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Electronic cigarettes are a popular nicotine consumption product that have risen in popularity as an alternative to cigarettes. However, their recent meteoric rise in market size and various controversies have resulted in the analyses of e-liquid ingredients to be focused on powerful laboratory-based slow methods such as chromatography and mass spectrometry. Here we present a complementary technology based on Raman spectroscopy combined with chemometrics as a fast, inexpensive, and highly portable screening tool to detect and quantify the propylene glycol : glycerol (PG : VG) ratio and nicotine content of e-cigarette liquids. Through this, the PG : VG ratio of 20 out of 23 commercial samples was quantified to within 3% of their stated value, while nicotine was successfully quantified to within 1 mg g−1 for 16 out of 23 samples without the need for accurate knowledge of flavonoid composition. High linearity was also achieved when flavours were kept constant. Finally, the limitations of Raman spectroscopy are discussed, and potential solutions are suggested. [ABSTRACT FROM AUTHOR]

This Commentary for the Research Colloquium on "Geopolitical Imaginaries of Regional Cooperation and National Identity: A Central European Perspective" foregrounds the significance of imagined geographies for driving policies, shaping nations, and making identities. It highlights the urgency of countering the self-aggrandizing, ethno-nationalist, illiberal, reductionist, and conservative imagined geographies that have emerged in recent years across Central Europe, in particular in Hungary. A more critical, pluralistic, and inclusive geopolitics of the region is presented in this Research Colloquium, which is in stark contrast to the attempts of certain political and intellectual elites to fix identities that foment mistrust and division within and between societies. The regional imaginaries espoused by some political leaders, and their tenuous historical and geographical grounding, tell us little about the geographical concepts and areas they purport to represent but much about the insecurities and agendas of the political elites who directly benefit from the uptake of these imaginings. [ABSTRACT FROM AUTHOR]

Background: The primary analysis of the ICARIA-MM study showed significant improvement in progression-free survival with addition of isatuximab to pomalidomide-dexamethasone in relapsed and refractory multiple myeloma. Here, we report a prespecified updated overall survival analysis at 24 months after the primary analysis.Methods: In this randomised, multicentre, open-label, phase 3 study adult patients (aged ≥18 years) with relapsed and refractory multiple myeloma who had received at least two previous lines of therapy, including lenalidomide and a proteasome inhibitor, and had an Eastern Cooperative Oncology Group performance status of 0-2 were recruited from 102 hospitals in 24 countries across Europe, North America, and the Asia-Pacific regions. Patients were excluded if they had anti-CD38 refractory disease or previously received pomalidomide. Patients were randomly assigned (1:1), using an interactive response technology with permuted blocked randomisation (block size of four) and stratified by number of previous treatment lines (2-3 vs >3) and aged (<75 vs ≥75 years), to isatuximab-pomalidomide-dexamethasone (isatuximab group) or pomalidomide-dexamethasone (control group). In the isatuximab group, intravenous isatuximab 10 mg/kg was administered on days 1, 8, 15, and 22 of the first 4-week cycle, and then on days 1 and 15 of subsequent cycles. Both groups received oral pomalidomide 4 mg on days 1-21 of each cycle, and weekly oral or intravenous dexamethasone 40 mg (20 mg if aged ≥75 years) on days 1, 8, 15, and 22 of each cycle. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent. Here' we report a prespecified second interim analysis of overall survival (time from randomisation to any-cause death), a key secondary endpoint, in the intention-to-treat population (ie, all patients who provided informed consent and allocated a randomisation number) at 24 months after the primary analysis. Safety was assessed in all patients who received at least one dose or part dose of study treatment. The prespecified stopping boundary for the overall survival analysis was when the derived p value was equal to or less than 0·0181. This study is registered with ClinicalTrials.gov, NCT02990338, and is active, but not recruiting.Findings: Between Jan 10, 2017, and Feb 2, 2018, 387 patients were screened and 307 randomly assigned to either the isatuximab (n=154) or control group (n=153). Median follow-up at data cutoff (Oct 1, 2020) was 35·3 months (IQR 33·5-37·4). Median overall survival was 24·6 months (95% CI 20·3-31·3) in the isatuximab group and 17·7 months (14·4-26·2) in the control group (hazard ratio 0·76 [95% CI 0·57-1·01]; one-sided log-rank p=0·028, not crossing prespecified stopping boundary). The most common grade 3 or worse treatment-emergent adverse events in the isatuximab group versus the control group were neutropenia (76 [50%] of 152 patients vs 52 [35%] of 149 patients), pneumonia (35 [23%] vs 31 [21%]), and thrombocytopenia (20 [13%] vs 18 [12%]). Serious treatment-emergent adverse events were observed in 111 (73%) patients in the isatuximab group and 90 (60%) patients in the control group. Two (1%) treatment-related deaths occurred in the isatuximab group (one due to sepsis and one due to cerebellar infarction) and two (1%) occurred in the control group (one due to pneumonia and one due to urinary tract infection).Interpretation: Addition of isatuximab plus pomalidomide-dexamethasone resulted in a 6·9-month difference in median overall survival compared with pomalidomide-dexamethasone and is a new standard of care for lenalidomide-refractory and proteasome inhibitor-refractory or relapsed multiple myeloma. Final overall survival analysis follow-up is ongoing.Funding: Sanofi. [ABSTRACT FROM AUTHOR]

