'Effects of dehydration on central blood pressure in young healthy adults'.

PURPOSE: Brachial blood pressure (BP) is the current gold standard for BP assessment; however, measures of pulse wave velocity (PWV) and central blood pressure (CBP) may contribute uniquely to assessment of cardiovascular health status. As of yet, standards for assessment of CBP and PWV have not addressed the impact of hydration status on proper measurement. To understand the impact of hydration, PWV and CBP should be measured in a euhydrated and hypohydrated state. METHODS: Forty-three young, healthy participants (21 ± 2 years) completed a dehydration protocol utilizing moderate aerobic activity until they lost 1%-2% of their body weight. PWV and CBP were measured before and following the dehydration protocol. Linear regression was utilized to assess change in hydration status and change in PWV and CBP. RESULTS: No significant relationships were observed between the change in hydration status (% body weight lost) and PWV (ß = 0.05, p = 0.78) or central diastolic BP (ß = -3.8, p = 0.10), however, a significant relationship was observed with central systolic BP (ß = -5.0, p = 0.03). DISCUSSION: In conclusion, the assessment of hydration status before measurement of CBP or PWV may not be necessary in young, healthy individuals.

Test-retest reliability of Doppler ultrasound-based leg blood flow assessments during exercise in patients with chronic obstructive pulmonary disease.

Doppler ultrasound may be used to assess leg blood flow ( Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ ), but the reliability of this method remains unexplored in patients with chronic obstructive pulmonary disease (COPD), where between-subject variability may be larger than healthy due to peripheral vascular changes. This study aimed to investigate the reliability of Doppler ultrasound in quantifying Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ during single-leg knee-extensor exercise (KEE) in COPD patients compared with those obtained from healthy matched controls. In this case-control study, 16 participants with COPD were matched based on sex and age with 16 healthy controls. All participants underwent measurement of Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ using Doppler ultrasound in a KEE set-up at various intensities on two separate visits. Confounding factors on Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ were controlled for, and the ultrasound scans were consistently performed by the same sonographer. During exercise, smallest real difference (SRD) ranged from 367 mL to 583 mL in COPD and 438 mL to 667 mL in the control group. The coefficient of variation (CV) ranged from 7.9% to 14.3% in COPD and 9.4% to 10.4% in the control group. The intraclass correlation coefficient ranged from 0.75 to 0.92 in COPD and 0.67 to 0.84 in the control group. CV was lower in the control group during exercise at 0 W, but apart from that, reliability was not different between groups during exercise. Doppler ultrasound showed nearly equal reliability when evaluating Q ̇ leg ${{\dot{Q}}_{{\mathrm{leg}}}}$ in COPD patients and healthy individuals with a CV below 15% during exercise for both groups. HIGHLIGHTS: What is the central question of this study? What is the between-day reliability of Doppler ultrasound when quantifying leg blood flow during single-leg knee-extensor exercise in COPD patients compared to healthy matched controls? What is the main finding and its importance? This study demonstrates a coefficient of variation ranging from 7.9 to 14.3% during single-leg knee-extensor exercise for between-day reliability when applying Doppler ultrasound to assess leg blood flow in patients with COPD. Furthermore, it offers insights into the peripheral circulatory constraints in COPD, as evidenced by diminished leg blood flow. This study is the first of its kind to evaluate the reliability of Doppler ultrasound in the assessment of the peripheral circulation during exercise in COPD.

Predicting Psoriatic Arthritis in Psoriasis Patients - A Swiss Registry Study.

Background: Psoriatic arthritis (PsA) is a prevalent comorbidity among patients with psoriasis, heavily contributing to their burden of disease, usually diagnosed several years after the diagnosis of psoriasis. Objectives: To investigate the predictability of psoriatic arthritis in patients with psoriasis and to identify important predictors. Methods: Data from the Swiss Dermatology Network on Targeted Therapies (SDNTT) involving patients treated for psoriasis were utilized. A combination of gradient-boosted decision trees and mixed models was used to classify patients based on their diagnosis of PsA or its absence. The variables with the highest predictive power were identified. Time to PsA diagnosis was visualized with the Kaplan-Meier method and the relationship between severity of psoriasis and PsA was explored through quantile regression. Results: A diagnosis of psoriatic arthritis was registered at baseline of 407 (29.5%) treatment series. 516 patients had no registration of PsA, 257 patients had PsA at inclusion, and 91 patients were diagnosed with PsA after inclusion. The model's AUROCs was up to 73.7%, and variables with the highest discriminatory power were age, PASI, physical well-being, and severity of nail psoriasis. Among patients who developed PsA after inclusion, significantly more first treatment series were classified in the PsA-group, compared to those with no PsA registration. PASI was significantly correlated with the median burden/severity of PsA (P = .01). Conclusions: Distinguishing between patients with and without PsA based on clinical characteristics is feasible and even predicting future diagnoses of PsA is possible. Patients at higher risk can be identified using important predictors of PsA.

