Plasmacytoid dendritic cells are not major producers of type 1 interferon in cutaneous lupus: An in depth immunoprofile of subacute and discoid lupus.

The immunologic drivers of cutaneous lupus erythematosus (CLE) and its clinical subtypes remains poorly understood. We sought to characterize the immune landscape of discoid lupus erythematosus (DLE) and subacute CLE (SCLE) using multiplexed immunophenotyping. We found no significant differences in immune cell percentages between DLE and SCLE (p>0.05) with the exception of an increase in TANK binding kinase 1 (TBK1) in DLE (p<0.05). Unbiased clustering grouped subjects into two major clusters without respect to clinical subtype. Subjects with a history of smoking had increased percentages of neutrophils, disease activity, and endothelial granzyme B than non-smokers. Despite previous assumptions, plasmacytoid dendritic cells (pDCs) did not stain for type 1 interferon (IFN-1). Skin-eluted and circulating pDCs from CLE subjects expressed significantly less IFNα than healthy control pDCs upon toll like receptor (TLR) 7 stimulation ex vivo (p<0.0001). These data suggest that DLE and SCLE have similar immune microenvironments in a multiplexed investigation. Our aggregated analysis of CLE revealed that smoking may modulate disease activity in CLE via neutrophils and endothelial GZMB. Notably, our data suggest that pDCs are not the major producers of IFN-1 in CLE. Future in vitro studies to investigate the role of pDCs in CLE are needed.

Herbal supplement Spirulina stimulates inflammatory cytokine production in patients with dermatomyositis in vitro.

Spirulina, an herbal supplement and popular ingredient in health foods, is a potent stimulant of the immune system. Spirulina use is temporally associated with the onset or exacerbation of Dermatomyositis (DM), an autoimmune connective tissue disease that frequently affects the skin and muscle. In this study, we investigated the effect of Spirulina on peripheral blood mononuclear cells (PBMCs) in DM and Healthy Controls (HCs), showing that Spirulina stimulates Interferon ß (IFNß), Tumor necrosis factor α (TNFα), and Interferon γ (IFNγ) production of DM PBMCs primarily via Toll-Like Receptor 4 (TLR4) activation using ELISA (enzyme linked immunosorbent assay) and flow cytometry. We show that classical monocytes and monocyte-derived dendritic cells are stimulated by Spirulina and are activated via TLR4. Skin from patients with Spirulina-associated DM exhibits an inflammatory milieu similar to that of idiopathic DM but with a stronger correlation of TLR4 and IFNγ.

Effects of the COVID-19 pandemic on maternal and perinatal health service utilisation and outcomes in Mozambique: an interrupted time series analysis.

OBJECTIVES: To measure the effects of the COVID-19 pandemic on maternal and perinatal health services and outcomes in Mozambique. DESIGN: This is an observational study analysing routine service delivery data using interrupted time series analysis. We used 43 months of district-level panel data with April 2020 as the point of interruption, adjusting for seasonality and population growth to analyse service utilisation outcomes. SETTING: The 222 public health facilities in Nampula Province, Mozambique, from January 2018 to July 2021. OUTCOME MEASURES: The change in the number of antenatal care (ANC) visits and facility deliveries, and the change in the rate of adverse birth outcomes at pandemic onset and over time compared with expected levels and trends, respectively. RESULTS: There were no significant disruptions to ANC at pandemic onset. Following this, there was a significant monthly increase of 29.8 (18.2-41.4) first ANC visits and 11.3 (5.5-17.2) ANC visits within the first trimester per district above prepandemic trends. There was no significant change in the number of fourth ANC visits completed. At the onset of COVID-19, districts experienced a significant decrease of 71.1 (-110.5 to -31.7) facility deliveries, but the rate then increased significantly above prepandemic trends. There was no significant increase in any adverse birth outcomes during the pandemic. Conversely, districts observed a significant monthly decrease of 5.3 uterine rupture cases (-9.9 to -0.6) and 19.2 stillbirths (-33.83 to -4.58) per 100 000 facility deliveries below prepandemic trends. There was a significant drop of 23.5 cases of neonatal sepsis/100 000 facility deliveries per district at pandemic onset. CONCLUSION: Despite pandemic interference, Nampula Province saw no disruptions to ANC, only temporary disruptions to facility deliveries and no increases in adverse birth outcomes. ANC visits surprisingly increased, and the rates of uterine rupture, stillbirth and neonatal sepsis decreased, suggesting that Nampula Province may offer insights about health system resilience.