Objective: We evaluated the efficacy and safety of pomalidomide, bortezomib, and dexamethasone (PVd) vs bortezomib and dexamethasone (Vd) by age, renal function, and high‐risk cytogenetic abnormalities in lenalidomide‐pretreated patients with multiple myeloma at first relapse. Methods: OPTIMISMM was a phase 3, multicenter, open‐label, randomized study (NCT01734928; N = 559). The primary endpoint was progression‐free survival (PFS). Results: Overall, 226 patients had received one prior line of therapy. PVd significantly prolonged PFS vs Vd in patients aged ≤65 years (median, 22.0 vs 13.1 months; P =.0258) and >65 years (median, 17.6 vs 9.9 months; P =.0369). Median PFS in patients with renal impairment (RI; creatinine clearance <60 mL/min) was 15.1 months with PVd vs 9.5 months with Vd (hazard ratio [HR], 0.67 [95% CI, 0.34‐1.34]). In patients without RI, median PFS was 22.0 vs 13.1 months (HR, 0.45 [95% CI, 0.27‐0.76]). In patients with high‐risk cytogenetics, median PFS was 14.7 vs 9.9 months (HR, 0.39 [95% CI, 0.13‐1.17]). PVd significantly improved overall response rate vs Vd in all subgroups. The safety profile of PVd was consistent with previous reports. Conclusions: These findings confirmed the benefits of PVd at first relapse, including in patients with poor prognostic factors. [ABSTRACT FROM AUTHOR]

We report the formation of a tetranuclear lanthanide cluster, [Yb4(bpzch)2(fod)10] (1), which occurs from a serendipitous ring opening of the functionalised tetrazine bridging ligand, bpztz (3,6‐dipyrazin‐2‐yl‐1,2,4,5‐tetrazine) upon reacting with Yb(fod)3 (fod−=6,6,7,7,8,8,8‐heptafluoro‐2,2‐dimethyl‐3,5‐octandionate). Compound 1 was structurally elucidated via single‐crystal X‐ray crystallography and subsequently magnetically and spectroscopically characterised to analyse its magnetisation dynamics and its luminescence behaviour. Computational studies validate the observed MJ energy levels attained by spectroscopy and provides a clearer picture of the slow relaxation of the magnetisation dynamics and relaxation pathways. These studies demonstrate that 1 acts as a single‐molecule magnet (SMM) under an applied magnetic field in which the relaxation occurs via a combination of Raman, direct, and quantum tunnelling processes, a behaviour further rationalised analysing the luminescent properties. This marks the first lanthanide‐containing molecule that forms by means of an asymmetric tetrazine decomposition. [ABSTRACT FROM AUTHOR]

Alcohol-related brain injury (ARBI) is an unrecognized and therefore untreated consequence of alcohol use disorder. Here, we explore a 12-month period prevalence of alcohol-related brain injury (ARBI) in alcohol use disorder patients. Inpatients aged ≥18 years reviewed by the Alcohol Care Team's Specialist Nurses between April 1, 2017 and March 31, 2018 were eligible for the study (n = 1276). Screening identified a high-risk subset of patients who matched at least one of the following: 1) more than three alcohol-related admissions in one year; 2) two alcohol-related admissions in any given 30-day period; 3) patient or their significant other had concerns regarding cognition. The high-risk patients were assessed for evidence of ARBI using the Montreal Cognitive Assessment Tool (MoCA). The primary measure of interest was MoCA ≤23. Analysis was conducted between subgroups of the study population to identify prevalence rate ratios for matching the high-risk screening criteria, and MoCA ≤23 in high-risk patients. Two hundred and five patients were identified as high risk for ARBI. The period prevalence rates in this high-risk group for patients with a MoCA ≤23 was 36.1%. Those under the age of 35 years were significantly less likely to match the high-risk criteria. Patients that were homeless or staying in hostels were more likely to match the high-risk criteria and were also at increased risk of MoCA ≤23, compared with those living with family members. In summary, ARBI is common in patients with AUD attending acute hospitals. ARBI is often not diagnosed, and thus further work is required to improve screening for, and identification of, these patients to develop evidence-based clinical pathways that optimize care. [ABSTRACT FROM AUTHOR]

Most patients with overt hepatic encephalopathy are managed in an acute hospital setting. The mainstays of treatment are non-absorbable disaccharides, To prevent a recurrence, and thus further hospital admission, the focus is on identifying and avoiding precipitants, optimising nutrition and prescribing medication including rifaximin-α [ABSTRACT FROM AUTHOR]

Most patients with overt hepatic encephalopathy are managed in an acute hospital setting. The mainstays of treatment are non-absorbable disaccharides, To prevent a recurrence, and thus further hospital admission, the focus is on identifying and avoiding precipitants, optimising nutrition and prescribing medication including rifaximin-α [ABSTRACT FROM AUTHOR]

Summary: For patients with untreated hepatic veno‐occlusive disease (VOD)/sinusoidal obstruction syndrome (SOS) with multi‐organ dysfunction (MOD), mortality is >80%. We conducted a pooled analysis of three studies that assessed Day 100 survival in relationship to MOD severity, with dialysis and/or ventilator dependence representing the most severe organ dysfunction. All patients in the analysis were diagnosed using Baltimore criteria/biopsy. This analysis of patients with VOD/SOS and MOD after haematopoietic cell transplantation (HCT; n = 651) demonstrated higher Day 100 survival rates amongst defibrotide‐treated patients with VOD/SOS with less versus more severe forms of MOD. Even patients with severe forms of MOD post‐HCT benefitted from defibrotide. [ABSTRACT FROM AUTHOR]

