A new approach methodology to identify tumorigenic chemicals using short-term exposures and transcript profiling.

Current methods for cancer risk assessment are resource-intensive and not feasible for most of the thousands of untested chemicals. In earlier studies, we developed a new approach methodology (NAM) to identify liver tumorigens using gene expression biomarkers and associated tumorigenic activation levels (TALs) after short-term exposures in rats. The biomarkers are used to predict the six most common rodent liver cancer molecular initiating events. In the present study, we wished to confirm that our approach could be used to identify liver tumorigens at only one time point/dose and if the approach could be applied to (targeted) RNA-Seq analyses. Male rats were exposed for 4 days by daily gavage to 15 chemicals at doses with known chronic outcomes and liver transcript profiles were generated using Affymetrix arrays. Our approach had 75% or 85% predictive accuracy using TALs derived from the TG-GATES or DrugMatrix studies, respectively. In a dataset generated from the livers of male rats exposed to 16 chemicals at up to 10 doses for 5 days, we found that our NAM coupled with targeted RNA-Seq (TempO-Seq) could be used to identify tumorigenic chemicals with predictive accuracies of up to 91%. Overall, these results demonstrate that our NAM can be applied to both microarray and (targeted) RNA-Seq data generated from short-term rat exposures to identify chemicals, their doses, and mode of action that would induce liver tumors, one of the most common endpoints in rodent bioassays.

Doppler ultrasound, a noninvasive tool for the study of mesenteric arterial flow in systemic sclerosis: a cross-sectional study of a patient cohort with review and meta-analysis of the literature.

Gastrointestinal involvement (GI) is a frequent and troublesome complication of systemic sclerosis (SSc), whose etiology is poorly understood, though it is hypothesized that autoimmunity and progressive vasculopathy may play a role. Vasculopathy is considered one of the main pathogenetic pathways responsible for many of the clinical manifestations of SSc, and, therefore, studying the principal splanchnic vessels (i.e., superior mesenteric artery-SMA and inferior mesenteric artery-IMA) with Doppler Ultrasound (DUS) may provide further insights into measuring the progression of vasculopathy, evaluating its possible association with SSc GI symptoms, and determining whether it plays a role in the development or severity of SSc GI disease. A cohort of SSc patients consecutively recruited underwent DUS examination, and associations with GI (UCLA-GIT 2.0 questionnaire) and extraintestinal SSc characteristics were evaluated. Semiquantitative DUS parameters (resistive index-RI and pulsatility index-PI), were applied for splanchnic vessel assessment in SSc patients and healthy subjects (HS). Moreover, a review and meta-analysis of the literature to understand which the values of the main semiquantitative DUS parameters (RI and PI) are both in SSc patients and HS has been conducted. Seventy-eight patients completed DUS examinations and clinical assessments. 30 (39%) were classified as diffuse cutaneous SSc (dcSSC), 35 (45%) as limited cutaneous SSc (lcSSc) and 13 (17%) as sine scleroderma. A significant difference was found both for SMA RI (p for trend = 0.032) and SMA PI (p for trend = 0.004) between patients with sine scleroderma, lcSSc and dcSSc, with lower values observed in the sine scleroderma and lcSSc groups. IMA RI and PI were significantly correlated with GI symptoms such as fecal incontinence (á¿¥ - 0.33, p = 0.008 and á¿¥ - 0.30, p = 0.021, respectively). By multivariate analysis, significant associations were confirmed between SMA RI and SMA PI and mRSS (ß 0.248, p = 0.030 and ß 2.995, p = 0.004, respectively) and with bosentan (ß 0.400, p = 0.003 and ß 3.508, p = 0.001, respectively), but not with anticentromere antibody (ACA). No significant differences were found between the weighted median values of SMA RI and SMA PI of SSc patients compared to those of HS that were derived from the meta-analysis of the literature (p = 0.72 and p = 0.64, respectively). This cross-sectional study confirms that the splanchnic vasculature of SSc patients can noninvasively been studied with DUS. Vascular splanchnic involvement correlates with the presence and/or severity of specific clinical features in SSc, including GI. Larger and prospective studies are needed to confirm these preliminary observations and to examine the role of DUS in SSc-risk stratification and GI progression and to obtain definitive data regarding both HS and SSc patients splanchnic DUS parameters.

