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Implantable brain machine interfaces for treatment of neurological disorders require on-chip, real-time signal processing of action potentials (spikes). In this work, we present the first spike sorting SoC with integrated neural recording front-end and analog unsupervised classifier. The event-driven, low power spike sorter features a novel hardware-optimized, K-means based algorithm that effectively eliminates duplicate clusters and is implemented using a novel clockless and ADC-less analog architecture. The $1.4\ {\boldsymbol{m}}{{\boldsymbol{m}}^2}$ chip is fabricated in a 180-nm CMOS SOI process. The analog front-end achieves a 3.3 ${\boldsymbol{\mu }}{{{\bf V}}_{{{\bf rms}}}}$ noise floor over the spike bandwidth (400 – 5000 Hz) and consumes 6.42 ${\boldsymbol{\mu }}$ W from a 1.5 V supply. The analog spike sorter consumes 4.35 ${\boldsymbol{\mu }}$ W and achieves 93.2% classification accuracy on a widely used synthetic test dataset. In addition, higher than 93% agreement between the chip classification result and that of a standard spike sorting software is observed using pre-recorded real neural signals. Simulations of the implemented spike sorter show robust performance under process-voltage-temperature variations.

Background Sugammadex binds progesterone with high affinity and may interfere with hormonal contraceptive effectiveness. The clinical, economical, and ethical implications of unintended pregnancy should prompt anesthesiologists to actively consider and manage this pharmacologic interaction. We surveyed anesthesiology providers at our institution about knowledge of this potential adverse drug interaction, how they manage it clinically, and the extent to which they involve patients in shared decision-making regarding choice of neuromuscular blocker antagonist. Methods A survey instrument was distributed to anesthesiology providers at a large, tertiary-care medical center. The survey explored prior experience using neostigmine and sugammadex, knowledge about potential sugammadex interference with hormonal contraception, pre-/postoperative counseling practices, clinical management, and shared decision-making regarding potential use of neostigmine in lieu of sugammadex to avoid this drug-drug interaction. Results Of 259 surveys distributed, 155 were fully completed, and 10 were partially completed. Overall response rate was 60% (residents 85%, student nurse anesthetists 53%, certified registered nurse anesthetists 58%, attendings 48%). All but 1 respondent recognized the potential for sugammadex interference with oral hormonal contraception. Far fewer accurately identified potential interference with hormonal intrauterine devices (44%) and hormonal contraceptive implants (55%). The manufacturer's recommended 7-day duration of alternative contraception was correctly identified by 72% of respondents; others (22%) reported longer durations (range 10-30 days). Most (78% overall) agreed/strongly agreed that potential interference with contraceptive effectiveness should be discussed with patients preoperatively. Despite the majority (86% overall) that endorsed shared decision-making and inviting patient input regarding choice between sugammadex and neostigmine, many respondents reported "rarely/never" having discussed this drug interaction with patients in actual clinical practice, either preoperatively (67%) or postoperatively (80%). Furthermore, most respondents (79%) reported "rarely/never" administering neostigmine to intentionally avoid this drug interaction. Conclusions Two years after designating sugammadex as antagonist of choice, physician and nurse anesthesia providers reported seldom inquiring about contraceptive use among women of childbearing potential and rarely discussing potential risk of contraceptive failure from sugammadex exposure. Most lack accurate knowledge of sugammadex interference with hormonal intrauterine and subcutaneous contraceptive devices. Although most endorse preoperative counseling and support patient autonomy or shared decision-making regarding choice of reversal agent, the same respondents report rarely, if ever, actualizing these positions in clinical practice. These conflicting findings highlight the need for education regarding residual neuromuscular block versus adverse drug interactions, collaboration among providers involved in patient counseling, and intentional mindfulness of reproductive justice when caring for women of childbearing potential.

A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in human immunodeficiency virus (HIV) maintenance therapy. We previously characterized RPV metabolism after oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV after injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect 2 metabolites after intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV, and RPV N-glucuronide. Of the total of 80 individuals, 72 participants exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. In addition, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, four missense variants were detected for CYP3A4 whereas one missense variant and one frameshift variant were detected for CYP3A5. A total of eight missense variants of UGT1A4 were detected, whereas two variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to an overall understanding of metabolism after oral dosing versus injection. ClinicalTrials.gov Identifier: NCT02165202

Background Individuals who are obese in childhood have an elevated risk of disease in adulthood. However, whether childhood adiposity directly impacts intermediate markers of this risk, independently of adult adiposity, is unclear. In this study, we have simultaneously evaluated the effects of childhood and adulthood body size on 123 systemic molecular biomarkers representing multiple metabolic pathways. Methods Two-sample Mendelian randomization (MR) was conducted to estimate the causal effect of childhood body size on a total of 123 nuclear magnetic resonance-based metabolic markers using summary genome-wide association study (GWAS) data from up to 24 925 adults. Multivariable MR was then applied to evaluate the direct effects of childhood body size on these metabolic markers whilst accounting for adult body size. Further MR analyses were undertaken to estimate the potential mediating effects of these circulating metabolites on the risk of coronary artery disease (CAD) in adulthood using a sample of 60 801 cases and 123 504 controls. Results Univariable analyses provided evidence that childhood body size has an effect on 42 of the 123 metabolic markers assessed (based on P Conclusions Our findings suggest that childhood adiposity predominantly exerts its detrimental effect on adult systemic metabolism along a pathway that involves adulthood body size.

PURPOSE Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that targets aminopeptidases and rapidly and selectively releases alkylating agents into tumor cells. The phase II HORIZON trial evaluated the efficacy of melflufen plus dexamethasone in relapsed and refractory multiple myeloma (RRMM), a population with an important unmet medical need. PATIENTS AND METHODS Patients with RRMM refractory to pomalidomide and/or an anti-CD38 monoclonal antibody received melflufen 40 mg intravenously on day 1 of each 28-day cycle plus once weekly oral dexamethasone at a dose of 40 mg (20 mg in patients older than 75 years). The primary end point was overall response rate (partial response or better) assessed by the investigator and confirmed by independent review. Secondary end points included duration of response, progression-free survival, overall survival, and safety. The primary analysis is complete with long-term follow-up ongoing. RESULTS Of 157 patients (median age 65 years; median five prior lines of therapy) enrolled and treated, 119 patients (76%) had triple-class–refractory disease, 55 (35%) had extramedullary disease, and 92 (59%) were refractory to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple-class–refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months. Grade ≥ 3 treatment-emergent adverse events occurred in 96% of patients, most commonly neutropenia (79%), thrombocytopenia (76%), and anemia (43%). Pneumonia (10%) was the most common grade 3/4 nonhematologic event. Thrombocytopenia and bleeding (both grade 3/4 but fully reversible) occurred concomitantly in four patients. GI events, reported in 97 patients (62%), were predominantly grade 1/2 (93%); none were grade 4. CONCLUSION Melflufen plus dexamethasone showed clinically meaningful efficacy and a manageable safety profile in patients with heavily pretreated RRMM, including those with triple-class–refractory and extramedullary disease.

