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Background: Cold agglutinin disease (CAD) is a rare autoimmune haemolytic anaemia mediated by the classical complement pathway (CP). Sutimlimab selectively targets complement C1s inhibiting classical CP activation. In CADENZA Part A (26-weeks), a placebo-controlled study in patients without recent transfusion history, sutimlimab reduced haemolysis, anaemia, and fatigue, and was generally well tolerated. Methods: The CADENZA study (NCT03347422) started in March 2018 (Part A) and completed in December 2021 (Part B). All patients in Part B were eligible to receive sutimlimab for up to 1 year after the last patient completed Part A. Efficacy and safety was assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings: In total, 32/39 patients completed Part B; median treatment duration: 99 weeks. Similar sustained improvements in haemolysis, anaemia, and quality of life were observed in patients switching to sutimlimab and those continuing sutimlimab. Mean LV values for the combined group (ie, placebo-to-sutimlimab group and sutimlimab-to-sutimlimab group) improved from baseline for haemoglobin (≥11.0 g/dL on-treatment vs 9.3 g/dL at baseline), bilirubin (≤20.0 µmol/L on-treatment vs 35.0 µmol/L at baseline), and FACIT-Fatigue scores. Following a 9-week washout, inhibition of CP activity was reversed, and haemolytic markers approached baseline levels. Overall, sutimlimab was generally well tolerated throughout the study. No patients developed systemic lupus erythematosus or meningococcal infections. During the 9-week washout, most adverse events could be attributed to recurrence of underlying CAD. Interpretation: The CADENZA Part B results support the sustained efficacy and safety of sutimlimab for treatment of CAD; however, upon discontinuation disease activity reoccurs. Funding: Sanofi.
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Pathogenic infectious diseases have persistently posed significant threats to public health. Phototheranostics, which combines the functions of diagnostic imaging and therapy, presents an extremely promising solution to block the spread of pathogens as well as the outbreak of epidemics owing to its merits of a wide-spectrum of activity, high controllability, non-invasiveness, and difficult to acquire resistance. Among multifarious phototheranostic agents, second near-infrared (NIR-II, 1000-1700 nm) aggregation-induced emission luminogens (AIEgens) are notable by virtue of their deep penetration depth, excellent biocompatibility, balanced radiative and nonradiative decay and aggregation-enhanced theranostic performance, making them an ideal option for combating pathogens. This minireview provides a systematical summary of the latest advancements in NIR-II AIEgens with emphasis on the molecular design and nanoplatform formulation to fulfill high-efficiency in treating bacterial and viral pathogens, classified by disease models. Then, the current challenges, potential opportunities, and future research directions are presented to facilitate the further progress of this emerging field.
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Background: Cold agglutinin disease (CAD) is a rare subtype of autoimmune haemolytic anaemia characterised by classical complement pathway-mediated haemolysis, fatigue, and poor quality of life (QoL). Sutimlimab, a C1s inhibitor, rapidly halted haemolysis, and improved patient-reported outcomes (PROs) in patients with CAD in two phase 3 trials (CARDINAL and CADENZA). Here we report PROs from the CADENZA open-label extension (Part B). Methods: The first patient was enrolled in CADENZA (NCT03347422) in March 2018 (Part A) and the last patient completed the study in December 2021 (Part B). All patients who completed the 26-week Part A were eligible to receive biweekly doses of sutimlimab in Part B for up to 1 year after the last patient completed Part A. PROs were assessed throughout Part B, until the last on-treatment visit with available assessment (LV), and after a 9-week washout. Findings: In total, 32/39 patients completed Part B; median Part B treatment duration: 99 weeks. Patients switching from placebo to sutimlimab in Part B experienced rapid improvement in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score and other PROs. Sustained, clinically important improvements in FACIT-Fatigue were observed throughout Part B in patients who switched to sutimlimab and those continuing sutimlimab treatment (combined-group mean [SE] change from baseline at LV: 8.8 [2.1]). Similarly, the combined-group mean [SE] change for 12-Item Short Form Health Survey physical (4.9 [1.7]) and mental (4.0 [1.8]) component scores exceeded clinically important changes from baseline at LV. EuroQol visual analogue scale showed consistent and sustained increases from baseline with sutimlimab treatment. Following a 9-week washout, all PROs approached baseline values. Interpretation: Continued inhibition of the classical complement pathway with sutimlimab results in meaningful long-term improvements in PROs (fatigue and QoL) in patients with CAD. Funding: Sanofi.
