively; all but 2 patients (96.3%) had sustained engraftment. Overall survival was 70% at 5 years. Neither the choice of conditioning intensity nor PNH subtype affected survival. Nineteen patients died during follow-up, including 12 patients before day +365. Six patients received treatment with eculizumab before HCT, and 2 were treated after HCT. All patients treated with eculizumab were alive at a median follow-up of 2.3 years (range, .2 to 6.9 years). Both patients treated with eculizumab after HCT had minimal to no acute GVHD (aGVHD), with grade I skin aGVHD in 1 patient and no aGVHD in the other patient, and no chronic GVHD at 2.1 and 4.1 years post-HCT, respectively. With the approval of eculizumab, the indications for HCT include persistent hemolysis, persistent thrombosis, and associated marrow failure. Administration of eculizumab before and after HCT warrants further study, particularly considering our observation of minimal to no GVHD in 2 patients who received eculizumab after HCT., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Patients with chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy are at increased risk of developing therapy-related (t-) myelodysplastic syndrome (MDS). It is unclear whether antecedent CLL adds prognostic value to the revised International Prognostic Scoring System (IPSS-R) for MDS. We performed a retrospective analysis to evaluate the significance of a previous CLL diagnosis as an independent adverse prognostic factor., Patients and Methods: We identified 18 consecutive patients with t-MDS, previously treated for CLL (CLL-MDS) from 2002 to 2016. For each CLL-MDS patient, we identified 2 control patients with de novo MDS matched for age (≤ 65 or > 65 years), IPSS-R (≤ 3 or > 3), and year of MDS diagnosis (before or after 2008). Multivariable models were developed to test for independent predictors of progression to acute myeloid leukemia (AML) and overall survival (OS)., Results: Median time from CLL to MDS diagnosis was 58.8 months (range, 12-280 months) and median number of treatment lines for CLL was 1 (range, 1-5), including alkylating agents in 15 patients (83%) and fludarabine, cyclophosphamide, rituximab in 12 patients (67%). Hypomethylating agents were administered in 13 (72%) of CLL-MDS patients and 33 (91%) of de novo MDS patients. After a median follow-up of 19.2 months, OS was not different between CLL-MDS and matched de novo MDS patients. CLL-MDS patients with IPSS-R score ≤ 3 had better OS compared with those with IPSS-R score > 3. In multivariate analysis, there was no significant independent association between history of CLL OS or progression to AML., Conclusion: History of CLL did not independently affect OS in t-MDS patients beyond IPSS-R score., (Copyright © 2019 Elsevier Inc. All rights reserved.)

A non-myeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive non-myeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low risk (n=36); and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m 2 for three days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary end point was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to <20%. The primary end point was reached on Arm A at dose Level-1 (300 cGy total body irradiation) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 11%, and on Arm B at dose Level-3 (450 cGy) with a cumulative incidence of day 200 hematopoietic cell transplant failure of 9%. Increasing the total body irradiation dose leads to a higher success rate with non-myeloablative conditioning by reducing relapse and rejection. Further studies are necessary to decrease non-relapse mortality, especially among patients with high-risk disease. Trial registered under clinicaltrials.gov identifier: NCT00397813 ., (Copyright© 2019 Ferrata Storti Foundation.)

The use of nickel complexes utilizing non-innocent ligands based on picolinamide to function as redox carriers in flow batteries was explored. The picolinamide moiety was linked together with -CH 2 CH 2 - (bpen), -CH 2 CH 2 CH 2 - (bppn), and -C 6 H 4 - (bpb) moieties, resulting in two, three, and four quasi-reversible waves, respectively, for the nickel complexes and >3 V difference between the outermost positive and negative waves. The redox events were theoretically modelled for each complex, showing excellent agreement (<0.3 V difference) between the experimental and modelled potentials. Bulk cycling of the most soluble complex, Ni(bppn), indicated only one of the three waves was reversible. Therefore, Ni(bppn) has the ability to act as a negative charge redox carrier in flow cells., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Airway mucin secretion is necessary for ciliary clearance of inhaled particles and pathogens but can be detrimental in pathologies such as asthma and cystic fibrosis. Exocytosis in mammals requires a Munc18 scaffolding protein, and airway secretory cells express all 3 Munc18 isoforms. Using conditional airway epithelial cell-deletant mice, we found that Munc18a has the major role in baseline mucin secretion, Munc18b has the major role in stimulated mucin secretion, and Munc18c does not function in mucin secretion. In an allergic asthma model, Munc18b deletion reduced airway mucus occlusion and airflow resistance. In a cystic fibrosis model, Munc18b deletion reduced airway mucus occlusion and emphysema. Munc18b deficiency in the airway epithelium did not result in any abnormalities of lung structure, particle clearance, inflammation, or bacterial infection. Our results show that regulated secretion in a polarized epithelial cell may involve more than one exocytic machine at the apical plasma membrane and that the protective roles of mucin secretion can be preserved while therapeutically targeting its pathologic roles.

