Cardiogenic Shock Intravascular Cooling Trial (CHILL-SHOCK).

BACKGROUND: Cardiogenic shock (CS) is complicated by high mortality rates. Targeted temperature control (TTC) has been proposed as an adjunct therapy in CS. This study aims to examine the safety of TTC in patients presenting with CS. METHODS AND RESULTS: In this open-label, randomized controlled pilot trial, 20 patients with hemodynamic criteria for CS were assigned to standard of care plus TTC vs standard of care alone. The primary outcome was a composite safety outcome, including well-described complications of TTC. Secondary outcomes included mortality at 90 days, invasive hemodynamic and echocardiographic parameters, electrocardiographic measurements, and inotrope dosing. There were no significant differences in the composite analysis of prespecified safety outcomes (3 events in the TTC group vs 0 events in the control group; P = 0.24). Patients randomized to TTC demonstrated a statistically significant increase in cardiac index and cardiac power index compared to the control group at 48-96 hours after randomization (3.6 [3.1, 3.9] L/min/m2 vs 2.6 [2.5, 3.15] L/min/m2; P = 0.029 and 0.61 [0.55, 0.7] W/m2 vs 0.53 [0.435, 0.565] W/m2; P = 0.029, respectively). CONCLUSION: TTC may be a safe adjunct therapy for patients presenting with CS and may yield improvement in specific hemodynamic parameters.

The skin microbiome in pediatric atopic dermatitis and food allergy.

The skin microbiome is an extensive community of bacteria, fungi, mites, viruses and archaea colonizing the skin. Fluctuations in the composition of the skin microbiome have been observed in atopic dermatitis (AD) and food allergy (FA), particularly in early life, established disease, and associated with therapeutics. However, AD is a multifactorial disease characterized by skin barrier aberrations modulated by genetics, immunology, and environmental influences, thus the skin microbiome is not the sole feature of this disease. Future research should focus on mechanistic understanding of how early-life skin microbial shifts may influence AD and FA onset, to guide potential early intervention strategies or as microbial biomarkers to identify high-risk infants who may benefit from possible microbiome-based biotherapeutic strategies. Harnessing skin microbes as AD biotherapeutics is an emerging field, but more work is needed to investigate whether this approach can lead to sustained clinical responses.

Response to Comment on "Dying in the Sun: Direct evidence for elevated UV-B radiation at the end-Permian mass extinction".

Seddon and Zimmermann have raised questions about the evidence for increased UV-B flux across the end-Permian mass extinction (EPME) that was presented in our recent study, specifically regarding the measurement of UV-B-absorbing compound (UAC) levels in fossil pollen. We respond to these points, arguing that the comparison of FTIR spectra of >250 million-year-old Permian fossil pollen with ~700-year-old subfossil pollen is not valid and that negligible nonrandom interference derived from water vapor fluctuations during data generation cannot coincidentally produce a substantial UAC peak during the EPME. Furthermore, we refute the suggestion that the measured aromatic peak at 1600 cm-1 could have been influenced by diagenetic products from other organic constituents of pollen. The most productive route forward will be to generate sporomorph geochemical data from additional Permian-Triassic boundary sections to test the results put forward in our study.

Diphtheria toxin activates ribotoxic stress and NLRP1 inflammasome-driven pyroptosis.

The ZAKα-driven ribotoxic stress response (RSR) is activated by ribosome stalling and/or collisions. Recent work demonstrates that RSR also plays a role in innate immunity by activating the human NLRP1 inflammasome. Here, we report that ZAKα and NLRP1 sense bacterial exotoxins that target ribosome elongation factors. One such toxin, diphtheria toxin (DT), the causative agent for human diphtheria, triggers RSR-dependent inflammasome activation in primary human keratinocytes. This process requires iron-mediated DT production in the bacteria, as well as diphthamide synthesis and ZAKα/p38-driven NLRP1 phosphorylation in host cells. NLRP1 deletion abrogates IL-1ß and IL-18 secretion by DT-intoxicated keratinocytes, while ZAKα deletion or inhibition additionally limits both pyroptotic and inflammasome-independent non-pyroptotic cell death. Consequently, pharmacologic inhibition of ZAKα is more effective than caspase-1 inhibition at protecting the epidermal barrier in a 3D skin model of cutaneous diphtheria. In summary, these findings implicate ZAKα-driven RSR and the NLRP1 inflammasome in antibacterial immunity and might explain certain aspects of diphtheria pathogenesis.