Investigating the effect of reduced temperatures on the efficacy of rhabdovirus-based viral vector platforms.

Rhabdoviral vectors can induce lysis of cancer cells. While studied almost exclusively at 37 °C, viruses are subject to a range of temperatures in vivo, including temperatures ≤31 °C. Despite potential implications, the effect of temperatures <37 °C on the performance of rhabdoviral vectors is unknown. We investigated the effect of low anatomical temperatures on two rhabdoviruses, vesicular stomatitis virus (VSV) and Maraba virus (MG1). Using a metabolic resazurin assay, VSV- and MG1-mediated oncolysis was characterized in a panel of cell lines at 28, 31, 34 and 37 °C. The oncolytic ability of both viruses was hindered at 31 and 28 °C. Cold adaptation of both viruses was attempted as a mitigation strategy. Viruses were serially passaged at decreasing temperatures in an attempt to induce mutations. Unfortunately, the cold-adaptation strategies failed to potentiate the oncolytic activity of the viruses at temperatures <37 °C. Interestingly, we discovered that viral replication was unaffected at low temperatures despite the abrogation of oncolytic activity. In contrast, the proliferation of cancer cells was reduced at low temperatures. Equivalent oncolytic effects could be achieved if cells at low temperatures were treated with viruses for longer times. This suggests that rhabdovirus-mediated oncolysis could be compromised at low temperatures in vivo where therapeutic windows are limited.

Abrocitinib may improve itch and quality of life in patients with itch-dominant atopic dermatitis.

Background: Patients with atopic dermatitis (AD) exhibit heterogeneous clinical phenotypes, reflecting different combinations of itch and lesional severity. AD with severe itch but clear-moderate lesions, also known as itch-dominant AD, is a common clinical phenotype. Objectives: To evaluate abrocitinib efficacy in patients with moderate-to-severe AD who have itch-dominant AD. Methods: This post hoc analysis includes pooled data from clinical trials of patients with moderate-to-severe AD receiving abrocitinib (100 or 200 mg) as monotherapy (phase 2b; phase 3 JADE MONO-1 and JADE MONO-2) or in combination with topical therapy (phase 3 JADE COMPARE). Data from the ongoing long-term JADE EXTEND trial (data cutoff April 2020) were also evaluated. Itch-dominant AD was defined as baseline Peak Pruritus Numerical Rating Scale (PP-NRS) score of 7-10 and Investigator's Global Assessment of 0-3 or Eczema Area and Severity Index of 0‒21. Assessments included a ≥4-point improvement in PP-NRS (PP-NRS4), PP-NRS score of 0 (no itch) or 1 (little itch) in patients with PP-NRS score ≥2 at baseline, ≥4-point improvement from baseline in Patient-Oriented Eczema Measure (POEM-4), Patient Global Assessment (PtGA) of clear or almost clear, and Dermatology Life Quality Index (DLQI) score of 0 or 1 (no impact or little impact of AD on quality of life [QoL]). Results: In the pooled monotherapy trials, 37% of patients had itch-dominant AD at baseline. As early as Week 2, more patients with itch-dominant AD achieved PP-NRS4 with abrocitinib 100 mg (35%) and abrocitinib 200 mg (57%) versus placebo (7%); 6% and 22% versus 0%, respectively, achieved PP-NRS 0/1. More patients achieved a PtGA of clear/almost clear at Week 12 with abrocitinib 100 mg (28%) and abrocitinib 200 mg (45%) than placebo (9%). Additionally, abrocitinib led to clinically meaningful improvements in POEM and DLQI. Most patients with itch-dominant AD experienced itch improvement over time with abrocitinib monotherapy or with concomitant topical therapy; 86%-87% and 62%-67% of patients had no itch-moderate itch and clear-moderate lesions by weeks 24 and 48, respectively. Conclusions: Abrocitinib is highly efficacious in patients with itch-dominant AD, demonstrating rapid, deep, and sustained improvements in itch and clinically meaningful improvements in patients' QoL. Trial Registration Numbers: NCT02780167; NCT03349060; NCT03575871; NCT03720470; NCT03422822.

Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation.

Objectives: Chondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development. Methods: Human and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed in Sirt5 -/- and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB). Results: We found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK's predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation in SIRT5 that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe-F) to leucine (Leu-L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes. Conclusions: We found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.

FAST-EM array tomography: a workflow for multibeam volume electron microscopy.

Elucidating the 3D nanoscale structure of tissues and cells is essential for understanding the complexity of biological processes. Electron microscopy (EM) offers the resolution needed for reliable interpretation, but the limited throughput of electron microscopes has hindered its ability to effectively image large volumes. We report a workflow for volume EM with FAST-EM, a novel multibeam scanning transmission electron microscope that speeds up acquisition by scanning the sample in parallel with 64 electron beams. FAST-EM makes use of optical detection to separate the signals of the individual beams. The acquisition and 3D reconstruction of ultrastructural data from multiple biological samples is demonstrated. The results show that the workflow is capable of producing large reconstructed volumes with high resolution and contrast to address biological research questions within feasible acquisition time frames.

Machine learning identifies clusters of the normal adolescent spine based on sagittal balance.

PURPOSE: This study applied a machine learning semi-supervised clustering approach to radiographs of adolescent sagittal spines from a single pediatric institution to identify patterns of sagittal alignment in the normal adolescent spine. We sought to explore the inherent variability found in adolescent sagittal alignment using machine learning to remove bias and determine whether clusters of sagittal alignment exist. METHODS: Multiple semi-supervised machine learning clustering algorithms were applied to 111 normal adolescent sagittal spines. Sagittal parameters for resultant clusters were determined. RESULTS: Machine learning analysis found that the spines did cluster into distinct groups with an optimal number of clusters ranging from 3 to 5. We performed an analysis on both 3 and 5-cluster groups. The 3-cluster groups analysis found good consistency between methods with 96 of 111, while the analysis of 5-cluster groups found consistency with 105 of 111 spines. When assessing for differences in sagittal parameters between the groups for both analyses, there were differences in T4-12 TK, L1-S1 LL, SS, SVA, PI-LL mismatch, and TPA. However, the only parameter that was statistically different for all groups was SVA. CONCLUSIONS: Based on machine learning, the adolescent sagittal spine alignments do cluster into distinct groups. While there were distinguishing features with TK and LL, the most important parameter distinguishing these groups was SVA. Further studies may help to understand these findings in relation to spinal deformities.

Determinants of Health Care Dissatisfaction among a US Population-based Cohort of Women with Polycystic Ovary Syndrome.

CONTEXT: The 2018 International Evidence Based Guidelines (IEBG) for PCOS were created, in part, in response to poor patient satisfaction on international surveys. Patient satisfaction in the US, before and after these guidelines has not yet been characterized. OBJECTIVE: To evaluate care patterns and patient attitudes among women with PCOS in the US before and after IEBG. DESIGN: Cross-sectional. SETTING: A population-based community sample of women in the US. PATIENTS OR OTHER PARTICIPANTS: Women with PCOS confirmed by a care provider. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Standardized questionnaires on care patterns and satisfaction in care. RESULTS: 1056 respondents, aged 23±6 years at diagnosis were included. 69.2% had to wait >1 year and 72.9% saw >1 provider prior to receiving a diagnosis. <45% strongly agreed or agreed with statements regarding trusting their doctor. <27% were very or somewhat satisfied with care across all questions. In multivariable analyses, composite outcome of trusting your physician was associated with insurance type (uninsured vs private) (OR (95% CI), 0.5 (0.3-0.9), p=0.020)), race (Hispanic vs Caucasian) (0.6 (0.5-0.9), p=0.007), (Black vs Caucasian) (1.6 (1.0-2.4), p=0.045) and timing of diagnosis (within 5 years vs >5 years) (1.3 (1.0-1.7), p=0.038). Care satisfaction was associated with insurance type (public vs private) (0.6 (0.4-0.9), p=0.010), (uninsured vs private) (0.5 (0.3-0.9), p=0.021), and timing of diagnosis (within 5 years vs >5 years) (1.4 (1.1-1.9), p=0.010). CONCLUSIONS: Satisfaction and trust in care is overall poor among patients with PCOS in the US. Higher scores among those diagnosed within the past 5 years, compared to those with a more remote diagnosis, may indicate an improving trend in care.

