The structure and mechanics of the cell cortex depend on the location and adhesion state.

Cells exist in different phenotypes and can transition between them. A phenotype may be characterized by many different aspects. Here, we focus on the example of whether the cell is adhered or suspended and choose particular parameters related to the structure and mechanics of the actin cortex. The cortex is essential to cell mechanics, morphology, and function, such as for adhesion, migration, and division of animal cells. To predict and control cellular functions and prevent malfunctioning, it is necessary to understand the actin cortex. The structure of the cortex governs cell mechanics; however, the relationship between the architecture and mechanics of the cortex is not yet well enough understood to be able to predict one from the other. Therefore, we quantitatively measured structural and mechanical cortex parameters, including cortical thickness, cortex mesh size, actin bundling, and cortex stiffness. These measurements required developing a combination of measurement techniques in scanning electron, expansion, confocal, and atomic force microscopy. We found that the structure and mechanics of the cortex of cells in interphase are different depending on whether the cell is suspended or adhered. We deduced general correlations between structural and mechanical properties and show how these findings can be explained within the framework of semiflexible polymer network theory. We tested the model predictions by perturbing the properties of the actin within the cortex using compounds. Our work provides an important step toward predictions of cell mechanics from cortical structures and suggests how cortex remodeling between different phenotypes impacts the mechanical properties of cells.

2-Hydroxyethyl methacrylate (HEMA): A clinical review of contact allergy and allergic contact dermatitis. Part 2. Cross- and co-sensitization, other skin reactions to HEMA, position of HEMA among (meth)acrylates, sensitivity as screening agent, presence of HEMA in commercial products and practical information on patch test procedures.

This is the second part of a literature review of the clinical aspects of contact allergy to and allergic contact dermatitis from 2-hydroxyethyl methacrylate (HEMA). Topics include cross- and co-sensitization, atypical manifestations of contact allergy, frequency of positive patch tests to HEMA compared with other (meth)acrylates, sensitivity of HEMA as a screening agent, the presence of HEMA in commercial products, and practical information on patch testing procedures. Primary sensitization to methacrylates including HEMA may result in methacrylate and acrylate cross-sensitization. There is a strong cross-allergy between HEMA, ethylene glycol dimethacrylate (EGDMA), and hydroxypropyl methacrylate; many reactions to EGDMA are cross-reactions to primary HEMA sensitization. Rare atypical manifestations of HEMA-allergy include lichen planus, lymphomatoid papulosis, systemic contact dermatitis, leukoderma after positive patch tests, and systemic side effects such as nausea, diarrhoea, malaise, and palpitations. The occurrence of respiratory disease caused by methacrylates such as asthma is not infrequent. HEMA is the most frequently patch test-positive methacrylate. It is a good screening agent for allergy to other (meth)acrylates. Patch test sensitization to HEMA 2% pet. is extremely rare. There are (some) indications that HEMA is frequently used in dental products and nail cosmetics.

2-Hydroxyethyl methacrylate (HEMA): A clinical review of contact allergy and allergic contact dermatitis-Part 1. Introduction, epidemiology, case series and case reports.

2-Hydroxyethyl methacrylate (HEMA) has been increasingly recognised as a contact allergen and was added to the European baseline series in 2019. In this article (2 parts), the results of an extensive literature review of the clinical aspects of contact allergy/allergic contact dermatitis to HEMA are presented. In part 1, the epidemiology of HEMA contact allergy is discussed and detailed information on published case series and case reports presented. HEMA is an important cause of contact allergy/allergic contact dermatitis in North America and Europe with recent prevalences of >3% in the USA + Canada and 1.5%-3.7% in Europe. Currently, most cases are caused by nail cosmetics, both in consumers and professional nail stylists. In our literature review, we have found 24 studies presenting case series of patients with allergic contact dermatitis attributed to HEMA and 168 case reports. However, the presence of HEMA in the products causing ACD was established in only a minority. Part 2 will discuss cross- and co-sensitisation, and other skin reactions to HEMA, will assess whether HEMA is the most frequent (meth)acrylate allergen and how sensitive HEMA as a screening agent is, investigate the presence of HEMA in commercial products and provide practical information on patch testing procedures.

