Infections in Children Aged 6 Months to 5 Years Treated with Dupilumab in a Placebo-Controlled Clinical Trial of Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Patients with atopic dermatitis (AD), particularly infants and young children, are at greater risk of developing skin infections. In this study, we assessed infection rates in AD patients aged 6 months to 5 years treated with dupilumab. METHODS: In LIBERTY AD PRESCHOOL, a double-blind, placebo-controlled, phase III clinical trial, children aged 6 months to 5 years with moderate-to-severe AD were randomized 1:1 to subcutaneous dupilumab or placebo, with concomitant low-potency topical corticosteroids, every 4 weeks for 16 weeks. Exposure-adjusted infection rates were used to compare treatment groups. RESULTS: The analysis included 162 patients, of whom 83 received dupilumab and 79 received placebo. Total infection rates were not significantly different between the dupilumab and placebo groups (rate ratio [RR] 0.75, 95% CI 0.48-1.19; p = 0.223). Non-herpetic adjudicated skin infections and bacterial infections were significantly less frequent with dupilumab versus placebo (non-herpetic skin infections: RR 0.46, 95% CI 0.21-0.99; p = 0.047; bacterial infections: RR 0.09, 95% CI 0.01-0.67; p = 0.019), and the number of patients using systemic anti-infective medication was significantly lower in the dupilumab group (RR 0.52, 95% CI 0.30-0.89; p = 0.019). There were no significant differences in the number of herpetic infections between the dupilumab and placebo groups (RR 1.17, 95% CI 0.31-4.35; p = 0.817). The number of patients with two or more infection events was significantly higher in the placebo group (RR 0.29, 95% CI 0.12-0.68; p = 0.004), and no severe or serious infections (including eczema herpeticum) were observed among patients receiving dupilumab. CONCLUSIONS: These data suggest that dupilumab treatment in infants and children younger than 6 years with AD does not increase overall risk of infections and is associated with a reduced risk of bacterial and non-herpetic skin infections compared with placebo, resulting in a reduced need for anti-infective medication. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov with ID number NCT03346434 on November 17, 2017. INFOGRAPHIC.

Patients with atopic dermatitis (AD), a chronic disease of the skin, are at greater risk of developing skin infections, particularly infants and young children. Several medications for AD may weaken the patient's immune system, further increasing the risk of infections. Dupilumab is a recently developed drug for AD that should not interfere with the patient's immune defenses against bacterial, viral, or fungal infections. In this study, we evaluated the effect of dupilumab on infections in children aged 6 months to 5 years with moderate-to-severe AD. Patients received 200 or 300 mg of dupilumab (depending on the child's weight) or placebo, together with ointments containing mild steroids, every 4 weeks for 16 weeks. At the end of treatment, total infections were not significantly different between patients receiving dupilumab and placebo. Furthermore, patients receiving dupilumab experienced significantly less bacterial and non-herpetic skin infections and used significantly less anti-infective medication compared with patients receiving placebo. Herpetic infections were also not significantly different between dupilumab- and placebo-treated patients. Finally, significantly more patients in the placebo group experienced two or more infections. This study demonstrates that dupilumab does not increase the risk of infections in infants and young children with AD and can decrease the use of anti-infective medication.

Type 2 cytokines sensitize human sensory neurons to itch-associated stimuli.

Introduction: Chronic itch is a central symptom of atopic dermatitis. Cutaneous afferent neurons express receptors interleukins (IL)-4, IL-13, and IL-33, which are type 2 cytokines that are elevated in atopic dermatitis. These neuronal cytokine receptors were found to be required in several murine models of itch. Prior exposure of neurons to either IL-4 or IL-33 increased their response to subsequent chemical pruritogens in mice but has not been previously examined in humans. The objective of the present study was to determine if type 2 cytokine stimulation sensitizes sensory neurons to future itch stimuli in a fully human ex vivo system. Methods: We measured calcium flux from human dorsal root ganglia cultures from cadaveric donors in response to pruritogens following transient exposure to type 2 cytokines. We also measured their effect on neuronal calcium flux and changes in gene expression by RNA sequencing. Results: Type 2 cytokines (IL-4, IL-13, and IL-33) were capable of sensitizing human dorsal root ganglia neurons to both histaminergic and nonhistaminergic itch stimuli. Sensitization was observed after only 2 h of pruritogen incubation. We observed rapid neuronal calcium flux in a small subset of neurons directly in response to IL-4 and to IL-13, which was dependent on the presence of extracellular calcium. IL-4 and IL-13 induced a common signature of upregulated genes after 24 h of exposure that was unique from IL-33 and non-type 2 inflammatory stimuli. Discussion: This study provides evidence of peripheral neuron sensitization by type 2 cytokines as well as broad transcriptomic effects in human sensory ganglia. These studies identify both unique and overlapping roles of these cytokines in sensory neurons.