Complete genome of a rare Salmonella enterica subsp. enterica serovar Hessarek from human stool.

We present a complete genome of Salmonella enterica subsp. enterica serovar Hessarek isolated from a human stool from an outbreak linked to egg consumption in South Australia. Orientation of the rrn operon and characteristics of the Salmonella virulence plasmid indicates that this serovar is virulent toward humans and birds.

Prevalence and clinical impact of topical corticosteroid phobia among patients with chronic hand eczema-Findings from the Danish Skin Cohort.

BACKGROUND: Topical corticosteroid phobia (TOPICOP) is associated with poor treatment adherence and is common among patients with skin disease. Knowledge about corticosteroid phobia and treatment adherence among patients with chronic hand eczema (CHE) is limited. OBJECTIVES: To investigate patient-reported outcomes regarding topical corticosteroids (TCSs), and their impact on treatment adherence in patients with CHE. METHODS: Patients with CHE from the Danish Skin Cohort answered a questionnaire including the TOPICOP scale and Medication Adherence Report Scale. Response rate was 69.2%. RESULTS: Of 927 with CHE, 75.5% totally or almost agreed that TCS damage the skin, 48.9% totally or almost agreed that TCS would affect their future health and 36.3% reported some degree of fear of TCS although they were unaware of any TCS-associated risks. Most patients (77.9%) always or often stop treatment as soon as possible, whereas 54.8% always or often wait as long as possible before starting treatment. Overall, 38.8% reported that they had taken less medicine than prescribed and 54.0% had stopped treatment throughout a period. Treatment adherence decreased with increasing corticosteroid phobia (P = .004). LIMITATIONS: TOPICOP has not been validated in patients with CHE. CONCLUSIONS: Corticosteroid phobia is common among patients with CHE and negatively associated with treatment adherence.

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes.

The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells, increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.

Impact of the pre-biologic treatment journey on biologic drug survival in psoriasis: A nationwide cohort study.

BACKGROUND: It is unknown whether the pre-biologic treatment journey affects subsequent biologic drug survival. OBJECTIVE: To examine the potential impact of a complex treatment journey on subsequent biologic drug survival in patients with psoriasis. METHODS: The study utilized longitudinal data from Danish national registries and included all patients who, for the first time, initiated a biological treatment for psoriasis. Maximum follow-up was 5 years and patients were included from 1 January 2010 to 30 June 2021. The study used three definitions of exposure to a complex treatment journey and the following conventional systemic treatments: acitretin, cyclosporine, dimethyl fumarate and methotrexate. The first definition was the cumulative number of treatment series. The second definition comprised the number of unique treatments. The third definition was time from the first conventional systemic treatment to biological therapy. Drug survival for the three definitions were illustrated using Kaplan-Meier curves and compared using log-rank test. The sensitivity analysis largely confirmed these findings by grouping patients according to pharmacotherapy. RESULTS: A total of 2496 patients were included in the study, with 1380 (55.3%) receiving adalimumab, 608 (24.4%) receiving ustekinumab, 271 (10.9%) receiving secukinumab, 166 (6.7%) receiving etanercept and 71 (2.8%) receiving infliximab. The mean age at initiation of biologics was 43.6 years (standard deviation (SD) 15.2 years), and most patients were male (62.9%). During the follow-up of 5477 patient years, 1953 patients (78.2%) reached the main endpoint of discontinuation. Using a log-rank test, the probability of remaining on treatment was unaffected by the three definitions of complexity of the treatment journey. CONCLUSION: None of the three exposures used to assess the complexity of the pre-biologic treatment journey appeared to impact drug survival. As long as patients experience adequate disease control, these results suggest that conventional systemic treatment do not negatively impact the drug survival of subsequent biologics.