Separation of U, Np, and Pu from used nuclear fuel (UNF) would result in lower long-term radiotoxicity, alleviating constraints on the storage and handling of the material. The complexity of UNF requires several industrial-scale processes with multiple waste streams. A one-step solution to the group removal of the elements, U-Pu, is desirable. Here we present a possible solution to group actinide separation utilizing the unique dioxy conformation of An(V/VI) cations and demonstrate the ability of a tetradentate lipophilic Schiff base ligand (L) to yield isostructural complexes of the general formula [(An VI O 2 )(L)(CH 3 CN)] (where An = U, Np, or Pu). Extraction of An(VI) with the ligand follows the order U > Pu > Np, likely reflecting the decreased stability of the hexavalent actinide across the series. While the results indicate a promising path toward a one-step process, further improvement in the ligand stability and control of the redox chemistry is required.

Three new uranium species (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)([double bond, length as m-dash]S), (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)(η2-S2), and (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)(S[double bond, length as m-dash]PMe3) were synthesized and fully characterized by a combination of NMR, IR, and UV/vis-NIR spectroscopies, elemental analysis, and cyclic voltammetry. The solid state structures of (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)([double bond, length as m-dash]S) and (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)(η2-S2) were also determined. The compound (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)([double bond, length as m-dash]S) is the first neutral uranium complex with a terminal sulphido ligand, and (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)(S[double bond, length as m-dash]PMe3) is the first uranium compound with a coordinated phosphine sulphide ligand. The phosphine sulphide adduct, (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)(S[double bond, length as m-dash]PMe3), can be synthesized either by reaction of the uranium(iv) complex (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)(thf) with S[double bond, length as m-dash]PMe3 or by the reaction of the uranium(vi) terminal sulphido complex (C5Me5)2U([double bond, length as m-dash]N-2,6-iPr2-C6H3)([double bond, length as m-dash]S) with PMe3.

Complexation of Pu(iv) with the actinide extractant CyMe 4 -BTPhen (2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-1,10-phenanthroline) was followed by vis-NIR spectroscopy in acetonitrile solution. The solid-state structure of the crystallized product suggests that Pu(iv) is reduced to Pu(iii) upon complexation. Analysis by DFT modeling is consistent with metal-based rather than ligand-based reduction.

Outcomes with "7 + 3" are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21-81) years, were enrolled. In phase 1, cohorts of 6-12 patients were assigned to 12-18 mg/m 2 /day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m 2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRD neg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRD neg ) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRD neg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m 2 /day is safe and induces high-quality remissions in adults with newly-diagnosed AML.

Characterizing how actinide properties change across the f-element series is critical for improving predictive capabilities and solving many nuclear problems facing our society. Unfortunately, it is difficult to make direct comparisons across the 5f-element series because so little is known about trans-plutonium elements. Results described herein help to address this issue through isolation of An(S2CNEt2)3(N2C12H8) (Am, Cm, and Cf). These findings included the first single crystal X-ray diffraction measurements of Cm-S (mean of 2.86 ± 0.04 Å) and Cf-S (mean of 2.84 ± 0.04 Å) bond distances. Furthermore, they highlight the potential of An(S2CNEt2)3(N2C12H8) for providing a test bed for comparative analyses of actinide versus lanthanide bonding interactions.

Fluorescence resonance energy transfer (FRET) is a powerful tool to study macromolecular interactions such as protein-protein interactions (PPIs). Fluorescent protein (FP) fusions enable FRET-based PPI analysis of signaling pathways and molecular structure in living cells. Despite FRET's importance in PPI studies, FRET has seen limited use in quantifying the affinities of PPIs in living cells. Here, we have explored the relationship between FRET efficiency and PPI affinity over a wide range when expressed from a single plasmid system in Escherichia coli. Using live-cell microscopy and a set of 20 pairs of small interacting proteins, belonging to different structural folds and interaction affinities, we demonstrate that FRET efficiency can reliably measure the dissociation constant (K D ) over a range of mM to nM. A 10-fold increase in the interaction affinity results in 0.05 unit increase in FRET efficiency, providing sufficient resolution to quantify large affinity differences (> 10-fold) using live-cell FRET. This approach provides a rapid and simple strategy for assessment of PPI affinities over a wide range and will have utility for high-throughput analysis of protein interactions., (© 2018 The Protein Society.)

