Benchmarking performance of SENS-IS assay against weight of evidence skin sensitization potency categories.

Potency determination of potential skin sensitizers in humans is essential for quantitative risk assessment and proper risk management. SENS-IS is an in vitro test based on a reconstructed human skin model, that was developed to predict the hazard and potency of potential skin sensitizers. The performance of the SENS-IS assay in potency prediction for 174 materials was evaluated for this work. The potency used as a benchmark was determined based on the weight of evidence approach, by collectively considering all well-established test data, including human, animal, in chemico, in vitro, and in silico data. Based on this weight of evidence approach, the dataset was composed of 5, 19, 34, 54, and 38 extreme, strong, moderate, weak, and very weak sensitizers, respectively, as well as 24 non-sensitizers. SENS-IS provided good prediction of the skin sensitization potency for 85% of this dataset, with precise and approximate prediction on 46% and 39% of the 174 materials, respectively. Our evaluation showed that SENS-IS provides a good approximation of the skin sensitization potency.

Updating the Dermal Sensitisation Thresholds using an expanded dataset and an in silico expert system.

The Dermal Sensitisation Thresholds (DST) are Thresholds of Toxicological Concern, which can be used to justify exposure-based waiving when conducting a skin sensitisation risk assessment. This study aimed to update the published DST values by expanding the size of the Local Lymph Node Assay dataset upon which they are based, whilst assigning chemical reactivity using an in silico expert system (Derek Nexus). The potency values within the expanded dataset fitted a similar gamma distribution to that observed for the original dataset. Derek Nexus was used to classify the sensitisation activity of the 1152 chemicals in the expanded dataset and to predict which chemicals belonged to a High Potency Category (HPC). This two-step classification led to three updated thresholds: a non-reactive DST of 710 µg/cm2 (based on 79 sensitisers), a reactive (non-HPC) DST of 73 µg/cm2 (based on 331 sensitisers) and an HPC DST of 1.0 µg/cm2 (based on 146 sensitisers). Despite the dataset containing twice as many sensitisers, these values are similar to the previously published thresholds, highlighting their robustness and increasing confidence in their use. By classifying reactivity in silico the updated DSTs can be applied within a skin sensitisation risk assessment in a reproducible, scalable and accessible manner.

Left ventricular fibroma presenting as esophageal spasm: A case report.

Primary tumors of the heart are rare with fibromas most commonly identified in utero or infancy and rarely developing in adulthood. Patients with cardiac fibromas are often asymptomatic until tumor enlargement results in obstructive and nonspecific symptoms. A 39-year-old female presented with 5-year history of recurrent chest pain with functional dysphagia, indicative of esophageal spasm. Imaging identified a large left ventricular (LV) fibroma compressing the esophagus provoking esophageal spasm. The fibroma was excised measuring 51 × 39 mm. This case describes presentation with esophageal spasm, contributing a novel presentation of LV fibroma to the literature.

Clustering a Chemical Inventory for Safety Assessment of Fragrance Ingredients: Identifying Read-Across Analogs to Address Data Gaps.

A valuable approach to chemical safety assessment is the use of read-across chemicals to provide safety data to support the assessment of structurally similar chemicals. An inventory of over 6000 discrete organic chemicals used as fragrance materials in consumer products has been clustered into chemical class-based groups for efficient search of read-across sources. We developed a robust, tiered system for chemical classification based on (1) organic functional group, (2) structural similarity and reactivity features of the hydrocarbon skeletons, (3) predicted or experimentally verified Phase I and Phase II metabolism, and (4) expert pruning to consider these variables in the context of specific toxicity end points. The systematic combination of these data yielded clusters, which may be visualized as a top-down hierarchical clustering tree. In this tree, chemical classes are formed at the highest level according to organic functional groups. Each subsequent subcluster stemming from classes in this hierarchy of the cluster is a chemical cluster defined by common organic functional groups and close similarity in the hydrocarbon skeleton. By examining the available experimental data for a toxicological endpoint within each cluster, users can better identify potential read-across chemicals to support safety assessments.

Muscle mass drives cost in sexually selected arthropod weapons.