Viral and symptom rebound following anti-SARS-CoV-2 monoclonal antibody therapy in a randomized placebo-controlled trial.

We explored viral and symptom rebound after COVID-19 amubarvimab/romlusevimab monoclonal antibody therapy vs placebo in the randomized ACTIV-2/A5401 trial. Participants underwent nasal SARS-CoV-2 PCR at study days 3, 7, 14, and 28. Viral rebound was defined as RNA ≥3 and ≥0.5 log10 copies/mL increase from day 3 or 7, and symptom rebound as hospitalization or any moderate/severe symptom for ≥2 days after initial symptom improvement. There was no difference in viral rebound (∼5%/arm) (analysis population n=713) or symptom rebound among participants who initially improved (hazard ratio 0.95 (95% CI 0.52, 1.75, analysis population) n=574); <1% had both viral/symptom rebound.

Self-reported skin severity and quality of life in systemic sclerosis: multicentre validation of PASTUL.

OBJECTIVES: The aim of this study was to validate the Patient self-Assessment of Skin Thickness in Upper Limb questionnaire (PASTUL) in systemic sclerosis (SSc) and assess impact of skin involvement on health-related quality of life (HRQoL). METHODS: Participants were included in four UK centres. PASTUL specifies a grading of skin at 8 sites corresponding to the modified Rodnan Skin Score (mRSS). Construct validity was assessed by comparing PASTUL scores with mRSS. HRQoL was evaluated with EQ5D5L and Leeds SSc HRQoL questionnaires. Additionally, correlation between PASTUL and Scleroderma Skin Patient reported Outcome (SSPRO) was explored. Follow-up was 12 months. RESULTS: In total, 196 participants were included, mean age was 56.4 years (SD 13.9), 80.6% female (n = 158), mean disease duration 11.9 years (SD 9.9), 110 (56.1%) had limited cutaneous (lcSSc) and 81 (41.3%) diffuse cutaneous SSc (dcSSc). PASTUL and upper limb mRSS were well correlated at baseline, 6 and 12 months (ICC = 0.67, 0.78 and 0.62, p< 0.001). Test-retest reliability was good (ICC = 0.83, p< 0.001). There was a stronger correlation between PASTUL and upper limb mRSS in dcSSc compared with lcSSc (0.69 vs 0.51, p< 0.001). In participants with early disease (< 4 years) PASTUL was moderately correlated with HRQoL (r = 0.53, p< 0.001), correlations were weaker in the whole group. Mean time to do the PASTUL self-assessment was 5.0 min (SD 3.7). CONCLUSION: PASTUL is a feasible outcome tool that adds to assessments as SSPRO. Skin thickening is correlated with HRQoL, particularly in early disease.

Nailfold Video-Capillaroscopy in Sarcoidosis: New Perspectives and Challenges.

INTRODUCTION: Nailfold video-capillaroscopy (NVC) is a non-invasive cost-effective technique involving the microscopic examination of small blood vessels of the distal nailfold with a magnification device. It provides valuable information regarding the microcirculation including anomalies such as tortuous or dilated capillaries, hemorrhages, and avascular areas, which can characterize connective tissue diseases. The utility of NVC in the diagnosis and monitoring of systemic sclerosis (SSc) has been investigated in numerous studies allowing the distinction of the specific microvascular pattern of scleroderma from different conditions other than scleroderma (non-scleroderma pattern). Sarcoidosis (SA) is a systemic inflammatory disease that can affect various organs, including the lungs, skin, and lymph nodes. The purpose of our review was to evaluate the current state of the art in the use of NVC in the diagnosis of SA, to understand the indications for its use and any consequent advantages in the management of the disease in different settings in terms of benefits for patients. MATERIALS AND METHODS: We searched for the key terms "sarcoidosis" and "video-capillaroscopy" in a computerized search of Pub-Med, extending the search back in time without setting limits. We provided a critical overview of the literature, based on a precise evaluation. After our analysis, we examined the six yielded works looking for answers to our questions. RESULTS: Few studies have evaluated that microcirculation is often compromised in SA, with alterations in blood flow and consequent tissue damage. DISCUSSION: Basing on highlighted findings, NVC appears to be a useful tool in the initial evaluation of sarcoidosis patients. Furthermore, capillaroscopy is useful in the evaluation of the coexistence of sarcoidosis and scleroderma spectrum disorder or overlap syndromes. CONCLUSIONS: In conclusions, no specific pattern has been described for sarcoidosis, and further re-search is needed to fully understand the implications of nailfold capillaroscopy find-ings in this disease and to establish standardized guidelines for its use in clinical practice.

