A phase 2 trial investigating the efficacy and safety of the mPGES-1 inhibitor vipoglanstat in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our objective was to test the hypothesis, in a double-blind, placebo-controlled study that vipoglanstat, an inhibitor of microsomal prostaglandin E synthase-1 (mPGES-1) which decreases prostaglandin E2 (PGE2) and increases prostacyclin biosynthesis, improves RP. METHODS: Patients with systemic sclerosis (SSc) and ≥7 RP attacks during the last screening week prior to a baseline visit were randomised to four weeks treatment with vipoglanstat 120 mg or placebo. A daily electronic diary captured RP attacks (duration and pain) and Raynaud's Condition Score, with change in RP attacks/week as primary end point. Cold challenge assessments were performed at baseline and end of treatment. Exploratory endpoints included patients' and physicians' global impression of change, Assessment of Scleroderma-associated Raynaud's Phenomenon questionnaire, mPGES-1 activity, and urinary excretion of arachidonic acid metabolites. RESULTS: Sixty-nine subjects received vipoglanstat (n = 33) or placebo (n = 36). Mean weekly number of RP attacks (baseline; vipoglanstat 14.4[SD 6.7], placebo 18.2[12.6]) decreased by 3.4[95% CI -5.8;-1.0] and 4.2[-6.5;-2.0] attacks per week (p= 0.628) respectively. All patient reported outcomes improved, with no difference between the groups. Mean change in recovery of peripheral blood flow after cold challenge did not differ between the study groups. Vipoglanstat fully inhibited mPGES-1, resulting in 57% reduction of PGE2 and 50% increase of prostacyclin metabolites in urine. Vipoglanstat was safe and well tolerated. CONCLUSION: Although vipoglanstat was safe, and well tolerated in a dose achieving full inhibition of mPGES-1, it was ineffective in SSc-related RP. Further development and evaluation of vipoglanstat will therefore be in other diseases where mPGES-1 plays a pathogenetic role.

A review of a strategic roadmapping exercise to advance clinical translation of photoacoustic imaging: From current barriers to future adoption.

Photoacoustic imaging (PAI), also referred to as optoacoustic imaging, has shown promise in early-stage clinical trials in a range of applications from inflammatory diseases to cancer. While the first PAI systems have recently received regulatory approvals, successful adoption of PAI technology into healthcare systems for clinical decision making must still overcome a range of barriers, from education and training to data acquisition and interpretation. The International Photoacoustic Standardisation Consortium (IPASC) undertook an community exercise in 2022 to identify and understand these barriers, then develop a roadmap of strategic plans to address them. Here, we outline the nature and scope of the barriers that were identified, along with short-, medium- and long-term community efforts required to overcome them, both within and beyond the IPASC group.

Non-invasive imaging and clinical skin scores in juvenile localised scleroderma.

OBJECTIVES: To evaluate whether in juvenile localised scleroderma (JLS), non-invasive imaging can differentiate affected from non-affected skin and whether imaging correlates with a validated skin score (Localised Scleroderma Cutaneous Assessment Tool, LoSCAT). METHODS: 25 children with JLS were recruited into a prospective study and a single 'target' lesion selected. High frequency ultrasound (HFUS, measuring skin thickness), infrared thermography (IRT, skin temperature), laser Doppler imaging (LDI, skin blood flow) and multispectral imaging (MSI, oxygenation), were performed at four sites: two of affected skin (centre and inner edge of lesion) and two of non-affected skin (one cm from edge of lesion 'outer' and contralateral non-affected side), at 4 visits at 3 monthly intervals. RESULTS: Differences between affected and non-affected skin were detected with all 4 techniques. Compared with non-affected skin, affected skin was thinner (p< 0.001) with higher temperature (p< 0.001-0.006), perfusion (p< 0.001-0.039) and oxygenation (p< 0.001-0.028). Lesion skin activity (LoSCAT) was positively correlated with centre HFUS (r = 0.32; 95% CI [0.02, 0.61]; p= 0.036) and negatively correlated with centre LDI (r=-0.26; 95% CI [-0.49, -0.04]; p= 0.022). Lesion skin damage was positively correlated with centre and inner IRT (r = 0.43; 95% CI [0.19, 0.67]; p< 0.001, r = 0.36, 95% CI [0.12, 0.59]; p= 0.003, respectively) and with centre and inner LDI (r = 0.37; 95% CI [0.05, 0.69]; p= 0.024, r = 0.41; 95% CI [0.08, 0.74]; p= 0.015, respectively). CONCLUSION: Non-invasive imaging can detect differences between affected and non-affected skin in JLS and may help to differentiate between activity (thicker, less well perfused skin) and damage (thinner, highly perfused skin).