Sexually selected weapons often function as honest signals of fighting ability. If poor-quality individuals produce high-quality weapons, then receivers should focus on other, more reliable signals. Cost is one way to maintain signal integrity. The costs of weapons tend to increase with relative weapon size, and thereby restrict large weapons to high-quality individuals who can produce and maintain them. Weapon cost, however, appears to be unpredictably variable both within and across taxa, and the mechanisms underlying this variation remain unclear. We suggest variation in weapon cost may result from variation in weapon composition-specifically, differences in the amount of muscle mass directly associated with the weapon. We test this idea by measuring the metabolic cost of sexually selected weapons in seven arthropod species and relating these measures to weapon muscle mass. We show that individuals with relatively large weapon muscles have disproportionately high resting metabolic rates and provide evidence that this trend is driven by weapon muscle mass. Overall, our results suggest that variation in weapon cost can be partially explained by variation in weapon morphology and that the integrity of weapon signals may be maintained by increased metabolic cost in species with relatively high weapon muscle mass.

Making reliable negative predictions of human skin sensitisation using an in silico fragmentation approach.

A previously published fragmentation method for making reliable negative in silico predictions has been applied to the problem of predicting skin sensitisation in humans, making use of a dataset of over 2750 chemicals with publicly available skin sensitisation data from 18 in vivo assays. An assay hierarchy was designed to enable the classification of chemicals within this dataset as either sensitisers or non-sensitisers where data from more than one in vivo test was available. The negative prediction approach was validated internally, using a 5-fold cross-validation, and externally, against a proprietary dataset of approximately 1000 chemicals with in vivo reference data shared by members of the pharmaceutical, nutritional, and personal care industries. The negative predictivity for this proprietary dataset was high in all cases (>75%), and the model was also able to identify structural features that resulted in a lower accuracy or a higher uncertainty in the negative prediction, termed misclassified and unclassified features respectively. These features could serve as an aid for further expert assessment of the negative in silico prediction.

A quantitative in silico model for predicting skin sensitization using a nearest neighbours approach within expert-derived structure-activity alert spaces.

Dermal contact with chemicals may lead to an inflammatory reaction known as allergic contact dermatitis. Consequently, it is important to assess new and existing chemicals for their skin sensitizing potential and to mitigate exposure accordingly. There is an urgent need to develop quantitative non-animal methods to better predict the potency of potential sensitizers, driven largely by European Union (EU) Regulation 1223/2009, which forbids the use of animal tests for cosmetic ingredients sold in the EU. A Nearest Neighbours in silico model was developed using an in-house dataset of 1096 murine local lymph node (LLNA) studies. The EC3 value (the effective concentration of the test substance producing a threefold increase in the stimulation index compared to controls) of a given chemical was predicted using the weighted average of EC3 values of up to 10 most similar compounds within the same mechanistic space (as defined by activating the same Derek skin sensitization alert). The model was validated using previously unseen internal (n = 45) and external (n = 103) data and accuracy of predictions assessed using a threefold error, fivefold error, European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC) and Globally Harmonized System of Classification and Labelling of Chemicals (GHS) classifications. In particular, the model predicts the GHS skin sensitization category of compounds well, predicting 64% of chemicals in an external test set within the correct category. Of the remaining chemicals in the previously unseen dataset, 25% were over-predicted (GHS 1A predicted: GHS 1B experimentally) and 11% were under-predicted (GHS 1B predicted: GHS 1A experimentally). Copyright © 2017 John Wiley & Sons, Ltd.

The Use of the Ascyrus Medical Dissection Stent in Acute Type A Aortic Dissection Repair Reduces Distal Anastomotic New Entry Tear.

BACKGROUND: A distal anastomotic new entry tear (DANE) can occur at the time of surgical repair for acute type A aortic dissection (ATAAD). This study aimed to compare the occurrence of DANE following a standard hemiarch repair with that following a hemiarch repair with an uncovered arch dissection stent. METHODS: All patients who received a hemiarch repair or a hemiarch repair with an Ascyrus Medical Dissection Stent (AMDS) for ATAAD from 2017 to 2021 were included. Baseline and intra- and postoperative characteristics were collected. All available pre- and postoperative computed tomographic scans were analysed. The primary outcome measures were the incidence of DANE, positive aortic remodelling, mortality, and aortic reintervention rates at last follow-up. RESULTS: A total of 114 patients underwent repair of Debakey I ATAAD during the study period with either an isolated hemiarch (n = 77) or a hemiarch with AMDS (n = 37). There was no significant difference in mortality (P = 0.768) or other in-hospital adverse events. During the follow-up period, DANE occurred in 43.3% (n = 26) of the isolated hemiarch group and in 11.8% (n = 4) of the hemiarch with AMDS group (P = 0.002). The incidence of false lumen thrombosis and obliteration favoured the AMDS group in the aortic arch (P = 0.029), the proximal descending thoracic aorta (P = 0.031), and level of pulmonary artery bifurcation (P = 0.044). CONCLUSIONS: The incidence of DANE is significantly reduced with the addition of an AMDS at the time of hemiarch repair for ATAAD repair. Further follow-up is necessary to identify late aortic complications that may have been prevented by reducing the incidence of postoperative DANE.