The phase 2 GRIFFIN study of daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) for transplant-eligible, newly diagnosed multiple myeloma included a safety run-in phase followed by a randomized phase. The ongoing randomized phase has met its prespecified primary end point of an improved stringent complete response (sCR) rate after consolidation for D-RVd (reported elsewhere). Final analysis of the safety run-in cohort is reported herein and provides longer follow-up (median, 40.8 months) encompassing daratumumab plus lenalidomide (D-R) maintenance therapy. Patients in the safety run-in cohort (N = 16) received 4 induction cycles (D-RVd), high-dose melphalan supported by autologous stem cell transplant, 2 consolidation cycles (D-RVd), and 24 months of maintenance (D-R). By the end of consolidation, all patients had responded, with a best response of sCR in 9 (56.3%) patients; 8 (50.0%) patients were minimal residual disease (MRD) negative (10‒5 threshold). After maintenance, 15 (93.8%) patients had achieved a best response of sCR, and 13 (81.3%) patients were MRD (10‒5) negative. Estimated 36-month progression-free and overall survival rates were 78.1% and 93.8%, respectively. One death from progressive disease occurred in the patient who did not achieve sCR. Observed safety profiles were consistent with daratumumab and RVd. With >3 years of median follow-up, D-RVd achieved durable responses that deepened with D-R maintenance. This study was registered at www.clinicaltrials.gov as #NCT02874742.

A key assumption of Mendelian randomization (MR) analysis is that there is no association between the genetic variants used as instruments and the outcome other than through the exposure of interest. One way in which this assumption can be violated is through population stratification, which can introduce confounding of the relationship between the genetic variants and the outcome and so induce an association between them. Negative control outcomes are increasingly used to detect unobserved confounding in observational epidemiological studies. Here we consider the use of negative control outcomes in MR studies to detect confounding of the genetic variants and the exposure or outcome. As a negative control outcome in an MR study, we propose the use of phenotypes which are determined before the exposure and outcome but which are likely to be subject to the same confounding as the exposure or outcome of interest. We illustrate our method with a two-sample MR analysis of a preselected set of exposures on self-reported tanning ability and hair colour. Our results show that, of the 33 exposures considered, genome-wide association studies (GWAS) of adiposity and education-related traits are likely to be subject to population stratification that is not controlled for through adjustment, and so any MR study including these traits may be subject to bias that cannot be identified through standard pleiotropy robust methods. Negative control outcomes should therefore be used regularly in MR studies to detect potential population stratification in the data used.

The coronavirus disease 2019 (COVID‐19) pandemic, a viral illness caused by the severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), 1 has produced at the time of this writing nearly 33 million cases of infection, with over a million deaths in 235 countries, 2 causing an unprecedented burden on healthcare systems and a severe global socioeconomic crisis. As the pandemic spreads, knowledge on the disease course, as well as potential risk factors and predictors of severity is increasing daily, and initial data from randomised controlled studies have allowed care providers to refine therapeutic strategies. Nonetheless, mortality is markedly elevated among those presenting with severe disease, long‐term sequelae among survivors are unknown, and vaccine‐based therapies currently remain at early stages of development. Most reported cases are asymptomatic or present with mild symptoms; however, 7–26% of hospitalised patients experience severe disease, often requiring admission to intensive care units (ICUs), with progressive multiple organ dysfunction and high mortality. 3 , 4 , 5 Such differences in clinical outcomes have led physicians to initiate diverse pharmacological therapies at various stages of the disease, generating challenges as to the most appropriate therapeutic choice for COVID‐19. In this context, the use of dexamethasone has significantly reduced mortality rates in critically ill patients requiring supplemental oxygen or mechanical ventilation, 6 and remdesivir has demonstrated clinical benefit in hospitalised patients, but with unknown survival benefit to date 7 ; additional effective treatment options are therefore urgently needed. In an initial attempt to provide a uniform and widely reproducible methodology to guide systematic treatment strategies, a three‐stage classification of COVID‐19 has been proposed. 8 The Stage I or ‘early infection’ occurs at the initial establishment of disease with high viral replication, and commonly presents with a range of complaints that can include mild and often non‐specific influenza‐like signs and symptoms. Stage II is the ‘pulmonary phase’, with preferential viral‐mediated injury of the lung parenchyma and this is characterised by shortness of breath, hypoxia and pulmonary infiltrates with some degree of lung inflammation. Stage III is characterised by an exaggerated host immune‐inflammatory response to the virus, leading to acute respiratory distress syndrome (ARDS) and multi‐organ failure (MOF).

Additional therapeutic options are needed for relapsed and refractory multiple myeloma (RRMM). We present data from a phase 1b, open-label, dose-escalation study (NCT01965353) of 20 patients with RRMM (median age: 63 years [range: 50–77]) and a median of four prior regimens (range: 2–14); 85% had refractory disease (lenalidomide [80%]; bortezomib [75%]; lenalidomide and bortezomib [50%]). Patients received a median of six cycles (range: 1–74) of panobinostat (10 or 15 mg), lenalidomide 15 mg, bortezomib 1 mg/m2, and dexamethasone 20 mg (pano-RVd). Median follow-up was ~14 months. Six dose-limiting toxicities were reported (mostly hematological); maximum tolerated dose of panobinostat (primary endpoint) was 10 mg. Most common adverse events (AEs) were diarrhea (60%) and peripheral neuropathy (60%); all grade 1/2. Grade 3/4 AEs occurred in 80% of patients and included decreased neutrophil (45%), platelet (25%) and white blood cell (25%) counts, anemia (25%) and hypophosphatemia (25%). No treatment-related discontinuations or mortality occurred. In evaluable patients (n = 18), overall response rate was 44%, and clinical benefit rate was 61%. Median duration of response was 9.2 months; progression-free survival was 7.4 months; overall survival was not reached. Pano-RVd proved generally well-tolerated and demonstrated potential to overcome lenalidomide and/or bortezomib resistance.

