Applying the win ratio method in clinical trials of orphan drugs: an analysis of data from the COMET trial of avalglucosidase alfa in patients with late-onset Pompe disease.

BACKGROUND: Clinical trials for rare diseases often include multiple endpoints that capture the effects of treatment on different disease domains. In many rare diseases, the primary endpoint is not standardized across trials. The win ratio approach was designed to analyze multiple endpoints of interest in clinical trials and has mostly been applied in cardiovascular trials. Here, we applied the win ratio approach to data from COMET, a phase 3 trial in late-onset Pompe disease, to illustrate how this approach can be used to analyze multiple endpoints in the orphan drug context. METHODS: All possible participant pairings from both arms of COMET were compared sequentially on changes at week 49 in upright forced vital capacity (FVC) % predicted and six-minute walk test (6MWT). Each participant's response for the two endpoints was first classified as a meaningful improvement, no meaningful change, or a meaningful decline using thresholds based on published minimal clinically important differences (FVC ± 4% predicted, 6MWT ± 39 m). Each comparison assessed whether the outcome with avalglucosidase alfa (AVA) was better than (win), worse than (loss), or equivalent to (tie) the outcome with alglucosidase alfa (ALG). If tied on FVC, 6MWT was compared. In this approach, the treatment effect is the ratio of wins to losses ("win ratio"), with ties excluded. RESULTS: In the 2499 possible pairings (51 receiving AVA × 49 receiving ALG), the win ratio was 2.37 (95% confidence interval [CI], 1.30-4.29, p = 0.005) when FVC was compared before 6MWT. When the order was reversed, the win ratio was 2.02 (95% CI, 1.13-3.62, p = 0.018). CONCLUSION: The win ratio approach can be used in clinical trials of rare diseases to provide meaningful insight on treatment benefits from multiple endpoints and across disease domains.

Belimumab versus anifrolumab in adults with systemic lupus erythematosus: an indirect comparison of clinical response at 52 weeks.

OBJECTIVE: To generate comparative efficacy evidence of belimumab versus anifrolumab in SLE that can inform treatment practices. METHODS: The SLE Responder Index (SRI)-4 response at 52 weeks of belimumab versus anifrolumab was evaluated with an indirect treatment comparison. The evidence base consisted of randomised trials that were compiled through a systemic literature review.A feasibility assessment was performed to comprehensively compare the eligible trials and to determine the most appropriate indirect treatment comparison analysis method. A multilevel network meta-regression (ML-NMR) was implemented that adjusted for differences across trials in four baseline characteristics: SLE Disease Activity Index-2K, anti-double-stranded DNA antibody positive, low complement (C)3 and low C4. Additional analyses were conducted to explore if the results were robust to different sets of baseline characteristics included for adjustment, alternative adjustment methods and changes to the trials included in the evidence base. RESULTS: The ML-NMR included eight trials: five belimumab trials (BLISS-52, BLISS-76, NEA, BLISS-SC, EMBRACE) and three anifrolumab trials (MUSE, TULIP-1, TULIP-2). Belimumab and anifrolumab were comparable in terms of SRI-4 response (OR (95% credible interval), 1.04 (0.74-1.45)), with the direction of the point estimate slightly favouring belimumab. Belimumab had a 0.58 probability of being the more effective treatment. The results were highly consistent across all analysis scenarios. CONCLUSIONS: Our results suggest that the SRI-4 response of belimumab and anifrolumab are similar at 52 weeks in the general SLE population, but the level of uncertainty around the point estimate means we cannot rule out the possibility of a clinically meaningful benefit for either treatment. It remains to be seen if specific groups of patients could derive a greater benefit from anifrolumab or from belimumab, and there is certainly an unmet need to identify robust predictors towards more personalised selection of available biological agents in SLE.

Phytoremediation potential of Solanum viarum Dunal and functional aspects of their capitate glandular trichomes in lead, cadmium, and zinc detoxification.