Clinical, logistic, and geographic factors in ensuring adequate access to implant removals: A cross-sectional survey of public facilities and GIS modeling of geographic access in two districts of Senegal.

Introduction: Ensuring adequate access to contraceptive implant removal services requires an understanding of potential clinical, logistical, and geographic challenges. Methods: We conducted a cross-sectional survey of 39 public health facilities in two districts of Senegal. To assess facility readiness, we reported the proportion of facilities meeting all minimum conditions for regular and difficult implant removals. We then describe characteristics of referral networks. Geographic access modeling was conducted in a geographic information system to estimate the proportion of women of reproductive age living within specific travel times of facilities ready for regular and difficult removals. Results: 72% of facilities met all conditions for regular removals, and 8% for difficult removals. In both cases, the main gaps related to equipment availability (79% of facilities had the minimum equipment for regular removals and 8% for difficult removals). 72% of facilities organized in three referral networks sent clients to other facilities for cases they could not manage. Of 11 receiving or single-network facilities, seven were ready for regular removals and one for difficult removals. Altogether, 36% of women in Dakar Centre and 99% of women in Kolda lived within two hours of a facility that was equipped to handle regular removals, compared to 15% and 69%, respectively, for difficult removals. Conclusion: Data such as those provided in this assessment are important to provide a realistic picture of the state of readiness of the health system and its ability to meet the inevitable demand for implant removals. Referral networks should be considered as an emerging strategy to avail sufficient capacity at the systems level, including for managing difficult removals. However, careful thought should be given to the location of facilities that are ready to receive cases in order to target upgrades.

Autoimmune Skin Disease Exacerbations Following COVID-19 Vaccination.

Background: Vaccination against COVID-19 reduces the risk of severe COVID-19 disease and death. However, few studies have examined the safety of the COVID-19 vaccine in patients with autoimmune skin disease. Objectives: We sought to determine the incidence of disease exacerbation in this population following COVID-19 vaccination as well as the associated factors. Methods: We performed a chart review of all patients seen in the autoimmune skin disease clinic of the principal investigator during the study period. All patients included for analysis were systematically and prospectively asked about COVID-19 vaccination status, manufacturers, vaccine dates, autoimmune symptoms after the vaccine, and timing of symptom onset using a standardized template as part of their visit. Demographics and autoimmune disease diagnosis were also collected. Analysis used Chi-square and Fisher's exact tests. Results: 402 subjects were included for analysis. 85.6% of patients were fully vaccinated, with 12.9% unvaccinated and 1.5% partially vaccinated. 14.8% of fully vaccinated patients reported worsening autoimmune signs and symptoms after the vaccine. Fully vaccinated dermatomyositis patients were more likely to report worsening autoimmune signs and symptoms after the vaccine (22.7%) than fully vaccinated lupus erythematosus patients (8.6%) (p=0.009). Patients fully vaccinated with the Moderna vaccine trended towards an increased likelihood of reporting worsening autoimmune signs and symptoms after the vaccine (19.1%) than those with the Pfizer-BioNTech vaccine (12.0%) (p=0.076). Of the patients who had autoimmune symptoms after vaccination, 20% had symptoms after the 1st dose, 82% after the 2nd dose, and 4% after the 3rd dose with median onset (95% confidence interval) of 7 (2,14), 14 (14,21), and 18 (7,28) days later, respectively. Conclusions: More fully vaccinated dermatomyositis patients had exacerbation of autoimmune signs and symptoms after the vaccine than fully vaccinated lupus erythematosus patients. However, given the risks of COVID-19, clinicians should still promote vaccination in most patients with autoimmune skin disease.

Multidimensional Immune Profiling of Cutaneous Lupus Erythematosus In Vivo Stratified by Patient Response to Antimalarials.