Though often used as the precursor in energetic materials research and organic synthesis, 3,6-dihydrazinyl-1,2,4,5-tetrazine (dhtz) has not been previously explored in coordination chemistry. Herein, we present the first crystalline coordination compound with dhtz, [Yb2(dhtz)(fod)6] (fod− = 6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanedionate). This compound exhibits Single-Molecule Magnet behaviour under an applied magnetic field, and mJ states were resolved through luminescence studies. [ABSTRACT FROM AUTHOR]

When a dot moves horizontally across a set of tilted lines of alternating orientations, the dot appears to be moving up and down along its trajectory. This perceptual phenomenon, known as the slalom illusion, reveals a mismatch between the veridical motion signals and the subjective percept of the motion trajectory, which has not been comprehensively explained. In the present study, we investigated the empirical boundaries of the slalom illusion using psychophysical methods. The phenomenon was found to occur both under conditions of smooth pursuit eye movements and constant fixation, and to be consistently amplified by intermittently occluding the dot trajectory. When the motion direction of the dot was not constant, however, the stimulus display did not elicit the expected illusory percept. These findings confirm that a local bias towards perpendicularity at the intersection points between the dot trajectory and the tilted lines cause the illusion, but also highlight that higher-level cortical processes are involved in interpreting and amplifying the biased local motion signals into a global illusion of trajectory perception. [ABSTRACT FROM AUTHOR]

Background: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma.Methods: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338.Findings: Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).Interpretation: The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor.Funding: Sanofi. VIDEO ABSTRACT. [ABSTRACT FROM AUTHOR]

This article explores one of the most pressing and challenging issues of our time—the disjuncture between populist images of absolute sovereignty and its practical, functional, and material operation. It seeks to connect postmodern conceptualizations of sovereignty to the challenges shaping national and global politics. Drawing on the work of Jean Baudrillard, it highlights the ways in which the operation of sovereignty has become conflated and confused with imaginaries of sovereignty. Through Baudrillard's lens of the hyperreal, sovereignty can be seen as increasingly functioning beyond a delusionary parody and instead as an unverifiable truth. The sovereignty of the hyperreal, which is explored in the first half of this article, foregrounds a theoretical disconnect between truth and falsehood; the latter half attempts to connect postmodern interpretations of sovereignty with Britain's efforts to exit the European Union and the negotiation of waning U.S. hegemony. Using the two case studies of Brexit and the "America First" presidency of Donald Trump, the article analyzes political speeches and media accounts to explore how the hyperreal provides a logic for decoding populist sociospatial imaginaries of sovereignty, while also anticipating the fallout from an eventual and inevitable realization of loyalty and obedience to an illusion. Key Words: Baudrillard, Brexit, hyperreality, sovereignty, United States. [ABSTRACT FROM AUTHOR]

• Teachers' own goal orientations are strongly associated with their perceptions of how they would act in the classroom. • The relational goal orientation is a strong predictor of how teachers believe they would behave or act in the classroom. • Work-avoidance goal orientation plays a decisive role in teachers' classroom behaviours and actions. Achievement Goal Theory has been adapted as a useful framework for studying teacher motivation in terms of their different goal orientations. This paper reports findings from an Australian study with 257 teachers, that explored their mastery, work-avoidance, and relational goal orientations and four dimensions of self-reported classroom behaviours: expectation, structure, autonomy support, and relatedness. Structural equation modelling underscored the importance of mastery and relational goal orientations as adaptive goal orientations that positively predicted teachers' perceptions about their expectation, structure, and relatedness with students. Interestingly neither of these adaptive goal orientations predicted teachers' self-reported behavior of autonomy support. The only significant predictor was work-avoidance goal orientations, which negatively predicted teachers' discernments of supporting student autonomy. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) diagnostics and therapeutics have improved dramatically over the past two decades, with increased adoption of advanced imaging techniques, improved prognostic risk stratification tools, including fluorescence in situ hybridization (FISH) studies and minimal residual disease (MRD) testing, and the development of highly effective novel agents including next-generation immunomodulatory drugs (IMIDs), proteasome inhibitors (PIs), and monoclonal antibodies (MoABs). Daratumumab-based maintenance strategies are currently under investigation and may be utilized for patients who receive daratumumab as part of induction therapy. As the guidelines correctly emphasize, the role of ASCT in MM remains an integral part of therapy for transplant-eligible patients, based on the improvement in PFS demonstrated in the IFM/DFCI 2009 trial, as well as multiple other studies. However, specific agents or treatment modalities may not be appropriate for certain patients. [Extracted from the article]

Background: As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.Methods: We did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled.Findings: Between Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]).Interpretation: Patients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.Funding: Celgene. [ABSTRACT FROM AUTHOR]

Hillslopes constitute the majority of Earth's land surface area and dominate the supply of sediment to rivers. Hillslope sediment transport is commonly modeled with a rate law that depends on slope and a rate coefficient, D, that is understood to represent the intensity of transport mechanisms. Although many transport mechanisms are related to water and biota, it is unclear whether D varies predictably with climate and life. We compiled previous estimates of D from around the world and also made new estimates for additional sites. The compilation reveals an overall trend in which D increases strongly with increasing moisture among relatively dry sites and less strongly with increasing moisture among relatively wet sites. Vegetation type has a secondary effect on D among drier sites, with D increasing from deserts to grasslands to forests, but not among wetter sites. These trends suggest that the establishment of life in a landscape substantially accelerates soil creep, whereas differences in biological communities among sites with abundant moisture have a relatively small effect on creep. [ABSTRACT FROM AUTHOR]

