Prevalence of people living with multidrug-resistant HIV and limited treatment options in Spain.

OBJECTIVES: Our aim was to determine the prevalence and characteristics of people with HIV on antiretroviral therapy (ART) with multidrug resistance (MDR; confirmed resistance to three or more [or resistance to two or more plus contraindication to one or more] core ART classes) and limited treatment options (LTOs) in Spain. METHODS: This was an observational, retrospective, multicentre, cross-sectional chart review study undertaken in five reference Spanish centres. Participants were people with HIV on ART with MDR and LTOs (detectable viral load [HIV-RNA >200 copies/mL], treatment-limiting drug-drug interaction [DDI], or intolerance precluding the use of one or more ART classes). Prevalence, demographic/clinical characteristics, and treatment options were assessed. Logistic regression analyses were used to identify MDR-associated variables. RESULTS: Of 14 955 screened people with HIV, 69 (0.46%) presented with MDR and 23 (0.15%) had LTOs. The population analysed was 73.9% male with a median age of 54.0 years; the median time since HIV diagnosis was 26.5 years, and median CD4+ cell count was 511.0 cells/µL. The only factor significantly associated with MDR (univariate analysis) was CD4+ cell count. Injection drug use was the most common transmission route. Comorbidities (mainly endocrine and cardiovascular disorders; 34.8% affecting HIV management) and concomitant treatments were frequent. No recent opportunistic infections were reported. Patients had been exposed to the following ART: nucleoside analogue reverse transcriptase inhibitors (100%), protease inhibitors (95.6%), non-nucleoside analogue reverse transcriptase inhibitors (87.0%), and integrase strand transfer inhibitors (82.6%). The available fully active drugs were dolutegravir (39.1%), bictegravir (30.4%), and raltegravir (21.7%). CONCLUSIONS: The prevalence of people with HIV with MDR and LTOs in Spain is very low, with approximately half of those studied not exhibiting virological suppression. Low CD4+ cell counts were associated with MDR. These findings may help address the impact and treatment needs of these patients and prevent clinical progression and transmission of MDR HIV.

Preferences of people living with HIV for injectable and oral antiretroviral treatment in the Netherlands: a discrete choice experiment.

ABSTRACTInjectable antiretroviral treatment (ART) represents a new effective and potentially more convenient alternative to oral ART for people living with HIV (PLWH). This study assessed preferences of PLWH for long-acting injectable compared with oral ART in the Netherlands. A labelled discrete choice experiment presented 12 choice sets of long-acting injectable and oral ART. PLWH were asked to select their preferred ART, described by six attributes: location of administration, dosing frequency, risk of short-term side effects, drug-drug interaction, forgivability, and food and mealtime restrictions. Random parameters logit and latent class models were used to estimate preferences of PLWH. 98.6% of 76 respondents were experienced oral ART users that had taken ART for a median of 12 years (Q1-Q3: 7.0-20.0). 30 (39.5%) respondents chose long-acting injectable ART in all choice tasks and 22 (28.9%) always chose oral ART. The random parameter model showed that, on average, respondents significantly favoured long-acting injectable ART over oral ART, preferred administration of the long-acting injectable ART at home, and a less frequent regimen. The latent class model confirmed one class strongly preferring long-acting injectable ART and one class slightly preferring oral ART. This study highlights the value for both long-acting injectable and oral ART.

The long-term clinical and economic benefits of treating advanced COPD patients with single-inhaler triple therapy in Quebec, Canada - the IMPACT trial.

BACKGROUND: This cost-utility analysis assessed the long-term clinical and economic benefits of fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy vs FF/VI or UMEC/VI from a Quebec societal perspective in patients with chronic obstructive pulmonary disease (COPD) with ≥1 moderate/severe exacerbation in the previous year. METHODS: The validated GALAXY disease progression model was utilized, with parameters set to baseline and efficacy data from IMPACT. Treatment costs (2017 Canadian dollars [C$]) were estimated using Quebec-specific unit costs. Costs and health outcomes were discounted at 1.5%/year. A willingness-to-pay threshold of C$50,000/quality-adjusted life year (QALY) was considered cost-effective. Outcomes modeled were exacerbation rates, QALYs, life years (LYs), costs and incremental cost-effectiveness ratios (ICERs). Subgroup analyses were performed according to prior treatment, exacerbation history in the previous year, and baseline lung function. RESULTS: Over a lifetime horizon, FF/UMEC/VI resulted in more QALYs and LYs gained, at a small incremental cost compared with FF/VI and UMEC/VI. From a societal perspective, the estimated ICER for the base case was C$18,152/QALY vs FF/VI, and C$15,847/QALY vs UMEC/VI. For the subgroup analyses (FF/UMEC/VI compared with FF/VI and UMEC/VI), ICERs ranged from: C$17,412-25,664/QALY and C$16,493-18,663/QALY (prior treatment); C$15,247-19,924/QALY and C$15,444-28,859/QALY (exacerbation history); C$14,025-34,154/QALY and C$16,083-17,509/QALY (baseline lung function). INTERPRETATION: FF/UMEC/VI was predicted to improve outcomes and be cost-effective vs both comparators in the base case and all subgroup analyses, and based on this analysis would be an appropriate investment of health service funds in Quebec. CLINICAL TRIAL REGISTRATION NUMBER: IMPACT trial NCT02164513.