OBJECTIVE: The pathogenesis of cutaneous lupus erythematosus (CLE) is multifactorial, and CLE is difficult to treat due to the heterogeneity of inflammatory processes among patients. Antimalarials such as hydroxychloroquine (HCQ) and quinacrine (QC) have long been used as first-line systemic therapy; however, many patients do not respond to treatment with antimalarials and require systemic immunosuppressants that produce undesirable side effects. Given the complexity and the unpredictability of responses to antimalarial treatments in CLE patients, we sought to characterize the immunologic profile of patients with CLE stratified by subsequent treatment outcomes to identify potential biomarkers of inducible response. METHODS: We performed mass cytometry imaging of multiple immune cell types and inflammation markers in treatment-naive skin biopsy samples from 48 patients with CLE to identify baseline immunophenotypes that may predict the response to antimalarial therapy. Patients were stratified according to their response to treatment with antimalarials, as HCQ responders, QC responders, or nonresponders. RESULTS: HCQ responders demonstrated increased CD4+ T cells compared to the QC responder group. Patients in the nonresponder group were found to have decreased Treg cells compared to QC responders and increased central memory T cells compared to HCQ responders. QC responders expressed increased phosphorylated stimulator of interferon genes (pSTING) and interferon-κ (IFNκ) compared to HCQ responders. Phosphorylated STING and IFNκ were found to be localized to conventional dendritic cells (cDCs), and the intensity of pSTING and IFNκ staining was positively correlated with the number of cDCs on a tissue and cellular level. Neighborhood analysis revealed decreased regulatory cell interactions in nonresponder patients. Hierarchical clustering revealed that nonresponder patients could be further differentiated based on expression of pSTAT2, pSTAT3, pSTAT4, pSTAT5, phosphorylated interferon regulatory factor 3 (pIRF3), granzyme B, pJAK2, interleukin-4 (IL-4), IL-17, and IFNγ. CONCLUSION: These findings indicate differential immune cell compositions between patients with CLE, offering guidance for future research on precision-based medicine and treatment response.

Keeping essential reproductive, maternal and child health services available during COVID-19 in Kenya, Mozambique, Uganda and Zimbabwe: analysis of early-pandemic policy guidelines.

BACKGROUND: The COVID-19 pandemic has disrupted the provision of essential reproductive, maternal, newborn, and child health (RMNCH) services in sub-Saharan Africa to varying degrees. Original models estimated as many as 1,157,000 additional child and 56,700 maternal deaths globally due to health service interruptions. To reduce potential impacts to populations related to RMNCH service delivery, national governments in Kenya, Mozambique, Uganda, and Zimbabwe swiftly issued policy guidelines related to essential RMNCH services during COVID-19. The World Health Organization (WHO) issued recommendations to guide countries in preserving essential health services by June of 2020. METHODS: We reviewed and extracted content related to family planning (FP), antenatal care (ANC), intrapartum and postpartum care and immunization in national policies from Kenya, Uganda, Mozambique, and Zimbabwe from March 2020 to February 2021, related to continuation of essential RMNCH services during the COVID-19 pandemic. Using a standardized tool, two to three analysts independently extracted content, and in-country experts reviewed outputs to verify observations. Findings were entered into NVivo software and categorized using pre-defined themes and codes. The content of each national policy guideline was compared to WHO guidance related to RMNCH essential services during COVID-19. RESULTS: All four country policy guidelines considered ANC, intrapartum care, FP, and immunization to be essential services and issued policy guidance for continuation of these services. Guidelines were issued in April 2020 by Mozambique, Kenya, and Uganda, and in June 2020 by Zimbabwe. Many elements of WHO's 2020 recommendations were included in country policies, with some notable exceptions. Each policy guideline was more detailed in some aspects than others - for example, Kenya's guidelines were particularly detailed regarding FP service provision, while Uganda's guidelines were explicit about immediate breastfeeding. All policy guidance documents contained a balance of measures to preserve essential RMNCH services while reducing COVID-19 transmission risk within these services. CONCLUSIONS: The national policy guidelines to preserve essential RMNCH services in these four countries reflected WHO recommendations, with some notable exceptions for ANC and birth companionship. Ongoing revision of country policy guidelines to adapt to changing pandemic conditions is recommended, as is further analysis of subnational-level policies.

