pinecone/core-2020-05-10-deduplication huggingface dataset:
Interleukin 23-Helper T Cell 17 Axis as a Treatment Target for Pityriasis Rubra Pilaris.

Treatment of pityriasis rubra pilaris (PRP) is solely based on its resemblance to psoriasis rather than any knowledge of its pathomechanism. Insight into pathogenic mediators of inflammation is essential for targeted and valid treatment options that could replace previous serendipitous therapeutic approaches in refractory PRP.
To determine whether blockade of the interleukin 23-helper T cell 17 (IL-23-TH17) pathway with ustekinumab represents an efficacious and, based on its proinflammatory cytokine profile, targeted treatment option in PRP.
In this case report, a patient with PRP received outpatient treatment at a university hospital department of dermatology with ustekinumab according to the dosing regimen approved for psoriasis. Lesional skin biopsy samples were taken from this patient and 2 others with refractory PRP. Messenger RNA (mRNA) expression of proinflammatory innate and T-cell-derived cytokines were measured and compared with skin samples from patients with psoriasis and healthy donors. From 1 patient, lesional skin samples were taken before ustekinumab treatment and 4 and 28 weeks after treatment initiation. Follow-up was completed after 6 months.
Subcutaneous ustekinumab, 45 mg, at weeks 0 and 4 and quarterly thereafter.
The primary outcome was to determine the changes in expression of proinflammatory innate and T-cell-derived cytokines during ustekinumab therapy. The secondary objective was to evaluate the clinical and histopathologic phenotype in relation to the mRNA expression profile of proinflammatory cytokines.
In lesional PRP skin samples from a single patient, upregulated expression levels were found for most proinflammatory innate cytokines, including tumor necrosis factor (TNF), IL-6, IL-12, IL-23, and IL-1β. Among adaptive T-cell cytokines, an increase of TH1 cytokines and, in particular, TH17 cytokines IL-17A, IL-17F, and IL-22 was seen in PRP. The patient with PRP who received ustekinumab showed regression of skin lesions after 2 weeks and almost complete resolution after 1 month. Clinical and histopathologic improvement paralleled the expression levels of TH17 cytokines but not of interferon-γ and TNF, which lagged behind the amelioration.
In this case report, a role of the IL-23-TH17-axis in PRP was identified, suggesting a shared pathogenic inflammatory pathway with psoriasis, despite evident clinical and histopathologic differences. In addition, this report provides a rationale for targeting the IL-23-TH17-pathway as a treatment option for refractory PRP
Global skin disease morbidity and mortality an update from the global burden of disease study 2013

IMPORTANCE Disability secondary to skin conditions is substantial worldwide. The Global Burden of Disease Study 2013 includes estimates of global morbidity and mortality due to skin diseases.  \ud
OBJECTIVE To measure the burden of skin diseases worldwide.  \ud
DATA SOURCES For nonfatal estimates, data were found by literature search using PubMed and Google Scholar in English and Spanish for years 1980 through 2013 and by accessing administrative data on hospital inpatient and outpatient episodes. Data for fatal estimates were based on vital registration and verbal autopsy data.  \ud
STUDY SELECTION Skin disease data were extracted from more than 4000 sources including systematic reviews, surveys, population-based disease registries, hospital inpatient data, outpatient data, cohort studies, and autopsy data. Data metrics included incidence, prevalence, remission, duration, severity, deaths, and mortality risk.  \ud
DATA EXTRACTION AND SYNTHESIS Datawere extracted by age, time period, case definitions, and other study characteristics. Data points were modeled with Bayesian meta-regression to generate estimates of morbidity and mortalitymetrics for skin diseases. All estimates were made with 95%uncertainty intervals.  \ud
MAIN OUTCOMES AND MEASURES Disability-adjusted life years (DALYs), years lived with disability, and years of life lost from 15 skin conditions in 188 countries.  \ud
RESULTS Skin conditions contributed 1.79% to the global burden of disease measured in DALYs from 306 diseases and injuries in 2013. Individual skin diseases varied in size from 0.38%of total burden for dermatitis (atopic, contact, and seborrheic dermatitis), 0.29% for acne vulgaris, 0.19% for psoriasis, 0.19% for urticaria, 0.16%for viral skin diseases, 0.15%for fungal skin diseases, 0.07%for scabies, 0.06%for malignant skin melanoma, 0.05%for pyoderma, 0.04%for cellulitis, 0.03%for keratinocyte carcinoma, 0.03%for decubitus ulcer, and 0.01% for alopecia areata. All other skin and subcutaneous diseases composed 0.12%of total DALYs.  \ud
CONCLUSIONS AND RELEVANCE Skin and subcutaneous diseases were the 18th leading cause of global DALYs in Global Burden of Disease 2013. Excluding mortality, skin diseases were the fourth leading cause of disability worldwide
Current Status of Fractional Laser Resurfacing