A characterization of the HIV population with limited/exhausted treatment options: a multicenter Belgian study.

OBJECTIVE: Describe the prevalence and characteristics of people living with HIV (PLWH) in Belgium with limited/exhausted treatment options. METHODS: A cross-sectional, multicenter study involving adult treatment-experienced individuals with limited/exhausted treatment options defined as having a multi-drug resistant HIV-1 or a history of multiple treatment changes. The primary outcome was to determine the prevalence of these individuals and classify them based on their two most recent consecutive HIV-1 viral loads (VLs): suppressed (2 VLs < 50 copies/mL), intermediate (≥1 VL between 50-200 copies/mL), or unsuppressed (2 VLs > 200 copies/mL). Secondary outcome was to characterize the participants included in this analysis. RESULTS: There were 119 individuals included (prevalence of 0.97%; 119 of 12 282 in care). The majority were aged > 50 years (88.2%), women represented 35.3%, and individuals were primarily White (54.7%). Median (IQR) CD4+ T-cell count was 635 (400-875) cells/µL and most (42%) were on a 3-drug ART regimen. Overall, 87.4% were classified as suppressed, 9.2% as intermediate, and 3.4% as unsuppressed. On multivariable analysis, CD4+ T-cell count < 200 cells/µL was associated with being classified as intermediate or unsuppressed (p = 0.004). CONCLUSION: In this analysis of PLWH in Belgium, individuals with limited/exhausted treatment options represented a small fraction. Most were on a 3-drug ART regimen, were virologically suppressed, and had a CD4+ T-cell count within normal range. A small proportion were not virologically suppressed while others, despite being suppressed, were on ≥ 4-drug ART regimens. As such, new therapeutic options are needed to achieve and maintain virologic suppression in such individuals while decreasing their pill burden.

Li(x)FeF6 (x = 2, 3, 4) battery materials: structural, electronic and lithium diffusion properties.

Lithium iron fluoride materials have attracted recent interest as cathode materials for lithium ion batteries. The electrochemical properties of the high energy density Li(x)FeF6 (x = 2, 3, 4) materials have been evaluated using a combination of potential-based and DFT computational methods. Voltages of 6.1 V and 3.0 V are found for lithium intercalation from Li2FeF6 to α-Li3FeF6 and α-Li3FeF6 to Li4FeF6 respectively. The calculated density of states indicate that Li2FeF6 possesses metallic states that become strongly insulating after lithium intercalation to form α-Li3FeF6. The large energy gain associated with this metal-insulator transition is likely to contribute to the associated large voltage of 6.1 V. Molecular dynamics simulations of lithium diffusion in α-Li3FeF6 at typical battery operating temperatures indicate high lithium-ion mobility with low activation barriers. These results suggest the potential for good rate performance of lithium iron fluoride cathode materials.

Cabotegravir and Rilpivirine Long-Acting Antiretroviral Therapy Administered Every 2 Months is Cost-Effective for the Treatment of HIV-1 in Spain.