Changing protein-DNA interactions promote ORC binding site exchange during replication origin licensing.

During origin licensing, the eukaryotic replicative helicase Mcm2-7 forms head-to-head double hexamers to prime origins for bidirectional replication. Recent single-molecule and structural studies revealed that one molecule of the helicase loader ORC can sequentially load two Mcm2-7 hexamers to ensure proper head-to-head helicase alignment. To perform this task, ORC must release from its initial high-affinity DNA binding site and "flip" to bind a weaker, inverted DNA site. However, the mechanism of this binding-site switch remains unclear. In this study, we used single-molecule Förster resonance energy transfer (sm-FRET) to study the changing interactions between DNA and ORC or Mcm2-7. We found that the loss of DNA bending that occurs during DNA deposition into the Mcm2-7 central channel increases the rate of ORC dissociation from DNA. Further studies revealed temporally-controlled DNA sliding of helicase-loading intermediates, and that the first sliding complex includes ORC, Mcm2-7, and Cdt1. We demonstrate that sequential events of DNA unbending, Cdc6 release, and sliding lead to a stepwise decrease in ORC stability on DNA, facilitating ORC dissociation from its strong binding site during site switching. In addition, the controlled sliding we observed provides insight into how ORC accesses secondary DNA binding sites at different locations relative to the initial binding site. Our study highlights the importance of dynamic protein-DNA interactions in the loading of two oppositely-oriented Mcm2-7 helicases to ensure bidirectional DNA replication. Significance Statement: Bidirectional DNA replication, in which two replication forks travel in opposite directions from each origin of replication, is required for complete genome duplication. To prepare for this event, two copies of the Mcm2-7 replicative helicase are loaded at each origin in opposite orientations. Using single-molecule assays, we studied the sequence of changing protein-DNA interactions involved in this process. These stepwise changes gradually reduce the DNA-binding strength of ORC, the primary DNA binding protein involved in this event. This reduced affinity promotes ORC dissociation and rebinding in the opposite orientation on the DNA, facilitating the sequential assembly of two Mcm2-7 molecules in opposite orientations. Our findings identify a coordinated series of events that drive proper DNA replication initiation.

Changing protein-DNA interactions promote ORC binding-site exchange during replication origin licensing.

During origin licensing, the eukaryotic replicative helicase Mcm2-7 forms head-to-head double hexamers to prime origins for bidirectional replication. Recent single-molecule and structural studies revealed that one molecule of the helicase loader ORC (origin recognition complex) can sequentially load two Mcm2-7 hexamers to ensure proper head-to-head helicase alignment. To perform this task, ORC must release from its initial high-affinity DNA-binding site and "flip" to bind a weaker, inverted DNA site. However, the mechanism of this binding-site switch remains unclear. In this study, we used single-molecule Förster resonance energy transfer to study the changing interactions between DNA and ORC or Mcm2-7. We found that the loss of DNA bending that occurs during DNA deposition into the Mcm2-7 central channel increases the rate of ORC dissociation from DNA. Further studies revealed temporally controlled DNA sliding of helicase-loading intermediates and that the first sliding complex includes ORC, Mcm2-7, and Cdt1. We demonstrate that sequential events of DNA unbending, Cdc6 release, and sliding lead to a stepwise decrease in ORC stability on DNA, facilitating ORC dissociation from its strong binding site during site switching. In addition, the controlled sliding we observed provides insight into how ORC accesses secondary DNA-binding sites at different locations relative to the initial binding site. Our study highlights the importance of dynamic protein-DNA interactions in the loading of two oppositely oriented Mcm2-7 helicases to ensure bidirectional DNA replication.

Dupilumab Provides Clinically Meaningful Responses in Children Aged 6-11 Years with Severe Atopic Dermatitis: Post Hoc Analysis Results from a Phase III Trial.

