A set-analytic approach to intersectionality.

In this paper, we propose a set-analytic approach to the study of intersectionality. Our approach builds on the intersectional view that combinations of attributes, such as black females, should be understood as qualitatively distinct states, not reducible to their component attributes. We show that interaction-based, quantitative approaches are not only inconsistent with the core assumptions of intersectionality but also may underestimate the presence of penalties linked to multi-category memberships. In contrast, we show that truth table analysis, a core feature of Qualitative Comparative Analysis, directly implements several of the core methodological concerns of the intersectionality perspective. The truth table approach offers two important advantages. (1) It provides a foundation for the comparison of logically 'adjacent' configurations-combinations of case characteristics that differ by only a single attribute. (2) It can accommodate case attributes that vary by level or degree in a set-theoretic, intersectional framework.

Stigmatization of Chinese and Asian-looking people during the COVID-19 pandemic in Germany.

BACKGROUND: The outbreak and global spread of COVID-19 was accompanied by an increase in reports of stigmatization of Chinese and Asian-looking people. The behavioral immune system provides a framework for stigmatization in response to infectious disease threats. Specifically, stigmatization might increase with rising levels of infectious disease threat. The present study aimed to examine this hypothesis during the early phase of the COVID-19 pandemic. METHODS: As part of the "EUCLID" project ( https://euclid.dbvis.de ), a total of 5011 persons from Germany were surveyed via an online-questionnaire between February 2nd and April 3rd, 2020, covering the progression of the COVID-19 pandemic over three time periods which were defined by critical events. RESULTS: There was no evidence for an increase in the stigmatization of Chinese and Asian-looking people across three topics, that is personal proximity, air travel, and medical measures upon arrival from China. CONCLUSIONS: The present findings provide good news in that participants showed an adaptive response to the infectious disease threat rather than displaying increased stigmatization. Further research is necessary to specify the conditions that increase the risk of stigmatization in response to infectious disease threats.

The Relation of Threat Level and Age With Protective Behavior Intentions During Covid-19 in Germany.

To contain the spread of Covid-19, engagement in protective behaviors across the population is of great importance. The present study investigated protective behavior intentions during the early phases of Covid-19 in Germany (February 2-April 3, 2020) as a function of threat level and age using data from 4,940 participants in the EUCLID project. Results indicated that the intention to engage in social distancing increased sharply with threat level. Intentions for personal hygiene also increased, although to a lesser extent. While age only had a small overall effect on behavioral intentions, differential patterns emerged. After the lockdown was introduced, the impact of age decreased for social distancing and hygiene behavior intentions but increased for seeing a doctor. Since containing the Covid-19 pandemic depends on high adoption rates of protective behaviors, future research should track sustained phases of the pandemic, including the easing of restrictions and possible new waves of infections.

ANG1005 for breast cancer brain metastases: correlation between 18F-FLT-PET after first cycle and MRI in response assessment.

PURPOSE: Improved therapies and imaging modalities are needed for the treatment of breast cancer brain metastases (BCBM). ANG1005 is a drug conjugate consisting of paclitaxel covalently linked to Angiopep-2, designed to cross the blood-brain barrier. We conducted a biomarker substudy to evaluate 18F-FLT-PET for response assessment. METHODS: Ten patients with measurable BCBM received ANG1005 at a dose of 550 mg/m2 IV every 21 days. Before and after cycle 1, patients underwent PET imaging with 18F-FLT, a thymidine analog, retention of which reflects cellular proliferation, for comparison with gadolinium-contrast magnetic resonance imaging (Gd-MRI) in brain metastases detection and response assessment. A 20 % change in uptake after one cycle of ANG1005 was deemed significant. RESULTS: Thirty-two target and twenty non-target metastatic brain lesions were analyzed. The median tumor reduction by MRI after cycle 1 was -17.5 % (n = 10 patients, lower, upper quartiles: -25.5, -4.8 %) in target lesion size compared with baseline. Fifteen of twenty-nine target lesions (52 %) and 12/20 nontarget lesions (60 %) showed a ≥20 % decrease post-therapy in FLT-PET SUV change (odds ratio 0.71, 95 % CI: 0.19, 2.61). The median percentage change in SUVmax was -20.9 % (n = 29 lesions; lower, upper quartiles: -42.4, 2.0 %), and the median percentage change in SUV80 was also -20.9 % (n = 29; lower, upper quartiles: -49.0, 0.0 %). Two patients had confirmed partial responses by PET and MRI lasting 6 and 18 cycles, respectively. Seven patients had stable disease, receiving a median of six cycles. CONCLUSIONS: ANG1005 warrants further study in BCBM. Results demonstrated a moderately strong association between MRI and 18F-FLT-PET imaging.

Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer.

The eukaryotic translation initiation factor 4E (eIF4E) is a potent oncogene that is found to be dysregulated in 30% of human cancer, including colorectal carcinogenesis (CRC). ISIS 183750 is a second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the eIF4E protein. In preclinical studies we found that EIF4e ASOs reduced expression of EIF4e mRNA and inhibited proliferation of colorectal carcinoma cells. An additive antiproliferative effect was observed in combination with irinotecan. We then performed a clinical trial evaluating this combination in patients with refractory cancer. No dose-limiting toxicities were seen but based on pharmacokinetic data and tolerability the dose of irinotecan was reduced to 160 mg/m(2) biweekly. Efficacy was evaluated in 15 patients with irinotecan-refractory colorectal cancer. The median time of disease control was 22.1 weeks. After ISIS 183750 treatment, peripheral blood levels of eIF4E mRNA were decreased in 13 of 19 patients. Matched pre- and posttreatment tumor biopsies showed decreased eIF4E mRNA levels in five of nine patients. In tumor tissue, the intracellular and stromal presence of ISIS 183750 was detected by IHC in all biopsied patients. Although there were no objective responses stable disease was seen in seven of 15 (47%) patients who were progressing before study entry, six of whom were stable at the time of the week 16 CT scan. We were also able to confirm through mandatory pre- and posttherapy tumor biopsies penetration of the ASO into the site of metastasis.

Are radiologists superior to orthopaedic surgeons in diagnosing instability-related shoulder lesions on magnetic resonance arthrography? A multicenter reproducibility and accuracy study.

BACKGROUND: We compared the diagnostic reproducibility and accuracy of musculoskeletal radiologists with orthopaedic shoulder surgeons in 2 large medical centers in assessing magnetic resonance arthrograms (MRAs) of patients with traumatic anterior shoulder instability. METHODS: Forty-five surgically confirmed MRAs were assessed by 4 radiologists, 4 orthopaedic surgeons, 2 radiologic teams, and 2 orthopaedic teams. During MRA assessment and surgery, the same 7-lesion scoring form was used. κ Coefficients, sensitivity, specificity, and differences in percentage of agreement or correct diagnosis (P < .05, McNemar test) were calculated per lesion and overall per the 7 lesion types. RESULTS: The overall κ between the individual radiologists (κ = 0.51, κ = 0.46) and orthopaedic surgeons (κ = 0.46, κ = 0.41) was moderate. Although the overall percentage of agreement between the radiologists was slightly higher than that between the orthopaedic surgeons in both centers (80.0% vs 77.5% and 75.2% vs 73.7%), there was no significant difference. In each medical center, however, the most experienced orthopaedic surgeon was exceedingly more accurate than both radiologists per the 7 lesion types (81.9% vs 72.4%/74.6% and 76.5% vs 67.3%/73.7%). In 3 of 4 cases, this difference was significant. Overall accuracy improvement through consensus assessment was merely established for the weakest member of each team. CONCLUSION: Experienced orthopaedic surgeons are more accurate than radiologists in assessing traumatic anterior shoulder instability-related lesions on MRA. In case of diagnosis disagreement, these orthopaedic surgeons should base their treatment decision on their own MRA interpretation.

Sural artery injury with arteriovenous fistula: case report about a rare complication following arthroscopic medial meniscectomy.

This case report presents a patient with hematoma and pain after a knee arthroscopy with partial medial meniscectomy. A lesion of the sural artery was treated by endovascular coiling. The level of evidence is IV.

Imaging of spatial many-body wave functions via linear momentum measurements.

The equivalence of a complete characterization of linear momenta of fragments from a many-body fragmentation process and the spatial wave function of the many-body system is discussed. Our experiment on three-body dissociation of state selected H3 and D3 molecules into ground-state hydrogen atoms strongly suggests the existence of such a close relationship as it is also predicted by theory in the form of the imaging theorem. We conclude that prudent imaging of many-body fragmentation provides a laboratory view of the squared many-body wave function at a spatial scale of molecular dimensions at which fragments exit into the realm of independent free particles.