Expanding opportunities for chronic disease prevention for Hispanics: the Better Together REACH program in Pennsylvania.

Background: Hispanics in Lebanon and Reading, Pennsylvania, experience high levels of socioeconomic and health disparities in risk factors for chronic disease. In 2018, our community-academic coalition "Better Together" received a Racial and Ethnic Approaches to Community Health (REACH) award to improve healthy lifestyles. This report describes our work-in-progress and lessons learned to date from our REACH-supported initiatives in Lebanon and Reading. Methods: For the past 4 years, our coalition has leveraged strong community collaborations to implement and evaluate culturally-tailored practice- and evidence-based activities aimed at increasing physical activity, healthy nutrition, and community-clinical linkages. This community case report summarizes the context where our overall program was implemented, including the priority population, target geographical area, socioeconomic and health disparities data, community-academic coalition, conceptual model, and details the progress of the Better Together initiative in the two communities impacted. Results: To improve physical activity, we are: (1) creating new and enhancing existing trails connecting everyday destinations through city redesigning and master planning, (2) promoting outdoor physical activity, (3) increasing awareness of community resources for chronic disease prevention, and (4) supporting access to bikes for youth and families. To improve nutrition, we are: (1) expanding access to locally-grown fresh fruit and vegetables in community and clinical settings, through the Farmers Market Nutrition Program to beneficiaries of the Women, Infants, and Children (WIC) program and the Veggie Rx to patients who are at risk for or have diabetes, and (2) providing bilingual breastfeeding education. To enhance community-clinical linkages, we are training bilingual community health workers to connect at-risk individuals with diabetes prevention programs. Conclusions: Intervening in areas facing high chronic disease health disparities leads us to develop a community-collaborative blueprint that can be replicated across Hispanic communities in Pennsylvania and the United States.

A deep learning system for quantitative assessment of microvascular abnormalities in nailfold capillary images.

OBJECTIVES: Nailfold capillaroscopy is key to timely diagnosis of SSc, but is often not used in rheumatology clinics because the images are difficult to interpret. We aimed to develop and validate a fully automated image analysis system to fill this gap. METHODS: We mimicked the image interpretation strategies of SSc experts, using deep learning networks to detect each capillary in the distal row of vessels and make morphological measurements. We combined measurements from multiple fingers to give a subject-level probability of SSc.We trained the system using high-resolution images from 111 subjects (group A) and tested on images from subjects not in the training set: 132 imaged at high-resolution (group B); 66 imaged with a low-cost digital microscope (group C). Roughly half of each group had confirmed SSc, and half were healthy controls or had primary RP ('normal'). We also estimated the performance of SSc experts. RESULTS: We compared automated SSc probabilities with the known clinical status of patients (SSc versus 'normal'), generating receiver operating characteristic curves (ROCs). For group B, the area under the ROC (AUC) was 97% (94-99%) [median (90% CI)], with equal sensitivity/specificity 91% (86-95%). For group C, the AUC was 95% (88-99%), with equal sensitivity/specificity 89% (82-95%). SSc expert consensus achieved sensitivity 82% and specificity 73%. CONCLUSION: Fully automated analysis using deep learning can achieve diagnostic performance at least as good as SSc experts, and is sufficiently robust to work with low-cost digital microscope images.

