Purpose of Review
Despite recognition of rising prevalence and significant burden, migraine remains underestimated, underdiagnosed, and undertreated. This is especially true among groups who have ...been historically, socially, and economically marginalized such as communities of color, women, people experiencing poverty, people with lower levels of education, and people who hold more than one of these marginalized identities. While there is growing public and professional interest in disparities in migraine prevalence, there is a paucity of research focusing on racial/ethnic and socioeconomic disparities, and the social and structural determinants of health and equity that perpetuate these disparities. From a health equity perspective, migraine research and treatment require an examination not only of biological and behavioral factors, but of these identities and underlying, intersecting social and structural determinants of health.
Recent Findings
Significant disparities in migraine incidence, prevalence, migraine-related pain and disability, access to care, and quality of care persist among marginalized and underserved groups: African Americans, Hispanics, people experiencing poverty, un- or under-employment, the un- and under-insured, people who have been exposed to stressful and traumatic events across the lifespan, and people experiencing multiple, overlapping marginalized identities. These same groups are largely underrepresented in migraine research, despite bearing disproportionate burden. Current approaches to understanding health disparities in migraine largely assume an essentializing approach, i.e., documenting differences between single identity groups—e.g., race or income or education level—rather than considering the mechanisms of disparities: the social and structural determinants of health.
Summary
While disparities in migraine are becoming more widely acknowledged, we assert that migraine is more aptly understood as a health equity issue, that is, a condition in which many of the health disparities are avoidable. It is important in research and clinical practice to consider perspectives that incorporate a cultural understanding of racial, ethnic, and socioeconomic identity within and across all levels of society. Incorporating perspectives of intersectionality provides a strong foundation for understanding the role of these complex combination of factors on migraine pain and treatment. We urge the adoption of intersectional and systems perspectives in research, clinical practice, and policy to examine (1) interplay of race, gender, and social location as key factors in understanding, diagnosing, and treating migraine, and (2) the complex configurations of social and structural determinants of health that interact to produce health inequities in migraine care. An intentional research and clinical focus on these factors stands to improve how migraine is identified, documented, and treated among marginalized populations.
Graphic
The flavonol myricetin, reacts with oxygen-centred galvinoxyl radicals 28 times faster than d-α-tocopherol (vitamin E), the main lipid-soluble antioxidant in biological membranes. Moreover, ...each myricetin molecule reduces twice as many such radicals as vitamin E. However, myricetin fails to protect vitamin E-deficient microsomes from lipid peroxidation as assessed by the formation of thiobarbituric acid reactive substances (TBARS). Novel and potentially therapeutic antioxidants have been prepared that combine the radical-scavenging ability of a myricetin-like head group with a lipophilic chain similar to that of vitamin E. C
6–C
12 alkyl chains are attached to the A-ring of either a 3,3
′,4
′,5
′-tetrahydroxyflavone or a 3,2
′,4
′,5
′-tetrahydroxyflavone head group to give lipophilic flavonoids (
Clog
P=4 to 10) that markedly inhibit iron-ADP catalysed oxidation of microsomal preparations. Orientation of the head group as well as total lipophilicity are important determinants of antioxidant efficacy. MM2 models indicate that our best straight chain 7-alkylflavonoids embed to the same depth in the membrane as vitamin E. The flavonoid head groups are prepared by aldol condensation followed by Algar–Flynn–Oyamada (AFO) oxidation or by Baker–Venkataraman rearrangement. The alkyl tails are introduced by Suzuki or Negishi palladium-catalysed cross-coupling or by cross-metathesis catalysed by first generation Grubbs catalyst, which tolerate phenolic hydroxyl and ketone groups.
Abstract
Background
The severity of the 2017–2018 influenza season in the United States was high, with influenza A(H3N2) viruses predominating. Here, we report influenza vaccine effectiveness (VE) ...and estimate the number of vaccine-prevented influenza-associated illnesses, medical visits, hospitalizations, and deaths for the 2017–2018 influenza season.
Methods
We used national age-specific estimates of 2017–2018 influenza vaccine coverage and disease burden. We estimated VE against medically attended reverse-transcription polymerase chain reaction–confirmed influenza virus infection in the ambulatory setting using a test-negative design. We used a compartmental model to estimate numbers of influenza-associated outcomes prevented by vaccination.
Results
The VE against outpatient, medically attended, laboratory-confirmed influenza was 38% (95% confidence interval CI, 31%–43%), including 22% (95% CI, 12%–31%) against influenza A(H3N2), 62% (95% CI, 50%–71%) against influenza A(H1N1)pdm09, and 50% (95% CI, 41%–57%) against influenza B. We estimated that influenza vaccination prevented 7.1 million (95% CrI, 5.4 million–9.3 million) illnesses, 3.7 million (95% CrI, 2.8 million–4.9 million) medical visits, 109 000 (95% CrI, 39 000–231 000) hospitalizations, and 8000 (95% credible interval CrI, 1100–21 000) deaths. Vaccination prevented 10% of expected hospitalizations overall and 41% among young children (6 months–4 years).
