Increasing the calcium sensitivity of muscle using trifluoperazine-induced manipulations in silico, in vitro and in vivo systems.

Many therapeutics for cardiomyopathy treat the symptoms of the disease rather than the underlying mechanism. The mechanism of cardiomyopathy onset is believed to include two means: calcium sensitivity changes and myosin activity alteration. Trifluoperazine is a compound that binds troponin, and other components of the calcium pathway, which impacts calcium regulation of contraction. Here, the ability of TFP to shift calcium sensitivity was examined in vitro with purified proteins and the impact of TFP on heart function was assessed in vivo using embryonic zebrafish. The binding of TFP to troponin was modeled in silico and a model of zebrafish troponin was generated. TFP increased regulated cardiac actomyosin activity in vitro and elevated embryonic zebrafish heart rates at effective drug concentrations. Troponin structural changes predicted in silico suggest altered protein interactions within thin filaments that would affect the regulation of heart function.

The risk of venous thromboembolism in atopic dermatitis: a matched cohort analysis in UK primary care.

BACKGROUND: Atopic dermatitis (AD) is a common chronic inflammatory skin condition. While other chronic inflammatory conditions are associated with increased risk of venous thromboembolism (VTE), associations between AD and VTE have not been established. OBJECTIVES: We examined whether AD is associated with an increased risk of VTE in a population-based study. METHODS: Electronic health records were extracted from UK general practices contributing to the Optimum Patient Care Research Database (1 January 2010 to 1 January 2020). All adults with AD were identified (n = 150 975) and age- and sex-matched with unaffected controls (n = 603 770). The risk of VTE, consisting of pulmonary embolism (PE) or deep-vein thrombosis (DVT), was compared in people with AD vs. controls using Cox proportional hazard models. PE and DVT were examined separately as secondary outcomes. RESULTS: We identified 150 975 adults with active AD and matched them with 603 770 unaffected controls. During the study, 2576 of those with active AD and 7563 of the matched controls developed VTE. Individuals with AD had a higher risk of VTE than controls [adjusted hazard ratio (aHR) 1.17, 95% confidence interval (CI) 1.12-1.22]. When assessing VTE components, AD was associated with a higher risk of DVT (aHR 1.30, 95% CI 1.23-1.37) but not PE (aHR 0.94, 95% CI 0.87-1.02). The VTE risk was greater in older people with AD (≥ 65 years: aHR 1.22, 95% CI 1.15-1.29; 45-65 years: aHR 1.15, 95% CI 1.05-1.26; < 45 years: aHR 1.07, 95% CI 0.97-1.19) and those with obesity [body mass index (BMI) ≥ 30: aHR 1.25, 95% CI 1.12-1.39; BMI < 30: aHR 1.08, 95% CI 1.01-1.15). Risk was broadly consistent across mild, moderate or severe AD. CONCLUSIONS: AD is associated with a small increase in risk of VTE and DVT, with no increase in risk of PE. The magnitude of this risk increase is modest in younger people, and those without obesity.

Skin programming of inflammatory responses to Staphylococcus aureus is compartmentalized according to epidermal keratinocyte differentiation status.

BACKGROUND: Acute cutaneous inflammation causes microbiome alterations as well as ultrastructural changes in epidermis stratification. However, the interactions between keratinocyte proliferation and differentiation status and the skin microbiome have not been fully explored. OBJECTIVES: Hypothesizing that the skin microbiome contributes to regulation of keratinocyte differentiation and can modify antimicrobial responses, we examined the effect of exposure to commensal (Staphylococcus epidermidis, SE) or pathogenic (Staphylococcus aureus, SA) challenge on epidermal models. METHODS: Explant biopsies were taken to investigate species-specific antimicrobial effects of host factors. Further investigations were performed in reconstituted epidermal models by bulk transcriptomic analysis alongside secreted protein profiling. Single-cell RNA sequencing analysis was performed to explore the keratinocyte populations responsible for SA inflammation. A dataset of 6391 keratinocytes from control (2044 cells), SE challenge (2028 cells) and SA challenge (2319 cells) was generated from reconstituted epidermal models. RESULTS: Bacterial lawns of SA, not SE, were inhibited by human skin explant samples, and microarray analysis of three-dimensional epidermis models showed that host antimicrobial peptide expression was induced by SE but not SA. Protein analysis of bacterial cocultured models showed that SA exposure induced inflammatory mediator expression, indicating keratinocyte activation of other epidermal immune populations. Single-cell DropSeq analysis of unchallenged naive, SE-challenged and SA-challenged epidermis models was undertaken to distinguish cells from basal, spinous and granular layers, and to interrogate them in relation to model exposure. In contrast to SE, SA specifically induced a subpopulation of spinous cells that highly expressed transcripts related to epidermal inflammation and antimicrobial response. Furthermore, SA, but not SE, specifically induced a basal population that highly expressed interleukin-1 alarmins. CONCLUSIONS: These findings suggest that SA-associated remodelling of the epidermis is compartmentalized to different keratinocyte populations. Elucidating the mechanisms regulating bacterial sensing-triggered inflammatory responses within tissues will enable further understanding of microbiome dysbiosis and inflammatory skin diseases, such as atopic eczema.