Dying in the Sun: Direct evidence for elevated UV-B radiation at the end-Permian mass extinction.

Land plants can adjust the concentration of protective ultraviolet B (UV-B)-absorbing compounds (UACs) in the outer wall of their reproductive propagules in response to ambient UV-B flux. To infer changes in UV-B radiation flux at Earth's surface during the end-Permian mass extinction, we analyze UAC abundances in ca. 800 pollen grains from an independently dated Permian-Triassic boundary section in Tibet. Our data reveal an excursion in UACs that coincide with a spike in mercury concentration and a negative carbon-isotope excursion in the latest Permian deposits, suggesting a close temporal link between large-scale volcanic eruptions, global carbon and mercury cycle perturbations, and ozone layer disruption. Because enhanced UV-B radiation can exacerbate the environmental deterioration induced by massive magmatism, ozone depletion is considered a compelling ecological driver for the terrestrial mass extinction.

Expression of Staphylococcus aureus Virulence Factors in Atopic Dermatitis.

Atopic dermatitis (AD) is a skin inflammatory disease in which the opportunistic pathogen Staphylococcus aureus is prevalent and abundant. S. aureus harbors several secreted virulence factors that have well-studied functions in infection models, but it is unclear whether these extracellular microbial factors are relevant in the context of AD. To address this question, we designed a culture-independent method to detect and quantify S. aureus virulence factors expressed at the skin sites. We utilized RNase-H‒dependent multiplex PCR for preamplification of reverse-transcribed RNA extracted from tape strips of patients with AD sampled at skin sites with differing severity and assessed the expression of a panel of S. aureus virulence factors using qPCR. We observed an increase in viable S. aureus abundance on sites with increased severity of disease, and many virulence factors were expressed at the AD skin sites. Surprisingly, we did not observe any significant upregulation of the virulence factors at the lesional sites compared with those at the nonlesional control. Overall, we utilized a robust assay to directly detect and quantify viable S. aureus and its associated virulence factors at the site of AD skin lesions. This method can be extended to study the expression of skin microbial genes at the sites of various dermatological conditions.

Competing Models of Work in Quadrupedal Walking: Center of Mass Work is Insufficient to Explain Stereotypical Gait.

The walking gaits of cursorial quadrupedal mammals tend to be highly stereotyped as a four-beat pattern with interspersed periods of double and triple stance, often with double-hump ground reaction force profiles. This pattern has long been associated with high energetic economy, due to low apparent work. However, there are differing ways of approximating the work performed during walking and, consequently, different interpretations of the primary mechanism leading to high economy. A focus on Net Center of Mass (COM) Work led to the claim that quadrupedal walking is efficient because it effectively trades potential and kinetic energy of the COM. Individual Limbs COM Work instead focuses on the ability of the limbs to manage the trajectory of the COM to limit energetic losses to the ground ("collisions"). By focusing on the COM, both these metrics effectively dismiss the importance of rotation of the elongate quadrupedal body. Limb Extension Work considers work required to extend and contract each limb like a strut, and accounts for the work of body pitching. We tested the prescriptive ability of these approximations of work by optimizing them within a quadrupedal model with two approximations of the body as a point-mass or a rigid distributed mass. Perfect potential-kinetic energy exchange of the COM was possible when optimizing Net COM Work, resulting in highly compliant gaits with duty factors close to one, far different than observed mammalian gaits. Optimizing Individual Limbs COM Work resulted in alternating periods of single limb stance. Only the distributed mass model, with Limb Extension Work as the cost, resulted in a solution similar to the stereotypical mammalian gait. These results suggest that maintaining a near-constant limb length, with distributed contacts, are more important mechanisms of economy than either transduction of potential-kinetic energy or COM collision mitigation for quadrupedal walking.

Distinct skin microbiome community structures in congenital ichthyosis.