Relapse is the main cause of treatment failure after allogeneic stem cell transplant (alloSCT) in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Injectable azacitidine can improve post-transplant outcomes but presents challenges with exposure and compliance. Oral CC-486 allows extended dosing to prolong azacitidine activity. We investigated use of CC-486 maintenance therapy after alloSCT. Adults with MDS or AML in morphologic complete remission at CC-486 initiation (42 to 84 days after alloSCT) were included. Patients received 1 of 4 CC-486 dosing schedules per 28-day cycle for up to 12 cycles. Endpoints included safety, pharmacokinetics, graft-versus-host disease (GVHD) incidence, relapse/progression rate, and survival. Of 30 patients, 7 received CC-486 once daily for 7 days per cycle (200 mg, n = 3; 300 mg, n = 4) and 23 for 14 days per cycle (150 mg, n = 4; 200 mg, n = 19 [expansion cohort]). Grades 3 to 4 adverse events were infrequent and occurred with similar frequency across regimens. Standard concomitant medications did not alter CC-486 pharmacokinetic parameters. Three patients (10%) experienced grade III acute GVHD and 9 experienced chronic GVHD. Of 28 evaluable patients, 6 (21%) relapsed or had progressive disease: 3 of 7 patients (43%) who had received 7-day dosing and 3 of 23 (13%) who had received 14-day dosing. Transplant-related mortality was 3%. At 19 months of follow-up, median overall survival was not reached. Estimated 1-year survival rates were 86% and 81% in the 7-day and 14-day dosing cohorts, respectively. CC-486 maintenance was generally well tolerated, with low rates of relapse, disease progression, and GVHD. CC-486 maintenance may permit epigenetic manipulation of the alloreactive response postallograft. Findings require confirmation in randomized trials. (ClinicalTrials.gov NCT01835587.)., (Copyright © 2018. Published by Elsevier Inc.)

Host genetics shape the gut microbiota, and gut dysbiosis increases the risk of acute graft-versus-host disease (aGVHD). Paneth cells and microbiota have interactions that contribute to immune regulation. α-defensin-5 (HD5) and regenerating islet-derived protein 3 alpha (Reg3A) are the most abundant Paneth cell antimicrobial peptides (AMPs). We hypothesized that single nucleotide polymorphisms (SNPs) in the genes for HD5 (DEFA5) and Reg3A (REG3A) predict aGVHD risk. We analysed pre-transplant recipient peripheral blood mononuclear cell samples from randomized Blood and Marrow Transplant Clinical Trials Network (BMT CTN) studies 0201 (94 patients with bone marrow and 93 with peripheral blood grafts) and 0901 (86 patients with myeloablative and 77 with reduced-intensity conditioning; all using peripheral blood grafts). In multivariable analysis (with a SNP × graft source interaction term in CTN-0201 and a SNP × conditioning intensity term in CTN-0901), DEFA5 rs4415345 and rs4610776 were associated with altered incidence of aGVHD grade II-IV [rs4415345 G vs. C: hazard ratio (HR) 0·58, 95% confidence interval (95% CI) 0·37-0·92, P = 0·02; rs4610776 T vs. A: HR 1·53, 95% CI 1·01-2·32, P = 0·05] in CTN-0201, but not CTN-0901, suggesting a stronger effect in bone marrow allografts. REG3A SNP was not associated with aGVHD. Host genetics may influence aGVHD risk by modulating Paneth cell function., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Thrombocytopenia is among the strongest predictors of decreased survival for patients with myelodysplastic syndromes (MDS) across all prognostic risk groups. The safety and efficacy of CC-486 (oral azacitidine) was investigated in early-phase studies; we assessed clinical outcomes among subgroups of MDS patients from these studies, defined by presence or lack of pretreatment thrombocytopenia (≤75 × 10 9 /L platelet count). Patients received CC-486 300 mg once-daily for 14 or 21 days of repeated 28-day cycles. Overall, 81 patients with MDS, median age 72 years, comprised the Low Platelets (n = 45) and High Platelets (n = 36) cohorts. Pretreatment median platelet counts were 34 × 10 9 /L and 198 × 10 9 /L, respectively. Grade 3-4 bleeding events occurred in 2 patients in the Low Platelets and 1 patient in the High Platelets groups; events resolved without sequelae. Treatment-related mortality was reported for 7 patients, 5 of whom had pretreatment platelet values <25 × 10 9 /L. Overall response rates were 38% and 46% in the Low Platelets and High Platelets groups, respectively. Five thrombocytopenic patients attained complete remission and 9 attained platelet hematologic improvement. In both cohorts, platelet counts dropped during the first CC-486 treatment cycle, then increased thereafter. Extended CC-486 dosing was generally well tolerated and induced hematologic responses in these patients regardless of pretreatment thrombocytopenia., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report the structural and electrochemical characterization of the binuclear complex [μ-(C 24 H 16 N 6 ){RuCl(C 10 H 8 N 2 )} 2 ](PF 6 ) 2 , which contains the bis-tridentate bridging ligand 2,3,5,6-tetra-kis-(pyridin-2-yl)pyrazine (tppz), the monodentate ligand Cl - , and the bidentate ligand 2,2'-bi-pyridine (bpy) {systematic name: μ-2,3,5,6-tetra-kis-(pyridin-2-yl)pyrazine-bis-[(2,2'-bi-pyridine)-chlorido-ru-thenium(II)] bis-(hexa-fluorido-phosphate)}. The complete [(bpy)(Cl)Ru(tppz)Ru(Cl)(bpy)] 2+ dication is generated by crystallographic twofold symmetry; the tppz bridging ligand has a significantly twisted conformation, with an average angle of 42.4° between the mean planes of adjacent pyridyl rings. The metal-coordinated chloride ligands are in a trans configuration relative to each other across the {Ru(tppz)Ru} unit. The Ru II ion exhibits a distorted octa-hedral geometry due to the restricted bite angle [160.6 (3)°] of the tppz ligand. For bpy, the bond lengths of the Ru-N bonds are 2.053 (8) and 2.090 (8) Å, with the shorter bond being opposite to Ru-Cl. For the tridentate tppz, the Ru-N distances involving the outer N atoms trans to each other are 2.069 (8) and 2.072 (9) Å, whereas the Ru-N bond involving the central N atom has the much shorter length of 1.939 (7) Å as a result of the geometric constraints and stronger π-acceptor ability of the pyrazine-centered bridge. The Ru-Cl distance is 2.407 (3) Å and the intra-molecular distance between Ru centers is 6.579 (4) Å. In the crystal, weak C-H⋯Cl and C-H⋯F inter-actions consolidate the packing.