Mapping exercise and status update of eight established registries within the TREatment of ATopic eczema Registry Taskforce.

BACKGROUND: The TREatment of ATopic eczema (TREAT) Registry Taskforce is a collaborative international network of registries collecting data of atopic eczema (AE) patients receiving systemic and phototherapy with the common goal to provide long-term real-world data on the effectiveness, safety and cost-effectiveness of therapies. A core dataset, consisting of domains and domain items with corresponding measurement instruments, has been developed to harmonize data collection. OBJECTIVES: We aimed to give an overview of the status and characteristics of the eight established TREAT registries, and to perform a mapping exercise to examine the degree of overlap and pooling ability between the national registry datasets. This will allow us to determine which research questions can be answered in the future by pooling data. METHODS: All eight registries were asked to share their dataset and information on the current status and characteristics. The overlap between the core dataset and each registry dataset was identified (according to the domains, domain items and measurement instruments of the TREAT core dataset). RESULTS AND CONCLUSIONS: A total of 4702 participants have been recruited in the eight registries as of 1st of May 2022. Of the 69 core dataset domain items, data pooling was possible for 69 domain item outcomes in TREAT NL (the Netherlands), 61 items in A-STAR (UK and Ireland), 38 items in TREATgermany (Germany), 36 items in FIRST (France), 33 items in AtopyReg (Italy), 29 items in Biobadatop (Spain), 28 items in SCRATCH (Denmark) and 20 items in SwedAD (Sweden). Pooled analyses across all registries can be performed on multiple important domain items, covering the main aims of analysing data on the (cost-)effectiveness and safety of AE therapies. These results will facilitate future comparative or joint analyses.

Electromagnetic Sensing Techniques for Monitoring Atopic Dermatitis-Current Practices and Possible Advancements: A Review.

Atopic dermatitis (AD) is one of the most common skin disorders, affecting nearly one-fifth of children and adolescents worldwide, and currently, the only method of monitoring the condition is through an in-person visual examination by a clinician. This method of assessment poses an inherent risk of subjectivity and can be restrictive to patients who do not have access to or cannot visit hospitals. Advances in digital sensing technologies can serve as a foundation for the development of a new generation of e-health devices that provide accurate and empirical evaluation of the condition to patients worldwide. The goal of this review is to study the past, present, and future of AD monitoring. First, current medical practices such as biopsy, tape stripping and blood serum are discussed with their merits and demerits. Then, alternative digital methods of medical evaluation are highlighted with the focus on non-invasive monitoring using biomarkers of AD-TEWL, skin permittivity, elasticity, and pruritus. Finally, possible future technologies are showcased such as radio frequency reflectometry and optical spectroscopy along with a short discussion to provoke research into improving the current techniques and employing the new ones to develop an AD monitoring device, which could eventually facilitate medical diagnosis.

Correction: Todorov et al. Electromagnetic Sensing Techniques for Monitoring Atopic Dermatitis-Current Practices and Possible Advancements: A Review. Sensors 2023, 23, 3935.

**Mahmoud Wagih** was not included as an author in the original publication [...].

Dynamics of diverse coherences in primary charge separation of bacterial reaction center at 77 K revealed by wavelet analysis.