Here, we applied NMR spectroscopy in combination with chemometrics to quantify the adulteration of fresh coconut water, stretched with water–sugar mixtures. Coconut water was extracted from young Costa Rican coconuts and adulterated with concentrations of various sugar solutions. A total of 45 samples were analysed by 1D proton NMR spectroscopy and chemometrics. Results showed highly sensitive quantification, with a limit of detection of adulteration with sugars of 1.3% and a root-mean-squared error of prediction of 0.58%. Interestingly, we identified a regular drift in the chemical shift and a change in the lineshape of malic acid signals concomitant with increasing levels of adulteration. On further investigation, this was found to originate from changes in the concentration of divalent cations, such as magnesium, within the samples. It can be concluded that 1H NMR spectroscopy enables accurate quantification for the degree of adulteration in this product, with the added discovery finding that the shift and lineshape of the malic acid signal can be utilised as a potential diagnostic marker for partial substitution of fresh coconut water with extrinsic components such as sugar mixtures. [ABSTRACT FROM AUTHOR]

Highlights • Raman spectroscopy was developed for the first time to detect adulteration in coconut water. • Adulteration with water, single sugars, mixtures of sugars and HFCS were investigated. • Spectra showed concentration-based quantification of dilution and masking by adulteration with single sugars. • Small abnormalities in sugar ratios in coconut water could be discerned. • Raman spectroscopy has potential for rapid on-site detection of adulteration in this product. Abstract Here, for the first time, we developed Raman spectroscopy in combination with chemometrics for the quantification of adulteration of fresh coconut water by dilution, and its masking with sugars. Coconut water was extracted from young Costa Rican coconuts and heat treated to emulate pasteurization. Samples were then adulterated by dilution with water and single sugars, mixtures of sugars, and high-fructose corn syrup (HFCS). A total of 155 samples were analysed with Raman spectroscopy at 785 nm excitation and 620 spectra analysed with chemometrics. Results showed successful quantification of dilution and adulteration with single sugars between 1.9 and 2.6%, masking of dilution with mixtures of sugars at 9.8%, and masking of dilution with HFCS at 7.1%. It can be concluded that Raman spectroscopy has significant potential as a rapid accurate analytical method for the detection of adulteration in this product, with the ability to discern small abnormalities in sugar ratios within coconut water. [ABSTRACT FROM AUTHOR]

The structures and properties of several energetic compounds based on a high-nitrogen-content anion, namely 2,3,5,6-tetra (1H-tetrazol-5-yl)pyrazine (H4TTP) are reported here for the first time. These energetic salts were synthesized by reacting H4TTP with various alkali metal hydroxides (sodium, potassium, rubidium, caesium) and N-based (ammonia, hydrazine, hydroxylamine, guanidine carbonate, aminoguanidine bicarbonate). The resulting materials were comprehensively characterized by multinuclear (¹H, 13C) NMR spectroscopy, infrared spectroscopy, elemental analysis, DSC, as well as low-temperature singlecrystal X-ray diffraction. Heats of formation for the metal-free species as well as detonation parameters were calculated. The presented energetic materials (EMs) show high thermal stability (207 °C≤Tdec≤300°C), while the metal-free ionic derivatives exhibit desirable properties such as detonation velocity (6873 m s-1 ≤VC-J≤8364 m s-1), detonation pressure (14.3 GPa≤ pC-J≤24.9 GPa), and specific impulse (141.4≤Isp≤192.5 s). [ABSTRACT FROM AUTHOR]

Two new hexadecanuclear lanthanide complexes employing the 1,5-bis(salicylidene)carbohydrazide (H2bsc) ligand are reported herein. These polynuclear aggregates crystallize in the R3̅ space group, which is unprecedented in a family of lanthanide complexes with such high nuclearity. Magnetic susceptibility measurements reveal weak intramolecular interactions between the magnetic centres, and in the case of compound 2 (DyIII), single-molecule magnet properties are observed. [ABSTRACT FROM AUTHOR]

Although Bandura had proposed that self-efficacy once established is relatively stable, it remains a topic of debate, as empirical evidence has shown different patterns of changes in self-efficacy across different career stages. The current study presents longitudinal data from 74 beginning school teachers in Victoria, Australia to discern changes during their first five years. Their increase in self-efficacy is discussed with reference to existing (primarily cross-sectional) studies, and policy implications for supporting early career teachers. [ABSTRACT FROM AUTHOR]

Summary: Weekly ixazomib with lenalidomide‐dexamethasone (Rd) is feasible and has shown activity in newly diagnosed multiple myeloma (NDMM) patients. This phase 1/2 study (NCT01383928) evaluated the recommended phase 2 dose (RP2D), pharmacokinetics, safety and efficacy of twice‐weekly ixazomib plus Rd in NDMM; 64 patients were enrolled across both phases. Patients received twice‐weekly oral ixazomib 3·0 or 3·7 mg plus lenalidomide 25 mg and dexamethasone 20 mg (10 mg in cycles 9–16) for up to sixteen 21‐day cycles, followed by maintenance with twice‐weekly ixazomib alone. No dose‐limiting toxicities were reported in cycle 1; the RP2D was 3·0 mg based on overall tolerability across multiple cycles. In 62 evaluable patients, the confirmed overall response rate was 94% (68% ≥very good partial response; 24% complete response). Median progression‐free survival was 24·9 months. Responses (median duration 36·9 months for patients receiving the RP2D) deepened during treatment. Grade 3 drug‐related adverse events (AEs) occurred in 64% of patients, including: rash, 13%; peripheral neuropathy, 8%; hyperglycaemia, 8%. There were no grade 4 drug‐related AEs. Thirteen patients discontinued due to AEs. Twice‐weekly ixazomib‐Rd offers substantial activity with promising long‐term outcomes in NDMM patients but may be associated with greater toxicity compared with weekly ixazomib‐Rd in this setting. [ABSTRACT FROM AUTHOR]