Objectives: Treatment patterns for patients with myelodysplastic syndromes (MDS) outside clinical trials are not well described. Our objective was to evaluate treatment patterns and patient characteristics that influence time to disease-modifying therapy in patients with MDS in the USA., Design, Participants and Outcome Measures: Patients with MDS treated with erythropoiesis-stimulating agents (ESAs), iron chelation therapy, lenalidomide (LEN) and the hypomethylating agents (HMAs) azacitidine and decitabine, were retrospectively identified in the GE Centricity Electronic Medical Record database between January 2006 and February 2014; LEN and HMAs were defined as 'disease-modifying' therapies. Multivariable Cox regression models were used to ascertain patient characteristics associated with time to disease-modifying therapy., Results: Of the 5162 patients with MDS, 35.7%, 40.3% and 4.6% received 1, ≥1 and ≥2 therapies, respectively. ESAs were the first-line (72.5%) and only (64.0%) treatment in the majority of patients who received ≥1 therapy. ESA-only patients were older and had more comorbidities, including isolated anaemia. LEN and HMAs were first-line treatment in 12.4% of patients each; 32.7% received LEN or HMAs at any time. The majority of del(5q) patients (77.6%) received ≥1 therapy, most commonly LEN, compared with 40% of patients without del(5q). A shorter time to disease-modifying therapy was significantly associated with absence of comorbidities, diagnosis after February 2008, lower baseline haemoglobin level, age <80 years and male gender (p<0.002 for all)., Conclusions: A high proportion of patients diagnosed with MDS in the USA do not receive approved disease-modifying therapies. It is important to improve access to these therapies., Competing Interests: Competing interests: XM is a consultant for Celgene Corporation and Incyte. DPS is a consultant for Celgene Corporation, Amgen, Genoptix, Janssen, and Millennium/Takeda, and owns equity in Ariad. BLS is a consultant for Celgene Corporation, and has membership of an entity’s board of directors or advisory committees. PK and ASS are employees of and own equity in Celgene Corporation. MMS is a former employee of and owns equity in Celgene Corporation., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

We report a new formal oxidation state for neptunium in a crystallographically characterizable molecular complex, namely Np 2+ in [K(crypt)][Np II Cp″ 3 ] [crypt = 2.2.2-cryptand, Cp″ = C 5 H 3 (SiMe 3 ) 2 ]. Density functional theory calculations indicate that the ground state electronic configuration of the Np 2+ ion in the complex is 5f 4 6d 1 .