To uncover the mechanism behind the high photo-electronic conversion efficiency in natural photosynthetic complexes it is essential to trace the dynamics of electronic and vibrational quantum coherences. Here we apply wavelet analysis to two-dimensional electronic spectroscopy data for three purple bacterial reaction centers with mutations that produce drastically different rates of primary charge separation. From the frequency distribution and dynamic evolution features of the quantum beating, electronic coherence with a dephasing lifetime of ~50 fs, vibronic coherence with a lifetime of ~150 fs and vibrational/vibronic coherences with a lifetime of 450 fs are distinguished. We find that they are responsible for, or couple to, different specific steps during the primary charge separation process, i.e., intradimer charge transfer inside the special bacteriochlorophyll pair followed by its relaxation and stabilization of the charge-transfer state. The results enlighten our understanding of how quantum coherences participate in, and contribute to, a biological electron transfer reaction.

Obtaining QM/MM binding free energies in the SAMPL8 drugs of abuse challenge: indirect approaches.

Accurately predicting free energy differences is essential in realizing the full potential of rational drug design. Unfortunately, high levels of accuracy often require computationally expensive QM/MM Hamiltonians. Fortuitously, the cost of employing QM/MM approaches in rigorous free energy simulation can be reduced through the use of the so-called "indirect" approach to QM/MM free energies, in which the need for QM/MM simulations is avoided via a QM/MM "correction" at the classical endpoints of interest. Herein, we focus on the computation of QM/MM binding free energies in the context of the SAMPL8 Drugs of Abuse host-guest challenge. Of the 5 QM/MM correction coupled with force-matching submissions, PM6-D3H4/MM ranked submission proved the best overall QM/MM entry, with an RMSE from experimental results of 2.43 kcal/mol (best in ranked submissions), a Pearson's correlation of 0.78 (second-best in ranked submissions), and a Kendall [Formula: see text] correlation of 0.52 (best in ranked submissions).

Hospital outcomes in pediatric patients with Prader-Willi syndrome (PWS) undergoing orthopedic surgery: A 12-year analysis of national trends in surgical management and inpatient hospital outcomes.

BACKGROUND: The incidence of orthopedic disorders amongst patients with Prader-Willi Syndrome (PWS) is high when compared to the general pediatric population. The purpose of this retrospective study was to define the most commonly performed orthopedic procedures in pediatric patients with PWS and to characterize the peri-operative outcomes of these patients. METHODS: The Kids Inpatient Database (KID) was queried to collect data and identify all pediatric patients with PWS who underwent orthopedic procedures from 2001 to 2012. A total of 3684 patients with PWS were identified, 334 of who underwent an orthopedic procedure. Population demographics, comorbidities, and specific procedures undergone were defined. The incidences of postoperative complications and length of associated hospital stay were additionally evaluated. RESULTS: Mean age of patients in this sample was 10.33 years (SD 4.5). The most common comorbidities included obesity (18.1%), chronic pulmonary disease (14.1%), hypothyroidism (5.1%), hypertension (5.1%), and uncomplicated diabetes (4%). Common procedures were spinal fusion (165/334, 49%) and lower extremity procedures (50/334, 15%). Complications included acute blood loss anemia, device related complications, pneumonia, sepsis, and urinary tract infections. The overall complication rate was 35.6%. Average hospital lengths of stay for patients undergoing spinal fusion was 6.68 days (SD 4.13), lower extremity orthopedic procedure was 5.65 days (SD 7.4), and all other orthopedic procedures was 7.74 days (SD 16.3). CONCLUSIONS: Orthopedic disorders are common in patients with PWS. Consequently, spinal fusions and lower extremity procedures are commonly performed in this patient population. Associated comorbid conditions may negatively impact surgical outcomes in these patients. This information should prove useful in the peri-operative management of patients with PWS undergoing orthopedic surgery and for shared decision making with families.

Sustaining Electron Transfer Pathways Extends Biohybrid Photoelectrode Stability to Years.

The exploitation of natural photosynthetic enzymes in semi-artificial devices constitutes an attractive and potentially sustainable route for the conversion of solar energy into electricity and solar fuels. However, the stability of photosynthetic proteins after incorporation in a biohybrid architecture typically limits the operational lifetime of biophotoelectrodes to a few hours. Here, we demonstrate ways to greatly enhance the stability of a mesoporous electrode coated with the RC-LH1 photoprotein from Rhodobacter sphaeroides. By preserving electron transfer pathways, we extended operation under continuous high-light to 33 days, and operation after storage to over two years. Coupled with large photocurrents that reached peak values of 4.6 mA cm-2 , the optimized biophotoelectrode produced a cumulative output of 86 C cm-2 , the largest reported performance to date. Our results demonstrate that the factor limiting stability is the architecture surrounding the photoprotein, and that biohybrid sensors and photovoltaic devices with operational lifetimes of years are feasible.