BACKGROUND: The ichthyoses are rare genetic keratinizing disorders that share the characteristics of an impaired epidermal barrier and increased risk of microbial infections. Although ichthyotic diseases share a T helper (Th) 17 cell immune signature, including increased expression of antimicrobial peptides, the skin microbiota of ichthyoses is virtually unexplored. OBJECTIVES: To analyse the metagenome profile of skin microbiome for major congenital ichthyosis subtypes. METHODS: Body site-matched skin surface samples were collected from the scalp, upper arm and upper buttocks of 16 healthy control participants and 22 adult patients with congenital forms of ichthyosis for whole metagenomics sequencing analysis. RESULTS: Taxonomic profiling showed significant shifts in bacteria and fungi abundance and sporadic viral increases across ichthyosis subtypes. Cutibacterium acnes and Malassezia were significantly reduced across body sites, consistent with skin barrier disruption and depletion of lipids. Microbial richness was reduced, with specific increases in Staphylococcus and Corynebacterium genera, as well as shifts in fungal species, including Malassezia. Malassezia globosa was reduced at all body sites, whereas M. sympodialis was reduced in the ichthyotic upper arm and upper buttocks. Malassezia slooffiae, by contrast, was strikingly increased at all body sites in participants with congenital ichthyosiform erythroderma (CIE) and lamellar ichthyosis (LI). A previously undescribed Trichophyton species was also detected as sporadically colonizing the skin of patients with CIE, LI and epidermolytic ichthyosis subtypes. CONCLUSIONS: The ichthyosis skin microbiome is significantly altered from healthy skin with specific changes predominating among ichthyosis subtypes. Skewing towards the Th17 pathway may represent a response to the altered microbial colonization in ichthyosis. What is already known about this topic? The skin microbiome of congenital ichthyoses is largely unexplored. Microbes play an important role in pathogenesis, as infections are common. The relative abundances of staphylococci and corynebacteria is increased in the cutaneous microbiome of patients with Netherton syndrome, but extension of these abundances to all congenital ichthyoses is unexplored. What does this study add? A common skin microbiome signature was observed across congenital ichthyoses. Distinct microbiome features were associated with ichthyosis subtypes. Changes in microbiome may contribute to T helper 17 cell immune polarization. What is the translational message? These data provide the basis for comparison of the microbiome with lipidomic and transcriptomic alterations in these forms of ichthyosis and consideration of correcting the dysbiosis as a therapeutic intervention.

Shared signatures and divergence in skin microbiomes of children with atopic dermatitis and their caregivers.

BACKGROUND: Atopic dermatitis (AD) is a common chronic skin condition in children (15-20%) that can significantly impair their quality of life. As a result of its relapsing nature and enrichment of Staphylococcus aureus during flares, clinical management can include eradicating S aureus from the skin of children; however, this does not extend to their healthy caregivers, who are potential reservoirs. OBJECTIVE: Our aim was to understand skin microbiome sharing and microbial features in children with AD and their healthy adult caregivers. METHODS: We utilized whole-metagenome profiling at 4 body sites (volar forearm, antecubital fossae, cheeks, and lesions) in combination with sequencing of S aureus isolates to characterize a cohort of children with AD and their healthy caregivers (n = 30 families) compared to matched pairs from control households (n = 30 families). RESULTS: Metagenomic analysis revealed distinct microbiome configurations in the nonlesional skin of AD children and their healthy caregivers versus controls, which were sufficient to accurately predict case-control status (area under the receiver operating characteristic curve > 0.8). These differences were accompanied by significant microbiome similarity between children and their caregivers, indicating that microbiome sharing may play a role in recurrent disease flares. Whole-genome comparisons with high-quality S aureus isolate genomes (n = 55) confirmed significant strain sharing between AD children and their caregivers and AD-specific enrichment of strains expressing enterotoxins Q and K/K2. CONCLUSION: Our results highlight the distinctive skin microbiome features of healthy caregivers for children with AD and support their inclusion in strategies for the treatment of recurrent pediatric AD.

Low tropical diversity during the adaptive radiation of early land plants.

The latitudinal biodiversity gradient, with tropical regions acting as 'evolutionary cradles', is a cornerstone of current biogeographical and ecological theory1. In the modern world floral biodiversity and biomass are overwhelmingly concentrated in the tropics, and it is often assumed that the tropics were evolutionary cradles throughout land plant evolutionary history. For example, the origination and diversification of angiosperms is believed to have taken place in the Cretaceous tropics2 and modern gymnosperms in the Permian tropics3. Here, we show that during the first major diversification of land plants, in the Late Silurian-Early Devonian, land plant biodiversity was much lower at the equator compared to medium-high southern latitudes. Throughout this crucial interval of plant evolution, tropical vegetation remained depauperate and of very low taxonomic biodiversity, although with similar morphological disparity to the more diverse higher latitude floras. Possible explanations for this low tropical floral biodiversity include palaeocontinental configuration or adverse palaeotropical environmental conditions. We discount the possibility that it was simply a fortuitous feature of the biogeographical spread of the earliest vascular land plants.