Solvent exchange of NpCl4(DME)2 with THF proceeds simply to yield NpCl4(THF)3, whereas PuCl4(DME)2 is unstable in THF, partially decomposing to the mixed valent [PuIIICl2(THF)5][PuIVCl5(THF)] salt. Reduction of NpCl4(THF)3 with CsC8 ultimately afforded NpCl3(py)4, the only example of a structurally characterized solvated Np(iii) halide. The method demonstrates a route to a well-defined Np(iii) starting material without the need to employ scarcely available Np metal.

In this prospective, randomized, phase II "pick the winner" trial we assessed the efficacy of transplant conditioning with treosulfan/fludarabine ± 2 Gy total body irradiation (TBI) in reducing post-transplant relapse in 100 patients, aged 2 to 70 years (median, 57), with myelodysplastic syndrome (MDS)/chronic myelomonocytic leukemia (n = 51) or acute myeloid leukemia (AML; n = 49). Patients received i.v. treosulfan, 14 g/m 2 /day on days -6 to -4 and i.v. fludarabine, 30 mg/m 2 /day on days -6 to -2, alone or combined with 2 Gy TBI (day 0). Donors were related (n = 43) or unrelated (n = 57). When a planned interim analysis showed superior progression-free survival in the TBI arm (P = .04), all subsequent patients received TBI. With a follow-up of 12 to 40 months (median, 20), the 1-year overall survival was 80% for the TBI arm and 69% for the non-TBI arm. The 1-year cumulative incidence of relapse was 22% and 34%, respectively (P = .06). Among patients with low-risk disease the 1-year relapse incidence was 15% and 31% (P = .20) and for patients with high-risk disease, 26% and 36% (P = .18), respectively. Among MDS patients the 1-year relapse incidence was 27% versus 33% (P = .49) and among AML patients 16% versus 35% (P = .05), respectively. The largest difference was among patients with unfavorable cytogenetics, with 1-year relapse incidences of 31% and 63% (P = .18), respectively. Nonrelapse mortality in this high-risk patient population was 9% at 6 months and did not differ between arms. Thus, treosulfan/fludarabine/low-dose TBI provided effective conditioning for allogeneic hematopoietic cell transplantation in high-risk patients up to 70 years of age. The addition of TBI had a more profound effect in patients with AML than in those with MDS. High-risk disease features were associated with a lower overall success rate. Further studies are warranted., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Thenoyltrifluoroacetone (HTTA)-based extractions represent popular methods for separating microscopic amounts of transuranic actinides (i.e., Np and Pu) from macroscopic actinide matrixes (e.g. bulk uranium). It is well-established that this procedure enables +4 actinides to be selectively removed from +3, + 5, and +6 f-elements. However, even highly skilled and well-trained researchers find this process complicated and (at times) unpredictable. It is difficult to improve the HTTA extraction-or find alternatives-because little is understood about why this separation works. Even the identities of the extracted species are unknown. In addressing this knowledge gap, we report here advances in fundamental understanding of the HTTA-based extraction. This effort included comparatively evaluating HTTA complexation with +4 and +3 metals (M IV = Zr, Hf, Ce, Th, U, Np, and Pu vs M III = Ce, Nd, Sm, and Yb). We observed +4 metals formed neutral complexes of the general formula M IV (TTA) 4 . Meanwhile, +3 metals formed anionic M III (TTA) 4 - species. Characterization of these M(TTA) 4 x- ( x = 0, 1) compounds by UV-vis-NIR, IR, 1 H and 19 F NMR, single-crystal X-ray diffraction, and X-ray absorption spectroscopy (both near-edge and extended fine structure) was critical for determining that Np IV (TTA) 4 and Pu IV (TTA) 4 were the primary species extracted by HTTA. Furthermore, this information lays the foundation to begin developing and understanding of why the HTTA extraction works so well. The data suggest that the solubility differences between M IV (TTA) 4 and M III (TTA) 4 - are likely a major contributor to the selectivity of HTTA extractions for +4 cations over +3 metals. Moreover, these results will enable future studies focused on explaining HTTA extractions preference for +4 cations, which increases from Np IV to Pu IV , Hf IV , and Zr IV .