Morphological and functional analyses for investigation of sexually selected legs in the frog legged beetle Sagra femorata (Coleoptera: Chrysomelidae).

Mate choice and male-male combat over successful mating often cause disproportionate exaggeration of male trait relative to body size. However, the exaggeration is often not the only trait involved with male-male combat and mate choice: suites of co-expressed traits may function together as a coordinated unit. When this occurs, dimorphism may be expected for these additional, non-exaggerated, structures. S. femorata males have disproportionately large hind-legs used in male-male combat over females. During the fights, fore- and mid-legs are used to keep males in positions where advantageous for leverage. Because use of the exaggerated hind-legs is coordinated with the other legs, they will coevolve as a functional unit. Here, we show that 1) S. femorata has sexual size differences in all three legs; 2) males show positive allometry in the relative sizes of all three legs; and 3) microstructures of tarsi on the fore- and mid-legs are also sexually dimorphic. Despite these differences in the tarsal microstructure, 4) adhesion forces of the tarsi had no sexual difference in flat surface. The microstructure would be specialized on attaching elytra surface. These results suggest that the three pairs of legs function together during fighting behavior, with hind-legs employed primarily for fighting, and the fore- and mid-legs functioning to grip females, keeping males positioned on the back of the female during combat.

Right ventricular laceration caused by sternal wire fracture following cardiac surgery: a case report.

Sternal dehiscence and sternal wire fractures are of significant concern for patients post cardiac surgery. Right ventricular laceration resulting from injury secondary to fractured sternal wires is a rare cause of life-threatening postoperative hemorrhage. A 68-year-old male presented for coronary artery bypass grafting (CABG). Postoperatively, he experienced an exacerbation of chronic obstructive pulmonary disease (COPD) which initially responded to medical treatment. While mobilizing, the patient experienced acute hemodynamic decompensation. Chest X-ray revealed a new left pleural effusion and a bedside echocardiogram revealed significant pericardial effusion. The patient was taken urgently for re-exploration with a diagnosis of cardiac tamponade. All sternal wires were found to be fractured and a right ventricular laceration was identified. The laceration was repaired primarily with sutures and the sternum was closed with reinforced sternal wires. The patient recovered well postoperatively and was discharged without further complication. Postoperative hemorrhage is a known complication of cardiac surgery but is rarely caused by laceration secondary to sternal wire fracture. Alternative sternal closure techniques should be considered in high-risk groups of patients. A high index of suspicion should be maintained for patients with sternal dehiscence. Furthermore, these patients should be monitored closely and definitive management implemented immediately when sternal wire fracture and resulting injury are suspected.

Expression Analysis in a Dispersal-Fecundity Polyphenism Identifies Growth Regulators and Effectors.

Polyphenism allows organisms to respond to varying environmental conditions by adopting alternative collections of morphological traits, often leading to different reproductive strategies. In many insects, polyphenism affecting the development of flight trades dispersal ability for increased fecundity. The soapberry bug Jadera haematoloma (Hemiptera: Rhopalidae) exhibits wing polyphenism in response to juvenile nutritional resources and cohort density. Development of full-length wings and flight-capable thoracic muscles occurs more frequently in cohorts raised under low food density conditions, and these features are correlated to reduced female fecundity. Soapberry bugs represent an example of polyphenic dispersal-fecundity trade-off. Short-wing development is not sex-limited, and morphs can also differ in male fertility. We have previously shown, via a candidate gene approach, that manipulation of insulin signaling can alter the threshold for nutritional response and that changes in the activity of this pathway underlie, at least in part, differences in the polyphenic thresholds in different host-adapted populations of J. haematoloma. We now expand the examination of this system using transcriptome sequencing across a multidimensional matrix of life stage, tissue, sex, food density, and host population. We also examine the use of wing and thorax shape as factors modeling gene expression. In addition to insulin signaling, we find that components of the TOR, Hippo, Toll, and estrogen-related receptor pathways are differentially expressed in the thorax of polyphenic morphs. The transcription factor Sox14 was one of the few genes differentially expressed in the gonads of morphs, being up-regulated in ovaries. We identify two transcription factors as potential mediators of morph-specific male fertility differences. We also find that bugs respond to nutrient limitation with expression of genes linked to cuticle structure and spermatogenesis. These findings provide a broad perspective from which to view this nutrition-dependent polyphenism.