In the present scenario, remediation of heavy metals (HMs) contaminated soil has become an important work to be done for the well-being of human and their environment. Phytoremediation can be regarded as an excellent method in environmental technologies. The present contemporary research explores the Solanum viarum Dunal function as a potential accumulator of hazardous HMs viz. lead (Pb), cadmium (Cd), zinc (Zn), and their combination (CHM). On toxic concentrations of Pb, Cd, Zn, and their synergistic exposure, seeds had better germination percentage and their 90d old aerial tissues accumulated Pb, Cd, and Zn concentrations ranging from 44.53, 84.06, and 147.29 mg kg-1 DW, respectively. Pattern of accumulation in roots was as Zn 70.08 > Pb 48.55 > Cd 42.21 mg kg-1DW. Under HMs treatment, positive modulation in physiological performances, antioxidant activities suggested an enhanced tolerance along with higher membrane stability due to increased levels of lignin, proline, and sugar. Phenotypic variations were recorded in prickles and roots of 120 d old HM stressed plants, which are directly correlated with better acclimation. Interestingly, trichomes of the plant also showed HM accumulation. Later, SEM-EDX microanalysis suggested involvement of S. viarum capitate glandular trichomes as excretory organs for Cd and Zn. Thus, the present study provides an understanding of the mechanism that makes S. viarum to function as potent accumulator and provides information to generate plants to be used for phytoremediation.

A universal dimensionless length scale in medium range order amorphous structures.

Our theoretical analysis reveals the existence of a previously unknown universality, namely, a dimensionless length scale, related to a ratio of medium and short range order structures of amorphous systems that originates from a conspiracy between dispersion forces among molecules and their phonon mediated coupling. The scale in turn gives rise to the structure lying underneath the low temperature universalities of many other properties e.g. specific heat, internal friction, boson peak characteristics, Meissner-Berret ratio etc.

Universality of ultrasonic attenuation coefficient of amorphous systems at low temperatures.

The competition between unretarded dispersion interactions between molecules prevailing at medium range order length scales and their phonon induced coupling at larger scales leads to appearance of nano-scale sub structures in amorphous systems. The complexity of intermolecular interactions gives rise to randomization of their operators. Based on a random matrix modelling of the Hamiltonian and its linear response to an external strain field, we show that the ultrasonic attenuation coefficient can be expressed as a ratio of two crucial length-scales related to molecular dynamics. A nearly constant value of the ratio for a wide range of materials then provides a theoretical explanation of the experimentally observed qualitative universality of the ultrasonic attenuation coefficient at low temperatures.

Average density of states of amorphous Hamiltonians: role of phonon mediated coupling of nano-clusters.

Based on a description of an amorphous solid as a collection of coupled nanosize molecular clusters referred as basic blocks, we analyse the statistical properties of its Hamiltonian. The information is then used to derive the ensemble averaged density of the vibrational states (non-phonon) which turns out to be a Gaussian in the bulk of the spectrum and an Airy function in the low frequency regime. A comparison with experimental data for six glasses confirms validity of our theoretical predictions.

Low temperature heat capacity of nanosize amorphous solids.

Contrary to previous studies based on bulk materials, we analyze the behavior of the vibrational density of states (VDOS) and specific heat of an amorphous solid of nano-scales (∼3 nm) at low temperature. With Hamiltonian formulation based on the intermolecular dispersion forces, our analysis indicates a universal semi-circle form of the average VDOS in the bulk of the spectrum along with a super-exponentially increasing behavior in its edge. The latter in turn leads to a specific heat with a superlinear temperature (T) dependence belowT< 1Keven at nano-scales, and, surprisingly agreeing with the experiments although the latter are carried out at macroscopic scales. The omnipresence of dispersion forces at microscopic scales indicates the application of our results to other disordered materials too.

Spectral statistics of multiparametric Gaussian ensembles with chiral symmetry.

The statistics of chiral matrix ensembles with uncorrelated but multivariate Gaussian distributed elements is intuitively expected to be driven by many parameters. Contrary to intuition, however, our theoretical analysis reveals the existence of a single parameter, a function of all ensemble parameters, which governs the dynamics of spectral statistics. The analysis not only extends the formulation (known as complexity parameter formulation) for Hermitian ensembles without chirality to those with it but also reveals the underlying connection between chiral complex systems with seemingly different system conditions as well as between other complex systems, e.g., multiparametric Wishart ensembles as well as generalized Calogero-Sutherland Hamiltonians.