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BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin disorder that is common in children and associated with medical and psychosocial comorbidities. Previous studies have shown that there exist significant racial disparities in healthcare utilization in children with AD; however, literature on disparities in dermatology access is limited. OBJECTIVES: The primary aim of this study was to identify differences in diagnosis of AD and access to dermatologic care by race and ethnicity in infants with AD. METHODS: We conducted a retrospective chart review of infants diagnosed with AD at Boston Children's Hospital from January 1, 2015 - December 31, 2019. Race and ethnicity were categorized as Native American or Alaska Native, Asian, non-Hispanic Black, Hispanic, Native Hawaiian or Other Pacific Islander, non-Hispanic white, and other. Outcomes included time to diagnosis and dermatology visit from rash onset and were analyzed utilizing a Kruskal-Wallis test. Severity of presentation at first dermatology visit, presentation to the emergency department (ED), medications prescribed, and follow up were analyzed using Chi-squared tests. RESULTS: Significantly more non-Hispanic white infants received a prescription by their pediatrician for AD than Hispanic infants (p = 0.002). Non-Hispanic Black and Asian infants waited longer to see a dermatologist after receiving a prescription for AD by their pediatrician compared to non-Hispanic white patients (p < 0.001; p = 0.007). Significantly more non-Hispanic Black and Hispanic infants presented to the ED for AD within the first year of life than non-Hispanic white patients (p < 0.001; p = 0.003). CONCLUSIONS: Our study suggests disparities in diagnosis and access to care for non-Hispanic Black and Hispanic infants with AD, with differences in prescriptions, time to see a dermatologist, and presentation to the ED compared to non-Hispanic white infants.
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Importance: Abiraterone acetate and enzalutamide are recommended as preferred treatments for metastatic castration-resistant prostate cancer (mCRPC), but differences in their relative efficacy are unclear due to a lack of head-to-head clinical trials. Clear guidance is needed for making informed mCRPC therapeutic choices. Objective: To compare clinical outcomes in patients with mCRPC treated with abiraterone acetate or enzalutamide. Design, Setting, and Participants: This retrospective, multicenter cohort study included patients with mCRPC in the US Department of Veterans Affairs health care system who initiated treatment with abiraterone acetate or enzalutamide between January 1, 2014, and October 30, 2022. Exposures: Abiraterone acetate or enzalutamide. Main Outcomes and Measures: The study used inverse probability of treatment weighting to balance baseline characteristics between patients initiating abiraterone acetate or enzalutamide and evaluated restricted mean survival time (RMST) differences in overall survival (OS), prostate cancer-specific survival (PCS), time to next treatment switching or death (TTS), and time to prostate-specific antigen (PSA) response (TTR) at different time points after treatment initiation. Results: The study included 5779 patients (median age, 74.42 years [IQR, 68.94-82.14 years]). Median follow-up was between 38 and 60 months. Patients initiating enzalutamide on average had longer OS than those initiating abiraterone acetate, with RMSTs of 24.29 months (95% CI, 23.58-24.99 months) and 23.38 months (95% CI, 22.85-23.92 months), respectively, and a difference in RMST of 0.90 months (95% CI, 0.02-1.79 months) at 4 years. Similarly, TTS and TTR were improved in patients initiating enzalutamide, with an RMST at 4 years of 1.95 months (95% CI, 0.92-2.99 months) longer for TTS and 3.57 months (95% CI, 1.76-5.38 months) shorter for TTR. For PCS, the RMST at 2 years was 0.48 months (95% CI, 0.01-0.95 months) longer. An examination of subgroups identified that enzalutamide initiation was associated with longer RMST in OS among patients without prior docetaxel treatment (1.14 months; 95% CI, 0.19-2.10 months) and in those with PSA doubling time of 3 months or longer (2.23 months; 95% CI, 0.81-3.66 months) but not among patients with prior docetaxel (-0.25 months; 95% CI, -2.59 to 2.09 months) or with PSA doubling time of less than 3 months (0.05 months; 95% CI, -1.05 to 1.15 months). Conclusions and Relevance: In this cohort study of patients with mCRPC, initiation of enzalutamide was associated with small but statistically significant improvements in OS, PCS, TTS, and TTR compared with initiation of abiraterone acetate. The improvements were more prominent in short-term outcomes, including TTS and TTR, and in patient subgroups without prior docetaxel or with PSA doubling time longer than 3 months.
