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Importance: Hidradenitis suppurativa (HS) is a chronic inflammatory disease with a high burden for patients and limited existing therapeutic options., Objective: To evaluate the efficacy and safety of bimekizumab, a monoclonal IgG1 antibody that selectively inhibits interleukin 17A and 17F in individuals with moderate to severe HS., Design, Setting, and Participants: This phase 2, double-blind, placebo-controlled randomized clinical trial with an active reference arm was performed from September 22, 2017, to February 21, 2019. The study included a 2- to 4-week screening period, a 12-week treatment period, and a 20-week safety follow-up. Of 167 participants screened at multiple centers, 90 were enrolled. Eligible participants were 18 to 70 years of age with a diagnosis of moderate to severe HS 12 months or more before baseline., Interventions: Participants with HS were randomized 2:1:1 to receive bimekizumab (640 mg at week 0, 320 mg every 2 weeks), placebo, or reference arm adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg every week for weeks 4-10)., Main Outcomes and Measures: The prespecified primary efficacy variable was the proportion of participants with a 50% or greater reduction from baseline in the total abscess and inflammatory nodule count with no increase in abscess or draining fistula count (Hidradenitis Suppurativa Clinical Response [HiSCR] at week 12. Exploratory variables included proportion achieving a modified HiSCR with 75% reduction of HiSCR criteria (HiSCR75) or a modified HiSCR with 90% reduction of HiSCR criteria (HiSCR90), change in Patient's Global Assessment of Pain, and Dermatology Life Quality Index total scores., Results: Eighty-eight participants received at least 1 dose of study medication (61 [69%] female; median age, 36 years; range, 18-69 years). Seventy-three participants completed the study, including safety follow-up. Bimekizumab demonstrated a higher HiSCR rate vs placebo at week 12 (57.3% vs 26.1%; posterior probability of superiority equaled 0.998, calculated using bayesian analysis). Bimekizumab demonstrated greater clinical improvements compared with placebo. Improvements in the International Hidradenitis Suppurativa Severity Score (IHS4) were seen at week 12 with bimekizumab (mean [SD] IHS4, 16.0 [18.0]) compared with placebo (mean [SD] IHS4, 40.2 [32.6]). More bimekizumab-treated participants achieved positive results on stringent outcome measures compared with placebo. At week 12, 46% of bimekizumab-treated participants achieved HiSCR75 and 32% achieved HiSCR90, whereas 10% of placebo-treated participants achieved HiSCR75 and none achieved HiSCR90; in adalimumab-treated participants, 35% achieved HiSCR75 and 15% achieved HiSCR90. One participant withdrew because of adverse events. Serious adverse events occurred in 2 of 46 bimekizumab-treated participants (4%), 2 of 21 placebo-treated participants (10%), and 1 of 21 adalimumab-treated participants (5%)., Conclusions and Relevance: In this phase 2 randomized clinical trial, bimekizumab demonstrated clinically meaningful improvements across all outcome measures, including stringent outcomes. Bimekizumab's safety profile was consistent with studies of other indications, supporting further evaluation in participants with HS., Trial Registration: ClinicalTrials.gov Identifier: NCT03248531.

Background: Traditional in-person psychotherapies are incapable of addressing global mental health needs. Use of computer-based interventions is one promising solution for closing the gap between the amount of global mental health treatment needed and received., Objective: Although many meta-analyses have provided evidence supporting the efficacy of self-guided, computer-based interventions, most report low rates of treatment engagement (eg, high attrition and low adherence). The aim of this study is to investigate the efficacy of an adjunctive treatment component that uses task shifting, wherein mental health care is provided by nonspecialist peer counselors to enhance engagement in an internet-based, self-directed, evidence-based mindfulness intervention among Chinese university students., Methods: From 3 universities across China, 54 students who reported at least mild stress, anxiety, or depression were randomly assigned to a 4-week internet-based mindfulness intervention (MIND) or to the intervention plus peer counselor support (MIND+), respectively. Be Mindful delivers all the elements of mindfulness-based cognitive therapy in an internet-based, 4-week course. Participants completed daily monitoring of mindfulness practice and mood, as well as baseline and posttreatment self-reported levels of depression, anxiety, stress, and trait mindfulness. We screened 56 volunteer peer counselor candidates who had no former training in the delivery of mental health services. Of these, 10 were invited to participate in a day-long training, and 4 were selected. Peer counselors were instructed to provide 6 brief (15-20 minute) sessions each week, to help encouraging participants to complete the internet-based intervention. Peer counselors received weekly web-based group supervision., Results: For both conditions, participation in the internet-based intervention was associated with significant improvements in mindfulness and mental health outcomes. The pre-post effect sizes (Cohen d) for mindfulness, depression, anxiety, and stress were 0.55, 0.95, 0.89, and 1.13, respectively. Participants assigned to the MIND+ (vs MIND) condition demonstrated significantly less attrition and more adherence, as indicated by a greater likelihood of completing posttreatment assessments (16/27, 59% vs 7/27, 26%; χ 2 1 =6.1; P=.01) and a higher percentage of course completion (72.6/100, 72.6% vs 50.7/100, 50.7%; t 52 =2.10; P=.04), respectively. No significant between-group differences in daily frequency and duration of mindfulness practice were observed. Multilevel logistic growth models showed that MIND+ participants reported significantly greater pre-post improvements in daily stress ratings (interaction estimate 0.39, SE 0.18; t 317 =2.29; P=.02) and depression (interaction estimate 0.38, SE 0.16; t 330 =2.37; P=.02) than those in the MIND condition., Conclusions: This study provides new insights into effective ways of leveraging technology and task shifting to implement large-scale mental health initiatives that are financially feasible, easily transportable, and quickly scalable in low-resource settings. The findings suggest that volunteer peer counselors receiving low-cost, low-intensity training and supervision may significantly improve participants' indices of treatment engagement and mental health outcomes in an internet-based mindfulness intervention among Chinese university students., (©Marcus Rodriguez, Tory A Eisenlohr-Moul, Jared Weisman, M Zachary Rosenthal. Originally published in JMIR Formative Research (https://formative.jmir.org), 13.10.2021.)