An intense solar energetic particle (SEP) event was observed on 2021 October 9 by multiple spacecraft distributed near the ecliptic plane at heliocentric radial distances R ≲ 1 au and within a narrow range of heliolongitudes. A stream interaction region (SIR), sequentially observed by Parker Solar Probe (PSP) at R = 0.76 au and 48° east from Earth (ϕ = E48°), STEREO-A (at R = 0.96 au, ϕ = E39°), Solar Orbiter (SolO; at R = 0.68 au, ϕ = E15°), BepiColombo (at R = 0.33 au, ϕ = W02°), and near-Earth spacecraft, regulated the observed intensity-time profiles and the anisotropic character of the SEP event. PSP, STEREO-A, and SolO detected strong anisotropies at the onset of the SEP event, which resulted from the fact that PSP and STEREO-A were in the declining-speed region of the solar wind stream responsible for the SIR and from the passage of a steady magnetic field structure by SolO during the onset of the event. By contrast, the intensity-time profiles observed near Earth displayed a delayed onset at proton energies ≳13 MeV and an accumulation of ≲5 MeV protons between the SIR and the shock driven by the parent coronal mass ejection (CME). Even though BepiColombo, STEREO-A, and SolO were nominally connected to the same region of the Sun, the intensity-time profiles at BepiColombo resemble those observed near Earth, with the bulk of low-energy ions also confined between the SIR and the CME-driven shock. This event exemplifies the impact that intervening large-scale interplanetary structures, such as corotating SIRs, have in shaping the properties of SEP events., Solar Orbiter is a space mission of international collaboration between ESA and NASA, operated by ESA. The STEREO SECCHI data are produced by a consortium of RAL (UK), NRL (USA), LMSAL (USA), GSFC (USA), MPS (Germany), CSL (Belgium), IOTA (France), and IAS (France). SOHO is a mission of international cooperation between ESA and NASA. The SDO/AIA data are provided by the Joint Science Operations Center (JSOC) Science Data Processing (SDP). Parker Solar Probe was designed, built, and is now operated by the Johns Hopkins University Applied Physics Laboratory as part of NASA's LWS program (contract NNN06AA01C). We thank the German Federal Ministry for Economic Affairs and Energy and the German Space Agency (Deutsches Zentrum für Luft- und Raumfahrt, e.V., (DLR)) for their unwavering support of STEP, EPT, and HET under grants Nos. 50OT0901, 50OT1202, 50OT1702, and 50OT2002. N.W. acknowledges funding from the Research Foundation—Flanders (FWO–Vlaanderen, fellowship No. 1184319N). This project has received funding from the European Union's Horizon 2020 research and innovation programs under grant agreement No. 870405 (EUHFORIA 2.0). These results were also obtained in the framework of the ESA project "Heliospheric modeling techniques" (contract No. 4000133080/20/NL/CRS) and the projects C14/19/089 (C1 project Internal Funds KU Leuven), G.0D07.19N (FWO–Vlaanderen), SIDC Data Exploitation (ESA Prodex-12), and Belspo project B2/191/P1/SWiM. E.P. acknowledges support from NASA's PSP-GI (grant No. 80NSSC22K0349) and O2R (grant No. 80NSSC20K0285) programs. B.S.-C. acknowledges support through UK-STFC Ernest Rutherford Fellowship ST/V004115/1 and STFC grants ST/W00089X/1 and ST/V000209/1. R.G.H. acknowledges the financial support by the Spanish MICIU (project PID2019-104863RB-I00/AEI/10.13039/501100011033). R.V. and N.D. acknowledge funding from the European Union's Horizon 2020 research and innovation program under grant agreement No. 101004159 (SERPENTINE). N.D. also acknowledges support from the Turku Collegium for Science, Medicine and Technology of the University of Turku, Finland. A.A. acknowledges the support by the Spanish Ministerio de Ciencia e Innovación (MICINN) under grant PID2019-105510GB-C31 and through the "Centre of Excellence María de Maeztu 2020-2023" award to the ICCUB (CEX2019-000918-M). D.L. and I.G.R. acknowledge support from NASA Living With a Star (LWS) programs NNH17ZDA001N-LWS and NNH19ZDA001N-LWS, the Goddard Space Flight Center Internal Scientist Funding Model (competitive work package) program, and the Heliophysics Innovation Fund (HIF) program. I.G.R. also acknowledges support from the ACE mission. The data used in this paper can be downloaded from spdf.gsfc.nasa.gov, www.srl.caltech.edu/ACE/ASC/, soar.esac.esa.int/soar/, stereo.gsfc.nasa.gov, gong.nso.edu/data/magmap/, sdo.gsfc.nasa.gov/data/aiahmi/. See also 10.48322/7gr7-1791, 10.48322/97te-0132, 10.48322/wpk2-yq48, and 10.48322/c0zj-xf76. BepiColombo data used in Figures 11 and 12 can be downloaded from 10.25392/leicester.data.19447259.v1.

Background Observational studies have linked childhood obesity with elevated risk of colorectal cancer; however, it is unclear if this association is causal or independent from the effects of obesity in adulthood on colorectal cancer risk. Methods We conducted Mendelian randomization (MR) analyses to investigate potential causal relationships between self-perceived body size (thinner, plumper, or about average) in early life (age 10) and measured body mass index in adulthood (mean age 56.5) with risk of colorectal cancer. The total and independent effects of body size exposures were estimated using univariable and multivariable MR, respectively. Summary data were obtained from a genome-wide association study of 453,169 participants in UK Biobank for body size and from a genome-wide association study meta-analysis of three colorectal cancer consortia of 125,478 participants. Results Genetically predicted early life body size was estimated to increase odds of colorectal cancer (odds ratio [OR] per category change: 1.12, 95% confidence interval [CI]: 0.98–1.27), with stronger results for colon cancer (OR: 1.16, 95% CI: 1.00–1.35), and distal colon cancer (OR: 1.25, 95% CI: 1.04–1.51). After accounting for adult body size using multivariable MR, effect estimates for early life body size were attenuated towards the null for colorectal cancer (OR: 0.97, 95% CI: 0.77–1.22) and colon cancer (OR: 0.97, 95% CI: 0.76–1.25), while the estimate for distal colon cancer was of similar magnitude but more imprecise (OR: 1.27, 95% CI: 0.90–1.77). Genetically predicted adult life body size was estimated to increase odds of colorectal (OR: 1.27, 95% CI: 1.03, 1.57), colon (OR: 1.32, 95% CI: 1.05, 1.67), and proximal colon (OR: 1.57, 95% CI: 1.21, 2.05). Conclusions Our findings suggest that the positive association between early life body size and colorectal cancer risk is likely due to large body size retainment into adulthood.

