Well-Being Inequality Among Adolescents and Young Adults.

PURPOSE: This study aimed to examine patterns of well-being across developmental stages and patterns of inequality in well-being among young adults and adolescents. Well-being exists when adolescents and young adults thrive and can achieve their full potential. METHODS: We used individual-level survey data from the Gallup World Poll from 164 countries between 2009 and 2017 (N = 446,934). Regression analyses were used to determine associations. RESULTS: We documented substantial inequality in well-being across three developmental stages (adolescence, early adulthood, young adulthood). Health, education, income, and social relations are strongly associated with mean well-being and well-being inequality. We showed, for mean well-being, the relative importance of these factors varies over life-cycle stages. For inequality, most factors were consistent across developmental groups; however, we identified certain characteristics that were only relevant at certain developmental stages. DISCUSSION: Given the policy importance of well-being at all stages of life and the significance of adolescence and early adulthood in developing positive health-related behaviors, policies and programs targeting the highlighted characteristics are likely to be effective but require a multisectoral approach.

Global evidence of inequality in well-being among older adults.

BACKGROUND: By 2030, the UN expects 1.4 billion older adults and 2.1 billion by 2050. By 2050, 80 percent of older persons will live in developing nations. This demographic shift will present new challenges and opportunities in several areas, including health, migration, employment, and social safety nets. This study's aims were to: (1) present novel evidence on the trends and determinants of well-being and well-being inequality among older people around the world; and (2) highlight variation across World Bank development groups. METHODS: The study utilizes individual-level survey data from nine waves of the Gallup World Poll (2009-2017), which is representative of about 99.5% of the global population. First, we report country-level panel evidence on well-being and well-being inequality for adults over 60 years of age. Second, we estimate regressions to identify the individual-level determinants of well-being and well-being inequality. RESULTS: Our results indicate that average levels of happiness vary little over time. This holds for all World Bank development groups. In contrast, we show that inequality in well-being increases for all categories except in high-income countries. Examining the factors that influence well-being and well-being inequality reveals the particular importance of income, social ties, and health. We also reveal gender differences in global well-being; women tend to be happier than men. Lastly, whereas variations in inequity-causing factors are minimal when comparing older to younger individuals, they vary substantially when comparing across development groups. CONCLUSIONS: Our findings suggest that rather than focusing on the average level of well-being among older people, governments should consider the full distribution of well-being. This requires a special emphasis on health, social networks, and education, as well as the assessment of distributional impacts in policy proposals.

Evaluation of patient-reported outcome measures for on-demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (HAE-C1-INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on-demand treatment of HAE-C1-INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo-controlled, three-way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE-C1-INH. METHODS: To determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation-based approach using phase 2 data. RESULTS: Patient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI-C) over other measures and indicated a rating of "A Little Better" as a clinically meaningful milestone. In phase 2, a rating of "A Little Better" demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than "Better." Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI-C rating of at least "A Little Better" for two time points in a row. CONCLUSIONS: Patient feedback and phase 2 data support PGI-C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on-demand treatment for HAE-C1-INH attacks.

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.

Food insecurity predicts well-being inequality.

The concept of well-being offers researchers an alternative to understanding inequality and poverty primarily through income and consumption, and recent research has emphasized the importance of examining well-being inequality. Food insecurity has been identified as an important driver of average levels of well-being; in this paper, we show it also predicts changes in the distribution of well-being. We use individual-level data from the Gallup World Poll for 135 countries between 2014 and 2017 (N = 446,741) and apply a flexible moments-based approach. We use the estimated conditional variance as a measure of inter-personal inequality in subjective well-being at the individual-level. Findings indicate that higher food insecurity is associated with higher inequality in well-being in middle- and high-income countries, but not in low-income countries. We also find that being severely food insecure correlates with peoples' well-being inequality in every income group. Understanding disparities in peoples' lives offers important, policy-relevant information that cannot be inferred from mean values alone and offers important insights to achieve SDG Goals 2 and 3 for all people.

Distinct adaptation processes underlie multidigit force coordination for dexterous manipulation.