Subject(s)
Benzamides , Nitriles , Phenylthiohydantoin , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Phenylthiohydantoin/therapeutic use , Nitriles/therapeutic use , Benzamides/therapeutic use , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/mortality , Aged , Retrospective Studies , Androstenes/therapeutic use , Antineoplastic Agents/therapeutic use , Aged, 80 and over , Middle Aged , United States , Abiraterone Acetate/therapeutic use , Treatment Outcome , Neoplasm MetastasisABSTRACT
BACKGROUND: To investigate impact of frozen elephant trunk (FET) on long-term distal aortic remodeling in acute A aortic dissection (AAD) according to the latest recommended standards from the Society for Vascular Surgery (SVS)/Society of Thoracic Surgeons (STS). METHODS: Clinical data and imaging of patients who underwent FET to treat acute AAD over the last 8 years were retrospectively reviewed. Patients were included if a pre and postoperative computed angio tomographies at least 30 days from surgery was available for comparison. Contrasted postprocessed imaging were analyzed with Aquarius iNtuition (TeraRecon Inc., Foster City, CA, USA) to analyze long-term positive aortic remodeling, false lumen thrombosis, and aortic expansion according to the SVS or STS recommendations. Secondary endpoints were the rate of in-hospital and long-term mortality, spinal cord ischemia (SCI), and aortic-related reinterventions. RESULTS: Out of 75 patients who underwent FET for type A AAD, n = 41 (54.6%) were included. Significant positive aortic remodeling was reported in Ishimaru zone 1-4 but not in visceral or infrarenal aorta (P < 0.001), and the overall rate of false lumen thrombosis was 95.1% (n = 39). Aortic expansion rates were as follows: 4.9% in zones 1-4, 8.3% in zones 5-6, and 15% in zone 7. The rates of in-hospital mortality and long-term mortality were 7.3% (n = 3) and 9.7% (n = 4), respectively. At a median follow-up of 11 months (range 1-141, reintervention rate was 17.1%. CONCLUSIONS: We report positive aortic remodeling of the distal thoracic aorta in patients who underwent FET for acute AAD according to the SVS or STS reporting standards. The positive effect on the distal aorta is limited to the thoracic segments but not in the visceral aorta.
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This minireview provides an overview of the recent advancements in the development of biomimetic Aggregation-Induced Emission (AIE) nanoparticles and their applications in disease diagnosis, phototherapy, and photoimmunotherapy. AIE nanoparticles can be engineered to enable efficient image-guided photodynamic and photothermal therapies, however, challenges related to immune defense and target specificity persist. To overcome these, coating biomimetic materials on the surface of AIE nanoparticles, which mimic the features and functions of native cells, have emerged as a promising solution. This minireview will highlight the synthesis strategies and discuss the biomedical application of biomimetic AIE nanoparticles.