Fractional lasers were first developed based on observations of lasers designed for hair transplantation. In 2007, ablative fractional laser resurfacing was introduced. The fractionation allowed deeper tissue penetration, leading to greater tissue contraction, collagen production and tissue remodeling. Since then, fractional erbium:YAG resurfacing lasers have also been introduced. These lasers have yielded excellent results in treating photoaging, acne scarring, and dyschromia. With the adjustment of microspot density, pulse duration, number of passes, and fluence, the surgeon can adjust the treatment effects. These lasers have allowed surgeons to treat patients with higher Fitzpatrick skin types (types IV to VI) and greater individualize treatments to various facial subunits. Immunohistochemical analysis has demonstrated remodeling effects of the tissues for several months, producing longer lasting results. Adjuvant treatments are also under investigation, including concomitant face-lift, product deposition, and platelet-rich plasma. Finally, there is a short recovery time from treatment with these lasers, allowing patients to resume regular activities more quickly. Although there is a relatively high safety profile for ablative fractionated lasers, surgeons should be aware of the limitations of specific treatments and the associated risks and complications
Transcutaneous Skin-Muscle Flap Suspension Lower-Eyelid Blepharoplasty

The transcutaneous lower-eyelid blepharoplasty is a commonly performed surgical technique and an important tool in the armamentarium of facial plastic surgeons. The facets of lower-eyelid blepharoplasty begin with proper patient selection and rely on several technical subtleties that are crucial to achieve an excellent cosmetic and functional result while avoiding potential complications. The senior author (S.W.P) has been using the transcutaneous approach with orbicularis oculi muscle suspension for 30 years to address redundant or excessive skin and muscle while gaining wide exposure to treat pseudoherniation of the orbital fat compartments
Resveratrol Levels and All-Cause Mortality in Older Community-Dwelling Adults

Importance Resveratrol, a polyphenol found in grapes, red wine, chocolate, and certain berries and roots, is considered to have antioxidant, anti-inflammatory, and anti-cancer effects in humans and is related to longevity in some lower organisms. Objective To determine whether resveratrol levels achieved with diet are associated with inflammation, cancer, cardiovascular disease, and mortality in humans. Design Prospective cohort study, the Invecchiare in Chianti (InCHIANTI) Study ("Aging in the Chianti Region"), 1998-2009. Setting Two villages in the Chianti area, Tuscany region of Italy. Participants Population-based sample of 783 community-dwelling men and women, ≥65 y Exposure 24-h urinary resveratrol metabolites Main outcomes and measures Primary outcome measure was all-cause mortality. Secondary outcomes were markers of inflammation (serum C-reactive protein [CRP], interleuki
β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia: A Randomized Noninferiority Trial.

IMPORTANCE: The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial.
OBJECTIVE: To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia.
DESIGN, SETTING, AND PARTICIPANTS: Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation.
INTERVENTIONS: Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm.
MAIN OUTCOMES AND MEASURES: Proportion of patients not reaching clinical stability (heart rate &lt;100/min, systolic blood pressure &gt;90 mm Hg, temperature &lt;38.0°C, respiratory rate &lt;24/min, and oxygen saturation &gt;90% on room air) at day 7.
RESULTS: After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms.
CONCLUSIONS AND RELEVANCE: We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy.
TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00818610
Mediterranean diet and invasive breast cancer risk among women at high cardiovascular risk in the PREDIMED Trial: A randomized clinical trial