INTRODUCTION: Current antiretroviral therapies (ARTs) have improved outcomes for people living with HIV. However, the requirement to adhere to lifelong daily oral dosing may be challenging for some people living with HIV, leading to suboptimal adherence and therefore reduced treatment effectiveness. Treatment with long-acting (LA) ART may improve adherence and health-related quality of life. The objective of this study was to evaluate the cost-effectiveness of cabotegravir + rilpivirine (CAB+RPV) LA administered every 2 months (Q2M) compared with current ART administered as daily oral single-tablet regimens (STRs) from a Spanish National Healthcare System perspective. METHODS: A hybrid decision-tree and Markov state-transition model was used with pooled data from three phase III/IIIb trials (FLAIR, ATLAS, and ATLAS-2M) over a lifetime horizon, with health states defined by viral load and CD4+ cell count. Direct costs (in €) were taken from Spanish public sources from 2021 and several deterministic and probabilistic analyses were carried out. An annual 3% discount rate was applied to both costs and utilities. RESULTS: Over the lifetime horizon, CAB+RPV LA Q2M was associated with an additional 0.27 quality-adjusted life years (QALYs) and slightly greater lifetime costs (€4003) versus daily oral ART, leading to an incremental cost-effectiveness ratio of €15,003/QALY, below the commonly accepted €30,000/QALY willingness-to-pay threshold in Spain. All scenario analyses showed consistent results, and the probabilistic sensitivity analysis showed cost-effectiveness compared with daily oral STRs in 62.4% of simulations, being dominant in 0.3%. CONCLUSION: From the Spanish National Health System perspective, CAB+RPV LA Q2M is a cost-effective alternative compared with the current options of daily oral STR regimens for HIV treatment. CLINICAL TRIALS REGISTRATION: ATLAS, NCT02951052; ATLAS-2M, NCT03299049; FLAIR, NCT02938520.

Over the past decades, treatments for HIV infection have improved outcomes for people living with HIV. However, most of the treatments available consist of daily oral administration, which may present challenges for some people. These challenges may lead to a less optimal intake of the medicines and, therefore, to a potential reduction of treatment effectiveness. A new long-acting treatment alternative for HIV with two drugs is now available: cabotegravir + rilpivirine long-acting is the first injectable treatment administered in the muscle every 2 months by a healthcare professional. Long-acting injectables may improve treatment administration and health-related quality of life of people living with HIV. This study estimated the cost-effectiveness of cabotegravir + rilpivirine long-acting in Spain compared with daily oral single-tablet treatment for HIV. An economic model using clinical data and Spanish inputs was used to estimate cost-effectiveness and health outcomes over a lifetime. Cabotegravir + rilpivirine long-acting compared with daily oral single-tablet treatment showed an increase in health-related quality of life, leading to a cost-effectiveness ratio of €15,003, below the Spanish willingness-to-pay threshold of €30,000. All different scenarios tested showed consistent results, with cabotegravir + rilpivirine long-acting being cost-effective in 62.4% of the simulations and less costly and more effective in 0.3%. This study demonstrated that, in Spain, cabotegravir + rilpivirine long-acting administered every 2 months is a cost-effective alternative to the current daily oral single-tablet treatment options for HIV.

Mitochondrial thioredoxin reductase is essential for early postischemic myocardial protection.

BACKGROUND: Excessive formation of reactive oxygen species contributes to tissue injury and functional deterioration after myocardial ischemia/reperfusion. Especially, mitochondrial reactive oxygen species are capable of opening the mitochondrial permeability transition pore, a harmful event in cardiac ischemia/reperfusion. Thioredoxins are key players in the cardiac defense against oxidative stress. Mutations in the mitochondrial thioredoxin reductase (thioredoxin reductase-2, Txnrd2) gene have been recently identified to cause dilated cardiomyopathy in patients. Here, we investigated whether mitochondrial thioredoxin reductase is protective against myocardial ischemia/reperfusion injury. METHODS AND RESULTS: In mice, α-MHC-restricted Cre-mediated Txnrd2 deficiency, induced by tamoxifen (Txnrd2-/-ic), aggravated systolic dysfunction and cardiomyocyte cell death after ischemia (90 minutes) and reperfusion (24 hours). Txnrd2-/-ic was accompanied by a loss of mitochondrial integrity and function, which was resolved on pretreatment with the reactive oxygen species scavenger N-acetylcysteine and the mitochondrial permeability transition pore blocker cyclosporin A. Likewise, Txnrd2 deletion in embryonic endothelial precursor cells and embryonic stem cell-derived cardiomyocytes, as well as introduction of Txnrd2-shRNA into adult HL-1 cardiomyocytes, increased cell death on hypoxia and reoxygenation, unless N-acetylcysteine was coadministered. CONCLUSIONS: We report that Txnrd2 exerts a crucial function during postischemic reperfusion via thiol regeneration. The efficacy of cyclosporin A in cardiac Txnrd2 deficiency may indicate a role for Txnrd2 in reducing mitochondrial reactive oxygen species, thereby preventing opening of the mitochondrial permeability transition pore.

Synthesis, structure, and properties of the new mixed-valent dodecahalogenotrimetallate In4Ti3Br12 and its relation to compounds A3Ti2X9 (A = K, In; X = Cl, Br).