Mortality and Associated Risk Factors Among People Living With HIV With Kaposi Sarcoma: A5263/AMC066 and A5264/AMC067.

BACKGROUND: AIDS-related Kaposi sarcoma (AIDS-KS) remains a leading cause of morbidity and mortality among people living with HIV in Africa. Mortality among people with AIDS-KS on antiretroviral therapy remains high compared with people on antiretroviral therapy who do not have AIDS-KS. SETTING: People living with HIV with Kaposi sarcoma (KS) who participated in 2 randomized trials (A5263/AMC066 [advanced stage] and A5264/AMC067 [mild-to-moderate stage]) conducted by AIDS Clinical Trials Group/AIDS Malignancy Consortium in low- and middle-income countries. METHODS: We estimated mortality rates over the trial period. Cox proportional hazards regressions were used to identify baseline characteristics associated with mortality and compared mortality rates between participants who had KS progression within 12 weeks of treatment initiation (early progression of KS [KS-PD]) and those who did not. RESULTS: Of the 329 and 189 eligible participants in A5263/AMC066 and A5264/AMC067, 71 (21.6%) and 24 (12.7%) died, respectively. In both trials, hypoalbuminemia was associated with increased hazards of death compared with normal albumin; A5263/AMC066: mild hypoalbuminemia (adjusted hazard ratio [aHR] = 3.01; 95% CI: 1.42 to 6.29), moderate hypoalbuminemia (aHR = 5.11; 95% CI: 2.54 to 10.29), and severe hypoalbuminemia (aHR = 14.58; 95% CI: 6.32 to 35.60), and A5264/AMC067: mild hypoalbuminemia (aHR = 5.66; 95% CI: 1.90 to 16.93) and moderate hypoalbuminemia (aHR = 7.02; 95% CI: 2.57 to 19.15). The rate of death was higher among participants who had early KS-PD than those without early KS-PD in A5263/AMC066 (HR = 5.09; 95% CI: 1.71 to 15.19) but not in A5264/AMC067 (HR = 1.74; 95% CI: 0.66 to 4.62). CONCLUSIONS: Albumin measurements may be used to identify individuals at higher risk of death after initiating KS treatment and for evaluation of interventions that can reduce AIDS-KS mortality.

Capitalizing on Dementia Care Mapping in an Evaluation of a Montessori-Based Intervention for Individuals Living with Dementia.

BACKGROUND AND OBJECTIVES: Montessori-based interventions (MBIs) promote quality of life among older adults living with dementia. We used Dementia Care Mapping (DCM) to evaluate the impact of a small-scale MBI. DCM is a systematic observation tool that records the behavior and mood/engagement of individuals living with dementia and can be used to improve quality of care and well-being. RESEARCH DESIGN AND METHODS: Pre- and post-intervention data from 15 care community residents compared: 1) residents' range and types of behaviors, 2) their mood/engagement and 3) staff behaviors that facilitated and impeded residents' personhood. In this mixed-methods study, deductive qualitative content analysis of DCM field notes further explored staff behaviors. RESULTS: Post-intervention, a significantly higher proportion of residents' behaviors had the potential to promote their well-being, although there was little change in mood/engagement while engaging in those behaviors. Post-intervention, there was also a significant increase in staff behaviors that facilitated, and a decrease in staff behaviors that impeded, residents' personhood. Further, post-intervention, staff interactions with residents were more open-ended and inclusive. Although some staff behaviors still excluded residents, the exclusion was more benign than pre-intervention. DISCUSSION AND IMPLICATIONS: DCM documented incremental changes toward person-centered care, and DCM field notes provided insight into missed opportunities for effective staff interactions with residents. Taken together, findings provide additional support for the use of MBIs and highlights the usefulness of DCM, especially its associated field notes, to help researchers and practitioners create environments that promote the personhood that individuals living with dementia deserve.