Although the results of MM-014 Cohort A strongly and encouragingly suggest that they do, the ongoing phase 2 Alliance study of pomalidomide-dexamethasone with or without ixazomib for patients who are refractory to lenalidomide in the first line (NCT02004275), will hopefully provide further confirmatory evidence to this end (Voorhees I et al i , [8]). In the context of the relevant studies of pomalidomide in multiple myeloma to date, the data collectively suggest that consideration of cytogenetic risk is important for, if not critical to, the informed selection of treatment regimens for patients with relapsed/refractory disease. A phase I/II study of pomalidomide, dexamethasone and ixazomib versus pomalidomide and dexamethasone for patients with multiple myeloma refractory to lenalidomide and proteasome inhibitor-based therapy: phase I results. [Extracted from the article]

Summary: The phase 3 PANORAMA‐1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient‐reported outcomes (PROs) were assessed in PANORAMA‐1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ‐Myeloma module (EORTC QLQ‐MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group‐Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients’ QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed. [ABSTRACT FROM AUTHOR]

Novel therapies with unique new targets are needed for patients who are relapsed/refractory to current treatments for multiple myeloma. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of Bruton tyrosine kinase, which is overexpressed in the myeloma stem cell population. This study examined various doses of ibrutinib ± low-dose dexamethasone in patients who received ≥2 prior lines of therapy, including an immunomodulatory agent. Daily ibrutinib ± weekly dexamethasone 40 mg was assessed in 4 cohorts using a Simon 2-stage design. The primary objective was clinical benefit rate (CBR; ≥minimal response); secondary objectives included safety. Patients (n = 92) received a median of 4 prior regimens. Ibrutinib + dexamethasone produced the highest CBR (28%) in Cohort 4 (840 mg + dexamethasone; n = 43), with median duration of 9·2 months (range, 3·0–14·7). Progression-free survival was 4·6 months (range, 0·4– 17·3). Grade 3–4 haematological adverse events included anaemia (16%), thrombocytopenia (11%), and neutropenia (2%); grade 3–4 non-haematological adverse events included pneumonia (7%), syncope (3%) and urinary tract infection (3%). Ibrutinib + dexamethasone produced notable responses in this heavily pre-treated population. The encouraging efficacy, coupled with the favourable safety and tolerability profile of ibrutinib, supports its further evaluation as part of combination treatment. [ABSTRACT FROM AUTHOR]

This paper draws on the notion of "geopolitical culture" as a conceptual tool for understanding debates over the formulation of foreign policy in contemporary Russia. To draw out the value of this concept, the paper explores the symbolism of territory as a means for restoring Russia's status, respect, and power. However, in contrast to previous studies, it traces the ways in which a concession of territory has been promoted as a device for achieving Russia's great power ambitions. More broadly, the paper seeks to stimulate a wider debate on reconceptualizing the relationship between territory and identity in Russia, at the same time as it places Russia's Far Eastern borderlands at the heart of debates on the spatial imaginaries of the Russian homeland. By drawing on and advancing recent theoretical innovations in critical geopolitics, and recognizing the significance of the discourse of nationalism within these framings, the paper explores the nuanced and multiple story lines that constitute Russia's geopolitical culture. Through this approach, intriguing and complex plot lines and unexpected twists are revealed, which have at times been obscured by nationalist-territorial-revanchist narratives on Putin's Russia. It is suggested that such approaches can also provide insights for interpreting cases and contexts beyond Russia and Eurasia. [ABSTRACT FROM AUTHOR]

CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD381 immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ~30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and highrisk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors. [ABSTRACT FROM AUTHOR]

Ixazomib is the first oral proteasome inhibitor to be approved, in combination with lenalidomide and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was on the basis of results from the phase 3, double-blind, placebo-controlled TOURMALINE-MM1 study, which demonstrated a 35% improvement in progression-free survival with the all-oral combination of ixazomib plus lenalidomide-dexamethasone versus lenalidomide-dexamethasone alone (median: 20.6 vs 14.7 months; hazard ratio: 0.74, p=0.012; median follow-up 14.7 months). The addition of ixazomib to the lenalidomide-dexamethasone regimen was associated with limited additional toxicity and had no adverse impact on patient-reported quality of life. Common grade =3 adverse events with ixazomib include gastrointestinal adverse events, rash, and thrombocytopenia. Here, we review the efficacy, safety, pharmacokinetics, and patient-reported quality of life data seen with ixazomib, and discuss the role of this oral agent in the treatment of patients with relapsed/refractory multiple myeloma, including in patients with high-risk cytogenetic abnormalities and those with multiple prior therapies. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease/sinusoidal obstruction syndrome ( VOD/ SOS) is a progressive, potentially fatal complication of conditioning for haematopoietic stem cell transplant ( HSCT). The VOD/ SOS pathophysiological cascade involves endothelial-cell activation and damage, and a prothrombotic-hypofibrinolytic state. Severe VOD/ SOS (typically characterized by multi-organ dysfunction) may be associated with >80% mortality. Defibrotide is approved for treating severe hepatic VOD/ SOS post- HSCT in the European Union, and for hepatic VOD/ SOS with renal or pulmonary dysfunction post- HSCT in the United States. Previously, defibrotide (25 mg/kg/day in 4 divided doses for a recommended ≥21 days) was available through an expanded-access treatment protocol for patients with VOD/ SOS. Data from this study were examined post-hoc to determine if the timing of defibrotide initiation post- VOD/ SOS diagnosis affected Day +100 survival post- HSCT. Among 573 patients, defibrotide was started on the day of VOD/ SOS diagnosis in approximately 30%, and within 7 days in >90%. The relationship between Day +100 survival and treatment initiation before/after specific days post-diagnosis showed superior survival when treatment was initiated closer to VOD/ SOS diagnosis with a statistically significant trend over time for better outcomes with earlier treatment initiation ( P < 0·001). These results suggest that initiation of defibrotide should not be delayed after diagnosis of VOD/ SOS. [ABSTRACT FROM AUTHOR]