Background: Children with severe atopic dermatitis (AD) have limited treatment options., Objective: We report the efficacy and safety of dupilumab + topical corticosteroids (TCS) in children aged 6-11 years with severe AD inadequately controlled with topical therapies., Methods: In this double-blind, 16-week, phase 3 trial (NCT03345914), 367 patients were randomized 1:1:1 to 300 mg dupilumab every 4 weeks (300 mg q4w), a weight-based regimen of dupilumab every 2 weeks (100 mg q2w, baseline weight <30 kg; 200 mg q2w, baseline weight ≥30 kg), or placebo; with concomitant medium-potency TCS., Results: Both the q4w and q2w dupilumab + TCS regimens resulted in clinically meaningful and statistically significant improvement in signs, symptoms, and quality of life (QOL) versus placebo + TCS in all prespecified endpoints. For q4w, q2w, and placebo, 32.8%, 29.5%, and 11.4% of patients, respectively, achieved Investigator's Global Assessment scores of 0 or 1; 69.7%, 67.2%, and 26.8% achieved ≥75% improvement in Eczema Area and Severity Index scores; and 50.8%, 58.3%, and 12.3% achieved ≥4-point reduction in worst itch score. Response to therapy was weight-dependent: optimal dupilumab doses for efficacy and safety were 300 mg q4w in children <30 kg and 200 mg q2w in children ≥30 kg. Conjunctivitis and injection-site reactions were more common with dupilumab + TCS than with placebo + TCS., Limitations: Short-term 16-week treatment period; severe AD only., Conclusion: Dupilumab + TCS is efficacious and well tolerated in children with severe AD, significantly improving signs, symptoms, and QOL., (Copyright © 2020 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

We propose a new route to accelerate molecular dynamics through the use of velocity jump processes allowing for an adaptive time step specific to each atom-atom pair (two-body) interactions. We start by introducing the formalism of the new velocity jump molecular dynamics, ergodic with respect to the canonical measure. We then introduce the new BOUNCE integrator that allows for long-range forces to be evaluated at random and optimal time steps, leading to strong savings in direct space. The accuracy and computational performances of a first BOUNCE implementation dedicated to classical (non-polarizable) force fields are tested in the cases of pure direct-space droplet-like simulations and of periodic boundary conditions (PBC) simulations using Smooth Particle Mesh Ewald method. An analysis of the capability of BOUNCE to reproduce several condensed-phase properties is provided. Since electrostatics and van der Waals two-body contributions are evaluated much less often than with standard integrators using a 1 fs time step, up to a 400% direct-space acceleration is observed. Applying the reversible reference system propagator algorithms [RESPA(1)] to reciprocal-space (many-body) interactions allows BOUNCE-RESPA(1) to maintain large speedups in PBC while maintaining precision. Overall, we show that replacing the BAOAB standard Langevin integrator by the BOUNCE adaptive framework preserves a similar accuracy and leads to significant computational savings.

Objectives: The objective of this study was to determine whether adolescents in emergency departments (EDs) who report engaging in high-risk sexual behaviors are less likely to identify a primary care provider (PCP) and more likely to access the ED than their sexually inexperienced peers., Methods: This was a secondary analysis of adolescents presenting to a pediatric ED with non-sexually transmitted infection (STI)-related complaints who completed surveys to assess sexual behavior risk and health care access. We measured differences in self-reported PCP identification, preferential use of the ED, and number of ED visits over a 12-month period by sexual experience. Secondary outcomes included clinician documented sexual histories and STI testing., Results: Of 758 patients meeting inclusion criteria, 341 (44.9%) were sexually experienced, and of those, 129 (37.8%) reported engaging in high-risk behavior. Participants disclosing high-risk behavior were less likely to identify a PCP (adjusted odds ratio, 0.5; 95% confidence interval [CI], 0.3-0.9), more likely to prefer the ED for acute care issues (adjusted odds ratio, 1.6; 95% CI, 1.0-2.6), and had a higher rate of ED visits (adjusted relative risk, 1.2; 95% CI, 1.0-1.3) compared with sexually inexperienced peers. Among patients disclosing high-risk behavior, 10.9% had clinician-documented sexual histories and 2.6% underwent STI testing., Conclusion: Adolescents who reported engaging in high-risk sexual behaviors were less likely to identify a PCP, as well as more likely to prefer ED-based care and make more ED visits. However, ED clinicians infrequently obtained sexual histories and performed STI testing in asymptomatic youth, thereby missing opportunities to screen high-risk adolescents who may lack access to preventive care.