A phase 2 trial investigating the effects of the angiotensin II type 2 receptor agonist C21 in systemic sclerosis-related Raynaud's.

OBJECTIVE: Our main aim was to investigate the effect of a single oral dose of C21, a selective angiotensin II type 2 receptor agonist, on cold-induced vasoconstriction in SSc-related RP. METHODS: This was a phase IIa, randomized, double-blind, cross-over, single-dose, placebo-controlled, single-centre study. Twelve female patients with SSc (median age 58.5 years, median duration of RP 19.0 years) attended on four occasions: screening, treatment visits 1 and 2 (separated by 3-7 days) and follow-up. At the first treatment visit, patients were randomized to receive either a single oral dose of C21 (200 mg) or placebo, then the opposite treatment on the second visit. Forty min after each treatment, each patient underwent a standard hand cold challenge. The primary end point was the area under the curve (AUC) for rewarming for each finger (eight fingers) over 15 min. Secondary end points included the maximum finger temperature after rewarming (MAX). Statistical analyses were performed by multiplicative ANCOVA models. RESULTS: For all eight fingers combined, mean AUC for rewarming was higher after treatment with C21 than after placebo (geometric mean 20 046°C*s vs 19 558°C*s), but not significantly (P = 0.380) and MAX (at 15 min) was also higher (geometric mean 23.5°C vs 22.5°C; P = 0.036). C21 was well tolerated. CONCLUSION: Despite the small trial size, a signal emerged suggesting that even in patients with established SSc, C21 may confer benefit for RP and deserves further investigation. TRIAL REGISTRATION: ClinicalTrials.gov, https://clinicaltrials.gov, NCT04388176.

Feasibility study of mobile phone photography as a possible outcome measure of systemic sclerosis-related digital lesions.

Objective: Clinical trials assessing systemic sclerosis (SSc)-related digital ulcers have been hampered by a lack of reliable outcome measures of healing. Our objective was to assess the feasibility of patients collecting high-quality mobile phone images of their digital lesions as a first step in developing a smartphone-based outcome measure. Methods: Patients with SSc-related digital (finger) lesions photographed one or more lesions each day for 30 days using their smartphone and uploaded the images to a secure Dropbox folder. Image quality was assessed using six criteria: blurriness, shadow, uniformity of lighting, dot location, dot angle and central positioning of the lesion. Patients completed a feedback questionnaire. Results: Twelve patients returned 332 photographs of 18 lesions. Each patient sent a median of 29.5 photographs [interquartile range (IQR) 15-33.5], with a median of 15 photographs per lesion (IQR 6-32). Twenty-two photographs were duplicates. Of the remaining 310 images, 256 (77%) were sufficiently in focus; 268 (81%) had some shadow; lighting was even in 56 (17%); dot location was acceptable in 233 (70%); dot angle was ideal in 107 (32%); and the lesion was centred in 255 (77%). Patient feedback suggested that 6 of 10 would be willing to record images daily in future studies, and 9 of 10 at least one to three times per week. Conclusion: Taking smartphone photographs of digital lesions was feasible for most patients, with most lesions in focus and central in the image. These promising results will inform the next research phase (to develop a smartphone monitoring application incorporating photographs and symptom tracking).

Multispectral imaging of nailfold capillaries using light-emitting diode illumination.

Significance: The capillaries are the smallest blood vessels in the body, typically imaged using video capillaroscopy to aid diagnosis of connective tissue diseases, such as systemic sclerosis. Video capillaroscopy allows visualization of morphological changes in the nailfold capillaries but does not provide any physiological information about the blood contained within the capillary network. Extracting parameters such as hemoglobin oxygenation could increase sensitivity for diagnosis and measurement of microvascular disease progression. Aim: To design, construct, and test a low-cost multispectral imaging (MSI) system using light-emitting diode (LED) illumination to assess relative hemoglobin oxygenation in the nailfold capillaries. Approach: An LED ring light was first designed and modeled. The ring light was fabricated using four commercially available LED colors and a custom-designed printed circuit board. The experimental system was characterized and results compared with the illumination model. A blood phantom with variable oxygenation was used to determine the feasibility of using the illumination-based MSI system for oximetry. Nailfold capillaries were then imaged in a healthy subject. Results: The illumination modeling results were in close agreement with the constructed system. Imaging of the blood phantom demonstrated sensitivity to changing hemoglobin oxygenation, which was in line with the spectral modeling of reflection. The morphological properties of the volunteer capillaries were comparable to those measured in current gold standard systems. Conclusions: LED-based illumination could be used as a low-cost approach to enable MSI of the nailfold capillaries to provide insight into the oxygenation of the blood contained within the capillary network.