Elucidation of the GSK3α Structure Informs the Design of Novel, Paralog-Selective Inhibitors.

Glycogen synthase kinase 3 (GSK3) remains a therapeutic target of interest for diverse clinical indications. However, one hurdle in the development of small molecule GSK3 inhibitors has been safety concerns related to pan-inhibition of both GSK3 paralogs, leading to activation of the Wnt/ß-catenin pathway and potential for aberrant cell proliferation. Development of GSK3α or GSK3ß paralog-selective inhibitors that could offer an improved safety profile has been reported but further advancement has been hampered by the lack of structural information for GSK3α. Here we report for the first time the crystal structure for GSK3α, both in apo form and bound to a paralog-selective inhibitor. Taking advantage of this new structural information, we describe the design and in vitro testing of novel compounds with up to ∼37-fold selectivity for GSK3α over GSK3ß with favorable drug-like properties. Furthermore, using chemoproteomics, we confirm that acute inhibition of GSK3α can lower tau phosphorylation at disease-relevant sites in vivo, with a high degree of selectivity over GSK3ß and other kinases. Altogether, our studies advance prior efforts to develop GSK3 inhibitors by describing GSK3α structure and novel GSK3α inhibitors with improved selectivity, potency, and activity in disease-relevant systems.

Rivastigmine for ECT-induced cognitive adverse effects in late life depression (RECALL study): A multicenter, randomized, double blind, placebo-controlled, cross-over trial in patients with depression aged 55 years or older: Rationale, objectives and methods.

Background: Cognitive side-effects are an important reason for the limited use of electroconvulsive therapy (ECT). Cognitive side-effects are heterogeneous and occur frequently in older persons. To date, insight into these side-effects is hampered due to inconsistencies in study designs and small sample sizes. Among all cognitive side-effects, confusion and delirious states are especially troublesome for patients, relatives and clinicians. In particular inter-ictal delirium-like states are worrisome, since they may lead to premature treatment discontinuation. Besides a need for further insight into determinants of cognitive side-effects of ECT, there is a great need for treatment options. Methods and design: The Rivastigmine for ECT-induced Cognitive Adverse effects in Late Life depression (RECALL) study combines a multicenter, prospective cohort study on older patients with depression, treated with ECT, with an embedded randomized, placebo-controlled cross-over trial to examine the effect of rivastigmine on inter-ictal delirium. Patients are recruited in four centers across the Netherlands and Belgium. We aim to include 150 patients into the cohort study, in order to be able to subsequently include 30 patients into the trial. Patients are included in the trial when inter-ictal delirium, assessed by the Confusion Assessment method (CAM), or a drop in Mini Mental State Examination (MMSE) score of ≥4 during ECT, develops. In the cohort study, comprehensive measurements of ECT-related cognitive side-effects-and their putative determinants-are done at baseline and during the ECT-course. The primary outcome of the clinical trial is the effectiveness of rivastigmine on inter-ictal delirium-severity, assessed with a change in the Delirium Rating Scale-Revised-98. Secondary outcomes of the clinical trial are several ECT-characteristics and side-effects of rivastigmine. Discussion: This study is the first clinical trial with a focus on ECT-induced, inter-ictal delirium. The cohort provides the basis for recruitment of patients for the cross-over trial and additionally provides an excellent opportunity to unravel cognitive side-effects of ECT and identify putative determinants. This paper describes the rationale and study protocol. Clinical trial registration: EudraCT 2014-003385-24.

Patch testing in drug reaction with eosinophilia and systemic symptoms (DRESS): A literature review.