Influence of anion induced geometry change in Zn(ii) on the magnetization relaxation dynamics of Dy(iii) in Zn-Dy-Zn complexes.

A family of hetero-trinuclear metal complexes with the general molecular formula [Zn2Dy(L1)2(OAc)4] (X) where X = (NO3)0.92(Br)0.08 (1), ClO4 (2), Cl (3) and PF6 (4) were structurally characterized using a Schiff base ligand (HL1). The Dy(iii) ion in 1-4 exhibits distorted square anti-prism geometry; however, the extent of distortion observed around Dy(iii) in these complexes differ from each other. Consequently, 1-4 show distinct magnetization relaxation dynamics, with the anisotropic energy barrier of 25.4 cm-1, 12.9 cm-1, 14.08 cm-1 and 55.5 cm-1, respectively. The detailed electronic structure of 1-4 and the experimentally observed magnetization relaxation dynamics trends were rationalized using ab initio calculations. The detailed investigation discloses the non-zero influence of the anion themselves and the anion induced geometry change in Zn(ii) affects the electronic structure of Dy(iii), which in turn affects the magnetization relaxation dynamics. Overall, the study unveils an unprecedented methodology i.e. change in geometry of Zn(ii) by altering the anion in the crystal lattice to modulate the relaxation dynamics of Dy(iii).

Systematic review and network meta-analysis of the efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler in comparison with other long-acting muscarinic antagonist/long-acting ß2-agonist fixed-dose combinations in COPD.

BACKGROUND: Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for chronic obstructive pulmonary disease (COPD). The relative efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 18/9.6 µg) in patients with moderate-to-very severe COPD, compared with other licensed LAMA/LABA FDCs, was investigated using an integrated Bayesian network meta-analysis (NMA). METHODS: A systematic literature review and subsequent screening process identified randomized controlled trials of ⩾10 weeks' duration that enrolled patients aged ⩾40 years with moderate-to-very severe COPD and included at least one LAMA/LABA FDC or open LAMA + LABA treatment arm. NMAs were conducted for outcomes including change from baseline in forced expiratory volume in 1 s (FEV1), St George's Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI) parameters, annualized rate of exacerbations, use of rescue medication, adverse events, and all-cause withdrawals. Meta-regression and sensitivity analyses accounted for heterogeneity across studies. RESULTS: In total, 29 studies including 34,617 patients contributed to the NMA for efficacy or safety outcomes at week 24 or exacerbations. For all LAMA/LABA FDCs with data available, significantly greater improvements in FEV1 [trough, peak, and area under the curve (AUC)0-4], SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed versus placebo. Where indirect comparisons were possible, differences between GFF MDI and other LAMA/LABA FDCs were small relative to established margins of clinical relevance, and not statistically significant. The safety and tolerability profile of GFF MDI was consistent with other LAMA/LABA FDCs and placebo. The results of the meta-regression were generally similar to the base case. CONCLUSIONS: GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs. Personalization of treatment choice within the class on the basis of other factors such as patient preference may be appropriate.

Statistical analysis of chiral structured ensembles: Role of matrix constraints.

We analyze the statistical properties of complex systems with specific conservation laws and symmetry conditions which lead to various constraints and thereby structures in their matrix representation. An increase of constraints leads to a variation of the spectral statistics from Wigner-Dyson to Poisson limits, but the eigenfunction statistics remains weakly multifractal in the bulk. For some constraints, the statistics not only lies between the two limits but is size-independent too, thus indicating a critical point. Our results also reveal an important trend: While the spectral statistics is strongly sensitive to the number of independent matrix elements, the eigenfunction statistics seems to be affected mainly by their relative strengths. This is contrary to a previously held belief of a one-to-one relation between the statistics of the eigenfunctions and eigenvalues (e.g., associating Poisson statistics to the localized eigenfunctions and Wigner-Dyson statistics to delocalized ones). This also indicates the existence of new universality classes based on the matrix constraints (different from the 10 already-known symmetry-based classes).

Stabilizing Terminal Ni(III)-Hydroxide Complex Using NNN-Pincer Ligands: Synthesis and Characterization.