Importance: Adolescents with atopic dermatitis (AD) have high disease burden negatively affecting quality of life, with limited treatment options. The efficacy and safety of dupilumab, a monoclonal antibody, approved for treatment in adolescent patients with inadequately controlled AD, remain unknown in this patient population., Objective: To assess the efficacy and safety of dupilumab monotherapy in adolescents with moderate to severe inadequately controlled AD., Design, Setting, and Participants: A randomized, double-blind, parallel-group, phase 3 clinical trial was conducted at 45 US and Canadian centers between March 21, 2017, and June 5, 2018. A total of 251 adolescents with moderate to severe AD inadequately controlled by topical medications or for whom topical therapy was inadvisable were included., Interventions: Patients were randomized (1:1:1; interactive-response system; stratified by severity and body weight) to 16-week treatment with dupilumab, 200 mg (n = 43; baseline weight <60 kg), or dupilumab, 300 mg (n = 39; baseline weight ≥60 kg), every 2 weeks; dupilumab, 300 mg, every 4 weeks (n = 84); or placebo (n = 85)., Main Outcomes and Measures: Proportion of patients with 75% or more improvement from baseline in Eczema Area and Severity Index (EASI-75) (scores range from 0 to 72, with higher scores indicating greater severity) and Investigator's Global Assessment (IGA) 0 or 1 on a 5-point scale (scores range from 0 to 4, with higher scores indicating greater severity) at week 16., Results: A total of 251 patients were randomized (mean [SD] age, 14.5 [1.7] years; 148 [59.0%] male). Of 250 patients with data available on concurrent allergic conditions, most had comorbid type 2 diseases (asthma, 134 [53.6%]; food allergies, 60.8%; allergic rhinitis, 65.6%). A total of 240 patients (95.6%) completed the study. Dupilumab achieved both coprimary end points at week 16. The proportion of patients with EASI-75 improvement from baseline increased (every 2 weeks, 41.5%; every 4 weeks, 38.1%; placebo, 8.2%) with differences vs placebo of 33.2% (95% CI, 21.1%-45.4%) for every 2 weeks and 29.9% (95% CI, 17.9%-41.8%) for every 4 weeks (P < .001). Efficacy of the every-2-week regimen was generally superior to the every-4-week regimen. Patients in the dupilumab arms had higher percentage values of conjunctivitis (every 2 weeks, 9.8%; every 4 weeks, 10.8%; placebo, 4.7%) and injection-site reactions (every 2 weeks, 8.5%; every 4 weeks, 6.0%; placebo, 3.5%), and lower nonherpetic skin infections (every 2 weeks, 9.8%; every 4 weeks, 9.6%; placebo, 18.8%)., Conclusions and Relevance: In this study, dupilumab significantly improved AD signs, symptoms, and quality of life in adolescents with moderate to severe AD, with an acceptable safety profile. Placebo-corrected efficacy and safety of dupilumab were similar in adolescents and adults., Trial Registration: ClinicalTrials.gov identifier: NCT03054428.

Dupilumab, a monoclonal antibody that blocks the shared receptor subunit for interleukin (IL)-4 and IL-13, is currently approved for the treatment of adults with inadequately controlled moderate-to-severe atopic dermatitis (AD). The efficacy and safety of dupilumab for AD among racial subgroups is unknown. This post hoc analysis from three phase 3 trials assessed the efficacy and safety of dupilumab vs placebo by racial subgroup (White, Asian, Black/African American). Data from LIBERTY AD SOLO 1 (NCT02277743), SOLO 2 (NCT02277769), and CHRONOS (NCT02260986) were pooled. Outcomes included mean and percent change from baseline to week 16 in the key therapeutic domains Eczema Area and Severity Index (EASI), Peak Pruritus Numerical Rating Scale (NRS), Dermatology Life Quality Index (DLQI), and Patient-Oriented Eczema Measure, as well as Investigator’s Global Assessment and pain or discomfort assessed by the European Quality of Life-5 Dimensions 3 level questionnaire. A total of 2,058 patients (White n=1,429, Asian n=501, Black/African American n=128) were included in the current analysis. Baseline demographics and disease characteristics were balanced between treatment groups and racial subgroups. In the three trials, dupilumab significantly (P<0.0001) improved all assessed outcomes compared with placebo in the White and Asian subgroups. In the smaller Black/African American subgroup, dupilumab significantly (P<0.0001) improved EASI endpoints and mean changes in Peak Pruritus NRS and DLQI vs placebo, with positive numeric trends favoring dupilumab in all other endpoints. Dupilumab was generally well tolerated, with an acceptable safety profile in all racial subgroups. Serious adverse events occurred more frequently with placebo; treatment discontinuations due to adverse events were rare in all treatment groups. Significant clinical improvement and a favorable benefit-risk profile can be achieved with dupilumab treatment in patients of White, Asian, and Black/African American racial subgroups with moderate-to-severe AD inadequately controlled with topical medications. ClinicalTrials.gov identifiers: NCT02277743, NCT02277769, NCT02260986