Severe recalcitrant hidradenitis suppurativa in a 2-year-old boy with partial trisomy 13.

We report the case of a 2-year-old boy with mosaic trisomy 13 and immunodeficiency who developed severe hidradenitis suppurativa beginning at the age of 18 months. Unresponsive to standard therapies, he exhibited a partial response to immunoglobulin replacement therapy.

Assessment and management of the heightened risk for atherosclerotic cardiovascular events in patients with lupus erythematosus or dermatomyositis.

For patients with lupus erythematosus (LE) or dermatomyositis (DM), there is an urgent need to address a heightened risk of clinical events, chiefly heart attacks and strokes, caused by atherosclerotic cardiovascular disease (ASCVD). Patients with LE or DM frequently exhibit high levels of conventional risk factors for ASCVD events, particularly dyslipoproteinemia and hypertension; an amplified burden of atherosclerotic plaques; and increased age- and sex-adjusted rates of ASCVD events compared with the general population. The rate of ASCVD events exceeds what would be expected from conventional risk factors, suggesting that disease-specific autoimmune processes exacerbate specific, known pathogenic steps in atherosclerosis. Importantly, despite their heightened risk, patients with LE or DM are often undertreated for known causative agents and exacerbators of ASCVD. Herein, we propose an approach to assess and manage the heightened risk of ASCVD events in patients with LE or DM. Our approach is modeled in large part on established approaches to patients with diabetes mellitus or stage 3 or 4 chronic kidney disease, which are well-studied conditions that also show heightened risk for ASCVD events and have been explicitly incorporated into standard clinical guidelines for ASCVD. Based on the available evidence, we conclude that patients with LE or DM require earlier and more aggressive screening and management of ASCVD. We suggest that physicians consider implementing multipliers of conventional risk calculators to trigger earlier initiation of lifestyle modifications and medical therapies in primary prevention of ASCVD events, employ vascular imaging to quantify the burden of subclinical plaques, and treat to lower lipid targets using statins and newer therapies, such as PCSK9 inhibitors, that decrease ASCVD events in nonautoimmune cohorts. More clinical vigilance is needed regarding surveillance, prevention, risk modification, and treatment of dyslipidemias, hypertension, and smoking in patients with LE or DM. All of these goals are achievable.

Practical Implications of Policy Guidelines: A GIS Model of the Deployment of Community Health Volunteers in Madagascar.

BACKGROUND: With increasing interest in strengthening community health programs nationally comes a need for operationalizing them in a realistic and achievable way. Limited information is available to help program managers establish appropriate parameters for their context. We examined aspects of program implementation related to deployment patterns of community health workers, called agents communautaires or ACs, in 2 districts of Madagascar. METHODS: By analyzing program data and publicly available datasets in a geographic information system (GIS), we estimated the population and surface area coverage expected of ACs in 445 fokontany (communities). Additional modeling on travel time demands examined 1-way pedestrian travel time for ACs to receive routine support from their assigned health facilities and from socially marketed supply points under dry season conditions, as well as the impact on travel time based on ACs being reassigned to other facilities or supply points. RESULTS: With the current distribution, ACs in 90% of fokontany have a catchment population of 1,000 or fewer people (2020 estimates) and ACs in 84% of fokontany have a catchment area of 25 km2 or less. We estimated that ACs in 58% of fokontany were located more than 2 hours from their supporting health facility, and the proportion of fokontany with ACs more than 2 hours away from their assigned supply point was 61%. Reassigning ACs to the closest facility or supply point led to modest improvements in those figures (7 and 4 percentage points, respectively). CONCLUSION: Findings allow visualizing the practical implications of coverage ratios for ACs to assess whether current demands are realistic. The physical access between ACs and the health system warrants significant attention due to challenges in transport and logistics. Analyses are timely to inform the Ministry of Public Health's strategic thinking in the context of the development of the National Strategic Plan on Strengthening Community Health.