IMPORTANCE: Breast cancer is the leading cause of female cancer burden, and its incidence has increased by more than 20% worldwide since 2008. Some observational studies have suggested that the Mediterranean diet may reduce the risk of breast cancer. OBJECTIVE: To evaluate the effect of 2 interventions with Mediterranean diet vs the advice to follow a low-fat diet (control) on breast cancer incidence. DESIGN, SETTING, AND PARTICIPANTS: The PREDIMED study is a 1:1:1 randomized, single-blind, controlled field trial conducted at primary health care centers in Spain. From 2003 to 2009, 4282 women aged 60 to 80 years and at high cardiovascular disease risk were recruited after invitation by their primary care physicians. INTERVENTIONS: Participants were randomly allocated to a Mediterranean diet supplemented with extra-virgin olive oil, a Mediterranean diet supplemented with mixed nuts, or a control diet (advice to reduce dietary fat). MAIN OUTCOMES AND MEASURES: Breast cancer incidence was a prespecified secondary outcome of the trial for women without a prior history of breast cancer (n = 4152). RESULTS: After a median follow-up of 4.8 years, we identified 35 confirmed incident cases of breast cancer. Observed rates (per 1000 person-years) were 1.1 for the Mediterranean diet with extra-virgin olive oil group, 1.8 for the Mediterranean diet with nuts group, and 2.9 for the control group. The multivariable-adjusted hazard ratios vs the control group were 0.32 (95% CI, 0.13-0.79) for the Mediterranean diet with extra-virgin olive oil group and 0.59 (95% CI, 0.26-1.35) for the Mediterranean diet with nuts group. In analyses with yearly cumulative updated dietary exposures, the hazard ratio for each additional 5% of calories from extra-virgin olive oil was 0.72 (95% CI, 0.57-0.90). CONCLUSIONS AND RELEVANCE: This is the first randomized trial finding an effect of a long-term dietary intervention on breast cancer incidence. Our results suggest a beneficial effect of a Mediterranean diet supplemented with extra-virgin olive oil in the primary prevention of breast cancer. These results come from a secondary analysis of a previous trial and are based on few incident cases and, therefore, need to be confirmed in longer-term and larger studies
Evaluation of Stepped Care for Chronic Pain (ESCAPE) in Veterans of the Iraq and Afghanistan Conflicts A Randomized Clinical Trial

IMPORTANCE:
Despite the prevalence and the functional, psychological, and economic impact of chronic pain, few intervention studies of treatment of chronic pain in veterans have been performed.
OBJECTIVE:
To determine whether a stepped-care intervention is more effective than usual care, as hypothesized, in reducing pain-related disability, pain interference, and pain severity.
DESIGN, SETTING, AND PARTICIPANTS:
We performed a randomized clinical trial comparing stepped care with usual care for chronic pain. We enrolled 241 veterans from Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn with chronic (>3 months) and disabling (Roland Morris Disability Scale score, ≥7) musculoskeletal pain of the cervical or lumbar spine or extremities (shoulders, knees, and hips) in the Evaluation of Stepped Care for Chronic Pain (ESCAPE) trial from December 20, 2007, through June 30, 2011. The 9-month follow-up was completed by April 2012. Patients received treatment at a postdeployment clinic and 5 general medicine clinics at a Veterans Affairs medical center.
INTERVENTIONS:
Step 1 included 12 weeks of analgesic treatment and optimization according to an algorithm coupled with pain self-management strategies; step 2, 12 weeks of cognitive behavioral therapy. All intervention aspects were delivered by nurse care managers.
MAIN OUTCOMES AND MEASURES:
Pain-related disability (Roland Morris Disability Scale), pain interference (Brief Pain Inventory), and pain severity (Graded Chronic Pain Scale).
RESULTS:
The primary analysis included 121 patients receiving the stepped-care intervention and 120 patients receiving usual care. At 9 months, the mean decrease from baseline in the Roland Morris Disability Scale score was 1.7 (95% CI, -2.6 to -0.9) points in the usual care group and 3.7 (95% CI, -4.5 to -2.8) points in the intervention group (between-group difference, -1.9 [95% CI, -3.2 to -0.7] points; P=.002). The mean decrease from baseline in the Pain Interference subscale score of the Brief Pain Inventory was 0.9 points in the usual care group and 1.7 points in the intervention group (between-group difference, -0.8 [95% CI, -1.3 to -0.3] points; P=.003). The Graded Chronic Pain Scale severity score was reduced by 4.5 points in the usual care group and 11.1 points in the intervention group (between-group difference, -6.6 [95% CI, -10.5 to -2.7] points; P=.001).
CONCLUSIONS AND RELEVANCE:
A stepped-care intervention that combined analgesics, self-management strategies, and brief cognitive behavioral therapy resulted in statistically significant reductions in pain-related disability, pain interference, and pain severity in veterans with chronic musculoskeletal pain
Controlled interventions to reduce burnout in physicians a systematic review and meta-analysis