BACKGROUND: Children with severe atopic dermatitis (AD) have a multidimensional disease burden. OBJECTIVE: Here we assess the clinically meaningful improvements in AD signs, symptoms, and quality of life (QoL) in children aged 6-11 years with severe AD treated with dupilumab compared with placebo. METHODS: R668-AD-1652 LIBERTY AD PEDS was a randomized, double-blinded, placebo-controlled, parallel-group, phase III clinical trial of dupilumab with concomitant topical corticosteroids (TCS) in children aged 6-11 years with severe AD. This post hoc analysis focuses on 304 patients receiving either dupilumab or placebo with TCS and assessed the percentage of patients considered responsive to dupilumab treatment at week 16. RESULTS: At week 16, almost all patients receiving dupilumab + TCS (95%) demonstrated clinically meaningful improvements in AD signs, symptoms, or QoL compared with placebo + TCS (61%, p < 0.0001). Significant improvements were seen as early as week 2 and sustained through the end of the study in the full analysis set (FAS) and the subgroup of patients with an Investigator's Global Assessment score greater than 1 at week 16. LIMITATIONS: Limitations include the post hoc nature of the analysis and that some outcomes were not prespecified; the small number of patients in some subgroups potentially limits generalizability of findings. CONCLUSION: Treatment with dupilumab provides significant and sustained improvements within 2 weeks in AD signs, symptoms, and QoL in almost all children with severe AD, including those who did not achieve clear or almost clear skin by week 16. TRIAL REGISTRATION: NCT03345914. Video Abstract: Does dupilumab provide clinically meaningful responses in children 6 to 11 years old with severe atopic dermatitis? (MP4 99484 kb).

Survival in elderly patients with breast cancer with and without autoimmune disease.

BACKGROUND: Patients with certain autoimmune conditions are at a reduced risk of developing breast cancer compared to the general population. Despite this, little is known about outcomes in patients with breast cancer who have a concurrent autoimmune diagnosis. METHODS: This study compared differences in outcomes between women with breast cancer who had or did not have an autoimmune diagnosis. The SEER-Medicare databases (2007-2014) were used to identify patients with breast cancer and diagnosis codes were used to identify those with an autoimmune disorder. RESULTS: The studied autoimmune diseases had a prevalence of 27% among the 137,324 patients with breast cancer. Autoimmune disease was associated with significantly longer overall survival (OS) and significantly lower cancer-specific mortality (CSM) among stage IV breast cancer patients (p < 0.0001). After controlling for the effects of age, race, chronic kideny disease, chemotherapy, and radiation therapy autoimmune disease was still predictive of improved OS (HR: 1.45, 95% CI: 1.35-1.55, p < 0.0001) and CSM (HR: 1.40, 95% CI: 1.29-1.5, p < 0.0001). By contrast, in patients with stage I-III breast cancer, the presence of an autoimmune diagnosis was associated with a lower OS (p < 0.0001, p < 0.0001, and p = 0.026, respectively), compared to patients without autoimmune disease. CONCLUSIONS: We found a higher prevalence of rheumatoid arthritis, Crohn's disease, ulcerative colitis, and systemic lupus erythematosus in patients with breast cancer compared to age matched cohorts in the general population. The presence of an autoimmune diagnosis was associated with a lower OS in stages I-III breast cancer and improved OS and CSM in patients with stage IV disease. These results suggest that anti-tumor immunity plays an important role in late stage breast cancer and could potentially be exploited to improve the effectiveness of immunotherapy.

NSCLC in the Era of Targeted and Immunotherapy: What Every Pulmonologist Must Know.

The treatment of non-small cell lung cancer has dramatically changed over the last decade through the use of targeted therapies and immunotherapies. Implementation of these treatment regimens relies on detailed knowledge regarding each tumor's specific genomic profile, underscoring the necessity of obtaining superior diagnostic tissue specimens. While these treatment approaches are commonly utilized in the metastatic setting, approval among earlier-stage disease will continue to rise, highlighting the importance of early and comprehensive biomarker testing at the time of diagnosis for all patients. Pulmonologists play an integral role in the diagnosis and staging of non-small cell lung cancer via sophisticated tissue sampling techniques. This multifaceted review will highlight current indications for the use of targeted therapies and immunotherapies in non-small cell lung cancer and will outline the quality of various diagnostic approaches and subsequent success of tissue biomarker testing. Pulmonologist-specific methods, including endobronchial ultrasound and guided bronchoscopy, will be examined as well as other modalities such as CT-guided transthoracic biopsy and more.