Concomitant Lower-Extremity Deep Vein Thrombosis in Patients With Pulmonary Embolism Undergoing Catheter-Directed Therapy.

BACKGROUND: Deep vein thrombosis (DVT) is often seen in patients with acute pulmonary embolism (PE). Risk stratification of PE patients is useful in predicting mortality risk and hospital course. However, rates or predictors of DVT or proximal DVT (popliteal, femoral, common femoral, or iliac thrombosis) have not been studied in the highest-risk patients who receive catheter-directed therapy (CDT) for their PE. A single-center retrospective analysis of patients referred for CDT for confirmed PE was conducted to evaluate rates and predictors of DVT or proximal DVT and the impact on short-term outcomes. In 137 consecutive patients undergoing CDT for PE with available lower-extremity ultrasound, the rates of DVT and proximal DVT in PE patients receiving CDT were 76.6% and 65.0%, respectively. Rates of DVT (P=.68) and proximal DVT (P=.72) did not differ between high-risk or non-high risk PE patients. The only significant factor associated with presence of concomitant DVT was previous DVT (P=.045). The presence of a concomitant DVT or proximal DVT was not associated with an increase in all-cause mortality or hospitalization at 30 days or 1 year compared with an absence of concomitant DVT or proximal DVT. The results of this study suggest that patients with PE clinically requiring CDT have high rates of concomitant DVT and proximal DVT, prior DVT predicts concomitant DVT, and the presence of DVT is not associated with additional risk in this already high-risk population of patients.

A cell-based drug discovery assay identifies inhibition of cell stress responses as a new approach to treatment of epidermolysis bullosa simplex.

In the skin fragility disorder epidermolysis bullosa simplex (EBS), mutations in keratin 14 (K14, also known as KRT14) or keratin 5 (K5, also known as KRT5) lead to keratinocyte rupture and skin blistering. Severe forms of EBS are associated with cytoplasmic protein aggregates, with elevated kinase activation of ERK1 and ERK2 (ERK1/2; also known as MAPK3 and MAPK1, respectively), suggesting intrinsic stress caused by misfolded keratin protein. Human keratinocyte EBS reporter cells stably expressing GFP-tagged EBS-mimetic mutant K14 were used to optimize a semi-automated system to quantify the effects of test compounds on keratin aggregates. Screening of a protein kinase inhibitor library identified several candidates that reduced aggregates and impacted on epidermal growth factor receptor (EGFR) signalling. EGF ligand exposure induced keratin aggregates in EBS reporter keratinocytes, which was reversible by EGFR inhibition. EBS keratinocytes treated with a known EGFR inhibitor, afatinib, were driven out of activation and towards quiescence with minimal cell death. Aggregate reduction was accompanied by denser keratin filament networks with enhanced intercellular cohesion and resilience, which when extrapolated to a whole tissue context would predict reduced epidermal fragility in EBS patients. This assay system provides a powerful tool for discovery and development of new pathway intervention therapeutic avenues for EBS.

Evaluating the energetics of entrainment in a human-machine coupled oscillator system.

During locomotion, humans sometimes entrain (i.e. synchronize) their steps to external oscillations: e.g. swaying bridges, tandem walking, bouncy harnesses, vibrating treadmills, exoskeletons. Previous studies have discussed the role of nonlinear oscillators (e.g. central pattern generators) in facilitating entrainment. However, the energetics of such interactions are unknown. Given substantial evidence that humans prioritize economy during locomotion, we tested whether reduced metabolic expenditure is associated with human entrainment to vertical force oscillations, where frequency and amplitude were prescribed via a custom mechatronics system during walking. Although metabolic cost was not significantly reduced during entrainment, individuals expended less energy when the oscillation forces did net positive work on the body and roughly selected phase relationships that maximize positive work. It is possible that individuals use mechanical cues to infer energy cost and inform effective gait strategies. If so, an accurate prediction may rely on the relative stability of interactions with the environment. Our results suggest that entrainment occurs over a wide range of oscillation parameters, though not as a direct priority for minimizing metabolic cost. Instead, entrainment may act to stabilize interactions with the environment, thus increasing predictability for the effective implementation of internal models that guide energy minimization.