The essays collected in this forum discuss the geopolitical legacy of the Russian Revolution of 1917, one of the most momentous political events of the twentieth century. From a range of different academic disciplines and perspectives, the authors consider how the profound transformations in society and politics were refracted through space and geography, and how enduring these refractions proved to be. The authors focus on three themes that have been dominant in Russian affairs over the past century: 1)the problem of center-periphery relations, 2)the civilizational dynamics of Russia’s self-identification in relation to Europe and to Asia, and 3)the geopolitics of national identity. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease, or sinusoidal obstruction syndrome (VOD/SOS), is a serious and potentially fatal complication of conditioning for hematopoietic stem cell transplantation (HSCT) or of chemotherapy regimens alone. Defibrotide is a complex mixture of single-stranded polydeoxyribonucleotides that is approved in the United States for treating hepatic VOD/SOS with renal or pulmonary dysfunction post-HSCT and in the European Union, Israel, and South Korea for treating severe hepatic VOD/SOS post-HSCT. Defibrotide was previously available in the United States as an investigational drug through a treatment protocol (treatment IND) study. Interim results of that large, treatment IND study of patients with VOD/SOS and with or without multiorgan dysfunction (MOD; also known as multiorgan failure) are presented here. Defibrotide was administered i.v. at 6.25 mg/kg every 6 hours (25 mg/kg/day), with a recommended treatment duration of at least 21 days. Enrolled patients (n = 681) were diagnosed with VOD/SOS based on Baltimore or modified Seattle criteria or liver biopsy analysis. Among the 573 HSCT recipients, 288 (50.3%; 95% confidence interval [CI], 46.2% to 54.4%) were alive at day +100 post-HSCT. Day +100 survival for the pediatric (≤16 years) and adult (>16 years) subgroups was 54.5% (95% CI, 49.1% to 60.0%; n = 174 of 319) and 44.9% (95% CI, 38.8% to 51.0%; n = 114 of 254), respectively. In the MOD subgroup, 159 of 351 patients (45.3%; 95% CI, 40.1% to 50.5%) of patients were alive at day +100 post-HSCT. Treatment with defibrotide was generally well tolerated, and drug-related toxicities were consistent with previous studies. Adverse events were reported in 69.6% of safety-evaluable patients (399 of 573). Other than VOD/SOS and associated MOD symptoms, the most commonly reported treatment-emergent adverse event was hypotension (13.8%). Day +100 survival results observed in this trial were consistent with results seen in previous trials of defibrotide for VOD/SOS in adult and pediatric patients. These data support the potential benefit of defibrotide in treating a VOD/SOS patient population that includes those with and without MOD. [ABSTRACT FROM AUTHOR]

The employment of the tetradentate ligand acenaphthenequinone dioxime (acndH2) for a first time in heterometallic CuII/LnIII (Ln = Gd and Dy) chemistry has afforded the one-dimensional coordination polymers [Cu6Gd2(acnd)6(acndH)6(MeOH)6] n (1) and [Cu6Dy2(acnd)6(acndH)6(MeOH)2] n (2), which consist of repeating {Cu6Ln2} clusters that are intermolecularly linked to each other through the oximate groups of two η²:η¹:η¹:μ3 acnd2- ligands. The [Cu6Ln2(μ3-NO)6(μ-NO)8]4+ core is unprecedented in heterometallic cluster chemistry and comprises two symmetry-related {Cu3Ln} subunits, each with a distorted trigonal pyramidal topology. Magnetic susceptibility studies revealed the presence of predominant ferromagnetic exchange interactions within the {Cu3Ln} subunits and weak antiferromagnetic interactions between them. As a result, the magnetic and magnetocaloric properties of the {Cu6Gd2} n compound could be rationalized in terms of two weakly coupled S = 5 spins that yield a magnetic entropy change of -ΔS m = 11.8 J kg-1 K-1 at T = 1.6 K for μ0ΔH = 7 T. [ABSTRACT FROM AUTHOR]

Deacetylase enzymes remove acetyl groups from histone and nonhistone proteins. Dysregulation of deacetylase activity is a hallmark of malignancy, including multiple myeloma (MM). Deacetylase inhibitors (DACi) cause epigenetic modification and inhibition of the aggresome pathway, resulting in death of MM cells. Panobinostat, a pan-DACi, has shown significant clinical benefit and is the first DACi approved for the treatment of MM. It is approved for use in combination with bortezomib and dexamethasone for the treatment of patients with relapsed or relapsed and refractory MM who have received ≥2 prior regimens including bortezomib and an immunomodulatory drug. Ricolinostat and ACY-241, which selectively inhibit HDAC6 and the aggresome pathway, are currently being studied in combination with dexamethasone and bortezomib or an immunomodulatory drug for the treatment of relapsed and refractory MM. In this review, we discuss the data from key clinical trials investigating deacetylase inhibitors as novel treatment options for MM. [ABSTRACT FROM AUTHOR]