The human sensorimotor system can adapt to various changes in the environmental dynamics by updating motor commands to improve performance after repeated exposure to the same task. However, the characteristics and mechanisms of the adaptation process remain unknown for dexterous manipulation, a unique motor task in which the body physically interacts with the environment with multiple effectors, i.e., digits, in parallel. We addressed this gap by using robotic manipulanda to investigate the changes in the digit force coordination following mechanical perturbation of an object held by tripod grasps. As the participants gradually adapted to lifting the object under perturbations, we quantified two components of digit force coordination. One is the direction-specific manipulation moment that directly counteracts the perturbation, whereas the other one is the direction-independent internal moment that supports the stability and stiffness of the grasp. We found that trial-to-trial improvement of task performance was associated with increased manipulation moment and a gradual decrease of the internal moment. These two moments were characterized by different rates of adaptation. We also examined how these two force coordination components respond to changes in perturbation directions. Importantly, we found that the manipulation moment was sensitive to the extent of repetitive exposure to the previous context that has an opposite perturbation direction, whereas the internal moment did not. However, the internal moment was sensitive to whether the postchange perturbation direction was previously experienced. Our results reveal, for the first time, that two distinct processes underlie the adaptation of multidigit force coordination for dexterous manipulation.NEW & NOTEWORTHY Changes in digit force coordination in multidigit object manipulation were quantified with a novel experimental design in which human participants adapted to mechanical perturbations applied to the object. Our results show that the adaptation of digit force coordination can be characterized by two distinct components that operate at different timescales. We further show that these two components respond to changes in perturbation direction differently.

Pharmacokinetics and Pharmacodynamics of TAK-164 Antibody Drug Conjugate Coadministered with Unconjugated Antibody.

The development of new antibody-drug conjugates (ADCs) has led to the approval of 7 ADCs by the FDA in 4 years. Given the impact of intratumoral distribution on efficacy of these therapeutics, coadministration of unconjugated antibody with ADC has been shown to improve distribution and efficacy of several ADCs in high and moderately expressed tumor target systems by increasing tissue penetration. However, the benefit of coadministration in low expression systems is less clear. TAK-164, an ADC composed of an anti-GCC antibody (5F9) conjugated to a DGN549 payload, has demonstrated heterogeneous distribution and bystander killing. Here, we evaluated the impact of 5F9 coadministration on distribution and efficacy of TAK-164 in a primary human tumor xenograft mouse model. Coadministration was found to improve the distribution of TAK-164 within the tumor, but it had no significant impact (increase or decrease) on efficacy. Experimental and computational evidence indicates that this was not a result of tumor saturation, increased binding to perivascular cells, or compensatory bystander effects. Rather, the cellular potency of DGN549 was matched with the single-cell uptake of TAK-164 making its IC50 close to its equilibrium binding affinity (KD), and as such, coadministration dilutes total DGN549 in cells below the maximum cytotoxic concentration, thereby offsetting an increased number of targeted cells with decreased ability to kill each cell. These results provide new insights on matching payload potency to ADC delivery to help identify when increasing tumor penetration is beneficial for improving ADC efficacy and demonstrate how mechanistic simulations can be leveraged to design clinically effective ADCs.

Radiation and Dust Sensor for Mars Environmental Dynamic Analyzer Onboard M2020 Rover.

The Radiation and Dust Sensor is one of six sensors of the Mars Environmental Dynamics Analyzer onboard the Perseverance rover from the Mars 2020 NASA mission. Its primary goal is to characterize the airbone dust in the Mars atmosphere, inferring its concentration, shape and optical properties. Thanks to its geometry, the sensor will be capable of studying dust-lifting processes with a high temporal resolution and high spatial coverage. Thanks to its multiwavelength design, it will characterize the solar spectrum from Mars' surface. The present work describes the sensor design from the scientific and technical requirements, the qualification processes to demonstrate its endurance on Mars' surface, the calibration activities to demonstrate its performance, and its validation campaign in a representative Mars analog. As a result of this process, we obtained a very compact sensor, fully digital, with a mass below 1 kg and exceptional power consumption and data budget features.

O-GlcNAc transferase regulates glioblastoma acetate metabolism via regulation of CDK5-dependent ACSS2 phosphorylation.