The literature on positive patch test results in drug reaction with eosinophilia and systemic symptoms (DRESS) is reviewed. One hundred and five drugs were identified that have together caused 536 positive patch tests in 437 DRESS patients. By far, the most reactions (n = 145) were caused by carbamazepine, followed by amoxicillin, isoniazid, phenytoin, ethambutol, fluindione, phenobarbital, rifampicin, and ceftriaxone; 43 drugs each caused a single case only. The drug classes causing the highest number of reactions were anticonvulsants (39%), beta-lactam antibiotics (20%), antituberculosis agents (11%), non-beta-lactam antibiotics (6%), and iodinated contrast media (5%). The sensitivity of patch testing (percentage of positive reactions) is high for anticonvulsants (notably carbamazepine), beta-lactam antibiotics (notably amoxicillin), and, possibly, iodinated contrast media. Allopurinol and sulfasalazine frequently cause DRESS but never give positive patch tests. Patch testing in DRESS appears to be safe, although mild recurrence of DRESS symptoms, mostly skin reactions, may not be rare. Multiple drug hypersensitivity was found to occur in 16% of all patients, but it is argued that the true frequency is higher. Clinical aspects of DRESS, including diagnosing the disease and identifying culprit drugs (patch tests, intradermal tests, in vitro tests, challenge tests) are also provided, emphasizing the role of patch testing.

Results of patch testing in acute generalized exanthematous pustulosis (AGEP): A literature review.

The literature on positive patch-test results in acute generalized exanthematous pustulosis (AGEP) is reviewed. Ninety-three drugs were identified that have together caused 259 positive patch tests in 248 patients with AGEP. The drug classes causing the highest number of reactions are beta-lactam antibiotics (25.9%), other antibiotics (20.8%), iodinated contrast media (7.3%), and corticosteroids (5.4%), together accounting for nearly 60% of all reactions. The highest number of reactions to individual drugs was to amoxicillin (n = 36), followed by pristinamycin (n = 25), diltiazem (n = 14), amoxicillin-clavulanic acid (n = 13), clindamycin (n = 11), and iomeprol (n = 8); 59 of the 93 drugs each caused a single case only. The "Top-10" drugs together caused over 50% of all reactions. The sensitivity of patch testing (percentage of positive reactions) in patients with AGEP is largely unknown, but may generally be ~50%, which also applies to pristinamycin. Patch testing in AGEP appears to be safe, although mild recurrence of AGEP skin symptoms or other rashes may occur occasionally. Clinical aspects of AGEP, including epidemiology, etiology and pathophysiology, clinical features, histology, treatment, and prognosis are briefly presented, as are diagnosing the disease and identifying the culprit drugs with patch tests, intradermal tests, in vitro tests, and challenge tests.

Patch Testing in Drug Eruptions: Practical Aspects and Literature Review of Eruptions and Culprit Drugs.

ABSTRACT: There is overwhelming evidence that many delayed cutaneous adverse drug reactions (beginning >6 hours after drug intake) are mediated by delayed-type (type IV) hypersensitivity, including maculopapular eruptions, erythroderma, symmetrical drug-related intertriginous and flexural exanthema/baboon syndrome, eczematous eruptions, fixed drug eruptions, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome. Therefore, after resolution of the reaction, patch tests should be performed as first diagnostic method to identify the culprit drug(s). This article provides tools to perform drug patch tests properly and safely, discussing clinical history, indications, procedure, drug patch test materials, sensitivity, the meaning of negative patch tests, and safety of the procedure. In addition, a literature review of eruptions and culprit drugs is provided in tabular format.

Systemic allergic dermatitis (systemic contact dermatitis) from pharmaceutical drugs: A review.

The literature on systemic allergic dermatitis (SAD; also known as systemic contact dermatitis) is reviewed. Both topical drugs (from absorption through mucosae or skin) and systemic drugs (oral, parenteral, rectal) may be responsible for the disorder. The topical route appears to be rare with 41 culprit topical drugs found to cause SAD in 95 patients. Most reactions are caused by budesonide (especially from inhalation), bufexamac, and dibucaine. SAD from systemic drugs is infrequent with 95 culprit drugs found to cause SAD in 240 patients. The drugs most frequently implicated are mitomycin C, methylprednisolone (salt, ester), and hydrocortisone (salt). The largest group of culprit drugs consisted of corticosteroids (19%), being responsible for >30% of the reactions, of which nearly 40% were not caused by therapeutic drugs, but by drug provocation tests. The most frequent manifestations of SAD from drugs are eczematous eruptions (scattered, widespread, generalized, worsening, reactivation), maculopapular eruptions, symmetrical drug-related intertriginous and flexural exanthema (SDRIFE [baboon syndrome]) and widespread erythema or erythroderma. Therapeutic systemic drugs hardly ever cause reactivation of previously positive patch tests and infrequently of previous allergic contact dermatitis. The pathophysiology of SAD has received very little attention. Explanations for the rarity of SAD are suggested.