Photoacoustic imaging is a novel tool to measure finger artery structure and oxygenation in patients with SSc.

Systemic sclerosis (SSc)-related digital ischaemia is a major cause of morbidity, resulting from a combination of microvascular and digital artery disease. Photoacoustic imaging offers a newly available, non-invasive method of imaging digital artery structure and oxygenation. The aim of this study was to establish whether photoacoustic imaging could detect and measure vasculopathy in digital arteries, including the level of oxygenation, in patients with SSc and healthy controls. 22 patients with SSc and 32 healthy controls (HC) underwent photoacoustic imaging of the fingers. Vascular volume and oxygenation were assessed across eight fingers at the middle phalanx. In addition, oxygenation change during finger occlusion was measured at the non-dominant ring finger and the vascular network was imaged along the length of one finger for qualitative assessment. There was no statistically significant difference in vascular volume between patients with SSc and HC (mean of eight fingers; SSc, median 118.6 IQR [95.0-130.5] vs. HC 115.6 [97.8-158.9]) mm3. However, baseline oxygenation (mean 8 fingers) was lower in SSc vs. HC (0.373 [0.361-0.381] vs. 0.381 [0.373-0.385] arbitrary sO2 units respectively; p = 0.03). Hyperaemic oxygenation response following occlusion release was significantly lower in SSc compared to HC (0.379 [0.376-0.381] vs. 0.382 [0.377-0.385]; p = 0.03). Whilst vascular volume was similar between groups, digital artery oxygenation was decreased in patients with SSc as compared to HC, indicative of functional deficit. Photoacoustic imaging offers an exciting new method to image the vascular network in patients with SSc and the possibility to capture oxygenation as a functional measure.

Implementing Locally Tailored Strategies to Promote Redemption of Farmers' Market Nutrition Program Vouchers Among WIC Participants in Central Pennsylvania.

The Pennsylvania Farmers' Market Nutrition Program (FMNP) provides vouchers to participants of the Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) to purchase locally grown fruits, vegetables (F&V), and herbs every year from June to November. Voucher redemption is suboptimal among WIC participants in Lebanon County, a community with high numbers of low-income and Hispanic families. Supported by a Racial and Ethnic Approaches to Community Health (REACH) award, our community-academic coalition partnered with the local WIC provider to implement locally tailored strategies to promote redemption of FMNP vouchers. In 2019, we surveyed FMNP participants (n = 100) to examine opportunities for improved voucher redemption. Increasing sites for voucher use (47%) and a larger variety of F&V (27%) were the most commonly selected improvements participants identified. Participants also supported improvements to increase awareness of available seasonal produce (14%), text/phone reminders to redeem vouchers (13%), and having recipes to cook meals with FMNP-approved F&V (12%). These findings led us to implement a weekly, Farm-to-WIC "grab bag" program in 2020/2021. We partnered with a local farmer to offer a variety of FMNP-approved produce in $3 and $6 grab bags at the local WIC provider. Each grab bag included healthy recipes using the included produce. In 2021, we launched a text/phone reminder intervention to encourage voucher redemption among FMNP participants (n = 57). Our work demonstrates the value of community-academic partnerships to identify and implement feasible strategies that are responsive to local needs as well as supporting existing programs providing greater access to affordable produce.

Nailfold capillaroscopy: a survey of current UK practice and 'next steps' to increase uptake among rheumatologists.