A wide variety of new therapeutic options for Multiple Myeloma (MM) have recently become available, extending progression-free and overall survival for patients in meaningful ways. However, these treatments are not curative, and patients eventually relapse, necessitating decisions on the appropriate choice of treatment(s) for the next phase of the disease. Additionally, an important subset of MM patients will prove to be refractory to the majority of the available treatments, requiring selection of effective therapies from the remaining options. Immunomodulatory agents (IMiDs), proteasome inhibitors, monoclonal antibodies, and alkylating agents are the major classes of MM therapies, with several options in each class. Patients who are refractory to one agent in a class may be responsive to a related compound or to a drug from a different class. However, rules for selection of alternative treatments in these situations are somewhat empirical and later phase clinical trials to inform those choices are ongoing. To address these issues the NCI Multiple Myeloma Steering Committee formed a relapsed/refractory working group to review optimal treatment choices, timing, and sequencing and provide recommendations. Additional issues considered include the role of salvage autologous stem cell transplantation, risk stratification, targeted approaches for genetic subsets of MM, appropriate clinical trial endpoints, and promising investigational agents. This report summarizes the deliberations of the working group and suggests potential avenues of research to improve the precision, timing, and durability of treatments for Myeloma.

Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM).This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed.Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study - currently under discussion with regulatory agencies in the United States and Europe - are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide-drug conjugate platform in relapsed/refractory MM.

ObjectivesMultimorbidity, typically defined as having two or more long-term health conditions, is a common patient characteristic that is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity may help with the design and prioritisation of interventions to prevent multimorbidity. This study examined potential causal determinants (education, BMI, smoking and alcohol consumption) of multimorbidity, and assessed the extent to which BMI, smoking and alcohol consumption explain observed educational inequalities in multimorbidity.DesignMendelian randomization study; an approach that uses genetic variants as instrumental variables to interrogate causality.Participants181,214 females and 155,677 males, mean ages 56.7 and 57.1 years respectively, from UK Biobank.Main outcome measuresMultimorbidity status (2+ self-reported health conditions); secondary analyses considered complex multimorbidity defined as 3+ or 4+ conditions, and a continuous multimorbidity score.ResultsMendelian randomization suggests that lower education, higher BMI and higher levels of smoking causally increase the risk of multimorbidity. For example, one standard deviation (equivalent to 5.1 years) increase in years of education decreases the risk of multimorbidity by 9.0% (95% CI: 6.5 to 11.4%). A 5 kg/m2 increase in BMI is associated with a 9.2% increased risk of multimorbidity (95% CI: 8.1 to 10.3%) and a one SD higher lifetime smoking index is associated with a 6.8% increased risk of multimorbidity (95% CI: 3.3 to 10.4%). Evidence for a causal effect of alcohol consumption on multimorbidity was less strong; an increase of 5 units of alcohol per week increases the risk of multimorbidity (2+ conditions) by 1.3% (95% CI: 0.2 to 2.5%). The proportions of the association between education and multimorbidity explained by BMI and smoking are 20.4% and 17.6% respectively. Collectively, BMI and smoking account for 31.8% of the educational inequality in multimorbidity.ConclusionsEducation, BMI, smoking and alcohol consumption are intervenable risk factors that our results suggest have a causal effect on multimorbidity. Furthermore, BMI and lifetime smoking make a considerable contribution to the generation of educational inequalities in multimorbidity. Public health interventions that improve population-wide levels of these risk factors are likely to reduce multimorbidity and inequalities in its occurrence.SUMMARY BOXSECTION 1: WHAT IS ALREADY KNOWN ON THIS TOPIC-Multimorbidity has several known lifestyle and anthropometric risk factors and is associated with deprivation.-The effect of education (proxying deprivation) on multimorbidity is likely mediated by some of these intervenable risk factors.-These associations are likely to be confounded and their causality is not well understood.SECTION 2: WHAT THIS STUDY ADDS-Analyses using genetically predicted effects suggest that education, BMI, smoking and alcohol consumption each have a causal effect on multimorbidity and that 32% of the educational inequality in multimorbidity is attributable to BMI and smoking combined.

Orthostatic hypotension (OH) is a well-recognized phenomenon occurring in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT), and is associated with significant morbidity and mortality. A retrospective analysis of patients admitted for first ASCT between June 2012 and April 2014 found that 161/222 (73%) patients were diagnosed with OH during the course of ASCT, including 51 patients who were found to have OH on the day of first orthostatic vitals check. Excluding these 51 patients, 110/171 (64%) patients developed OH during the peri-transplant period, at a median of 7 days post ASCT (95% CI: 6.5–8.5). OH did not significantly impact length of hospitalization, progression free and overall survival. Multivariable analysis revealed four risk factors (i.e. ≥0.5% weight loss/day, white race, gabapentin, antihypertensives) and two protective factors (i.e. antihistamine, proton pump inhibitor) associated with the development of peri-transplant OH.

BACKGROUND: In patients with newly diagnosed multiple myeloma, the effect of adding autologous stem-cell transplantation (ASCT) to triplet therapy (lenalidomide, bortezomib, and dexamethasone [RVD]), followed by lenalidomide maintenance therapy until disease progression, is unknown. METHODS: In this phase 3 trial, adults (18 to 65 years of age) with symptomatic myeloma received one cycle of RVD. We randomly assigned these patients, in a 1:1 ratio, to receive two additional RVD cycles plus stem-cell mobilization, followed by either five additional RVD cycles (the RVD-alone group) or high-dose melphalan plus ASCT followed by two additional RVD cycles (the transplantation group). Both groups received lenalidomide until disease progression, unacceptable side effects, or both. The primary end point was progression-free survival. RESULTS: Among 357 patients in the RVD-alone group and 365 in the transplantation group, at a median follow-up of 76.0 months, 328 events of disease progression or death occurred; the risk was 53% higher in the RVD-alone group than in the transplantation group (hazard ratio, 1.53; 95% confidence interval [CI], 1.23 to 1.91; P