Mud runs are an increasingly popular recreational fitness activity across the United States, combining a running race through an obstacle course with submersion in mud. Recent reports estimate 4 million people have participated in these types of events over the last 5 years. We describe an atypical case of myocarditis and multiorgan failure from disseminated histoplasmosis in a previously healthy pediatric patient, likely acquired during participation in a mud run. Although cases of histoplasmosis-associated endocarditis and pericarditis have been reported in the literature, cases of histoplasmosis myocarditis are rare., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)

The structural determination of the ionic liquid, caesium bis-[(tri-fluoro-meth-yl)sulfon-yl]imide or poly[[μ 4 -bis-[(tri-fluoro-meth-yl)sulfon-yl]imido]caesium(I)], Cs[N(SO 2 CF 3 ) 2 ] or Cs[Tf 2 N], reveals a second polymorph that also crystallizes in a layer structure possessing monoclinic P 2 1 / c symmetry at 120 K instead of C 2/ c for the known polymorph [Xue et al. (2002 ▸). Solid State Sci. 4 , 1535-1545]. The caesium ions in the cationic layers are coordinated by the sulfonyl groups of the bis-triflimide mol-ecules from anion layers while the tri-fluoro-methyl groups are oriented in the opposite direction, forming a non-polar surface separating the layers. The layer direction is (100).

Hematopoietic cell transplantation (HCT) provides potentially curative treatment for patients with myelofibrosis (MF). HCT outcomes are associated with the Dynamic International Prognostic Scoring System (DIPSS) risk scores. In the present study we analyzed results in 233 patients to determine if the DIPSS plus classification, which adds cytogenetics, thrombocytopenia, and RBC transfusion dependence as risk factors, would better predict post-HCT outcomes than the original DIPSS. Multivariate analysis showed that each risk parameter incorporated into the DIPPS plus model contributed to its predictive power of overall mortality, relapse-free survival, and nonrelapse mortality. The 5-year overall survival (OS), relapse, and treatment-related mortality (TRM) rates for patients with low/intermediate-1 risk MF were 78%, 5%, and 20%, respectively. The 5-year OS, relapse, and TRM rates for patients with high-risk MF were 35%, 28%, and 40%, respectively. The HCT-specific comorbidity index of 3 or greater was associated with higher nonrelapse and overall mortality and reduced relapse-free survival. The relapse incidence was significantly increased in older patients (HR, 3.02; P = .0007). With a median follow-up of 8 years 124 patients (53%) were surviving. The components of the DIPSS plus classification still have prognostic relevance after adjustment by the DIPSS classification. This information should enhance our ability to advise patients when making decisions regarding timing of transplant., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Clathrin-mediated endocytosis (CME) internalizes plasma membrane by reshaping small regions of the cell surface into spherical vesicles. The key mechanistic question of how coat assembly produces membrane curvature has been studied with molecular and cellular structural biology approaches, without direct visualization of the process in living cells; resulting in two competing models for membrane bending. Here we use polarized total internal reflection fluorescence microscopy (pol-TIRF) combined with electron, atomic force, and super-resolution optical microscopy to measure membrane curvature during CME. Surprisingly, coat assembly accommodates membrane bending concurrent with or after the assembly of the clathrin lattice. Once curvature began, CME proceeded to scission with robust timing. Four color pol-TIRF showed that CALM accumulated at high levels during membrane bending, implicating its auxiliary role in curvature generation. We conclude that clathrin-coat assembly is versatile and that multiple membrane-bending trajectories likely reflect the energetics of coat assembly relative to competing forces.

DNA methyltransferase inhibitors sensitize leukemia cells to chemotherapeutics. We therefore conducted a phase 1/2 study of mitoxantrone, etoposide and cytarabine following 'priming' with 5-10 days of decitabine (dec/MEC) in 52 adults (median age 55 (range: 19-72) years) with relapsed/refractory acute myeloid leukemia (AML) or other high-grade myeloid neoplasms. During dose escalation in cohorts of 6-12 patients, all dose levels were well tolerated. As response rates appeared similar with 7 and 10 days of decitabine, a 7-day course was defined as the recommended phase 2 dose (RP2D). Among 46 patients treated at/above the RP2D, 10 (22%) achieved a complete remission (CR), 8 without measurable residual disease; five additional patients achieved CR with incomplete platelet recovery, for an overall response rate of 33%. Seven patients (15%) died within 28 days of treatment initiation. Infection/neutropenic fever, nausea and mucositis were the most common adverse events. While the CR rate compared favorably to a matched historic control population (observed/expected CR ratio=1.77), CR rate and survival were similar to two contemporary salvage regimens used at our institution (G-CLAC (granulocyte colony-stimulating factor (G-CSF); clofarabine; cytarabine) and G-CLAM (G-CSF; cladribine; cytarabine; mitoxantrone)). Thus, while meeting the prespecified efficacy goal, we found no evidence that dec/MEC is substantially better than other cytarabine-based regimens currently used for relapsed/refractory AML.