Trends and outcomes in primary health care expenditures in low-income and middle-income countries, 2000-2017.

INTRODUCTION: As the world responds to COVID-19 and aims for the Sustainable Development Goals, the potential for primary healthcare (PHC) is substantial, although the trends and effectiveness of PHC expenditure are unknown. We estimate PHC expenditure for each low-income and middle-income country between 2000 and 2017 and test which health outputs and outcomes were associated with PHC expenditure. METHODS: We used three data sources to estimate PHC expenditures: recently published health expenditure estimates for each low-income and middle-income country, which were constructed using 1662 country-reported National Health Accounts; proprietary data from IQVIA to estimate expenditure of prescribed pharmaceuticals for PHC; and household surveys and costing estimates to estimate inpatient vaginal delivery expenditures. We employed regression analyses to measure the association between PHC expenditures and 15 health outcomes and intermediate health outputs. RESULTS: PHC expenditures in low-income and middle-income countries increased between 2000 and 2017, from $41 per capita (95% uncertainty interval $33-$49) to $90 ($73-$105). Expenditures for low-income countries plateaued since 2014 at $17 per capita ($15-$19). As national income increased, the proportion of health expenditures on PHC generally decrease; however, the fraction of PHC expenditures spent via ambulatory care providers grew. Increases in the fraction of health expenditures on PHC was associated with lower maternal mortality rate (p value≤0.001), improved coverage of antenatal care visits (p value≤0.001), measles vaccination (p value≤0.001) and an increase in the Health Access and Quality index (p value≤0.05). PHC expenditure was not systematically associated with all-age mortality, communicable and non-communicable disease (NCD) burden. CONCLUSION: PHC expenditures were associated with maternal and child health but were not associated with reduction in health burden for other key causes of disability, such as NCDs. To combat changing disease burdens, policy-makers and health professionals need to adapt primary healthcare to ensure continued impact on emerging health challenges.

18F-FDG-PET/CT in SARS-CoV-2 infection and its sequelae.

In recent months, much of the scientific efforts have focused on research on SARSCoV-2 infection and its consequences in humans. Still, many aspects remain unknown. It is known that the damage caused by SARS-CoV-2 is multifactorial and that its extension goes beyond lung inflammation and the acute phase, with the appearance of numerous complications and sequelae. To date, knowledge about the usefulness of 18F-FDG-PET/CT in the acute phase has been limited to the incidental detection of SARS-CoV-2 unsuspected pneumonia. Recent studies have been appearing collecting the findings of 18F-FDG-PET/CT in long COVID-19 or persistent COVID-19 state as well as the alterations caused after mass vaccination of the population in the metabolic studies. This work aims to review the existing literature focusing on these three issues and to briefly present our own preliminary experience.

Health expenditures by services and providers for 195 countries, 2000-2017.