Drugs targeting 5-hydroxytryptamine receptors in acute treatments of migraine attacks. A review of new drugs and new administration forms of established drugs.

INTRODUCTION: The development of sumatriptan, more than 20 years ago, added substantially to the characterization of 5-hydroxytryptamine (5-HT) receptors and their relevance to acute migraine therapy. Recently, 5-HT1F receptor agonists, with no vascular effects, have shown efficacy in the treatment of migraines. AREAS COVERED: This evaluation reviews the recent advances in acute migraine therapy targeting the 5-HT receptor. Specifically, the authors review the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of 5-HT1F receptor agonists and new formulations of sumatriptan and dihydroergotamine (DHE). EXPERT OPINION: Lasmiditan, a non-vascular acting 5-HT1F receptor agonist, is effective in migraine but causes central nervous system-related adverse events, which may considerably limit its clinical use. The efficacy of transdermal sumatriptan is too low for general use in migraine. Intranasal sumatriptan powder could be a step forward compared with oral sumatriptan, but comparative trials are needed. Orally inhaled DHE has a very quick systemic absorption but the onset of effect in migraine is relatively slow with a maximum effect after 2 h. In contrast, orally inhaled DHE results in a low incidence of recurrence. None of these reviewed treatments are likely to fulfill patients' expectations, and the advancement of acute migraine drugs should likely depend on different mechanisms from current 5-HT-related drugs.

The CYP2C19*17 variant is not independently associated with clopidogrel response.

BACKGROUND: Cytochrome P450 2C19 (CYP2C19) is the principal enzyme responsible for converting clopidogrel into its active metabolite, and common genetic variants have been identified, most notably CYP2C19*2 and CYP2C19*17, that are believed to alter its activity and expression, respectively. OBJECTIVE: We evaluated whether the consequences of the CYP2C19*2 and CYP2C19*17 variants on clopidogrel response were independent of each other or genetically linked through linkage disequilibrium (LD). PATIENTS/METHODS: We genotyped the CYP2C19*2 and CYP2C19*17 variants in 621 members of the Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study and evaluated the effects of these polymorphisms singly and then jointly, taking into account LD, on clopidogrel prodrug level, clopidogrel active metabolite level, and adenosine 5'-diphosphate (ADP)-stimulated platelet aggregation before and after clopidogrel exposure. RESULTS: The CYP2C19*2 and CYP2C19*17 variants were in LD (|D'| = 1.0; r(2)  = 0.07). In association analyses that did and did not account for the effects of CYP2C19*17, CYP2C19*2 was strongly associated with levels of clopidogrel active metabolite (ß = -5.24, P = 3.0 × 10(-9) and ß = -5.36, P = 3.3 × 10(-14) , respectively) and posttreatment ADP-stimulated platelet aggregation (ß = 7.55, P = 2.9 × 10(-16) and ß = 7.51, P = 7.0 × 10(-15) , respectively). In contrast, CYP2C19*17 was marginally associated with clopidogrel active metabolite levels and ADP-stimulated platelet aggregation before (ß = 1.57, P = 0.04 and ß = -1.98, P = 0.01, respectively) but not after (ß = 0.40, P = 0.59 and ß = -0.13, P = 0.69, respectively) adjustment for the CYP2C19*2 variant. Stratified analyses of CYP2C19*2/CYP2C19*17 genotype combinations revealed that CYP2C19*2, and not CYP2C19*17, was the primary determinant in altering clopidogrel response. CONCLUSIONS: Our results suggest that CYP2C19*17 has a small (if any) effect on clopidogrel-related traits and that the observed effect of this variant is due to LD with the CYP2C19*2 loss-of-function variant.

Relatively slow and long-lasting antimigraine effect of dihydroergotamine is most likely due to basic pharmacological attributes of the drug: a review.