Callous--Unemotional (CU) traits are personality attributes, which are associated with a deficit of affective valence and reduced empathetic responding in high CU trait clinical populations. The aim of the research was to explore whether a similar pattern of empathy and emotional responding correlated with CU trait manifestation in the general population. A total of 124 participants completed the Inventory of Callous- Unemotional Traits, the Interpersonal Reactivity Index, the Empathy Quotient, an expression recognition task, and a measure of affective response. Negative correlations with CU trait score were observed for both cognitive empathy and emotional empathy. Accuracy in the identification of fearful expressions presented a negative association with CU trait score. Self-rating of affective valence, when viewing both positive and negative images, indicated a universal reduction in emotional response associated with increased CU trait manifestation. [ABSTRACT FROM AUTHOR]

Veno-occlusive disease (VOD) is an early and serious complication of hematopoietic cell transplantation (HCT) that is associated with inferior survival, particularly when it is complicated by multiorgan failure (severe VOD). We evaluated the efficacy of defibrotide in the treatment of severe VOD using observational data from the Center for International Blood and Marrow Transplant Research (CIBMTR). Eight thousand three hundred forty-one patients treated by HCT between 2008 and 2011 were identified from the CIBMTR clinical database; 3.2% met criteria for VOD and 1.2% met criteria for severe VOD. Patients with a diagnosis of VOD as reported to the CIBMTR by their transplanting centers, who had no prior history of cirrhosis, and who had a maximum total bilirubin level > 2.0 mg/dL by day +100 post-HCT were selected for study. Severe VOD was defined as VOD occurring in the setting of renal impairment requiring dialysis or any noninfectious pulmonary abnormality. Patients with severe VOD were divided into 2 groups for analysis: those treated with defibrotide (n = 41) and those not treated with defibrotide (n = 55). Patients in the nondefibrotide group were older, were more likely to be male, were more likely to have a history of previous fungal infection, and had a higher proportion of clinically significant pre-existing disease or organ impairment. Survival rate at day +100 was 39% (95% CI, 24.8% to 54.3%) in patients receiving defibrotide and 30.9% (95% CI, 19.5% to 43.6%) in those not receiving defibrotide. Resolution rate of VOD at day +100 was 51% in the defibrotide group and 29% in the nondefibrotide group (difference, 22.1%; 95% CI, 2.6% to 42%). The results of our study are consistent with previously reported experiences with defibrotide, confirm the poor outcome of this syndrome, and suggest defibrotide is effective in the treatment of severe VOD. [ABSTRACT FROM AUTHOR]

Marizomib (MRZ) is a novel, irreversible proteasome inhibitor in clinical development for the treatment of relapsed or relapsed and refractory multiple myeloma (RRMM). MRZ inhibits the 3 proteolytic activities of the 20S proteasome with specificity distinct from bortezomib and carfilzomib. StudyNPI-0052-101 Part 1 enrolled relapsed or RRMMpatients into an open-label, dose-escalation design to determine the maximum tolerated dose and recommended phase 2 dose (RP2D) of MRZ administered intravenously on 2 different schedules: scheduleA (0.025-0.7mg/m2 once weekly on days 1, 8, and 15 of 4-week cycles) and schedule B (0.15-0.6 mg/m2 twice weekly on days 1, 4, 8, and 11 of 3-week cycles; concomitant dexamethasone was allowed with schedule B). Patients had received an average of 4.9 and 7.3 prior treatment regimens (schedules A and B, respectively). MRZ schedule A was administered to 32 patients, and theRP2D was established as 0.7mg/m2 infused over 10 minutes. ScheduleBwas administered to 36 patients, and the RP2D was determined to be 0.5 mg/m2 infused over 2 hours. The most common (>20% of patients) related adverse events were fatigue, headache, nausea, diarrhea, dizziness, and vomiting.Six patients achieved clinical benefit responses (defined as minimal response or better), including 5 partial responses (1 patient on schedule A and 4 on schedule B; 3 of these 4 patients received concomitant dexamethasone). MRZ was generallywell tolerated, and results suggest activity in previously treated RRMM vpatients. Combination studies using pomalidomide and dexamethasone are now underway. The trial was registered at www.clinicaltrials.gov as #NCT00461045. [ABSTRACT FROM AUTHOR]

The case of the disputed Southern Kuril Islands/Northern Territories is used to introduce the term 'hyper-border' in order to examine the instrumental and pragmatic nature of identity. It seeks to capture how, on one of Russia's most isolated borders, the quotidian realities and challenges of life 'beyond' the state had profound implications for how discourses around state, nation, sovereignty and identity are conceived. During the 1990s these islands became a site neither fully within, nor without the state. As the functions of the Russian state diminished and the border with Japan dematerialised, it was the Japanese state that came to provide welfare, infrastructure and economic opportunities for the islanders. This paper attempts to capture how the identity of islanders became articulated not on ethnic, religious or linguistic grounds, but on a purely pragmatic desire for a better life. Among some Kuril islanders an alternative vision of belonging was formulated, which sought to take them beyond the nation and into the state. This paper also traces the counter-function of the hyper-border and how an immense material and discursive response to these circumstances by the Russian state led to the recovery of the meaning of these distant islands. On a site between sovereignty regimes, this idea of the hyper-border attempts to capture how the fluctuating political authority of the state can render identity as contingent, malleable and instrumental. [ABSTRACT FROM AUTHOR]