Glioblastomas (GBMs) preferentially generate acetyl-CoA from acetate as a fuel source to promote tumor growth. O-GlcNAcylation has been shown to be elevated by increasing O-GlcNAc transferase (OGT) in many cancers and reduced O-GlcNAcylation can block cancer growth. Here, we identify a novel mechanism whereby OGT regulates acetate-dependent acetyl-CoA and lipid production by regulating phosphorylation of acetyl-CoA synthetase 2 (ACSS2) by cyclin-dependent kinase 5 (CDK5). OGT is required and sufficient for GBM cell growth and regulates acetate conversion to acetyl-CoA and lipids. Elevating O-GlcNAcylation in GBM cells increases phosphorylation of ACSS2 on Ser-267 in a CDK5-dependent manner. Importantly, we show that ACSS2 Ser-267 phosphorylation regulates its stability by reducing polyubiquitination and degradation. ACSS2 Ser-267 is critical for OGT-mediated GBM growth as overexpression of ACSS2 Ser-267 phospho-mimetic rescues growth in vitro and in vivo. Importantly, we show that pharmacologically targeting OGT and CDK5 reduces GBM growth ex vivo. Thus, the OGT/CDK5/ACSS2 pathway may be a way to target altered metabolic dependencies in brain tumors.

KVD900, an oral on-demand treatment for hereditary angioedema: Phase 1 study results.

BACKGROUND: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin. OBJECTIVE: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults. METHODS: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 × 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals. RESULTS: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC0-24) of 18,600 (22.5) h⋅ng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours. CONCLUSION: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves near-complete PKa inhibition and is generally safe and well tolerated. GOV IDENTIFIER: NCT04349800.

Extensor Retinaculum Reconstruction of the Distal Radioulnar Joint in Adolescents.

BACKGROUND: This study characterizes the outcomes and complications of surgical reconstruction of distal radioulnar joint (DRUJ) instability using the extensor retinaculum (Herbert sling). Our hypothesis was that extensor retinaculum reconstruction is a reliable method of DRUJ stabilization in adolescents. METHODS: This was a retrospective study of pediatric patients treated surgically using the Herbert sling for DRUJ instability at a single institution. We identified 22 subjects who underwent surgery at an average of 16.2 years of age (range, 12-18 years). Medical records and available imaging were reviewed for all subjects, and patients were contacted to participate in the prospective completion of the Quick Disabilities of the Arm, Shoulder, and Hand (QuickDASH) questionnaire. RESULTS: Preoperative symptoms were more commonly pain (95%) than feelings of DRUJ instability (45%), although 100% had instability on physical examination. Eight (36%) patients demonstrated limited supination preoperatively. Twenty-one subjects (95%) noted prior injury to that wrist, 15 of which were distal radius fractures. Surgery consisted of stabilization of the DRUJ using extensor retinaculum, in concert with other procedures to address all potential causes of wrist pain. Postoperatively, DRUJ stability was maintained in 21 of 22 subjects. Of the 12 patients who provided functional outcome scores, median QuickDASH score was 7.6 (range, 0-45). CONCLUSIONS: Distal radioulnar joint instability in adolescents is often preceded by fracture of the distal radius. Surgeons must maintain a high level of suspicion to appropriately diagnose DRUJ instability, which is often not an isolated pathoanatomical problem. The Herbert sling technique using extensor retinaculum can successfully confer DRUJ stability in this population.

The Emirates Mars Mission (EMM) Emirates Mars InfraRed Spectrometer (EMIRS) Instrument.