INTRODUCTION: If a drug has a slow dissociation from the receptor this can result in a long duration of effect and a slow effect. The long duration of the antimigraine effect of dihydroergotamine (DHE) has been reported previously whereas a possible slow onset of DHE's antimigraine effect, which is the subject of this review, has only rarely been mentioned. METHODS: Eight randomised, controlled trials (RCT) with DHE for acute treatment with migraine were selected from the literature. The speed of the effect of DHE in migraine was evaluated by plotting the effect up to four hours against time. FINDINGS: Subcutaneous DHE 1 mg was inferior to subcutaneous sumatriptan 6 mg for headache relief for the first two hours but equally effective after three hours. After intranasal DHE 2 mg the mean therapeutic gain increased slowly up to four hours. For orally inhaled DHE 0.5 mg there was a considerable time lag between therapeutic gain (maximum after two hours) and plasma concentrations of DHE (Tmax = 12 min). CONCLUSION: DHE has a slow dissociation from the receptor; and this basic attribute of the drug is the most likely cause of the general relatively slow anti-migraine effect of DHE.

OATP1B1 polymorphism as a determinant of erythromycin disposition.

Previous studies have demonstrated that the pharmacokinetic profile of erythromycin, a probe for CYP3A4 activity, is affected by inhibitors or inducers of hepatic solute carriers. We hypothesized that these interactions are mediated by OATP1B1 (gene symbol, SLCO1B1), a polypeptide expressed on the basolateral surface of hepatocytes. Using stably transfected Flp-In T-Rex293 cells, erythromycin was found to be a substrate for OATP1B1*1A (wild type) with a Michaelis-Menten constant of ~13 µmol/l, and that its transport was reduced by ~50% in cells expressing OATP1B1*5 (V174A). Deficiency of the ortholog transporter Oatp1b2 in mice was associated with a 52% decrease in the metabolic rate of erythromycin (P = 0.000043). In line with these observations, in humans the c.521T>C variant in SLCO1B1 (rs4149056), encoding OATP1B1*5, was associated with a decline in erythromycin metabolism (P = 0.0072). These results suggest that impairment of OATP1B1 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

Management of cluster headache.

The prevalence of cluster headache is 0.1% and cluster headache is often not diagnosed or misdiagnosed as migraine or sinusitis. In cluster headache there is often a considerable diagnostic delay - an average of 7 years in a population-based survey. Cluster headache is characterized by very severe or severe orbital or periorbital pain with a duration of 15-180 minutes. The cluster headache attacks are accompanied by characteristic associated unilateral symptoms such as tearing, nasal congestion and/or rhinorrhoea, eyelid oedema, miosis and/or ptosis. In addition, there is a sense of restlessness and agitation. Patients may have up to eight attacks per day. Episodic cluster headache (ECH) occurs in clusters of weeks to months duration, whereas chronic cluster headache (CCH) attacks occur for more than 1 year without remissions. Management of cluster headache is divided into acute attack treatment and prophylactic treatment. In ECH and CCH the attacks can be treated with oxygen (12 L/min) or subcutaneous sumatriptan 6 mg. For both oxygen and sumatriptan there are two randomized, placebo-controlled trials demonstrating efficacy. In both ECH and CCH, verapamil is the prophylactic drug of choice. Verapamil 360 mg/day was found to be superior to placebo in one clinical trial. In clinical practice, daily doses of 480-720 mg are mostly used. Thus, the dose of verapamil used in cluster headache treatment may be double the dose used in cardiology, and with the higher doses the PR interval should be checked with an ECG. At the start of a cluster, transitional preventive treatment such as corticosteroids or greater occipital nerve blockade can be given. In CCH and in long-standing clusters of ECH, lithium, methysergide, topiramate, valproic acid and ergotamine tartrate can be used as add-on prophylactic treatment. In drug-resistant CCH, neuromodulation with either occipital nerve stimulation or deep brain stimulation of the hypothalamus is an alternative treatment strategy. For most cluster headache patients there are fairly good treatment options both for acute attacks and for prophylaxis. The big problem is the diagnosis of cluster headache as demonstrated by the diagnostic delay of 7 years. However, the relatively short-lasting attack of pain in one eye with typical associated symptoms should lead the family doctor to suspect cluster headache resulting in a referral to a neurologist or a headache centre with experience in the treatment of cluster headache.

The 5-HT1F receptor agonist lasmiditan as a potential treatment of migraine attacks: a review of two placebo-controlled phase II trials.