Determination of γ/γ' interface free energy for solid state precipitation in Ni-Al alloys from molecular dynamics simulation.

Interface free energy is a fundamental material parameter needed to predict the nucleation and growth of new phases. The high cost of experimentally determining this parameter makes it an ideal target for calculation through a physically informed simulation. Direct determination of interface free energy has many challenges, especially for solid-solid transformations. Indirect determination of the interface free energy from the nucleation data has been done in the case of solidification. However, a slow on molecular dynamics (MD) simulation time scale atomic diffusion makes this method not applicable to the case of nucleation from the solid phase when precipitate composition is different from that in matrix. To address this challenge, we outline the development of a new technique for determining the critical nucleus size from an MD simulation using a recently developed method to accelerate solid-state diffusion. The accuracy of our approach for the Ni-Al system for Ni3Al (γ') precipitates in a Ni-Al (γ) matrix is demonstrated well within experimental accuracy and greatly improves upon previous computational methods [Herrnring et al., Acta Mater. 215(8), 117053 (2021)].

Skin and systemic inflammation in adults with atopic dermatitis before and after whole-body topical betamethasone 17-valerate 0.1% or tacrolimus 0.1% treatment: A randomized controlled study.

BACKGROUND: Atopic dermatitis (AD) is mainly driven by type 2 inflammation and often treated with topical agents. Studies comparing differences in biomarkers between these treatments are lacking. OBJECTIVES: The aim of this study was to evaluate the effects of topical betamethasone 17-valerate 0.1% and tacrolimus 0.1% ointment on skin barrier function and inflammatory biomarkers in skin and blood in adults with AD. METHODS: In this randomized parallel-group double-blind double-dummy active-comparator study design, 36 adults with AD were treated with either whole-body topical corticosteroid (betamethasone ointment 0.1% plus placebo once daily, n = 18) or calcineurin inhibitor (tacrolimus ointment 0.1% twice daily, n = 18). At baseline, after 2 weeks of daily treatment and after further 4 weeks of twice-weekly maintenance treatment, we evaluated AD severity, levels of natural moisturizing factor (NMF) and cytokines in the skin and blood and characterized circulating T cells. RESULTS: Mean AD severity at baseline corresponded to moderate disease and decreased significantly in both groups. Levels of NMF increased significantly in the tacrolimus group after 2 weeks of treatment (p = 0.002) and tended to increase more than betamethasone at week 6 (p = 0.06). Most skin cytokines decreased with both treatments. However, IL-8, IL-18, IL-22, IP-10, MDC, MMP-9 and TARC were significantly more decreased with betamethasone than tacrolimus after 2 weeks, while after 6 weeks this was only the case for IL-8 and MMP-9. Approximate half of the systemic cytokines decreased significantly with both treatments, but betamethasone decreased MDC significantly more after 2 weeks of treatment. T-cell characterization analyses indicated slight differences in the expression and activation of T cells between groups. CONCLUSION: Topical treatment of AD with betamethasone and tacrolimus ointment effectively reduced disease severity, cutaneous and systemic inflammatory markers. Betamethasone was more effective in decreasing inflammation, but tacrolimus improved skin hydration (NMF levels) more than betamethasone.

A Practitioner's Guide to Measuring Procedural Fidelity.

Ensuring high levels of procedural fidelity during behavior-analytic interventions is a crucial component of providing effective behavior-analytic services. However, few resources are available to help guide practitioners through measuring procedural fidelity. In fact, most published behavior-analytic research on procedural fidelity analyzes a single treatment procedure, which might not completely reflect the process of monitoring and addressing the procedural fidelity of a robust treatment package that might be necessary in clinical settings. The purpose of this article is to guide behavior analysts through the process of creating and using procedural fidelity measurement systems, with a focus on direct observation of implementation as a means of fidelity data collection. This process consists of six steps: (1) task analyze treatment procedures into measurable units; (2) assign measures to each treatment component; (3) plan the direct observation; (4) collect procedural fidelity data; (5) analyze and interpret procedural fidelity data; and (6) take action to improve procedural fidelity. Each step is described and discussed in the article.