Weight of Evidence Approach for Skin Sensitization Potency Categorization of Fragrance Ingredients.

BACKGROUND: Reliable human potency data are necessary for conducting quantitative risk assessments, as well as development and validation of new nonanimal methods for skin sensitization assessments. Previously, human skin sensitization potency of fragrance materials was derived primarily from human data or the local lymph node assay. OBJECTIVES: This study aimed to define skin sensitization potency of fragrance materials via weight of evidence approach, incorporating all available human, animal, in vitro, in chemico, and in silico data. METHODS: All available data on 106 fragrance materials were considered to assign each material into 1 of the 6 defined potency categories (extreme, strong, moderate, weak, very weak, and nonsensitizer). RESULTS: None of the 106 materials were considered an extreme sensitizer, whereas a total of 6, 23, 41, and 26 materials were categorized as strong, moderate, weak, and very weak sensitizers, respectively. Ten materials lacked evidence for the induction of skin sensitization. CONCLUSIONS: Skin sensitization potency categorization of the 106 fragrance materials based on the described weight of evidence approach can serve as a useful resource in evaluation of nonanimal methods, as well as in risk assessment.

Thoracic Endovascular Aortic Repair Stent Deployed in the Ascyrus Medical Dissection Stent.

The Ascyrus Medical Dissection Stent (AMDS) has proved to promote false lumen closure at the distal anastomosis in type A dissection repairs. During the past 20 years, open techniques have developed into endovascular repairs. We report a case of thoracic endovascular aortic repair (TEVAR) landed inside an AMDS. A 63-year-old man with hypertension presented with type A aortic dissection. After initial repair with AMDS, he returned for TEVAR to fix residual type B dissection. A proper seal was created between the AMDS and TEVAR stents, demonstrating a successful off-label use of the AMDS stent.

Assessment of the skin sensitization potential of fragrance ingredients using the U-SENS™ assay.

The U-SENS™ assay was developed to address the third key event of the skin sensitization adverse outcome pathway (AOP) and is described in OECD test guideline 442E, Annex II. A dataset of 68 fragrance ingredients comprised of 7 non-sensitizers and 61 sensitizers was tested in the U-SENS™ assay. The potential for fragrance ingredients to activate dendritic cells, measured by U-SENS™, was compared to the sensitization potential determined by weight of evidence (WoE) from historical data. Of the non-sensitizers, 4 induced CD86 cell surface marker ≥1.5-fold while 3 did not. Of the sensitizers, 50 were predicted to be positive in U-SENS™, while the remaining 11 were negative. Positive and negative predictive values (PPV and NPV) of U-SENS™ were 93% and 21%, respectively. No specific chemical property evaluated could account for misclassified ingredients. Assessment of parent and metabolite protein binding alerts in silico suggests that parent chemical metabolism may play a role in CD86 activation in U-SENS™. Combining the U-SENS™ assay in a "2 out of 3" defined approach with the direct peptide reactivity assay (DPRA) and KeratinoSens™ predicted sensitization hazard with PPV and NPV of 97% and 24%, respectively. Combining complementary in silico and in vitro methods to the U-SENS™ assay should be integrated to define the hazard classification of fragrance ingredients, since a single NAM cannot replace animal-based methods.

Blunt cardiac trauma: a narrative review.

OBJECTIVE: This review aims to summarize the literature regarding blunt cardiac trauma (BCT), focusing on the mechanism of injury, presentations, diagnostic, and treatment approaches to provide an up-to-date perspective and to identify the areas requiring further investigation. BACKGROUND: BCT is a relatively rare, but likely underdiagnosed, consequence of blunt chest trauma. BCT occurs in less than 10% of all trauma admissions although it is responsible for approximately 25% of traumatic deaths. BCT often occurs due to forceful impact, rapid deceleration, or crush injuries and the most common causes include motor vehicle accidents, pedestrians struck by motor vehicles, and falls from a significant height. While BCT is certainly an important condition with significant clinical implications, the current literature is limited comprised of mainly case reports. BCTs are often complex cases with various presentations, comorbid injuries, diagnostic modalities, and treatments. METHODS: PubMed was searched for retrospective, prospective, randomized control trials, case report studies, and previous related reviews investigating BCT published from January 1, 1985 to February 1, 2021. Exclusion criteria included if the full length manuscript was not available and if insufficient data was provided regarding the patient outcomes or the case presented in case reports. CONCLUSIONS: A wide variety of injuries, mechanisms, presentations, and treatments are possible with BCT. Commonalities in initial investigations include a thorough history and physical exam where appropriate, lab work to evaluate patient status, and imaging to diagnose structural injuries. Treatment often begins with stabilization of the patient and rapid initiation of interventions aimed at underlying structural or rhythm abnormalities. As the current literature is limited, further study into BCT is necessary. As BCT is relatively rare and occurs sporadically at individual centers, widespread data collection from BCT patients regarding their treatment and outcomes is essential in order to collect the required data for retrospective or prospective studies. The widespread establishment of multicenter or national databases may be a solution to address the limited data in this field allowing identification of optimal treatments for BCT patients, addressing the limitations in the field of BCT, and allow the continued improvement in the outcomes of patients who experience BCT.