The Phase 3 ICARIA-MM (NCT02990338) and IKEMA (NCT03275285) studies demonstrated that isatuximab (Isa) plus pomalidomide (P) and dexamethasone (d; Isa-Pd) or carfilzomib (K) and d (Isa-Kd) improved progression-free survival (PFS) versus Pd or Kd in patients with relapsed and/or refractory multiple myeloma. In this post hoc analysis of patients with soft-tissue plasmacytomas, we evaluated Isa-Pd/Isa-Kd efficacy using central radiology and central laboratory assessments. Given the low incidence of soft-tissue plasmacytomas (7.8 %, ICARIA-MM; 6.3 %, IKEMA), efficacy data were pooled across the two studies. PFS (HR, 0.47; 95 % CI, 0.21-1.08), overall response rate (50.0 % vs 17.7 %), and very good partial response or better rate (26.9 % vs 11.8 %) were improved with Isa-Pd/Isa-Kd versus Pd/Kd, with consistent improvements within individual studies. Patients with soft-tissue plasmacytomas who received Isa-Pd/Isa-Kd had similar median PFS compared with those without soft-tissue plasmacytomas and received Pd/Kd. Safety is reported individually per study. Longer median treatment duration and more Grade ≥ 3 treatment-emergent adverse events occurred in the Isa versus control arms in ICARIA-MM (36.9 vs 8.4 weeks; 85.7 % vs 70.0 %) and IKEMA (41.9 vs 29.9 weeks; 100.0 % vs 57.1 %); however, Isa did not increase the percentage of patients with fatal events or drug discontinuation. Isa-Pd or Isa-Kd is a potential new treatment option and partially overcomes the poor prognosis associated with soft-tissue plasmacytomas in relapsed and/or refractory multiple myeloma.

BackgroundVitamin D supplements are widely prescribed to help reduce disease risk. However, this strategy is based on findings using conventional epidemiological methods which are prone to confounding and reverse causation.MethodsIn this short report, we leveraged genetic variants which differentially influence body size during childhood and adulthood within a multivariable Mendelian randomization (MR) framework, allowing us to separate the genetically predicted effects of adiposity at these two timepoints in the lifecourse.ResultsUsing data from the Avon Longitudinal Study of Parents and Children (ALSPAC), there was strong evidence that higher childhood body size has a direct effect on lower vitamin D levels in early life (mean age: 9.9 years, range=8.9 to 11.5 years) after accounting for the effect of the adult body size genetic score (Beta=-0.32, 95% CI=-0.54 to -0.10, P=0.004). Conversely, we found evidence that the effect of childhood body size on vitamin D levels in midlife (mean age: 56.5 years, range=40 to 69 years) is putatively mediated along the causal pathway involving adulthood adiposity (Beta=-0.17, 95% CI=-0.21 to -0.13, P=4.6×10−17).ConclusionsOur findings have important clinical implications in terms of the causal influence of vitamin D deficiency on disease risk. Furthermore, they serve as a compelling proof of concept that the timepoints across the lifecourse at which exposures and outcomes are measured can meaningfully impact overall conclusions drawn by MR studies.

The dark matter halo sparsity, i.e. the ratio between spherical halo masses enclosing two different overdensities, provides a non-parametric proxy of the halo mass distribution which has been shown to be a sensitive probe of the cosmological imprint encoded in the mass profile of haloes hosting galaxy clusters. Mass estimations at several overdensities would allow for multiple sparsity measurements, that can potentially retrieve the entirety of the cosmological information imprinted on the halo profile. Here, we investigate the impact of multiple sparsity measurements on the cosmological model parameter inference. For this purpose, we analyse N-body halo catalogues from the Raygal and M2Csims simulations and evaluate the correlations among six different sparsities from Spherical Overdensity halo masses at $\Delta=200,500,1000$ and $2500$ (in units of the critical density). Remarkably, sparsities associated to distinct halo mass shells are not highly correlated. This is not the case for sparsities obtained using halo masses estimated from the Navarro-Frenk-White (NFW) best-fit profile, that artificially correlates different sparsities to order one. This implies that there is additional information in the mass profile beyond the NFW parametrization and that it can be exploited with multiple sparsities. In particular, from a likelihood analysis of synthetic average sparsity data, we show that cosmological parameter constraints significantly improve when increasing the number of sparsity combinations, though the constraints saturate beyond four sparsity estimates. We forecast constraints for the CHEX-MATE cluster sample and find that systematic mass bias errors mildly impact the parameter inference, though more studies are needed in this direction., Comment: 16 pages, 11 figures, novel analyses including marginalisation over baryon systematics, updated to match MNRAS accepted version

Summary Background The introduction of immunomodulatory agents, proteasome inhibitors, and autologous haematopoietic stem-cell transplantation has improved outcomes for patients with multiple myeloma, but patients with high-risk multiple myeloma have a poor long-term prognosis. We aimed to address optimal treatment for these patients. Methods SWOG-1211 is a randomised phase 2 trial comparing eight cycles of lenalidomide (25 mg orally on days 1–14 every 21 days), bortezomib (1·3 mg/m2 subcutaneously on days 1, 4, 8, and 11 every 21 days), and dexamethasone (20 mg orally on days 1, 2, 4, 5, 8, 9, 11, and 12 every 21 days; RVd) induction followed by dose-attenuated RVd maintenance (bortezomib 1 mg/m2 subcutaneously on days 1, 8, and 15; lenalidomide 15 mg orally on days 1–21; dexamethasone 12 mg orally on days 1, 18, and 15 every 28 days) until disease progression with or without elotuzumab (10 mg/kg intravenously on days 1, 8, and 15 for cycles 1–2, on days 1 and 11 for cycles 3–8, and on days 1 and 15 during maintenance). Patients were randomly assigned (1:1) to either RVd or RVd-elotuzumab. High-risk multiple myeloma was defined by one of the following: gene expression profiling high risk (GEPhi), t(14;16), t(14;20), del(17p) or amp1q21, primary plasma cell leukaemia and elevated serum lactate dehydrogenase (two times the upper limit of normal or more). The primary endpoint was progression-free survival, and all analyses were done on intention-to-treat basis among eligible patients who were evaluable for response. This study is registered with ClinicalTrials.gov , NCT01668719 . Findings 100 (RVd n=52, RVd-elotuzumab n=48) patients were enrolled between Oct 27, 2013, and May 15, 2016, across 26 cooperative group institutions in the USA. Median age was 64 years (IQR 57–70, range 36–85). 74 (75%) of 99 had International Staging System stage II or stage III disease, 47 (47%) of 99 had amp1q21, 37 (37%) of 100 had del17p, 11 (11%) of 100 had t(14;16), eight (9%) of 90 were GEPhi, seven (7%) of 100 had primary plasma cell leukaemia, five (5%) of 100 had t(14;20), four (4%) of 100 had elevated serum lactate dehydrogenase, and 17 (17%) had two or more features. With a median follow-up of 53 months (IQR 46–59), no difference in median progression-free survival was observed (RVd 33·64 months [95% CI 19·55–not reached], RVd-elotuzumab 31·47 months [18·56–53·98]; hazard ratio 0·968 [80% CI 0·697–1·344]; one-sided p=0·45]. 37 (71%) of 52 patients in the RVd group and 37 (77%) of 48 in the RVd-elotuzumab group had grade 3 or worse adverse events. No significant differences in the safety profile were observed, although some notable results included grade 3–5 infections (four [8%] of 52 in the RVd group, eight [17%] of 48 in the RVd-elotuzumab group), sensory neuropathy (four [8%] of 52 in the RVd group, six [13%] of 48 in the RVd-elotuzumab group), and motor neuropathy (one [2%] of 52 in the RVd group, four [8%] of 48 in the RVd-elotuzumab group). There were no treatment-related deaths in the RVd group and one death in the RVd-elotuzumab group for which study treatment was listed as possibly contributing by the investigator. Interpretation In the first randomised study of high-risk multiple myeloma reported to date, the addition of elotuzumab to RVd induction and maintenance did not improve patient outcomes. However, progression-free survival in both study groups exceeded the original statistical assumptions and supports the role for continuous proteasome inhibitors and immunomodulatory drug combination maintenance therapy for this patient population. Funding National Institutes of Health, National Cancer Institute, Bristol Myers Squibb, Celgene, Leukemia and Lymphoma Society.