Dupilumab Inhibits Vascular Leakage of Blood Proteins Into Atopic Dermatitis Skin.

BACKGROUND: Atopic dermatitis (AD) skin lesions are associated with oozing, bleeding, and erythema. This suggests that AD is associated with vascular changes. Dupilumab is an antibody to the alpha subunit of IL-4 receptor that demonstrates strong efficacy in the treatment of AD. IL-4 is known to reduce the permeability barrier function of vascular endothelium. OBJECTIVE: To examine the effects of dupilumab on vascular barrier function in AD skin. METHODS: Using proteomic analysis, we evaluated the plasma protein composition in skin tapes of lesional and nonlesional skin of adults and adolescents with moderate to severe AD over the course of a 16-week treatment with dupilumab and compared those with matched healthy subjects. RESULTS: At baseline, 115 plasma proteins were detected in AD skin and globally increased (1.5-fold or greater) compared with healthy skin. Functionally, these proteins included immunoglobulins, proteins involved in the coagulation process, enzymes, protease inhibitors, transport proteins, acute-phase proteins, complement proteins, and other pleiotropic proteins. Noteworthy, fibrinogens, fibronectin, and heme-binding proteins haptoglobin and hemopexin were among the top proteins originating from plasma and were increased in AD lesional versus healthy skin at baseline (P < .0001). Dupilumab treatment resulted in significantly reduced levels of plasma proteins in AD skin (P < .0001), with most dropping to levels seen in healthy skin or no longer detectable at week 16. CONCLUSIONS: Inhibition of IL-4/IL-13 action by dupilumab significantly reduces the efflux of plasma proteins into AD skin. Several of these proteins, such as fibrinogens and fibronectin, are known to enhance Staphylococcus aureus colonization and are associated with AD skin severity.

Comparing Survival in Patients With Lung Cancer With and Without a History of Common Autoimmune Disease.

Introduction: Autoimmune disease has both a predisposing and a protective effect toward malignancy. Though studies have investigated the risk of malignancy in patients with autoimmune disease, there is limited research on how autoimmunity affects survival. Methods: This study compared survival in patients with lung cancer with and without autoimmune disease. Patients with lung cancer were culled from the Surveillance, Epidemiology, and End Results Medicare databases (2007-2014), and autoimmune diseases were identified using diagnosis codes. Results: The overall prevalence of investigated autoimmune diseases among the 112,445 patients was 22.7%. Overall survival (OS) (p < 0.0001) was longer and cancer-specific mortality (CSM) (p < 0.0001) reduced among patients with autoimmune disease. Median OS was 5 months higher. Improved OS and CSM were also apparent in disease stages 1, 3, and 4 in the NSCLC and SCLC subgroups (p < 0.0001) and across most specific autoimmune diseases. After adjusting for the effects of age, sex, race, disease stage, and chronic kidney disease, autoimmune disease was still predictive of higher OS (hazard ratio = 1.23, 95% confidence interval: 1.21-1.25, p < 0.0001) and reduced CSM (hazard ratio = 1.16, 95% confidence interval: 1.14-1.18, p < 0.0001). Conclusions: The prevalence of rheumatoid arthritis, inflammatory bowel disease, and systemic lupus erythematous was highly enriched compared with the general population. The improvement in OS and CSM was larger in NSCLC than in SCLC, suggesting a larger role for the immune system in NSCLC. Alternate explanations for the improved survival include lead time bias, better access to health care, and a survival or autoimmunity-inducing genetic factor.

Differential Susceptibility of Retinal Neurons to the Loss of Mitochondrial Biogenesis Factor Nrf1.