Demographics and Clinical Features Associated with Abnormal Small Bowel Motility in Systemic Sclerosis.

OBJECTIVE: The small bowel is affected in up to 50% of systemic sclerosis (SSc) patients, and some patients experience severe complications. Our aim was to use specific statistical methods to compare demographic and clinical features of SSc patients with and without abnormal small bowel to better characterize patients at risk for this complication. METHODS: SSc patients with gastrointestinal symptoms were prospectively enrolled and underwent a scintigraphy-based whole gut transit (WGT) study. A cross-sectional analysis was performed comparing clinical features between patients with and without abnormal small bowel transit by WGT. Univariate logistic regression models and multivariable models were used to examine the relationship between clinical features and abnormal small bowel transit. RESULTS: Of 130 patients enrolled in this study, 22 had abnormal small bowel transit. SSc patients with abnormal small bowel transit were more likely to be male [Odds Ratio(OR)=3.70, Confidence Interval(CI) 1.07-12.50, p= 0.038], and have more severe cardiac involvement (OR = 3.98, CI 1.10-14.38, p= 0.035), while they were less likely to have sicca symptoms (OR = 0.30, CI 0.10-0.94, p= 0.039). In multivariable analyses, sicca symptoms (OR = 0.28, CI 0.08-0.96, p= 0.043) remained negatively associated with abnormal small bowel transit. Additionally, SSc patients with abnormal small bowel transit had higher mortality than patients with normal small bowel transit [Hazard ratio(HR)=4.57, CI 1.58-13.24, p= 0.005]. CONCLUSIONS: These findings suggest that patients with abnormal small bowel transit in SSc are more likely to be male, have more severe cardiac involvement, higher mortality, and less sicca symptoms. Recognizing this patient subgroup is essential for risk stratification and optimizing clinical care.

Adolescent Compressive Epiphysitis of the Spine: A Diagnosis for Adolescent Back Pain.

Adolescent back pain is a difficult problem to diagnose owing to the variability in diagnoses that can stem from this symptom. It may be due to simple myalgias or something as complex as a neoplastic or infectious process, and the consequences of missing the latter are detrimental. The authors theorize that the increased forces seen in the lower back owing to posture in conjunction with the increase in smartphone usage over the last decade and heavy backpack use have led to an increased prevalence of a phenomenon of adolescent compressive epiphysitis of the spine (ACES). In this article, the authors describe ACES as a diagnosis for nonspecific low back pain in adolescents and reiterate the red flag symptoms associated with adolescent back pain that warrant further workup. Furthermore, they describe their treatment algorithm for these patients. (Journal of Surgical Orthopaedic Advances 33(3):135-137, 2024).

ACTIV trials: Lessons learned in trial design in the setting of an emergent pandemic.

Accelerating COVID-19 Treatment Interventions and Vaccines (ACTIV) was initiated by the US government to rapidly develop and test vaccines and therapeutics against COVID-19 in 2020. The ACTIV Therapeutics-Clinical Working Group selected ACTIV trial teams and clinical networks to expeditiously develop and launch master protocols based on therapeutic targets and patient populations. The suite of clinical trials was designed to collectively inform therapeutic care for COVID-19 outpatient, inpatient, and intensive care populations globally. In this report, we highlight challenges, strategies, and solutions around clinical protocol development and regulatory approval to document our experience and propose plans for future similar healthcare emergencies.

Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial.

Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

The 2024 British Society for Rheumatology guideline for management of systemic sclerosis-executive summary.

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1.

The 2024 British Society for Rheumatology guideline for management of systemic sclerosis.

This guideline was developed according to the British Society for Rheumatology Guidelines Protocol by a Guideline Development Group comprising healthcare professionals with expertise in SSc and people with lived experience, as well as patient organization representatives. It is an update of the previous 2015 SSc guideline. The recommendations were developed and agreed by the group and are underpinned by published evidence, assessed by systematic literature review and reinforced by collective expert opinion of the group. It considers all aspects of SSc including general management, treatment of organ-based complications, including cardiopulmonary, renal and gastrointestinal tract manifestations, as well as broader impact of disease. Whilst it is focused on adults with SSc we expect that the guideline will be relevant to people of all ages and expert input and review by paediatric rheumatologists and other relevant specialists considered where the guideline was, or may not be, applicable to young people with SSc and juvenile-onset disease. In addition to providing guidance on disease assessment and management the full guideline also considers service organization within the National Health Service and future approaches to audit of the guideline. The lay summary that accompanies this abstract can be found in Supplemental information 1.

Presentation to the Emergency Department Increases the Likelihood of Surgical Management of Minimally Displaced Gartland Type IIa Pediatric Supracondylar Humerus Fractures.

BACKGROUND: Few studies have explored factors influencing the clinical decision-making process in the management of Gartland type IIa supracondylar humerus fractures (SCHFs). This study sought to determine whether the location of patient presentation and patient socioeconomic status are associated with the treatment of type IIa SCHFs. METHODS: This was a retrospective review of 262 patients younger than 13 years of age seen for acute Gartland type II SCHFs between 2012 and 2022. Pre-treatment radiographs were reviewed to measure Baumann angle and the location of the anterior humeral line relative to the capitellum. Demographic characteristics and socioeconomic status, measured through Child Opportunity Index (COI) scores, were generated and logistic regression analysis was performed to evaluate the relationship between location of presentation and fracture management. Logistic regressions were also used to evaluate the relationship between COI and location of presentation and treatment. RESULTS: 137 male and 125 female patients met the inclusion criteria with a mean age of 5.95 (0.13) years at the time of presentation. Presentation to the emergency department (ED) demonstrated reduced odds of closed reduction and casting compared to outpatient clinic presentation [0.13 (95% CI: 0.02-0.98), P=0.048]. 27.5% of minimally displaced fractures that presented to the ED and 20.0% of minimally displaced fractures that presented to an outpatient clinic were treated surgically. There was no association between COI and the location of patient presentation [1.2 (95% CI: 0.9-1.5), P=0.226] or treatment received [1.04 (95% CI: 0.48-2.26), P=0.922]. CONCLUSION: These results suggest that patients who present to the ED after type IIa SCHFs are more likely to receive surgical treatment. COI does not appear to be associated with the location of presentation or treatment received. LEVEL OF EVIDENCE: Prognostic level III.

Spatiotemporal Forecasting of Opioid-Related Fatal Overdoses: Towards Best Practices for Modeling and Evaluation.

To inform public health interventions, researchers have developed models to forecast opioid-related overdose mortality. These efforts often have limited overlap in the models and datasets employed, presenting challenges to assessing progress in this field. Furthermore, common error-based performance metrics, such as root mean squared error (RMSE), cannot directly assess a key modeling purpose: the identification of priority areas for interventions. We recommend a new intervention-aware performance metric, Percentage of Best Possible Reach (%BPR). We compare metrics for many published models across two distinct geographic settings, Cook County, Illinois and Massachusetts, assuming the budget to intervene in 100 census tracts out of 1000s in each setting. The top-performing models based on RMSE recommend areas that do not always reach the most possible overdose events. In Massachusetts, the top models preferred by %BPR could have reached 18 additional fatal overdoses per year in 2020-2021 compared to models favored by RMSE. In Cook County, the different metrics select similar top-performing models, yet other models with similar RMSE can have significant variation in %BPR. We further find that simple models often perform as well as recently published ones. We release open code and data for others to build upon.