The reaction of [Ni(COD)2] (COD; cyclooctadiene) in THF with the NNN-pincer ligand bis(imino)pyridyl (L1) reveals a susceptibility to oxidation in an inert atmosphere ([O2] level <0.5 ppm), resulting in a transient Ni:dioxygen adduct. This reactive intermediate abstracts a hydrogen atom from THF and stabilizes an uncommon Ni(III) complex. The complex is crystallographically characterized by a molecular formula of [NiIII(L1··)2-(OH)] (1). Various isotopically labeled experiments (16O/18O) assertively endorse the origin of terminal oxygen based ligand in 1 due to the activation of molecular dioxygen. The presence of proton bound to the terminal oxygen in 1 is well supported by NMR, IR spectroscopy, DFT calculations, and hydrogen atom transfer (HAT) reactions promoted by 1. The observation of shakeup satellite peaks for the primary photoelectron lines of Ni(2p) in the X-ray photoelectron spectroscopy (XPS) unambiguously confirms the paramagnetic signature associated with the distorted square planar nickel ion, which is consistent with the trivalent oxidation state assigned for the nickel ion in 1. The variable temperature magnetic susceptibility data of 1 shows dominant antiferromagnetic interactions exist among the paramagnetic centers, resulting in an overall S = 1/2 ground state. Variable temperature X-band EPR studies performed on 1 show evidence for the S = 1/2 ground state, which is consistent with magnetic data. The unusual g-tensor extracted for the ground state S = 1/2 is analyzed under a strong exchange limit of spin-coupled centers. The electronic structure predicted for 1 is in good agreement with theoretical calculations.

Physical state of the culture medium triggers shift in morphogenetic pattern from shoot bud formation to somatic embryo in Solanum khasianum.

Solanum khasianum is a rich source of steroidal alkaloids that are important secondary metabolites with enormous pharmaceutical uses. Development of plantlets from somatic tissues, under in vitro conditions, takes place both through adventitious shoot bud differentiation or somatic embryogenesis (SE) pathway. We observed that the physical state of medium, solid or liquid, determined the regenerant differentiation patterns from root segment explants in S. khasianum. In the solidified medium, the root segments developed adventitious shoot buds whereas somatic embryos were regenerated in the liquid medium. Varying gradients from liquid to solid medium were further used to confirm the effect of solidified condition on regeneration pathway. Histological analysis of developing shoot buds and somatic embryos was also performed to confirm their development and differentiation patterns. In order to further confirm the developmental pathways, qRT-PCR analysis of the marker genes of SE and shoot regeneration was also performed. While SOMATIC EMBRYOGENESIS RECEPTOR KINASE1 (SkSERK1) expression was significantly up-regulated during the early embryogenic stage, the LATE EMBRYOGENESIS ABUNDANT (SkLEA) protein was found to be highly expressed in the mature embryos. Expression of the HISTONE DEACETYLASE (HDA6), a repressor of SE related genes, was highly decreased during embryogenesis in the liquid culture. Furthermore, expression of the ENHANCER OF SHOOT REGENERATION  (ESR) gene was comparatively increased during shoot regeneration in the culture using solid medium. Our results point out that the physical state of the medium in S. khasianum plays a decisive role in differentiation pattern which was independent of hormonal supplements.

Substituted versus Naked Thiourea Ligand Containing Pseudotetrahedral Cobalt(II) Complexes: A Comparative Study on Its Magnetization Relaxation Dynamics Phenomenon.