The Emirates Mars Mission Emirates Mars Infrared Spectrometer (EMIRS) will provide remote measurements of the martian surface and lower atmosphere in order to better characterize the geographic and diurnal variability of key constituents (water ice, water vapor, and dust) along with temperature profiles on sub-seasonal timescales. EMIRS is a FTIR spectrometer covering the range from 6.0-100+ µm (1666-100 cm-1) with a spectral sampling as high as 5 cm-1 and a 5.4-mrad IFOV and a 32.5×32.5 mrad FOV. The EMIRS optical path includes a flat 45° pointing mirror to enable one degree of freedom and has a +/- 60° clear aperture around the nadir position which is fed to a 17.78-cm diameter Cassegrain telescope. The collected light is then fed to a flat-plate based Michelson moving mirror mounted on a dual linear voice-coil motor assembly. An array of deuterated L-alanine doped triglycine sulfate (DLaTGS) pyroelectric detectors are used to sample the interferogram every 2 or 4 seconds (depending on the spectral sampling selected). A single 0.846 µm laser diode is used in a metrology interferometer to provide interferometer positional control, sampled at 40 kHz (controlled at 5 kHz) and infrared signal sampled at 625 Hz. The EMIRS beamsplitter is a 60-mm diameter, 1-mm thick 1-arcsecond wedged chemical vapor deposited diamond with an antireflection microstructure to minimize first surface reflection. EMIRS relies on an instrumented internal v-groove blackbody target for a full-aperture radiometric calibration. The radiometric precision of a single spectrum (in 5 cm-1 mode) is <3.0×10-8 W cm-2 sr-1/cm-1 between 300 and 1350 cm-1 over instrument operational temperatures (<∼0.5 K NE Δ T @ 250 K). The absolute integrated radiance error is < 2% for scene temperatures ranging from 200-340 K. The overall EMIRS envelope size is 52.9×37.5×34.6 cm and the mass is 14.72 kg including the interface adapter plate. The average operational power consumption is 22.2 W, and the standby power consumption is 18.6 W with a 5.7 W thermostatically limited, always-on operational heater. EMIRS was developed by Arizona State University and Northern Arizona University in collaboration with the Mohammed bin Rashid Space Centre with Arizona Space Technologies developing the electronics. EMIRS was integrated, tested and radiometrically calibrated at Arizona State University, Tempe, AZ.

Water heavily fractionated as it ascends on Mars as revealed by ExoMars/NOMAD.

Isotopic ratios and, in particular, the water D/H ratio are powerful tracers of the evolution and transport of water on Mars. From measurements performed with ExoMars/NOMAD, we observe marked and rapid variability of the D/H along altitude on Mars and across the whole planet. The observations (from April 2018 to April 2019) sample a broad range of events on Mars, including a global dust storm, the evolution of water released from the southern polar cap during southern summer, the equinox phases, and a short but intense regional dust storm. In three instances, we observe water at very high altitudes (>80 km), the prime region where water is photodissociated and starts its escape to space. Rayleigh distillation appears the be the driving force affecting the D/H in many cases, yet in some instances, the exchange of water reservoirs with distinctive D/H could be responsible.

Quantifying ADC bystander payload penetration with cellular resolution using pharmacodynamic mapping.

With the recent approval of 3 new antibody drug conjugates (ADCs) for solid tumors, this class of drugs is gaining momentum for the targeted treatment of cancer. Despite significant investment, there are still fundamental issues that are incompletely understood. Three of the recently approved ADCs contain payloads exhibiting bystander effects, where the payload can diffuse out of a targeted cell into adjacent cells. These effects are often studied using a mosaic of antigen positive and negative cells. However, the distance these payloads can diffuse in tumor tissue while maintaining a lethal concentration is unclear. Computational studies suggest bystander effects partially compensate for ADC heterogeneity in tumors in addition to targeting antigen negative cells. However, this type of study is challenging to conduct experimentally due to the low concentrations of extremely potent payloads. In this work, we use a series of 3-dimensional cell culture and primary human tumor xenograft studies to directly track fluorescently labeled ADCs and indirectly follow the payload via an established pharmacodynamic marker (γH2A. X). Using TAK-164, an anti-GCC ADC undergoing clinical evaluation, we show that the lipophilic DNA-alkylating payload, DGN549, penetrates beyond the cell targeted layer in GCC-positive tumor spheroids and primary human tumor xenograft models. The penetration distance is similar to model predictions, where the lipophilicity results in moderate tissue penetration, thereby balancing improved tissue penetration with sufficient cellular uptake to avoid significant washout. These results aid in mechanistic understanding of the interplay between antigen heterogeneity, bystander effects, and heterogeneous delivery of ADCs in the tumor microenvironment to design clinically effective therapeutics.