Gastrointestinal Manifestations of Sarcoidosis: A State-of-the-Art, Comprehensive Review of the Literature-Practical Clinical Insights and Many Unmet Needs on Diagnosis and Treatment.

This comprehensive literature review explores the involvement of the gastrointestinal (GI) tract in sarcoidosis, a multisystem granulomatous disorder of unknown etiology. GI sarcoidosis presents a diagnostic and therapeutic challenge due to its rarity and nonspecific clinical manifestations, including overlap with other gastrointestinal diseases. We conducted a comprehensive screening of articles addressing the clinical features, diagnostic approaches, and treatment strategies for GI sarcoidosis. Our findings reveal that GI sarcoidosis can affect any part of the gastrointestinal tract, with the stomach and small intestine being the most involved. Clinical presentations range from asymptomatic cases to severe complications such as obstruction and perforation, with reflux being a common symptom. Diagnosis is often delayed due to the nonspecific nature of symptoms and the need for histopathological confirmation. Therapeutic approaches are poorly defined, typically involving corticosteroids as the mainstay of treatment. However, the long-term efficacy and safety of these treatments remain uncertain in this patient group, given the significant risks and complications associated with prolonged glucocorticoid therapy. There is a clear need to develop accurate diagnostic protocols to distinguish GI sarcoidosis from other conditions and to establish standardized therapeutic guidelines to optimize patient outcomes. Further research is essential to enhance our understanding and management of this complex condition.

Safety of Nintedanib in a Patient with Chronic Pulmonary Fibrosis and Kidney Disease.

Nintedanib, an intracellular inhibitor that targets multiple tyrosine kinase, is an important drug for the treatment of pulmonary fibrosis. Until now, no studies have been published reporting the nintedanib tolerability or its efficacy in patients with chronic pulmonary lung disease and chronic kidney disease comorbidity. The safety, efficacy and pharmacokinetics of nintedanib have not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) and for this reason it is contraindicated in these patients. We describe a case of use of nintedanib in a patient affected by idiopathic pulmonary fibrosis (IPF) who started, from 2022, nintedanib 150 mg twice a day with careful monitoring of liver and kidney function. Due to the onset of stage 3/4 chronic kidney disease associated with proteinuria, nintedanib was suspended for two months, and the patient received Prednisone at a dose of 12.5 mg/day. During the two months of suspension, the renal function did not improve, unlike the respiratory status worsened. In the past a renal biopsy was performed which showed no correlation with nintedanib use. Nintedanib therapy started again following the decline in lung function and desaturation below 90% in the 6-min walking test (6MWT). Patient showed a good tolerability of nintedanib with sporadic episode of diarrhea and an improvement of pulmonary function leading to a stable state of chronic pulmonary fibrosis disease. For this reason, in mutual agreement with the patient, we decided to maintain nintedanib therapy even when the patient required hemodialysis. No toxic effects appeared. This case report revealed the safety of nintedinab in patient with concomitant kidney failure, but more studies are necessary.

Label-free, non-contact determination of resting membrane potential using dielectrophoresis.

Measurement of cellular resting membrane potential (RMP) is important in understanding ion channels and their role in regulation of cell function across a wide range of cell types. However, methods available for the measurement of RMP (including patch clamp, microelectrodes, and potential-sensitive fluorophores) are expensive, slow, open to operator bias, and often result in cell destruction. We present non-contact, label-free membrane potential estimation which uses dielectrophoresis to determine the cytoplasm conductivity slope as a function of medium conductivity. By comparing this to patch clamp data available in the literature, we have demonstratet the accuracy of this approach using seven different cell types, including primary suspension cells (red blood cells, platelets), cultured suspension cells (THP-1), primary adherent cells (chondrocytes, human umbilical mesenchymal stem cells), and adherent (HeLa) and suspension (Jurkat) cancer cell lines. Analysis of the effect of ion channel inhibitors suggests the effects of pharmaceutical agents (TEA on HeLa; DMSO and neuraminidase on red blood cells) can also be measured. Comparison with published values of membrane potential suggest that the differences between our estimates and values recorded by patch clamp are accurate to within published margins of error. The method is low-cost, non-destructive, operator-independent and label-free, and has previously been shown to allow cells to be recovered after measurement.