A series of mononuclear tetrahedral cobalt(II) complexes with the general molecular formula [Co(L1)2X2] [where L1 = tetramethylthiourea ([(CH3)2N]2C═S) and X = Cl (1), Br (2), and I (3)] were isolated, and their structures were characterized by single-crystal X-ray diffraction. The experimental direct-current magnetic data are excellently reproduced by fitting both χM T( T) and M( H) simultaneously using the spin Hamiltonian (SH) parameters D1 = -18.1 cm-1 and g1,iso = 2.26, D2 = -16.4 cm-1 and g2,iso = 2.33, and D3 = -22 cm-1 and g3,iso = 2.4 for 1-3, respectively, and the sign of D was unambiguously confirmed from X-band electron paramagnetic resonance measurements. The effective energy barrier extracted for the magnetically diluted complexes 1-3 (10%) is larger than the barrier observed for the pure samples and implies a nonzero contribution of dipolar interaction to the magnetization relaxation dynamics. The SH parameters extracted for the three complexes drastically differ from their respective parent complexes that possess the general molecular formula [Co(L)2X2] [where L = thiourea [(NH2)2C═S] and X = Cl (1a), Br (2a), and I (3a)], which is rationalized by detailed ab initio calculations. An exhaustive theoretical study reveals that both the ground and excited states are not pure but rather multideterminental in nature (1-3). Noticeably, the substitution of L by L1 induces structural distortion in 1-3 on the level of the secondary coordination sphere compared to 1a-3a. This distortion leads to an overall reduction in | E/ D| of 1-3 compared to 1a-3a. This may be one of the reasons for the origin of the slower relaxation times of 1-3 compared to 1a-3a.

Chronic Myeloid Leukemia with a Complex Variant 'Ph' Translocation That Develops in Breast Carcinoma, Postchemotherapy: A Rare but Treatable Entity.

We report a case of chronic myeloid leukemia (CML) that developed after postoperative chemotherapy with cyclophosphamide, doxorubicin and 5-fluorouracil (CAF) for breast cancer. A 55-year-old woman was diagnosed with invasive ductal carcinoma which was treated with a modified radical mastectomy followed by six cycles of CAF chemotherapy. Nine years later, she developed CML and locoregional recurrence. Her breast recurrence showed strong estrogen receptor, weak progesterone receptor and strong human epidermal growth factor 2 (score 3+) expression. Her secondary CML in the chronic phase showed a complex variant translocation (CVT) involving chromosomes 9, 22, and 17. Considering that the HER2/neu gene is also located on chromosome 17, this secondary CML in chronic phase with CVT is indeed a rare occurrence. We discuss the associated genetic factors and the possible role of breast cancer chemo/radiotherapy in the development of such CML as well as its treatment and prognosis compared with de novo CML.

Extended states with Poisson spectral statistics.

Contrary to the prevailing notion, we find that the spectrum associated with the extended states in a complex system may belong to the Poisson universality class if the system is subjected to a specific set of constraints. Our results are based on an exact theoretical as well as numerical analysis of column constrained chiral ensembles with circulant off-diagonal blocks and are relevant for a complete understanding of the eigenfunction localization and related physical properties.

Role of Halide Ions in the Nature of the Magnetic Anisotropy in Tetrahedral CoII Complexes.

A series of mononuclear tetrahedral CoII complexes with a general molecular formula [CoL2 X2 ] [L=thiourea and X=Cl (1), Br (2) and I (3)] were synthesized and their structures were characterized by single-crystal X-ray diffraction. Direct-current (dc) magnetic susceptibility [χM T(T) and M(H)] and its slow relaxation of magnetization were measured for all three complexes. The experimental dc magnetic data are excellently reproduced by fitting both χM T(T) and M(H) simultaneously with the parameters D=+10.8 cm-1 , g1 =2.2, g2 =2.2, and g3 =2.4 for 1; D=-18.7 cm-1 , giso =2.21 for 2; and D=-19.3 cm-1 , giso =2.3 for 3. The replacement of chloride in 1 by bromide or iodide (in 2 and 3, respectively) was accompanied by a change in both sign and magnitude of the magnetic anisotropy D. Field-induced out-of-phase susceptibility signals observed in 10 % diluted samples of 1-3 imply slow relaxation of magnetization of molecular origin. To better understand the magnetization relaxation dynamics of complexes 1-3, detailed ab initio CASSCF/NEVPT2 calculations were performed. The computed spin Hamiltonian parameters are in good agreement with experimental data. In particular, the calculations unveil the role of halide ions in switching the sign of D on moving from Cl- to I- . The large spin-orbit coupling constant associated with the heavier halide ion and weaker π donation reduces the ground state-excited state gap, which leads to a larger contribution to negative D for complex 3 compared to complex 1. Further magnetostructural D correlations were developed to understand the role of structural distortion in the sign and magnitude of D values in this family of complexes.