Conclusions
Despite 38% VE, influenza vaccination reduced a substantial burden of influenza-associated illness, medical visits, hospitalizations, and deaths in the United States during the 2017–2018 season. Our results demonstrate the benefit of current influenza vaccination and the need for improved vaccines.
During the 2017–2018 influenza season, we estimate that influenza vaccination reduced the risk of medically attended influenza by 38% and prevented 7 million illnesses, 4 million medical visits, 109 000 hospitalizations, and 8000 deaths in the United States.
•New thunderstorm antennas allow long-term electrical monitoring of active volcanoes.•Thunderstorm detectors efficiently detect relatively small ash-rich eruptions.•Electrical discharges mark the ...inception of consecutive explosion pulses.•Electrical activity increases overall with increasing plume height.•Fracto- and tribo-electrification dominate in Vulcanian plumes.
Very low frequency and wide-band lightning detection networks can detect major volcanic plumes via their intense electrical and lightning activity. However, the high number of non-detected explosive episodes confirmed by direct observations, reveals the limits of these systems in the detection of the more frequent smaller ash-rich explosive events. Here, we use a data-efficient thunderstorm detector to observe electrical discharges generated from July 2018 to January 2020 by the persistent Vulcanian activity of Minamidake crater at Sakurajima volcano in Japan.
Two thunderstorm detectors recorded the electrical activity produced by explosions at Minamidake crater from a distance of 3 and 4 km from the active vents. The instruments measured the induced current due to the change in electric field with time within the extremely low frequency range (1-45 Hz). Using a volcanic lightning detection algorithm together with the catalogue of volcanic explosions compiled by the Japan Meteorological Agency (JMA) and Tokyo Volcanic Ash Advisory Center (Tokyo VAAC), the number of electrical discharges, the electrical discharge rate and the total amount of measured voltage were determined for each individual explosive event. In addition, the start of the electrical discharges was compared to the explosion onset as provided by the JMA (with a one-minute time resolution).
The sensors detected electrical discharges in 71% of the 724 recorded explosions. Our detection algorithm successfully recognises the presence/absence of electrical discharges with an accuracy of 73%. We find a non-linear positive correlation between the number of discharges and the plume height. Moreover, we find that the maximum electrical discharge rate and the maximum amount of measured voltage by a single discharge also increase with plume height. Fracto- and tribo-electrification appear to be the dominant plume electrification mechanisms. Even for the few explosive events that exceeded the −10°C isotherm, the timescale of electrical activity seems to be too short for ice nucleation to make a significant contribution to the plume electrification. Finally, for 12% of the electrically-active explosive events, discharges were detected by the sensors more than a minute before the JMA explosion onset.
Our results show the capability of our detectors in pinpointing the inception of electrified explosive episodes in real-time and in providing an indication of the magnitude of each explosion, demonstrating their effectiveness as a cost- and data-efficient instrumentation for the monitoring of explosive ash emissions at active volcanoes.
3-(Imidazo1,2-
apyridin-3-yl)-, its aza-analogs, and 3-(pyrazolo1,5-
apyridin-3-yl)-4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl))maleimides are very potent inhibitors of GSK3 (⩽5
nM) ...with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII.
Many 3-aryl-4-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)maleimides exhibit potent GSK3 inhibitory activity (<100
nM IC
50), although few show significant selectivity (>100
×) versus CDK2, CDK4, or PKCβII. However, combining 3-(imidazo1,2-
apyridin-3-yl), 3-(pyrazolo1,5-
apyridin-3-yl) or aza-analogs with a 4-(2-acyl-(1,2,3,4-tetrahydro1,4diazepino6,7,1-
hiindol-7-yl)) group on the maleimide resulted in very potent inhibitors of GSK3 (⩽5
nM) with >160 to >10,000-fold selectivity versus CDK2/4 and PKCβII. These compounds also inhibited tau phosphorylation in cells and were effective in lowering plasma glucose in a rat model of type 2 diabetes (ZDF rat).
Objective.—The primary objectives of the present study were to (1) contrast reproductive hormone levels and ratings of menstrual distress of female migraineurs with those of a control group in each ...menstrual cycle phase, (2) examine correlations between hormone levels and migraine frequency, severity, and migraine‐related disability, and (3) examine correlations between menstrual distress and migraine frequency, severity, and migraine‐related disability. A secondary objective was to evaluate the validity of a migraine disability measure modified to reflect 7‐day recall.
Background.—Further controlled, prospective study is needed regarding the temporal relationships between reproductive hormones at each stage of the menstrual cycle and fluctuations in migraine activity across the cycle.
Methods.—Twenty‐three women (17 with migraine, 6 control participants) completed laboratory hormone assays and measures of menstrual distress and disability at each phase of one menstrual cycle, and monitored their headache activity daily during the same cycle.