Summary Background Improved therapeutic options are needed for patients with relapsed or relapsed and refractory multiple myeloma. Subcutaneous bortezomib has replaced intravenous bortezomib as it is associated with a more favourable toxicity profile. We investigated the activity and safety of three different dosing regimens of oral panobinostat in combination with subcutaneous bortezomib and oral dexamethasone for this indication. Methods PANORAMA 3 is an open-label, randomised, phase 2 study being done at 71 sites (hospitals and medical centres) across 21 countries. Patients aged 18 years or older with relapsed or relapsed and refractory multiple myeloma (as per International Myeloma Working Group 2014 criteria), who had received one to four previous lines of therapy (including an immunomodulatory agent), and had an Eastern Cooperative Oncology Group performance status of 2 or lower, were randomly assigned (1:1:1) to receive oral panobinostat 20 mg three times weekly, 20 mg twice weekly, or 10 mg three times weekly, plus subcutaneous bortezomib and oral dexamethasone. All study drugs were administered in 21-day cycles. Randomisation was done by an interactive response technology provider, and stratified by number of previous treatment lines and age. The primary endpoint was overall response rate after up to eight treatment cycles (analysed in all randomly assigned patients by intention to treat). Safety analyses included all patients who received at least one dose of any study drug. No statistical comparisons between groups were planned. This trial is ongoing and registered with ClinicalTrials.gov , NCT02654990 . Findings Between April 27, 2016, and Jan 17, 2019, 248 patients were randomly assigned (82 to panobinostat 20 mg three times weekly, 83 to panobinostat 20 mg twice weekly, and 83 to 10 mg panobinostat three times weekly). Median duration of follow-up across all treatment groups was 14·7 months (IQR 7·8–24·1). The overall response rate after up to eight treatment cycles was 62·2% (95% CI 50·8–72·7; 51 of 82 patients) for the 20 mg three times weekly group, 65·1% (53·8–75·2; 54 of 83 patients) for the 20 mg twice weekly group, and 50·6% (39·4–61·8; 42 of 83 patients) for the 10 mg three times weekly group. Grade 3–4 adverse events occurred in 71 (91%) of 78 patients in the 20 mg three times weekly group, 69 (83%) of 83 patients in the 20 mg twice weekly group, and 60 (75%) of 80 patients in the 10 mg three times weekly group; the most common (≥20% patients in any group) grade 3–4 adverse events were thrombocytopenia (33 [42%] of 78, 26 [31%] of 83, and 19 [24%] of 83 patients) and neutropenia (18 [23%], 13 [16%], and six [8%]). Serious adverse events occurred in 42 (54%) of 78 patients in the 20 mg three times weekly group, 40 (48%) of 83 patients in the 20 mg twice weekly group, and 35 (44%) of 83 patients in the 10 mg three times weekly group; the most common serious adverse event (≥10% patients in any group) was pneumonia (nine [12%] of 78, ten [12%] of 83, and nine [11%] of 80 patients). There were 14 deaths during the study (five [6%] of 78 patients in the 20 mg three times weekly group, three [4%] of 83 in the 20 mg twice weekly group, and six [8%] of 80 in the 10 mg three times weekly group); none of these deaths was deemed treatment related. Interpretation The safety profile of panobinostat 20 mg three times weekly was more favourable than in previous trials of this regimen with intravenous bortezomib, suggesting that subcutaneous bortezomib improves the tolerability of the panobinostat plus bortezomib plus dexamethasone regimen. The overall response rate was highest in the 20 mg three times weekly and 20 mg twice weekly groups, with 10 mg three times weekly best tolerated. Funding Novartis Pharmaceuticals and Secura Bio.

Herein the solid state structure and crystalline orbital hierarchy of a new extended-ligand platinum(II) bis(1,2-dioximato) complex is evaluated. The lack of direct stacking of Pt centres in the solid state, caused by the steric bulk on the exterior of the ligand, results in highly localised frontier bands, and thus minimal band gap compression upon the application of pressure. This is in contrast to its parent complex [Pt(bqd)2] which undergoes a semiconductor-to-metal transition by 1 GPa.

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.

High-pressure studies have been performed on the e-form of the powerful explosive CL-20. Hydrostatic compression over the pressure range 0–12 GPa has been monitored using synchrotron X-ray powder d...