OBJECTIVES: To identify barriers to the use of nailfold capillaroscopy as a diagnostic tool for patients presenting with Raynaud's phenomenon in UK rheumatology centres and to obtain rheumatologists' views on a proposed internet-based standardized system for clinical reporting of nailfold capillaroscopy images. METHODS: An online survey was developed using expert opinion from clinicians, scientists and health service researchers. The survey was piloted and sent to UK-based rheumatologists using established electronic mailing lists between October 2020 and March 2021. Survey data were analysed using descriptive statistics. RESULTS: A total of 104 rheumatologists representing rheumatology centres across the UK responded to the survey. Wide variations in terms of workloads and practices were described. Thirty-four (33%) respondents reported using nailfold capillaroscopy only at their own centre, 33 (32%) referred to other centres, 9 (9%) did both and 28 (27%) did not use capillaroscopy at all. Of the 43 respondents using capillaroscopy on site, 25 (58%) used either a dermatoscope or universal serial bus microscope and 9 (21%) used videocapillaroscopy. Among the 61 respondents not undertaking capillaroscopy on site, barriers included lack of equipment (85%), lack of experience in acquiring images (69%) and lack of expertise in interpreting images (67%). Sixty-six respondents (63%) expressed interest in an internet-based, standardized automated system for reporting images. CONCLUSION: Most UK rheumatologists currently do not perform nailfold capillaroscopy on site. An internet-based nailfold capillaroscopy system for use with low-cost microscopes as well as with videocapillaroscopy could help increase uptake of capillaroscopy and thereby facilitate early diagnosis of SSc across the UK.

Enhancing community engagement in Patient-Centered Outcomes Research: Equipping learners to thrive in translational efforts.

Community engagement is a critical component of translational research. Innovative educational approaches to support meaningful involvement of stakeholders in clinical research allows for bidirectional learning and greater engagement in translational efforts. Our Penn State Community-Engaged Research Core (CeRC) team has developed an innovative research curriculum for a variety of stakeholders, including patient partners, organizational representatives, and Community Health Workers (CHWs). This brief report will outline unique curricular approaches, guided by adult learning principles, to enhance stakeholder education and engagement in activities. Initial evidence of impact on learning is also reported.

Perceptions of Diseases of Despair by Members of Rural and Urban High-Prevalence Communities: A Qualitative Study.

Importance: Diseases of despair (ie, mortality or morbidity from suicidality, drug abuse, and alcoholism) were first characterized as increasing in rural White working-class populations in midlife with low educational attainment and associated with long-term economic decline. Excess mortality now appears to be associated with working-class citizens across demographic and geographic boundaries, but no known qualitative studies have engaged residents of rural and urban locales with high prevalence of diseases of despair to learn their perspectives. Objective: To explore perceptions about despair-related illness and potential intervention strategies among diverse community members residing in discrete rural and urban hotspots. Design, Setting, and Participants: In this qualitative study, high-prevalence hotspots for diseases of despair were identified from health insurance claims data in Central Pennsylvania. Four focus groups were conducted with 60 community members in organizations and coalitions from 3 census block group hotspot clusters in the health system between September 2019 and January 2020. Focus groups explored awareness and beliefs about causation and potential intervention strategies. Main Outcomes and Measures: A descriptive phenomenological approach was applied to thematic analysis, and a preliminary conceptual model was constructed to describe how various factors may be associated with perpetuating despair and with public health. Results: In total, 60 adult community members participated in 4 focus groups (44 women, 16 men; 40 White non-Hispanic, 17 Black, and 3 Hispanic/Latino members). Three focus groups with 43 members were held in rural areas with high prevalence of diseases of despair, and 1 focus group with 17 members in a high-prevalence urban area. Four themes emerged with respect to awareness and believed causation of despair-related illness, and participants identified common associated factors, including financial distress, lack of critical infrastructure and social services, deteriorating sense of community, and family fragmentation. Intervention strategies focused around 2 themes: (1) building resilience to despair through better community and organizational coordination and peer support at the local level and (2) encouraging broader state investments in social services and infrastructure to mitigate despair-related illness. Conclusions and Relevance: In this qualitative study, rural and urban community members identified common factors associated with diseases of despair, highlighting the association between long-term political and economic decline and public health and a need for both community- and state-level solutions to address despair. Health care systems participating in addressing community health needs may improve processes to screen for despair (eg, social history taking) and codesign primary, secondary, and tertiary interventions aimed at addressing factors associated with distress. Such actions have taken on greater urgency with the COVID-19 pandemic.