Left Ventricular Pressure Ratio Predicts In-Hospital Outcomes in Hospitalized Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Given the risk of hemodynamic compromise in heart failure with reduced ejection fraction (HFrEF) patients undergoing left heart catheterization (LHC), there is a need for a simple parameter that can predict clinical outcomes. We hypothesize that left ventricular pressure ratio (LVPR), calculated as left ventricle systolic/left ventricle end-diastolic pressure, is a strong predictor of hemodynamic collapse in these patients. METHODS: Retrospective analysis of consecutive hospitalized HFrEF patients undergoing combined LHC and right heart catheterization (RHC) at a single institution from 2015-2017 was performed. LVPR was compared with standard RHC hemodynamic variables. The primary outcome was in-hospital escalation of therapy, defined as ≥40 mm Hg drop in systolic blood pressure (SBP), SBP ≤90 mm Hg for ≥15 minutes, start or escalation of vasoactive medications, cardiopulmonary resuscitation, or in-hospital death. Receiver-operating characteristic (ROC) analysis and Kaplan-Meier survival analysis were performed for prediction of the primary outcome. RESULTS: A total of 176 patients were included in this study. ROC analysis determined an optimal cut-off value of ≤3.96, which correlated with an area under the curve (AUC) of 0.65 (sensitivity, 45.9%; specificity, 83.2%; correctly classified, 64.9%). AUC was similar to other variables obtained using RHC. In-hospital survival free of escalation of therapy was lower in the low LVPR group vs the high LVPR group (0% vs 33%, respectively; P<.01). CONCLUSION: LVPR is an easily measured index obtained during LHC that can risk stratify hospitalized patients with HFrEF at the time of LHC.

Aortic Pulsatility Index: A Novel Hemodynamic Variable for Evaluation of Decompensated Heart Failure.

BACKGROUND: Right heart catheterization for invasive hemodynamics has shown only modest correlation with clinical outcomes. We designed a novel hemodynamic variable that incorporates ventricular output and filling pressure. We anticipated that the aortic pulsatility index (API) would correlate with clinical outcomes in patients with heart failure. METHODS AND RESULTS: We retrospectively analyzed consecutive patients undergoing right heart catheterization with milrinone drug study at our institution (February 2013 to November 2019). The API was calculated as (systolic blood pressure - diastolic blood pressure)/pulmonary capillary wedge pressure. The primary outcome was freedom from advanced therapies, defined as the need for inotropes, temporary mechanical circulatory support, a left ventricular assist device, or orthotopic heart transplantation, or death at 30 days. A total of 224 patient encounters, age 57 years (48-66 years; 34% women; 31% ischemic cardiomyopathy) were included. In univariable analysis, lower baseline API was significantly associated with progression to advanced therapies or death at 30-days (odds ratio 0.43, 95% confidence interval 0.30-0.61; P < .001) compared with those on continued medical management. Receiver operator characteristic analysis specified an optimal cutpoint of 1.45 for API. A Kaplan-Meier analysis indicated an association of API with the primary outcome (79% for API ≥ 1.45 vs 48% for API < 1.45). In multivariable analysis, higher API was strongly associated with freedom from advanced therapies or death (odds ratio 0.38, 95% confidence interval 0.22-0.65, P ≤ .001), even when adjusted for baseline characteristics and routine right heart catheterization measurements. CONCLUSIONS: The API is a novel invasive hemodynamic measurement that is associated independently with freedom from advanced therapies or death at 30-day follow-up.

The Polyamine Regulator AMD1 Upregulates Spermine Levels to Drive Epidermal Differentiation.

Maintaining tissue homeostasis depends on a balance between cell proliferation, differentiation, and apoptosis. Within the epidermis, the levels of the polyamines putrescine, spermidine, and spermine are altered in many different skin conditions, yet their role in epidermal tissue homeostasis is poorly understood. We identify the polyamine regulator, Adenosylmethionine decarboxylase 1 (AMD1), as a crucial regulator of keratinocyte (KC) differentiation. AMD1 protein is upregulated on differentiation and is highly expressed in the suprabasal layers of the human epidermis. During KC differentiation, elevated AMD1 promotes decreased putrescine and increased spermine levels. Knockdown or inhibition of AMD1 results in reduced spermine levels and inhibition of KC differentiation. Supplementing AMD1-knockdown KCs with exogenous spermidine or spermine rescued aberrant differentiation. We show that the polyamine shift is critical for the regulation of key transcription factors and signaling proteins that drive KC differentiation, including KLF4 and ZNF750. These findings show that human KCs use controlled changes in polyamine levels to modulate gene expression to drive cellular behavior changes. Modulation of polyamine levels during epidermal differentiation could impact skin barrier formation or can be used in the treatment of hyperproliferative skin disorders.