In this phase 2 multicenter study, we evaluated the incorporation of autologous stem cell transplantation (ASCT) into a carfilzomib-lenalidomide-dexamethasone (KRd) regimen for patients with newly diagnosed multiple myeloma (NDMM). Transplant-eligible patients with NDMM received 4 cycles of KRd induction, ASCT, 4 cycles of KRd consolidation, and 10 cycles of KRd maintenance. The primary end point was rate of stringent complete response (sCR) after 8 cycles of KRd with a predefined threshold of ≥50% to support further study. Seventy-six patients were enrolled with a median age of 59 years (range, 40-76 years), and 35.5% had high-risk cytogenetics. The primary end point was met, with an sCR rate of 60% after 8 cycles. Depth of response improved over time. On intent-to-treat (ITT), the sCR rate reached 76%. The rate of minimal residual disease (MRD) negativity using modified ITT was 70% according to next-generation sequencing (

OBJECTIVE Vietnam, Indonesia, and Ukraine have major burdens of IDU and HIV. We estimated the prevalence of depressive symptoms at baseline among people living with HIV who inject drugs, evaluated associations between depression at baseline and 12-month HIV care outcomes and medication-assisted treatment (MAT), and evaluated the study intervention effect by baseline depression subgroups. DESIGN HPTN 074 was a randomized study. The study intervention included psychosocial counseling, systems navigation, and antiretroviral treatment (ART) at any CD4+ cell count. METHODS Moderate-to-severe depression was defined as a Patient Health Questionnaire-9 score of 10 or above. ART and MAT were self-reported. Eligibility criteria were: 18-60 years of age, active IDU, and viral load of at least 1000 copies/ml. Adjusted probability differences (aPD) were estimated using inverse-probability weighting. RESULTS A total of 502 participants enrolled from April 2015 to June 2016. Median age was 35 years; 85% identified as men. Prevalence of baseline moderate-to-severe depression was 14% in Vietnam, 14% in Indonesia, and 56% in Ukraine. No evident associations were detected between baseline depression and ART, viral suppression, or MAT at 12-month follow-up. The study intervention improved the proportions of people who inject drugs achieving 12-month viral suppression in both the depressed [intervention 44%; standard of care 24%; estimated aPD = 25% (95% confidence interval: 4.0%, 45%)] and nondepressed subgroups [intervention 38%; standard of care 24%; aPD = 13% (95% confidence interval: 2.0%, 25%)]. CONCLUSION High levels of depressive symptoms were common among people living with HIV who inject drugs in Ukraine but were less common in Vietnam and Indonesia. The study intervention was effective among participants with or without baseline depression symptoms.

Purpose The purpose of this paper is to understand a spontaneous movement of social mobilization and protest known as the yellow vests and their unrelenting demand for increased buying power. Design/methodology/approach A capsule history of France and the universal struggle for a living wage lead to a post-Marxian process of intensified civic action to support the universal aims of well-being and fair play. Findings The yellow vests appear to be assuming the proportions of an unorthodox labor fraternity, a novel pressure network transcending the usual time-and-money quests of integrated trade unions. Research limitations/implications Little attention is paid to the changing nature of employment, work itself and labor competitiveness. These require further research. Originality/value Internal and external factors are identified, combining to explain the lack of discipline and orderly evolution by both animators and demonstrators.

Summary Background Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT). Methods In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1–8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1–14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1–21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing. Findings Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5–23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8–37·8) in the KRd group and 34·4 months (30·1–not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83–1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3–4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [ Interpretation The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs. Funding US National Institutes of Health, National Cancer Institute, and Amgen.

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here, we estimated the effects of 1002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium (LD) is widespread in naive phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes (www.epigraphdb.org/pqtl/). Evaluation of data from historic drug development programmes showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of our approach in identifying and prioritising potential therapeutic targets.

A field study investigated penetration of outdoor ground ultra-low–volume (ULV) aerosol and thermal fog adulticide applications into a dwelling to control the dengue vector Aedes aegypti (L). Four applications of Kontrol 4-4 (4.6% permethrin active ingredient [AI], 4.6% piperonyl butoxide) at the maximum label rate were made at 25–30 m in front of a house at Camp Blanding Joint Training Center, Starke, FL, during summer 2016. The ULV sprayer and thermal fogger nozzles were oriented horizontally, and vehicle travel speeds were 16 and 24 km/h, respectively. All doors and windows of the house were left open. Spray efficacy was assessed using caged female mosquitoes positioned 30 cm above ground, outside and inside of the house. Interior cages were placed in open areas and cryptic sites (i.e., in a closet or cardboard box). A spinner holding 2 rods sized 3 mm × 75 mm was deployed next to each cage (except cryptic sites) to sample droplets and to quantify AI deposition. Thirty minutes after application, cages were removed, slides collected, and mosquitoes transferred to clean cages in the laboratory where mortality was assessed at 24 h posttreatment. The ULV application to the south side of the house produced 100% mortality in outdoor and indoor cages and 24% mortality at cryptic sites. Similarly applied thermal fog resulted in 85% mortality outdoors, 34% indoors, and only 4% in cages at cryptic sites. Application of either method from the west resulted in 19–61% mortality outdoors and 0.5–6.5% indoors. Droplet volume median diameter (Dv0.5) on rods from the ULV application was significantly larger compared with the thermal fogger outdoors, but similar indoors. Outdoors and indoors, the AI deposition from ULV was significantly higher than from thermal fog. Our results show the potential for controlling dengue vectors inside houses with outdoor ground ULV applications in areas where doors and windows are left open for ventilation.

Herein, we report a highly effective protocol for the cross-coupling of (hetero)aryl bromides with fluorinated alcohols using the commercially available precatalyst tBuBrettPhos Pd G3 and Cs2CO3 in toluene. This Pd-catalyzed coupling features a short reaction time, excellent functional group tolerance, and compatibility with electron-rich and -poor (hetero)arenes. The method provides access to 18F-labeled trifluoroethyl ethers by cross-coupling with [18F]trifluoroethanol.

CALGB (Alliance) 100001 was a phase II study evaluating autologous stem cell transplant (ASCT) followed by nonmyeloablative allogeneic stem cell transplant (alloSCT) in patients with multiple myeloma who had received no more than 18 months of prior therapy and had experienced no more than 1 prior progression event. Conditioning for ASCT was with high-dose melphalan (200 mg/m2). The alloSCT reduced-intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2/d i.v. on days -7 through -3) and cyclophosphamide (1 g/m2/d i.v. on days -4 through -3). The primary objective was to determine the 6-month post-alloSCT treatment-related mortality (TRM) rate. Additional objectives included determining the proportion of patients who could complete this tandem ASCT-alloSCT approach in a cooperative group setting, overall response rates, rates of donor chimerism, rates of graft-versus-host disease (GVHD), disease-free survival, and overall survival (OS). Sixty patients were enrolled, of whom 57 (95%) completed ASCT and 49 (82%) completed tandem ASCT-alloSCT. The TRM rate was 2% (1/49; 90% confidence interval, 0.10% to 9.3%). Moderate to severe (grades 2 to 3) acute GVHD was observed in 13 of 49 alloSCT patients (27%). One patient died due to GVHD within 9 months of alloSCT. Twenty-seven of the 49 patients (55%) who underwent alloSCT reported chronic GVHD as either limited (15/49; 31%) or extensive (12/49; 24%) in the first year post-alloSCT and prior to the start of nonprotocol therapy for progressive disease. With a median follow-up for survival of 11 years, the median OS time is 6.6 years and the median time to disease progression is 3.6 years. Similar to other studies, this study confirmed that tandem ASCT/alloSCT is associated with durable disease control in a subset of patients. This study demonstrated the feasibility of performing tandem ASCT/alloSCT in a cooperative group setting and determined that a fludarabine/cyclophosphamide RIC regimen is associated with a very low TRM rate.