The retina, the accessible part of the central nervous system, has served as a model system to study the relationship between energy utilization and metabolite supply. When the metabolite supply cannot match the energy demand, retinal neurons are at risk of death. As the powerhouse of eukaryotic cells, mitochondria play a pivotal role in generating ATP, produce precursors for macromolecules, maintain the redox homeostasis, and function as waste management centers for various types of metabolic intermediates. Mitochondrial dysfunction has been implicated in the pathologies of a number of degenerative retinal diseases. It is well known that photoreceptors are particularly vulnerable to mutations affecting mitochondrial function due to their high energy demand and susceptibility to oxidative stress. However, it is unclear how defective mitochondria affect other retinal neurons. Nuclear respiratory factor 1 (Nrf1) is the major transcriptional regulator of mitochondrial biogenesis, and loss of Nrf1 leads to defective mitochondria biogenesis and eventually cell death. Here, we investigated how different retinal neurons respond to the loss of Nrf1. We provide in vivo evidence that the disruption of Nrf1-mediated mitochondrial biogenesis results in a slow, progressive degeneration of all retinal cell types examined, although they present different sensitivity to the deletion of Nrf1, which implicates differential energy demand and utilization, as well as tolerance to mitochondria defects in different neuronal cells. Furthermore, transcriptome analysis on rod-specific Nrf1 deletion uncovered a previously unknown role of Nrf1 in maintaining genome stability.

Dupilumab significantly improves skin barrier function in patients with moderate-to-severe atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is characterized by abnormal skin lipids that are largely driven by hyperactivated type 2 immune responses. The antibody to the α-subunit of interleukin (IL)-4 receptor, dupilumab, was recently approved to treat AD and demonstrated strong efficacy. However, the role of dupilumab therapy in the regulation of skin barrier structure and function has not been fully explored. METHODS: We have evaluated the content of lipids and transepidermal water loss (TEWL) in lesional and non-lesional skin of adults and adolescents with moderate-to-severe AD over the course of 16-week treatment with dupilumab and compared those values with that of matched healthy volunteers. RESULTS: Dupilumab treatment provided a significant decrease in TEWL in AD lesions, lowering it almost to the levels seen in the skin of healthy subjects. Blocking IL-4/IL-13 signaling with dupilumab normalized lipid composition (decreased levels of ceramides with non-hydroxy fatty acids and C18-sphingosine and increased the level of esterified omega-hydroxy fatty acid-containing ceramides) and increased ceramide chain length in lesional as well as non-lesional stratum corneum of AD patients. Partial changes for these parameters were already observed after 2 weeks, with a full response achieved after 8 weeks of dupilumab treatment. CONCLUSIONS: Inhibition of IL-4/IL-13 signaling by dupilumab allows restoration of skin lipid composition and barrier function in patients with moderate-to-severe AD.

Effect of Inpatient Integrative Medicine Consultation on 30-Day Readmission Rates: A Retrospective Observational Study at a Major U.S. Academic Hospital.

Objectives: The prevalence of inpatient integrative medicine (IM) consult services is increasing among academic health care institutions. The diversity of services between institutions, as well as the novel nature of such interventions, makes it challenging for health care administrators to determine the cost/benefit of adding such a program to their institution. The main purpose of this study was to examine the performance of the new University of California, Los Angeles (UCLA) East-West (EW) consult service as measured by 30-day readmission rates and lengths of stay. Design: This is a retrospective observational case-control study with participants matched to themselves. Setting: UCLA Santa Monica Hospital, a 281-bed academic tertiary care hospital near Los Angeles, California. Subjects: Patients who had received an EW consultation during the inaugural 20 months of the program (2018-2020), and who had been hospitalized in the prior 2 years from the date of their first EW consult. Intervention: Inpatient East-West consultation, which may include counseling, acupuncture and/or trigger point injections depending on medical necessity. Outcome Measures: Thirty-day readmission rates and lengths of hospital admission were compared between the hospitalization that included an EW consult (which included the use of acupuncture and/or trigger point injections when appropriate) and any prior admissions during the 2 years before that EW consult. Secondary outcomes included quantitative analysis of average number of treatments and qualitative assessment of integrative treatment(s) received, conditions treated, and reasons that EW treatment may have been deferred during a consult. Results: One hundred sixty-five unique patients met the study criteria. The EW consultation was associated with clinically relevant, statistically significant decreased 30-day readmission rates (33.0% vs. 4.6%, p < 0.001, odds ratio [OR] 0.10, 95% confidence interval [CI] 0.06-0.17). This effect was similar when limiting the analysis to pain-related admissions (32.3% vs. 3.4%, p < 0.001, OR = 0.07, 95% CI 0.03-0.16). Hospital admissions with EW consults were found to have a statistically significant increased length of stay (7.03 days vs. 5.40 days, p < 0.001). Conclusion: The EW medicine, an example of IM, correlates with a reduced risk of 30-day readmission and with modestly increased lengths of stay.