IMPORTANCE Burnout is prevalent in physicians and can have a negative influence on performance, career continuation, and patient care. Existing evidence does not allow clear recommendations for the management of burnout in physicians. OBJECTIVE To evaluate the effectiveness of interventions to reduce burnout in physicians and whether different types of interventions (physician-directed or organization-directed interventions), physician characteristics (length of experience), and health care setting characteristics (primary or secondary care) were associated with improved effects. DATA SOURCES MEDLINE, Embase, PsycINFO, CINAHL, and Cochrane Register of Controlled Trials were searched from inception to May 31, 2016. The reference lists of eligible studies and other relevant systematic reviews were hand searched. STUDY SELECTION Randomized clinical trials and controlled before-after studies of interventions targeting burnout in physicians. DATA EXTRACTION AND SYNTHESIS Two independent reviewers extracted data and assessed the risk of bias. The main meta-analysis was followed by a number of prespecified subgroup and sensitivity analyses. All analyses were performed using random-effects models and heterogeneity was quantified. MAIN OUTCOMES AND MEASURES The core outcomewas burnout scores focused on emotional exhaustion, reported as standardized mean differences and their 95confidence intervals. RESULTS Twenty independent comparisons from 19 studieswere included in the meta-analysis (n = 1550 physicians; mean SD age, 40.3 9.5 years; 49%male). Interventionswere associated with small significant reductions in burnout (standardized mean difference SMD = ?0.29; 95%CI, ?0.42 to ?0.16; equal to a drop of 3 points on the emotional exhaustion domain of the Maslach Burnout Inventory above change in the controls). Subgroup analyses suggested significantly improved effects for organization-directed interventions (SMD = ?0.45; 95%CI, ?0.62 to ?0.28) compared with physician-directed interventions (SMD = ?0.18; 95%CI, ?0.32 to ?0.03). Interventions delivered in experienced physicians and in primary care were associated with higher effects compared with interventions delivered in inexperienced physicians and in secondary care, but these differences were not significant. The results were not influenced by the risk of bias ratings. CONCLUSIONS AND RELEVANCE Evidence from this meta-analysis suggests that recent intervention programs for burnout in physicians were associated with small benefits that may be boosted by adoption of organization-directed approaches. This finding provides support for the view that burnout is a problem of the whole health care organization, rather than individuals
Cross-sectional and Longitudinal Analysis of the Relationship Between A beta Deposition, Cortical Thickness, and Memory in Cognitively Unimpaired Individuals and in Alzheimer Disease

IMPORTANCE beta-amyloid (A beta) deposition is one of the hallmarks of Alzheimer disease. A beta deposition accelerates gray matter atrophy at early stages of the disease even before objective cognitive impairment is manifested. Identification of at-risk individuals at the presymptomatic stage has become a major research interest because it will allow early therapeutic interventions before irreversible synaptic and neuronal loss occur. We aimed to further characterize the cross-sectional and longitudinal relationship between A beta deposition, gray matter atrophy, and cognitive impairment
The role of clusterin in amyloid-β-associated neurodegeneration