INTRODUCTION: National Health Accounts are a significant source of health expenditure data, designed to be comprehensive and comparable across countries. However, there is currently no single repository of this data and even when compiled major gaps persist. This research aims to provide policymakers and researchers with a single repository of available national health expenditures by healthcare functions (ie, services) and providers of such services. Leveraging these data within statistical methods, a complete set of detailed health expenditures is estimated. METHODS: A methodical compilation and synthesis of all available national health expenditure reports including disaggregation by healthcare functions and providers was conducted. Using these data, a Bayesian multivariate regression analysis was implemented to estimate national-level health expenditures by the cross-classification of functions and providers for 195 countries, from 2000 to 2017. RESULTS: This research used 1662 country-years and 110 070 data points of health expenditures from existing National Health Accounts. The most detailed country-year had 52% of the categories of interest reported. Of all health functions, curative care and medical goods were estimated to make up 51.4% (uncertainty interval (UI) 33.2% to 59.4%) and 17.5% (UI 13.0% to 26.9%) of total global health expenditures in 2017, respectively. Three-quarters of the global health expenditures are allocated to three categories of providers: hospital providers (35.4%, UI 30.3% to 38.9%), providers of ambulatory care (25.5%, UI 21.1% to 28.8%) and retailers of medical goods (14.4%, UI 12.4% to 16.3%). As gross domestic product increases, countries spend more on long-term care and less on preventive care. CONCLUSION: Disaggregated estimates of health expenditures are often unavailable and unable to provide policymakers and researchers a holistic understanding of how expenditures are used. This research aggregates reported data and provides a complete time-series of estimates, with uncertainty, of health expenditures by health functions and providers between 2000 and 2017 for 195 countries.

Bright Polarized Single-Photon Source Based on a Linear Dipole.

Semiconductor quantum dots in cavities are promising single-photon sources. Here, we present a path to deterministic operation, by harnessing the intrinsic linear dipole in a neutral quantum dot via phonon-assisted excitation. This enables emission of fully polarized single photons, with a measured degree of linear polarization up to 0.994±0.007, and high population inversion-85% as high as resonant excitation. We demonstrate a single-photon source with a polarized first lens brightness of 0.50±0.01, a single-photon purity of 0.954±0.001, and single-photon indistinguishability of 0.909±0.004.

Hong-Ou-Mandel Interference with Imperfect Single Photon Sources.

Hong-Ou-Mandel interference is a cornerstone of optical quantum technologies. We explore both theoretically and experimentally how unwanted multiphoton components of single-photon sources affect the interference visibility, and find that the overlap between the single photons and the noise photons significantly impacts the interference. We apply our approach to quantum dot single-photon sources to access the mean wave packet overlap of the single-photon component. This study provides a consistent platform with which to diagnose the limitations of current single-photon sources on the route towards the ideal device.

[18F-FDG-PET/CT in SARS-CoV-2 infection and its sequelae]. / 18F-FDG-PET/TC ante la infección por SARS-CoV-2 y sus secuelas.

In recent months, much of the scientific efforts have focused on research on SARSCoV-2 infection and its consequences in humans. Still, many aspects remain unknown. It is known that the damage caused by SARS-CoV-2 is multifactorial and that its extension goes beyond lung inflammation and the acute phase, with the appearance of numerous complications and sequelae. To date, knowledge about the usefulness of 18F-FDG-PET/CT in the acute phase has been limited to the incidental detection of SARS-CoV-2 unsuspected pneumonia. Recent studies have been appearing collecting the findings of 18F-FDG- PET/CT in long COVID-19 or persistent COVID-19 state as well as the alterations caused after mass vaccination of the population in the metabolic studies. This work aims to review the existing literature focusing on these three issues and to briefly present our own preliminary experience.

Impact of optimized PET imaging conditions on 18F-FDG uptake quantification in patients with apparently normal aortas.

BACKGROUND: The cardiovascular committee of the European Association of Nuclear Medicine (EANM) recently published recommendations on imaging conditions to be observed during 18F-FDG PET imaging of vascular inflammation. This study aimed to evaluate the impact of applying these optimized imaging conditions on PET quantification of arterial 18F-FDG uptake. METHODS AND RESULTS: Fifty-seven patients were prospectively recruited to undergo an early 18F-FDG PET/CT imaging at 60 minutes and repeat delayed imaging at ≥ 120 minutes post tracer injection. Routine oncologic 18F-FDG PET protocol was observed for early imaging, while delayed imaging parameters were optimized for vascular inflammation imaging as recommended by the EANM. Aortic SUVmax of the ascending aorta and SUVmean from the lumen of the superior vena cava (SVC SUVmean) were obtained on early and delayed imaging. Target-to-background ratio (TBR) was obtained for the early and delayed imaging. Aortic SUVmax increased by a mean of 70%, while SVC SUVmean decreased by a mean of 52% between early and delayed imaging (P < 0.001). TBR increased by 122% following delayed imaging. TBR increased, while SVC SUVmean declined across all time-points from 120 to > 180 minutes. Aortic SUVmax significantly increased at imaging time-points between 120 and 180 minutes. No significant improvement in aortic SUVmax was seen at imaging time-points beyond 180 minutes. CONCLUSIONS: 18F-FDG PET imaging conditions optimized for vascular inflammation imaging lead to an improved quantification through an increase in the quantified vascular tracer uptake and decrease in blood-pool background activity.