Cardiovascular sequel of neck irradiation in head and neck cancer patients.

PURPOSE: The baroreflex is an important afferent mechanism controlling autonomic functions. As afferent nerves course through the neck, they are susceptible to damage by neck irradiation in head and neck cancer patients. With increased survival of head and neck cancer patients because of improved therapy, the cardiovascular morbidity and mortality in them have become apparent and this is of clinical concern. There are few case reports of baroreflex failure as a chronic sequel to neck irradiation. OBJECTIVES: The present study evaluated the changes in cardio-autonomic tone and postural cardiovascular reflex in neck-irradiated patients. METHODS: Head and neck cancer patients who had received neck irradiation (n = 15) and healthy controls (n = 15) were evaluated for heart rate variability with time domain analysis of 5 min ECG recording. Postural cardiovascular reflexes were studied with changes in blood pressure and heart rate in the lying to standing test. RESULTS: Our results suggest that there is a reduction in overall time domain measures of heart rate variability and weakened postural reflexes in neck-irradiated patients. CONCLUSION: Decreased heart rate variability in neck-irradiated patients reflects an independent risk of cardiovascular morbidity. The early detection of cardiovascular impairment in such patients may help healthcare professionals in providing better care. Furthermore, the dose delivered to the carotid sinus should be monitored and restricted.

Structural and magnetic properties of semiquinonate based Al(iii) and Ga(iii) complexes.

The reaction of anhydrous MCl3 (M = Al(iii) or Ga(iii)) with one-electron-reduced 3,5-di-tert-butyl-1,2-ortho-benzoquinone (using metallic sodium) led us to isolate two distinct metal complexes of Al(iii) and Ga(iii), which were structurally and magnetically characterized. Complex 1 crystallized in the monoclinic P21/n space group, whereas 2 crystallized in the triclinic P1[combining macron] space group. Interestingly, whereas the Al(iii) derivative was obtained as a dimer with the molecular formula [Al2(µ-HL-)2(L˙-)4] (1) (where L˙- is a semiquinonate radical and HL- is a monoanionic catecholate ligand), the Ga(iii) derivative crystallized as [Ga(L˙-)3] (2), which is a polymorph of a previously reported complex. The presence of both catecholate and/or semiquinonate ligands in 1 and 2 was confirmed by single-crystal X-ray diffraction, mass spectrometry, and NMR and infrared spectroscopy techniques. The crystalline phase purity of the complexes was confirmed by powder X-ray diffraction (PXRD). Measurements of direct-current magnetic susceptibility, which were performed on a polycrystalline samples, revealed that in both complexes the semiquinonate radical anions are coupled ferromagnetically via the diamagnetic metal ion. The magnetism data of both complexes were modelled using the Heisenberg-Van Vleck-Dirac (HDVV) Hamiltonian, and the extracted parameters are consistent with the literature reports. The details of the electronic structures of the ground states of 1 and 2 were further investigated via X-band (ca. 9 GHz) electron paramagnetic resonance (EPR). The EPR spectrum of 2 could be reproduced by considering a quartet ground state with zero-field splitting and hyperfine coupling, whereas attempts to simulate all the EPR spectral features observed in a frozen solution of 1 by assuming it was a pure phase failed. A correct simulation required the simultaneous inclusion of contributions from a quartet and a triplet state. This evidently suggests that the dimeric complex of 1 is in equilibrium with a monomeric [Al(L˙-)3] complex in solution.

Criticality in Brownian ensembles.

A Brownian ensemble appears as a nonequilibrium state of transition from one universality class of random matrix ensembles to another one. The parameter governing the transition is, in general, size-dependent, resulting in a rapid approach of the statistics, in infinite size limit, to one of the two universality classes. Our detailed analysis, however, reveals the appearance of a new scale-invariant spectral statistics, nonstationary along the spectrum, associated with multifractal eigenstates, and different from the two end-points if the transition parameter becomes size-independent. The number of such critical points during transition is governed by a competition between the average perturbation strength and the local spectral density. The results obtained here have applications to wide-ranging complex systems, e.g., those modeled by multiparametric Gaussian ensembles or column constrained ensembles.