Subject(s)
Biomimetic Materials , Nanoparticles , Phototherapy , Biomimetic Materials/chemistry , Biomimetic Materials/therapeutic use , Humans , Nanoparticles/chemistry , Nanoparticles/therapeutic use , AnimalsABSTRACT
Atypical hemolytic uremic syndrome (aHUS) is a complement-mediated thrombotic microangiopathy sometimes associated with germline variants in genes of the complement system. Clinical findings of microangiopathic hemolytic anemia, thrombocytopenia, and acute kidney injury arise due to aberrant complement protein activation in the circulation. A 13-month-old boy with metastatic neuroblastoma (NB) developed aHUS during his first cycle of induction chemotherapy with germline testing revealing a complement factor H (CFH) gene mutation, currently classified as a variant of uncertain significance (VUS). Now he is in disease remission after successful complement blockade therapy, thus highlighting a unique presentation of aHUS in a patient with newly diagnosed NB.
Subject(s)
Atypical Hemolytic Uremic Syndrome , Induction Chemotherapy , Neuroblastoma , Humans , Neuroblastoma/drug therapy , Neuroblastoma/pathology , Neuroblastoma/genetics , Male , Atypical Hemolytic Uremic Syndrome/drug therapy , Atypical Hemolytic Uremic Syndrome/genetics , Atypical Hemolytic Uremic Syndrome/pathology , Induction Chemotherapy/adverse effects , Infant , Complement Factor H/genetics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Germ-Line MutationABSTRACT
The origin of rupture segmentation along subduction zone megathrusts and linkages to the structural evolution of the subduction zone are poorly understood. Here, regional-scale seismic imaging of the Cascadia margin is used to characterize the megathrust spanning ~900 km from Vancouver Island to the California border, across the seismogenic zone to a few tens of kilometers from the coast. Discrete domains in lower plate geometry and sediment underthrusting are identified, not evident in prior regional plate models, which align with changes in lithology and structure of the upper plate and interpreted paleo-rupture patches. Strike-slip faults in the lower plate associated with oblique subduction mark boundaries between regions of distinct lower plate geometry. Their formation may be linked to changes in upper plate structure across long-lived upper plate faults. The Juan de Fuca plate is fragmenting within the seismogenic zone at Cascadia as the young plate bends beneath the heterogeneous upper plate resulting in structural domains that coincide with paleo-rupture segmentation.
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Type A aortic dissection is a life-threatening emergency requiring prompt surgical treatment. The dissection itself and use of cardiopulmonary bypass can lead to further postoperative complications, including aortic branch occlusion, thrombosis, ischemia, and fatal end-organ damage. Celiac artery occlusion with consequent hepatic malperfusion is one feared complication of aortic dissection, which requires urgent surgical intervention. Optimal management of celiac artery dissection in the setting of type A aortic dissection has not yet been described in the literature. In this report, we describe a 39-year-old female patient with hypertension who was found to have celiac artery dissection and impending hepatic failure less than 48 hours after emergent ascending aortic replacement for type A aortic dissection. Placement of an ultrasound-guided endovascular celiac artery stent enabled reperfusion of the liver, ultimately saving the patient's life.