Lasmiditan is a novel selective 5-HT(1F) receptor agonist. It is both scientifically and clinically relevant to review whether a 5-HT(1F) receptor agonist is effective in the acute treatment of migraine. Two RCTs in the phase II development of lasmiditan was reviewed. In the intravenous placebo-controlled RCT, lasmiditan doses of 2.5-45 mg were used, and there was a linear association between headache relief (HR) rates and dose levels (P < 0.02). For lasmiditan 20 mg, HR was 64 % and for placebo it was 45 % (NS). In the oral placebo-controlled RCT, lasmiditan doses of 50, 100, 200 and 400 mg were used. For HR, all doses of lasmiditan were superior to placebo (P < 0.05). For lasmiditan 400 mg, HR was 64 % and it was 25 % for placebo. Adverse events (AEs) emerging from the treatment were reported by 22 % of the patients receiving placebo and by 65, 73, 87 and 87 % of patients receiving 50, 100, 200 and 400 mg, respectively. The majority of AEs after lasmiditan 100 and 400 mg were moderate or severe. For the understanding of migraine pathophysiology, it is very important to note that a selective 5-HT(1F) receptor agonist like lasmiditan is effective in the acute treatment of migraine. Thus, migraine can be treated with a drug that has no vasoconstrictor ability. While lasmiditan most likely is effective in the treatment of migraine attacks it had, unfortunately, a high incidence of CNS related AEs in the oral RCT. If confirmed in larger studies in phase III, this might adversely limit the use of this highly specific non-vascular acute treatment of migraine. Larger studies including the parameters of patients' preferences are necessary to accurately position this new treatment principle in relation to the triptans.

Effect of ABCC2 (MRP2) transport function on erythromycin metabolism.

The macrolide antiobiotic erythromycin undergoes extensive hepatic metabolism and is commonly used as a probe for cytochrome P450 (CYP) 3A4 activity. By means of a transporter screen, erythromycin was identified as a substrate for the transporter ABCC2 (MRP2) and its murine ortholog, Abcc2. Because these proteins are highly expressed on the biliary surface of hepatocytes, we hypothesized that impaired Abcc2 function may influence the rate of hepatobiliary excretion and thereby enhance erythromycin metabolism. Using Abcc2 knockout mice, we found that Abcc2 deficiency was associated with a significant increase in erythromycin metabolism, whereas murine Cyp3a protein expression and microsomal Cyp3a activity were not affected. Next, in a cohort of 108 human subjects, we observed that homozygosity for a common reduced-function variant in ABCC2 (rs717620) was also linked to an increase in erythromycin metabolism but was not correlated with the clearance of midazolam. These results suggest that impaired ABCC2 function can alter erythromycin metabolism, independent of changes in CYP3A4 activity.

One hundred years of migraine research: major clinical and scientific observations from 1910 to 2010.

Pain research, and headache research in particular, during the 20th century, has generated an enormous volume of literature promulgating theories, questions, and temporary answers. This narrative review describes the most important events in the history of migraine research between 1910 and 2010. Based on the standard textbooks of headache: Wolff's Headache (1948 and 1963) and The Headaches (1993, 2000, and 2006) topics were selected for a historical review. Most notably these included: isolation and clinical introduction of ergotamine (1918); further establishment of vasodilation in migraine and the constrictive action of ergotamine (1938); identification of pain-sensitive structures in the head (1941); Lashley's description of spreading scotoma (1941); cortical spreading depression (CSD) of Leão (1944); serotonin and the introduction of methysergide (1959); spreading oligemia in migraine with aura (1981); oligemia in the wake of CSD in rats (1982); neurogenic inflammation theory of migraine (1987); a new headache classification (1988); the discovery of sumatriptan (1988); migraine and calcitonin gene-related peptide (1990); the brainstem "migraine generator" and PET studies (1995); migraine as a channelopathy, including research from the genetic perspective (1996); and finally, meningeal sensitization, central sensitization, and allodynia (1996). Pathophysiological ideas have evolved within a limited number of paradigms, notably the vascular, neurogenic, neurotransmitter, and genetic/molecular biological paradigm. The application of various new technologies played an important role within these paradigms, in particular neurosurgical techniques, EEG, methods to measure cerebral blood flow, PET imaging, clinical epidemiological, genetic, and molecular biological methods, the latter putting migraine (at least hemiplegic migraine) within a completely new classification of diseases.