Results.—The migraine group evidenced lower premenstrual luteinizing hormone and more menstrual distress symptoms at each phase of the menstrual cycle. Hormones were associated with migraine activity and disability within cycle phases, and across phases in a time‐lagged manner. Menstrual distress was associated with ovulatory phase migraine activity and with migraine‐related disability across the menstrual cycle. A retrospective 7‐day migraine disability measure appeared to be a consistently valid index.
Conclusions.—Both reproductive hormones and menstrually related distress appear to predict migraine activity and disability. These associations were evident not only for perimenstrual migraine, but also for migraine at each phase of the menstrual cycle.
Structure-activity studies have been pursued on cyclo-S,S-Ac-Cys-(N alpha-Me)Arg-Gly-Asp-Pen-NH2, 2 (SK&F 106760), a potent inhibitor of platelet aggregation, in an effort to improve potency and ...affinity for the GPIIb/IIIa receptor. Modifications on the N- and C-termini of 2 produced a series of peptides which indicate that the C-terminal carboxylate group may be a secondary receptor-binding element. Further modification by replacing the disulfide tether N alpha-acetylcysteine/penicillamineamide with the novel, inexpensive, achiral, constrained, and more lipophilic tether 2-mercaptobenzoyl/2-mercaptoaniline (Mba/Man) afforded the semipeptide cyclo-S,S-Mba-(N alpha-Me)Arg-Gly-Asp-Man, 18 (SK&F 107260), which exhibited significant enhancement in both affinity and potency. To further investigate the effect of the phenyl ring at the C-terminus, peptides bearing the novel (2R,3S)- and (2R,3R)-beta-phenylcysteines were synthesized, which culminated in the cyclo-S,S-Ac-Cys-(N alpha-Me)Arg-Gly-Asp-(2R,3S)-beta-phenylCys-OH peptide, 22, which displayed substantial affinity and potency. We describe, herein, the development of both 18 and 22 and the additional structural modifications within the constrained cyclic disulfide ring to probe the stereochemical and steric requirements for receptor interaction.
To gauge the experimental variability associated with Biacore analysis, 36 different investigators analyzed a small molecule/enzyme interaction under similar conditions. Acetazolamide (222
g/mol) ...binding to carbonic anhydrase II (CAII; 30,000
Da) was chosen as a model system. Both reagents were stable and their interaction posed a challenge to measure because of the low molecular weight of the analyte and the fast association rate constant. Each investigator created three different density surfaces of CAII and analyzed an identical dilution series of acetazolamide (ranging from 4.1 to 1000
nM). The greatest variability in the results was observed during the enzyme immobilization step since each investigator provided their own surface activating reagents. Variability in the quality of the acetazolamide binding responses was likely a product of how well the investigators’ instruments had been maintained. To determine the reaction kinetics, the responses from the different density surfaces were fit globally to a 1:1 interaction model that included a term for mass transport. The averaged association and dissociation rate constants were 3.1
±
1.6
×
10
6
M
−1
s
−1 and 6.7
±
2.5
×
10
−2
s
−1, respectively, which corresponded to an average equilibrium dissociation constant (
K
D) of 2.6
±
1.4
×
10
−8
M. The results provide a benchmark of variability in interpreting binding constants from the biosensor and highlight keys areas that should be considered when analyzing small molecule interactions.
A surface plasmon resonance (SPR) biosensor was used to study the interaction of human interleukin-5 (hIL5) with its receptor. IL5 is a major growth factor in the production and activation of ...eosinophils. The receptor for IL5 is composed of two subunits, alpha and beta. The alpha subunit provides the specificity for IL5 and consists of an extracellular soluble domain, a single transmembrane region and a cytoplasmic tail. We expressed the soluble domain of the human IL5 receptor alpha subunit (shIL5R alpha) and human IL5 (hIL5) in Drosophila. Both hIL5 and shIL5R alpha were immobilized separately through amine groups onto the carboxylated dextran layer of sensor chips of the BIAcore (Pharmacia) SPR biosensor after N-hydroxysuccinimide/carbodiimide activation of the chip surface. Interactions were measured for the complementary macromolecule, either shIL5R alpha or hIL5, in solution. Kinetics of binding of soluble analyte to immobilized ligand were measured and from this the association rate constant, dissociation rate constant and equilibrium dissociation constant (Kd) were derived. With immobilized shIL5R alpha and soluble hIL5, the measured Kd was 2 nM. A similar value was obtained by titration calorimetry. The Kd for Drosophila expressed receptor and IL5 is higher than the values reported for proteins expressed in different systems, likely due to differences in the methods of interaction analysis used or differences in protein glycosylation. Receptor-IL5 binding was relatively pH independent between pH 6.5 and 9.5. Outside this range, the dissociation rate increased with comparatively little increase in association rate.
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