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We assessed early antibody responses after two doses of JYNNEOS (IMVANEX) mpox vaccine in the District of Columbia (D.C.) in persons at high risk for mpox without characteristic lesions or rash. Participants with PCR mpox negative specimens (oral swab, blood, and/or rectal swab) on the day of receipt of the first vaccine dose and who provided a baseline (day 0) serum sample and at least one serum sample at â¼28, â¼42-56 days, or 180 days post vaccination were included in this analysis. Orthopoxvirus (OPXV)-specific IgG and IgM ELISAs and neutralizing antibody titers were performed, and longitudinal serologic responses were examined. Based on participants' IgG and IgM antibody levels at baseline, they were categorized as naïve or non-naïve. Linear mixed effects regression models were conducted to determine if IgG antibody response over time varied by age, sex, HIV status, and route of administration for both naïve and non-naïve participants. Among both naïve and non-naïve participants IgG seropositivity rates increased until day 42-56, with 89.4 % of naïve and 92.1 % of non-naïve participants having detectable IgG antibodies. The proportion of naive participants with detectable IgG antibodies declined by day 180 (67.7 %) but remained high among non-naïve participants (94.4 %). Neutralizing antibody titers displayed a similar pattern, increasing initially post vaccination but declining by day 180 among naïve participants. There were no significant serologic response differences by age, sex, or HIV status. Serologic response did vary by route of vaccine administration, with those receiving a combination of intradermal and subcutaneous doses displaying significantly higher IgG values than those receiving both doses intradermally. These analyses provide initial insights into the immunogenicity of a two-dose JYNNEOS PEP regimen in individuals at high risk of mpox exposure in the United States.
Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , Immunoglobulin G , Immunoglobulin M , Humans , Male , Female , Antibodies, Viral/blood , Antibodies, Viral/immunology , Immunoglobulin G/blood , Adult , Antibodies, Neutralizing/blood , Middle Aged , Young Adult , Immunoglobulin M/blood , Smallpox Vaccine/immunology , Smallpox Vaccine/administration & dosage , Adolescent , Orthopoxvirus/immunology , Vaccinia/immunology , Vaccination/methods , Cohort StudiesABSTRACT
BACKGROUND: The potential health effects of taxing sugar-sweetened beverages (SSBs) has been insufficiently examined in Asian contexts. This study aimed to assess the impact of SSB taxation on the prevalence of obesity/overweight and type 2 diabetes mellitus (T2DM) in Hong Kong using a willingness-to-pay (WTP) survey and simulation analysis. METHODS: A random telephone survey was conducted with 1000 adults from May to June 2020. We used a contingent valuation approach to assess individuals' WTP for SSBs under four tax payment scenarios (5%, 10%, 40%, and 50% of the current market price). Based on the WTP, a simulation analysis was conducted to project changes in SSB purchase and associated reductions in the prevalence of obesity/overweight and T2DM over a 10-year simulation period. FINDINGS: When 5% and 10% taxation rates were introduced, approximately one-third of the population were unwilling to maintain their SSB purchase. Our simulation demonstrated a gradual decline in the prevalence of obesity/overweight and diabetes with a more pronounced decrease when higher taxation rates were introduced. 10% taxation resulted in a mean reduction of 1532.7 cases of overweight/obesity per 100 thousand population at the sixth year, while T2DM prevalence decreased by 267.1 (0.3%). CONCLUSIONS: This study underscores the effects of an SSB tax on purchase behaviors and health outcomes in an affluent Asia setting, with a more pronounced influence on adult population. These findings are expected to inform policymakers in making decisions regarding an effective and equitable tax rate on SSBs.