Clinically relevant differences between primary Raynaud's phenomenon and secondary to connective tissue disease.

OBJECTIVES: Raynaud's phenomenon (RP) is a symptom complex associated with digital vascular compromise. Our aim was to examine for clinically relevant differences between primary RP (PRP) and secondary RP (SRP) to connective tissue disease. METHODS: We report cross-sectional results from the Patient Survey of experiences of Raynaud's Phenomenon (PASRAP), which aimed to explore the broad-ranging impact of RP. The survey was widely distributed online including via social medial. Participation was voluntary and responses were anonymous. RESULTS: 1229 respondents completed PASRAP with self-reported RP: PRP 218 (17.7 %) and SRP 1011 (82.3 %) of which 903 (92.9 %) Systemic Sclerosis. The mean (SD) age was significantly lower in respondents with PRP (41.7 [11.8] vs 54.2 [12.4] years, P<0.0001). During attacks, more subjects with SRP reported cyanotic colour changes (92.2 % vs 86.5 %, P=0.0089). Patients with PRP experienced more pain (72.1 % vs 55.9 %, P<0.0001), numbness (80.3 % vs 69.4 %, P=0.0016), stinging/throbbing (93.4 % vs 80.8 %, P<0.0001), and tingling (84.0 % vs 77.5 %, P=0.0345). Only half of respondents' symptoms were adequately controlled by their current medication(s), more commonly in SRP (55.2 % vs 45.2 %, P=0.0084). There were important differences in the triggers, number, and seasonal variation of RP attacks. CONCLUSION: There are clinically relevant differences between PRP and SRP concerning the multifaceted lived patient experience of RP. Neurosensory symptoms are more common in PRP. Patients with SRP are older and present with more colour changes, overrepresented by cyanosis, and with less complete resolution of symptoms between attacks. These data provide novel insights for future RP clinical trial design.

Microbial intestinal dysbiosis drives long-term allergic susceptibility by sculpting an ILC2-B1 cell-innate IgE axis.

BACKGROUND: The abundance and diversity of intestinal commensal bacteria influence systemic immunity with impact on disease susceptibility and severity. For example, loss of short chain fatty acid (SCFA)-fermenting bacteria in early life (humans and mice) is associated with enhanced type 2 immune responses in peripheral tissues including the lung. OBJECTIVE: Our goal was to reveal the microbiome-dependent cellular and molecular mechanisms driving enhanced susceptibility to type 2 allergic lung disease. METHODS: We used low-dose vancomycin to selectively deplete SCFA-fermenting bacteria in wild-type mice. We then examined the frequency and activation status of innate and adaptive immune cell lineages with and without SCFA supplementation. Finally, we used ILC2-deficient and signal transducer and activator of transcription 6 (STAT6)-deficient transgenic mouse strains to delineate the cellular and cytokine pathways leading to enhanced allergic disease susceptibility. RESULTS: Mice with vancomycin-induced dysbiosis exhibited a 2-fold increase in lung ILC2 primed to produce elevated levels of IL-2, -5, and -13. In addition, upon IL-33 inhalation, mouse lung ILC2 displayed a novel ability to produce high levels of IL-4. These expanded and primed ILC2s drove B1 cell expansion and IL-4-dependent production of IgE that in turn led to exacerbated allergic inflammation. Importantly, these enhanced lung inflammatory phenotypes in mice with vancomycin-induced dysbiosis were reversed by administration of dietary SCFA (specifically butyrate). CONCLUSION: SCFAs regulate an ILC2-B1 cell-IgE axis. Early-life administration of vancomycin, an antibiotic known to deplete SCFA-fermenting gut bacteria, primes and amplifies this axis and leads to lifelong enhanced susceptibility to type 2 allergic lung disease.