To Give or Not To Give: Pandemic Vaccine Donation Policy

The global SARS-CoV-2 (COVID-19) pandemic highlighted the challenge of equitable vaccine distribution between high- and low-income countries. Many high-income countries were reluctant or slow to distribute extra doses of the vaccine to lower-income countries via the COVID-19 Vaccines Global Access (COVAX) collaboration. In addition to moral objections to such vaccine nationalism, vaccine inequity during a pandemic could contribute to the evolution of new variants of the virus and possibly increase total deaths, including in the high-income countries. Using the COVID-19 pandemic as a case study, we use the epidemiological model of Holleran et al. that incorporates virus mutation. We identify realistic scenarios under which a donor country prefers to donate vaccines before distributing them locally in order to minimize local deaths during a pandemic. We demonstrate that a nondonor-first vaccination policy can delay, sometimes dramatically, the emergence of more-contagious variants. Even more surprising, donating all vaccines is sometimes better for the donor country than a sharing policy in which half of the vaccines are donated and half are retained because of the impact donation can have on delaying the emergence of a more contagious virus. Nondonor-first vaccine allocation is optimal in scenarios in which the local health impact of the vaccine is limited or when delaying emergence of a variant is especially valuable. In all cases, we find that vaccine distribution is not a zero-sum game between donor and nondonor countries. Thus, in addition to moral reasons to avoid vaccine nationalism, donor nations can also realize local health benefits from donating vaccines. The insights yielded by this framework can be used to guide equitable vaccine distribution in future pandemics.Comment: 21 pages, 4 figures. arXiv admin note: substantial text overlap with arXiv:2303.0591

Implementation of wearable sensing technology for movement: Pushing forward into the routine physical rehabilitation care field

While the promise of wearable sensor technology to transform physical rehabilitation has been around for a number of years, the reality is that wearable sensor technology for the measurement of human movement has remained largely confined to rehabilitation research labs with limited ventures into clinical practice. The purposes of this paper are to: (1) discuss the major barriers in clinical practice and available wearable sensing technology; (2) propose benchmarks for wearable device systems that would make it feasible to implement them in clinical practice across the world and (3) evaluate a current wearable device system against the benchmarks as an example. If we can overcome the barriers and achieve the benchmarks collectively, the field of rehabilitation will move forward towards better movement interventions that produce improved function not just in the clinic or lab, but out in peoples\u27 homes and communities

Organic Cation Transporter 3 and the Dopamine Transporter Differentially Regulate Catecholamine Uptake in the Basolateral Amygdala and Nucleus Accumbens

Regional alterations in kinetics of catecholamine uptake are due in part to variations in clearance mechanisms. The rate of clearance is a critical determinant of the strength of catecholamine signaling. Catecholamine transmission in the nucleus accumbens core (NAcc) and basolateral amygdala (BLA) is of particular interest due to involvement of these regions in cognition and motivation. Previous work has shown that catecholamine clearance in the NAcc is largely mediated by the dopamine transporter (DAT), but clearance in the BLA is less DAT‐dependent. A growing body of literature suggests that organic cation transporter 3 (OCT3) also contributes to catecholamine clearance in both regions. Consistent with different clearance mechanisms between regions, catecholamine clearance is more rapid in the NAcc than in the BLA, though mechanisms underlying this have not been resolved. We compared the expression of DAT and OCT3 and their contributions to catecholamine clearance in the NAcc and BLA. We found DAT protein levels were ~ 4‐fold higher in the NAcc than in the BLA, while OCT3 protein expression was similar between the two regions. Immunofluorescent labeling of the two transporters in brain sections confirmed these findings. Ex vivo voltammetry demonstrated that the magnitude of catecholamine release was greater, and the clearance rate was faster in the NAcc than in the BLA. Additionally, catecholamine clearance in the BLA was more sensitive to the OCT3 inhibitor corticosterone, while clearance in the NAcc was more cocaine sensitive. These distinctions in catecholamine clearance may underlie differential effects of catecholamines on behavioral outputs mediated by these regions

Effect of age on the pharmacokinetics of busulfan in patients undergoing hematopoietic cell transplantation; an alliance study (CALGB 10503, 19808, and 100103)

Older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome have often been excluded from myeloablative-conditioning regimens containing busulfan because of non-disease-related morbidity and mortality. We hypothesized that busulfan clearance (BuCL) in older patients (\u3e 60 years) would be reduced compared to that in younger patients, potentially explaining observed differences in busulfan tolerability. AML patients in three CALGB hematopoietic cell transplantation studies were treated with a conditioning regimen using IV busulfan, dosed at 0.8 mg/kg. Plasma busulfan concentrations were determined by LC-MS and analyzed by non-compartmental methods. BuCL was normalized to actual (ABW), ideal (IBW), or corrected (CBW) body weight (kg). Differences in BuCL between age groups were examined using the Wilcoxon rank sum test. One hundred and eighty-five patients were accrued; 174 provided useable pharmacokinetic data. Twenty-nine patients a parts per thousand yen60 years old (median 66; range 60-74) had a significantly higher BuCL versus those \u3c 60 years old (median 50; range 18-60): BuCL 236 versus 168 mL/min, p = 0.0002; BuCL/ABW 3.0 versus 2.1 mL/min/kg, p = 0.0001; BuCL/IBW 3.8 versus 2.6 mL/min/kg, p = 0.0035; BuCL/CBW 3.4 versus 2.6 mL/min/kg, p = 0.0005. Inter-patient variability in clearance (CV %) was up to 48 % in both age groups. Phenytoin administration, a potential confounder, did not affect BuCL, regardless of weight normalization (p \u3e 0.34). Contrary to our hypothesis, BuCL was significantly higher in older patients compared to younger patients in these studies and does not explain the previously reported increase in busulfan toxicity observed in older patients