The prognosis of patients with myelodysplastic syndromes (MDS) after failure of hypomethylating agent (HMA) therapy is poor. Allogeneic hematopoietic cell transplantation (HCT) can be effective in curing patients who have failed therapy with HMA. However, published results have not addressed the outcomes with HCT in this setting. We identified 125 MDS patients who had been treated with HMA and underwent subsequent HCT. Among these, 68 were considered HMA failures and 57 responders. Failure was defined as progression to higher grade MDS or acute myeloid leukemia, lack of hematologic improvement after at least 4 HMA cycles, or loss of response after initial improvement. Response was defined as showing at least hematologic improvement. Outcomes were compared using Cox regression. Overall, 73 of 125 HMA-treated patients (58%) had died by the time of last contact. Median follow-up of survivors, measured from HCT, was 41.9 months (range, 2.7 to 98.5). The estimated probability of relapse at 3 years was 56.6% and 34.2% among failing and responding patients, respectively (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.2 to 3.66; P < .01). The estimated probability of relapse-free survival at 3 years was 23.8% and 42% in failing and responding patients, respectively (HR for relapse/death, 1.88; 95% CI, 1.19 to 2.95; P < .01). The risk of nonrelapse mortality was similar for both groups (HR, 1.12; 95% CI, .52 to 2.39; P = .77). Failure of treatment with HMA was associated with higher risk of post-HCT relapse than observed in patients responding to HMA. Prospective trials are needed to evaluate the efficacy of novel conditioning regimens and post-HCT maintenance strategies in patients who have failed HMA pre-HCT., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

The reaction of (C 5 Me 5 ) 2 AnCl 2 (An = Th, U) with 2.8 or 4 equivalents of LiNMe 2 , respectively, affords (C 5 Me 5 ) 2 An(NMe 2 ) 2 in high yields. In addition to improved syntheses, the solid-state structures, voltammetric data, and UV-visible-NIR spectra for these classic actinide bis(dimethylamido) complexes are presented for the first time.

Importance: Tetrabenazine is efficacious for chorea control; however, tolerability concerns exist. Deutetrabenazine, a novel molecule that reduces chorea, was well tolerated in a double-blind, placebo-controlled study., Objectives: To evaluate the safety and explore the efficacy of conversion from tetrabenazine to deutetrabenazine in patients with chorea associated with Huntington disease (HD)., Design, Setting, and Participants: In this ongoing, open-label, single-arm study that started on December 21, 2013, 37 patients at 13 Huntington Study Group sites in the United States and Australia who were taking stable doses of tetrabenazine that provided a therapeutic benefit were switched overnight to deutetrabenazine therapy. After week 1, the deutetrabenazine dose was titrated on a weekly basis for optimal chorea control., Interventions: Deutetrabenazine administration at a dosage thought to provide comparable systemic exposure to the active metabolites of the prior, stable tetrabenazine regimen., Main Outcomes and Measures: Safety measures included adverse events (AEs), clinical laboratory tests, vital signs, electrocardiograms, and validated scales. Changes in the Unified Huntington's Disease Rating Scale total maximal chorea score and total motor score were efficacy end points., Results: Of the 53 patients with HD screened for the study, 37 ambulatory patients with manifest HD (mean [SD] age, 52.4 [11.5] years; 22 [59%] male and 15 [41%] female; 36 white [97.3%]) were enrolled. Deutetrabenazine was generally well tolerated, with low rates of neuropsychiatric AEs. Safety scales did not reveal subclinical toxicity with deutetrabenazine treatment. Rates of dose reduction or suspension attributable to AEs were also low. Chorea control, as measured by the total maximal chorea score, was maintained at week 1 and significantly improved at week 8 (mean [SD] change from baseline, 2.1 [3.2]; P < .001)., Conclusions and Relevance: In patients with chorea, overnight conversion to deutetrabenazine therapy provided a favorable safety profile and effectively maintained chorea control.

We present a combined ab initio theoretical and experimental study of the magnetic circular dichroism (MCD) spectrum of the octahedral UCl 6 - complex ion in the UV-Vis spectral region. The ground state is an orbitally non-degenerate doublet E 5/2u and the MCD is a -term spectrum caused by spin-orbit coupling. Calculations of the electronic spectrum at various levels of theory indicate that differential dynamic electron correlation has a strong influence on the energies of the dipole-allowed transitions and the envelope of the MCD spectrum. The experimentally observed bands are assigned to dipole-allowed ligand-to-metal charge transfer into the 5f shell, and 5f to 6d transitions. Charge transfer excitations into the U 6d shell appear at much higher energies. The MCD-allowed transitions can be assigned via their signs of the -terms: Under O h double group symmetry, E 5/2u → E 5/2g transitions have negative -terms whereas E 5/2u → F 3/2g transitions have positive -terms if the ground state g-factor is negative, as it is the case for UCl 6 - .