Baseline Cognitive Impairment in Patients With Asymptomatic Carotid Stenosis in the CREST-2 Trial.

BACKGROUND AND PURPOSE: Studies of carotid artery disease have suggested that high-grade stenosis can affect cognition, even without stroke. The presence and degree of cognitive impairment in such patients have not been reported and compared with a demographically matched population-based cohort. METHODS: We studied cognition in 1000 consecutive CREST-2 (Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial) patients, a treatment trial for asymptomatic carotid disease. Cognitive assessment was after randomization but before assigned treatment. The cognitive battery was developed in the general population REGARDS Study (Reasons for Geographic and Racial Differences in Stroke), involving Word List Learning Sum, Word List Recall, and Word List fluency for animal names and the letter F. The carotid stenosis patients were >45 years old with ≥70% asymptomatic carotid stenosis and no history of prevalent stroke. The distribution of cognitive performance for the patients was standardized, accounting for age, race, and education using performance from REGARDS, and after further adjustment for hypertension, diabetes, dyslipidemia, and smoking. Using the Wald Test, we tabulated the proportion of Z scores less than the anticipated deviate for the population-based cohort for representative percentiles. RESULTS: There were 786 baseline assessments. Mean age was 70 years, 58% men, and 52% right-sided stenosis. The overall Z score for patients was significantly below expected for higher percentiles (P<0.0001 for 50th, 75th, and 95th percentiles) and marginally below expected for the 25th percentile (P=0.015). Lower performance was attributed largely to Word List Recall (P<0.0001 for all percentiles) and for Word List Learning (50th, 75th, and 95th percentiles below expected, P≤0.01). The scores for left versus right carotid disease were similar. CONCLUSIONS: Baseline cognition of patients with severe carotid stenosis showed below normal cognition compared to the population-based cohort, controlling for demographic and cardiovascular risk factors. This cohort represents the largest group to date to demonstrate that poorer cognition, especially memory, in this disease. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02089217.

Temperature dependence of nanosecond charge recombination in mutant Rhodobacter sphaeroides reaction centers: modelling of the protein dynamics.

We investigated the influence of a range of factors-temperature, redox midpoint potential of an electron carrier, and protein dynamics-on nanosecond electron transfer within a protein. The model reaction was back electron transfer from a bacteriopheophytin anion, HA-, to an oxidized primary electron donor, P+, in a wild type Rhodobacter sphaeroides reaction center (RC) with a permanently reduced secondary electron acceptor (quinone, QA-). Also used were two modified RCs with single amino acid mutations near the monomeric bacteriochlorophyll, BA, located between P and HA. Both mutant RCs showed significant slowing down of this back electron transfer reaction with decreasing temperature, similar to that observed with the wild type RC, but contrasting with a number of single point mutant RCs studied previously. The observed similarities and differences are explained in the framework of a (P+BA- ↔ P+HA-) equilibrium model with an important role played by protein relaxation. The major cause of the observed temperature dependence, both in the wild type RC and in the mutant proteins, is a limitation in access to the thermally activated pathway of charge recombination via the state P+BA- at low temperatures. The data indicate that in all RCs both charge recombination pathways, the thermally activated one and a direct one without involvement of the P+BA- state, are controlled by the protein dynamics. It is concluded that the modifications of the protein environment affect the overall back electron transfer kinetics primarily by changing the redox potential of BA and not by changing the protein relaxation dynamics.

A replica exchange umbrella sampling (REUS) approach to predict host-guest binding free energies in SAMPL8 challenge.

In this study, we report binding free energy calculations of various drugs-of-abuse to Cucurbit-[8]-uril as part of the SAMPL8 blind challenge. Force-field parameters were obtained from force-matching with different quantum mechanical levels of theory. The Replica Exchange Umbrella Sampling (REUS) approach was used with a cylindrical restraint to enhance the sampling of host-guest binding. Binding free energy was calculated by pulling the guest molecule from one side of the symmetric and cylindrical host, then into and through the host, and out the other side (bidirectional) as compared to pulling only to the bound pose inside the cylindrical host (unidirectional). The initial results with force-matched MP2 parameter set led to RMSE of 4.68 [Formula: see text] from experimental values. However, the follow-up study with CHARMM generalized force field parameters and force-matched PM6-D3H4 parameters resulted in RMSEs from experiment of [Formula: see text] and [Formula: see text], respectively, which demonstrates the potential of REUS for accurate binding free energy calculation given a more suitable description of energetics. Moreover, we compared the free energies for the so called bidirectional and unidirectional free energy approach and found that the binding free energies were highly similar. However, one issue in the bidirectional approach is the asymmetry of profile on the two sides of the host. This is mainly due to the insufficient sampling for these larger systems and can be avoided by longer sampling simulations. Overall REUS shows great promise for binding free energy calculations.