Providing support in a pandemic: A medical student telehealth service for ambulatory patients with COVID-19.

During the early months of the COVID-19 pandemic, when health systems were overwhelmed with surging hospitalizations and a novel virus, many ambulatory patients diagnosed with COVID-19 lacked guidance and support as they convalesced at home. This case report offers insight into the implementation of a telehealth service utilizing third- and fourth-year medical students to provide follow-up to ambulatory patients diagnosed with COVID-19. The service was evaluated using medical student surveys and retrospective chart review to assess the clinical and social needs of patients during the spring of 2020. Students assessed symptoms for 416 patients with COVID-19 from April 8 to May 20 and provided clinical information and resources. Eighteen percent of these patients sought higher levels of medical care, in part from student referrals. Three key implementation lessons from this experience that may be relevant for others include: 1) Vulnerable patient populations face unique stressors exacerbated by the pandemic and may benefit from intensive follow-up after COVID-19 diagnosis to address both medical and social needs; 2) Medical students can play value-added roles in providing patient education to prevent the spread of COVID-19, assisting patients with escalating care or resource connection, and providing emotional support to those who have lost loved ones; 3) Continuous re-assessment of the intervention was important to address evolving patient needs during the COVID-19 outbreak. Future work should focus on identifying high-risk patient populations and tailoring follow-up interventions to meet the unique needs of these patient populations.

Dupilumab Treatment Reduces Hospitalizations in Adults With Moderate-to-Severe Atopic Dermatitis.

BACKGROUND: Refractory disease, flares, or infections in atopic dermatitis (AD) can lead to hospitalizations. OBJECTIVE: To compare hospitalization rates among adults with moderate-to-severe AD treated with dupilumab versus control. METHODS: Data from 7 randomized, placebo-controlled trials of dupilumab (300 mg every 2 weeks [q2w] and/or weekly [qw]; with or without topical corticosteroids) were analyzed. RESULTS: Patients in the dupilumab 300 mg q2w, qw, and combined dupilumab (q2w and qw; n = 1,841) groups compared with patients in the control group (n = 1,091) had lower rates of all-cause hospitalizations (5.8, 2.7, and 3.8 events, respectively, vs 9.0 events per 100 patient-years [PY]; all P < .05 [49%, 71%, and 62% risk reduction, respectively]); AD-related hospitalizations (2.0, 0.4, 1.0 events vs 4.1 events per 100 PY; P < .05 for qw and dupilumab combined [91% and 79% risk reduction, respectively]); as well as reduced overall duration of AD-related hospitalization (10.9, 7.3, and 8.6 d vs 38.9 d per 100 PY). CONCLUSIONS: Among adults with moderate-to-severe AD, treatment with dupilumab versus control was associated with significant reductions in all-cause and AD-related hospitalization rates, and shorter duration of AD-related hospitalization.

Infections in children and adolescents treated with dupilumab in pediatric clinical trials for atopic dermatitis-A pooled analysis of trial data.

BACKGROUND/OBJECTIVE: Patients with moderate-to-severe atopic dermatitis (AD) have increased risk of cutaneous and extracutaneous infections. Dupilumab has previously been associated with reduced risk of serious/severe infections and non-herpetic skin infections in adults with moderate-to-severe AD. This analysis assessed infection rates with dupilumab versus placebo in pediatric patients with moderate-to-severe and severe AD participating in clinical trials. METHODS: This is a pooled analysis from two 16-week, randomized, placebo-controlled, phase 3 clinical trials of dupilumab: monotherapy in adolescents aged 12-17 years with moderate-to-severe AD (LIBERTY AD ADOL, NCT03054428) and with concomitant topical corticosteroids in children aged 6-11 years with severe AD (LIBERTY AD PEDS, NCT03345914). Data were pooled according to treatment received: placebo/approved dupilumab doses/other studied dupilumab doses/all dupilumab doses. Exposure-adjusted rates (patients with ≥1 event per 100 patient-years [nP/100 PY]) were used to compare treatment groups. RESULTS: Overall, 612 patients were included: 205 received placebo and 407 received dupilumab (261 received approved dupilumab doses and 146 received other studied dupilumab doses). Overall infection rates were numerically lower with dupilumab versus placebo (nP/100 PY: placebo, 227; approved dupilumab, 173; other dupilumab, 206; all dupilumab, 184). Total skin infections were numerically less frequent in all dupilumab-treated groups versus placebo (nP/100 PY: placebo, 67; approved dupilumab, 30; other dupilumab, 46; all dupilumab, 36). CONCLUSIONS: These data suggest that dupilumab treatment in children and adolescents with AD does not increase infection risk overall and is associated with lower rates of skin infections compared with placebo.