Subject(s)
Diabetes Mellitus, Type 2 , Obesity , Overweight , Sugar-Sweetened Beverages , Taxes , Humans , Diabetes Mellitus, Type 2/epidemiology , Sugar-Sweetened Beverages/economics , Sugar-Sweetened Beverages/statistics & numerical data , Male , Female , Obesity/epidemiology , Adult , Overweight/epidemiology , Middle Aged , Hong Kong/epidemiology , Prevalence , Surveys and QuestionnairesABSTRACT
Objective: There is an assumption that because EBLVR requires less use of hospital resources, offsetting the higher cost of endobronchial valves, it should therefore be the treatment of choice wherever possible. We have tested this hypothesis in a retrospective analysis of the two in similar groups of patients. Methods: In a 4-year experience, we performed 177 consecutive LVR procedures: 83 patients underwent Robot Assisted Thoracoscopic (RATS) LVRS and 94 EBLVR. EBLVR was intentionally precluded by evidence of incomplete fissure integrity or intra-operative assessment of collateral ventilation. Unilateral RATS LVRS was performed in these cases together with those with unsuitable targets for EBLVR. Results: EBLVR was uncomplicated in 37 (39%) cases; complicated by post-procedure spontaneous pneumothorax (SP) in 28(30%) and required revision in 29 (31%). In the LVRS group, 7 (8%) patients were readmitted with treatment-related complications, but no revisional procedure was needed. When compared with uncomplicated EBLVR, LVRS had a significantly longer operating time: 85 (14-82) vs 40 (15-151) minutes (p<0.001) and hospital stay: 7.5 (2-80) vs 2 (1-14) days (p<0.01). However, LVRS had a similar total operating time to both EBLVR requiring revision: 78 (38-292) minutes and hospital stay to EBLVR complicated by pneumothorax of 11.5 (6.5-24.25) days. Use of critical care was significantly longer in RATS group, and it was also significantly longer in EBV with SP group than in uncomplicated EBV group. Conclusion: Endobronchial LVR does use less hospital resources than RATS LVRS in comparable groups if the recovery is uncomplicated. However, this advantage is lost if one includes the resources needed for the treatment of complications and revisional procedures. Any decision to favour EBLVR over LVRS should not be based on the assumption of a smoother, faster perioperative course.
Subject(s)
Bronchoscopy , Lung , Pneumonectomy , Pulmonary Emphysema , Robotic Surgical Procedures , Humans , Retrospective Studies , Pneumonectomy/adverse effects , Pneumonectomy/methods , Male , Middle Aged , Bronchoscopy/instrumentation , Bronchoscopy/methods , Bronchoscopy/adverse effects , Pulmonary Emphysema/surgery , Pulmonary Emphysema/physiopathology , Aged , Female , Treatment Outcome , Robotic Surgical Procedures/adverse effects , Robotic Surgical Procedures/methods , Time Factors , Lung/surgery , Lung/physiopathology , Length of Stay , Postoperative Complications/etiology , Operative Time , Risk Factors , Pneumothorax/surgery , Clinical Decision-Making , Patient ReadmissionABSTRACT
Deep venous arterialization (DVA) is a final option for limb salvage in patients with end stage arterial anatomy. We report a 66-year-old dialysis dependent male with forefoot gangrene, Rutherford class 6 chronic limb ischemia, who required a redo endovascular DVA. On initial presentation an angiogram was demonstrated a desert foot with absent tibial runoff to his bilateral lower extremities. After discussion, patient elected to trial DVA in hope of avoiding a major amputation. A hybrid DVA was performed using a Pioneer Plus and .018â³ Viabahn stents from the peroneal artery into the peroneal venous system; following this, the peroneal vein was anastomosed to the lesser saphenous vein via an open posterior approach at the ankle. 3 months later, a second DVA was performed by exposing the above knee popliteal artery and vein and creating an end-to-side anastomosis. Of note, the great saphenous vein was less than 2 mm in diameter and no arm vein was available due to history of prior fistulas in bilateral arms. Via the popliteal vein, the posterior tibial vein was selected and additional .018â³ Viabahn stents were deployed from the malleolus to the P2 segment of the popliteal vein. Three months after the second hybrid DVA, the patient's forefoot had healed after split thickness skin grafting. Continued patency is noted of the re-do hybrid DVA with minimal calf edema. Newer creative strategies are required for "No Option Chronic Limb Ischemia" which is becoming more relevant in diabetic and dialysis dependent patients. This case illustrates the potential to convert a deep venous arterialization to a superficial venous arterialization for improved venous outflow and wound healing.