Hepatic veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS withmulti-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated safety and efficacy of defibrotide in patients with established hepatic VOD/SOS and advanced MOF. Patients (n 5 102) given defibrotide 25 mg/kg per day were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by blinded independent reviewers. Baseline characteristics between groups were well balanced. The primary endpoint was survival at day 1100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25% in the controls (23% estimated difference; 95.1% confidence interval [CI], 5.2-40.8; P 5 .0109, using a propensityadjusted analysis). Observed day 1100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% for controls (19% difference using similar methodology; 95.1% CI, 3.5-34.6; P 5 .0160). Defibrotide was generally well tolerated with manageable toxicity. Related adverse events (AEs) included hemorrhage or hypotension; incidence of common hemorrhagic AEs (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal bleeding [7.8% and 9.4%])was similar between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in day 1100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. [ABSTRACT FROM AUTHOR]

Panobinostat is a potent pan-deacetylase inhibitor that affects the growth and survival of multiple myeloma (MM) cells through alteration of epigenetic mechanisms and protein metabolism. Panobinostat plus bortezomib and dexamethasone (PAN-BTZ-Dex) led to a significant increase in progression-free survival (PFS) vs placebo plus bortezomib and dexamethasone (Pbo-BTZ-Dex) in patients with relapsed or relapsed and refractory MM in the phase 3 PANORAMA 1 trial. This subgroup analysis evaluated outcomes in patients in the PANORAMA 1 trial based on prior treatment: a prior immunomodulatory drug (IMiD; n = 485), prior bortezomib plus an IMiD (n = 193), and ≥2 prior regimens including bortezomib and an IMiD (n = 147). Median PFS with PAN-BTZ-Dex vs Pbo-BTZ-Dex across subgroups was as follows: prior IMiD (12.3 vs 7.4 months; hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.43-0.68), prior bortezomib plus IMiD (10.6 vs 5.8 months; HR, 0.52; 95% CI, 0.36-0.76), and ≥2 prior regimens including bortezomib and an IMiD (12.5 vs 4.7 months; HR, 0.47; 95% CI, 0.31-0.72). Common grade 3/4 adverse events and laboratory abnormalities in patients who received PAN-BTZ-Dex across the prior treatment groups included thrombocytopenia, lymphopenia, neutropenia, diarrhea, and asthenia/fatigue. Incidence of on-treatment deaths among patients who received prior bortezomib and an IMiD (regardless of number of prior regimens) was similar between treatment arms. This analysis demonstrated a clear PFS benefit of 7.8 months with PAN-BTZ-Dex among patients who received ≥2 prior regimens including bortezomib and an IMiD, a population with limited treatment options and poorer prognosis. [ABSTRACT FROM AUTHOR]

Progress in medical research has enhanced our understanding of tumor biology, delineated genetic and molecular mechanisms of tumor growth and survival, and defined the impact of the microenvironment in cancer pathogenesis. As a consequence of these advances, cancers deemed rapidly fatal only a few decades ago can now be treated effectively, with prolonged survival in an increasing proportion of patients. This is particularly true for multiple myeloma (MM), in which the introduction of drugs targeting the tumor in its microenvironment, such as the proteasome inhibitor bortezomib and the immunomodulatory drugs (IMiDs) thalidomide and lenalidomide, into initial, consolidation, maintenance, and salvage therapies has markedly improved patient outcome. In this perspective, we discuss the most promising therapies to even further improve MM treatment, with a focus on drugs inhibiting the ubiquitin-proteasome pathway; histone deacetylase (HDAC) inhibitors (HDACIs); immune therapies including IMiDs, monoclonal antibodies (mAbs), immune checkpoint inhibitors, agents targeting accessory plasmacytoid dendritic cells (pDCs), vaccines, and chimeric antigen receptor-engineered T (CAR-T) cells; drugs targeting tumor cell homing to, and exploiting hypoxia in, the bone marrow (BM) microenvironment; molecularly targeted therapies against kinesin spindle protein (KSP), v-akt murine thymoma viral oncogene homolog 1 (AKT), exportin 1 (XPOl), cyclin-dependent kinases (CDKs), bromodomain and extraterminal (BET) bromodomain 4, and serine/threonine kinase 4 (STK4); as well as delineating the impact of genomics on MM therapy. These advances in understanding the biology of MM will allow for earlier treatment of patients using rationally informed combination therapies with curative potential. [ABSTRACT FROM AUTHOR]

This piece is a very personal tribute to Gordon Graham, as one of those exceptional publishers who managed to combine extremely effective business skills with a love of books and the ideas in them. His professional success at McGraw and Butterworth was highly visible, but his subtler intellectual talents flourished especially after his corporate retirement, notably as the founder and editor of Logos and various associated publications. During this time he also played an exceptional, but little recognized, part in nurturing young publishing talent from around the world. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (ASCT) remains a standard of care for multiple myeloma patients who are eligible to receive high-dose therapy, recognizing that the optimal timing and integration of this approach is now under study in a number of randomized trials. Despite the improved response rates with induction therapy consisting of immunomodulatory drugs and/or proteasome inhibitors, as well as the increasing use of post-ASCT maintenance therapy, most myeloma patients relapse and die of their disease. Here we discuss the options for managing post-ASCT relapse, including the role of various salvage regimens in the setting of relapsed and refractory myeloma, salvage ASCT, and salvage allogeneic SCT. [ABSTRACT FROM AUTHOR]

The article discusses a randomized trial to test the efficacy of prednisolone and pentoxyfylline in treating severe alcoholic hepatitis. It discusses the trial's 2-by-2 factorial design, its primary end point of mortality at 28 days and secondary endpoints of death or liver transplantation at 90 days and at 1 year. It concluded that pentoxyfylline did not improve survival and that prednisolone did not significantly reduce 28-day mortality nor improve outcomes at 90 days or 1 year later.