Background: The optimal long-term dosing strategy for adalimumab (ADA) in hidradenitis suppurativa/acne inversa (HS) was evaluated by pooling the results of the PIONEER phase 3 trials and an open-label extension (OLE) study., Objective: To assess the response to and tolerability of long-term administration of ADA in HS., Methods: The durations of the PIONEER I/II periods A, B, and OLE were 12, 24, and 52 or more weeks, respectively. Patients who entered the OLE and received ADA (40 mg every week continuously) and responders plus partial responders (PRRs) were evaluated. Primary efficacy assessments included measurement of HS clinical response (HiSCR), lesion counts, skin pain, and Dermatology Life Quality Index (DLQI). Treatment-emergent adverse events were assessed., Results: At week 12, 52.3% of those receiving ADA weekly and 73.0% of PRRs achieved HiSCR. Achievement of HiSCR was maintained through week 168 in 52.3% of patients who received ADA weekly and 57.1% of PRRs. Sustained improvement in lesion counts, skin pain, and DLQI score were also observed. The safety profile throughout the OLE was similar to the profiles observed in the PIONEER studies., Limitations: The OLE was uncontrolled., Conclusion: Continuous weekly dosing with ADA, 40 mg, is a reasonable treatment option for long-term control of moderate-to-severe HS., (Copyright © 2018 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Streptococcus mutans , one of ∼600 bacterial species in the human oral cavity, is among the most acidogenic constituents of the plaque biofilm. Considered to be the primary causative agent of dental caries, S. mutans harbors a 25-kDa SloR metalloregulatory protein which controls metal ion transport across the bacterial cell membrane to maintain essential metal ion homeostasis. The expression of SloR derives in part from transcriptional readthrough of the sloABC operon, which encodes a Mn 2+ /Fe 2+ ABC transport system. Here we describe the details of the sloABC promoter that drives this transcription as well as those for a novel independent promoter in an intergenic region (IGR) that contributes to downstream sloR expression. Reverse transcriptase PCR (RT-PCR) studies support the occurrence of sloR transcription that is independent of sloABC expression, and the results of 5' rapid amplification of cDNA ends (5' RACE) revealed a sloR transcription start site in the IGR, from which the -10 and -35 promoter regions were predicted. The results of gel mobility shift assays support direct SloR binding to the IGR, albeit with a lower affinity than that for SloR binding to the sloABCR promoter. The function of the sloR promoter was validated by semiquantitative real-time PCR (qRT-PCR) experiments. Interestingly, sloR expression was not significantly affected when bacteria were grown in the presence of a high manganese concentration, whereas expression of the sloABC operon was repressed under these conditions. The results of in vitro transcription studies support the occurrence of SloR-mediated transcriptional activation of sloR and repression of sloABC Taken together, these findings implicate SloR as a bifunctional regulator that represses sloABC promoter activity and encourages sloR transcription from an independent promoter. IMPORTANCE Tooth decay is a ubiquitous infectious disease that is especially pervasive in underserved communities worldwide. S. mutans -induced carious lesions cause functional, physical, and/or esthetic impairment in the vast majority of adults and in 60 to 90% of schoolchildren in industrialized countries. Billions of dollars are spent annually on caries treatment, and productivity losses due to absenteeism from the workplace are significant. Research aimed at alleviating S. mutans -induced tooth decay is important because it can address the socioeconomic disparity that is associated with dental cavities and improve overall general health, which is inextricably linked to oral health. Research focused on the S. mutans SloR metalloregulatory protein can guide the development of novel therapeutics and thus alleviate the burden of dental cavities., (Copyright © 2018 American Society for Microbiology.)

The article Efficacy and Safety of Switching to Ixekizumab in Etanercept Non-Responders: A Subanalysis from Two Phase III Randomized Clinical Trials in Moderate-to-Severe Plaque Psoriasis (UNCOVER-2 and -3) written by Andrew Blauvelt.

Four of eleven affected dogs died despite aggressive treatment during a 2015 focal outbreak of hemorrhagic gastroenteritis following a stay in a pet housing facility. Routine diagnostic investigations failed to identify a specific cause. Virus isolation from fresh necropsy tissues yielded a calicivirus with sequence homology to a vesivirus within the group colloquially known as the vesivirus 2117 strains that were originally identified as contaminants in CHO cell bioreactors. In situ hybridization and reverse transcription-PCR assays of tissues from the four deceased dogs confirmed the presence of canine vesivirus (CaVV) nucleic acids that localized to endothelial cells of arterial and capillary blood vessels. CaVV nucleic acid corresponded to areas of necrosis and hemorrhage primarily in the intestinal tract, but also in the brain of one dog with nonsuppurative meningoencephalitis. This is the first report of an atypical disease association with a putative hypervirulent vesivirus strain in dogs, as all other known strains of CaVV appear to cause nonclinical infections or relatively mild disease. After identification of the CU-296 vesivirus strain from this outbreak, four additional CaVV strains were amplified from unrelated fecal specimens and archived stocks provided by other laboratories. Broader questions include the origins, reservoir(s), and potential for reemergence and spread of these related CaVVs., (Copyright © 2018 American Society for Microbiology.)

Osteomyelitis is typically a bacterial infection (usually from Staphylococcus) or, more rarely, a fungal infection of the bone. It can occur in any bone in the body, but it most often affects the long bones (leg and arm), vertebral (spine), and bones of the foot. Microbial success in osteomyelitis is due to their ability to form biofilms which inhibit the wound healing process and increases resistance to anti-infective agents. Also, biofilms do not allow easy penetration of antibiotics into their matrix making clinical treatment a challenge. The development of local antibiotic delivery systems that deliver high concentrations of antibiotics to the affected site is an emerging area of research with great potential. Standard treatment includes antibiotic therapy, either locally or systemically and refractory cases of osteomyelitis may lead to surgical intervention and a prolonged course of antibiotic treatment involving placement of antibiotic-doped beads or spacers within the wound site. There are disadvantages with this treatment modality including insufficient mixing of the antibiotic, lack of uniform bead size, resulting in lower antibiotic availability, and limitations on the antibiotics employed. Thus, a method is needed to address biofilm formations in the wound and on the surface of the surgical implants to prevent osteomyelitis. In this study, we show that all antibiotics studied were successfully doped into PMMA and antibiotic-doped 3D printed beads, disks, and filaments were easily printed. The growth inhibition capacity of the antibiotic-loaded PMMA 3D printed constructs was also demonstrated.

Introduction: Increased admissions occur in small animal veterinary emergency clinics during some holidays, and some of the increased caseload is due to ingestion of toxic substances. This report documents zinc toxicosis contributing to the death of a dog after ingestion of holiday tinsel garland., Case Study: A mature boxer dog presented with a 4-day history of vomiting and diarrhea. Radiodense foreign material was detected in the stomach and removed via gastrotomy. The patient clinically worsened over the next several days with evidence of hemolytic anemia, severe hypernatremia, and an elevated WBC count with a suspected dehiscence of the surgical site and acute renal failure. The serum zinc concentration was moderately elevated. Postmortem findings included surgical dehiscence from the gastrotomy and enterotomy sites, hepatic extramedullary hematopoiesis, hemoglobinuric nephrosis, and pancreatic fibrosis. The foreign material removed from the stomach also contained zinc., Discussion: Ingestion of holiday tinsel garland made from metal-coated plastic film has not previously been implicated in zinc toxicosis. Zinc toxicosis has a good prognosis in veterinary medicine when diagnosed and treated promptly, but the unique source of zinc in this dog contributed to the delay in diagnosis and grave outcome in this case.