Developing a better understanding of covalency (or orbital mixing) is of fundamental importance. Covalency occupies a central role in directing chemical and physical properties for almost any given compound or material. Hence, the concept of covalency has potential to generate broad and substantial scientific advances, ranging from biological applications to condensed matter physics. Given the importance of orbital mixing combined with the difficultly in measuring covalency, estimating or inferring covalency often leads to fiery debate. Consider the 60-year controversy sparked by Seaborg and co-workers ( Diamond, R. M.; Street, K., Jr.; Seaborg, G. T. J. Am. Chem. Soc. 1954 , 76 , 1461 ) when it was proposed that covalency from 5f-orbitals contributed to the unique behavior of americium in chloride matrixes. Herein, we describe the use of ligand K-edge X-ray absorption spectroscopy (XAS) and electronic structure calculations to quantify the extent of covalent bonding in-arguably-one of the most difficult systems to study, the Am-Cl interaction within AmCl 6 3- . We observed both 5f- and 6d-orbital mixing with the Cl-3p orbitals; however, contributions from the 6d-orbitals were more substantial. Comparisons with the isoelectronic EuCl 6 3- indicated that the amount of Cl 3p-mixing with Eu III 5d-orbitals was similar to that observed with the Am III 6d-orbitals. Meanwhile, the results confirmed Seaborg's 1954 hypothesis that Am III 5f-orbital covalency was more substantial than 4f-orbital mixing for Eu III .

Purpose The optimal regimen intensity before allogeneic hematopoietic cell transplantation (HCT) is unknown. We hypothesized that lower treatment-related mortality (TRM) with reduced-intensity conditioning (RIC) would result in improved overall survival (OS) compared with myeloablative conditioning (MAC). To test this hypothesis, we performed a phase III randomized trial comparing MAC with RIC in patients with acute myeloid leukemia or myelodysplastic syndromes. Patients and Methods Patients age 18 to 65 years with HCT comorbidity index ≤ 4 and < 5% marrow myeloblasts pre-HCT were randomly assigned to receive MAC (n = 135) or RIC (n = 137) followed by HCT from HLA-matched related or unrelated donors. The primary end point was OS 18 months post-random assignment based on an intent-to-treat analysis. Secondary end points included relapse-free survival (RFS) and TRM. Results Planned enrollment was 356 patients; accrual ceased at 272 because of high relapse incidence with RIC versus MAC (48.3%; 95% CI, 39.6% to 56.4% and 13.5%; 95% CI, 8.3% to 19.8%, respectively; P < .001). At 18 months, OS for patients in the RIC arm was 67.7% (95% CI, 59.1% to 74.9%) versus 77.5% (95% CI, 69.4% to 83.7%) for those in the MAC arm (difference, 9.8%; 95% CI, -0.8% to 20.3%; P = .07). TRM with RIC was 4.4% (95% CI, 1.8% to 8.9%) versus 15.8% (95% CI, 10.2% to 22.5%) with MAC ( P = .002). RFS with RIC was 47.3% (95% CI, 38.7% to 55.4%) versus 67.8% (95% CI, 59.1% to 75%) with MAC ( P < .01). Conclusion OS was higher with MAC, but this was not statistically significant. RIC resulted in lower TRM but higher relapse rates compared with MAC, with a statistically significant advantage in RFS with MAC. These data support the use of MAC as the standard of care for fit patients with acute myeloid leukemia or myelodysplastic syndromes.

Over 70 years of chemical investigations have shown that plutonium exhibits some of the most complicated chemistry in the periodic table. Six Pu oxidation states have been unambiguously confirmed (0 and +3 to +7), and four different oxidation states can exist simultaneously in solution. We report a new formal oxidation state for plutonium, namely Pu 2+ in [K(2.2.2-cryptand)][Pu II Cp″ 3 ], Cp″ = C 5 H 3 (SiMe 3 ) 2 . The synthetic precursor Pu III Cp″ 3 is also reported, comprising the first structural characterization of a Pu-C bond. Absorption spectroscopy and DFT calculations indicate that the Pu 2+ ion has predominantly a 5f 6 electron configuration with some 6d mixing.