Importance  Converging evidence indicates that clusterin, a chaperone glycoprotein, influences Alzheimer disease neurodegeneration. However, the precise role of clusterin in Alzheimer disease pathogenesis is still not well understood.
Objective  To elucidate the relationship between clusterin, amyloid-β (Aβ), phosphorylated tau (p-tau), and the rate of brain atrophy over time among nondemented older individuals.
Design, Setting, and Participants  This longitudinal cohort included cognitively normal older participants and individuals with mild cognitive impairment assessed with baseline lumbar puncture and longitudinal structural magnetic resonance imaging. We examined 241 nondemented older individuals from research centers across the United States and Canada (91 participants with a Clinical Dementia Rating score of 0 and 150 individuals with a Clinical Dementia Rating score of 0.5).
Main Outcomes and Measures  Using linear mixed-effects models, we investigated interactions between cerebrospinal fluid (CSF) clusterin, CSF Aβ1-42, and CSF p-tau at threonine 181 (p-tau181p) on the atrophy rate of the entorhinal cortex and hippocampus.
Results  Across all participants, we found a significant interaction between CSF clusterin and CSF Aβ1-42 on the entorhinal cortex atrophy rate but not on the hippocampal atrophy rate. Cerebrospinal fluid clusterin was associated with the entorhinal cortex atrophy rate among CSF Aβ1-42–positive individuals but not among CSF Aβ1-42–negative individuals. In secondary analyses, we found significant interactions between CSF Aβ1-42 and CSF clusterin, as well as CSF Aβ1-42 and CSF p-tau181p, on the entorhinal cortex atrophy rate. We found similar results in subgroup analyses within the mild cognitive impairment and cognitively normal cohorts.
Conclusions and Relevance  In nondemented older individuals, Aβ-associated volume loss occurs in the presence of elevated clusterin. The effect of clusterin on Aβ-associated brain atrophy is not confounded or explained by p-tau. These findings implicate a potentially important role for clusterin in the earliest stages of the Alzheimer disease neurodegenerative process and suggest independent effects of clusterin and p-tau on Aβ-associated volume loss
Aggressive Course in Encephalitis With Opsoclonus, Ataxia, Chorea, and Seizures. The First Pediatric Case of γ-Aminobutyric Acid Type B Receptor Autoimmunity

IMPORTANCE: Autoantibodies to the γ-aminobutyric acid type B (GABAB) receptor have recently been identified as a cause of autoimmune encephalitis. Most patients with GABAB encephalitis have presented with limbic encephalitis. About half of the cases reported have been paraneoplastic in origin, with the majority of tumors representing small cell lung cancer. OBSERVATIONS: We describe a 3-year-old boy who presented with a mixed movement disorder (opsoclonus, ataxia, and chorea) as well as seizures refractory to treatment. His seizures required continuous pentobarbital sodium infusion to be controlled. Despite treatment with intravenous corticosteroids and immunoglobulins, the patient ultimately died of overwhelming sepsis. CONCLUSIONS AND RELEVANCE: To our knowledge, this report represents the first pediatric case of GABAB-associated encephalitis. Our patient presented with encephalopathy, refractory seizures, and a mixed movement disorder rather than limbic encephalitis. γ-Aminobutyric acid type B receptor autoimmunity deserves consideration in pediatric patients presenting with encephalitis. Immune-mediated encephalitis with autoantibodies directed against synaptic proteins has become an important component of the differential diagnosis of patients with encephalitis. Current estimates suggest that a substantial proportion of patients once suspected to have viral encephalitis in fact have an autoimmune etiology for their symptoms.1 Additional autoantigen targets continue to be identified, and the phenotypic spectrum associated with autoimmune encephalitis continues to expand. We describe a 3-year-old patient who presented with acute-onset confusion, opsoclonus, chorea, and intractable seizures. Neuroimaging disclosed involvement of the brainstem, basal ganglia, and hippocampi. γ-Aminobutyric acid type B (GABAB) receptor autoantibodies were identified in the serum and cerebrospinal fluid (CSF). Despite immunomodulating therapy, the patient died of overwhelming sepsis. To our knowledge, this is the first description of a pediatric patient with GABAB receptor autoantibodies. The presence of opsoclonus, ataxia, and chorea expands the clinical phenotype and indicates that GABAB receptor autoimmunity should be considered in cases of pediatric encephaliti