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Fibrocystic changes are commonly seen in clinically symptomatic patients and during imaging workup of screening-detected findings. The term "fibrocystic changes" encompasses a broad spectrum of specific benign pathologic entities. Recognition of classically benign findings of fibrocystic changes, including cysts and layering calcifications, can prevent unnecessary follow-ups and biopsies. Imaging findings such as solid masses, nonlayering calcifications, and architectural distortion may require core needle biopsy for diagnosis. In these cases, understanding the varied appearances of fibrocystic change aids determination of radiologic-pathologic concordance. Management of fibrocystic change is typically conservative.
Subject(s)
Breast , Humans , Female , Diagnosis, Differential , Breast/diagnostic imaging , Breast/pathology , Fibrocystic Breast Disease/diagnostic imaging , Fibrocystic Breast Disease/pathology , Mammography/methodsABSTRACT
BACKGROUND: Epidermolysis bullosa (EB), characterized by skin fragility and blistering, often requires hospitalization. Training for inpatient management of EB is limited, with no unified recommendations available in North America. OBJECTIVE: To develop consensus-derived best practices for hands-on inpatient management of EB in both the neonatal and postneonatal period. METHODS: A modified Delphi method (expert-based input via 2 surveys and a final review) was implemented. Available guidelines from EB Clinical Research Consortium centers were analyzed to determine areas of focus and formulate statements to be voted on by EB Clinical Research Consortium members, experienced EB nurses, and select family members. Study participants evaluated statements using a Likert scale: statements with at least 70% agreement were accepted; statements with 30% or more disagreement were rejected. RESULTS: Ten areas of focus were identified. Delphi participants included 15 dermatologists, 8 nurses, and 6 nonhealth care caregivers. Consensus was established on 103/119 neonatal statements and 105/122 postneonatal statements; no statements were rejected. Most recommendations applied to both age groups. LIMITATIONS: Recommendations may require adjustment based on individual patient's clinical context. CONCLUSION: Using the Delphi method, a consensus-derived resource for hospital-based health care professionals who manage patients with EB has been developed to improve the quality of inpatient care.
Subject(s)
Consensus , Delphi Technique , Epidermolysis Bullosa , Humans , Infant, Newborn , Epidermolysis Bullosa/therapy , Hospitalization , Practice Guidelines as Topic , Infant , Female , Dermatology/methods , Dermatology/standards , MaleABSTRACT
Zika virus (ZIKV) is a mosquito-borne flavivirus that caused an epidemic in the Americas in 2016 and is linked to severe neonatal birth defects, including microcephaly and spontaneous abortion. To better understand the host response to ZIKV infection, we adapted the 10× Genomics Chromium single-cell RNA sequencing (scRNA-seq) assay to simultaneously capture viral RNA and host mRNA. Using this assay, we profiled the antiviral landscape in a population of human monocyte-derived dendritic cells infected with ZIKV at the single-cell level. The bystander cells, which lacked detectable viral RNA, expressed an antiviral state that was enriched for genes coinciding predominantly with a type I interferon (IFN) response. Within the infected cells, viral RNA negatively correlated with type I IFN-dependent and -independent genes (the antiviral module). We modeled the ZIKV-specific antiviral state at the protein level, leveraging experimentally derived protein interaction data. We identified a highly interconnected network between the antiviral module and other host proteins. In this work, we propose a new paradigm for evaluating the antiviral response to a specific virus, combining an unbiased list of genes that highly correlate with viral RNA on a per-cell basis with experimental protein interaction data. IMPORTANCE: Zika virus (ZIKV) remains a public health threat given its potential for re-emergence and the detrimental fetal outcomes associated with infection during pregnancy. Understanding the dynamics between ZIKV and its host is critical to understanding ZIKV pathogenesis. Through ZIKV-inclusive single-cell RNA sequencing (scRNA-seq), we demonstrate on the single-cell level the dynamic interplay between ZIKV and the host: the transcriptional program that restricts viral infection and ZIKV-mediated inhibition of that response. Our ZIKV-inclusive scRNA-seq assay will serve as a useful tool for gaining greater insight into the host response to ZIKV and can be applied more broadly to the flavivirus field.