Background: Dupilumab (an anti-interleukin-4-receptor-α monoclonal antibody) blocks signalling of interleukin 4 and interleukin 13, type 2/Th2 cytokines implicated in numerous allergic diseases ranging from asthma to atopic dermatitis. Previous 16-week monotherapy studies showed that dupilumab substantially improved signs and symptoms of moderate-to-severe atopic dermatitis with acceptable safety, validating the crucial role of interleukin 4 and interleukin 13 in atopic dermatitis pathogenesis. We aimed to evaluate the long-term efficacy and safety of dupilumab with medium-potency topical corticosteroids versus placebo with topical corticosteroids in adults with moderate-to-severe atopic dermatitis., Methods: In this 1-year, randomised, double-blinded, placebo-controlled, phase 3 study (LIBERTY AD CHRONOS), adults with moderate-to-severe atopic dermatitis and inadequate response to topical corticosteroids were enrolled at 161 hospitals, clinics, and academic institutions in 14 countries in Europe, Asia-Pacific, and North America. Patients were randomly assigned (3:1:3) to subcutaneous dupilumab 300 mg once weekly (qw), dupilumab 300 mg every 2 weeks (q2w), or placebo via a central interactive voice/web response system, stratified by severity and global region. All three groups were given concomitant topical corticosteroids with or without topical calcineurin inhibitors where inadvisable for topical corticosteroids. Topical corticosteroids could be tapered, stopped, or restarted on the basis of disease activity. Coprimary endpoints were patients (%) achieving Investigator's Global Assessment (IGA) 0/1 and 2-point or higher improvement from baseline, and Eczema Area and Severity Index 75% improvement from baseline (EASI-75) at week 16. Week 16 efficacy and week 52 safety analyses included all randomised patients; week 52 efficacy included patients who completed treatment by US regulatory submission cutoff. This study is registered with ClinicalTrials.gov, NCT02260986., Findings: Between Oct 3, 2014, and July 31, 2015, 740 patients were enrolled: 319 were randomly assigned to dupilumab qw plus topical corticosteroids, 106 to dupilumab q2w plus topical corticosteroids, and 315 to placebo plus topical corticosteroids. 623 (270, 89, and 264, respectively) were evaluable for week 52 efficacy. At week 16, more patients who received dupilumab plus topical corticosteroids achieved the coprimary endpoints of IGA 0/1 (39% [125 patients] who received dupilumab plus topical corticosteroids qw and 39% [41 patients] who received dupilumab q2w plus topical corticosteroids vs 12% [39 patients] who received placebo plus topical corticosteroids; p<0·0001) and EASI-75 (64% [204] and 69% [73] vs 23% [73]; p<0·0001). Week 52 results were similar. Adverse events were reported in 261 (83%) patients who received dupilumab qw plus topical corticosteroids, 97 (88%) patients who received dupilumab q2w, and 266 (84%) patients who received placebo, and serious adverse events in nine (3%), four (4%), and 16 (5%) patients, respectively. No significant dupilumab-induced laboratory abnormalities were noted. Injection-site reactions and conjunctivitis were more common in patients treated with dupilumab plus topical corticosteroids-treated patients than in patients treated with placebo plus topical corticosteroids., Interpretation: Dupilumab added to standard topical corticosteroid treatment for 1 year improved atopic dermatitis signs and symptoms, with acceptable safety., Funding: Sanofi and Regeneron Pharmaceuticals Inc., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: Patients with psoriasis who have an inadequate response to one biologic may benefit from switching to a new biologic, such as ixekizumab, a high affinity monoclonal antibody that selectively targets interleukin (IL)-17A., Objective: Our aim was to assess the response to ixekizumab in patients with moderate-to-severe plaque psoriasis who did not respond adequately to etanercept using a post-hoc analysis in two phase III studies., Methods: For the subanalyses in two phase III trials (UNCOVER-2 and -3), non-response was defined by either failure to have a static physician global assessment (sPGA) of 0/1 in UNCOVER-2 or failure to have at least 75% improvement in psoriasis area and severity index (PASI 75) in UNCOVER-3 at Week 12 of each study. Non-responders treated with twice-weekly etanercept 50 mg in the first 12 weeks received two injections of placebo at Week 12 (4-week wash-out period), followed by ixekizumab every 4 weeks (Q4W) for Weeks 16-60. Non-responders to placebo in the first 12 weeks were administered ixekizumab 160 mg at Week 12, followed by ixekizumab Q4W for Weeks 16-60., Results: After switching to ixekizumab Q4W, a substantial proportion of patients with moderate-to-severe psoriasis who did not respond to etanercept experienced rapid and durable improvement in all efficacy evaluations. Among sPGA 0/1 (UNCOVER-2) and PASI 75 (UNCOVER-3) non-responders to etanercept, 73.0% achieved sPGA 0/1 and 78.2% achieved PASI 75, respectively, after 12 weeks of ixekizumab treatment. Safety profiles in patients switched from etanercept to ixekizumab were similar to those in patients switched from placebo to ixekizumab., Conclusion: Patients who were non-responders to etanercept after 12 weeks, as defined by failure to meet sPGA 0/1 (UNCOVER-2) or PASI 75 (UNCOVER-3), achieved high levels of response 12 weeks after switching to ixekizumab. Studies are registered with ClinicalTrials.gov (NCT01597245 and NCT01646177).