High-pressure tuning of primary photochemistry in bacterial photosynthesis: membrane-bound versus detergent-isolated reaction centers.

While photosynthesis thrives at close to normal pressures and temperatures, it is presently well known that life is similarly commonplace in the hostile environments of the deep seas as well as around hydrothermal vents. It is thus imperative to understand how key biological processes perform under extreme conditions of high pressures and temperatures. Herein, comparative steady-state and picosecond time-resolved spectroscopic studies were performed on membrane-bound and detergent-purified forms of a YM210W mutant reaction center (RC) from Rhodobacter sphaeroides under modulating conditions of high hydrostatic pressure applied at ambient temperature. A previously established breakage of the lone hydrogen bond formed between the RC primary donor and the protein scaffold was shown to take place in the membrane-bound RC at an almost 3 kbar higher pressure than in the purified RC, confirming the stabilizing role of the lipid environment for membrane proteins. The main change in the multi-exponential decay of excited primary donor emission across the experimental 10 kbar pressure range involved an over two-fold continuous acceleration, the kinetics becoming increasingly mono-exponential. The fastest component of the emission decay, thought to be largely governed by the rate of primary charge separation, was distinctly slower in the membrane-bound RC than in the purified RC. The change in character of the emission decay with pressure was explained by the contribution of charge recombination to emission decreasing with pressure as a result of an increasing free energy gap between the charge-separated and excited primary donor states. Finally, it was demonstrated that, in contrast to a long-term experimental paradigm, adding a combination of sodium ascorbate and phenazine methosulfate to the protein solution potentially distorts natural photochemistry in bacterial RCs.

Quantum chemical predictions of water-octanol partition coefficients applied to the SAMPL6 logP blind challenge.

Theoretical approaches for predicting physicochemical properties are valuable tools for accelerating the drug discovery process. In this work, quantum chemical methods are used to predict water-octanol partition coefficients as a part of the SAMPL6 blind challenge. The SMD continuum solvent model was employed with MP2 and eight DFT functionals in conjunction with correlation consistent basis sets to determine the water-octanol transfer free energy. Several tactics towards improving the predictions of the partition coefficient were examined, including increasing the quality of basis sets, considering tautomerization, and accounting for inhomogeneities in the water and n-octanol phases. Evaluation of these various schemes highlights the impact of modeling approaches across different methods. With the inclusion of tautomers and adjustments to the permittivity constants, the best predictions were obtained with smaller basis sets and the O3LYP functional, which yielded an RMSE of 0.79 logP units. The results presented correspond to the SAMPL6 logP submission IDs: DYXBT, O7DJK, and AHMTF.

Multi-phase Boltzmann weighting: accounting for local inhomogeneity in molecular simulations of water-octanol partition coefficients in the SAMPL6 challenge.

Accurately computing partition coefficients is a pivotal part of drug discovery. Specifically, octanol-water partition coefficients can provide information into hydrophobicity of drug-like molecules, as well as a de facto representation of membrane permeability. However, one challenge facing the computation of partition coefficients is the need to encapsulate various microscopic environments. These include areas of largely bulk solvent (i.e., either water or octanol) or regions where octanol is saturated with water or areas of higher salt concentration. Also, tautomeric effects require consideration. Thus, we present a Boltzmann weighting approach that incorporates transfer free energies across varying microscopic media, as well as varying tautomeric state, to compute partition coefficients in the SAMPL6 challenge.

SAMPL6 logP challenge: machine learning and quantum mechanical approaches.