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

Summary Background Long-acting injectable cabotegravir is a novel integrase inhibitor currently in advanced clinical development for HIV prevention and treatment. We aimed to assess the terminal phase pharmacokinetics and safety of long-acting injectable cabotegravir in participants included in the HPTN 077 trial. Methods HPTN 077 was a multicentre, double-blind, randomised, placebo-controlled phase 2a trial done at eight sites in Brazil, Malawi, South Africa, and the USA. Participants (aged 18–65 years), who were HIV-uninfected and at low-risk for HIV, were randomly assigned (3:1) to long-acting injectable cabotegravir (800 mg given three times at 12 week intervals or 600 mg given five times, administered at one 4 week interval, and every 8 weeks thereafter) or placebo. Participants were followed up to 76 weeks after final injection. In a prespecified analysis of secondary and exploratory outcomes, we assessed the safety, measured by the proportion of participants with grade 2 or worse adverse events, and pharmacokinetics, measured by apparent terminal phase half-life (t1/2app) and estimated time to lower limit of quantification (LLOQ) of long-acting injectable cabotegravir during the injection phase (defined as the time between first injection and 12 weeks or 8 weeks after the last injection in cohort 1 or cohort 2 respectively) and tail phase (defined as the time between final injection and 52–76 weeks post-final injection). Safety was analysed in all participants who received at least one injection. Pharmacokinetic analyses included all participants who had received at least one injection and had at least three cabotegravir measurements higher than the LLOQ after the final injection. Pharmacokinetic outcomes were estimated using non-compartmental methods. The trial is completed, and was registered with ClinicalTrials.gov , NCT02178800 . Findings Between Feb 9, 2015, and May 27, 2016, 177 participants (134 participants in the cabotegravir group [74 participants in cohort 1; 60 participants in cohort 2] and 43 participants in the placebo group [25 participants in cohort 1; 18 participants in cohort 2) were enrolled and received at least one injection and thus were included in the safety analysis. The incidence of grade 2 or worse adverse events was significantly lower during the tail phase than the injection phase (p Interpretation The clinical significance of the long pharmacokinetic tail of cabotegravir observed in female participants compared with male participants, and those with higher BMI compared with a lower BMI, need to be addressed in future trials. Funding National Institute of Allergy and Infectious Diseases.

Veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of hematopoietic cell transplantation (HCT) that is traditionally diagnosed using Baltimore or modified Seattle criteria. Whereas the Baltimore criteria require the presence of hyperbilirubinemia (bilirubin ≥2 mg/dL) for a diagnosis of VOD/SOS, the modified Seattle criteria do not. Before approval by the US Food and Drug Administration, defibrotide was available in the United States through an expanded-access study (T-IND). The T-IND protocol initially required post-HCT diagnosis of VOD/SOS by the Baltimore criteria or biopsy but was later amended to include patients diagnosed using the modified Seattle criteria. This post hoc analysis examined the incidence of VOD/SOS with a bilirubin level

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003–2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p, Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.

Objectives Evaluating potential relationships between progression‐free survival (PFS) and tumor gene expression patterns and mutational status was an exploratory objective of the phase 3 TOURMALINE‐MM1 study (NCT01564537) of ixazomib‐lenalidomide‐dexamethasone (IRd) vs placebo‐Rd in 722 patients with relapsed/refractory multiple myeloma (MM). Methods We utilized gene expression and mutation data from screening bone marrow aspirates to identify tumors with non‐canonical nuclear factor‐κB (NF‐κB) signaling pathway activation. Results DNA/RNA sequencing data were available for 339 (47.0%)/399 (55.2%) patients; 49/339 (14.5%) patients had non‐canonical NF‐κB pathway gene mutations (tumor‐necrosis‐factor receptor‐associated factor 2, 3 [TRAF2, TRAF3], baculoviral‐inhibitor‐of‐apoptosis repeat‐containing 2/3 [BIRC2/3]), and PFS was significantly longer with IRd vs placebo‐Rd in these patients (hazard ratio [HR] 0.23). In patients with lower TRAF3 expression (median not reached vs 11 months, HR 0.47) and higher NF‐κB‐inducing kinase (NIK) expression (median not reached vs 14 months, HR 0.45), both associated with non‐canonical NF‐κB pathway activation, PFS was significantly longer with IRd vs placebo‐Rd. TRAF3 expression was decreased in patients harboring t(4;14) and 1q21 amplification, suggesting increased non‐canonical NF‐κB pathway activation. Conclusions Adding ixazomib to Rd provides clinical benefit in MM tumors with increased non‐canonical NF‐κB pathway activity. This is a potential mechanism for activity in 1q21 amplified high‐risk tumors.

In the phase 3 OPTIMISMM trial, pomalidomide, bortezomib and dexamethasone (PVd) significantly improved the progression‐free survival (PFS) and the overall response rate (ORR) vs bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma. All patients were previously treated with lenalidomide (70% refractory to lenalidomide) and had received one to three prior regimens. Here we report the first efficacy and safety analysis of PVd vs Vd in Japanese patients with relapsed or refractory multiple myeloma. Seventeen patients enrolled in the OPTIMISMM trial in Japan. With a median follow‐up of 14.8 months, the median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and the ORR was 100% vs 60.0%, respectively. The safety profile was as expected for PVd. Toxicities were managed with dose reductions and interruptions, and no patients discontinued PVd due to treatment‐emergent adverse events. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients., Here we report the efficacy and safety of PVd vs Vd in 17 patients with relapsed refractory multiple myeloma enrolled in the OPTIMISMM trial in Japan. With a median follow‐up of 14.8 months, median PFS was 17.6 months with PVd (n = 12) vs 4.4 months with Vd (n = 5), and ORR was 100% vs 60.0%, respectively; the safety profile with PVd was as expected. These results are consistent with those in the overall OPTIMISMM patient population and confirm the clinical benefit of PVd in Japanese patients.