Black single crystals of the new dodecahalogenotrimetallate In(4)Ti(3)Br(12) were obtained by reacting InBr(3) with Ti-wire at 450 °C in a silica tube sealed under vacuum. In(4)Ti(3)Br(12) (Pearson symbol hR57, space group R3m, Z = 3, a = 7.3992(8) Å, c = 36.673(6) Å, 643 refl., 25 param., R(1)(F) = 0.025; wR(2)(F(2)) = 0.046) is a defect variant of a 12 L-perovskite. In(+) cations are 12-fold coordinated in two different ways: In1 as an anticuboctahedron and In2 as a cuboctahedron. In both cases the 5s(2) configuration results in 3 short, 6 medium, and 3 long In-Br distances which might be explained as lone pair effect or second order Jahn-Teller instability. Furthermore there are isolated linear trimers [Ti(3)Br(12)](4-) consisting of facesharing octahedra similar to [Ru(3)Cl(12)](4-). The [Ti(3)Br(12)](4-)-unit has to be described as a mixed-valent d(1)-d(2)-d(1) system. According to magnetic measurements, the Ti-atoms in In(4)Ti(3)Br(12) show strong antiferromagnetic interactions (Θ = -1216(6) K) which might be addressed as weak Ti(3+)-Ti(2+)-Ti(3+) bonds. For comparison, single crystals of K(3)Ti(2)X(9) (X = Cl, Br) were synthesized and their structures refined. The rotation of the Ti(2)X(9)(3-) dimers reduced the symmetry of the well-known Cs(3)Cr(2)Cl(9) type from P6(3)/mmc to P6(3)/m and resulted in the formation of merohedral twins. According to the unit cell volumes In(+) is smaller than K(+) in all cases.

Comparative Efficacy and Safety of Fostemsavir in Heavily Treatment-Experienced People With HIV-1.

PURPOSE: Heavily treatment-experienced (HTE) people with multidrug-resistant HIV-1 have limited treatment options. Treatment with the first-in-class attachment inhibitor fostemsavir in addition to optimized background therapy (OBT) resulted in sustained virologic and immunologic responses in HTE participants throughout 96 weeks in the BRIGHTE trial. In the absence of long-term direct comparative evidence between fostemsavir-based and other antiretroviral regimens, this analysis indirectly compares efficacy and safety across relevant available trials, adjusting for demographic and baseline characteristics. METHODS: A systematic literature review was conducted to identify trials with designs and populations comparable to BRIGHTE. Using matching-adjusted indirect comparison analyses, individual participant data from BRIGHTE were reweighted to create balanced populations across trials, and efficacy and safety outcomes were compared. FINDINGS: Three comparator trials were identified, 2 of which reflected an optimized therapy without fostemsavir (OBT alone): TMB-301 (ibalizumab and OBT), BENCHMRK-1/-2 (OBT alone), and VIKING-3 (OBT alone). Compared with ibalizumab and OBT (N = 40), fostemsavir and OBT (unadjusted, N = 347; adjusted, N = 236) were associated with numerically higher nonsignificant odds of virologic suppression (odds ratio [OR] = 1.44; 95% CI, 0.74-2.80; P = 0.284) and a similar increase in CD4+ cell count of approximately 65 cells/mm3 from baseline through week 24 (mean difference = 7.05 cells/mm3; 95% CI, -60.88 to 74.98 cells/mm3; P = 0.834). Compared with OBT from BENCHMRK-1/-2 (N = 237), fostemsavir and OBT (adjusted, N = 126) were associated with significantly higher odds of virologic suppression (OR = 3.26; 95% CI, 2.08-5.11; P < 0.001) and increased CD4+ cell count (135.78 cells/mm3; 95% CI, 91.93-179.63 cells/mm3; P < 0.001) at week 96. Compared with OBT from VIKING-3 (N = 183), fostemsavir and OBT (adjusted, N = 78) were associated with numerically higher odds of virologic suppression (OR = 1.34; 95% CI, 0.78-2.30; P = 0.297) and a modest CD4+ cell count increase (26.86 cells/mm3; 95% CI, -10.79 to 64.52; P = 0.162) through week 48; however, differences were not significant. All-cause discontinuations and safety comparisons varied across studies. IMPLICATIONS: Although matching-adjusted indirect comparison analyses have limitations, these results support the use of fostemsavir and OBT as an important treatment option in HTE people with multidrug-resistant HIV-1.

Is single-inhaler triple therapy for COPD cost-effective in the UK? The IMPACT trial.