Sequential generation of linear cluster states from a single photon emitter.

Light states composed of multiple entangled photons-such as cluster states-are essential for developing and scaling-up quantum computing networks. Photonic cluster states can be obtained from single-photon sources and entangling gates, but so far this has only been done with probabilistic sources constrained to intrinsically low efficiencies, and an increasing hardware overhead. Here, we report the resource-efficient generation of polarization-encoded, individually-addressable photons in linear cluster states occupying a single spatial mode. We employ a single entangling-gate in a fiber loop configuration to sequentially entangle an ever-growing stream of photons originating from the currently most efficient single-photon source technology-a semiconductor quantum dot. With this apparatus, we demonstrate the generation of linear cluster states up to four photons in a single-mode fiber. The reported architecture can be programmed for linear-cluster states of any number of photons, that are required for photonic one-way quantum computing schemes.

Tracking total spending on tuberculosis by source and function in 135 low-income and middle-income countries, 2000-17: a financial modelling study.

BACKGROUND: Estimates of government spending and development assistance for tuberculosis exist, but less is known about out-of-pocket and prepaid private spending. We aimed to provide comprehensive estimates of total spending on tuberculosis in low-income and middle-income countries for 2000-17. METHODS: We extracted data on tuberculosis spending, unit costs, and health-care use from the WHO global tuberculosis database, Global Fund proposals and reports, National Health Accounts, the WHO-Choosing Interventions that are Cost-Effective project database, and the Institute for Health Metrics and Evaluation Development Assistance for Health Database. We extracted data from at least one of these sources for all 135 low-income and middle-income countries using the World Bank 2019 definitions. We estimated tuberculosis spending by source and function for notified (officially reported) and non-notified tuberculosis cases separately and combined, using spatiotemporal Gaussian process regression to fill in for missing data and estimate uncertainty. We aggregated estimates of government, out-of-pocket, prepaid private, and development assistance spending on tuberculosis to estimate total spending in 2019 US$. FINDINGS: Total spending on tuberculosis in 135 low-income and middle-income countries increased annually by 3·9% (95% CI 3·0 to 4·6), from $5·7 billion (5·2 to 6·5) in 2000 to $10·9 billion (10·3 to 11·8) in 2017. Government spending increased annually by 5·1% (4·4 to 5·7) between 2000 and 2017, and reached $6·9 billion (6·5 to 7·5) or 63·5% (59·2 to 66·8) of all tuberculosis spending in 2017. Of government spending, $5·8 billion (5·6 to 6·1) was spent on notified cases. Out-of-pocket spending decreased annually by 0·8% (-2·9 to 1·3), from $2·4 billion (1·9 to 3·1) in 2000 to $2·1 billion (1·6 to 2·7) in 2017. Development assistance for country-specific spending on tuberculosis increased from $54·6 million in 2000 to $1·1 billion in 2017. Administrative costs and development assistance for global projects related to tuberculosis care increased from $85·3 million in 2000 to $576·2 million in 2017. 30 high tuberculosis burden countries of low and middle income accounted for 73·7% (71·8-75·8) of tuberculosis spending in 2017. INTERPRETATION: Despite substantial increases since 2000, funding for tuberculosis is still far short of global financing targets and out-of-pocket spending remains high in resource-constrained countries, posing a barrier to patient's access to care and treatment adherence. Of the 30 countries with a high-burden of tuberculosis, just over half were primarily funded by government, while others, especially lower-middle-income and low-income countries, were still primarily dependent on development assistance for tuberculosis or out-of-pocket health spending. FUNDING: Bill & Melinda Gates Foundation.