Stepwise Regression and Latent Profile Analyses of Locomotor Outcomes Poststroke

Background and purpose: Previous data suggest patient demographics and clinical presentation are primary predictors of motor recovery poststroke, with minimal contributions of physical interventions. Other studies indicate consistent associations between the amount and intensity of stepping practice with locomotor outcomes. The goal of this study was to determine the relative contributions of these combined variables to locomotor outcomes poststroke across a range of patient demographics and baseline function. Methods: Data were pooled from 3 separate trials evaluating the efficacy of high-intensity training, low-intensity training, and conventional interventions. Demographics, clinical characteristics, and training activities from 144 participants >1-month poststroke were included in stepwise regression analyses to determine their relative contributions to locomotor outcomes. Subsequent latent profile analyses evaluated differences in classes of participants based on their responses to interventions. Results: Stepwise regressions indicate primary contributions of stepping activity on locomotor outcomes, with additional influences of age, duration poststroke, and baseline function. Latent profile analyses revealed 2 main classes of outcomes, with the largest gains in those who received high-intensity training and achieved the greatest amounts of stepping practice. Regression and latent profile analyses of only high-intensity training participants indicated age, baseline function, and training activities were primary determinants of locomotor gains. Participants with the smallest gains were older (≈60 years), presented with slower gait speeds (<0.40 m/s), and performed 600 to 1000 less steps/session. Conclusions: Regression and cluster analyses reveal primary contributions of training interventions on mobility outcomes in patients >1-month poststroke. Age, duration poststroke, and baseline impairments were secondary predictors

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia.

Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = -0.71 to -1.37; P &lt; 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = -0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10-6, 1.7 × 10-9, 3.5 × 10-12 and 1.0 × 10-4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries.

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

3.9 day orbital modulation in the TeV gamma-ray flux and spectrum from the X-ray binary LS 5039

New observations of LS 5039, a High Mass X-ray Binary comprising a massive star and compact object, were carried out with the High Energy Stereoscopic System of Cherenkov Telescopes (H.E.S.S.) in 2005 at very high energy (VHE) gamma-ray energies. These observations reveal that its flux and energy spectrum are modulated with the 3.9 day orbital period of the binary system. This is the first time in gamma-ray astronomy that orbital modulation has been observed, and periodicity clearly established using ground-based gamma-ray detectors. The VHE gamma-ray emission is largely confined to half of the orbit, peaking around the inferior conjunction epoch of the compact object. For this epoch, there is also a hardening of the energy spectrum in the energy range between 0.2 TeV and a few TeV. The flux vs. orbital phase profile provides the first clear indication of gamma-ray absorption via pair production within an astrophysical source, a process which is expected to occur if the gamma-ray production site is situated within ~1 AU of the compact object. Moreover the production region size must be not significantly greater than the binary separation (~0.15 AU). Notably, these constraints are also considerably smaller than the collimated outflows or jets (extending out to ~1000 AU) observed in LS 5039. The spectral hardening could arise from variations with phase in the maximum electron energies, and/or the dominant VHE gamma-ray production mechanism.Comment: 8 pages, 8 figures, accepted for publication in Astronomy & Astrophysic

Discovery of VHE gamma-rays from the high-frequency-peaked BL Lac object RGB J0152+017

Aims: The BL Lac object RGB J0152+017 (z=0.080) was predicted to be a very high-energy (VHE; > 100 GeV) gamma-ray source, due to its high X-ray and radio fluxes. Our aim is to understand the radiative processes by investigating the observed emission and its production mechanism using the High Energy Stereoscopic System (H.E.S.S.) experiment. Methods: We report recent observations of the BL Lac source RGB J0152+017 made in late October and November 2007 with the H.E.S.S. array consisting of four imaging atmospheric Cherenkov telescopes. Contemporaneous observations were made in X-rays by the Swift and RXTE satellites, in the optical band with the ATOM telescope, and in the radio band with the Nancay Radio Telescope. Results: A signal of 173 gamma-ray photons corresponding to a statistical significance of 6.6 sigma was found in the data. The energy spectrum of the source can be described by a powerlaw with a spectral index of 2.95+/-0.36stat+/-0.20syst. The integral flux above 300 GeV corresponds to ~2% of the flux of the Crab nebula. The source spectral energy distribution (SED) can be described using a two-component non-thermal synchrotron self-Compton (SSC) leptonic model, except in the optical band, which is dominated by a thermal host galaxy component. The parameters that are found are very close to those found in similar SSC studies in TeV blazars. Conclusions: RGB J0152+017 is discovered as a source of VHE gamma-rays by H.E.S.S. The location of its synchrotron peak, as derived from the SED in Swift data, allows clearly classification it as a high-frequency-peaked BL Lac (HBL).Comment: Accepted for publication in A&A Letters (5 pages, 4 figures