BACKGROUND: The IMPACT trial demonstrated superior outcomes following 52 weeks of once-daily single-inhaler treatment with fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) (100/62.5/25 µg) compared with once-daily FF/VI (100/25 µg) or UMEC/VI (62.5/25 µg). This study evaluated the cost-effectiveness of FF/UMEC/VI compared with FF/VI or UMEC/VI for the treatment of chronic obstructive pulmonary disease (COPD) from a UK National Health Service perspective. METHODS: Patient characteristics and treatment effects from IMPACT were populated into a hybrid decision tree/Markov economic model. Costs (GB£ inflated to 2018 equivalents) and health outcomes were modelled over a lifetime horizon, with a discount rate of 3.5% per annum applied to both. Sensitivity analyses were performed to test the robustness of key assumptions and input parameters. RESULTS: Compared with FF/VI and UMEC/VI, FF/UMEC/VI provided an additional 0.296 and 0.145 life years (LYs) (discounted) and 0.275 and 0.118 quality-adjusted life years (QALYs), at an additional cost of £1129 and £760, respectively. Incremental cost-effectiveness ratios (ICERs) for FF/UMEC/VI were £4104/QALY and £3809/LY gained versus FF/VI and £6418/QALY and £5225/LY gained versus UMEC/VI. At a willingness-to-pay threshold of £20 000/QALY, the probability that FF/UMEC/VI was cost-effective was 96% versus FF/VI and 74% versus UMEC/VI. Results were similar in a subgroup of patients recommended triple therapy in the 2019 National Institute for Health and Care Excellence COPD guideline. CONCLUSIONS: FF/UMEC/VI single-inhaler triple therapy improved health outcomes and was a cost-effective option compared with FF/VI or UMEC/VI for patients with symptomatic COPD and a history of exacerbations in the UK at recognised cost-effectiveness threshold levels.

LiB12PC, the first boron-rich metal boride with phosphorus--synthesis, crystal structure, hardness, spectroscopic investigations.

We present synthesis, crystal structure, hardness, and IR/Raman and UV/Vis spectra of a new compound with the mean composition LiB(12)PC. Transparent single crystals were synthesised from Ga, Li, B, red phosphorus and C at 1500 °C in boron nitride crucibles welded in Ta ampoules. Depending on the type of boron used for the synthesis we obtained colourless, brown and red single crystals with slightly different P/C ratios. Colourless LiB(12)PC crystallizes orthorhombic in the space group Imma (No. 74) with a=10.188(2) Å, b=5.7689(11) Å, c=8.127(2) Šand Z=4. Brown LiB(12)P(0.89)C(1.11) is very similar, but with a lower P content. Red single crystals of LiB(12)P(1.13)C(0.87) have a larger unit cell with a=10.4097(18) Å, b=5.9029(7) Å, c=8.2044(12) Å. EDX measurements confirm that the red crystals contain more phosphorus than the other ones. The crystal structure is characterized by a covalent network of B(12) icosahedra connected by exohedral B-B bonds and P-P, P-C or C-C units. Li atoms are located in interstitials. The structure is closely related to MgB(7), LiB(13)C(2) and ScB(13)C. LiB(12)PC fulfils the electron counting rules of Wade and also Longuet-Higgins. Measurements of Vickers micro-hardness (H(V)=27 GPa) revealed that LiB(12)PC is a hard material. The optical band gaps obtained from UV/Vis spectra match the colours of the crystals. Furthermore we report on the IR and Raman spectra.

Cost-effectiveness analysis of a single-inhaler triple therapy for COPD in the UK.

UK management costs for COPD, estimated at £1.9 billion/year, are rising. In the FULFIL (Lung Function and Quality of Life Assessment in Chronic Obstructive Pulmonary Disease with Closed Triple Therapy) study, single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (100/62.5/25 µg) improved clinical outcomes versus budesonide/formoterol (400/12 µg) in patients with symptomatic COPD at risk of exacerbations. We assessed the cost-effectiveness of fluticasone furoate/umeclidinium/vilanterol versus budesonide/formoterol for treating COPD from a UK National Health Service perspective. A model was developed combining a trial-based and Markov component and populated with baseline and treatment effect data from FULFIL, together with UK healthcare resource costs and disease-related utilities. Costs per life year and per quality-adjusted life year gained (costing year 2017) for fluticasone furoate/umeclidinium/vilanterol versus budesonide/formoterol were calculated for a lifetime horizon. Results were explored using deterministic sensitivity, scenario and probabilistic analyses. Fluticasone furoate/umeclidinium/vilanterol was associated with gains in life years (0.533) and quality-adjusted life years (0.506) versus budesonide/formoterol, but at slightly increased total costs (£26 416 versus £25 860). This translated to incremental cost-effectiveness ratios of £1042/life year and £1098/quality-adjusted life year for fluticasone furoate/umeclidinium/vilanterol versus budesonide/formoterol. In scenario analyses, incremental cost-effectiveness ratios ranged from dominant to £1547/quality-adjusted life year gained. Fluticasone furoate/umeclidinium/vilanterol provides a cost-effective treatment option versus budesonide/formoterol for patients with symptomatic COPD in the UK.