Dupilumab with Topical Corticosteroids Provides Rapid and Sustained Improvement in Adults with Moderate-to-Severe Atopic Dermatitis Across Anatomic Regions Over 52 Weeks.

INTRODUCTION: In a 52-week, phase 3 clinical trial (LIBERTY AD CHRONOS) in adult patients with moderate-to-severe atopic dermatitis (AD), dupilumab in combination with topical corticosteroids (TCS) resulted in a significant improvement in overall Eczema Area and Severity Index (EASI) compared with placebo plus TCS. In a post hoc analysis, dupilumab significantly improved the overall extent and severity of AD across four anatomic regions (head and neck, trunk, upper extremities, lower extremities) over 16 weeks. However, as AD severity and presentation may vary by body region, this analysis sought to determine whether there are regional variations in dupilumab efficacy. METHODS: Using data from the LIBERTY AD CHRONOS study, we performed a post hoc analysis of the mean percentage change in individual EASI signs (erythema, infiltration/papulation, excoriation, lichenification) from baseline through week 52 across four anatomic regions (head and neck, trunk, upper extremities, lower extremities). RESULTS: Dupilumab plus TCS, compared with placebo plus TCS, significantly improved the severity of all individual AD signs to a similar extent across the four anatomic regions. Significant improvements in each sign were seen early, within the first 2-4 weeks of treatment, and were sustained through week 52 across all regions. CONCLUSIONS: In adult patients with moderate-to-severe AD, treatment with dupilumab resulted in rapid and sustained improvement in the signs of AD across all anatomic regions. TRIAL REGISTRATION: LIBERTY AD CHRONOS (NCT02260986).

Effects of Intensive Outpatient Integrative Medicine on Health Care Utilization on High Utilizer Patients at a Major Academic Health System.

Objective: To determine if integrative medicine (IM) involvement can reduce acute care utilization for patients with complex medical conditions and high health care utilization. Design: Prospective single-center cohort study. Interventions: Twenty-nine complex high utilizer patients were treated by the University of California, Los Angeles (UCLA) East-West Extensivist IM specialty clinic with acupuncture, trigger point injections, and Traditional Chinese Medicine dietary modifications. Number of hospitalizations, hospitalization days, and emergency room visits were tracked for 6 months. Results: There was a statistically significant decrease in number of hospitalizations (-31.4%, p = 0.021) and hospitalization days (-38.0%, p = 0.038) after 6 months. Subgroup analysis suggested greater improvement with more frequent visits. Conclusion: IM specialty care correlates with reduced hospitalization frequency and total hospitalization days among high utilizers of care.

Identifying airborne transmission as the dominant route for the spread of COVID-19.

Various mitigation measures have been implemented to fight the coronavirus disease 2019 (COVID-19) pandemic, including widely adopted social distancing and mandated face covering. However, assessing the effectiveness of those intervention practices hinges on the understanding of virus transmission, which remains uncertain. Here we show that airborne transmission is highly virulent and represents the dominant route to spread the disease. By analyzing the trend and mitigation measures in Wuhan, China, Italy, and New York City, from January 23 to May 9, 2020, we illustrate that the impacts of mitigation measures are discernable from the trends of the pandemic. Our analysis reveals that the difference with and without mandated face covering represents the determinant in shaping the pandemic trends in the three epicenters. This protective measure alone significantly reduced the number of infections, that is, by over 78,000 in Italy from April 6 to May 9 and over 66,000 in New York City from April 17 to May 9. Other mitigation measures, such as social distancing implemented in the United States, are insufficient by themselves in protecting the public. We conclude that wearing of face masks in public corresponds to the most effective means to prevent interhuman transmission, and this inexpensive practice, in conjunction with simultaneous social distancing, quarantine, and contact tracing, represents the most likely fighting opportunity to stop the COVID-19 pandemic. Our work also highlights the fact that sound science is essential in decision-making for the current and future public health pandemics.