White matter tracts related to memory and emotion in very preterm children.

BACKGROUND: Very preterm (VP) children are at risk of memory and emotional impairments; however, the neural correlates remain incompletely defined. This study investigated the effect of VP birth on white matter tracts traditionally related to episodic memory and emotion. METHODS: The cingulum, fornix, uncinate fasciculus, medial forebrain bundle and anterior thalamic radiation were reconstructed using tractography in 144 VP children and 33 full-term controls at age 7 years. RESULTS: Compared with controls, VP children had higher axial, radial, and mean diffusivities and neurite orientation dispersion, and lower volume and neurite density in the fornix, along with higher neurite orientation dispersion in the medial forebrain bundle. Support vector classification models based on tract measures significantly classified VP children and controls. Higher fractional anisotropy and lower diffusivities in the cingulum, uncinate fasciculus, medial forebrain bundle and anterior thalamic radiation were associated with better episodic memory, independent of key perinatal risk factors. Support vector regression models using tract measures did not predict episodic memory and emotional outcomes. CONCLUSIONS: Altered tract structure is related to adverse episodic memory outcomes in VP children, but further research is required to determine the ability of tract structure to predict outcomes of individual children. IMPACT: We studied white matter fibre tracts thought to be involved in episodic memory and emotion in VP and full-term children using diffusion magnetic resonance imaging and machine learning. VP children have altered fornix and medial forebrain bundle structure compared with full-term children. Altered tract structure can be detected using machine learning, which accurately classified VP and full-term children using tract data. Altered cingulum, uncinate fasciculus, medial forebrain bundle and anterior thalamic radiation structure was associated with poorer episodic memory skills using linear regression. The ability of tract structure to predict episodic memory and emotional outcomes of individual children based on support vector regression was limited.

Comparison between low cost USB nailfold capillaroscopy and videocapillaroscopy: a pilot study.

OBJECTIVES: Universal serial bus (USB) microscopy (capillaroscopy) could provide all rheumatologists with an easy-to-use, low-cost tool to examine the nailfold capillaries to facilitate early diagnosis of SSc. The objectives of this pilot study were to examine the feasibility of acquiring and analysing images using USB microscopy and to compare results to videocapillaroscopy. METHODS: Videocapillaroscopy and USB microscope images were obtained from the right and left ring fingers of 20 patients with SSc and 20 healthy control subjects. In addition to generating panoramic capillary mosaics from across the whole nailbed, custom software made fully automated measurements of vessel structure including capillary width and density. The area under the receiver operating characteristic curve (AZ) was used to measure separation between the SSc and healthy control groups. RESULTS: High quality images could be generated from the USB microscope, with reconstructed USB images comparing very favourably with those obtained using videocapillaroscopy. Using USB microscope images, the receiver operating characteristic curve AZ for group separation based on mean width was 0.81 (standard error 0.120) compared with 0.81 (standard error 0.095) for the (gold standard) videocapillaroscopy. The receiver operating characteristic curve AZ for group separation using capillary density was 0.48 (standard error 0.16) for USB microscope images, compared with 0.70 (standard error 0.10) for videocapillaroscopy. CONCLUSION: In this pilot study, USB capillaroscopy was able to discriminate between patients with SSc and controls as well as videocapillaroscopy on the basis of capillary width. This finding, together with the high-quality images obtained, highlights the potential of USB capillaroscopy as a low-cost, easily accessible clinical and research tool.