Fragrance Skin Sensitization Evaluation and Human Testing: 30-Year Experience.

BACKGROUND: The human repeated insult patch test (HRIPT) has a history of use in the fragrance industry as a component of safety evaluation, exclusively to confirm the absence of skin sensitization at a defined dose. OBJECTIVE: The aim of the study was to document the accumulated experience from more than 30 years of conducting HRIPTs. METHODS: A retrospective collation of HRIPT studies carried out to a consistent protocol was undertaken, with each study comprising a minimum of 100 volunteers. CONCLUSIONS: The HRIPT outcomes from 154 studies on 134 substances using 16,512 volunteers were obtained. Most studies confirmed that at the selected induction/challenge dose, sensitization was not induced. In 0.12% of subjects (n = 20), there was induction of allergy. However, in the last 11 years, only 3 (0.03%) of 9854 subjects became sensitized, perhaps because of improved definition of a safe HRIPT dose from the local lymph node assay and other skin sensitization methodologies, as well as more rigorous application of the standard protocol after publication in 2008. This experience with HRIPTs demonstrates that de novo sensitization induction is rare and becoming rarer, but it plays an important role as an indicator that toxicological predictions from nonhuman test methods (in vivo and in vitro methods) can be imperfect.

Overcoming mechanical adversity in extreme hindleg weapons.

The size of sexually selected weapons and their performance in battle are both critical to reproductive success, yet these traits are often in opposition. Bigger weapons make better signals. However, due to the mechanical properties of weapons as lever systems, increases in size may inhibit other metrics of performance as different components of the weapon grow out of proportion with one another. Here, using direct force measurements, we investigated the relationship between weapon size and weapon force production in two hindleg weapon systems, frog-legged beetles (Sagra femorata) and leaf-footed cactus bugs (Narnia femorata), to test for performance tradeoffs associated with increased weapon size. In male frog-legged beetles, relative force production decreased as weapon size increased. Yet, absolute force production was maintained across weapon sizes. Surprisingly, mechanical advantage was constant across weapon sizes and large weaponed males had disproportionately large leg muscles. In male leaf-footed cactus bugs, on the other hand, there was no relationship between weapon size and force production, likely reflecting the importance of their hindlegs as signals rather than force-producing structures of male-male competition. Overall, our results suggest that when weapon force production is important for reproductive success, large weaponed animals may overcome mechanical challenges by maintaining proportional lever components and investing in (potentially costly) compensatory mechanisms.

Selection on an extreme weapon in the frog-legged leaf beetle (Sagra femorata).

Biologists have been fascinated with the extreme products of sexual selection for decades. However, relatively few studies have characterized patterns of selection acting on ornaments and weapons in the wild. Here, we measure selection on a wild population of weapon-bearing beetles (frog-legged leaf beetles: Sagra femorata) for two consecutive breeding seasons. We consider variation in both weapon size (hind leg length) and in relative weapon size (deviations from the population average scaling relationship between hind leg length and body size), and provide evidence for directional selection on weapon size per se and stabilizing selection on a particular scaling relationship in this population. We suggest that whenever growth in body size is sensitive to external circumstance such as nutrition, then considering deviations from population-level scaling relationships will better reflect patterns of selection relevant to evolution of the ornament or weapon than will variation in trait size per se. This is because trait-size versus body-size scaling relationships approximate underlying developmental reaction norms relating trait growth with body condition in these species. Heightened condition-sensitive expression is a hallmark of the exaggerated ornaments and weapons favored by sexual selection, yet this plasticity is rarely reflected in the way we think about-and measure-selection acting on these structures in the wild.