Two different types of approaches: (a) approaches that combine quantitative structure activity relationships, quantum mechanical electronic structure methods, and machine-learning and, (b) electronic structure vertical solvation approaches, were used to predict the logP coefficients of 11 molecules as part of the SAMPL6 logP blind prediction challenge. Using electronic structures optimized with density functional theory (DFT), several molecular descriptors were calculated for each molecule, including van der Waals areas and volumes, HOMO/LUMO energies, dipole moments, polarizabilities, and electrophilic and nucleophilic superdelocalizabilities. A multilinear regression model and a partial least squares model were used to train a set of 97 molecules. As well, descriptors were generated using the molecular operating environment and used to create additional machine learning models. Electronic structure vertical solvation approaches considered include DFT and the domain-based local pair natural orbital methods combined with the solvated variant of the correlation consistent composite approach.

Mechanisms of Self-Assembly and Energy Harvesting in Tuneable Conjugates of Quantum Dots and Engineered Photovoltaic Proteins.

Photoreaction centers facilitate the solar energy transduction at the heart of photosynthesis and there is increasing interest in their incorporation into biohybrid devices for solar energy conversion, sensing, and other applications. In this work, the self-assembly of conjugates between engineered bacterial reaction centers (RCs) and quantum dots (QDs) that act as a synthetic light harvesting system is described. The interface between protein and QD is provided by a polyhistidine tag that confers a tight and specific binding and defines the geometry of the interaction. Protein engineering that changes the pigment composition of the RC is used to identify Förster resonance energy transfer as the mechanism through which QDs can drive RC photochemistry with a high energy transfer efficiency. A thermodynamic explanation of RC/QD conjugation based on a multiple/independent binding model is provided. It is also demonstrated that the presence of multiple binding sites affects energy coupling not only between RCs and QDs but also among the bound RCs themselves, effects which likely stem from restricted RC dynamics at the QD surface in denser conjugates. These findings are readily transferrable to many other conjugate systems between proteins or combinations of proteins and other nanomaterials.

Duration of asymptomatic status and outcomes following carotid endarterectomy and carotid artery stenting in the Carotid Revascularization Endarterectomy vs Stenting Trial.

BACKGROUND: Most carotid revascularization studies define asymptomatic as symptom-free for more than 180 days; however, it is unknown if intervention carries similar risk among those currently asymptomatic but with previous symptoms (PS) vs those who were always asymptomatic (AA). METHODS: We compared the periprocedural and 4-year risks of PS vs AA patients in the Carotid Revascularization Endarterectomy vs Stenting Trial (CREST) randomized to carotid endarterectomy (CEA) or carotid artery stenting (CAS)/angioplasty. Proportional hazards models adjusting for age, sex, and treatment were used to assess the risk of periprocedural stroke and/or death (S+D; any S+D during periprocedural period), stroke and death at 4 years (any S+D within the periprocedural period and ipsilateral stroke out to 4 years) and the primary end point at 4 years (any stroke, death, and myocardial infarction within the periprocedural period and ipsilateral stroke out to 4 years). Analysis was performed pooling the CEA-treated and CAS-treated patients, and separately for each treatment. RESULTS: Of 1181 asymptomatic patients randomized in CREST, 1104 (93%) were AA and 77 (7%) were PS. There was no difference in risk when comparing the AA and PS cohorts in the pooled CAS+CEA population for periprocedural S+D (2.0% vs 1.3%), S+D at 4 years (3.6% vs 3.2%), or the primary end point (5.2% vs 5.8%). There were also no differences among those assigned to CEA (periprocedural S+D, 1.5% vs 0%; S+D at 4 years, 2.7% vs 0%; or primary end point, 5.1% vs 2.4%) or CAS (periprocedural S+D, 2.5% vs 2.8%; S+D at 4 years, 4.4% vs 6.9%; or primary end point, 5.3% vs 9.8%) when analyzed separately. CONCLUSIONS: In CREST, only a small minority of asymptomatic patients had previous ipsilateral symptoms. The outcomes of periprocedural S+D, periprocedural S+D, and ipsilateral stroke up to 4 years, and the primary end point did not differ for AA patients compared with PS patients.

EAACI position paper on how to classify cutaneous manifestations of drug hypersensitivity.

Drug hypersensitivity reactions (DHRs) are common, and the skin is by far the most frequently involved organ with a broad spectrum of reaction types. The diagnosis of cutaneous DHRs (CDHR) may be difficult because of multiple differential diagnoses. A correct classification is important for the correct diagnosis and management. With these guidelines, we aim to give precise definitions and provide the background needed for doctors to correctly classify CDHR.