Treatment Preferences of Patients with Chronic Obstructive Pulmonary Disease: Results from Qualitative Interviews and Focus Groups in the United Kingdom, United States, and Germany.

BACKGROUND: A wide range of therapeutic regimens, including single-inhaler triple therapies (SITTs), are now available for the maintenance treatment of chronic obstructive pulmonary disease (COPD). Thus, an improved understanding of patient preferences may be valuable to inform physician prescribing decisions. This study was performed to assess the factors considered by patients when making decisions about their COPD treatments using qualitative techniques. METHODS: In the United Kingdom, United States and Germany, individual qualitative interviews (n=10 per country) and focus groups (1 per country; [United Kingdom, n=4; United States, n=6; Germany, n=6 participants]) were conducted. Interviews and focus groups were semi­structured, lasting approximately 60 minutes, and focused on treatment preferences. Data were analyzed according to emerging themes identified from the interviews; qualitative thematic analysis of the data was performed using specialist software. RESULTS: In interviews and focus groups, efficacy, ease of use, and lower frequency of use were favored attributes for current treatment, while side effects, medication taste, and more complex administration techniques were key dislikes. In interviews, most participants would consider a switch in medication, mainly for improved efficacy, but also to reduce medication frequency or following physician advice. Overall, efficacy and ease of use were the 2 most important attributes reported in interviews in all 3 countries. CONCLUSION: Patients with COPD have preferences for certain attributes of medication, highlighting the multi-faceted nature of treatment effectiveness and the importance of the delivery device.These results were subsequently used to inform the design of a discrete choice experiment.

Synthesis, crystal structure, and properties of Mg(x)B50C8 or Mg(x)(B12)4(CBC)2(C2)2 (x = 2.4-4).

Single crystals of a new magnesium boride carbide Mg(x)B(50)C(8) (x = 2.4-4) were synthesized from the elements in a metallic melt using tantalum ampules. Crystals were characterized by single crystal X-ray diffraction and electron microprobe analysis. The variation of the Mg content results from different reaction conditions. The composition Mg(∼3)B(50)C(8) is by far the most favored. It fulfills the electron counting rules of Wade and Longuet-Higgins and thus explains the light-green to yellow transparent color. The structure of Mg(∼3)B(50)C(8) (C2/m, Z = 1, a = 8.9384(12) Å, b = 5.6514(9) Å, c = 9.6021(13) Å, ß = 105.86(1)°) consists of B(12) icosahedra. The icosahedra are interconnected by four exohedral B-B bonds to layers. The layers are connected to a three-dimensional covalent network by C(2) and CBC units and further exohedral B-B bonds. The Mg sites are partially occupied. Different site occupation factors cause the various compositions and colors (Mg(2.4)B(50)C(8), brown; Mg(4)B(50)C(8), black). The vibrational spectra show the modes of B(12) icosahedra and C(2) and CBC units as well. Measurements of the microhardness according to Vickers and Knoop revealed remarkably high values of H(V) = 3286 (32.0 GPa) and H(K) = 3165 (31.5 GPa), which exceed the values of B(4)C. Optical spectra reveal a band gap of 2.7 eV for Mg(∼3)B(50)C(8), in agreement to the observed color. This justifies an ionic description, and the formula can be written as (Mg(2+))(3)(B(12)(2-))(4)(CBC(+))(2)(C(2))(2).

Binary boron-rich borides of magnesium: single-crystal investigations and properties of MgB(7) and the new boride Mg(∼5)B(44).