Purpose: To report the sequential placement of inferior vena cava filter (IVCF) and peripherally inserted central catheter (PICC) using the same upper extremity venous access., Material and Methods: This is a retrospective study that reviewed the medical records of 379 consecutive patients who underwent IVCF insertion during a 39-month period at our center. Of these 379 patients, 28 patients had sequential insertion of an IVCF and a PICC through the same upper extremity venous access. The same vein entry site was used for placement of the IVCF followed by PICC insertion. Data collected included: indication and duration of IVCF and PICC placement, access site location, complications, and the type of IVCF., Results: IVCFs were placed for prophylactic purposes in 15 patients (53.6%) and therapeutic purposes in 13 patients (46.4%). Right upper extremity veins were used for venous access in 27 patients (96.4%): brachial (n=16), basilic (n=9), and cephalic (n=2). The left basilic vein was used in one patient (3.6%). IVCFs were temporary in 20 patients (71.4%) and permanent in 8 patients (28.6%). There were no procedural complications. The OptEase filter was used in 23 patients (82.1%) and the TrapEase filter was used in 5 patients (17.9%)., Conclusion: Simultaneous IVCF and PICC insertion using the same upper extremity venous access was feasible and safe in our series. This combined technique provides the patient with central venous access for repeated blood collections and intravenous therapy., (Copyright © 2015 Éditions françaises de radiologie. Published by Elsevier Masson SAS. All rights reserved.)

Aim: To evaluate the influence of number and location of catheter shaft side holes regarding drainage efficiency in an in vitro model., Materials and Methods: Three different drainage catheter models were constructed: open-ended model with no side holes (one catheter), unilateral side hole model (six catheters with one to six unilateral side holes), and bilateral side hole model (six catheters with one to six bilateral side holes). Catheters were inserted into a drainage output-measuring device with a constant-pressure reservoir of water. The volume of water evacuated by each of the catheters at 10-second intervals was measured. A total of five trials were performed for each catheter. Data were analysed using one-way analysis of variance., Results: The open-ended catheter had a mean drainage volume comparable to the unilateral model catheters with three, four, and five side holes. Unilateral model catheters had significant drainage volume increases up to three side holes; unilateral model catheters with more than three side holes had no significant improvement in drainage volume. All bilateral model catheters had significantly higher mean drainage volumes than their unilateral counterparts. There was no significant difference between the mean drainage volume with one, two, or three pairs of bilateral side holes. Further, there was no drainage improvement by adding additional bilateral side holes., Conclusion: The present in vitro study suggests that beyond a critical side hole number threshold, adding more distal side holes does not improve catheter drainage efficiency. These results may be used to enhance catheter design towards improving their drainage efficiency., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Interactive games that highlight global health challenges and solutions are a potential tool for increasing interest in global health. To test this hypothesis, we developed an interactive "Polio Eradication" (PE) game and evaluated whether playing or watching was associated with increased public interest in global health., Materials and Methods: The PE game is a life-size, human board game that simulates PE efforts. Four players-a researcher, a transportation expert, a local community coordinator, and a healthcare worker-collaborate as an interdisciplinary team to help limit ongoing and future polio outbreaks in Pakistan, represented on the game board. Participants who played or observed the game and those who did not participate in the game, but visited noninteractive global health exhibits, completed a survey on participation outcomes. We used relative risk regression to examine associations between cofactors and change in global health interest., Results: Three variables predicted increased global health interest among the game participants: Having little or no previous global health knowledge prior to playing the game (risk ratio [RR]=1.28; 95 percent confidence interval [CI], 1.13-1.45), not currently being involved in global health (RR=1.41; 95 percent CI, 1.07-1.85), and visiting Seattle (RR=1.25; 95 percent CI, 1.04-1.51)., Conclusions: Our results suggest that a hands-on, interactive game may increase the public's interest in global health, particularly among those with minimal previous knowledge of or involvement in global health activities.

Introduction: The supine sleep position is recommended to reduce sudden infant death syndrome risk. Swaddling may improve adherence with supine placement., Aim: To assess knowledge, attitudes, and practice regarding swaddling among adult caregivers of 0- to 3-month-old infants., Methods: Cross-sectional descriptive survey., Results: All 103 adults interviewed had swaddled their infant. Common reasons for swaddling included infant comfort and warmth. Almost 80% of those who swaddled their infant found it effective, 80% believed it to be comfortable, and ~90% believed swaddling to be safe. Parents who routinely used swaddling were more likely to find it effective and to place their infant supine when swaddled (P < .01)., Conclusions: Parents often use swaddling to comfort the infant, and most find it effective. Parents who routinely use swaddling are more likely to place their infant supine if swaddled. Swaddling may be a strategy for parents of infants who have difficulty sleeping in the supine position.

EHR systems provide significant opportunities to enhance pediatric care. Well-constructed clinical content, HIE, automated reminders and alerts, and reporting at practice, community, and public health levels are available in several current systems and products. However, the general focus on inpatient and adult populations in the design and marketing of these systems should be seen as a significant barrier to EHR adoption among pediatric primary care providers. Weight-based medication dosing, specialty growth charts, units of measurement and time, and measures to address minor consent and adolescent confidentiality are not universal in quality and availability to the pediatric practice. However, there are opportunities for pediatricians to provide input and to clearly state minimum requirements when dealing with vendors or when government agencies (eg, ONCHIT and AHRQ) seek comment on standards, practices, and expectations. This article uses cases and examples to describe some areas in which pediatricians should take an active role to advocate for pediatric-appropriate EHR tools. Virtually every child born and cared for in the United States today will have their data and information recorded in an EHR. The quality of the information and the HIT in which it is recorded can affect the care they get as children, and the information they carry into adulthood.

Electronic health records have been recognized as essential for improving clinical documentation, coordination, and management of health care in addition to lowering costs and improving patient safety. In recent years, there has been a significant impetus for promoting the adoption of electronic health records, as evidenced by the numerous public and private initiatives across the United States. However, currently available electronic health records have not focused on the unique clinical, psychosocial, and health educational needs and requirements of the adolescent age group. In this chapter we discuss briefly the history, development, and adoption of electronic health records and provide examples of how electronic health records can be extended to focus on the needs of adolescents and those who care for them.