Single crystals of dark-red MgB(7) were grown from the elements in a Cu-melt. The crystal structure (Pearson symbol oI64; space group Imma; a = 10.478(2) Å, b = 5.977(1) Å, c = 8.125(2) Å, 2842 reflns, 48 params, R(1)(F) = 0.018, R(2)(I) = 0.034) consists of a hexagonal-primitive packing of B(12)-icosahedra and B(2)-units in trigonal-prismatic voids. According to the UV-vis spectra and band structure calculations MgB(7) is semiconducting with an optical gap of 1.9 eV. The long B-B distance of 2.278 Å within the B(2)-unit can be seen as a weak bonding interaction. The new Mg(∼5)B(44) occurs beside the well-known MgB(12) as a byproduct. Small fragments of the black crystals are dark-yellow and transparent. The crystal structure (Pearson symbol tP196, space group P4(1)2(1)2, a = 10.380(2) Å, c = 14.391(3) Å, 4080 reflns, 251 params, R(1)(F) = 0.025, R(2)(I) = 0.037) is closely related to tetragonal boron-II (t-B(192)). It consists of B(12)-icosahedra and B(19+1)-units. With a charge of -6 for the B(19+1)-units and a Mg-content of ∼20 Mg-atoms per unit cell the observed Mg content in Mg(∼5)B(44) is quite close to the expected value derived from simple electron counting rules. All compositions were confirmed by EDXS. The microhardness was measured on single crystals for MgB(7) (H(V) = 2125, H(K) = 2004) and MgB(12) (H(V) = 2360, H(K) = 2459).

Synthesis, structure, bonding, and properties of Sc(3)Al(3)O(5)C(2) and ScAl(2)ONC-unique compounds with ordered distribution of anions and cations.

Single crystals of the new compounds Sc(3)Al(3)O(5)C(2) and ScAl(2)ONC were obtained by reacting Sc(2)O(3) and C in an Al-melt at 1550 degrees C. Their crystal structures continue the row of transition metal oxide carbides with an ordered distribution of anions and cations with ScAlOC as the first representative. In the structure of Sc(3)Al(3)O(5)C(2) (P6(3)/mmc, Z = 2, a = 3.2399(8) A, c = 31.501(11) A, 193 refl., 23 param., R(1)(F) = 0.024, wR(2)(I) = 0.058) the anions form a closest packing with five layers of oxygen separated by two layers of carbon atoms. Sc is placed in octahedral voids and Al in tetrahedral voids thus forming layers of AlOC(3) tetrahedra and ScC(6)- and ScO(6)-octahedra, respectively. Surprisingly the layers of ScO(6) octahedra are connected by an additional layer of undistorted trigonal bipyramids AlO(5). The structure of ScAl(2)ONC (space group R3m, Z = 3, a = 3.2135(8) A, c = 44.636(1) A, 187 refl., 21 param., R(1)(F) = 0.023, wR(2)(F(2)) = 0.043) can directly be derived from the binary nitrides AlN (wurtzite-type) and ScN (rocksalt-type). The anions form a closest packing with alternating double layers of C and O separated by an additional layer of N. Again, Al and Sc occupy tetrahedral and octahedral voids, respectively. All compositions were confirmed by energy dispersive X-ray spectroscopy (EDXS) measurements on single crystals. According to band structure calculations Sc(3)Al(3)O(5)C(2) is electron precise with a band gap of 0.3 eV. Calculations of charges and charge densities reveal that the mainly ionic bonding contains significant covalent contributions, too. As expected Sc and C show higher covalent shares than Al and O. The different coordinations of O, Al, and Sc are clearly represented in the corresponding p and d states.

Cost-Effectiveness Analysis of a Once-Daily Single-Inhaler Triple Therapy for Patients with Chronic Obstructive Pulmonary Disease (COPD) Using the FULFIL Trial: A Spanish Perspective.

Purpose: To evaluate the cost-effectiveness of once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) vs twice-daily budesonide/formoterol (BUD/FOR) in patients with symptomatic chronic obstructive pulmonary disease (COPD) at risk of exacerbations, from the Spanish National Healthcare System perspective. Patients and Methods: The validated GALAXY-COPD model was used to simulate disease progression and predict healthcare costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) over a 3-year time horizon for a Spanish population. Patient characteristics from published literature were supplemented by data from FULFIL (NCT02345161), which compared FF/UMEC/VI vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations. Treatment effects, extrapolated to 3 years, were based on Week 24 results in the FULFIL intent-to-treat population, including change in forced expiratory volume in 1 second, St. George's Respiratory Questionnaire score, and exacerbation rates. Treatment, exacerbations, and COPD management costs (2019€) were informed by Spanish public sources and published literature. A 3% discount rate for costs and benefits was applied. One-way sensitivity and scenario analyses, and probabilistic sensitivity analysis (PSA), were performed. Results: FF/UMEC/VI treatment led to fewer moderate and severe exacerbations (2.126 and 0.306, respectively) vs BUD/FOR (2.608 and 0.515, respectively), with a mean incremental cost of €69 and gain of 0.107 QALYs, which resulted in an ICER of €642 per QALY gained. In sensitivity analyses, the ICER was most sensitive to treatment effect variations in exacerbations and healthcare resource utilization/event costs. Overall, 95% of 1000 PSA simulations resulted in an ICER less than €11,000 per QALY gained for FF/UMEC/VI vs BUD/FOR, confirming robustness of the results. The probability of FF/UMEC/VI being cost-effective vs BUD/FOR was 100% at a willingness-to-pay threshold of €30,000 per QALY gained. Conclusion: At the accepted Spanish ICER threshold of €30,000, FF/UMEC/VI represents a cost-effective treatment option vs BUD/FOR in patients with symptomatic COPD at risk of exacerbations.