In this article, the development of 2 sophisticated health information and education initiatives geared at adolescents, children, and their families are described. These initiatives leverage advanced information technologies in concert with novel pedagogies, peer internship programs, and informal education methods to achieve the intended goals. The initiatives have been successful since their respective inceptions and will form exportable models for other organizations and institutions that seek to create similar opportunities and resources for adolescents.

We investigate the assignment of electronic transitions in alkyl peroxy radicals. Past experimental work has shown that the phenyl peroxy radical exhibits a transition in the visible region; however, previous high level calculations have not reproduced this observed absorption. We use time dependent density functional theory (TDDFT) to characterize the electronic excitations of the phenyl peroxy radical as well as other hydrocarbon substituted peroxy radicals. TDDFT calculations of the phenyl peroxy radical support an excitation in the visible spectrum. Further, we investigate the nature of this visible absorption using electron attachment/detachment density diagrams of the peroxy radicals and present a qualitative picture of the origin of the visible absorption based on molecular orbital perturbations. The peroxy radical substituent is also compared against isoelectronic radical groups. The visible absorption is determined to be dependent on mixing of the alkyl and radical substituent orbitals.

We have reported that pretreatment with 1 alpha, 25(OH)2D3(1, 25) up-regulates responsiveness and sensitivity to 17 beta estradiol (E2) in osteoblast-like cells, as measured by parallel stimulation of [3H]thymidine incorporation into DNA and the specific activity of creatine kinase BB (CK). Increased responsiveness was correlated with increased E2 receptor concentration. In this study, we have extended these observations to new nonhypercalcemic analogs of 1,25. We compared the analogs hexafluoro vitamin D3 (FL), and the side chain modified derivatives: EB 1089 (EB), CB 1093 (CB) and MC 1288 (MC) with 1,25 and 25 (OH)D3(25 D3). Treatment with 30 nM E2 for 4 h stimulated CK activity in ROS 17/2-8 cells by 40%; there was no further increase after 3 daily additions of E2. Treatment by 3 daily additions, at 1 nM, of all analogs except 25 D3 caused a 2-3-fold increase in CK specific activity. This schedule of treatment also upregulated the response to 4 h exposure to 30 nM E2 by 30-70% above the response to vitamin D analogs alone, and by up to 2 fold compared to E2 without pretreatment. At 1 pM, the analogs doubled CK activity, and, except for 1,25, upregulated the response to E2 to levels characteristic of each analog. Pretreatment with vitamin D analogs also increased the sensitivity to E2 by lowering the dose for a comparable response to E2 by one or two orders of magnitude. Stimulation of specific activity of CK by the analogs was paralleled by increases in the steady state level of mRNA for CKB, but not in its half life. Whereas pretreatment by vehicle followed by E2 for 2 h was unable to increase CKB mRNA, pretreatment with the analogs made possible detection of mRNA responsiveness to E2. These results add to the evidence for the interaction of estrogens and antiestrogens with vitamin D metabolites in regulation of bone growth in vitro. They also strengthen the potential for treatment of bone loss, as occurs in postmenopausal osteoporosis, by a combination of nonhypercalcemic vitamin D analogs and estrogens.

A cross-sectional study was conducted in which level of mood recognition was assessed from early childhood through old age. Asymptotic performance was obtained on facial affect recognitions tasks from ages 3-34 yrs. There was a progressive decline in facial affect recognitions beginning at age 45, with the principal problem that of recognizing angry faces. With respect to auditory prosody, there was an improvement in recognition level from ages 3-12 yrs. Performance remained asymptotic through age 43 and then began to decline increasingly beyond age 45.

Welsh codes of Minnesota Multiphasic Personality Inventory-168 (MMPI-168) profiles were calculated for 151 HIV-1 seropositive gay men and 27 gay seronegative controls. Although 99% of seropositives' profiles were clinically elevated, the profile configurations among subjects were varied. These data document the presence of considerable emotional distress among HIV-infected individuals, yet the heterogeneity of codes encountered argues against generalizations of seropositive subjects based upon mean MMPI profiles.

Facial affect recognition was studied in groups of mildly retarded subjects, moderately retarded subjects, and nonretarded children. Subjects were tested under five conditions. In Condition 1, they were presented with happy, sad and angry faces simultaneously in each of 18 trials and were prompted with short commands to point to one of the affective faces. Conditions 2 and 3 were the same as the first, except that subjects were prompted with short affective vignettes. In Condition 2, the vignettes were followed by tag lines identifying the moods of the vignettes. There were no tag lines in Condition 3. Conditions 4 and 5 were identical to Conditions 2 and 3, except that the vignettes were longer. The error data were analyzed and results showed that the groups did not differ in response to short commands and vignette prompts produced more errors than short commands. Also, long vignettes gave rise to more mistakes than short vignettes, and vignettes without tag lines resulted in more errors than those with tag lines. Group differences emerged when vignettes were presented, with more errors made as level of retardation and length of vignettes increased. It was concluded that mental retardation is not associated with a disturbance in facial affect recognition.

The relationship between depression and neuropsychological test performance in HIV-1 seropositive individuals is unclear. The present study was conducted to determine whether different patterns of neuropsychological test performance would be present in depressed vs. nondepressed individuals infected by the Human Immunodeficiency Virus (HIV-1). It was hypothesized that subjects evidencing depressed mood would demonstrate greater difficulty on measures of neuropsychological function. The subjects were 54 mostly symptomatic HIV-1 seropositive homosexual/bisexual males aged 20 to 60. A neuropsychological test battery together with the Beck Depression Inventory (BDI) was administered to all subjects. Stepwise multiple regression analysis revealed a significant relationship only between scores on the BDI and the Grooved Pegboard test and Trial 6 of the RAVLT. Subjects were then dichotomized using the BDI into high-BDI (M = 28.9) and low-BDI (M = 6.3) groups. Analysis of variance failed to reveal significant group differences between the depressed vs. the non-depressed groups on the neuropsychological measures despite their marked separation on the BDI. Similarly, examination of individual neuropsychological outliers again failed to demonstrate an increased number of outliers in the high- and low-BDI groups. These results suggest that the presence of clinically significant levels of depression in a non-elderly HIV-1 seropositive sample does not necessarily lead to significant neuropsychological dysfunction.

Neuroretinitis is a clinical condition usually seen in young healthy adults that is characterized by rapid profound unilateral loss of vision. Funduscopic findings include swollen disc, splinter hemorrhages, and macular star. Catscratch fever and leptospirosis have been suggested as possible etiologies in this condition. We report a case of a patient with neuroretinitis whose only laboratory abnormality was an elevated enzyme-linked immunosorbent assay immunoglobulin G Toxoplasma titer. The patient responded favorably to treatment with clindamycin, triple sulfa, and systemic corticosteroids. We recommended toxoplasmic serology be added to the workup of patients with neuroretinitis.

We report the first case (to our knowledge) of a primary urethral T-cell lymphoma as the initial manifestation of the acquired immune deficiency syndrome. A 36-year-old white homosexual man with antibodies to human immunodeficiency virus type 1 was evaluated for a hemorrhagic urethral discharge. A 2-cm fleshy, polypoid mass in the bulbous urethra was removed, and the diagnosis of small non-cleaved cell (non-Burkitt's) lymphoma was made. Immunohistochemical analysis confirmed that the tumor was of T-cell lineage. Patients with the acquired immunodeficiency syndrome have an increased incidence of lymphomas, particularly extranodal high-grade non-Hodgkin's lymphomas. Primary urethral lymphomas are extremely rare, with only a handful of cases reported in the literature. This rare form and site of lymphoma should be considered in patients with the acquired immunodeficiency syndrome who have genitourinary symptoms.

The keyboard is the most commonly used input method for interfacing with computers. When using a keyboard is not possible, alternative computer input methods are needed. Three methods using head control are: Head Master by Prentke Romich, Free Wheel by Pointer Systems, and LROP by Words+. The purpose of this study was to compare these three methods for speed and accuracy using a single subject design for nine individuals with disabilities. Visual inspection of the data revealed that subjects obtained higher scores when using Head Master and LROP than Free Wheel. As a follow-up test, an analysis of variance test for repeated measures showed no difference between using Head Master and LROP but did show a significant difference between Head Master and Free Wheel, and LROP and Free Wheel.

Fibrous dysplasia is a developmental anomaly of bone, often affecting the facial bones. We treated a patient who had fibrous dysplasia involving the right maxillary and sphenoid bones. The patient had a sudden loss of visual acuity to R.E.: counting fingers. Visual fields demonstrated a central scotoma, and retrobulbar neuritis was diagnosed. When vision failed to improve spontaneously, however, radiologic studies were performed. These showed compromise of the optic canal by bony proliferation and an apparent mucocele at the orbital apex. Surgical exploration disclosed fibrous dysplastic bone and a cystic structure overlying the optic nerve. Successful surgical excision of the cyst and debulking of the fibrous dysplasia resulted in visual acuity returning to R.E.: 20/25.

Four previously healthy homosexual men contracted Pneumocystis carinii pneumonia, extensive mucosal candidiasis, and multiple viral infections. In three of the patients these infections followed prolonged fevers of unknown origin. In all four cytomegalovirus was recovered from secretions. Kaposi's sarcoma developed in one patient eight months after he presented with esophageal candidiasis. All patients were anergic and lymphopenic; they had no lymphocyte proliferative responses to soluble antigens, and their responses to phytohemagglutinin were markedly reduced. Monoclonal-antibody analysis of peripheral-blood T-cell subpopulations revealed virtual elimination of the Leu-3 / helper/inducer subset, an increased percentage of the Leu-2 + suppressor/cytoxic subset, and an increased percentage of cells bearing the thymocyte-associated antigen T10. The inversion of the T/ helper to suppressor/cytotoxic ratio suggested that cytomegalovirus infection was an important factor in the pathogenesis of the immunodeficient state. A high level of exposure of male homosexuals to cytomegalovirus-infected secretions may account for the occurrence of this immune deficiency.

2 cases of retinal detachment with ectopia lentis are described. In each, the retinal elevations had surface features consistent with exudative detachments. Following removal of the posteriorly displaced lenses spontaneous retinal attachment was noted. The clinical and surgical course of these patients suggest a diagnosis of lens-induced exudative retinal detachment.

Three cases of long-standing intranasal cocaine abuse were associated with orbitopathy or optic neuropathy. All three cases were characterized by chronic sinusitis. Histopathologic examination of involved sinus and orbital tissues revealed chronic and acute nonspecific inflammation, with no evidence of unusual infections or of idiopathic midline destructive disease. In two of the cases, there was radiographic evidence of contiguous orbital inflammation associated with sinusitis. The inflammatory orbital process in these two cases was steroid responsive, but in one case recurrent inflammation occurred in response to steroid tapering. One patient suffered a complete loss of vision in the involved eye due to fulminant orbital inflammation and optic nerve dysfunction.

The normal and post-traumatic appearances of the sub-talar joints are illustrated by means of a number of arthrograms. Special projections were used in order to demonstrate various parts of the joints. The mobility of the articulating bones and its relationship to the trabecular structure has been demonstrated. The mechanism of typical injuries in normal limbs, and in the presence of pes planus, is described. Radiological features of capsular injuries of the sub-talar joint have been studied by arthrography.

Contrast arrhrography has shown that this is a neccessary investigation in all cases of recurrent dislocation of the shoulder, in order to show the changes in the shoulder joint. The examination can be carried out in the early or late stages after trauma. The method is also indicated before carrying out reconstructive operations on the joint.