Evaluating Patient Preferences of Maintenance Therapy for the Treatment of Chronic Obstructive Pulmonary Disease: A Discrete Choice Experiment in the UK, USA and Germany.

Introduction: With increasing availability of different treatments for chronic obstructive pulmonary disease (COPD), we sought to understand patient preferences for COPD treatment in the UK, USA, and Germany using a discrete choice experiment (DCE). Methods: Qualitative research identified six attributes associated with COPD maintenance treatments: ease of inhaler use, exacerbation frequency, frequency of inhaler use, number of different inhalers used, side effect frequency, and out-of-pocket costs. A DCE using these attributes, with three levels each, was designed and tested through cognitive interviews and piloting. It comprised 18 choice sets, selected using a D-efficient experimental design. Demographics and disease history were collected and the final DCE survey was completed online by participants recruited from panels in the UK, USA and Germany. Responses were analyzed using mixed logit models, with results expressed as odds ratios (ORs). Results: Overall, 450 participants (150 per country) completed the DCE; most (UK and Germany, 97.3%; USA, 98.0%) were included in the final analysis. Based on relative attribute importance, avoidance of side effects was found to be most important (UK: OR 11.65; USA: OR 7.17; Germany: OR 11.45; all p<0.0001), followed by the likelihood of fewer exacerbations (UK: OR 2.22; USA: OR 1.63; Germany: OR 2.54; all p<0.0001) and increased ease of use (UK: OR 1.84; USA: OR 1.84; Germany: OR 1.60; all p<0.0001). Number of inhalers, out-of-pocket costs, and frequency of inhaler use were found to be less important. Preferences were relatively consistent across the three countries. All participants required a reduction in exacerbations to accept more frequent inhaler use or use of more inhalers. Conclusion: When selecting COPD treatment, individuals assigned the highest value to the avoidance of side effects, experiencing fewer exacerbations, and ease of inhaler use. Ensuring that patients' preferences are considered may encourage treatment compliance.

Synthesis, structure, bonding, and properties of the oxide carbide ScAlOC, a new type of compound.

Single crystals of ScAlOC were obtained by reacting Sc(2)O(3) and C in an Al melt at 1600 degrees C. The crystal structure (space group R3m, Z = 6, a = 3.2599(7) A, c = 30.116(9) A, 190 refl., 15 param., R(1)(F) = 0.0212, wR(2)(F(2)) = 0.0397) can directly be derived from the binary nitrides AlN and ScN. ScAlOC represents a new type of compound. It is the first oxide carbide of a transition metal with an ordered distribution of the anions. They form a cubic closest packing with alternating double layers of C and O while Al and Sc occupy tetrahedral and octahedral voids, respectively. The resulting polyhedra are AlC(3)O tetrahedra as well as ScO(6) and ScC(6) octahedra. According to band structure calculations ScAlOC is electron precise with an indirect band gap of 0.6 eV. Calculations of charges and charge densities reveal that the mainly ionic bonding contains significant covalent contributions, too. The black crystals of ScAlOC are very brittle and show a microhardness of 9.0 GPa. Thermal decomposition on air starts at 650 degrees C; in inert atmosphere ScAlOC is stable up to 1300 degrees C at least.

Small-molecule diffusion through polycrystalline triglyceride networks quantified using fluorescence recovery after photobleaching.

Fluorescence recovery after photobleaching (FRAP) has been used to quantify Nile red diffusion through five different triglyceride crystal networks composed of pure peanut oil (PeO), pure chemically interesterified fully hydrogenated palm oil (IHPO), two blends of PeO and IHPO blended in different mass ratios (70:30 and 30:70%, w/w), and pure cocoa butter. Calculated components from FRAP experiments (effective diffusion coefficient (D(eff)) and mobile fraction (Mr)) were correlated with crystal network structural characteristics (crystalline mass fraction and permeability coefficient) and illustrated that D(eff) can be predicted using this tool. Higher-permeability coefficients found for higher fractal dimensions, lower volume fraction of solids, and larger average particle sizes were significantly correlated to higher D(eff).